OA19170A

OA19170A - Inhibitors of receptor-interacting protein kinase 1.

Info

Publication number: OA19170A
Application number: OA1201800297
Authority: OA
Inventors: Anthony A. Estrada; Jianwen A. Feng; Brian Fox; Colin Philip Leslie; Joseph P. Lyssikatos; Alfonso Pozzan; Zachary K. Sweeney; Vicente Fidalgo Javier De
Original assignee: Denali Therapeutics Inc.
Priority date: 2016-02-05
Filing date: 2017-02-03
Publication date: 2020-03-09

Abstract

The present disclosure relates generally to compounds and compositions, and their use as kinase inhibitors.

Description

INHIBITORS OF RECEPTOR-INTERACTING PROTEIN KINASE 1

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. 119(e) of U.S. Provisional Application Nos. 62/292,202, filed February 5, 2016, 62/341,019, filed May 24, 2016, 62/363,775, filed July 18, 2016, 62/385,217, filed September 8, 2016, and 62/417,219, filed November 3, 2016. The entire contents of these applications are incorporated by reference into this application.

FIELD

[0002] The présent disclosure relates generally to inhibitors of kinase, therapeutic methods of use, and manufacture thereof

BACKGROUND

[0003] Although inflammation can be a protective mechanism in response to harmful stimuli such as invasion of pathogens and tissue damages, chronic inflammation is an important underlying factor in many human diseases such as neurodegeneration, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. Similarly, the activation of cell death pathways, such as necrosis and apoptosis which are usefiil in eliminating infected or damaged cells, is also an important underlying mechanism for human diseases, including acute and chronic neurodegenerative diseases.

[0004] Receptor-interacting protein kinase 1 is a key regulator of inflammation, apoptosis and necroptosis. Receptor-interacting protein kinase 1 has an important rôle in modulating inflammatory responses mediated by nuclear-factor kappa-light chain enhancer of activated B cells (NF-κΒ). More recent research has shown that its kinase activity controls necroptosis, a form of necrotic cell death, which was traditionally thought to be passive and unregulated, and is characterized by a unique morphology. Further, receptor-interacting protein kinase 1 is part of a pro-apoptotic complex indicating its activity in regulating apoptosis.

[0005] The receptor-interacting protein kinase 1 is subject to complex and intricate regulatory mechanisms, including ubiquitylation, deubiquitylation and phosphorylation. These regulatory events collectively détermine whether a cell will survive and activate an inflammatory response or die through apoptosis or necroptosis. Dysrégulation of receptor-interacting protein kinase 1 signaling can lead to excessive inflammation or cell death, and conversely, research has shown tirât inhibition of receptorinteracting protein kinase 1 can be effective thérapies for diseases involving inflammation or cell death.

DESCRIPTION

[0006] Provided herein are compounds that are usefiil as inhibitors of receptor-interacting protein kinase 1. The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds. The include the compounds, and methods of using (or administering) and making the compounds. The disclosure further provides compounds or compositions thereof for use in a method of treating a disease, disorder, or condition that is mediated by receptor-interacting protein kinase 1. Moreover, the disclosure provides uses of the compounds or compositions thereof in the manufacture of a médicament for the treatment of a disease, disorder or condition that is mediated by (or mediated, at least in part, by) receptor-interacting protein kinase 1.

[0007] In certain embodiments, provided is a compound of Formula I. In certain embodiments, provided is a compound of Formula Ile. In certain embodiments, provided is a compound of Formula Ile. In certain embodiments, provided is a compound of Formula Ilf. In certain embodiments, provided is a compound of Formula V. In certain embodiments, provided is a compound of Formula Va. In certain embodiments, provided is a compound of Formula VI. In certain embodiments, provided is a compound as in Table 1, or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. In certain embodiments, provided is a compound as in Table 2, or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. In certain embodiments, provided is a compound as in Table 3, or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. In certain embodiments, provided is a compound as in Table 4, or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0008] Provided herein is a pharmaceutical composition comprising a compound, including those of any Formula described herein, and an excipient.

[0009] Provided herein are compounds and compositions for use in medicine. In certain embodiments, the compounds and compositions are for use in the treatment of a receptor-interacting protein kinase 1mediated disease or disorder.

[0010] Provided herein is a method of treating a receptor-interacting protein kinase 1-mediated disease or disorder comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof.

[0011] In certain embodiments, the disease or disorder is inflammatory bowel disease, Crohn’s disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, maculai degeneration, pancreatitis, atopie dermatitis, rheumatoid arthritis, spondyloarthritis, goût, SoJIA, systemic lupus erythematosus, Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury' of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, allergie diseases, asthma, atopie dermatitis, multiple sclerosis, type I diabètes,

Wegener’s granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-l converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptorassociated periodic syndrome, or peridontitis. In certain embodiments, the disease or disorder is trauma, ischemia, stroke, cardiac infarction, infection, lysomal storage disease, Gaucher’s disease, Krabbe disease, Niemann-Pick disease, sepsis, Parkinson’s disease, Alzheimer’s disease, amyotrophie latéral scierosis (ALS/Lou Gehrig’s Disease), Huntington’s disease, HTV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease. In certain embodiments, the disease or disorder is Alzheimer’s disease, ALS, Friedreich’s ataxia, Huntington’s disease, Lewy body disease, Parkinson’s disease, or spinal muscular atrophy. In certain embodiments, the disease or disorder is brain injury, spinal cord injury, dementia, stroke, Alzheimer’s disease, ALS, Parkinson’s disease, Huntington’s disease, multiple scierosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cérébral ischemia, or aprion disorder.

1. Définitions

[0012] The following description sets forth exemplary embodiments of tire présent technology. It should be recognized, however, that such description is not intended as a limitation on tire scope of the présent disclosure but is instead provided as a description of exemplary embodiments.

[0013] As used in the présent spécification, the following words, phrases and symbols are generally intended to hâve the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0014] A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(0)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0015] The prefix “C_u-v” indicates that the following group has from u to v carbon atoms. For example, “Ci_6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0016] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In certain embodiments, the term “about” includes the indicated amount ± 5%. In certain embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural référencés unless the context clearly dictâtes otherwise. Thus, e.g., reference to the compound includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and équivalents thereof known to those skilled in the art.

[0017] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., Ci_s alkyl), 1 to 6 carbon atoms (i.e., Ci-6 alkyl), or 1 to 4 carbon atoms (i.e., Cu alkyl). In certain embodiments, alkyl has 1 to 12 carbon atoms (i.e., C1-12 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, secbutyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3methylpentyl. When an alkyl residue having a spécifie number of carbons is named by chemical name or identified by molecular formula, ail positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. -(CH₂)₃CH₃), sec-butyl (i.e. CH(CH₃)CH₂CH₃), isobutyl (i.e. -CH₂CH(CH₃)₂) and tert-butyl (i.e. -C(CH₃)₃); and “propyl” includes npropyl (i.e. -(CH₂)₂CH₃) and isopropyl (i.e. -CHfCHs)?).

[0018] “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C₂-s alkenyl), 2 to 6 carbon atoms (i.e., C₂_6 alkenyl), or 2 to 4 carbon atoms (i.e., C₂^ alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0019] “Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C₂-s alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0020] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2dimethylbutoxy.

[0021] “Alkylthio” refers to the group “alkyl-S-”.

[0022] “Acyl” refers to a group -C(O)R, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cyclcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0023] “Amido” refers to both a “C-amido” group which refers to the group -C(0)NR^yR^z and an “Namido” group which refers to the group -NR^yC(O)R^z, wherein R^y and R^z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0024] “Amino” refers to the group -NIUR² wherein R^y and R^z are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.

[0025] “Amidino” refers to -C(NH)(NH2). In certain embodiments, “Amidino” refers to -C(NR)(NR2), wherein each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0026] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fiised Systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., Cô-20 aryl), 6 to 12 carbon ring atoms (i.e., Cô-i2 aryl), or 6 to 10 carbon ring atoms (i.e., Ce-io aryl). In certain embodiments, aryl has 6 to 18 carbon ring atoms (i.e., Cô-is aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fiised with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fiised with a heterocyclyl, the resulting ring System is heterocyclyl.

[0027] “Azido” refers to -N₃.

[0028] “Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”

[0029] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NR^yR^zand an “N-carbamoyl” group which refers to the group -NR^yC(O)OR^z, wherein R^y and R^z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0030] “Carboxyl” refers to -C(O)OH.

[0031] “Carboxyl ester” or “ester” refer to both -0C(0)R and -C(O)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0032] “Cyano” or “carbonitrile” refers to the group -CN.

[0033] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fiised, bridged, and spiro ring Systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). In certain embodiments, cycloalkyl has from 3 to 15 ring carbon atoms (i.e., C3-15 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachaient to the remainder of the molécule.

[0034] In certain embodiments, cycloalkyl also includes “spiro cycloalkyl” when there are two positions for substitution on the same carbon atom. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.l]heptanyl and the like.

[0035] “Guanidino” refers to -NHC(NH)(NH2). In certain embodiments, “guanidino” refers to NRC(NR)(NR.2), wherein each R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0036] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.

[0037] “Hydrazino” refers to -NHNH₂.

[0038] “Imino” refers to a group -C(NR)R, wherein each R is independently hydrogen alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0039] “Imido” refers to a group -C(0)NRC(0)R, wherein each R is independently hydrogen alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0040] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

[0041] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF₂) and trifluoromethyl (-CF3). In certain embodiments, examples of haloalkyl include difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fhioropropyl, 1,2-dibromoethyl and the like.

[0042] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

[0043] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxy group.

[0044] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The terni “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, S(O)-, -S(O)₂-, and the like, where R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include OCH3, -CH2OCH3, -SCH₃, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. In certain embodiments, examples of heteroalkyl groups include -CH2OCH3, -CH2SCH3, and -CH2NRCH3, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In certain embodiments, the term “heteroalkyl” requires that the point of attachment to the remainder of the molécule is through a carbon atom.

[0045] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1.20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the term “heteroaryl” refers to a 514 membered ring System. In certain embodiments, heteroaryl includes 1 to 13 ring carbon atoms (i.e., C3-12 heteroaryl). In certain embodiments, heteroaryl includes 1 to 6 heteroatoms. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[l,5-a]pyridinyl, and imidazo[l,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused System. In certain embodiments, examples of heteroaryl groups include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][I,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyL dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, I -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl (i.e., thienyl). Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molécule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0046] “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.

[0047] “Heterocyclyl” refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The terni “heterocyclyl” includes heterocycloalkenyl groups (i.e. the heterocyclyl group having at least one double bond), bridgedheterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. In certain embodiments, heterocyclyl may comprise one or more oxo (C=O) or N-oxide (N-O-) moieties. Any nonaromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of Üie molécule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C₂-s heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C₃-s heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. In certain embodiments, examples of heterocyclyl groups include 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, l-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. Also used herein, the term “spiro-heterocyclyl” refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to tenmembered heterocyclyl. Examples of the spiro-heterocyclyl rings include bicyclic and tricyclic ring Systems, such as 2-oxa-7-azaspiro[3.5]nonanyL 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-lazaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0048] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0049] “Oxo” refers to the group (=0) or (O).

[0050] “Nitro” refers to the group -NO2.

[0051] “Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-”.

[0052] “Oxime” refers to the group -CR(=N0H) wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkvl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0053] “Sulfonyi” refers to the group -SCOfiR, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyi are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and tohienesulfonyl.

[0054] “Sulfinyl” refers to the group -S(O)R, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfmyl, ethylsulfmyl, phenylsulfinyl and toluenesulfinyl.

[0055] “Sulfonamido” refers to the groups -SO2NRR and -NRSO2R, where each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0056] “Alkylsulfonyl” refers to the group -S(O)2R, where R is alkyl.

[0057] “Alkylsulfinyl” refers to the group -S(O)R, where R is alkyl.

[0058] “Thiocyanate” refers to the group -SCN.

[0059] “Thiol” refers to the group -SH.

[0060] “Thioxo” or “thione” refer to the group (=S) or (S).

[0061] In certain embodiments of any of the terms defined above, R^y and R^z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0062] In certain embodiments of any of the terms defined above, R is hydrogen, alkyl, alkenyl, aikxnyi, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molécule.

[0063] The ternis “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 or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0064] The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfïnyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.

[0065] In certain embodiments, the term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfmyl, alkylsulfonyl, alkylsulfïnyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo, N-oxide, or -Si(R¹⁰⁰)3 wherein each R¹⁰⁰ is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.

[0066] In certain embodiments, the term “substituted” used herein means any of the above groups (i.e., alkyl, alkylene, alkoxy, haloalkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl, heteroaryl, hydroxyalkyl and/or alkoxyalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to: an alkyl group, a haloalkyl group, a halogen atom such as F, Cl, Br, and I; an alkenyl, a haloalkenyl group, an alkynyl group, a haloalkynyl group, a cyclic group such as an aryl, heteroaryl, cycloalkyl, or heterocyclyl group, an oxygen atom in groups such as hydroxy groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, thiohaloalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in varions other groups. “Substituted” also means any ofthe above groups in which one or more hydrogen atoms are replaced by a highcr-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, formyl, carboxyl, carbonate, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.

[0067] In certain embodiments, “substituted” includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups in which one or more hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR®R^h, -NR⁸C(=O)R^fa, -NR⁸C(=0)NR^gR^h, -NR⁸C(=0)0R^h, -NR⁸S(=O)i.2R^h, -C(=O)R^S, -C(=O)OR⁸, -OC(=O)OR⁸, -OC(=O)R⁸, -C(=0)NR⁸R^h, -OCLOjNR^¹¹, OR⁸, -SR⁸, -S(=O)R⁸, -S(=O)2R⁸, -08(=0)^, -S(=O)i_2OR⁸, -NR⁸S(=O)i_2NR⁸R^h, =NSO2R⁸, =N0R⁸, -S(=O)i_2NR⁸R^h, -SFs, -SCFs or -OCF3. In certain embodiments, “substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)R⁸, -C(=O)OR⁸, -CLOjNR^¹¹, -CH2SO2R^s, -CFLSOzNR^¹¹. In certain embodiments, “substituted” further means any of die above groups in which one or more hydrogen atoms are replaced by -NR⁸S(O)i_2NR⁸R^h, -CH2S(O)R⁸, -CH2S(O)NR^sR^h, -OC(=O)OR⁸, -SFs, -SCF3 or -OCF3. In certain embodiments, “substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl group. In the foregoing, R⁸ and R^h and R¹ are the same or different and independently hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R⁸ and R^h and R¹are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxy or alkoxy. In an embodiment, each of said alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl are independently optionally substituted with one or more oxo, alkyl, halo, amino, hydroxy or alkoxy. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.

[0068] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above définitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the tenu “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents ofthe group are themselves unsubstituted. For example, in certain embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxy, halo, alkoxy, acyl, oxo, arnino, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0069] Any compound or formula given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds hâve structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to ²H (deuterium, D), ³H (tritium), ”C, ¹³C, ¹⁴C, ¹⁵N, ^1SF, ^3lP, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopically labeled compounds of the présent disclosure, for example those into which radioactive isotopes such as Ή, ¹³C and ¹⁴C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, détection or imaging techniques, such as positron émission tomography (PET) or single-photon émission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0070] The disclosure also includes “deuterated anaiogs” of compounds of Formula I in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molécule. Such compounds exhibit increased résistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens hâve been replaced by deuterium.

[0071] Deuterium labelled or substituted therapeutic compounds of tire disclosure may hâve improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excrétion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ^ISF, ³H, ⁿC labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and préparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.

[0072] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to hâve hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0073] In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

[0074] Provided are also pharmaceutically acceptable salts, hydrates, solvatés, tautomeric forms, stereoisomers, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are usefiil in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0075] The term “pharmaceutically acceptable sait” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition sait, the free base can be obtained by basifying a solution of the acid sait. Conversely, if the product is a free base, an addition sait, particularly a pharmaceutically acceptable addition sait, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with convcntional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic méthodologies that may be used to préparé nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfiiric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fiimaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnésium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH₂(aikyl)), dialkyl amines (i.e., HN(alkyl)₂), trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e., NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e., N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)₂), trialkenyi amines (i.e., N(alkenyl)₃), substituted alkenyl amines (i.e., NFFisubstituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)s, mono-, di- or tri- cycloalkyl amines (i.e., NHz(cycloalkyl), HN(cycloalkyl)₂, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH₂(aryl), HN(aryl)₂, N(aryl)s), or mixed amines, etc. Spécifie examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0076] The term “hydrate” refers to the complex formed by the combining of a compound of Formula I and water.

[0077] A “solvaté” refers to an association or complex of one or more solvent molécules and a compound of the invention. Examples of solvents that form solvatés include, but are not limited to, water, isopropanol, éthanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid, and ethanolamine.

[0078] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0079] The compounds disclosed herein, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in ternis of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The disclosure is meant to include ail such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a sait or dérivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centres of géométrie asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z géométrie isomers. Likewise, ail tautomeric forms are also intended to be included.

[0080] “Stereoisomers are isomers that differ only in the way the atoms are arranged in space and include enantiomers and diastereomers. In certain embodiments, a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The présent disclosure contemplâtes varions stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molécules are nonsuperimposeable mirror images of one another.

[0081] “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture.

[0082] “Diastereoisomers” are stereoisomers that hâve at least two asymmetric atoms, but which are not mirror-images of each other.

[0083] The absolute stereochemistry is specifïed according to the Cahn Ingold Prelog R S System. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specifïed by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) that they rotate the plane of polarized light at the wavelength of the sodium D line.

[0084] “Prodrugs” means any compound which releases an active parent drug according to Formula I or any other formula described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula I or any other formula described herein are prepared by modifying functional groups présent in the compound of Formula I or any other formula described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups présent in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formula I or any other formula described herein wherein a hydroxy, amino, carboxyl or sulfhydryl group in a compound of Formula I or any other formula described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate dérivatives), amides, guanidines, carbamates (e.g., Ν,Ν-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula I or any other formula described herein and the like. Préparation, sélection and use of prodrugs is discussed in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Sériés; Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.

[0085] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” includes any and ail solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonie and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingrédient, its use in the therapeutic compositions is contemplated. Supplementary active ingrédients can also be incorporated into the compositions.

2. List of Abbreviations and Acronyms

Abbreviation aq.	Meaning Aqueous	Abbreviation HOBt	Meaning 1 -hydroxybenzotriazole
BOC	tert-butyloxycarbonyl	HPLC	High pressure liquid chromatography
br	Broad	hrs/h	Hours
d	Doublet	Hz	Hertz
DAD	Diode array detector	J	Coupling constant (MHz)
DAST	Diethylaminosulfur trifluoride	LCMS/LC-	Liquid chromatography-mass
		MS	spectrometry
dd	doublet of doublets	M	Molar
ddd	doublet of doublet of doublets	MeCN	Acetonitrile
dddd	doublet of doublet of doublet of doublets	MeOH	Methanol
dt	Doublet of triplets	m	Multiplet (when used with a J)
DIPEA/DIEA	Diisopropylethylamine	m/z	Mass-to-charge ratio
DMF	Dimethylformamide	[M+H]⁺	Mass peak plus hydrogen
DMSO	Dimethylsulfoxide	min	Minute(s)
ee/e.e.	Enantiomer excess	MS	Mass spectrometry
ES	Electrospray	N	Normal
ESI	Electrospray ion source	NCS	JV-Chlorosuccinimide
Et	Ethyl	NMR	Nuclear magnetic résonance
EtOH	Ethanol	o/n	Ovemight
EtOAC	Ethyl acetate	PDA	Photodiode array detector
H AT U	1- [Bis(dimethylamino)methylene]	quin	Quintuplet
	- \H-1,2,3 -triazolo [4,5 - &]pyridinium 3-oxid	rt	Room température Singlet (when used with J)
	hexafluorophosphate	s
HBTU	N,N,N ’,N ’-Tetramethyl-O-(l/fbenzotriazol-1 -yl)uronium hexafluorophosphate	s	Second(s)

Abbreviation sat.	Meaning Saturated
t	Triplet
THF	Tetrahydrofuran
TFA	Trifluoroacetic acid
TIC	Total ion current
TLC	Thin layer chromatography
TMEDA	ΑΛΛ’Λ’,- Tetramethylethylenediamine
TMIS	lodotrimethylsilane
v/v	Volume/volume
δ	Chemical shift (ppm)

3. Compounds

[0086] Provided herein are compounds that are useful as inhibitors of receptor-interacting protein kinase 1. In certain embodiments, provided is a compound of Formula I:

or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein

Y¹ is O or NR²;

X¹ and X² are each independently nitrogen or carbon and either

X¹ and X² together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R¹ is H or Ci-Cs alkyl optionally substituted with halo, hydroxy or cyano or when Y¹ is NR², then R² and R¹ together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or

X¹ and R¹ together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, and X² is -CH₂-;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Cô alkyl;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(0)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

each R⁶ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Cealken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted Ci-Ce alkyl, or R³ and R⁴ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

L is absent. -O-, -S-, -S(O)-, -S(O)2-, -NR⁷- or -C(R⁸)2-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Cg alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

optionally substituted then at least one of the following occurs:

(1) L is absent or -C(R⁸)2-, and each R⁸ is optionally substituted Ci-Câ alkyl or halo, or two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(2) Y² is -C(R⁶)₂- and at least one R⁶ is other than hydrogen;

(3) Y² is -0- and A is substituted with halo or cyano or A is thiazolyl or a 3- or 4-membered ring;

(4) Y² is -S-, -S(0)-, or -S(0)2-; and A is other than isoxazole and phenyl or Y² is -S(0)(NH)-;

(5) Y² is -NR^{4 5}- and A is other than isoxazole, pyrazole and triazole;

(6) the carbonyl moiety and L are substituted other than 1,3- on ring A; or (7) R⁹ is substituted cycloalkyl, substituted heterocyclyl, substituted aryl or substituted heteroaryl, wherein at least one substituent is cyano;

(8) R¹ is C2-C6 alkyl optionally substituted with halo, hydroxy or cyano; or (9) when X¹ and X² form an optionally substituted phenyl ring as in the moiety

⁴ , at least one substituent is at the 1 or 4 position and is (a) other than fluoro, chloro or methyi at the 1 position, and/or (b) other than fluoro or methyi for the 4 position; and further provided the moiety

wherein the nitrogen containing aromatic ring is optionally substituted;

and with the further proviso that the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo-

2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)isoxazole-3-carboxamide; 2-(4bromobenzyl)-N-(5-methyI-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4-carboxamide;

2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4-carboxamide; 4( 1,4-dihydro-2-oxo-3 (2H)-quinazolinyl)-N-[2,3,4,5 -tetrahydro-1 -( 1 -methylethyl)-2-oxo- 1H-1 benzazepin-3-yl]-l-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5tetrahydro-2-oxo-lH-l-benzazepin-3-yl]-l-piperazinecarboxamide; or 4-(2-aino-7-chloro-4-quinolinyl)N-[(3 S)-2,3,4,5 -tetrahydro-1 -methyl-2-oxo- 1H-1 -benzazepin-3 -yl]-1 -piperazinecarboxamide.

[0087] In certain embodiments, provided is a compound of Formula I or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof wherein

Y¹ isOorNR²;

X¹ and X² are each independently nitrogen or carbon and either

X¹ and X² together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R¹ is H or Ci-C₆ alkyl optionally substituted with halo, hydroxy or cyano or when Y¹ is NR², then R² and R¹ together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or

X¹ and R¹ together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, and X² is -CH?-;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(0)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

R³ and R⁴ are independently H, halo, or optionally substituted Ci-C₆ alkyl, or R³ and R⁴ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Câ alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and

)ί

X² / ^XY²'Y~R³provided that when the moiety R⁴is and the aromatic ring is optionally substituted then at least one ofthe following occurs:

(1) L is absent or -C(R^S)₂-, and each R⁸ is optionally substituted Ci-Ce alkyl or halo, or two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(2) Y² is -C(R⁶)₂- and at least one R⁶ is other than hydrogen;

(3) Y² is -O- and A is substituted with halo or cyano or A is thiazolyl or a 3- or 4-membered ring;

(4)

-S(0)(NH)-;

(5) (6) (7)

Y² is -S-, -S(O)-, or -S(O)₂-; and A is other than isoxazole and phenyl or Y² is

Y² is -NR⁵- and A is other than isoxazole, pyrazole and triazole; or the carbonyl moiety and L are substituted other than 1,3- on ring A;

R¹ is C₂-Ce alkyl optionally substituted with halo, hydroxy or cyano; or (8) when X¹ and X² form an optionally substituted phenyl ring as in the moiety

, at least one substituent is at the 1 or 4 position and is (a) other than fluoro, chloro or methyl at the 1 position, and/or (b) other than fluoro or methyl for the 4 position; and further provided the moiety

wherein the nitrogen containing aromatic ring is optionally substituted;

2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)isoxazole-3-carboxamide; 2-(4bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4-carboxamide;

2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4-carboxamide; 4(l,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-l-(l-methylethyl)-2-oxo-lH-lbenzazepin-3-yl]-l-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5tetrahydro-2-oxo- 1H-1 -benzazepin-3 -yl]-1 -piperazinecarboxamide; or 4-(2-amino-7-chloro-4quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-l-methyl-2-oxo-lH-l-benzazepin-3-yl]-l-piperazinecarboxamide. [0088] In certain embodiments, at least one of R³ and R⁴ are halo or optionally substituted Ci-Ce alkyl, or R³ and R⁴ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0089] In certain embodiments, L is absent or -C(R⁸)2-, and each R⁸ is optionally substituted Ci-Cé alkyl or halo, or two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0090] In certain embodiments, Y¹ is NR².

[0091] In certain embodiments, X¹ and X² are each independently nitrogen or carbon, and together form a 5 membered optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0092] In certain embodiments, X¹ and R¹ together with the atoms to which they are attached, form a 5 or 6 membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring; and X² is CH₂-,

[0093] In certain embodiments, Y² is -C(R⁶)2-; and one R⁶ is hydrogen, halo, or optionally substituted Ci-Ce alkyl, and the other R⁶ is halo or optionally substituted Ci-Ce alkyl; or two R⁶ together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0094] In certain embodiments, Y² is -O- and A is substituted with halo or cyano; or A is thiazolyl or a

3- or 4-membered ring.

[0095] In certain embodiments, Y² is -S-, -S(O)-, or -S(O)₂-; and A is other than isoxazole and phenyl orY²is -S(O)(NH)-.

[0096] In certain embodiments, Y² is -NR⁵-; X¹ and X² together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X¹ and X² together form an optionally substituted pyridyl, and A is other than triazole; or X¹ and X² are optionally substituted pyrimidyl, and A is other than pyrazole and triazole.

[0097] In certain embodiments, the carbonyl moiety and L are substituted other than 1,3- on ring A.

[0098] In certain embodiments, provided is a compound of Formula I or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein

Y¹ is OorNR²;

X¹ and X² are each independently nitrogen or carbon and either

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Cs alkyl;

each R⁶ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Côalken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted Ci-Cô alkyl, or R³ and R⁴ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Cô alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted Ci-Cô alkyl, or R³ and R⁴together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or -C(R⁸)2-, and each R⁸ is optionally substituted Ci-Cô alkyl or halo, or two R^s together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(3) Y¹ is NR²;

(4) X¹ and X² are each independently nitrogen or carbon, and together form a 5 membered optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

(5) X¹ and R¹ together with the atoms to which they are attached, form a 5 or 6 membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring; and X² is -CH₂-;

(6) Y² is -C(R⁶)2-; and one R⁶ is hydrogen, halo, or optionally substituted Ci-Cô alkyl, and the other R⁶ is halo or optionally substituted Ci-Cô alkyl; or two R⁶ together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(7) Y² is -O-; and A is substituted with halo or cyano; or A is thiazolyl or a 3 - or 4membered ring;

(8) Y² is -S-, -S(O)-, or -S(0)2-; and A is other than isoxazole and phenyl or Y² is -S(0)(NH)-;

(9) Y² is -NR⁵-; X¹ and X² together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X¹ and X² together form an optionally substituted pyridyl, and A is other than triazole; or X¹ and X² are optionally substituted pyrimidyl, and A is other than pyrazole and triazole;

(10) the carbonyl moiety and L are substituted other than 1,3- on ring A;

(11) Y² is -O-; X¹ and X² together form an optionally substituted pyridyl, and A is other than isoxazole;

(12) R¹ is C2-C6 alkyl optionally substituted with halo, hydroxy or cyano; or (13) when X¹ and X² form an optionally substituted phenyl ring as in the moiety

, at least one substituent is at the 1 or 4 position and is (a) other than fluoro, chloro or methyl at the 1 position, and/or (b) other than fluoro or methyl for the 4 position;

2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4-carboxamide; 4( 1,4-dihydro-2-oxo-3 (2H)-quinazolinyl)-N- [2,3,4,5 -tetrahydro-1 -( 1 -methylethyl) -2-oxo-1 H-1 benzazepin-3-yl]-1 -piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5tetrahydro-2-oxo-lH-l-benzazepin-3-yl]-l-piperazinecarboxamide; or 4-(2-amino-7-chloro-4quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-l-methyl-2-oxo-lH-l-benzazepin-3-yl]-l-piperazinecarboxamide.

[0099] In certain embodiments, the compound is not 5-(difluorophenylmethyl)-N-[(3S)-2,3,4,5tetrahydro-5 -methyl-4-oxo-1,5 -benzoxazepin-3 -yl] -3 -isoxazolecarboxamide or 5 (difluorophenylmethyi)-N-[(3S)-2,3,4,5-tetrahydro-4-oxo-l,5-benzoxazepin-3-yl]-3isoxazolecarboxamide.

[0100] Also provided herein are compounds that are useful as inhibitors of receptor-interacting protein kinase 1. In certain embodiments, provided is a compound of Formula I wherein

R¹ is H or optionally substituted Ci-Ce alkyl;

(a) X¹ and X² are each independently nitrogen or carbon, and together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or (b) X¹ and R¹ together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring; and X² is -CH2-;

Y¹ is O or NR², where R² and R¹ together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

each R⁶ is independently H, halo, optionally substituted Ci-Ce alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Côalken-l -yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted Ci-Ce alkyl, R³ and R⁴ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R’ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R^S)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R⁸ is independently H, halo, optionally substituted Ci-Ce alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted Ci-Ce alkyl, R³ and R⁴together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or -C(R⁸)2-, and each R⁸ is optionally substituted Ci-Ce alkyl or halo provided that the compound is not 5-(difhioro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-

3-yl)isoxazole-3-carboxamide or not 5-(difhioro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)isoxazole-3-carboxamide or two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(3) Y¹ is NR²;

(5) X¹ and R¹ together with the atoms to which they are attached, form a 5 or 6 membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring; and X² is -CH2-;

(6) Y² is -C(R⁶)2-; and one R⁶ is hydrogen, halo, or optionally substituted Ci-Cô alkyl, and the other R⁶ is halo or optionally substituted Ci-Ce alkyl; or two R⁶ together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(7) Y² is -O-; and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4membered ring; provided that the compound is not 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3 -yl)thiazole-4-carboxamide or 2-benzyl-N-(5 -methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4-carboxamide;

(8) Y² is -S-, -S(O)-, or -S(O)₂-; and A is other than 1,3-isoxazole or Y² is -S(0)N(H)-;

(9) Y² is -NR⁵-; X¹ and X² together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X¹ and X² together form an optionally substituted pyridyl, and A is other than triazole; or X¹ and X² are optionally substituted pyrimidyl, and A is other than pyrazole and triazole; or (10) the carbonyl moiety and L are substituted other than 1,3- on ring A;

or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0101] In certain embodiments, R¹ is Ci-Ce alkyl. In certain embodiments, R¹ is methyl.

[0102] In certain embodiments, the moiety:

wherein

X³, X⁴ and X⁵ are each S, O, N, NH, or CH;

X⁶, X⁷, X⁸ and X⁹ are each N or CH;

q is 0, 1 or 2;

each R¹⁰ is independently cyano, halo, optionally substituted Ci-Cô alkyl or -S(O)2-Ci-Ce alkyl.

[0103] In certain embodiments, the moiety:

wherein

X³, X⁴ and X⁵ are each S, O, N, NH, or CH;

X⁶, X⁷, X⁸ and X⁹ are each N or CH;

q is 0, 1 or 2;

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

[0104] In certain embodiments, the moiety:

X³, X⁴ and X⁵ are each S, O, N, NH, or CH;

X⁶, X⁷, X^s and X⁹ are each N or CH;

q is 0, 1 or 2;

each R¹⁰ is independently halo or optionally substituted alkyl.

[0105] In certain embodiments, the moiety:

R , or rs

[0106]

In certain embodiments, the moiety

[0107]

In certain embodiments, the moiety

[0108]

In certain embodiments, the moiety ^r4 is

[0109] In certain embodiments, Y¹ is O.

[0110] In certain embodiments, R¹ is methyi. In certain embodiments, R¹ is ethyl.

[0111]

In certain embodiments, Y² is

[0112] In certain embodiments, Y² is -O-; and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4-membered cycloalkyl or 3- or 4-membered heterocycloalkyl ring.

[0113] In certain embodiments, both R³ and R⁴ are fluoro, or either R³ or R⁴ are fluoro and tire other is hydrogen, or R³ and R⁴ form a cyclopropyl or R³ joins with R⁶ to form a cyclopropyl. In certain embodiments, R³ or R⁴ is methyi.

[0114] In certain embodiments, A is phenyl, phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.

[0115] In certain embodiments, A is isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4Hpyrrolo[l,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.

[0116] In certain embodiments, A is phenyl.

[0117] In certain embodiments, L is absent, -S (0)2- or -C(R⁸)2-.

[0118] In certain embodiments, two R⁵ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0119] In certain embodiments, R⁹is phenyl or 2,3-dihydro-lH-indenyl. In certain embodiments, R⁹is phenyl. In certain embodiments, R⁹is 2-F-phenyL In certain embodiments, R⁹is pyridyl. In certain embodiments, R⁹is optionally substituted pyridyl, phenyl or 2,3-dihydro-lH-indenyl.

[0120] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, R¹⁰ is methyl.

[0121] In one aspect, provided is a compound of Formula la:

wherein

Y¹ isOorNR²;

X¹ and X² are each independently nitrogen or carbon and either

X¹ and X² together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R¹ is H or Ci-Cô alkyl optionally substituted with halo, hydroxy or cyano or when Y’ is NR², then R² and R¹ together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

each R⁶ is independently H, halo, or optionally substituted Ci-Cô alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Csalken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R^s is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl.

embodiments, when the moiety R⁴ is

, q is 0 or R¹⁰ is halo or alkyl, and

L is absent, then ring A is a 3-, 4- or 5-membered monocyclic ring. In certain embodiments, the moiety

q is 0 or R¹⁰ is halo or alkyl, and L is absent, then ring A is a 3-, 4- or 5-membered monocyclic ring.

[0123] In certain embodiments, in any Formula disclosed herein, R⁹ is substituted with at least one cyano.

[0124] In certain embodiments, the compound is of Formula II:

wherein q is 0, 1, or 2;

X⁶, X⁷, X^s and X⁹ are each N or CH;

R¹ is H or Ci-Cô alkyl optionally substituted with halo, hydroxy or cyano;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Cg alkyl;

each R⁶ is independently H, halo, or optionally substituted Ci-C₆ alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Cealken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Cô alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R¹⁰ is independently cyano, halo or optionally substituted alkyl;

provided that at least one of the following occurs:

(2) L is absent or -C(R⁸)₂-, and each R⁸ is optionally substituted Ci-Cs alkyl or halo, or two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(3) Y² is -C(R⁶)₂-; and one R⁶ is hydrogen, halo, or optionally substituted Ci-Ce alkyl, and the other R⁶ is halo or optionally substituted Ci-Cô alkyl; or two R⁶ together with the carbon atom to which they are attached, form a Ci-Cô alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(4) Y² is -O-; and A is substituted with halo or cyano; or A is thiazolyl or a 3 - or 4membered ring;

(5) Y² is -S-, -S(O)-, or -S(O)2-; and A is other than isoxazole or Y² is -S(O)(NH)-;

(6) Y² is -NR^{4 5}-; X⁶, χζ X^s and X⁹ together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole: X⁶, X⁷, X⁸ and X⁹ together form an optionally substituted pyridyl, and A is other than triazole; or X⁶, X⁷, X⁸ and X⁹ are optionally substituted pyrimidyl, and A is other than pyrazole and triazole; or (7) Y² is -O-; X¹ and X² together form an optionally substituted pyridyl, and A is other than isoxazole;

(8) R¹ is Cz-Ce alkyl optionally substituted with halo, hydroxy or cyano; or (9) when X¹ and X² form an optionally substituted phenyl ring as in the moiety

⁴ , at least one substituent is at the 1 or 4 position and is (a) other than fluoro, chloro or methyl at the 1 position, and/or (b) other than fluoro or methyl for the 4 position;

2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4-carboxamide; 4(l,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-l-(l-methylethyl)-2-oxo-lH-lbenzazepin-3-yl]-l-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5tetrahydro-2-oxo- 1H-1 -benzazepin-3-yl]-1 -piperazinecarboxamide; or 4-(2-amino-7-chloro-4quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-l-methyl-2-oxo-lH-l-benzazepin-3-yl]-l-piperazinecarboxamide.

[0125] In certain embodiments, the compound is of Formula II wherein q is 0, 1, or 2;

X⁶, X⁷, X⁸ and X⁹ are each N or CH;

R¹ is H or optionally substituted Ci-Ce alkyl;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(0)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

each R⁶ is independently H, halo, optionally substituted Ci-Ce alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Cealken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted Ci-Ce alkyl, R³ and R⁴ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR⁷- or -C(R⁸)2-;

R⁷ is H or optionally substituted Ci-Cô alkyl;

each R⁸ is independently H, halo, optionally substituted Ci-Cô alkyl, or two R^s together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R¹⁰ is independently halo or optionally substituted alkyl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted Ci-Cô alkyl, R³ and R⁴together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or -C(R⁸)2-, and each R⁸ is optionally substituted Ci-Cô alkyl or halo provided that the compound is not 5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-

3-yl)isoxazole-3-carboxamide or not 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)isoxazole-3-carboxamide or two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(3) Y² is -C(R⁶)2-; and one R⁶ is hydrogen, halo, or optionally substituted Ci-Cô alkyl, and the other R⁶ is halo or optionally substituted Ci-Ce alkyl; or two R⁶ together with the carbon atom to which they are attached, form a Ci-Cô alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(4) Y² is -O-; and A is substituted with haio or cyano; or A is thiazolyl or a 3- or 4membered ring; provided that the compound is not 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4.5tetrahydrobenzofb] [ 1,4] oxazepin-3 -yl)thiazole-4-carboxamide or 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5 tetrahydrobenzofb]f l,4]oxazepin-3-yl)thiazole-4-carboxamide;

(5) Y² is -S-, -S(O)-, or -S(O)2-; and A is other than 1,3-isoxazole or Y² is -S(0)N(H)-;

(6) Y² is -NR⁵-; X⁶, X⁷, X⁸ and X⁹ together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X⁶, X⁷, X⁸ and X⁹ together form an optionally substituted pyridyl, and A is other than triazole; or X⁶, X⁷, X⁸ and X⁹ are optionally substituted pyrimidyl, and A is other than pyrazolc and triazole; or or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0126] In certain embodiments, the compound is of Formula II and L is absent or -C(R⁸)z-, and two R⁸together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0127] In any of the embodiments of Formula II (or subformula thereof), R¹ is H or optionally substituted Ci-Ce alkyl. In any of the embodiments of Formula II (or subformula thereof), R¹ is H or CiCô alkyl.

[0128] In any of the embodiments of Formula Π (or subformula thereof), q is 0, 1 or 2 and when présent, each R¹⁰ is independently cyano, halo, optionally substituted Ci-Ce alkyl or -S(O)2-Ci-Cô alkyl. In any of the embodiments of Formula II (or subformula thereof), q is 0, 1 or 2 and when présent, each R¹⁰ is independently cyano, halo or optionally substituted alkyl. In any of the embodiments of Formula II (or subformula thereof), each R¹⁰ is independently halo. In certain embodiments, each R¹⁰ is independently fluoro. In any of the embodiments of Formula II (or subformula thereof), q is 0. In any of the embodiments of Formula II (or subfomiula thereof), q is 1. In any of the embodiments of Formula II (or subformula thereof), q is 2.

[0129] In certain embodiments, the compound is of Formula lia:

wherein q is 0, 1 or 2;

R¹ is H or Cj-Cô alkyl optionally substituted with halo, hydroxy or cyano;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Cj-Cô alkyl;

each R⁶ is independently H, halo, or optionally substituted Cj-Cô alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Cj-Cealken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted Ci-Ce alkyl, or R³ and R⁴ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Cj-Cô alkyl;

each R⁸ is independently H, halo, or optionally substituted Cj-Cô alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;

provided that at least one of the following occurs:

(2) L is absent or -C(R⁸)₂-, and two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(3) Y² is -C(R⁶)₂-; and two R⁶ together with the carbon atom to which they are attached, form a Cj-Cô alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(4) R¹ is C₂-Cô alkyl optionally substituted with halo, hydroxy or cyano; or (5) when X¹ and X² form an optionally substituted phenyl ring as in the moiety

⁴ , at least one substituent is at the 1 or 4 position and is (a) other than fluoro. chloro or methyl at the 1 position, and/or (b) other than fluoro or methyl for the 4 position;

2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepm-3-yl)thiazole-4-carboxamide; 4( 1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-l -( 1 -methylethyl)-2-oxo-lH-1 benzazepin-3 -yl] -1 -piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3 S)-2,3,4,5tetrahydro-2-oxo-lH-l-benzazepin-3-yl]-l-piperazinecarboxamide; or 4-(2-amino-7-chloro-4quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-l-methyl-2-oxo-lH-l-benzazepin-3-yl]-l-piperazinecarboxamide.

[0130] In certain embodiments, the compound is of Formula Ha wherein

R¹ is H or optionally substituted Ci-Cs alkyl;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

R³ and R⁴ are independently H, halo, optionally substituted Ci-Ce alkyl, R³ and R⁴ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R^s is independently H, halo, optionally substituted Ci-C₆ alkyl, or two R⁸ together with tire carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring; and

provided that at least one of the following occurs:

(2) L is absent or -C(R^S)2-, and two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y² is -C(R⁶)2-; and two R⁶ together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[0131] In certain embodiments, the compound is of Formula lia-1 :

wherein one of R¹¹ or R¹² is halo and the other is Ci-e alkyl or Ci-6 cycloalkyl and the remaining variables are as defined throughout.

[0132] In certain embodiments, the compound is of Formula IIa-2:

IIa-2 or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;

R⁴ is H, halo, or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

[0133] In certain embodiments, the compound is of Formula IIa-2a. In certain embodiments, the compound is of Formula IIa-2b. In certain embodiments, the compound is of Formula IIa-3. In certain embodiments, the compound is of Formula IIa-4. In certain embodiments, the compound is of Formula IIa-5.

[0134] In certain embodiments, the compound is of Formula Ilb :

wherein q is 0, 1 or 2;

R¹ is H or Ci-Câ alkyl optionally substituted with halo, hydroxy or cyano;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Cé alkyl;

each R^s is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

provided that at least one of tire following occurs:

(3) Y² is -C(R⁶)₂-; and two R⁶ together with the carbon atom to which they are attached, form a Ci-Cs alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (4) the compound is not 5-(phenylmethyl)-N-[(3S)-l,2,3,4-tetrahydro-7-methyl-2oxopyrido[2,3-b][l,4]oxazepin-3-yl]-3-isoxazolecarboxamide; N-[(3S)-8-fluoro-2,3,4,5-tetrahydro-lmethyl-2-oxo-lH-pyrido[2,3-b][l,4]diazepin-3-yl]-3-(phenylmethyl)-lH-l,2,4-triazole-5-carboxamide;

-(phenylmethyl)-N-[(3 S)-1,2,3,4-tetrahydro-7-methyl-2-oxopyrido[2,3-b] [ 1,4]oxazepin-3-yl] -3 isoxazolecarboxamide; or N-[(3S)-8-fluoro-2,3,4,5-tetrahydro-l-methyl-2-oxo-lH-pyrido[2,3b] [ 1,4]diazepin-3 -yl]-3-(phenylmethyl)- 1H-1,2,4-triazole-5 -carboxamide.

[0135] In certain embodiments, the compound is of Formula Ilb wherein

R¹ is H or optionally substituted Ci-Cs alkyl;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and

provided that at least one of the following occurs:

(2) L is absent or -C(R⁸)2-, and two R^s together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y² is -C(R⁶)2-; and two R⁶ together with the carbon atom to which they are attached, form a Ci-Cô alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[0136] In certain embodiments, the compound is of Formula IIb-1 :

wherein q is 0, 1 or 2:

R¹ is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;

R⁴ is H, halo, or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Câ alkyl;

[0137] In certain embodiments, the compound is of Formula IIb-2. In certain embodiments, the compound is of Formula IIb-3. In certain embodiments, the compound is of Formula IIb-4. In certain embodiments, the compound is of Formula IIb-5. In certain embodiments, the compound is of Formula IIb-6.

[0138] In certain embodiments, the compound is of Formula Ile:

wherein q is 0, 1 or 2;

R¹ is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring, optionally substituted aryl or optionally substituted heteroaryl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

[0139] In certain embodiments, the compound is of Formula Ile wherein

R¹ is H or optionally substituted Ci-Ce alkyl;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

each R⁶ is independently H, halo, optionally substituted Ci-Ce alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Cj-C’ealken-l -yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted Ci-Cs alkyl, R³ and R⁴together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or -C(R⁸)₂-, and two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y² is -C(R^S)2-; and two R⁶ together with the carbon atom to which they are attached, form a Ci-Cô alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[0140] In certain embodiments, provided is a compound of Formula Ile or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-Ce alkyl;

Y² is -O- or -C(R⁶)₂-;

L is absent, -O- or -C(R⁸)2-;

each R⁸ is independently H, halo, or optionally substituted Ci-Cs alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-Ce alkyl or -S(O)2-Ci-Ce alkyl.

[0141] In certain embodiments, the compound is of Formula IIc-1:

L A ^A J-L-R⁹

R⁴ O

IIc-1 or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;

R⁴ is H, halo, or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

[0142] In certain embodiments, the compound is of Formula IIc-2. In certain embodiments, the compound is of Formula IIc-3. In certain embodiments, the compound is of Formula IIc-4. In certain embodiments, the compound is of Formula IIc-5. In certain embodiments, the compound is of Formula

IIc-6.

[0143] In certain embodiments, provided is a compound of Formula IIc-4:

IIc-4 or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-Ce alkyl;

Y² is -O- or -C(R⁶)₂-;

L is absent, -O- or -C(R⁸)₂-;

each R⁸ is independently H, halo, or optionally substituted Ci-Cô alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-Côalkyl or -S(O)₂-Ci-C₆ alkyl.

[0144] In certain embodiments, the compound is of Formula Ild:

wherein q is 0, 1 or 2;

R¹ is H or Ci-Cô alkyl optionally substituted with halo, hydroxy or cyano;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Cô alkyl;

each R⁶ is independently H, halo, or optionally substituted Ci-Cô alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Cô alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Cô alkyl;

provided that at least one of the following occurs:

(3) Y² is -C(R⁶)₂-; and two R⁶ together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (4) the compound is not 5-(phenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-4-oxopyrido[4,3-

b] [ 1,4]oxazepin-3 -yl] -3 -isoxazolecarboxamide; or

5-(phenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-4-oxopyrido[4,3-b][l,4]oxazepin-3-yl]-3isoxazolecarboxamide.

[0145] In certain embodiments, the compound is of Formula Ild wherein

R¹ is H or optionally substituted Ci-Cô alkyl;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted Ci-Ce alkyl, or R³ and R⁴together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or -C(R⁸)₂-, and two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y² is -C(R⁶)₂-; and two R⁶ together with the carbon atom to which they are attached, form a Ci-Cô alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof

[0146] In certain embodiments, the compound is of Formula IId-1 :

wherein q is 0, 1 or 2;

R¹ is H or Ci-Cs alkyl optionally substituted with halo, hydroxy or cyano;

R⁴ is H, halo, or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Cô alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁸ together with the carbon atonr to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;

[0147] In certain embodiments, the compound is of Formula IId-2. In certain embodiments, the compound is of Formula IId-3. In certain embodiments, the compound is of Formula IId-4. In certain embodiments, the compound is of Formula IId-5. In certain embodiments, the compound is of Formula IId-6.

R¹

[0148] In certain embodiments, provided is a compound of Formula Ile:

wherein q is 0, 1 or 2;

R¹ is H or Ci-C₆ alkyl optionally substituted with halo, hydroxy or cyano;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Cg alkyl;

each R⁶ is independently H, halo, or optionally substituted Ci-C₆ alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Cealkcn-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Cg alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Cg alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-Cgalkyl or -S(O)₂-Ci-C6 alkyl.

[0149] In certain embodiments, the compound is of Formula Ile or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-Cg alkyl optionally substituted with halo, hydroxy or cyano;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Cg alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

[0150] In certain embodiments, the compound is of Formula Ile wherein

R¹ is H or optionally substituted Ci-Câ alkyl;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Cg alkyl;

each R⁶ is independently H, halo, optionally substituted Ci-Cô alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Côalken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted Ci-Cs alkyl, R³ and R⁴ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R^S)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs:

(2) L is absent or -C(R⁸)₂-, and two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y² is -C(R⁶)₂-; and two R⁶ together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[0151] In certain embodiments, provided is a compound of Formula Ile or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-C₆ alkyl;

Y² is -O- or -C(R⁶)₂-;

each R⁶ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-C«alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O- or -C(R⁸)₂-;

each R⁸ is independently H, halo, or optionally substituted Ci-C₆ alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[0152] In certain embodiments, the compound is of Formula Ile-1 :

R¹

wherein or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

q is 0, 1 or 2;

R¹ is H or Ci-Cô alkyl optionally substituted with halo, hydroxy or cyano;

R⁴ is H, halo, or optionally substituted Ci-Cô alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Cô alkyl, or two R^s together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;

[0153] In certain embodiments, the compound is of Formula IIe-2. In certain embodiments, the compound is of Formula IIe-3. In certain embodiments, the compound is of Formula IIe-4. In certain embodiments, the compound is of Formula IIe-5. In certain embodiments, tire compound is of Formula IIe-6.

[0154] In certain embodiments, provided is a compound of Formula IIe-4 or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-Cô alkyl;

Y² is -O- or -C(R⁶)₂-;

L is absent, -O- or -C(R⁸)2-;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-C₆alkyl or -S(O)₂-Ci-C₆ alkyl.

[0155] In certain embodiments, provided is a compound of Formula Ilf:

O

Y R³ O R⁴ Ilf or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-Cg alkyl optionally substituted with halo, hydroxy or cyano;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Cô alkyl;

each R⁶ is independently H, halo, or optionally substituted Ci-Cô alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Cealken-l-yi, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R'° is independently cyano, halo, optionally substituted Ci-C« alkyl or -S(O)2-Ci-C₆ alkyl. [0156] In certain embodiments, the compound is of Formula Ilf or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-C₆ alkyl optionally substituted with halo, hydroxy or cyano;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

each R^s is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Cealken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

[0157] In certain embodiments, the compound is of Formula Ilf wherein

R¹ is H or optionally substituted Ci-Câ alkyl;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R^S)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

each R⁶ is independently H, halo, optionally substituted Ci-C6 alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Csalken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted Ci-Ce alkyl, R³ and R⁴ together with tire carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R⁸ is independently H, halo, optionally substituted Ci-Cs alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and

(2) L is absent or -C(R⁸)2-, and two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y² is -C(R⁶)₂-; and two R⁶ together with the carbon atom to which they are attached, form a Ci-Câ alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[0158] In certain embodiments, provided is a compound of Formula Ilf or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-Câ alkyl;

Y² is -O- or -C(R⁶)₂-;

each R⁶ is independently H, halo, or optionally substituted Ci-C6 alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-C6alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O- or -C(R⁸)2-;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-Côalkyl or -S(0)2-Ci-Cô alkyl.

[0159] In certain embodiments, the compound is of Formula IIf-1 :

R¹

IIf-1 wherein or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

q is 0, 1 or 2;

R¹ is H or Ci-Cô alkyl optionally substituted with halo, hydroxy or cyano;

R⁴ is H, halo, or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)2-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R^s is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;

[0160] In certain embodiments, the compound is of Formula IIf-2. In certain embodiments, the compound is of Formula IIf-3. In certain embodiments, the compound is of Formula IIf-4. In certain embodiments, the compound is of Formula IIf-5. In certain embodiments, the compound is of Formula IIf-6.

[0161] In certain embodiments, provided is a compound of Formula IIf-4 or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-Ce alkyl;

Y² is -O- or -C(R⁶)₂-;

each R⁶ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-C₆alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O- or -C(R⁸)₂-;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-Ce alkyl or -S(O)₂-Ci-C6 alkyl.

[0162] In certain embodiments of compounds of Formula I (or subformula thereof), R³ is H. In certain embodiments of compounds of Formula I (or subformula thereof), R⁴ is optionally substituted Ci-Ce alkyl. In certain embodiments of compounds of Formula I (or subformula thereof), R³ is H and R⁴ is optionally substituted Ci-Ce alkyl. In certain embodiments of compounds of Formula I (or subformula thereof), R³ is H and R⁴ is methyl.

[0163] In certain embodiments of compounds of Formula I (or subformula thereof), R³ is H and R⁴ is H.

[0164] In certain embodiments of compounds of Formula II (or subfonnula thereof), R³ is H. In certain embodiments of compounds of Formula II (or subformula thereof), R⁴ is optionally substituted Ci-Ce alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), R³ is H and R⁴is optionally substituted Ci-Ce alkyl. In certain embodiments of compounds of Formula II (or subfonnula thereof), R³ is H and R⁴ is Ci-Ce alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), R³ is H and R⁴ is methyl.

[0165] In certain embodiments of compounds of Formula lia, Ilb, Ile, Ild, Ile and Ilf (or subformula thereof), R³ is H and R⁴ is H. In certain embodiments of compounds of Formula IIe-4 and IIe-5, R³ is H and R⁴ is H.

[0166] In certain embodiments of compounds of Formula I (or subformula thereof), the A ring is an optionally substituted heteroaryl ring. In certain embodiments of compounds of Formula I (or subformula thereof), the A ring is an unsubstituted heteroaryl ring. In certain embodiments of compounds of Formula I (or subformula thereof), the A ring is a pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl. In certain embodiments of compounds of Formula I (or subformula thereof), the A ring is a oxadiazolyl. In certain embodiments of compounds of Formula I (or subformula thereof), the A ring is a triazolyl.

[0167] In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is an optionally substituted heteroaryl ring. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is an unsubstituted heteroaryl ring. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is an optionally substituted 5-membered heteroaryl ring. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is an unsubstituted 5-membered heteroaryl ring. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is an optionally substituted 6-membered heteroaryl ring. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is a heteroaryl ring substituted with at least one halo. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is a 5-membered heteroaryl ring substituted with at least one halo. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is a pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is oxadiazolyl. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is a triazolyl.

[0168] In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is of the formula:

wherein

X¹⁰, X¹’ and X¹² are each S, O, N, CR¹³ or NR¹³, and X¹³ is C or N; and each R¹³ is independently H, halo, cyano or optionally substituted Ci-Cô alkyl.

[0169] In certain embodiments, at least one of X¹⁰, X¹¹ and X¹² is CR¹³ or NR¹³ and at least one R¹³ is halo, cyano or optionally substituted Ci-Cô alkyl. In certain embodiments, at least one of X¹⁰, X¹¹ and X¹² is CR¹³ or NR¹³ and at least one R¹³ is halo. In certain embodiments, each R¹³ is independently H, fluoro, chloro, cyano or methyl.

[0170] In certain embodiments of compounds of Formula Π (or subformula thereof), the A ring is one of the following:

wherein each ring may optionally substituted with one or more halo, cyano or Ci-Cô alkyl.

[0171] In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is one of the following:

[0172] In certain embodiments of compounds of Formula I (or subformula thereof), L is absent, -O- or -C(R^S)₂-; and each R^s is independently H or Ci-Cg alkyl, or two R^s together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl. In certain embodiments of compounds of Formula I (or subformula thereof), L is -C(R⁸)2- and each R⁸ is taken together with the carbon atom to which they are attached to form cyclopropyl.

[0173] In certain embodiments of compounds of Formula II (or subformula thereof), L is absent, -O- or -C(R⁸)₂-; and each R⁸ is independently H, halo, or optionally substituted Ci-Cô alkyl, or two R⁸together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring. In certain embodiments of compounds of Formula II (or subformula thereof), L is absent, -O- or -C(R⁸)2-; and each R⁸ is independently H or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl.

[0174] In certain embodiments of compounds of Formula II (or subformula thereof), L is absent. In certain embodiments of compounds of Formula II (or subformula thereof), L is -O-. In certain embodiments of compounds of Formula II (or subformula thereof), L is -C(R⁸)2- and each R⁸ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring. In certain embodiments of compounds of Formula II (or subformula thereof), L is -C(R⁸)2- and each R⁸ is independently H, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl. In certain embodiments of compounds of Formula II (or subformula thereof), L is -C(R⁸)₂- and each R⁸ is taken together with the carbon atom to which they are attached to form cyclopropyl.

[0175] In certain embodiments of compounds of Formula I (or subformula thereof), R⁹ is optionally substituted aryl. In certain embodiments of compounds of Formula I (or subformula thereof), R⁹ is phenyl optionally substituted with one or more halo, cyano or Ci-Cô alkyl optionally substituted with halo. In certain embodiments of compounds of Formula I (or subformula thereof), R⁹ is phenyl.

[0176] In certain embodiments of compounds of Formula II (or subformula thereof), R⁹ is optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments of compounds of Formula II (or subformula thereof), R⁹ is phenyl, dihydroindenyl, pyridyl,

2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2,4difluorophenyl, 3-cyano-4-fluorophenyl, or 5-fluoropyridin-3-yl.

[0177] In certain embodiments of compounds of Formula II (or subformula thereof), q is 0. In certain embodiments of compounds of Formula II (or subformula thereof), q is 1 or 2; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-Cô alkyl, or -S(O)2-Ci-C6 alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), q is 1 or 2; and each R¹⁰ is independently cyano, halo, methyl, or -S(O)2-methyl.

[0178] In certain embodiments, the compound is of Formula III:

R⁴ III or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

wherein q is 0, 1 or 2;

R¹ is H or Ci-Cg alkyl optionally substituted with halo, hydroxy or cyano;

X¹ and X² are each N or CH;

X³, X⁴ and X⁵ are each S, O, N, NH, or CH

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(0)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

[0179] In certain embodiments, at least one of the following occurs:

(2) L is absent or -C(R^S)₂-, and each R^s is optionally substituted Ci-Cô alkyl or halo or two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y² is -C(R⁶)2-; and one R⁶ is hydrogen, halo, or optionally substituted Ci-C6 alkyl, and the other R⁶ is halo or optionally substituted Ci-Ce alkyl; or two R⁶ together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0180] In certain embodiments, the compound is of Formula III wherein

X¹ and X² are each N or CH;

X³, X⁴ and X⁵ are each S, O, N, NH, or CH

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Cô alkyl;

each R⁸ is independently H, halo, optionally substituted Ci-Cô alkyl, or two R⁸ together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and

[0181] In certain embodiments, the compound is of Formula Ilia, Illb, or IIIc:

wherein q is 0, 1 or 2;

R¹ is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;

X³, X⁴ and X⁵ are each S, O, N, NH, or CH

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R¹ is H or Ci-Ce alkyl;

R⁵ is H or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R^S)₂-;

R⁷ is H or optionally substituted Ci-Cô alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Cô alkyl, or two R^s together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[0182] In certain embodiments, the compound is of Formula IIIa-1, IIIb-1, or IIIc-1:

wherein q is 0, 1 or 2;

R¹ is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;

X³, X⁴ and X⁵ are each S, O, N, NH, or CH;

R¹ is H or Ci-Cô alkyl;

R⁴ is H, halo, or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

[0183] In certain embodiments, the compound is of Formula Ilia, Illb, or IIIc:

Illb

wherein

X³, X⁴ and X⁵ are each S, O, N, NH, or CH

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(0)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Ce alkyl;

each R⁶ is independently H, halo, optionally substituted Ci-Ce alkyl, or two R⁶ together with the carbon atom to which they are attached, form a Ci-Cgalken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

[0184] In certain embodiments, the compound is of Formula IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8 or IIIa-9:

wherein the variables of Formula IIIa-1 to IIIa-9 are defined throughout.

[0185] In certain embodiments, the compound is of Formula IVa, IVb, FVc, IVd, IVe, IVf or IVg:

wherein q is 0, 1 or 2;

R⁴ is H, halo, or optionally substituted Ci-Ce alkyl;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷- or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-Ce alkyl, or -S(O)₂-Ci-Cfi alkyl.

[0186] In certain embodiments, provided is a compound of Formula V :

R¹

or a pharmaceutically acceptable sait, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0, 1, or 2;

X⁶ and X⁹ are independently N or CR¹⁴;

R¹ is H or optionally substituted Ci-Cô alkyl;

Y² is -O- or -C(R⁶)₂-;

each R⁶ is independently H, halo, optionally substituted Ci-Cô alkyl;

R³ is H, halo, optionally substituted Ci-Cô alkyl, or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is -C(R⁸)₂-;

each R⁸ is independently H, halo, optionally substituted Ci-Cô alkyl, or two R⁸ together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R⁹ is optionally substituted aryl or optionally substituted heteroaryl;

each R¹⁰ is independently cyano, halo, optionally substituted Ci-Cô alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted Ci-Côalkoxy, or -S(O)₂-Ci-Côalkyl; and each R¹⁴ is independently hydrogen, cyano, halo, C1-C3 alkyl optionally substituted with halo, or C1-C3 alkoxy optionally substituted with halo;

provided that when both of X⁶ and X⁹ are CR¹⁴, one or more of (i), (ii), (iii), (iv) and (v) is true: (i) R³ and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, (ii) L is -C(R⁸)2- and each R⁸ is taken together with the carbon atom to which they are attached to form cyclopropyl, (iii) R⁹ is substituted with at least one cyano, (iv) X⁹ is other than C-H, C-F, C-Cl or C-CH3 and/or (v) X⁶ is other than C-H, C-F or C-CH3.

[0187] In certain embodiments of compounds of Formula V (or subformula thereof), X⁹ is N. In certain embodiments X⁹ is N and X⁶ is CR¹⁴. In certain embodiments X⁹ and X⁶ are N.

[0188] In certain embodiments of compounds of Formula V (or subformula thereof), Y² is O. In certain embodiments R³ is H. In certain embodiments R³ is methyl. In certain embodiments R³ and R⁶together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl. In certain embodiments R³ and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.

[0189] In certain embodiments of compounds of Formula V (or subformula thereof), X⁶ and X⁹ are CR¹⁴ and R³ and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl. In certain embodiments R³ and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring. In certain embodiments X⁹ is CH. In certain embodiments X⁹ is CF.

[0190] In certain embodiments of compounds of Formula V (or subformula thereof), X⁶ and X⁹ are CR¹⁴ and L is -C(R⁸)2- and each R⁸ is taken together with the carbon atom to which they are attached to form cyclopropyl.

[0191] In certain embodiments of compounds of Formula V (or subformula thereof), X⁶ and X⁹ are CR¹⁴, L is -C(R⁸)₂- and each R⁸ is taken together with the carbon atom to which they are attached to form cyclopropyl and R³ and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.

[0192] In certain embodiments of compounds of Formula V (or subformula thereof), each R¹⁰ is independently cyano, halo, or -S(O)2-Ci-Cêalkyl. In certain embodiments, q is 1 or 2 and each R¹⁰ is independently cyano, halo, or -S(O)2-Ci-Côalkyl. In certain embodiments, q is two and both R¹⁰ are halo. In certain embodiments, q is two and both R¹⁰ are fluoro. In certain embodiments, q is two and at least one R¹⁰ is fluoro.

[0193] In certain embodiments of compounds of Formula V (or subformula thereof), R¹ is H or methyl. In certain embodiments of compounds of Formula V (or subformula thereof), R¹ is H.

[0194] In certain embodiments of compounds of Formula V (or subformula thereof), R¹ is methyl.

[0195] In certain embodiments of compounds of Formula V (or subformula thereof), L is CH2 or two R⁸ together with the carbon atom to which they are attached form a cycloalkyl ring. In certain embodiments L is CH2. In certain embodiments R⁹ is optionally substituted phenyl. In certain embodiments R⁹ is phenyl. In certain embodiments R⁹ is phenyl substituted by one to two substituents independently seiected from the group consisting of cyano and halo. In certain embodiments R⁹ is phenyl substituted by cyano.

[0196] In certain embodiments of compounds of Formula V (or subformula thereof), R¹⁴ is hydrogen, halo or methyl optionally substituted with 1-3 fluoro. In certain embodiments, R¹⁴ is hydrogen or halo. In certain embodiments, R¹⁴ is hydrogen. In certain embodiments, R¹⁴ is halo. In certain embodiments, R¹⁴is fluoro.

[0197] In certain embodiments, provided is a compound of Formula Va:

X⁶ is N or CR¹⁴;

R¹ is H or optionally substituted Ci-Ce alkyl;

Y² is -O- or -C(R⁶)₂-;

each R⁶ is independently H, halo, optionally substituted Ci-Ce alkyl;

R³ is H, halo, optionally substituted Ci-Ce alkyl, or R³ and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is -C(R⁸)₂-;

each R⁸ is independently H, halo, optionally substituted Ci-Ce alkyl, or two R⁸ together with the carbon atom to which they are attached form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R⁹ is optionally substituted aryl or optionally substituted heteroaryl;

each R¹⁰ is independently cyano, halo, optionally substituted Ci-Ce alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted Ci-Cealkoxy, or -S(O)₂-Ci-C6 alkyl; and

R¹⁴ is hydrogen, cyano, halo, C1-C3 alkyl optionally substituted with halo or oxo, or C1-C3 alkoxy optionally substituted with halo or oxo.

[0198] In certain embodiments of compounds of Formula Va, X⁶ is CR¹⁴. In certain embodiments X⁶is N.

[0199] In certain embodiments of compounds of Formula Va, each R¹⁰ is independently cyano, halo, or -S(O)₂-Ci-C6 alkyl. In certain embodiments, q is at least one and at least one R¹⁰ is halo. In certain embodiments, q is at least one and at least one R¹⁰ is fluoro. In certain embodiments, q is at least one and at least one R¹⁰ is cyano.

[0200] In certain embodiments of compounds of Formula Va, q is 0.

[0201] In certain embodiments of compounds of Formula Va, Y² is O. In certain embodiments R³ is

H. In certain embodiments R³ is methyl. In certain embodiments R³ and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl. In certain embodiments R³and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.

[0202] In certain embodiments of compounds of Formula Va, R¹ is H or methyl.

[0203] In certain embodiments of compounds of Formula Va, R¹ is methyl.

[0204] In certain embodiments of compounds of Formula Va, L is CH2 or two R^s together with the carbon atom to which they are attached form a cycloalkyl ring. In certain embodiments L is CH2.

[0205] In certain embodiments of compounds of Formula Va, R⁹ is optionally substituted phenyl. In certain embodiments R⁹ is phenyl. In certain embodiments R⁹ is phenyl substituted by one to two substituents independently selected from the group consisting of cyano and halo. In certain embodiments R⁹ is phenyl substituted by cyano.

[0206] In certain embodiments of compounds of Formula Va (or subformula thereof), R¹⁴ is hydrogen, cyano, halo or methyl optionally substituted with 1-3 fluoro or oxo. In certain embodiments, R¹⁴ is hydrogen or halo. In certain embodiments, R¹⁴ is hydrogen. In certain embodiments, R¹⁴ is cyano.

[0207] In certain embodiments the compounds of Formula V and Va do not readily cross the blood brain barrier. In certain embodiments the compounds of Formula V and Va hâve a MDCKII-MDR1 efflux ratio of greater than 2.5. In certain embodiments the compounds of Formula II, Va and V wherein at least one of X⁶ and X⁹ are N, hâve a hepatic clearance of less than 5, 4, 3, 2, or 1 mL/min/kg when tested according to the human hepatic stability assay described below.

[0208] In certain embodiments, the compound is of Formula VI:

X⁶ is N or CR¹⁴;

R¹ is H or optionally substituted Ci-Cô alkyl;

Y² is -O- or -C(R⁶)₂-;

each R⁶ is independently H, halo, optionally substituted Ci-Ce alkyl;

R³ is H, halo, optionally substituted Ci-C₆ alkyl, or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is -C(R⁸)₂-;

each R⁸ is independently H, halo, optionally substituted Ci-C₆ alkyl, or two R⁸ together with the carbon atom to which they are attached form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

R⁹ is optionally substituted aryl;

each R¹⁰ is independently halo, optionally substituted Ci-Ce alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, or optionally substituted Ci-Cô alkoxy; and

[0209] In certain embodiments of compounds of Formula VI, X⁶ is CR¹⁴. In certain embodiments X⁶is N.

[0210] In certain embodiments of compounds of Formula VI, each R¹⁰ is independently halo. In certain embodiments, q is one and R¹⁰ is fluoro.

[0211] In certain embodiments of compounds of Formula VI, Y² is O. In certain embodiments R³ is H. In certain embodiments R³ is methyi. In certain embodiments R³ and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl. In certain embodiments R³ and R⁶together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.

[0212] In certain embodiments of compounds of Formula VI, R¹ is H or methyi. In certain embodiments of compounds of Formula VI, R¹ is methyi.

[0213] In certain embodiments of compounds of Formula VI, L is CH₂ or two R⁸ together with the carbon atom to which they are attached form a cycloalkyl ring. In certain embodiments L is CH₂.

[0214] In certain embodiments of compounds of Formula VI, R⁹ is phenyl. In certain embodiments R⁹is optionally substituted phenyl. In certain embodiments R⁹ is phenyl substituted by one to two halo.

[0215] In certain embodiments of compounds of Formula VI, R¹⁴ is hydrogen, halo or methyi optionally substituted with 1-3 fluoro or oxo. In certain embodiments, R¹⁴ is hydrogen or halo. In certain embodiments, R¹⁴ is hydrogen.

[0216] In certain embodiments the compounds of Formula VI readily cross the blood brain barrier. In certain embodiments the compounds of Formula VI hâve a MDCKII-MDR1 efflux ratio of 2.5 or less. In certain embodiments the compounds of Formula VT hâve a hepatic clearance of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 pL/min/kg when tested according to the human hepatic stability assay described below.

[0217] In any of the embodiments described throughout, q is 0, 1 or 2; and each R¹⁰ is independently cyano, halo or optionally substituted alkyl. In any of the embodiments described throughout, q is 0, 1 or 2; and each R¹⁰ is independently cyano, halo, or alkyl optionally substituted with 1-3 halo or oxo.

[0218] In any of the embodiments described throughout, q is 0, 1 or 2; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-C₆ alkyl, or -S(O)₂-Ci-C₆ alkyl. In any ofthe embodiments described throughout, q is l or 2; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-Cs alkyl, or -S(0)2-Ci-Cg alkyl. In any of the embodiments described throughout, q is 0, 1 or 2; and each R¹⁰ is independently cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, or -S(O)2-methyl. In any of the embodiments described throughout, q is 1 or 2; and each R¹⁰ is independently cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, or -S(O)2-methyl.

[0219] In any of the embodiments described throughout, the A ring is an optionally substituted heteroaryl ring. In any of the embodiments described throughout, the A ring is an unsubstituted heteroaryl ring. In any of the embodiments described throughout, the A ring is an optionally substituted

5-membered heteroaryl ring. In any of the embodiments described throughout, the A ring is an unsubstituted 5-membered heteroaryl ring. In any of the embodiments described throughout, the A ring is an optionally substituted 6-membered heteroaryl ring. In any of the embodiments described throughout, the A ring is a heteroaryl ring substituted with at least one halo. In any of the embodiments described throughout, the A ring is a 5-membered heteroaryl ring substituted with at least one halo.

[0220] In any of the embodiments described throughout, the A ring is optionally substituted isoxazolyl, pyrazolyl, oxadiazolyl or triazolyl; and L is -C(R⁸)2- and each R⁸ is taken together with the carbon atom to which they are attached to form cyclopropyl.

[0221] In any of the embodiments described throughout, the A ring is optionally substituted isoxazolyl, pyrazolyl, oxadiazolyl or triazolyl; and R³ and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.

[0222] In any of the embodiments described throughout, the A ring is of the formula:

wherein

X¹⁰, X¹¹ and X¹² are each S, O, N, CR¹³ or NR¹³, and X¹³ is C or N; and each R¹³ is independently H, halo, cyano or optionally substituted Ci-Cô alkyl.

[0223] In certain embodiments, at least one of X¹⁰, X¹¹ and X¹² is CR¹³ or NR¹³ and at least one R¹³ is halo, cyano or optionally substituted Ci-Ce alkyl. In certain embodiments, at least one of X¹⁰, X¹¹ and X¹² is CR¹³ or NR¹³ and at least one R¹³ is halo.

[0224] In any of the embodiments described throughout, the A ring is one of the following:

wherein each ring may be optionally substituted.

[0225] In any of the embodiments described throughout, the A ring is one of the following:

N-N

[0226] In any of the embodiments described throughout, the A ring is one of the following:

N=N \AX

[0227] In any of the embodiments described throughout, the A ring is one of the following:

[0228] It is appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features described herein, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. Ail combinations of the embodiments pertaining to the chemical groups represented by the variables contained within Formula I (and ail other Formulas described herein), are specifically embraced by herein just as if each and evcry combination was individually and explicitly recited, to the extent that such combinations embrace compounds that resuit in stable compounds (i.e., compounds that can be isolated, characterized and tested for biological activity). In addition, ail subcombinations of the chemical groups listed in the embodiments describing such variables, as well as ail subcombinations of uses and medical indications described herein, such as those conditions or disorders mediated by receptor-interacting protein kinase 1, are also specifically embraced herein just as if each and every subcombination of chemical groups and subcombination of uses and medical indications was individually and explicitly recited herein. In addition, some embodiments include every combination of one or more additional agents disclosed herein just as if each and every combination was individually and explicitly recited.

[0229] In certain embodiments, a compound may be selected from those compounds in Table 1, 2, 3 or 4. Also included within the disclosure are stereoisomers and mixtures of stereoisomers thereof. Also included within the disclosure is a compound selected from Table 1, 2, 3 or 4, or pharmaceutically acceptable sait thereof.

Table 1

No.	Structure
1	\ .O d—< \-NH sXX Xj l/l
IA	\ O .N-.Z/ ^sA-^v XX X o
IB	\ p ClXX\| ) NH ^S'^V-^/ XX X o YJv
2	\ O î Y Y^nh X--⁷ XX X F ⁰
3	\ p zx/^N{ \| ¥ )—NH NZ_n Xr XL X // o ^^XXX
4	\ o Y ci L A /^NH Lz /M I £ J
5	\ O 1 ï NH N^, jl f/)

No.	Structure
6	\ O p.,X ^F\ Γ jf XNH L/ Y I J J O N'ⁿYX
7	\ O N--/ AT y ^νΑ° A x/ q /^XpJ
7A	\ p ^NX i\| 1 X-NH N._n'YYX f\\ y o XAp
7B	\ p ÇQ-NH N-o
8	\ .o TA / ’NX'O ο XX
9	\ p 1 H Y^NH /L XX X
10	\ p L 1 / ^NH zⁿ-n f5 o nxaj

No. 42	Structure OcTt+x a o nAYxJ H
43	XÂA
43A	XA<A O
44	\ 0 ΥΛ / ^{NH N}'N -AA AY A 1 W o N\Y+Y H
45'	H z° X)n γ,θ
46	\ 0 aaAA L ï / ^{NH n}'n ^ v/ YA A 1 H
46A	\ O N-y/ ÎT AA An aa A f N N ο nAAJ H
46B	\ o γγΝ-Χ Îa /A zⁿ'n /r~\ Ll 1 II o nAXx a H
47	XX Y .q o N'^y^V

No.	Structure
48	\ .O ΤΤγ/χη o N\Y+Y ^H <> o
49	d Ί^^νη % Y\ -+- «nx_s,0 o^z 'o
50	\ .o A< _ ° TT
50A	yÆh VAX )/.....<i ° \ /⁼\ First eluting isomer
50B	\ O Γ JÏ Anh ^'-''rA ΑΆ _tt ° v AY Second eluting isomer
51	\ 0 TA'a Q Ν^ΛΑ // h F A'
52	aaAA L ï / ^{NH N}'N AA AAx^A \—(/ n FF O nAaA H
53	\ o xAⁿ A H ^Br<iAnAO

No. 54A	Structure o f+VA // h t m Diastereomer 1
54B	Q_o o n AA /) H [ MA Diastereomer 2
55	CCA.....5 F
56	çC/in CN O N-AAA
57	CC>Ü, Q
58	\ _zo ° ttN-^{N 5}
59	NM° °AKW
60	A kio
60A	Axo

No. 79	Structure 0
80A	A? XO
80B	ί J /Λ^Η Λ™ 0
81A
81B	I p QJ..NH Ν.θ
82A	^cAüx
82B	Yrko
83A	Γ H p l.N-p ί 1 / ^{NH n}^n A 11] H
83B	*? H O jf Ύ YNH \|\U_n F^^X-V YA ï fl] H

No.	Structure
99	Ο ΝΑ/χΑ ^H Δ
100 A	\ O ΛγΧ Il 1 y-NH OA # F
100B	\ O nAA i\| A )NH N-x\ AaAA^ Y_// Y A o^z /=\ °yj F
101A	\ p _ N-Y ^N 11 / ^NH Ν'-n /Ma Γ1 H
101B	\ p N if p-NH N~_waa îi f,) H
102A	ûΑγ ,n ϋ n^A\ // H [ First eluting isomer
102B	d nAA. // h F V-Y Second eluting isomer
103 A	f H p i\| 1 YNH _N oKAO H

No.	Structure
103B	’i H ,0 Ipp [\| Ύ \-NH _N H
104 A	H 0 —N J p'NH _M '^N<J oKW H
104B	H O ^N-p^ —N 1 Χ-ΝΗ m '^nAJ>aO H
105A	\ O —N J V-NH M H
105B	\ O N~p —N J )ΝΗ m '^NÀJ HU) H
106	\ .0 N N-X o NXppP ^H Δ
107A	\ O .NXP H
107B	\ p .N..PX ^10
108	.....O

No. 109 A	Structure \ .O __NXX X o n'ⁿ-Xv
109B	\ ,o -<ύ y ·*η v o n'ⁿ\Xv
110A	H P N^N-^ 1 1] y-NH _N H
110B	H P N.PX' \ T y-NH _N XXlo H
111A	Χ^χΧ.Ό
1I1B	\ p XX p .o
112	\ ,o uQklo
113	Χ+τρ..ο ^H Δ
114A	\ p <jf> '>..... ... > 'P P)

No. 114B	Structure \ p N )NH \
115	\ p υζρρρι rr^F ° cTn^-^AJ
116	V N I j }—NH N-N J \__// \\ O 4=\ r=\ F
117	\ p F
118A	H P N^H \NH _N
118B	H p nW\| p~nh _n^οΗΧΌ H
119A	^ζί4ρνο H
119B	\ p N^N^ 1 T /—nh _N _ ^V_OHW3 H

No. 120 A	Structure \ p Ν_γΝ^ I r-NH _N Whlo
120B	\ p Il ) NH _N
121A	\ P ,N I j )NH X__(/ y C> \=\ /=\ o—4 F
121B	\ p n^/ⁿ~~4 1 P Y-NH N-w v__// a o⁷ \ \ /=\ ° yu ^F F
122	\ p _N N^
123	W
124	Eh tco
125A	\ p f\| I YNH _NniKto n
125B	\ p pPM i\| Ύ Y-NH _M V_oHLO n

No. 126	______________Structure______________ CC^T+Yn o s^AYv
127	\ .0 Yw
128	\ .o γγχο
129A	\ Ό --<\ 1 YnH N-m A-Oooo
129B	\_N o YYJ'Nh n _n o nAM
130	\ .0 O^N^Z^NY ^F\ ^CN Yw,
131A	\ /° yyy <Υί YnH N~m A OA H
131B	«\5^NK^N'N on ^N oY Y) H
132	\ ,0 ci ^ΥΥ/ΥχΥ

No. 133	Structure \ .0 /VH _F F
134	\ O Ν_γΜ .....Ci........O
135	\ o N IW _F %AOO1 F
136	\ O \| ] YNH Υζ,ΥΥ
137	\ o 'Xa Ko. F
138	(Χ^·^ΝΚΥ γχ Y ο οΥγΥΥ
139	\ .o YaYY I }—NH N=N Υ>Υ₀Υγ \
140	\ ,o /N ΥοΥ^Υγ)
141A	O °ΥκΧ)

No. 141B	Structure N p_v ^NA ¥ >—NH N^K, AAfjQ
142	\ 0 n^n^ 1 Ύ Anh n^_o °
143	\ o x^Nx/^NT ^F\ ^a-LLkxr
144	L;. -
145A	\ Ό 1 I \-NH N^K, JJ
145B	\ o ί J /¥^H /ⁿn w il f π ο ο-^Χ^·ρ>¥
146	\ p ^a°<nW
147	peAxo
148A	\ p N^/N-L' lx FTP x o^Ho\O
148B	\ p N^/N-P' Œ /ⁿxⁿ~ⁿ x qAoXJQ \|

No. 149	Structure \ .0 I )—NH N=N t
150	\ .O /VH i\| ] >-NH N~_N NC''T-Αχθ A JI j j * O N \xV H
151	\ 0 ^a>nxro
152A	ΑΧ«;Χ1 CN
152B	CN
153	^CipA.....ç) NC
154A	n ° οΠ'^ΝΤυ
154B	A^N ^CiAt......o
155	Al.....ex

No. 156A	Structure À A.....o-
156B	ko-
157A	\ O .Ν._: ί JT )ⁿ\L//ⁿ'ⁿ a ₀H₀oX)
157B	\ p NA-/ LÀ ΤΑ <ha.aj
158	^CY A
159	Υκύτ
160A	Yb.....o
160B	Ymoo
161	\ p A; ο ν·^ΑοΛ h Y 'N
162	\ P N N--Z F Yap A ο nAzôA H A __________________Y]

No. 163	Structure οζΧκι /o o νάζ+Α h Y. ^XN
164	\ O bZA \| Ί Anh isk Y
165	\ p N N-A GatA n
166	Yoxo
167	\ p zApp Y
168	Υό,Λ o n'ⁿYv\ Y
169	D J-D DO P _N NA Cvⁿh ï n o nAAA H
170 A	’ï ^H p Y
170B	’î H O ^F\ jf T Y'iNH _r^_<x ^F O kAY_x^ Y

No. 171	Structure \ .O .....A A
172	\ ,o \| 1 Ynh
173	D Q O^Z
174	D ûÏhYO ^x ο οΆΑαΥ
175	D Αθ DY O
176	F H O Ατ^χχι
177A	\ p < X y ⁿ\L//^N^n ^N N ο^Ηο·υζ)
177B	'À H.....O

No. 178A	Structure cYy o n'ⁿYY F
178B	Ya.....O F
179A	F
179B	À ~ h..n F
180A	(ΧΤγ-Νθ o οΑγρ
180B	CÔ'yY ο oAAy
181A	*? H O ini-a AJ /^NLA γ-κ^ζ h r j H a 'N
181B	F H O i. Y jT Ύ Jnh N-_n f ^wY Y \ Λ f H y o nAA^sJE h A •N

No. 182A	Structure (ότΰ η Ο N'^Nv/Vn
182B	ζΧ+Χ·. η
183A	D U-D D^\ Ο
183B	D
184	\ .ο ^αΜι.^..
185	\ ρ 1VHW
186	( XJ’TA-N fAA oH-nAJ
187	\ Ό
188	CC^TxX 7Ί

No. 199	Structure \ .0 Ν^/Ν--Τ n LC y ^N\ //^N~ⁿ O^oAX)
200	\ Ό N^/^N¥
201	\ ,o ^a°<H:W
202
203
204	Τίκχ)
205
206
207	□V ' ,o /^Nte^N¥ UJte^-o Ν=Λ

No. 208	Structure \ .O
209	\ 0 Q_o>_n° O^N'Nte^⁰
210	\ ' z° ⁿ-vⁿ^ --Jl / ^N\^H Z^NN teX. ^oHLO
211	nJ-J —J 1] /—·ΝΗ N-m Vxo
212	\ .O —'y l] >NH N-iu X-texo
213	\ O il 1 y~NH hte _hlz. Mnuû
214	\ O cDte.,0·' O n-ⁿ^_nJ
215	CçLtt? n ° o^/
216	Tjè-.....v”
217

No. 218	Structure \ O <^Nx^NY Π W 7/^N'N X )r~\ u i il N O^Z N '\_xAX H
219	\ O ί A / ^{NH ν}~ί cT^'s-XXxjl
220	O N'^N-^X. A N ^XQ
221	\ ,o x * o^z f F
222	\ ,o
223	\ O N^/N-A'
224	^QA h.....o
225	\ o xxz ^ΝΎ Cx xⁿXⁿ'ⁿ a o^HoW
226	\ 0 N^/N-X [l \| )-NH IX X/ U.....ζ)

Table 2

No.	Structure
1	\ Ό z--z^NX Cl—<f » )—NH N-_n s-Άν γ-Y γ γ > o ^Xj:5AA+xXj
2	XXw
3	XA.....o
4	Axco
5	ΧΎ X-NH N +--7rXO
6	\ P kYYo
7	Ahj.....ζ)
8	cxXty n. O ^Vv
9	XA.....c/

No. 10	Structure \ O CX / ^NH A rYX /Y AÏ» F L o N^vAX F h
11	\ O Cl / \^H A ^AA /T \ il i » i o n^^AX F H
12	\ O nq CKa ΤγΧ ce F ° H'NAJ
13	Am° C θΑΑΪ 0 N'^N'^y
14	\ .O ΟζΧγ? o ^A^CFa
19	CT ^Vnh n-_o _
20	\ CX j ⁿï_7'ⁿ ax ο νΑΛχ H
23	/O z^NA °7AO H

Table 3

No. 14	Structure \ 0 0
15
18	aa \ 0 HN--/
20	\ OL/hJ Y O N J—AîU H
23	\ O N-U l Λ\^Η A r< A £ /) H
24	\ .O N A Γ jt / ⁿ\Lad ο νΆν
25	X¥ J-NH N'_N H
26	d .............

100

Table 4

No.	Structure
1	\ .O /^_/^NY C(—<fY ΗΝΗ N~r> ^sYHtO
2	Yw
3	\ O Yto
4	y%x.....o
5	^cY VLO
6	Υχο
7 8	Y%
Txx n o^z ΎχΧ
9	NX° ΧΧ.Ό

No.	Structure
10	\ O Y \-NH hU_NΥγ nXXJ
11	\ O ,.γ Οζγ Ty Y YY J nxYY f H
12	\ O XX/^N Y ΓΤ y ⁿ\L//ⁿ'n γχ p^; °
13	x° Q YoYrY
19	( /° CCxyXo ο YYJ
30	Yn χ. NX 1 Y \-NH N^_n ^uX<.v
32	ri Q Cl H
35	ΟζίYY x O^Z Ν''ΥΥχΧ ^H Δ

101

No. 38A	Structure \ O n-vⁿA -< 1 n~n y, A f i O H
38B	\ O nAA Al Λν ^sy—⁷ < Ail) O N-VU
40	ÇF₃ \ q H/N-A ^αΛγχΧ) H
41	Λ-νη n^_n'wrxo
42	\ .O kl H/ï kl ° ^xn^wAA
43	okp> p
44	\ p ~^N~Y Cl γΤΛν # \ IL ! H <1 o nA/PJ H
45	H O ^IPpxo
46A	\ p χ^/\/^ΝΊ ίΐ An H A 1 il N/ o nAAJ H

No.	Structure
46B	\ p N-Y Œ /Λ^Η Λν p=x )r-< Ali H
49	+·'>ΛΌ q' ^Kb
5 OA	\ .o N'Y 1 1-NH )/.....<3 ° \ / \ First eluting isomer
50B	1 blolw ° '^λ cc Second eluting isomer
51	\ O ζχθ>^Νρρ ° n pyp
52	O⁴ N~P L X / ^{NH N}'N Ail o N 'YV-^! H
54A	οζίρρ ° spl Diastereomer 1
54B	\ o ί 1 Z^Nx^H 7^N~n y \ E / \ ° sppP Diastereomer 2

102

No. 55	Structure \_N O CU’prO F
56	qXhjî n CN ° χΧ'Α
57	⁰ A ho
58	θΑ ζ/'Ό
59	ΧκΟ
60A	Χκ+ο
60B	\ ρ [QC) '^,nh ν-_νη A O^MÂJ
61	ΝΡ° CJat<Xo Ο /Λ.Ο W
62	Η ρ ΰΥκχη
63	\ ρ N Ν-Ρ I ΑνΗ Ν^ Μ;1 Π) ^{0 δ}χχΑ

No.	Structure
64	\ O C-Ap......0 F
66	\ O zⁿyⁿY ( 1 W /X AA a £ i) o oApA
67A	\ O N-p \| Ύ Anh n._n )r \ Ί I Π V o H
67B	\ O -Np⁷ ΓΎ )^N _X ^H n-n A 1 11 N o νΑΧ
68A	'XA - Np î JL /X^H Λν ^cA // \ a ί il 0 N 'Yv H
68B	COxi n H
69A	X 1 N CC A ^N\L/X^N A O N'xXpX H
69B	.N J N [f Ύ Υ·'ΝΗ l\k_N A 1 l) o nA./PJ
70A	Xp Qj-ⁿA n o ^^XXpA

103

No. 70B	Structure A' N CO'Ai n o⁷
71A	A ' /z^N^A 1 Ύ A NH N-_n A\A \_// Y 7 ii o
71B	V N zM/^NY 1 1 \NH \|\k_n YX)
72	A₀J^ⁿa ^nh m ⁰ ô^aAJ
73	1 o A₀J^aⁿ~^nh m
74	C/as a ⁰ oA'ⁿAJ
75A	\ p N.zNM' O\ J ^νμΛν a> V nAAa H
75B	\ O [f Ύ )NH Nk_N ^aa AA h f fl o N'\YA H
76	ΑχΑχ._

No. 77	Structure ' /° 1 Ύ ANH f\U₀ AaA y CA f j o A<^A
78	\ o rvY i i a^nh a ^{0 N} vXJ ^H A
79	q/y o A-A
80A	¹ /° A iw Ακχο
80B	1 Ό Α+ΑΑ AA'^,NM,^N'NH
8 ΙΑ	Aw
81B	1 ζθ N^zN-M [f Ύ Y-.NH N~_o v
82A	Ako
82B	1 o ··<·

104

No. 83A	Structure ’j H G ι,Ν-χ JJ V_NH M 7 \ A 1 H N o n\PA
83B	f H p X\z^N~X if Ύ YNH N-_nf^a-AA y_</ JJ ] > 0 N^vXJ H
84	o
85	o s-Α,ΑρΧ
86	^cXpw
87	(X ~5~ά^ν ^ν o
88	Q JyP^N 7}
89A	’ï H p 1n~X JJ >X^H _λχ_Ν Ail
89B	H P JJ 1 Y-nh r\k_N XX A i H N 0 o^AX

No. 90A	Structure 7 ^H /° jfl ^)NH N_;n
90B	’ÿ H O JL N A
91	o ^ΧχΧΧ
92	^CcX Ko
93	CXn -> o AAA
94	ûC^Trin o ΝΑΖΑ/ H
96	H 0 ^Ci-Xx.....o H
97	H O U4_oXⁿp\n π H
98B	H P f\| Ύ )—NH _NJXoHXX) il

105

No.	Structure
100A	\ p I j NH N—λ hpk/ \f y N G ^=\ /=\ ° Y Y F
100B	\ p /ⁿ\/ⁿ~¥ I \| YNH N-^x <__// J ο °—¥ Y F
101B	\ p N^Z \|ί Y-NH bX. ! Q N'AApp H
102B	C0-^NKl /x o // H [ XX Second eluting isomer
103B	H P fl J Vnh _n
104B	H P —N \| Y-NH _N _ H
105A	\ p NX —N j h“NH m H
106

No. 107B	Structure \ O ¥ Y-NH K, ri
108	\ p m nJ ¥ Y-NH _ ⁰ oHLO H
109A	\ p XfL ^F\
110B	H p _N N-X ¥ Vnh _n h / Ç......0
111B
112	°¥ X)
113	Αχ ,n o Νχχν ^H A
114A	\ p Ah h......o
115	\ p Apxxy

106

107

108

No. 152B	Structure ÙUUq CN
153	\ O ,N NU _F ^α°Α^γ NC
154B	An υίϋ,θ
155	\ o AjO
156B	Aûcr
157B	\ o Ν^,Ν-U aHw
158	uAu o N ^l4UU
159	\ p N NU _N A uⁿAA f-γ ° cOaxAJ
160A	Au.....o

No. 161	Structure \ O 1 Ύ AnH N-_n ^AU Y J1 f Y o nUuuA h U ^XN
162	\ o xAAX F \| Ύ Anh \|XU_N 1 Y \ K f H d nUUuA H U ^XN
163	oJkx U o nUAa h U ^XN
164	cJⁿuⁿi n, o s^Au^v A
165	Au
166	Au
167	Au A
168	\ p Au A
169	At a......o __y---------------

109

Νο. 170Α	Structure CrA A
171	\ p r^Nv A )-NH χ. o v y m i i o N'ⁿAv\
172	\ o ⁿ _v ⁿA 1 ANH hX ^x Ai
173	D A-D DA p cc5-ⁿaⁿi ja o oA Ap
174	D Jx-D DA p Apcxo
175	D A-d dA p AAlXj
176	e H p A A A\^h An F^AAxA ^-A jf f il o n^\A%A H
177 A	\ p ν^,να ^cAhw

No. 178A	______________Structure______________ \ p ^N M ^F\ ÇOxh n o n'ⁿAw F
179A	\ O _N N-A F ' ⁿ LAoHAjÇ F
180A	\ p (Jx5-^NKin o oAAA
181B	H o jf Ύ \-NH hk_Nf^aA7 AA n V o N vAJL H A A
182B	AAo
183B	D dX^d Ærko
184	\ p Ce Lⁿas /=ⁿ.
188	ο ^AA
190	ΑΑχγ

110

No.	Structure
192	\ ,O Cuhi n * ο οΥζΑχ
193	\ O ΧΧ/^ΝΎ ^N °a <MxX)
194	\ O y i γ*^{νη n}x x
195	\ Ό <^N<x^N'Y ( X /-'vAn ^N N X
197	\ ,o
198	\ Ό <ⁿvⁿ~T ZniO
200	\ Ό Νχ^ΝΤ
201
203	ZXksx
204

No. 205	Structure R D DX \ O ΑχΑχο
206
207	P D DXz ' P UkXX/'? N=\
208
209	Yâ.....»
213	\ O ^GX <1.....0
214	\ O ^α·ΧΖχ’
215	\ O ΥζΥΤχ? n O N^X/J
216

111

No. 217	Structure \ O .N. N-p/ (I 7 ^NL/^N'ⁿ _oh;aJ)
218	\ p JLaj ⁿV//ⁿ'n tex ix' Tç // xnx¥J H
219	\ p il 1 \*“ΝΗ hk
220	N p^
221	\ p N N-te O _n O F F
222	\ p n o nX>v
223	\ p N^N-te Wur
224	^c¥jç
226	\ O i\| \| \-NH Νχ -· w / J

112

4. Treatment Methods and Uses

[0230] “Treatment” or “treating” is an approach for obtaining bénéficiai or desired results including clinical results. Bénéficiai or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the régression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another médication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.

[0231] “Prévention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0232] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, tire subject is a human.

[0233] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide atherapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described herein. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and âge of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.

[0234] The term “trauma” as used herein refers to any physical damage to the body caused by violence, accident, fracture etc. The term “ischemia” refers to a cardiovascular disorder characterized by a low oxygen state usually due to the obstruction of the arterial blood supply or inadéquate blood flow leading to hypoxia in the tissue. The term “stroke” refers to cardiovascular disorders caused by a blood clôt or bleeding in the brain, most commonly caused by an interruption in the flow of blood in the brain as from clôt blocking a blood vessel and in certain embodiments of the disclosure the term stroke refers

113 to ischémie stroke or hémorrhagie stroke. The term “myocardial infarction” refers to a cardiovascular disorder characterized by localized necrosis resulting from obstruction of the blood supply.

[0235] The methods described herein may be applied to cell populations in vivo or ex vivo. ''In vivo” means within a living individual, as within an animai or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to détermine the optimal schedule and/or dosing of administration of a compound of tire présent disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolérance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled m the art.

[0236] Experiments with knockout animal models and Necrostatin 1, a receptor-interacting protein kinase 1 inhibitor, hâve demonstrated the effectiveness of receptor-interacting protein kinase 1 inhibition in protecting tissues from inflammatory bowel diseases (e.g., ulcerative colitis and Crohn’s disease), psoriasis, retinal-detachment-induced photoreceptor necrosis, retinitis pigmentosa, cerulein-induced acute pancreatitis, and sepsis/systemic inflammatory response syndrome (SIRS), and alleviating ischémie brain injury, retinal ischemia/reperfosion injury, Huntington’s disease, rénal ischemia reperfusion injury, cisplatin induced kidney injury, traumatic brain injury, hematological and solid organ malignancies, bacterial infections and viral infections (e.g., tuberculosis and influenza) and lysosomal storage diseases.

[0237] The receptor-interacting protein kinase 1 inhibitors of the présent disclosure are therefore useful for treating diseases and conditions mediated by receptor-interacting protein kinase 1, including but not limited to inflammatory diseases or disorders, necrotic cell diseases, neurodegenerative diseases, central nervous System (CNS) diseases, ocular diseases, infections, and malignancies. In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein can inhibit inflammation, protect tissue or cell from damage or undesired cell death (e.g., necrosis or apoptosis), ameliorate symptoms, and improve immune response or neuronal fonction in a patient suffering from any ofthe prescribed diseases or conditions. Moreover, the compounds may be suitable for treatment of immune-mediated disease, such as but not limited to, allergie diseases, autoimmune diseases, and prévention of transplant rejection.

114

[0238] Provided herein are compounds and compositions for use in medicine. In certain embodiments, the compounds and compositions are for use in the treatment of a receptor-interacting protein kinase 1mediated disease or disorder. Also provided is a method of treating a receptor-interacting protein kinase 1-mediated disease or disorder comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof In certain embodiments, the disease or disorder is an inflammatory disease associated with A20 SNPs.

[0239] Various spécifie diseases and disorders are described below. In certain embodiments, the disease or disorder is necrotizing enterocolitis, tuberous sclerosis, Tangier's Disease, Wohlman’s Syndrome, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis (e.g., acute pancreatitis), atopie dermatitis, rheumatoid arthritis, spondyloarthritis, goût, SoJIA, systemic lupus erythematosus, Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, allergie diseases, asthma, atopie dermatitis, multiple sclerosis, type I diabètes, Wegener’s granulomatosis, pulmonary sarcoidosis, Behçef s disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, bacterial infection, staphylococcus infection, mycobacterium infection, ofretinitis pigmentosa, influenza, transplant rejection, bums or hypoxia. In certain embodiments, the disease or disorder is trauma, ischemia, stroke, cardiac infarction, infection, lysosomal storage disease, Niemann-Pick disease, Gaucher’s disease, Krabbe disease, sepsis, Parkinson’s disease, Alzheimer’s disease, amyotrophie latéral sclerosis (ALS/Lou Gehrig’s Disease), Huntington’s disease, HIV-associated dementia, encephalopathy, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease. In certain embodiments, the disease or disorder is Alzheimer’s disease, ALS, Friedreich’s ataxia, Huntington’s disease, Lewy body disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cérébral ischemia, lysosomal storage disease or a prion disorder. In certain embodiments, the disease is ALS. In certain embodiments, tire disease is Alzheimer’s disease. In certain embodiments, the disease is lysosomal storage disease. In certain embodiments, the disease is Parkinson’s disease. In certain embodiments the disorder is an ischémie disease of organs including but not limited to brain, heart, kidney and liver. In some different embodiments, the disorder is an ocular disorder such as retinal degenerative disease, glaucoma or agerelated macular degeneration. In some different embodiments, the disorder is a central nervous system (CNS) disorder.

115

[0240] In certain embodiments, the compounds and compositions are useful for treating psoriasis.

[0241] In certain embodiments, the disorder is an inflammatory disease of the intestines such as

Crohn’s disease or ulcerative colitis (both generally known together as inflammatory bowel disease). In certain embodiments, the mammal is a primate, canine or feline subject. In certain embodiments, the mammal is a human subject. While not wishing to be bound by theory, it is believed that inhibition of receptor interacting protein kinase 1 by the presently disclosed compounds is responsible, at least in part, for their anti-inflammatory activity. Accordingly, embodiments of the disclosure also include methods for inhibiting receptor interacting protein kinase 1, either in vitro or in a subject in need thereof, the method comprises contacting a receptor interacting protein kinase 1 with a compound disclosed herein. In some of these embodiments, inhibiting receptor interacting protein kinase 1 is effective to block (partially or fully) the release of inflammatory mediators such as TNF and/or IL6.

[0242] In certain embodiments, provided is a method of treating a disease or disorder selected from the group consisting of rheumatoid arthritis, systemic onset juvénile idiopathic arthritis (SoJIA), spondyloarthritis, osteoarthritis, psoriasis, Crohn's disease, ulcerative colitis, and multiple sclerosis, comprising administering a therapeutically effective amount of a compound as provided herein to a subject in need thereof. In certain embodiments, provided is a method of treating a disease or disorder selected from the group consisting of autoimmune hepatitis, atherosclerosis, neutrophilie dermatoses, or a rare disease driven by A20, NEMO.. and/or LUBAC mutations, comprising administering a therapeutically effective amount of a compound as provided herein to a subject in need thereof. In certain embodiments, the compound is of Formula I (or any Formula described herein or tautomer thereof), wherein A is triazole. In certain embodiments, the compound is of Formula V or Va. In certain embodiments, the method comprises administering Compound 42 or tautomer thereof.

Inflammatory Diseases or Disorders

[0243] The receptor-interacting protein kinase 1 inhibitors described herein may be used to treat inflammatory diseases and disorders. Inflammatory diseases and disorders typically exhibit high levels of inflammation in the connective tissues, or degeneration of these tissues.

[0244] Non-limiting examples of inflammatory diseases and disorders include Alzheimer’s, ankylosing spondylitis, arthritis including osteoarthritis, rheumatoid arthritis (RA), psoriasis, asthma, atherosclerosis, Crohn’s disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), systemic lupus erythematous (SLE), nephritis, Parkinson’s disease, and ulcerative colitis.

[0245] In certain embodiments, the compounds and compositions of the présent disclosure are useful for treating rheumatoid arthritis (RA). In certain embodiments, the compounds and compositions of the présent disclosure are useful for treating ulcerative colitis. I In certain embodiments, the compounds and compositions of the présent disclosure are useful for treating psoriasis. In certain embodiments, the

116 compounds and compositions of the présent disclosure are usefol for treating psoriasis or psoriatic arthritis. In certain embodiments, the disease is spondyloarthritis.

Necrotic Cell Diseases

[0246] The compounds described herein may be used for the treatment of diseases/disorders caused or otherwise associated with necrosis. The term “necrotic cell disease” refers to diseases associated with or caused by cellular necrosis, for example tourna, ischemia, stroke, cardiac infarction, infection. Gaucher’s disease, Krabbe disease, sepsis, Parkinson’s disease, Alzheimer’s disease, amyotrophie latéral sclerosis, Huntington’s disease, HTV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease.

[0247] The necrotic cell diseases can be acute diseases such as tourna, ischemia, stroke, cardiac infarction, anthrax léthal toxin induced septic shock, sepsis, cell death induced by LPS, and HIV induced T-cell death leading to immunodeficiency. The necrotic cell diseases also include chronic neurodegenerative diseases, such as Parkinson’s disease, Huntington’s disease, amyotrophie latéral sclerosis, Alzheimer’s disease, infectious encelopathies, and dementia such as HIV associated dementia.

Neurodegenerative and CNS Diseases

[0248] The receptor-interacting protein kinase 1 inhibitors described herein may also be used to treat neurodegenerative diseases. Neurodegenerative diseases can affect many ofthe body’s activities, such as balance, movement, talking, breathing, and heart fonction. Neurodegenerative diseases can be genetic or caused by medical conditions such as alcoholism, tumors, strokes, toxins, chemicals, and viruses.

[0249] Non-limiting examples of neurodegenerative diseases include Alzheimer’s disease, amyotrophie latéral sclerosis (ALS), Friedreich’s ataxia, Huntington’s disease, Lewy body disease, Parkinson’s disease, and spinal muscular atrophy. In certain embodiments, neurodegenerative diseases and CNS diseases include Niemann-Pick disease, type Cl (NPC1), Alzheimer’s disease, amyotrophie latéral sclerosis (ALS), Friedreich’s ataxia, Huntington’s disease, Lewy body disease, Parkinson’s disease- and spinal muscular atrophy.

[0250] In certain embodiments, the receptor interacting protein kinase 1 inhibitors described herein may be used to treat NPC1 via inhibiting necroptosis that causes neuronal loss. In certain embodiments, the compounds and compositions ofthe présent disclosure are usefol for treating Alzheimer’s disease. In certain embodiments, the compounds and compositions of the présent disclosure are usefol for treating Parkinson’s disease. In certain embodiments, the compounds and compositions of the présent disclosure are usefol for treating amyotrophie latéral sclerosis (ALS).

[0251] More generally, the receptor-interacting protein kinase 1 inhibitors described herein can be used to preserve neuron viability and promote axon growth and nerve fonctions within the central nervous system (CNS). Accordingly, the compounds may be used to reduce or even reverse the loss of

117 cognitive, motor, and sensory functions associated with a CNS disease or disorder, by preserving neuron viability and/or promoting axon régénération and/or nerve functions.

[0252] The receptor-interacting protein kinase 1 inhibitors described herein can be used in a method for promoting axon régénération in a CNS neuron, such as a CNS sensory neuron, a motor neuron, a cortical neuron, a cerebellar neuron, a hippocampal neuron, and a midbrain neuron. The receptorinteracting protein kinase 1 inhibitors described herein can be used in a method for promoting nerve function or preserving the viability following injury to a CNS neuron. In another embodiments, these compounds can be used to promote régénération of an axon in a CNS neuron that is degenerated in the CNS disease or disorder. The RI P receptor-interacting protein kinase 1 inhibitors may be administered by any conventional means, such as locally to the neuron or applied ex vivo before re-implantation.

[0253] Accordingly, in one aspect, the disclosure provides a method of treating a CNS disorder in a subject in need thereof, wherein a symptom of the CNS disorder is axon degeneration or injury within a CNS neuron. The method comprises administering to the subject an effective amount of a compound or composition disclosed herein thereby to promote régénération of an axon in a CNS neuron affected by the CNS disorder. Following administration, neural functions may be measured, for example, as an indication of axon régénération. It is also contemplated that, following administration of the compound or composition, the neuron function of the CNS neuron is preserved or improved relative to the neuron function prior to administration.

[0254] Non-limiting examples of CNS diseases or disorders include brain injury, spinal cord injury, dementia, stroke, Alzheimer’s disease, amyotrophie latéral sclerosis (ALS/Lou Gehrig’s Disease), Parkinson’s disease, Huntington’s disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cérébral ischemia, and a prion disorder.

[0255] In exemplary embodiments, the CNS disorder is brain injury or spinal cord injury.

[0256] Also provided herein are methods for promoting neuron survival and axon régénération in the CNS. CNS disorders characterized by impaired or failing axon growth or axon degeneration may arise from CNS neuron injury (e.g., trauma, surgery, nerve compression, nerve contusion, nerve transection, neurotoxicity or other physical injury to the brain or spinal cord) or neurodegenerative CNS disease, wherein a symptom of the disorder is axon degeneration (e.g., Alzheimer's disease, amyotrophie latéral sclerosis (ALS/Lou Gehrig’s Disease), Parkinson’s disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cérébral ischemia, prion disorder (e.g., Creutzfeldt-Jakob disease). In certain embodiments, the CNS disorder is brain injury (e.g., traumatic brain injury) or spinal cord injury (e.g., chronic, acute or traumatic spinal cord injury). In certain embodiments, the CNS disorder affects a subject’s basic vital life functions such as breathing, heart beat and blood pressure, e.g., an injury to or aneurysm in the brain stem.

118

[0257] In certain embodiments, the CNS disease or disorder affects a subject’s cognitive ability. In certain embodiments, the CNS disease or disorder affects a subject’s movement and/or strength. In certain embodiments, the CNS disease or disorder affects a subject’s coordination.

[0258] In certain embodiments, the CNS disorder affects a subject’s cognitive ability, such as, brain injury to the cérébral cortex or a neurodegenerative CNS disorder, such as, Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy and prion disorders.

[0259] In certain embodiments, the CNS disorder affects a subject’s movement and/or strength, such as injury to the brain or spinal cord or a neurodegenerative CNS disorder such as Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progress supranuclear palsy, Huntington's disease, multiple System atrophy, amyotrophie latéral sclerosis and hcrcditary spastic paresis.

[0260] In certain embodiments, the CNS disorder affects a subject’s coordination, such as brain injury to the cerebellum or a neurodegenerative CNS disorder such as spinocerebellar atrophies, Friedreich's ataxia and prion disorders.

[0261] In each of the foregoing methods, the CNS disorder includes, but is not limited to, brain injury, spinal cord injury, Alzheimer's disease, amyotrophie latéral sclerosis (ALS/Lou Gehrig’s Disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke's disease, Wilson's disease, cérébral ischemia, a prion disorder (e.g., Creutzfeldt-Jakob disease), dementia (e.g., frontotemporal dementia, dementia with Lewy bodies), corticobasal degeneration, progressive supranuclear palsy, multiple System atrophy, hereditary spastic paraparesis and spinocerebellar atrophies.

[0262] Non-limiting examples of neurodegenerative diseases include Alzheimer’s disease, lysomal storage diseases, amyotrophie latéral sclerosis (ALS), Friedreich’s ataxia, Huntington’s disease, Lewy body disease, Parkinson’s disease, and spinal muscular atrophy.

[0263] In certain embodiments, the compounds and compositions of the présent disclosure are useful for treating Alzheimer’s disease. In certain embodiments, the compounds and compositions of the présent disclosure are useful for treating Parkinson’s disease. In certain embodiments, the compounds and compositions of the présent disclosure are useful for treating amyotrophie latéral sclerosis (ALS). In certain embodiments, the compounds and compositions of the présent disclosure are useful for treating lysosomal storage diseases.

[0264] In certain embodiments, the disorder is a brain disorders, such as, but not limited to, Alzheimer’s disease, ALS, frontotemporal dementias, vascular dementia, Huntington’s disease, Parkinson’s disease, Lewy Body dementia, Progressive Supranuclear Palsy, multiple sclerosis,

119 neuromyelitis optica, ischémie brain damage (stroke), hypoxie brain damage, traumatic brain injury, spinal cord injury, sepsis-induced brain damage, CNS infections, CNS abscesses, glioblastoma multiforme, epilepsy, neuropathie pain, major dépréssion, bipolar dépréssion, schizophrenia, autism, Niemann-Pick disease, neuro-Behçet's disease.

[0265] In certain embodiments, provided is a method of treating a CNS disease or disorder, comprising administering a therapeutically effective amount of a compound as provided herein to a subject in need thereof. In certain embodiments, the disease or disorder is Alzheimer’s disease or amyotrophie latéral sclerosis (ALS). In certain embodiments, the compound is of Formula I (or any Formula described herein), wherein A is other than triazole. In certain embodiments, the compound is of Formula VI.

Ocular Conditions

[0266] The receptor-interacting protein kinase 1 inhibitors described herein can also be used to treat ocular conditions, for example to reduce or prevent the loss of photoreceptor and/or retinal pigment épithélial cell viability.

[0267] In certain embodiments, the disclosure provides a method of preserving the visual fonction of an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is the loss of photoreceptor cell viability in the retina of the eye with the condition. The method comprises administering to the eye of the subject an effective amount of a compound or composition described herein, thereby preserving the viability of the photoreceptor cells disposed within the retina of the eye. After administration, the visual fonction (e.g., visual acuity) of the eye may be preserved or improved relative to the visual fonction of the eye prior to administration.

[0268] The ocular condition may be a condition seiected from the group consisting of age-related macular degeneration (AMD), retinosis pigmentosa (RP), macular edema, diabetic retinopatliy, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, myopie degeneration, central serous retinopathy, Stargardt’s disease, Cone-Rod dystrophy, North Carolina dystrophy, infections retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity. AMD may be the neovascular or the dry form of AMD. Retinal detachment may be a rhegmatogenous, a serous, and a tractional retinal detachment. In certain embodiments, the ocular condition may be a condition seiected from the group consisting of géographie atrophy, glaucoma, and other ischémie eye diseases.

[0269] In certain embodiments, the disclosure provides a method of preserving the viability of retinal pigment épithélial (RPE) cells within the retina of a subject with an ocular condition with administration of a compound of the présent disclosure. The subject being treated may hâve a loss of retinal pigment épithélial cells in the retina of the eye with the condition and the ocular condition may be seiected from the group consisting of age-related macular degeneration (AMD), BEST disease, myopie degeneration, Stargardt’s disease, uveitis, adult foveomacular dystrophy, fiindus falvimaculatus, multiple evanescent

120 white dot syndrome, serpiginous choroidopathy, acute multifocal posterior placoid epitheliopathy (AMPPE), and other uveitis disorders. In certain embodiments, the method comprises administering to the eye ofthe subject an effective amount of a compound or composition described herein, thereby preserving the viability of the retinal pigment épithélial cells.

[0270] Provided in another embodiment is a method of preserving the viability of photoreceptor cells disposed within a retina of a subject with an ocular condition selected from the group consisting of agerelated macular degeneration (AMD), retinosis pigmentosa (RP), macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, myopie degeneration, central serous retinopathy, Stargardt’s disease, Cone-Rod dystrophy, North Carolina dystrophy, infections retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity. Therefore, in certain embodiments, the method comprises administering to the eye an effective amount of a compound or composition described herein, thereby preserving the viability of the photoreceptor cells disposed within the retina of the subject with a condition.

[0271] Provided in another embodiment is a method of preserving the viability of photoreceptor cells disposed within a retina of a mammalian eye following retinal detachment. The retinal detacliment may be a rhegmatogenous retinal detachment, tractional retinal detachment, or serous retinal detachment. In other embodiments, the retinal detachment may occur as a resuit of a retinal tear, retinoblastoma, melanoma or other cancers, diabetic retinopathy, uveitis, choroidal neovascularization, retinal ischemia, pathologie myopia, or trauma. In certain embodiments, the method comprises administering a compound or composition described herein to the eye in which a région of the retina has been detached in amounts sufficient to preserve the viability of photoreceptor cells disposed within the région of the detached retina.

[0272] Provided in another embodiment is a method of preserving visual fonction of an eye of a subject with an ocular condition selected from the group consisting of age-related macular degeneration (AMD), retinosis pigmentosa (RP), macular edema, central areolar choroidal dystrophy, retinal detacliment, diabetic retinopathy, BEST disease, adult vitelliform disease, pattern dystrophy, myopie degeneration, central serous retinopathy, Stargardt’s disease, Cone-Rod dystrophy, North Carolina dystrophy, infections retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity, wherein a symptom ofthe ocular condition is the loss of photoreceptor cells viability in the retina ofthe eye , wherein the method comprises treating the subject with a compound or composition described herein to the subject.

[0273] In another aspect, the disclosure provides a method of preserving the visual function of an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is the loss of photoreceptor cell viability and/or RPE viability in the retina ofthe eye wherein the method comprises treating the subject with a compound or composition described herein to the subject.

121

[0274] In certain embodiments, provided a method of preserving the visual fonction of an eye of a subject with ocular conditions, wherein a symptom ofthe ocular condition is the loss of retinal ganglion cell viability in the retina ofthe eye with the conditions. The method comprises administering to the eye ofthe subject an effective amount of a compound or composition, thereby preserving the viability of the retinal ganglion cells disposed within the retina of the eye. After administration of the compound or composition, the visual fonction of the eye may be preserved or improved relative to the visual fonction ofthe eye prior to administration. Further, after the administration, the preserved retinal ganglion cell is capable of supporting axonal régénération.

[0275] Non-limiting examples of symptoms associated with the ocular conditions include the loss of retinal ganglion cell viability in the retina of the eye, glaucoma, optic nerve injury, optic neuritis, optic neuropathies, diabetic retinopathy, central retinal artery occlusion, and central retinal vein occlusion.

[0276] The compounds described herein may also be used for the treatment of optic neuropathies such as ischémie optic neuropathy (e.g., arteritic or non-arteritic anterior ischémie neuropathy and posterior ischémie optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber’s optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy, and hereditary optic neuropathy (e.g., Leber’s optic neuropathy, Dominant Optic Atrophy, Behr’s syndrome).

[0277] Also disclosed is a method of preserving the visual fonction of an eye of a subject with an ocular condition selected from the group consisting of glaucoma, optic nerve injury, optic neuropathies, diabetic retinopathy, central retinal artery occlusion and central retinal vein occlusion. The method comprises administering to the eye of the subject an effective amount of a compound or composition described herein, thereby preserving the viability of the retinal ganglion cells disposed within the retina of the eye and the visual fonction of the eye.

[0278] In another aspect, disclosed herein is a method of preserving the viability of retinal ganglion cells disposed within a retina of a mammalian eye affected by, for example, glaucoma, optic nerve injury, optic neuritis, optic neuropathies, diabetic retinopathy, central retinal artery occlusion and central retinal vein occlusion. The method comprises administering a compound or composition described herein to the eye in which a région ofthe retina has been affected in amounts sufficient to preserve the viability of retinal ganglion cells disposed within the région of tire affected retina. The preserved retinal ganglion cell is capable of supporting axonal régénération.

[0279] Also disclosed is a method for promoting axon régénération in an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is the loss of retinal ganglion cell viability in the retina ofthe eye with the condition. The method comprises administering to the eye ofthe subject an effective amount of a compound or composition described herein, thereby promoting axon régénération ofthe retinal ganglion cell within the retina ofthe eye.

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[0280] In each of the foregoing embodiments, it is understood that the methods and compositions described herein can be used to preserve the viability and/or promote axon régénération of retinal ganglion cells during treatment of the underlying conditions including, but not limited to, glaucoma, optic nerve injury, optic neuritis, optic neuropathies, diabetic retinopathy, central retinal artcry occlusion and central retinal vein occlusion.

Tissue Injuries or Damages

[0281] The ability of the compounds described herein to inhibit inflammation and cell death makes them suitable for ameliorating tissue injuries or damages. The tissue injuries or damages may be a resuit of any of the diseases or conditions described above. For example, the compounds may be used for amelioration of brain tissue injury or damage following ischémie brain injury or traumatic brain injury, or for amelioration of heart tissue injury or damage following myocardial infarction, or for amelioration of brain tissue injury or damage associated with Huntington’s disease, Alzheimer s disease or Parkinson s disease, or for amelioration of liver tissue injury or damage associated with non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, or primary sclerosing cholangitis, or for the amelioration of liver tissue injury or damage associated with overdose of acetaminophen, or for amelioration of kidney tissue injury or damage following rénal transplant or the administration of nephrotoxic drugs or substances. In certain embodiments, the For example, the compounds may be used for amelioration of brain tissue injury or damage following pulmonary injury or damage.

[0282] Non-limiting examples of brain injury or damage include stroke (e.g., hémorrhagie and nonhemorrhagic), traumatic brain injury (TBI), cérébral hemorrhage, subarachnoid hemorrhage, intracramal hemorrhage secondary to cérébral arterial malformation, cérébral infarction, périnatal brain injury, nontraumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington’s disease, multiple sclerosis, amyotrophie latéral sclerosis, brain hemorrhage, brain infections, brain tumor, subclinical brain injury, spinal cord injury, anoxic-ischemic brain injury, focal cérébral ischemia, global cérébral ischemia, and hypoxie hypoxia.

[0283] In an embodiment, the compounds and compositions of the présent disclosure may be used to treat peritoneal tissue injury. Non-limiting exampies of peritoneal tissue injury include peritoneal détérioration, peritoneal sclerosis, and peritoneal cancer. For example, the receptor interacting protein kinase 1 inhibitors described herein may be used to treat peritoneal damage caused by peritoneal dialysis fluid (PDF) and PD-related side effects.

Liver Injury and Diseases

[0284] In an embodiment, the compounds and compositions of the présent disclosure may be used to treat liver injury and diseases. Non-limiting examples of liver injury or damage include not only degeneration or necrosis of liver parenchyma cells which results from injury caused by a certain factor,

123 but also undcsirablc phenomena caused by biological reactions to the injury, such as mobilization, infiltration, activation of Kupffer cells, leukocytes and the like, fibrosis ofthe liver tissue, etc., which reactions occur alone or in combination. In certain embodiments, the receptor interacting protein kinase 1 inhibitors described herein may be used to treat steatohepatitis and hepatocellular carcinoma via inhibiting receptor interacting protein kinase 1 activity-dependent apoptosis of hépatocytes and hepatocarcinogenesis. In an embodiment, the receptor interacting protein kinase 1 inhibitors described herein may be used to treat alcoholic hepatitis, autoimmune hepatitis, fulminent hepatic failure, acute cholestasis and liver injury.

Kidney Injury and Diseases

[0285] In an embodiment, the compounds and compositions of the présent disclosure may be used to treat kidney injury and diseases. Non-limiting examples of kidney diseases include chrome kidney disease (CKD) (e.g., glomerular diseases, tubulointerstitial diseases, obstruction, polycystic kidney disease), acute kidney injury (AKI), diabetic nephropathy, fibrosis, glomerulonephntis, focal glomerulosclcrosis, immune complex nephropathy, crystalline nephropathy, or lupus nephritis. Kidney disease may be caused by drug-induced rénal injury or kidney graft rejection. Kidney disease may be characterized as nephrotic syndrome or rénal insufficiency. In an embodiment, the receptor interacting protein kinase 1 inhibitors described herein may be used to treat kidney diseases (e.g., AKI) via inhibiting cell death pathway in kidney diseases. In an embodiment, the receptor interacting protein kinase 1 inhibitors described herein may be used to treat patient with kidney stones and to prevent crystal-induced cytotoxicity and acute kidney injury via inhibiting receptor interacting protein kinase 3MLKL-mediated necroptosis.

Skin Diseases

[0286] In an embodiment, the compounds and compositions of the présent disclosure may be used to treat dermal (or skin) diseases, including but not limited to, inflammatory skin diseases or neutrophilie dermatosis.

Malignancies

[0287] In an embodiment, the compounds and compositions of the présent disclosure are useful for treating malignancies/cancers such as carcinoma, sarcoma, melanoma, lymphoma or leukemia. Nonlimiting examples of malignancies suitably treated by the receptor interacting protein kinase 1 inhibitors described herein include lung cancer (e.g. non-small cell lung cancer, small-cell lung cancer), hepatocellular cancer, melanoma, pancreatic cancer, urological cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, rénal cancer, thyroid cancer, gall bladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endométrial cancer, esophageal cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft

124 tissue sarcoma, retinoblastomas, neuroblastomas, peritoneal effusions, malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblastic neoplasms, hemangiopericytomas, Kaposi's sarcomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinomas, esophageal squamous cell carcinomas, oral carcinomas, vulval cancer, cancers of the adrenal cortex, ACTH producing tumors, lymphoma, and leukemia.

Infections Diseases

[0288] In an embodiment, the compounds and compositions of the présent disclosure are useful for treating infections diseases resulting from the presence of pathogenic agents, including pathogenic viruses, pathogenic bacteria, fungi, protozoa, multicellular parasites and aberrant proteins known as prions. Non-limiting examples of infections diseases suitably treated by the receptor interacting protein kinase 1 inhibitors described herein include virus infections diseases and bacterial infections diseases. The virus infections disease is not particularly limited and includes, for example, infections diseases with respiratory infections viruses (e.g., infections diseases due to respiratory infections viruses such as influenza virus, rhino virus, corona virus, parainfhienza virus, RS virus, adeno virus, reo virus and the like), Staphylococcus aureus (MRSA) pneumonia, Serratia marcescens hémorrhagie pneumonia, herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS and the like. The bacterial infections disease is not particularly limited and includes, for example, infections diseases caused by Bacillus cereus, Vibrio parahaemolyticus, Enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRSA, Salmonella, Botulinus, Candida and the like.

Bone Diseases

[0289] In an embodiment, the compounds and compositions of the présent disclosure are usefùl for treating bone diseases that may resuit from a bone remodeling disorder whereby the balance between bone formation and bone résorption is shifted. Non-limiting examples of bone remodeling disorders include osteoporosis, Paget's disease, osteoarthritis, rheumatoid arthritis, achondroplasia, osteochodrytis, hyperparathyroidism, osteogenesis imperfecta, congénital hypophosphatasia, fribromatous lésions, fibrous displasia, multiple myeloma, abnormal bone turnover, osteolytic bone disease and periodontal disease. Additional examples of bone diseases suitably treated by the receptor interacting protein kinase 1 inhibitors described herein include bone fracture, bone trauma, or a bone déficit condition associated with post-traumatic bone surgery, post-prosthetic joint surgery, post-plastic bone surgery, post-dental surgery, bone chemotherapy treatment or bone radiotherapy treatment. Additional examples of diseases affecting bone or bone joints suitably treated by the receptor interacting protein kinase 1 inhibitors described herein include metastatic bone cancer, rheumatic diseases such as rheumatoid arthritis, osteoarthritis and other inflammatory arthropathies. In an embodiment, the receptor interacting protein kinase 1 inhibitors described herein may be used to treat postmenopausal osteoporosis via inhibiting osteocyte necroptosis and trabecular détérioration.

125

Cardiovascular Diseases

[0290] In an embodiment, the compounds and compositions of the présent disclosure are usefiil for treating cardiovascular diseases that may be relate to the cardiovascular disorders of fragile plaque disorder, occlusive disorder and stenosis. Non-limiting cardiovascular diseases include coronary artery disorders and peripheral arterial disorders, including, among others, atherosclerosis, arterial occlusion, aneurysm formation, thrombosis, post-traumatic aneurysm formation, restenosis, and post-operative graft occlusion. It is believed that atherosclerosis results from maladaptive inflammation driven primarily by macrophages. Thus, the compounds and compositions of the présent disclosure may be used to treat atherosclerosis via inhibiting macrophage necroptosis.

Transplantation

[0291] In an embodiment, the compounds and compositions of the présent disclosure are usefiil for treating transplant patients. Non-limiting examples of transplant patient suitably treated by the receptor interacting protein kinase 1 inhibitors described herein include patients with solid and non-solid organ and tissue transplantations and transplants, such as liver, heart, kidney, and heterologous and autologous bone marrow transplantations/transplants. Typically, immunosuppressive therapy is used to avoid graft rejection in récipients of solid organ transplants. Récipients of bone marrow transplants are usually subjected to extensive irradiation and chemotherapy prior to transplantation. It is believed that receptor interacting protein kinase 1 and NF-κΒ signaling in dying cells détermines cross-priming of CD8⁺ T cells. Thus, the receptor interacting protein kinase 1 inhibitors described herein may be used to treat transplant patient and avoid graft rejection by modulating cross-priming of CD8⁺ T cells.

Other Diseases and Conditions

[0292] Additional examples of diseases and disorders suitably treated by the receptor-interacting protein kinase 1 inhibitors described herein include pancreatitis, atopie dermatitis, spondyloarthritis, goût, systemic onset juvénile idiopathic arthritis (SoJlA), systemic lupus erythematosus (SLE), Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, primary sclerosing cholangitis (PSC), acetaminophen toxicity, kidney damage/injury (nephritis, rénal transplant, surgery, administration of nephrotoxic drugs e.g. cisplatin, acute kidney injury(AKI)), Celiac disease, autoimmune idiopathic thrombocytopénie purpura (autoimmune ITP), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), allergie diseases (including asthma), diabètes, Wegener’s granulomatosis, pulmonary sarcoidosis, Behçef s disease, interleukin-1 converting enzyme (ICE/caspase1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), peridontitis, NEMO-deficiency syndrome ( F-kappa-B essential modulator gene (also known as IKK gamma or IKKG) defîciency syndrome), HOIL-1 deficiency ((also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1 defîciency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies,

126 bacterial infections and viral infections (e.g., tuberculosis and influenza), and lysosomal storage diseases. Additional examples of diseases and disorders suitably treated by the receptor-interacting protein kinase 1 inhibitors described herein include Gaucher disease or organ failure.

[0293] Non-limiting examples of lysosomal storage diseases include Gaucher disease, GM2 Gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvénile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs and Wolman disease.

5. Kits

[0294] Provided herein are also kits that include a compound of the disclosure, or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging. In certain embodiments, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and/or instructions for use ofthe compounds in the treatment ofthe indications, including the diseases or conditions, described herein.

[0295] Provided herein are also articles of manufacture that include a compound described herein or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.

6. Pharmaceutical Compositions and Modes of Administration

[0296] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including stérile aqueous solution and various organic solvents, perméation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modem Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

127

[0297] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0298] One mode for administration is parentéral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or émulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as élixirs, mannitol, dextrose, or a stérile aqueous solution, and similar pharmaceutical vehicles.

[0299] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making tire pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ingrédient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingrédient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, élixirs, suspensions, émulsions, solutions, syrups, aérosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight ofthe active compound, soft and hard gelatin capsules, stérile injectable solutions, and stérile packaged powders.

[0300] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, stérile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnésium stéarate, and minerai oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.

[0301] The compositions that include at least one compound described herein or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof can be formulated so as to provide quick, sustained or delayed release ofthe active ingrédient after administration to the subject by employing procedures known in the art. Controlled release drug delivery Systems for oral administration include osmotic pump Systems and dissolutional Systems containing polymer-coated réservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein employ transdermal delivery devices ( patches ). Such transdermal patches may be used to provide continuous or discontinuons infusion of the compounds described herein in

128 controlled amounts and may be constructed for continuons, pulsatile, or on demand delivery of pharmaceutical agents.

[0302] For preparing solid compositions such as tablets, the principal active ingrédient may be mixed with a pharmaceutical excipient to form a solid preformuiation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof. When referring to these preformuiation compositions as homogeneous, the active ingrédient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0303] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodénum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0304] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

7. Combination Therapy

[0305] In certain embodiments, the compounds described herein may be administered in combination with at least one other therapeutically active agent. The two or more agents can be coadministered, coformulated, or administered separately. In certain embodiments, the other therapeutically active agent is selected from a thrombolytic agent, a tissue plasminogen activator, an anticoagulant, a platelet aggregation inhibitor, an antimicrobial agent (an antibiotic, a broad-spectrum antibiotic, a lactam, an antimycobacterial agent, a bactericidal antibiotic, anti-MRSA therapy), a long acting beta agonist, a combination of an inhaled corticosteroid and a long acting beta agonist, a short acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, a protein

129 tyrosine kinase inhibitor, a CRTH2/Dprostanoid receptor antagonist, an epinephrine inhalation aérosol, a phosphodiesterase inhibitor, a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4 inhibitor, a long-acting inhaled anticholinergic, a muscarinic antagonist, a long-acting muscarinic antagonist. a low dose steroid, an inhaled corticosteroid, an oral corticosteroid, a topical corticosteroid, anti-thymocyte globulin, thalidomide, chlorambucil, a calcium channel blocker, a topical emollient, an ACE inhibitor a serotonin reuptake inhibitor, an endothelin-1 receptor inhibitor, an anti-fibrotic agent, a proton-pump inhibitor, a cystic fibrosis transmembrane conductance regulator potentiator, a mucolytic agent, pancreatic enzymes, a bronchodilator, an opthalmalic intravitreal injection, an anti-vascular endothélial growth factor inhibitor, a ciliary neurotrophic growth factor agent, a trivalent (IIV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent live attenuated influenza vaccine, an antiviral agent, inactivated influenza vaccine, a ciliary neurotrophic growth factor, a gene transfer agent, a topical immunomodulator, calcineurin inhibitor, an interferon gamma, an antihistamine, a monoclonal antibody, a polyclonal anti-T-cell antibody, an anti-thymocyte gamma globulin-equine antibody, an antithymocyte globulin- rabbit antibody, an anti-CD40 antagonist, a JAK inhibitor, and an anti-TCR murine mAb.

[0306] Exemplary other therapeutically active agents include heparin, coumadin, clopidrogel, dipyridamole, ticlopidine HCL, eptifibatide, aspirin, vacomycin, cefeprime, a combination of piperacillin and tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, hydrocortisone, vedolizumab, alicaforsen, remestemcel-L, ixekizumab, tildrakizumab, secukinumab, chlorhexidine, doxycycline, minocycline, fluticasone (fluticasone proprionate, fluticasone furoate), beclomethasone dipropionate, budesonide, trimcinolone acetonide, flunisolide, mometasone fuorate, ciclesonide, arformoterol tartrate, formoterol fumarate, salmeterol xinafoate, albuterol (albuterol sulfate), levalbuterol tartrate, ipratropium bromide, montelukast sodium, zafirlukast, zileuton, omalizumab, theophylline, cromulyn sodium, nedocromil sodium, masitinib, AMG 853, indacaterol, E004, reslizumab, salbutamol, tiotropium bromide, VR506, lebrikizumab, RPL554, afibercept, umeclidinium, indacterol maleate, aclidinium bromide, roflumilast, SCH527123, glycoprronium bromide, olodaterol, a combination of fluticasone furoate and vilanterol vilanterol, a combination of fluticasone propionate and salmeterol, a combination of fluticasone furoate and fluticasone proprionate, a combination of fluticasone propionate and eformoterol fumarate dihydrate, a combination of formoterol and budesonide, a combination of beclomethasone dipropionate and formoterol, a combination of mometasone furoate and formoterol fumarate dihydrate, a combination of umeclidinium and vilanterol, a combination of ipratropium bromide and albuterol sulfate, a combination of glycopyrronium bromide and indacaterol maleate, a combination of glycopyrrolate and formoterol fumarate, a combination of aclidinium and formoterol, isoniazid, ehambutol, rifampin, pyrazinamide, rifabutin, rifapentine, capreomycin, levofloxacin, moxifloxicin, ofloxacin, ehionamide, cycloserine, kanamycin, streptomycin, viomycin, bedaquiline fumarate, PNU-100480, delamanid, imatinib, ARG201, tocilizumab, muromonab

130

CD3, basiliximab, daclizumab, rituximab, prednisolone, anti-thymocyte globulin, FK506 (tacrolimus), methotrexate, cyclosporine, sirolimus, everolimus, mycophenolate sodium, mycophenolate mofetil, cyclophosphamide, azathioprine, thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin, lisinopril, diltaizem, fluoxetine, bosentan, epoprostenol, colchicine, para-aminobenzoic acid, dimethyl sulfoxide, D-penicillamine, interferon alpha, interferon gamma (INF-g)), omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole, imatinib, belimumab, ARG201, tocilizumab, ivacftor, domase alpha, pancrelipase, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin, ceftazidime, a combination of trimethoprim and sulfamethoxazole, chloramphenicol, a combination of ivacftor and lumacaftor, ataluren, NT-501-CNTF, a gene transfer agent encoding myosin VIIA (MY07A), ranibizumab, pcgaptanib sodium, NT501, humanized sphingomab, bevacizumab, oseltamivir, zanamivir, rimantadinc, amantadine, nafcillin, sulfamethoxazolem, trimethoprim, sulfasalazine, acetyl sulfisoxazole, vancomycin, muromonab-CD3, ASKP- 1240, ASP015K, TOL101, pimecrolimus, hydrocortizone , betamethasone, flurandrenolide, triamcinolone, fluocinonide, clobetasol, hydrocortisone, méthylprednisolone, prednisolone, a recombinant synthetic type I interferon, interferon alpha-2a, interferon alpha-2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin, and erythromycin.

[0307] A compound described herein may be administered in combination with other antiinflammatory agents for any of the indications above, including oral or topical corticosteroids, anti-TNF agents, 5-aminosalicyclic acid and mesalamine préparations, hydroxycloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, J AK inhibitors, Syk inhibitors, anti- inflammatory biologie agents, including anti-IL6 biologics, anti-ILl agents, anti-ILl 7 biologics, anti-CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biologics and other cytokine inhibitors or biologics to T-cell or B-cell receptors or interleukins. [0308] In the treatment of ALS, a compound described herein may be administered in combination with riluzole.

[0309] In the treatment of Parkinson’s disease, a compound described herein may be administered in combination with levodopa, carbodopa or a combination thereof, pramipexole, ropinirole, rotigotine, selegiline, rasagiline, entacapone, tolcapone, benztropine, trihexyphenidyl. or amantadine.

[0310] In the treatment of Alzheimer’s disease, a compound described herein may be administered in combination with donepezil, galantamine, memantine, rivastigmine, anti-ABeta (amyloid beta) thérapies including aducanumab, crenezumab, solanezumab, and gantenerumab, small molécule inhibitors of BACE1 including verubecestat, AZD3293 ( LY3314814), elenbecestat (E2609), LY2886721, PF05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854, CTS-21166, or anti-tau thérapies such as LMTM (leuco-methylthioninium-bis (hydromethanesulfonate)).

131

[0311] In the treatment of rheumatoid arthritis, a compound described herein may be administered in combination with ibuprofen, naproxen, prednisone, methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab or tofacitinib.

[0312] In the treatment of CVA, a compound described herein may be administered to in combination with a thrombolytic agent (such as tissue plasminogen activator (TPA®), Activase®, Lanoteplase®, Reteplase®, Staphylokinase®, Streptokinase®, Tenecteplase®, Urokinase®), an anticoagulant (such as heparin, coumadin, clopidrogel (Plavix®)), and a platelet aggregation inhibitor (such as dipyridamole (Persantine®), ticlopidine HCL (Ticlid®), eptifibatide (Integrillin®), and/or aspirin).

[0313] In the treatment of SIRS, a compound described herein may be administered in combination with a broad-spectrum antibiotic (such as vacomycin) or other anti-MRSA therapy (cefeprime (Maxipime®), piperacillin/tazobactam (Zosyn®), carbapenem (imipenem, meropenem, doripenem), quinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, etc.), and low dose steroids such as hydrocortisones.

[0314] In the treatment of inflammatory bowel disease (particularly, Crohn’s disease and/or ulcerative colitis), a compound of any formula described herein, may be administered in combination with vedolizumab (Entyvio®), alicaforsen, or remestemcel-L (Prochymal®). Specifically, in the treatment of inflammatory bowel disease (particularly, Crohn’s disease and/or ulcerative colitis), a compound described herein may be administered in combination with alicaforsen, or remestemcel-L (Prochymal®). In the treatment of psoriasis, a compound described herein may be administered in combination with ixekizumab, tildrakizumab (MK-3222), or secukinumab (AIN457).

[0315] Specifically, in the treatment of psoriasis, a compound described herein may be administered in combination with ixekizumab, or tildrakizumab (MK-3222). In the treatment of periodonitis, a compound of any formula described herein may be administered in combination with an antimicrobial agent, (such as chlorhexidine (Peridex®, PerioChip®, PerioGard®, etc.)) or an antibiotic (such as doxycycline (Vibrox®, Periostat®, Monodox®,Oracea®, Doryx®, etc.) or minocycline (Dynacin®, Minocin®, Arestin®, Dynacin®, etc.).

[0316] In the treatment of asthma, a compound of any formula described herein may be administered in combination with an inhaled corticosteroid ((ICS) such as fluticasone proprionate (Flovent®), beclomethasone dipropionate (QVAR®), budesonide (Pulmicort), triamcinolone acetonide (Azmacort®), flunisolide (Aerobid®), mometasone fuorate (Asmanex® Twisthaler®), or Ciclesonide (Alvesco®)), a long acting beta agonist ((LABA) such as formoterol fumaratc (Foradil®), sahneterol xinafoate (Serevent®)), a combination of an ICS and LABA (such as fluticasone furoate and vilanterol (Breo Ellipta®), formoterol/budesonide inhalation (Symbicort®), beclomethasone dipropionate/formoterol (Inuvair®), and fluticasone propionate/salmeterol (Advair®), a short acting beta agonist ((S AB A) such as

132 albuterol sulfate (ProAir®, Proventil HFA®, Ventolin HFA®, AccuNeb® Inhalation Solution), levalbuterol tartrate (Xopenex® HFA), ipratropium bromide/albuterol (Combivent® Respimat®), ipratropium bromide (Atrovent® HFA), a leukotriene modifier (such as montelukast sodium (Singulair®), zafirlukast (Accolate®),or zileuton (Zyflo®), and anti-IgE (such as omalizumab (Xolair®)), a methylxanthine bronchodilator (such as theophylline (Accurbron®, Aerolate®, Aquaphyllin®, Asbron®, Bronkodyl®, Duraphyl®, Elixicon®, Elixomin®, Elixophyllin®, Labid®, Lanophyllin®, Quibron-T®, Slo-Bid®, Slo-Phyllin®, Somophyllin®, Sustaire®, Synophylate®, TPhyll®, Theo-24®, Theo-Dur®, Theobid®, Theochron®, Theoclear®, Theolair®, Theolixir®, Theophyl®, Theovent®, Uni-dur®, Uniphyl®), a mast cell inhibitor (such as cromulyn sodium (Nasalcrom®) and nedocromil sodium (Tilade®)), a long-acting muscarinic antagonist ((LAMA) such as mometasone furoate/ formoterol fumarate dihydrate (Dulera®)).

[0317] Other agents that may be suitable for use in combination therapy in the treatment of asthma include a protein tyrosine kinase inhibitor (masitinib), CRTH2/D-prostanoid receptorantagonist (AMG 853), indacaterol (Arcapta® Neohaler®), an epinephrine inhalation aérosol (E004), fluticasone furoate/fluticasone proprionate, vilanterol inhalation/fluticasone furoate powder (Relovair™), fluticasone propionate/eformoterol fumarate dihydrate (Flutiform®), reslizumab, salbutamol dry-powder inhalation, tiotropium bromide (Spiriva®HandiHaler®), formoterol/budesonide (Symbicort®SMART®), fluticasone furoate (Veramyst®), Vectura’s VR506, lebrikizumab (RG3637), a combination phosphodiesterase (PDE)-3 and (PDE)-4 inhibitor (RPL554).

[0318] In the treatment of COPD, a compound of any formula described herein, may be administered in combination with a LABA (such as sahneterol xinafoate (Serevent), umeclidinium/vilanterol (Anuro Ellipta®), umeclidinium (Incruse Ellipta®), arformoterol tartrate (Brovana®), formoterol fumarate inhalation powder (Foradil®), indacterol maleate (Arcapta® Neohaler®), or fluticasone propionate/eformoterol fumarate dehydrate (Flutiform®)), a long-acting inhaled anticholinergic (or muscarinic antagonist, such as tiotropium bromide (Spiriva®), and aclidinium bromide (Tudorza® Pressair®), a phosphodiesterase (PDE-r) inhibitor (such as roflumilast, Daliresp®), a combination ICS/LABA (such as fluticasone furoate and vilanterol (Breo Ellipta®), fluticasone propionate/salmeterol (Advair®), budesonide/formoterol (Symbicort®),mometasone/formoterol (Dulera®), ipratropium bromide/albuterol sulfate (Duoneb®, Atrovent®), albuterol/ipratropium (Combivent Respimat®)), a SABA (such as ipratropium bromide (Atrovent®), and albuterol sulfate(ProAir®,Proventil®)), and an ICS (such as budesonide (Pulmicort®) and fluticasone propionate (Flovent®), beclometasone dipropionate (QVAR®).

[0319] Other agents that may be suitable for use in combination therapy in the treatment of COPD include SCH527123 (a CXCR2 antagonist), glycoprronium bromide ((NVA237) Seebri® Breezhaler®), glvcopyrronium bromide and indacaterol maleate ((QVA149) Ultibro® Breezhaler®), glycopyrrolate and

133 formoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol (Striverdi® Respimat®), tiotropium (Spiriva®)/olodaterol (Striverdi® Respimat®), and aclidinium/formoterol inhalation.

[0320] In the treatment of a mycobacterium infection (tuberculosis), a compound of any formula described herein may be administered in combination with an antimycobacterial agent (such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamidc (PZA)) a bactericidal antibiotic (such as rifabutin (Mycobutin®) or rifapentine (Priftin®)), an aminoglycoside (capreomycin), a fluorquinolone (levofloxacin, moxifloxicin, ofloxacin), thioamide (ehionamide), cyclosporine (Sandimmune®), para-aminosalicyclic acid (Paser®),cycloserine (Seromycin®), kanamycin (Kantrex®), streptomycin, viomycin, capreomycin (Capastat®)), bedaquiline fumarate (Sirturo®), oxazolidinone (Sutezolid®), or delamanid (OPC-67683).

[0321] Specifically, in the treatment of a mycobacterium infection (tuberculosis), a compound described herein may be administered in combination with an antimycobacterial agent (such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)) a bactericidal antibiotic (such as rifabutin (Mycobutin®) or rifapentine (Priftin®)), an aminoglycoside (Capreomycin®), a fluorquinolone (levofloxacin, moxifloxicin, ofloxacin), thioamide (ehionamide), cycloserine (Seromycin®), kanamycin (Kantrex®), streptomycin, viomycin, capreomycin (Capastat®)), bedaquiline fumarate (Sirturo®), oxazolidinone (Sutezolid®), or delamanid (OPC-67683).

[0322] In the treatment of systemic scleroderma, a compound of any formula described herein may be administered in combination with an oral corticosteroid (such as prednisolone (Delatsone®, Orapred, Millipred, Omnipred, Econopred, Flo-Pred), an immunosuppressive agent (such as méthotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®), anti- thymocyte globulin (Atgam®), mycophenolate mofetil (CellCept®), cyclophosphamide (Cytoxan®), FK506 (tacrolimus), thalidomide (Thalomid®), chlorambucil (Leukeran®), azathioprine (Imuran®, Azasan®)), a calcium channel blocker (such as nifedipine (Procardia®, Adalat®) or nicardipine (Cardene®), a topical emollient (nitroglycerin ointment), an ACE inhibitor (such as lisinopril (Zestril®, Prinivil®), diltaizem (Cardizem®, Cardizem SR®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®)), a serotonin reuptake inhibitor (such as fluoxetine (Prozac®)), an endothelin-1 receptor inhibitor (such as bosentan (Tracleer®) or epoprostenol (Flolan®, Veletri®, Prostacyclin®)) an anti-fibrotic agent (such as colchicines (Colcrys®), para-aminobenzoic acid (PAB A), dimethyl sulfoxide (KMSO), and D-penicillamine (Cuprimine®, Depen®), interferon alpha and interferon gamma (INF-g)), a proton-pump Inhibitor (such as omeprazole (Prilosec®), metoclopramide (Reglan®), lansoprazole (Prevacid®), esomeprazole (Nexium®), pantoprazole (Protonix®), rabeprazole (Aciphex®)) or imatinib (Gleevec®) ARG201 (arGentis Pharmaceutical), belimumab (Benlysta®), tocilizumab (Actema®).

[0323] Specifically, in the treatment of systemic scleroderma, a compound of any formula described herein may be administered in combination with an oral corticosteroid (such as prednisolone

134 (Delatsone®, Orapred, Millipred, Omnipred, Econopred, Flo-Pred), anti- thymocyte globulin (Atgam®), FK506 (tacrolimus), thalidomide (Thalomid®), chlorambucil (Leukeran®), a calcium channel blocker (such as nifedipine (Procardia®, Adalat®) or nicardipine (Cardene®), a topical emollient (nitroglycerin ointment), an ACE inhibitor (such as lismopril (Zestril®, Prinivil®), diltaizem (Cardizem®, Cardizem SR®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®)), a serotonin reuptake inhibitor (such as fluoxetine (Prozac®)), an endothelin-1 receptor inhibitor (such as bosentan (Tracleer®) or epoprostenol (Flolan®, Veletri®, Prostacyclin®)) an anti-fibrotic agent (such as colchicines (Colcrys®), para-aminobenzoic acid (PABA), dimethyl sulfoxide (KMSO), and D-penicillamine (Cuprimine®, Depen®), interferon alpha and interferon gamma (INF-g)), a proton-pump Inhibitor (such as omeprazole (Prilosec®), metoclopramide (Reglan®), lansoprazole (Prevacid®), esomeprazole (Nexium®), pantoprazole (Protonix®), rabeprazole (Aciphex®)) or imatinib (Gleevec®) ARG201 (arGentis Pharmaceutical), or tocilizumab (Actema®).

[0324] In the treatment of cystic fibrosis, a compound as described herein may be administered in combination with a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator (ivaeftor (Kalydeco®)) a mucolytic agent (such as domase alpha (Puhnozyme®)), pancreatic enzymes (such as Pancrelipase (Creon®, Pancreaze®, Ultresa®, Zenpep®)), a bronchodilator (such as albuterol (AccuNeb®, ProAir®, Proventil HFA®, VoSpire ER®, Ventolin HFA®)), an antibiotic (including inhaled, oral or parentéral, such as tobramycin solution for inhalation (TOBI®, Bethkis®, TOBI Podhaler®), aztreonam inhalation (Azactam®, Cayston®), colistimethate sodium (Coly- Mycin®), cephalosporins (cefadroxil monohydrate (Duricef®), cefazolin (Kefzol®), cephalexin (Keflex®), cefazolin (Ancef®, etc.), fluoroquinolones (moxifloxacin, levofloxacin, gemifloxacin, etc), azithromycin (Zithromax®), gentamicin (Garamycin®), piperacillin/tazobacam (Zosyn®), cephalexin (Keflex), ceftazidime (Fortaz, Tazicef), ciprofloxin (Cipro XR, Proquin XR), trimethoprim/sulfamethoxazole (Bactrim DS, Septra DS), chloramphenicol)), or ivaeftor (Kalydeco®)/lumacaftor (VX-809), ataluren (Translama®), or with tiopropium bromide (Spiriva® Handihaler®) as add on to standard therapy.

[0325] In the treatment ofretinitis pigmentosa, a compound as described herein maybe administered in combination with a ciliary neurotrophic growth factor (NT-501-CNTF) or gene transfer agent, UshStat®. [0326] In the treatment of macular degeneration, a compound of any formula described herein, may be administered in combination with opthalmalic intravitreal injections (afibercept (Eylea®)) or with an anti-vascular endothélial growth factor (VEGF) inhibitor (such as ranibizumab (Lucentis®) or pegaptanib sodium (Macugen®)), a ciliary neurotrophic growth factor agent (NT501), iSONEP®, or bevacizumab (Avastin®).

[0327] In the treatment of influenza, a compound as described herein may be administered in combination with a trivalent (IIV3) inactivated influenza vaccine (such as Afluria®, Fluarix®, Flucelvax®, FluLaval®, Fluvirin®, Fluzone®), a quadrivalent (IIV4) inactivated influenza vaccine (such as Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent), a trivalent recombinant

135 influenza vaccine (such as FluBlok®), a quadrivalent live attenuated influenza vaccine (such as FluMist® Quadrivalent), an antiviral agent (such as oseltamivir (Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®), or amantadine (Symmetrel®)), or Fluad®, Fludase, FluNhance®, Preflucel, or VaxiGrip®

[0328] In the treatment of a staphylococcus infection, a compound of any formula described herein may be administered in combination with an antibiotic (such as a-Lactam cephalosporin (Duricef®, Kefzol®, Ancef®, Biocef®, etc), nafcillin (Unipen®), a sulfonamide (sulfamethoxazole and trimethoprim (Bacrim®, Septra®,) sulfasalazine (Azulfidine®), acetyl sulfisoxazole (Gantrisin®), etc), or vancomycin (Vancocin®)).

[0329] In the treatment of transplant rejection, a compound of any formula described herein may be administered in combination with a high-dose corticosteroid (such as prednisone (Deltasone®), méthylprednisolone (SoluMedrol®) etc.) a calcineurin inhibitor (such as cyclosporine (Sandimmune®, Neoral®, Gengraf®), tacrolimus (Prograf®, Astragraf XL®)), an mTor inhibitor (such as sirolimus (Rapamune®) or everolimus (Afinitor®)), an anti-proliferative agent (such as azathioprine (Imuran®, Azasan®), mycophenolate mofetil (CellCept®), or mycophenolate sodium (Myfortic®)), a monoclonal antibody (such as muromonab-CD3 (Orthoclone OKT3®)), an interleukine-2 receptor antagonist ((Basiliximab®, Simulect®), daclizumab (Zenapax®), or rituximab (Rituxan®)), a polyclonal anti-T-cell antibody (such as anti-thymocyte gamma globulin-equine (Atgam®), or antithymocytc globulin-rabbit (Thymoglobulin®)) an anti-CD40 antagonist (ASKP- 1240), a JAK inhibitor (ASP015K), or an anti-TCR murine mAb (TOL101).

[0330] Specifically, in the treatment of transplant rejection, a compound of any formula described herein may be administered in combination with a monoclonal antibody (such as muromonab-CD3 (Orthoclone OKT3®)), a polyclonal anti-T-cell antibody (such as anti-thymocyte gamma globulin-equine (Atgam®), or antithymocyte globulin-rabbit (Thymoglobulin®)) an anti- CD40 antagonist (ASKP-1240), a JAK inhibitor (ASP015K), or an anti-TCR murine mAb (TOL101).

[0331] In tire treatment of atopie dermatitis, a compound of any formula described herein may be administered in combination with a topical immunomodulator or calcineurin inhibitor (such as pimecrolimus (Elidel®) or tacrolimus ointment (Protopic®)), a topical corticosteroid (such as hydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®), fhirandrenolide (Cordan®), fluticasone (Cutivate®), triamcinolone (Kenalog®), fhiocinonide (Lidex®), and clobetasol (Temovate®)), an oral corticosteroid (such as hydrocortisone (Cortef®), méthylprednisolone (Medrol®), or prednisolone (Pediapred®, Prelone®), an immunosuppressant (such as cyclosporine (Neoral®) or interferon gamma (Alferon N®, Infergen®, Intron A, Roferon-A®)), an antihistamine (for itching such as Atarax®, Vistaril®, Benadryl®), an antibiotic (such as penicillin dérivatives flucloxacillin (Floxapen®) or dicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra-Derm®, etc.)), anon

136 steroidal immunosuppressive agent (such as azathioprine (Imuran®, Azasan®), methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®), or mycophenolate mofetil (CellCept®)).

[0332] Specifîcally, in the treatment of atopie dermatitis, a compound of any formula described herein may be administered in combination with a topical immunomodulator or calcineurin inhibitor (such as pimecrolimus (Elidel®) or tacrolimus ointment (Protopic®)), a topical corticosteroid (such as hydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®), flurandrenolide (Cordan®), fluticasone (Cutivate®), triamcinolone (Kenalog®), fluocinonide (Lidex®), and clobetasol (Temovate®)), an oral corticosteroid (such as hydrocortisone (Cortef®), méthylprednisolone (Medrol®), or prednisolone (Pediapred®, Prelone®), an interferon gamma (Alferon N®, Infergen®, Intron A, Roferon- A®)), an antihistamine (for itching such as Atarax®, Vistaril®, Benadryl®), or an antibiotic (such as penicillin dérivatives flucloxacillin (Floxapen®) or dicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra-Derm®, etc.)).

[0333] In the treatment of bums, e.g. a bum injury or bum shock, a compound of any formula described herein may be administered alone, or in combination with an antimicrobial agent, typically a topical antibiotic (mafenide acetate cream, silver sulfadiazine cream) and/or a analgésie (opioid analgésies, e.g., morphine, oxycodone). Other therapeutic agents that may be useful for the treatment of bums include retinoids and pirfenidone.

[0334] In certain embodiments, the at least one other therapeutically active agent is selected from a thrombolytic agent, a tissue plasminogen activator, an anticoagulant, and a platelet aggregation inhibitor. In certain embodiments, the at least one other therapeutically active agent is selected from heparin, coumadin, clopidrogel, dipyridamole, ticlopidine HCL, eptifibatide, and aspirin. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is a cerebrovascular accident.

[0335] In certain embodiments, the at least one other therapeutically active agent is selected from broad-spectrum antibiotic, anti-MRSA therapy and a low dose steroid. In certain embodiments, tire at least one other therapeutically active agent is selected from vacomycin, cefeprime, a combination of piperacillin and tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, and hydrocortisone. In certain embodiments, the disease or disorder treated with these agents is systemic inflammatory response syndrome.

[0336] In certain embodiments, the at least one other therapeutically active agent is alicaforsen or remestemcel-L. In certain embodiments, the disease or disorder treated with these agents is Crohn’s disease or ulcerative colitis.

[0337] In certain embodiments, the at least one other therapeutically active agent is ixekizumab, or tildrakizumab. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is psoriasis.

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[0338] In certain embodiments, the at least one other therapeutically active agent is an antimicrobial agent or an antibiotic. In certain embodiments, the at least one other therapeutically active agent is selected from chlorhexidine, doxycycline and minocycline. In certain embodiments, the disease or disorder treated with these agents is periodonitis.

[0339] In certain embodiments, the at least one other therapeutically active agent is selected from an inhaled corticosteroid, a long acting beta agonist, a combination of an inhaled corticosteroid and a long acting beta agonist, a short acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist. In certain embodiments, the at least one other therapeutically active agent is selected from fluticasone proprionate, beclomethasone dipropionate, budesonide, trimcinolone acetonide, flunisolide, mometasone fuorate, or ciclesonide, formoterol fumarate, salmeterol xinafoate, a combination of fluticasone furoate and vilanterol, a combination of formoterol and budesonide inhalation, a combination of beclomethasone dipropionate and formoterol, a combination of fluticasone propionate and salmeterol, albuterol sulfate, levalbuterol tartrate, a combination of ipratropium bromide and albuterol, ipratropium bromide, montelukast sodium, zafirlukast, zileuton, omalizumab theophylline, cromulyn sodium, nedocromil sodium, and a combination of mometasone furoate and formoterol fumarate dihydrate. In certain embodiments, the at least one other therapeutically active agent is selected from protein tyrosine kinase inhibitor, a CRTH2/D-prostanoid receptor antagonist, an epinephrine inhalation aérosol, and a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4 inhibitor. In certain embodiments, the at least one other therapeutically active agent is selected from masitinib, AMG 853, indacaterol, E004, a combination of fluticasone furoate and fluticasone proprionate, a combination of vinanterol fluticasone furoate, a combination of fluticasone propionate and eformoterol fumarate dihydrate, reslizumab, salbutamol, tiotropium bromide, a combination of formoterol and budesonide, fluticasone furoate, VR506, lebrikizumab, and RPL554. In certain embodiments, tire kinase-mediated disease or disorder treated with these agents is asthma.

[0340] In certain embodiments, tire at least one other therapeutically active agent is selected from a long acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, a combination an inhaled corticosteroid long acting beta agonist, a short acting beta agonist, and an inhaled corticosteroid. In certain embodiments, the at least one other therapeutically active agent is selected from salmeterol xinafoate, a combination of umeclidinium and vilanterol, umeclidinium, arformoterol tartrate, formoterol fumarate, indacterol maleate, a combination of fluticasone propionate and eformoterol fumarate dihydrate, tiotropium bromide, aclidinium bromide, roflumilast, a combination of fluticasone furoate and vilanterol, a combination of fluticasone propionate and salmeterol, a combination of budesonide and formoterol, a combination of mometasone and formoterol, a combination of ipratropium bromide and albuterol sulfate, a combination of albuterol and ipratropium, ipratropium bromide, albuterol sulfate, budesonide, fluticasone propionate, and

138 beclometasone dipropionate. In certain embodiments, the at least one other therapeutically active agent is selected from SCH527123, glycoprronium bromide, a combination of glycopyrronium bromide and indacaterol maleate, a combination of glycopyrrolate and formoterol fumarate, indacaterol maleate, olodaterol, tiotropium, olodaterol, and a combination of aclidinium and formoterol. In certain embodiments, the disease or disorder treated with these agents is COPD.

[0341] In certain embodiments, the at least one other therapeutically active agent is an antimycobacterial agent or a bactericidal antibiotic. In certain embodiments, the at least one other therapeutically active agent is selected from isoniazid, ehambutol, rifampin, pyrazinamide, rifabutin, rifapentine, capreomycin, levofloxacin, moxifloxicin, ofloxacin, ehionamide, cycloserine, kanamycin, streptomycin, viomycin, bedaquiline fumarate, PNU-100480, and delamanid. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is a mycobacterium infection.

[0342] In certain embodiments, the at least one other therapeutically active agent is selected from an oral corticosteroid, anti-thymocyte globulin, thalidomide, chlorambucil, a calcium channel blocker, a topical emollient, an ACE inhibitor, a serotonin reuptake inhibitor, an endothelin-1 receptor inhibitor, an anti-fibrotic agent, a proton-pump inhibitor or imatinib, AR.G201, and tocilizumab. In certain embodiments, the at least one active agent is selected from prednisolone, anti-thymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin ointment, lisinopril, diltaizem, fluoxetine, bosentan, epoprostenol, colchicines, para- aminobenzoic acid, dimethyl sulfoxide, D-penicillamine, interferon alpha, interferon gamma (INF-g)), omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole, imatinib, ARG201, and tocilizumab. In certain embodiments, the disease or disorder treated with these agents is systemic scleroderma.

[0343] In certain embodiments, the at least one other therapeutically active agent is selected from a cvstic fibrosis transmembrane conductance regulator potentiator, amucolytic agent, pancreatic enzymes, a bronchodilator, an antibiotic, or ivacftor/lumacaftor, ataluren, and tiopropium bromide. In certain embodiments, the at least one other therapeutically active agent is selected from ivacftor, domase alpha, pancrelipase, albuterol, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin, piperacillin/tazobacam, ceftazidime, ciprofloxin, trimethoprim/sulfamethoxazole, chloramphenicol, or ivacftor/lumacaftor, ataluren, and tiopropium bromide. In certain embodiments, the disease or disorder treated with these agents is cystic fibrosis.

[0344] In certain embodiments, the at least one other therapeutically active agent is a ciliary neurotrophic growth factor or a gene transfer agent. In certain embodiments, the at least one other therapeutically active agent is NT-501-CNTF or a gene transfer agent encoding myosin VIIA (MY07A). In certain embodiments, the disease or disorder treated with these agents is retinitis pigmentosa.

139

[0345] In certain embodiments, the at least one other therapeutically active agent is selected from opthalmalic intravitreal injections, an anti-vascular endothélial growth factor inhibitor, and a ciliary neurotrophic growth factor agent. In certain embodiments, the at least one other therapeutically active agent is selected from afibercept, ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, and bevacizumab. In certain embodiments, the disease or disorder treated with these agents is macular degeneration.

[0346] In certain embodiments, the at least one other therapeutically active agent is selected from a trivalent (IIV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent live attenuated influenza vaccine, an antiviral agent, or inactivated influenza vaccine. In certain embodiments, the at least one other therapeutically active agent is selected from oseltamivir, zanamivir, rimantadine, or amantadine. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is influenza.

[0347] In certain embodiments, the at least one other therapeutically active agent is selected from a beta-Lactam, nafcillin, sulfamethoxazolem, trimethoprim, sulfasalazine, acetyl sulfisoxazole, and vancomycin. In certain embodiments, disease or disorder treated with these agents is a staphylococcus infection.

[0348] In certain embodiments, the at least one other therapeutically active agent is selected from a monoclonal antibody, a polyclonal anti-T-cell antibody, an anti- thymocyte gamma globulin-equine antibody, an antithymocyte globulin-rabbit antibody, an anti-CD40 antagonist, a JAK inhibitor, and an anti-TCR murine mAb.

[0349] In certain embodiments, the at least one other therapeutically active agent is selected from muromonab-CD3, ASKP-1240, ASP015K, and TOL101. In certain embodiments, the disease or disorder treated with these agents is transplant rejection.

[0350] In certain embodiments, the at least one other therapeutically active agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, an interferon gamma, an antihistamine, or an antibiotic. In certain embodiments, the at least one other therapeutically active agent is selected from pimecrolimus, tacrolimus, hydrocortizone , betamethasone, flurandrenolide, fluticasone, triamcinolone, fluocinonide, clobetasol, hydrocortisone, méthylprednisolone, prednisolone, an interferon alpha protein, a recombinant synthetic type I interferon, interferon alpha-2a, interferon alpha-2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin, and erythromycin. In certain embodiments, the disease or disorder treated with these agents is atopie dermatitis.

140

8. Dosing

[0351] The spécifie dose level of a compound of the présent application for any particular subject will dépend upon a variety of factors including the activity of the spécifie compound employed, the âge, body weight, general health, sex, diet, time of administration, route of administration, and rate of excrétion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In certain embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

[0352] The daily dosage may also be described as a total amount of a compound disclosed herein administered per dose or per day. Daily dosage of a compound disclosed herein may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.

[0353] When administered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.

[0354] The compounds of the présent application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently altemated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.

[0355] In certain embodiments, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by incréments until clinical efficacy is achieved. Incréments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.

9. Synthesis of the Compounds

[0356] The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art.

141

Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.

[0357] The compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein, e.g. compounds having structures described by one or more formulas or compounds disclosed herein, may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers.

[0358] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction températures, rimes, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0359] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene ’s protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and référencés cited therein.

[0360] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. Ail such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Altematively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and tire like.

[0361] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachern (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri,

142

USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplémentais (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 5* Edition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0362] The tenus “solvent,” “inert organic solvent” or “inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydroforan (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like). Unless specified to the contrary, the solvents used in tire reactions of the présent disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[0363] The term “q.s.” means adding a quantity sufficient to achieve a stated fonction, e.g., to bring a solution to the desired volume (i.e., 100%).

[0364] Scheme 1 shows the synthesis of compounds of Formula I, wherein LG is a leaving group and X¹, X², Y¹, Y², A, L, R², R³, R⁴, and R⁹, are as defined herein.

Scheme 1

As depicted in Scheme 1, the compounds of Formula I may be prepared by contacting a suitably substituted 1-a with compound 1-b, under standard amide bond forming reaction conditions. As is typical in peptide coupling reactions, an activating agent may be used to facilitate the reaction. Suitable coupling agents (or activating agents) are known in the art and include for example, carbodiimides (e.g., Ν,Ν’-dicyclohexylcarbodiimide (DCC), Ν,Ν’-dicyclopentylcarbodiimide, N,N’-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-t-butyl-N-methylcarbodiimide (BMC), N-t-butyl-N-ethylcarbodiimide (BEC), l,3-bis(2,2-dimethyl-l,3-dioxolan-4-ylmethyl)carbodiimide (BDDC), etc.), anhydrides (e.g., symmetric, mixed, or cyclic anhydrides), activated esters (e.g., phenyl activated ester dérivatives, p-hydroxamic activated ester, hexafluoroacetone (HFA), etc.), acylazoles (acylimidazoles using CDI, acylbenzotriazoles, etc.), acyl azides, acid halides, phosphonium salts (HOBt, PyBOP, HOAt, etc.), aminium/uronium salts (e.g., tetramethyl aminium salts, bispyrrolidino aminium salts, bispiperidino aminium salts, imidazolium uronium salts, pyrimidinium uronium salts, uronium salts

143 derived from N,N,N’-trimethyl-N’-phenylurea, morpholino-based aminium/uronium coupling reagents, antimoniate uronium salts, etc.), organophosphorus reagents (e.g., phosphinic and phosphoric acid dérivatives), organosulfur reagents (e.g., sulfonic acid dérivatives), triazine coupling reagents (e.g., 2chloro-4,6-dimethoxy-l,3,5-triazine, 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4 methylmorpliolinium chloride, 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4 methylmorpholiniumtetrafluoroborate, etc.), pyridinium coupling reagents (e.g., Mukaiyama’s reagent, pyridinium tetrafluoroborate coupling reagents, etc.), polymer-supported reagents (e.g., polymer-bound carbodiimide, polymer-bound TBTU, polymer-bound 2,4,6-trichloro-l,3,5-triazine, polymer-bound HOBt, polymer-bound HOSu, polymer-bound IIDQ, polymer-bound EEDQ, etc.), and the like (see, e.g., El-Faham, et al. Chem. Rev., 2011, 111(11): 65576602; Han, et al. Tetrahedron, 2004, 60:2447-2467). Compounds of formula 1-a and 1-b for use in Scheme 1 may be obtained as described in the schemes and Examples provided herein or from conventional synthetic methods known in the art using appropriate starting materials.

[0365] Scheme 2 shows an exemplary synthesis for compounds which contain a 6,7- fused ring and where Y¹ is O. In Scheme 2, PG is a protecting group (e.g., BOC) and X⁶, X⁷, X^s, X⁹, Y², q, R¹, R³, R⁴, and R¹⁰ are as defined herein.

Scheme 2 (R¹°)q

R¹

R⁴

2-b

[0366] In Scheme 2, appropriately substituted 2-a can be cyclized under standard amide bond forming reaction conditions (e.g., as described above). Compounds of formula 2-a may be obtained from commercial sources, or prepared as described in the Examples provided herein or from conventional synthetic methods known in the art using appropriate starting materials. Further, the desired functional groups at Y², R¹, R³, R⁴ and R¹⁰ may be installed prior to, or after, cyclization by employing conventional synthetic methods known in the art (e.g., halogénation, réduction, oxidation, olefmation, alkylation, etc.).

[0367] Scheme 3 shows an exemplary synthesis for compounds which contain a 5,7- fused ring and where Y¹ is O. In Scheme 3, Z is halo and X¹, X², X³, X⁴, X⁵, Y², q, R¹, R³, R⁴, and R¹⁰ are as defined herein.

144

[0368] In Scheme 3, appropriately substituted 3-a can be contacted with hydroxylamine hydrochloride under reaction conditions sufficient to provide 3-b. Ring expansion of 3-b to provide lactarn 3-c can be performed by contacting oxime 3-b with phosphorus pentoxide. Alternatively, lactarn 3-c can be provided by contacting 3-a with sodium azide in the presence of sulfuric acid. α-Halogenation of 3-c using a suitable reagent (e.g., NBS, iodotrimethylsilane, etc.) and optional N-alkylation of the azapanone nitrogen with a compound of formula R’-LG, where LG is a suitable leaving group (e.g., halo) provides

3-d. Contacting 3-d with sodium azide yields 3-e. Réduction of the azide in 3-e (e.g., hydrogénation, triphenylphosphine, etc.) provides 3-f. Compounds of formula 3-a may be obtained from commercial sources, or prepared as described in the Examples provided herein or from conventional synthetic methods known in the art using appropriate starting materials. Further, alternative fiinctional groups may be installed at any point prior to, during, or after, the steps shown in Scheme 3 by employing conventional synthetic methods known in the art (e.g., halogénation, réduction, oxidation, olefination, alkylation, etc.).

[0369] Also provided herein is a process for preparing a compound of Formula II:

or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, comprising contacting a compound of Formula XVI or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof:

145

and contacting a compound of Formula XVI or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, with a compound of Formula XVII:

HO

L—R⁹

XVII under reaction conditions sufficient to provide the compound of Formula II or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein

Y² is -O-, -S-, or -NR⁵-;

R⁵ is H or optionally substituted Ci-Ce alkyl; and

L, ring A, q, R¹, R³, R⁴, R⁹, R¹⁰, X⁶, X⁷, X⁸ and X⁹ are as defined herein.

[0370] In certain embodiments, provided is a process for preparing a compound of Formula II:

or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, comprising:

(a) contacting a compound of Formula X:

or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, with a compound of

Formula XI:

R³ R⁴ O

H-Y²

Y OH

HN

P

XI under reaction conditions sufficient to provide the compound of Formula XII or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof:

146

χπ (b) contacting a compound of Formula XII or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, under reaction conditions sufficient to provide the compound of Formula (XIII) or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof:

(c) contacting a compound of Formula XIII or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, under reaction conditions sufficient to provide the compound of Formula XIV or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof:

(d) optionally contacting a compound of Formula XIV or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, with an alkylating agent, under reaction conditions sufficient to provide the compound of Formula XV or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof:

(e) deprotecting the compound of Formula XV or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, under reaction conditions sufficient to provide the compound of Formula XVI or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof:

147 and contacting a compound of Formula XVI or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, with a compound of Formula XVII:

Ο XVII under reaction conditions sufficient to provide the compound of Formula II or a sait, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein

P is a protecting group;

Y² is -O-, -S-, or -NR⁵-;

R⁵ is H or optionally substituted Ci-Ce alkyl; and

[0371] In certain embodiments of the processes described above, at least one of X⁷ or X⁹ is N. In certain embodiments of the processes described above, X⁷ is N and X⁶, X⁸ and X⁹ are CH. In certain embodiments of the processes described above, X⁹ is N and X⁶, X⁷ and X⁸ are CH. In certain embodiments of the processes described above, R¹ is methyl. In certain embodiments of the processes described above, Y² is -O-.

[0372] In certain embodiments of the processes described above, P is tert-butoxycarbonyl. In certain embodiments of the processes described above, the reaction conditions of step (b) comprise hydrogen gas. In certain embodiments of the processes described above, the reaction conditions of step (c) comprise a peptide coupling agent. In certain embodiments of the processes described above, the alkylating agent of step (d) is methyliodide.

[0373] It will also be appreciated that in each of the above schemes, the addition of any substituent may resuit in the production of a number of isomeric products (including, but not limited to, enantiomers or one or more diastereomers) any or ail of which may be isolated and purified using conventional techniques. When enantiomerically pure or enriched compounds are desired, chiral chromatography and/or enantiomerically pure or enriched starting materials may be employed as conventionally used in the art or as described in tire Examples.

EXAMPLES

[0374] The following examples are included to demonstrate spécifie embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute spécifie modes for its practice. However, those of skill in the art should, in light of the présent disclosure, appreciate that many changes can be made in the spécifie embodiments which are

148 disclosed and still obtain a like or similar resuit without departing from the spirit and scope of tire disclosure.

General Procedures

[0375] Liquid Chromatography-Mass Spectrometry Method A: Total ion current (TIC) and DAD UV chromatographie traces together with MS and UV spectra associated with the peaks were taken on a UPLC/MS Acquity™ system equipped with PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in altemated positive and négative electrospray ionization mode. [LC/MSES (+/-): analyses performed using an Acquity UPLC™ CSH, C18 column (50 χ 2.1mm, 1.7 pm particle size), column température 40 °C, mobile phase: A-water + 0.1% HCOOH/ B- CH₃CN + 0.1% HCOOH, flow rate: 1.0 mL/min, run time = 2.0 min, gradient: t=0 min 3%B, t= 1.5 min 99.9% B, t = 1.9 min 99.9% B, t= 2.0 min 3% B, stop time 2.0 min. Positive ES 100-1000, Négative ES 100-1000, UV détection DAD 210-350 nm.

[0376] Liquid Chromatography-Mass Spectrometry Method B: Total ion current (TIC) and DAD UV chromatographie traces together with MS and UV spectra associated with the peaks were taken on a UPLC/MS Acquity™ system equipped with PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in altemated positive and négative electrospray ionization mode. [LC/MSES (+/-): analyses performed using an Acquity UPLC™ BEH, C18 column (50 x 2.1mm, 1.7 pm particle size), column température 40 °C, mobile phase: A- 0.1% v/v aqueous ammonia solution pH 10/ BCH₃CN, flow rate: 1.0 mL/min, run time = 2.0 min, gradient: t=0 min 3%B, t= 1.5 min 99.9% B, t = 1.9 min 99.9% B, t= 2.0 min 3% B, stop time 2.0 min. Positive ES 100-1000, Négative ES 100-1000, UV détection DAD 210-350 nm.

[0377] Liquid Chromatography-Mass Spectrometry Method C: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 1.0 s. The column used was a Shim-pack XR-ODS, 2.2 pm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 2.2 min with a total run time of 2.6 min. The column température was at 40 °C with a flow rate of 1.0 mL/min.

[0378] Liquid Chromatography-Mass Spectrometry Method D: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 1.0 s. The column used was a Shim-pack XR-ODS, 2.2 pm, 3.0 x 50 mm. A linear gradient was applied, starting at 95 % A (A: 0.05% TFA in water) and ending at 100% B

149 (B: 0.05% TFA in MeCN) over 3.2 min with a total run time of 3.6 min. The column température was at 40 °C with a flow rate of 1.0 mL/min.

[0379] Liquid Chromatography-Mass Spectrometry Method E: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 1.0 s. The column used was an Ascentis Express Cl8, 2.7 pm, 3.0 x 50 mm. A linear gradient was applied, starting at 95 % A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 1.8 min with a total run time of 2.0 min. The column température was at 45 °C with a flow rate of 1.5 mL/min.

[0380] Liquid Chromatography-Mass Spectrometry Method F: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 1.0 s. The column used was an Ascentis Express C18, 2.7 pm, 3.0 * 50 mm. A linear gradient was applied, starting at 95 % A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 2.8 min with a total nm time of 3.0 min. The column température was at 45 °C with a flow rate of 1.5 mL/min.

[0381] Liquid Chromatography-Mass Spectrometry Method G: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. Die mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 1.0 s. The column used was a Kinetex EVO, 2.6 pm, 3.0 χ 50 mm.

A linear gradient was applied, starting at 90% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: MeCN) over 1.7 min with a total run time of 2.0 min. The column température was at 40 °C with a flow rate of 1.3 mL/min.

[0382] Liquid Chromatography-Mass Spectrometry Method H: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 1.0 s. The column used was a Kinetex EVO, 2.6 pm, 3.0 x 50 mm. A linear gradient was applied, starting at 90% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: MeCN) over 2.7 min with a total run time of 3.0 min. The column température was at 40 °C with a flow rate of 1.3 mL/min.

150

[0383] Liquid Chromatography-Mass Spectrometry Method I: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a Scan time from 0.5 to 1.0 s. The column used was an Ascentis Express C18, 2.7 pm, 2.1 χ 50 mm. A linear gradient was applied, starting at 90 % A (A: 0.10% formic acid in water) and ending at 100% B (B: 0.10% formic acid in MeCN) over 1.70 min with a total run time of 2.0 min. The column température was at 45 °C with a flow rate of 1.0 mL/min.

[0384] Liquid Chromatography-Mass Spectrometry Method J: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 1.0 s. The column used was an Ascentis Express C18, 2.7 pm, 2.1 χ 50 mm. A linear gradient was applied, starting at 90 % A (A: 0.10% formic acid in water) and ending at 95% B (B: 0.10% formic acid in MeCN) over 2.70 min with a total run time of 3.0 min. The column température was at 45 °C with a flow rate of 1.0 mL/min.

[0385] Liquid Chromatography-Mass Spectrometry Method K: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a Scan time from 0.5 to 1.0 s. The column used was an Ascentis Express C18, 2.7 pm, 3.0 χ 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 1.6 min with a total run time of 2.0 min. The column température was at 40 °C with a flow rate of 1.5 mL/min.

[0386] Liquid Chromatography-Mass Spectrometry Method L: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 1.0 s. The column used was an Ascentis Express Cl8, 2.7 pm, 3.0 χ 50 mm. A linear gradient was applied, starting at 95 % A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 2.6 min with a total nm time of 3.0 min. The column température was at 40 °C with a flow rate of 1.5 mL/min.

[0387] Liquid Chromatography-Mass Spectrometry Method M: LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion

151 source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to L0 s. The column used was an Kinetex XB-C18, 2.6 pm, 3.0 * 50 mm. A linear gradient was applied, starting at 95 % A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 2.8 min with a total run time of 3.0 min. The column température was at 40 °C with a flow rate of 1.5 mL/min.

[0388] Liquid Chromatography-Mass Spectrometry Method N: LCMS analyses were performed on a SHIM ADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or négative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 1.0 s. The column used was an Ascentis Express Cl8, 2.7 pm, 3.0 χ 50 mm. A linear gradient was applied, starting at 95 % A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 1.7 min with a total run time of 2.0 min. The column température was at 40 °C with a flow rate of 1.5 mL/min.

[0389] Liquid Chromatography-Mass Spectrometry Method O: The column used was an Agilent Poroshell HPH-C18, 2.7 pm, 3.0 χ 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 2.7 min with a total run time of 3 min. The column température was at 45 °C with a flow rate of 1.5 mL/min.

[0390] Liquid Chromatography-Mass Spectrometry Method P: The column used was an Ascentis Express Cl8, 3.5 pm, 4.6 χ 50 mm. A linear gradient was applied, starting at 90% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 5.2 min with a total run time of 5.6 min. The column température was at 40 °C with a flow rate of 1.5 mL/min.

[0391] Liquid Chromatography-Mass Spectrometry Method Q: The column used was an Agilent Poroshell HPH-C18, 2.7 pm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 4.7 min with a total run time of 5.0 min. The column température was at 40 °C with a flow rate of 1.5 mL/min.

[0392] Liquid Chromatography-Mass Spectrometry Method R: The column used was an Agilent Poroshell HPH-C18, 2.7 pm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 1.8 min with a total run time of 2.0 min. The column température was at 40 °C with a flow rate of 1.5 mL/min.

[0393] Liquid Chromatography-Mass Spectrometry Method S: The column used was an Ascentis Express C18, 2.7 pm, 3.0 χ 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 1.8 min with a total runtime of2.0 min. The column température was at 40 °C with a flow rate of 1.5 mL/min.

152

[0394] Liquid Chromatography-Mass Spectrometry Method T: The column used was an Ascentis Express C18, 2.7 pm, 3.0 χ 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 2.7 min with a total run time of 3.0 min. The column température was at 40 °C with a flow rate of 1.5 mL/min.

[0395] Liquid Chromatography-Mass Spectrometry Method U: The column used was an Acquity UPLCTM BEH, C18 column (50 χ 2.1mm, 1.7 pm particle size), column température 40 °C, mobile phase: A- 10 mM aqueous ammonium bicarbonate solution adjusted to pH 10 with aqueous ammonia solution/ B- CH3CN, flow rate: 1.0 mL/min, runtime = 2.0 min, gradient: t=0 min 3%B, t= 1.5 min 99.9% B, t = 1.9 min 99.9% B, t= 2.0 min 3% B, stop time 2.0 min. Positive ES 100-1000, Négative ES 100-1000, UV détection DAD 210-350 nm.

[0396] Liquid Chromatography-Mass Spectrometry Method V: The column used was a Shim-pack XR-ODS, 2.2 pm, 3.0 χ 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 4.2 min with a total run time of 5.3 min. The column température was at 40 °C with a flow rate of 1.0 mL/min.

[0397] Liquid Chromatography-Mass Spectrometry Method W: The column used was an Shimpack XR-ODS, 2.2 pm, 3.0 χ 50 mm. A linear gradient was applied, starting at 95 % A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 4.2 min with a total run time of 5.3 min. The column température was at 40 °C with the flow rate of 1.0 mL/min.

[0398] Liquid Chromatography-Mass Spectrometry Method X: The column used was an Ascentis Express C18, 2.7 pm, 3.0 χ 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 95% B (B: 0.05% TFA in MeCN) over 4.1 min with a total run time of 5.3 min. The column température was at 40 °C with the flow rate of 1.5 mL/min.

[0399] Liquid Chromatography-Mass Spectrometry Method Y : The column used was an Poroshell HPH-C18, 2.7 pm, 3.0 χ 50 mm. A linear gradient was applied, starting at 95 % A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 1.8 min with a total run time of 2 min. Tire column température was at 45 °C with the flow rate of 1.5 mL/min.

[0400] HP LC analyses were performed on a SHIMADZU UFLC with two LC20 AD pump and a SPDM20A Photodiiode Array Detector. The column used was an XBridge C18, 3.5 pm, 4.6 χ 100 mm. A linear gradient was applied, starting at 90 % A (A: 0.05% TFA in water) and ending at 95% B (B: 0.05% TFA in MeCN) over 10 min with a total run time of 15 min. The column température was at 40 °C with the flow rate of 1.5 mL/min. The Diode Array Detector was scanned from 200-400 nm.

[0401] Thin layer chromatography (TLC) was performed on Alugram® (Silica gel 60 F254) from Mancherey-Nagel and UV was typically used to visualize the spots. Additional visualization methods were also employed in some cases. In these cases the TLC plate was developed with iodine (generated

153 by adding approximately 1 g of I₂ to 10 g silica gel and thoroughly mixing), ninhydrin (available commercially from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g (ΝΗ4)₆Μθ7θ₂4.4Η₂Ο, 5 g (NH4)₂Ce(IV)(NO₃)ô in 450 mL water and 50 mL concentrated H₂SC>4) to visualize the compound. Flash chromatography was performed using 40-63 μηι (230-400 mesh) silica gel from Silicycle following analogous techniques to those disclosed in Still, W.C.; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923. Typical solvents used for flash chromatography or thin layer chromatography were mixtures of chloroform/methanol, dichloromethane/methanol, ethyl acetate/methanol and hexanes/ethyl acetate.

Analytical Methods

[0402] ’H Nuclear magnetic résonance (NMR) spectroscopy was carried out using a Bruker Avance III equipped with a BBFO 300 MHz probe operating at 300 MHz or one of the following instruments: a Bruker Avance 400 instrument equipped with probe DUAL 400MHz SI, a Bruker Avance 400 instrument equipped with probe 6 SI 400 MHz 5mm 'H-¹³C ID, a Bruker Avance III 400 instrument with nanobay equipped with probe Broadband BBFO 5 mm direct, a Bruker Mercury Plus 400 NMR Spectrometer equipped with a Bruker 400 BBO probe ail operating at 400 MHz. The spectra were acquired in the stated solvent at around room température unless otherwise stated. In ail cases, NMR data were consistent with the proposed structures. Flash chromatography was performed using 40-63 μηι (230-400 mesh) silica gel from Silicycle following analogous techniques to those disclosed in Still, W.C.; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923.

Compound préparation

[0403] Where the préparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Where it is stated that compounds were prepared analogously to earlier examples or intermediates, it will be appreciated by the skilled person that the reaction time, number of équivalents of reagents and température can be modified for each spécifie reaction and that it may be necessary or désirable to employ different work-up or purification techniques. Where reactions are carried out using microwave irradiation, the microwave used is a Biotage Initiator. The actual power supplied varies during tire course of the reaction in order to maintain a constant température.

154

Example 1: 5-BenzyLN-(2-chloro-4-methyI-5-oxo-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-6-yl)-l,2oxazole-3-carboxamide

NH₂OH HCl EtOH

-OH

Step 1

N

Step 2 p₂o₅,

CH₃SO₃H

NCS, DMF

Step 3

ch₃i

Cs₂CO₃

DMF

Step 5

Step 1: Préparation ofN-[4,5,6,7-Tetrahydro-l-benzothiophen-4-ylidene]hydroxylamine

[0404] A solution of hydroxylamine hydrochloride (4.56 g, 65.7 mmol) in 5 N sodium acetate solution (120 mL) was added to a solution of 6,7-dihydro-l-benzothiophen-4(5H)-one (2.00 g, 13.1 mmol) in EtOH (200 mL). The reaction mixture was heated to 100 °C and stirred for 2 h. Volatiles were removed under reduced pressure and the crude product was dissolved in water and extracted with EtOAc. The organic portion was washed with brine, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexaneEtOAc, 100:0 to 50:50) to give the title compound (1.10 g, 51%). ’H NMR (400 MHz, CDCb) δ 7.76-

7.42 (m, 1H), 7.30 (d, J=5.3 Hz, 1H), 7.09 (d, J=5.3 Hz, 1H), 2.89 (t, J=6.1 Hz, 2H), 2.82-2.77 (m, 2H), 2.02 (quin, J=6.3 Hz, 2H). LC-MS (Method A): m/z = 168.0 [M+H]⁺, 0.83 min.

Step 2: Préparation of 4H,5H, 6H, 7H,8H-Thieno[3,2-b]azepin-5-one

[0405] Phosphorus pentoxide (11.3 g, 79.5 mmol) was added to methanesulfonic acid (10.9 g, 113.6 mmol) and the mixture was stirred for 2 h. N-[4,5,6,7-Tetrahydro-l-benzothiophen-4ylidene]hydroxylamine (1.10 g, 6.58 mmol) was then added to the above stirred solution, which had been previously warmed to 100 °C. After stirring for 4 h at 110 °C, the reaction was cooled and

155 quenched carefully by adding sat. NaHCO₃ solution. The mixture was extracted with chloroform. Tire combined organic portions were washed with sat. NaHCOs solution and water, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 80:20 to 0:100) to give the desired compound (450 mg, 41%). ’H NMR (400 MHz, CDC1₃) δ 7.90-7.69 (m, IH), 7.08 (d, <7=5.3 Hz, IH), 6.64 (d, .7=5.3 Hz, IH), 3.00 (t, <7=6.9 Hz, 2H), 2.67-2.60 (m, 2H), 2.26-2.14 (m, 2H).

Step 3: Préparation of2-Chloro-4H,5H,6H, 7H,8H-thieno[3,2-b]azepin-5-one

[0406] A-Chlorosuccinimidc (356 mg, 2.68 mmol) was added to a solution of 4H,5H,6H,7H,8Hthieno[3,2-b]azepin-5-one (450 mg, 2.69 mmol) in DMF (10 mL). The reaction was warmed to 50 °C and stirred at that température for 16 h. The reaction was diluted with EtOAc, washed twice with sat. NH4CI solution, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane/EtOAc, 100:0 to 0:100) to give the title compound (190 mg, 35%). Ή NMR (400 MHz, CDCI3) δ 7.73 (br.s, IH), 6.50 (s, IH), 2.89 (t, <7=6.9 Hz, 2H), 2.66-2.59 (m, 2H), 2.23-2.13 (m, 2H). LC-MS (Method A): m/z = 202.1 [M+H]⁺, 0.84 min.

Step 4: Préparation of 2-Chloro-6-iodo-4H,5H,6H, 7H,8H-thieno[3,2-b]azepin-5-one

[0407] lodotrimethylsilane (264 pL, 0.189 mmol) was added to a solution of 2-chloro4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (190 mg, 0.945 mmol) and TMEDA (430 pL, 22.8 mmol) in CH₂Ci2(3 mL) which had been pre-cooled to -10 °C. The reaction was stirred at -10 °C for 30 min. Powdered iodine (360 mg, 1.42 mmol) was added. The mixture was stirred at -10 °C for 1 h, allowed to reach room température over 1.5 h, stirred for a further 30 min and quenched with 1 M Na2S₂O3 solution. The layers were separated and the aqueous portion was extracted twice with CH2CI2. The combined organic portions were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was triturated with CH2CI2 to yield the title compound (135 mg, 44%). 'H NMR (400 MHz, DMSO-ri₆) δ 10.03 (s, IH), 6.69 (s, IH), 4.99-4.91 (m, IH), 3.15-3.06 (m, IH), 2.95 (ddd, <7=17.4, 11.9, 5.5 Hz, IH), 2.19-208 (m, IH), 1.88 (dddd, <7=14.9, 11.9, 5.1, 2.0 Hz, IH).

Step 5: Préparation of2-Chloro-6-iodo-4-methyl-4H,5H,6H, 7H,8H-thieno[3,2-b]azepin-5-one

[0408] lodomethane (29 pL, 0.460 mmol) was added to a mixture of 2-chloro-6-iodo4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (135 mg, 0.418 mmol) and Cs₂CO₃ (205 mg, 0.627 mmol) in DMF (6 mL). The reaction was stirred at room température for 4 h, cooled to 4 °C and stirred at that température for 36 h. Further iodomethane (29 pL, 0.460 mmol) was added and the mixture was stirred at room température for 5 h. EtOAc was added and the organic portion was washed twice with 0.5 M HCl solution, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane/EtOAc, 100:0 to 50:50) to give the title compound (72 mg, 51%). ’H NMR (400 MHz, DMSO-rig) δ 7.28 (s, IH), 4.82

156 (dd, 7=9.2, 6.7 Hz, IH), 3.17 (s, 3H), 2.90-2.56 (m, 4H). LC-MS (Method A): m/z = 342.0 [M+H]⁺, 1.10 min.

Step 6: Préparation of 6-Azido-2-chloro-4-methyl-4H,5H,6H, 7H,8H-thieno[3,2-b]azepin-5-one

[0409] A mixture of 2-chloro-6-iodo-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (70 mg, 0.205 mmol) and NaN₃ (20 mg, 0.307 mmol) in DMF (2 mL) was stirred at 33 °C for 2 h. EtOAc was added and the organic portion was washed twice with 0.5 M HCl solution, dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (52 mg), which was directly progressed to the next step. ’H NMR (400 MHz, DMSO-ch) δ 7.28 (s, IH), 4.11 (dd, 7=11.7, 7.4 Hz, IH), 3.20 (s, 3H), 2.88-2.77 (m, 2H), 2.53-2.40 (m, IH), 2.28-2.13 (m, IH). LC-MS (Method A): m/z = 257.1 [M+H]⁺, 1.04 min.

Step 7: Préparation of 6-Amino-2-chloro-4-methyl-4H,5H,6H, 7H,8H-thieno[3,2-b]azepin-5-one

[0410] A mixture of 6-azido-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (52 mg) and triphenylphosphine (60 mg, 0.229 mg) in 3:1 THF-H₂O (2 mL) was stirred at room température for 18 h. The reaction was diluted with EtOAc and washed twice with water. The organic portion was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane/EtOAc, 60:40) to afford the title compound (37 mg, 85% purity). ’H NMR (400 MHz, DMSO-7_tf) δ 7.25 (s, IH), 3.37-3.28 (m, IH), 3.16 (s, 3H), 2.71-2.64 (m, 2H), 2.37-2.26 (m, IH), 1.90-1.77 (m, IH), 1.66 (br. s, 2H). LC-MS (Method A): m/z = 231.1 [M+H]⁺, 0.41 min.

Amide Coupling Procedure A

Step 8: Préparation and Séparation of 5-Benzyl-N-(2-chloro-4-methyl-5-oxo-4H,5H, 6H, 7H,8Hthieno[3,2-b]azepin-6-yl) -1,2-oxazole-3-carboxamide

[0411] A solution of 6-amino-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (27 mg, -85% purity), HBTU (39.6 mg, 0.104 mmol), 1-hydroxybenzotriazole (14 mg, 0.104 mmol), DIPEA (45 uL, 0.261 mmol) and 5-benzyl-l,2-oxazole-3-carboxylic acid (19 mg, 0.092 mmol) in DMF (3.5 mL) was stirred at room température for 4 h. EtOAc was added and the organic portion was washed twice with sat. NELCl solution, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane/EtOAc, 100:0 to 50:50) to give the title compound as a mixture of enantiomers. This mixture was resolved by chiral HPLC on a Whelk O-l (R,R) (25 x 2.0 cm), 10 pm column using a mobile phase of nhexane/(EtOH/MeOH/CH₂Cl₂ 45/45/10+0.1% isopropylamine) 20/80% v/v to afford the two title compounds as separated enantiomers.

[0412] First eluting enantiomer, Enantiomer 1: ’H NMR (400 MHz, CDCh) δ 7.76 (d, 7=7.5 Hz, IH), 7.42-7.20 (m, 5H), 6.80 (s, IH), 6.34 (s, IH), 4.81 (dt, 7=11.2, 7.2 Hz, IH), 4.13 (s, 2H), 3.31 (s,

157

3H), 3.02-2.78 (m, 2H), 2.77-2.66 (m, 1H), 2.23-2.09 (m, 1H). LC-MS (Method A): m/z = 416.2 [M+H]⁺, 1.16 min. e.e. >99.5% as determined on a Whelk 0-1 (R,R) (25 x 2.0 cm), 10 pm column using a mobile phase of n-hexane/(EtOH/MeOH/CH2Cl₂ 45/45/10+0.1% isopropylamine) 20/80% v/v.

[0413] Second eluting enantiomer, Enantiomer 2: ’HNMR (400 MHz, CDCL) δ 7.82-7.71 (m, 1H), 7.39-7.23 (m, 5H), 6.80 (s, 1H), 6.34 (s, 1H), 4.81 (dt, 7=11.2, 7.1 Hz, 1H), 4.13 (s, 2H), 3.31 (s, 3H), 3.00-2.78 (m, 2H), 2.76-2.66 (m, 1H), 2.21-2.10 (m, 1H). LC-MS (Method A): m/z = 416.2 [M+H]⁺, 1.16 min. e.e.=98.4% as determined on a Whelk O-l (R,R) (25 x 2.0 cm), 10 pm column using a mobile phase of n-hexane/(EtOH/MeOH/CH₂Cl₂ 45/45/10+0.1% isopropylamine) 20/80% v/v.

Example 2: 5-benzyl-N-(5-fluoro-l-methyl-2-oxo-2,3,4,5-tetrabydro-lH-benzo[b]azepin-3yl)isoxazo!e-3-carboxamide

HATU, DIEA

DMF, rt, 2 h

Step 2

Mel, Cs₂CO₃, DMF rt, 3 h

Step 3

Pd/C, H₂

MeOH, rt, o/n

Step 4

DAST, DCM

0°C, 3h

Step 5

Step 1: Préparation of (2R)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid [0414] Di-tert-butyl dicarbonate (7.19 g, 32.9 mmol) was added to a solution of the sulphate of (2R)-

2-amino-4-(2-aminophenyl)-4-oxobutanoic acid (9.18 g, 29.9 mmol) and triethylamine (12.1 g, 119.6 mmol) in dioxane (50 mL) under nitrogen atmosphère with stirring. The resulting mixture was stirred ovemight at room température. The reaction mixture was concentrated under vacuum to afford the title compound (9.18 g crude). LC-MS (Method C): m/z = 309.1 [M+H]⁺, 1.307 min.

158

Step 2: Préparation of (P)-tert-butyl (2,5-dioxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)carbamate

[0415] 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafhiorophosphate (13.6 g,

35.9 mmol) and ethyldiisopropylamine (11.6 g, 89.7 mmol) were added to a stirred solution of (2R)-4(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid (9.21 g, 29.8 mmol) inN,Ndimethylformamide (50 mL). The resulting solution was stirred for 2 hours at room température. The reaction mixture was diluted with water (50 mL), and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to afford the title compound (2.2 g, 25%). LC-MS (Method C): m/z = 291.1 [M+H]⁺, 1.298 min.

Step 3: Préparation of tert-butyl (l-methyl-2,5-dioxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3yl)carbamate

[0416] lodomethane (1.08 g, 7.60 mmol) was added dropwise to a stirred solution of (R)-tert-butyl (2,5-dioxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)carbamate (2.01 g, 6.89 mmol) and césium carbonate (2.47 g, 7.58 mmol) in N,N-dimethylformamide (20 mL) with stirring. The resulting solution was stirred for 3 hours at room température. Water (10 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to afford the title compound (1.20 g, 57%). LC-MS (Method G): m/z = 305.0 [M+H]j 1.004 min.

Step 4: Préparation of tert-butyl (5-hydroxy-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3yl)carbamate

[0417] tert-Butyl (l-methyl-2,5-dioxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)carbamate (506.0 mg, 1.66 mmol) in methanol (20 mL) was hydrogenated in the presence of 10% palladium on carbon (50.0 mg) under hydrogen atmosphère (2-3 atomospheres). The resulting solution was stirred overnight at room température. The solids were removed by filtration and the filtrate was evaporated under vacuum to afford the title compound (0.5 g crude). LC-MS (Method C): m/z = 307.2 [M+H]⁺, 1.273 min.

Step 5: Préparation of tert-butyl N-[5-fluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-l-benzazepin-3yl]carbamate

[0418] Diethylaminosulfur trifluoride (40.3 mg, 0.25 mmol) was added to a solution of tert-butyl (5hydroxy-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)carbamate (30.6 mg, 0.10 mmol) in dichloromethane (2 mL) under nitrogen atmosphère at 0 °C. The resulting solution was stirred for 3 hours at 0 °C. The reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) and extracted with ethyl acetate (3x5 mL). The combined organic layers were dried over anhydrous sodium

159 sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (25 mg, 81%). LC-MS (Method K): m/z = 208.9 [M-Boc+H]⁺, 0.946 min.

Step 6: Préparation of 3-amino-5-fluoro-l-methyl-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one hydrochloride

[0419] A solution of tert-butyl N-[5-fluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-l-benzazepin-3yljcarbamate (25.0 mg, 0.08 mmol) in 4 N hydrogen chloride in dioxane (2 mL) was stirred for 0.5 hour at room température. The resulting mixture was concentrated under vacuum to afford the title compound (20 mg crude). LC-MS (Method K): m/z = 208.9 [M+H]⁺, 0.555 min

Step 7: Préparation of 5-benzyl-N-(5-fluoro-l -methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3yl) isoxazole-3-carboxamide

[0420] A solution of 5-benzyl-l,2-oxazole-3-carboxylic acid (16.0 mg, 0.08 mmol) in N,Ndimethylformamide (2 mL) was added to a stirred solution of 2-(7-aza-lH-benzotriazole-l-yl)-l,1,3,3tetramethyluronium hexafluorophosphate (45.6 mg, 0.12 mmol), ethyldiisopropylamine (38.7 mg, 0.30 mmol), 3-amino-5-fluoro-l-methyl-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one hydrochloride (20.0 mg, 0.08 mmol) in N,N-dimethylformamide (10 mL). The resulting solution was stirred for 2 hours at room température and then diluted with water (10 mL). The reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 pm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% in 7 min) to afford the title compound. ’H NMR (400 MHz, DMSO-de) δ 8.85 (d, J= 7.6 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.44 - 7.26 (m, 7H), 6.54 (s, 1H),

5.76 (dd, J= 4.4, 48.8 Hz, 1H), 4.52 - 4.45 (m, 1H), 4.22 (s, 2H), 3.25 (s, 3H), 2.74 - 2.71 (m, 1H),

2.66 - 2.61 (m, 1H). LC-MS (Method L): m/z = 394.1 [M+H]⁺, 1.482 min.

Amide Coupling Procedure B

Step 8: Préparation of 5-benzyl-N-(5-fluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3yl)isoxazole-3-carboxamide (first eluting isomer, example 2A) and 5-benzyl-N-(5-fluoro-l-methyl-2-oxo-

2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)isoxazole-3-carboxamide (second eluting isomer example 2B)

160

[0421] 3-Amino-5-fluoro-l-methyl-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (30 mg, 0.140 mmol) was added to a stirring solution of 5-benzyl-l,2-oxazole-3-carboxylic acid (32.3 mg, 0.159 mmol), N,N,N’,N’-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophospate (65.7 mg, 0.173 mmol) and N,N-diisopropylethylamine (55.7 mg, 0.432 mmol) in N,N-dimethylformamide (5 mL). After stirring for 3 hours at room température, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (0.05% TFA) and ACN (45.0% ACN to 70.0% over 7 min); Detector, UV 254/220 nm to afford the title compounds:

[0422] Example 2A, first eluting isomer: 'H NMR (300 MHz, CD₃OD) § 8.53 (d, J= 6.9 Hz, 1H), 7.55-7.50 (m, 1H), 7.50-7.42 (m, 1H), 7.40-7.14 (m, 7H), 6.36 (s, 1H), 5.79-5.28 (m, 1H), 4.73-4.48 (m, 1H), 4.13 (s, 2H), 3.32 (s, 3H), 2.91-2.72 (m, 1H), 2.64-2.40 (m, 1H). LC-MS (Method D): m/z = 394.1 [M+H]⁺, 2.075 min.

[0423] Example 2B, second eluting isomer: ’H NMR (300 MHz, DMSO-î/6) δ 8.84 (d, J= 7.5 Hz, 1H), 7.51-7.39 (m, 4H), 7.38-7.25 (m, 5H), 6.52 (s, 1H), 5.98-5.28 (m, 1H), 4.34-4.25 (m, 1H), 4.21 (s, 2H), 3.29 (s, 3H), 2.91-2.83 (m, 1H), 2.42-2.32 (m, 1H). LC-MS (Method D): m/z = 394.1 [M+H]⁺, 2.164 min.

Example 3: (S)-5-benzyl-N-(l-methyl-5-methyIene-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3yl)isoxazole-3-carboxamide

HATU, DIEA

DMF, rt, 2 h

Step 2

Mel, OS2CO3

DMF, rt, 6 h

Step 3

Step 6

161

Step 1: Préparation of (2S)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid

[0424] Di-tert-butyl dicarbonate (0.96 g, 4.39 mmol) was added to a solution of the sulphate of (2S)-

2-amino-4-(2-aminophenyl)-4-oxobutanoic acid (1.22 g, 4.00 mmol) and triethylamine (1.21 g, 11.98 mmol) in dioxane (10 mL) under nitrogen atmosphère with stirring. The resulting mixture was stirred for 4 hours at room température. The reaction mixture was concentrated under vacuum to afford the title compound (1.22 g crude). LC-MS (Method K): m/z = 309.1 [M+H]⁺, 1.549 min.

Step 2: Préparation of tert-butyl N-[(3S)-2,5-dioxo-2,3,4,5-tetrahydro-lH-l-benzazepin-3-yl]carbamate

[0425] 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (1.82 g, 4.80 mmol) and ethyldiisopropylamine (1.55 g, 11.99 mmol) were added to a stirred solution of (2S)-4(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]anrino]-4-oxobutanoic acid (1.23 g, 4.00 mmol) in N,Ndimethylformamide (10 mL). Tire resulting solution was stirred for 2 hours at room température. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic portions were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (850 mg). LC-MS (Method K): m/z = 291.1 [M+H]⁺, 0.850 min.

Step 3: Préparation of tert-butyl N-[(3S)-l-methyl-2,5-dioxo-2,3,4,5-tetrahydro-lH-l-benzazepin-3yljcarbamate

[0426] lodomethane (118 mg, 0.83 mmol) was added dropwise to a stirred mixture of tert-butyl N[(3S)-2,5-dioxo-2,3,4,5-tetrahydro-lH-l-benzazepin-3-yl]carbamate (220.0 mg, 0.76 mmol) and césium carbonate (272 mg, 0.83 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred for 6 hours at room température before water (10 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (130 mg, 56%). LCMS (Method K): m/z = 305.0 [M+H]⁺, 0.907 min.

Step 4: Préparation of tert-butyl N-[(3S)-l-methyl-5-methylidene-2-oxo-2,3,4,5-tetrahydro-lH-lbenzazepin-3-ylJcarbamate

[0427] A suspension of methyltriphenylphosphonium bromide (382 mg, 1.07 mmol) and sodium hydride (20.0 mg, 0.83 mmol) in tetrahydrofuran (2 mL) was stirred for 1 h at 50 °C under nitrogen atmosphère. Then a solution of tert-butyl N-[(3S)-l-methyl-2,5-dioxo-2,3,4,5-tetrahydro-lH-lbenzazepin-3-yl]carbamate (101.0 mg, 0.33 mmol) in tetrahydrofuran (2 mL) was added drop-wise to the reaction mixture with stirring. The resulting solution was stirred ovemight at room température. The reaction was then quenched by the addition of saturated aqueous ammonium chloride (5 mL). The resulting solution was extracted with ethyl acetate (3x10 mL) and the organic layers were combined,

162 dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to provide the title compound (75 mg, 75%). LC-MS (Method C): m/z = 303.2 [M+H]⁺, 1.531 min.

Step 5: Préparation of (S)-3-amino-l-methyl-5-methylene-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one hydrochloride

[0428] A solution of tert-butyl N-[(3S)-l-methyl-5-methylidene-2-oxo-2,3,4,5-tetrahydro-lH-lbenzazepin-3-yl]carbamate (40.0 mg, 0.13 mmol) in hydrogen chloride in dioxane (4 N, 6 mL) was stirred for 1 hour at room température. The reaction mixture was concentrated under vacuum to afford the title compound (25.2 mg crude). LC-MS (Method C): m/z = 203.2 [M+H]⁺, 0.635 min.

Amide Coupling Procedure C

Step 6: Préparation of (S)-5-benzyl-N-(l-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-lHbenzo[b]azepin-3-yl)isoxazole-3-carboxamide

[0429] A solution of (S)-3-amino-l-methyl-5-methylene-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one hydrochloride (25.4 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was added to a stirred solution of 5-benzyl-l,2-oxazole-3-carboxylic acid (20 mg, 0.10 mmol), 1-hydroxybenzotriazole (16 mg, 0.12 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (23 mg, 0.12 mmol), ethyldiisopropylamine (39 mg, 0.30 mmol) in N,N-dimethylformamide (8 mL). The resulting solution was stirred for 1 hour at room température. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 pm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% in 7 min) to afford the title compound (17.8 mg, 44%) as a white solid. This compound was further purified by chiral HPLC on a Chiralpak AS-H (25 x 2.0 cm), 5 pm column using a mobile phase of n-hexane/(2-propanol/MeOH 1/1+0.1 % isopropylamine) 60/40 % v/v to afford the title compound. Ή NMR (400MHz, CDC1₃) δ 7.87 (d, J=6.8 Hz, 1H), 7.44-7.22 (m, 8H), 7.18 (d, 7=7.8 Hz, 1H), 6.33 (s, 1H), 5.25-5.20 (m, 1H), 5.14-5.08 (m, 1H), 4.91 (td, J=6.9, 12.1 Hz, 1H), 4.13 (s, 2H), 3.55 (tdd, J=2.9, 6.5, 15.7 Hz, 1H), 3.39 (s, 3H), 2.84 (dd, 7=12.0, 15.6 Hz, 1H). LC-MS (Method A): m/z = 388.1 [M+H]\ 1.21 min. e.e. >99.5% as determined on a Chiralpak AS-H (25 x 0.46 cm), 5 pm column using a mobile phase of n-hexane/(2-propanol/MeOH 1/1+0.1 % isopropylamine) 60/40% v/v.

163

Example 4: (S)-l-benzyl-4-chloro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

NOS, DMF rt, o/n

Step 1

1) NaH, THF, 0 °C, 1 h

2) BnBr, rt, 2 h

Step 2

Cl

KOH, MeOH, H₂O rt, o/n

Step 3

Step 1 : Préparation of ethyl 4-chloro-5-methyl-lH-pyrazole-3-carboxylate

[0430] N-Chlorosuccinimide (0.81 g, 5.99 mmol) was added to a solution of ethyl 5-methyl-lHpyrazole-3-carboxylate (1.01 g, 6.49 mmol) in Ν,Ν-dimethylformamide (5 mL). The resulting solution was stirred overnight at room température. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (0.81 g, 65%). LC-MS (Method C): m/z = 230.1 [M+CH₃CN+H]⁺, 1.240 min.

Step 2: Préparation of ethyl l-benzyl-4-chloro-5-methyl-lH-pyrazole-3-carboxylate

[0431] Sodium hydride (108 mg, 4.50 mmol) was added to a solution of ethyl 4-chloro-5-methyl- 1Hpyrazole-3-carboxylate (600 mg, 3.18 mmol) in tetrahydrofuran (3 mL). After stirring for 1 h at 0 °C, benzyl bromide (550 mg, 3.22 mmol) was added. The resulting mixture was stirred for 2 hours at room température. After quenching with water (3 mL), the reaction mixture was extracted with ethyl acetate (2x3 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound (500 mg, 56%). LC-MS (Method E): m/z =278.9 [M+H]⁺, 0.986 min.

164

Step 3: Préparation of l-benzyl-4-chloro-5-methyl-lH-pyrazole-3-carboxylic acid

[0432] Potassium hydroxide (80 mg, 1.43 mmol) was added to a solution of ethyl l-benzyl-4-chloro5-methyl-lH-pyrazole-3-carboxylate (120 mg, 0.43 mmol) in methanol (1.5 mL) and water (0.5 mL). The resuiting solution was stirred overnight at room température. The reaction mixture was concentrated under vacuum and diluted with water (5 mL). 3 N Hydrochloride acid was added to adjust the pH to 3. The resuiting solid was collected by filtration to afford the title compound (110 mg). LCMS (Method F): m/z = 251.0 [M+H]⁺, 1.323 min.

Step 4: Préparation of (S)-l-benzyl-4-chloro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0433] The crude material obtained using Amide Coupling Procedure B was purified by reverse phase chromatography using an Xbridge Prep C18 5 μηι, 19 x 150 mm column; Mobile phase: Phase A: aqueous ammonium bicarbonate (0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to afford the title compound. ’H-NMR (400 MHz, DMSO-rig) δ 8.18 (d, 7=7.9 Hz, 1H), 7.50 (dd, «7=7.6, 1.9 Hz, 1H),

7.43 - 7.14 (m, 8H), 5.46 (s, 2H), 4.83 (dt, 7=11.5, 7.8 Hz, 1H), 4.56 (dd, 7=11.5, 9.8 Hz, 1H), 4.42 (dd, «7=9.8, 7.7 Hz, 1H), 3.32 (s, 3H), 2.20 (s, 3H). LC-MS (Method E); m/z = 425.0 [M+H]⁺, 1.488 min.

Example 5: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole2-carboxamide

(COCI)₂, EtOH

----------------B

DCM, rt, 2 h

NBS, BPO

CCI₄.75°C, 16 h

Step 1 Step 2

Pd(PPh₃)₄, Na₂CO₃toluene, EtOH, 85°C, o/n

LiOH, THF, H₂O rt, 2 h

Step 3

Step 4

EDCI, HOBT, DIEA, DMF rt, 4 h

Step 5

165

Step 1 : Préparation of ethyl 5-methylthiazole-2-carboxylate

[0434] Oxalyl chloride (5 mL, 50.0 mmol) was added to a stirring solution of 5-methylthiazole-2carboxylic acid (1.43 g, 10.0 mmol) in dichloromethane (10 mL). The resulting solution was stirred for 2 hours at room température and concentrated under vacuum. The residue was quenched by the addition of éthanol (50 mL) and concentrated under vacuum. The residue was diluted with water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (1.6 g, 90%) as a white solid. LC-MS (Method E): m/z = 172 [M+H]⁺, 0.607 min.

Step 2: Préparation of ethyl 5-(bromomethyl)thiazole-2-carboxylate

[0435] N-Bromosuccinimide (900 mg, 5.0 mmol) was added to a solution of ethyl 5-methylthiazole2-carboxylate (850 mg, 5.0 mmol) in carbon tetrachloride (20 mL). The reaction was initiated by benzoyl peroxide (1 mg) and then heated at 75 °Cand stirred for 16 hours. The reaction mixture was cooled to 0 °C and the solid was removed by filtration. The filtrate was diluted with water (20 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate, filtered and concentrated under vacuum. Tire residue was purified by column chromatography (ethyl acetate/hexane, 1/20) to afford the title compound (1.0 g, 80%). LC-MS (Method F): m/z = 250, 252 [M+H]⁺, 1.490 min.

Step 3: Préparation of ethyl 5-benzylthiazole-2-carboxylate

[0436] A 50-rnL round-bottomed flask was charged with ethyl 5-(bromomethyl)thiazole-2carboxylate (300 mg, 1.38 mmol), toluene (10 mL), éthanol (5 mL), phenylboronic acid (100 mg, 2.00 mmol) and sodium carbonate (372 mg, 5.52 mmol). The reaction mixture was placed under a nitrogen atmosphère andtetrakis(triphenylphosphine)palladium (147 mg, 0.13 mmol) was added. The resulting solution was stirred at 85 °C overnight under nitrogen atmosphère and was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/hexane, 1/15) to afford the title compound (250 mg, 56%). LC-MS (Method C): m/z = 248 [M+H]⁺, 1.971min.

Step 4: Préparation of 5-benzylthiazole-2-carboxylic acid

[0437] A solution of lithium hydroxide (5.4 mg, 2.02 mmol) in water (3 mL) was added to a solution of ethyl 5-benzylthiazole-2-carboxylate (100 mg, 0.405 mmol) in tetrahydrofuran (9 mL). The resulting solution was stirred for 2 hours at room température and diluted with water (10 mL). The pH value of the solution was adjusted to 3-4 with IN aqueous hydrogen chloride. The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were dried over anhydrous

166 sodium sulfate, filtered and concentrated under vacuum to afford the title compound (80 mg, 76%). LCMS (Method F): m/z =220 [M+H]⁺, 0.790 min.

Step 5: Préparation of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3yl) thlazole-2-carboxamide

[0438] The crude material obtained using Amide Coupling Procedure C was purified by reverse phase chromatography using an Xbridge Prep C18 5 pm, 19 x 150 mm column; Mobile phase: Phase A: aqueous ammonium bicarbonate (0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to afford the title compound. 'H NMR (300 MHz, Chloroform-ri) δ 8.12 (d, J= 7.3 Hz, 1H), 7.62 (s, 1H), 7.41-7.16 (m, 9H), 5.12-4.95 (m, 1H), 4.81-4.69 (m, 1H), 4.37-4.21 (m, 1H), 4.19 (s, 2H), 3.46 (s, 3H). LC-MS (Method D): m/z = 394 [M+H]⁺, 2.232 min.

Example 6: (S)-l-benzyl-4-fluoro-5-methyI-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

Selectfluor

MeCN, 65°C, o/n

Step 1 ,^N'NH 1) NaH, THF, 0°C, 1 h

2) BnBr, rt, 2 h Step 2

Ο

F

KOH, MeOH, H₂O rt, 2 h

HO

F

Step 3

NH₂

HATU, DIEA, DMF rt, 2 h

Step 4

Step 1: Préparation of ethyl 4-fluoro-5-methyl-lH-pyrazole-3-carboxylate

[0439] Selectfluor (3.5 g, 9.9 mmol) was added to a solution of ethyl 5-methyl-lH-pyrazole-3carboxylate (1.01 g, 6.49 mmol) in acetonitrile (10 mL). The resulting solution was stirred ovemight at 65 °C in an oil bath. The reaction mixture was cooled to room température and concentrated under vacuum. The residue was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound (660 mg, 59%). LC-MS (Method E): m/z = 172.9 [M+H] , 0.607 min.

167

Step 2: Préparation of ethyl l-benzyl-4-fluoro-5-methyl-lH-pyrazole-3-carboxylate

[0440] Sodium hydride (118 mg, 4.92 mmol) was added to a solution of ethyl 4-fluoro-5 -methyl- 1Hpyrazole-3-carboxylate (600 mg, 3.49 mmol) in tetrahydrofuran (3 mL). After stirring for 1 hour at 0 °C, benzyl bromide (595 mg, 3.48 mmol) was added. The resulting mixture was stirred for 2 hours at room température. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound (240 mg, 26%). LC-MS (Method C): m/z =263.1 [M+H]⁺, 1.490 min.

Step 3: Préparation of l-benzyl-4-fluoro-5-methyl-lH-pyrazole-3-carboxylic acid

[0441] Potassium hydroxide (80 mg, 1.43 mmol) was added to a solution of ethyl l-benzyl-4-fluoro5-methyl-lH-pyrazole-3-carboxylate (113 mg, 0.43 mmol) in methanol (1.5 mL), and water (0.5 mL). The resulting solution was stirred 2 hours at room température. The resulting mixture was concentrated under vacuum and the residue was diluted with water (1.5 mL). Hydrochloric acid (3N) was added to adjust the pH to 3. The resulting solid was collected by filtration to afford the title compound (110 mg). LC-MS (Method E): m/z = 235.1 [M+H]⁺, 1.257 min.

Step 4: Préparation of (S)-l-benzyl-4fluoro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzojb][1,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0442] The crude material obtained using Arnide Coupling Procedure B was purified by reverse phase chromatography using an Xbridge Prep C18 5 pm 19 x 150 mm column; Mobile phase: Phase A: aqueous ammonium bicarbonate (0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to afford the title compound. ’H-NMR (400 MHz, DMSO-7₆) δ 8.10 (d, J= 8.0 Hz, 1H), 7.50 (dd, 7= 7.6, 2.0 Hz, 1H), 7.43 - 7.20 (m, 6H), 7.20 - 7.13 (m, 2H), 5.39 (s, 2H), 4.83 (dt, 7= 11.4, 7.8 Hz, 1H), 4.56 (dd, J = 11.5, 9.8 Hz, 1H), 4.42 (dd, 7= 9.8, 7.7 Hz, 1H), 3.32 (s, 3H), 2.16 (d, 7= 1.4 Hz, 3H). LC-MS (Method F): m/z = 409.1 [M+H]⁺,1.412 min.

168

Example 7: 5-benzyI-N-((2S)-4-methyI-3-oxo-l,la,2,3,4,8b-hexahydrobenzo[b]cydopropa[d]azepin2-yl)isoxazole-3-carboxamide

O

Step 3

Step 4

Step 1: Préparation of (Z)-tert-butyl (l-methyl-2-oxo-2,3-dihydro-lH-benzo[b]azepin-3-yl)carbamate [0443] To a solution of tert-butyl (5-hydroxy-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-

3-yl)carbamate (918.0 mg, 3.00 mmol) and triethylamine (909.0 mg, 9.00 mmol) in dichloromethane (20 mL) was added dropwise a solution of methanesulfonyl chloride (687 mg, 6.00 mmol) in dichloromethane (2 mL) at 0 °C. After stirring ovemight at room température, the reaction mixture was quenched by the addition of water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. 1,8Diazabicyclo[5.4.0]undec-7-ene was added to the crude solid with stirring. The resuiting solution was stirred for 1 hour at 90 °C. Water (20 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (0.3 g crude). LCMS (Method C): m/z = 289.0 [M+H]⁺, 1.494 min.

Step 2: Préparation of tert-butyl N-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2,4]]dodeca-l (8),9,11 -trien5-yl]carhamate

[0444] A solution of 1 -methyl- 1-nitrosourea (1.073 g, 10.41 mmol) in ether (10 mL) was added to a solution of potassium hydroxide (1.166 g, 20.78 mmol) in water (1.75 mL) dropwise with stirring at 0

169 °C. After stirring for 1 hour at 0 °C, the organic phase was separated to provide a solution of diazomethane (10 mL). To a solution of (Z)-tert-butyl (l-methyl-2-oxo-2,3-dihydro-lH-benzo[b]azepin-

3-yl)carbamate (300.0 mg, 1,04 mmol) in tetrahydrofuran (4 mL) was added the solution of diazomethane (10 ml) with stirring at 0 °C. To this mixture was added a solution of palladium diacetate (23.3 mg, 0.10 mmol) in tetrahydrofuran (1 mL) dropwise with stirring at 0 °C. The resulting mixture was stirred overnight at room température. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (50 mg, 16%). LC-MS (Method N): m/z =

303.1 [M+H]⁺, 1.043 min.

Step 3: Préparation of 5-amino-7-methyl-7-azatricyclo [6.4.0.0-[2, 4]]dodeca-l(8),9,l l-trien-6-one hydrochloride

[0445] A solution of tert-butyl N-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2,4]]dodeca-l(8),9,11-trien5-yl]carbamate (151.0 mg, 0.50 mmol) was treated with 4N hydrogen chloride in dioxane (10 mL) for 1 hour at room température. The reaction mixture was concentrated under vacuum to provide the title compound (50 mg crude). LC-MS (Method C): m/z = 203.1 [M+H]⁺, 1.043 min.

Step 4: Préparation of 5-benzyl-N-((2S)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]c)>clopropa[d]azepin-2-yl)isoxazole-3-carboxamide

[0446] The crude product obtained using Amide Coupling Procedure C was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 pm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% in 7 min) to afford the title compound. 'H NMR (300 MHz, DMSO-ta) δ 8.82 (d, J= 7.5 Hz, 1H), 7.47 (d, 7= 7.5 Hz, 1H), 7.39-7.20 (m, 8H), 6.60 (s, 1H), 4.45 (d, 7=7.5 Hz, lH),4.22(s, 2H), 3.22 (s, 3H), 2.30-2.21 (m, 1H), 1.92-1.84 (m, 1H), 1.081.01 (m, 2H). LC-MS (Method H): m/z = 388.1 [M+H]⁺, 1.700 min.

[0447] This mixture was resolved by chiral HPLC on a Chiralpak IB (25 x 2.0 cm), 5 pm column using a mobile phase of n-hexane/(ethanol/methanol/dichloromethane 45/45/10 + 0.1% isopropylamine) 60/40% v/v with a flow rate of 18 mL/min to afford the two separated enantiomers.

[0448] First eluting enantiomer (6.3 min), Enantiomer 1: Ή NMR (400 MHz, CDCI3) δ 8.13 (d, 7=7.0 Hz, 1H), 7.40-7.16 (m, 8H), 7.10 (dd, 7=7.8, 1,4 Hz, 1H), 6.35 (s, 1H), 4.76 (d, 7=7.2 Hz, 1H), 4.12 (s, 2H), 3.35 (s, 3H), 2.17-2.08 (m, 1H), 2.02 (td, 7=8.7, 4.9 Hz, 1H), 1.22 (q, 7=5.3 Hz, 1H), 1.05 (td,7=8.5, 6.5 Hz, 1H). LC-MS (Method A): m/z = 388.3 [M+H]⁺, 1.17min. e.e>99.9%as determined on a Chiralpak IB (25 x 0.46 cm), 5 pm column using a mobile phase of nhexane/(ethanol/methanol/dichloromethane 45/45/10 + 0.1% isopropylamine) 60/40% v/v with a flow rate of 1 mL/min.

170

[0449] Second eluting enantiomer (7.9 min), Enantiomer 2: ^!H NMR (400 MHz, CDCh) δ 8.14 (d, 7=7.3 Hz, 1H), 7.41-7.17 (m, 8H), 7.12 (dd, 7=7.7, 1.6 Hz, 1H), 6.37 (s, 1H), 4.78 (d, 7=7.0 Hz, 1H),

4.14 (s, 2H), 3.36 (s, 3H), 2.14 (td, 7=9.2, 5.4 Hz, 1H), 2.03 (td, 7=8.7, 5.0 Hz, 1H), 1.23 (q, J=5.3 Hz, 1H), 1.07 (td, 7=8.5, 6.3 Hz, 1H). LC-MS (Method A): m/z = 388.3 [M+H]⁺, 1.17 min. e.e.>99.9% as determined on a Chiralpak IB (25 x 0.46 cm), 5 μηι column using a mobile phase of nhexane/(ethanol/methanol/dichloromethane 45/45/10 + 0.1% isopropylamine) 60/40% v/v with a flow rate of 1 mL/min.

Example 8: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-5-(lphenylcyclopropyI)isoxazole-3-carboxamide

NH₂

1) KOH, Et₂O, 0 °C, 0.5 h

2) Pd(OAc)₂, THF, 0 °C to rt, o/n

Step 1

Step 3

Step 1: Préparation of methyl 5-(l-phenylcyclopropyl)-l,2-oxazole-3-carboxylate

[0450] A solution of 1-methyl-1-nitrosourea (449:8 mg, 4.36 mmol) in ether (10 mL) was added dropwise to a solution of potassium hydroxide (359.1 mg, 6.40 mmol) in water (0.54 mL) with stirring at 0 °C. After stirring for 0.5 hour at 0 °C, the organic phase was separated to provide a solution of diazomethane (10 mL). To a solution of ethyl 5-(l-phenylethenyl)-l,2-oxazole-3-carboxylate (50.0 mg, 0.21 mmol) in tetrahydrofuran (3 mL) was added the solution of diazomethane (10 mL) with stirring at 0 °C followed by the addition of a solution of palladium diacetate (4.7 mg, 0.02 mmol) in tetrahydrofuran (1 mL) dropwise with stirring at 0 °C. Tire resulting solution was stirred ovemight at room température. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (30 mg, 57%) as a yellow solid. LC-MS (Method C): m/z = 244.0 [M+H]⁺, 1.519 min.

171

Step 2: Préparation of 5-(l-phenylcyclopropyl)-l,2-oxazole-3-carboxylic acid

[0451] A solution of methyl 5-(l-phenylcyclopropyl)-l,2-oxazole-3-carboxylate (25.0 mg, 0.10 mmol) and lithium hydroxide (4.8 mg, 0.20 mmol) in methanol/water = 3/1 (2 mL) was stirred for 2 hours at room température. The pH value of the solution was adjusted to 6-7 with IN hydrochloric acid. The resulting solution was extracted with ethyl acetate (3x10 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (20 mg crude). LC-MS (Method G): m/z = 230 [M+H]⁺, 0.700 min.

Step 3: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)isoxazole-3-carboxamide

[0452] The crude product obtained using Amide Coupling Procedure B was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 pm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% in 7 min) to afford the title compound. ’H NMR (300 MHz, DMSO-ri₆) δ 8.82 (d, J= 8.1 Hz, 1H), 7.52 - 7.48 (m, 1H), 7.38 - 7.25 (m, 7H),

7.24 - 7.20 (m, 1H), 6.36 (s, 1H), 4.87 - 4.77 (m, 1H), 4.55 (dd, J= 9.9, 11.7 Hz, 1H), 4.38 (dd, J = 8.1, 9.9 Hz, 1H), 3.30 (s, 3H), 1.57 - 1.52 (m, 2H), 1.45 - 1.41 (m, 2H). LC-MS (Method H): m/z =

404.2 [M+H]⁺, 1.766 min.

Example 9: (S)-5-benzyl-N-(l-methyI-2-oxo-l,2,3,4-tetrahydrospiro[benzo[b]azepine-5,l’cyclopropan]-3-yi)isoxazoIe-3-carboxamide

Step 1: Préparation of tert-butyl N-[(3S)-l-methyl-2-oxo-l, 2,3,4-tetrahydrospiro[l-benzazepine-5,lcyclopropaneJ-3-ylJcarbamate

[0453] A solution of 1-methyl-1-nitrosourea (255.8 mg, 2.48 mmol) in ether (10 mL) was added dropwise to a solution of potassium hydroxide (278 mg, 4.96 mmol) in water (0.4 mL) with stirring at 0 °C. After stirring for 0.5 hour at 0 °C, the organic phase was separated to provide a solution of

172 diazomethane (10 mL). To a solution of tert-butyl N-[(3R)-l-methyl-2-oxo-2,3-dihydro-lH-lbenzazepin-3-yl]carbamate (75.0 mg, 0.25 mmol) in tetrahydrofuran (1.5 mL) was added the solution of diazomethane (10 mL) dropwise followed by the addition of a solution of palladium diacetate (5.5 mg, 0.02 mmol) in tetrahydrofuran (0.5 mL) dropwise with stirring at 0 °C. The resulting solution was stirred overnight at room température. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (55 mg, 70%). LC-MS (Method C): m/z =

317.2 [M+H]⁺, 1.531 min.

Step 2: Préparation of (3S)-3-amino-l-methyl-l,2,3,4-tetrahydrospiro[l-benzazepine-5,l-cyclopropane]-

2- one hydrochloride

[0454] tert-Butyl N-[(3 S)-1 -methyl-2-oxo-1,2,3,4-tetrahydrospiro[ 1 -benzazepine-5,1 -cyclopropane]-

3- yl]carbamate (40.0 mg, 0.13 mmol) was treated with 4N hydrogen chloride in dioxane (6 mL) for 1 hour at room température. The resulting mixture was concentrated under vacuum to afford the title compound (25.2 mg) as a yellow solid. LC-MS (Method K): m/z = 217.2 [M+H]⁺, 0.635 min.

Step 3: Préparation of (S)-5-benzyl-N-(l-methyl-2-oxo-l,2,3,4-tetrahydrospiro[benzo[b]azepine-5,l cyclopropan]-3-yl)isoxazole-3-carboxamide

[0455] The crude product obtained using Amide Coupling Procedure C was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 pm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50% to 70% in 7 min) to afford the title compound (17.8 mg, 44%) as a white solid. This compound was further purified by chiral HPLC on a Chiralpak AS-H (25 x 2.0 cm), 5 pm column using a mobile phase of n-hexane/(2-propanol/MeOH 1/1+0.1 % isopropylamine) 60/40 % v/v to afford the title compound. H NMR (400 MHz, CDCI3) 5 7.78 (d, J=7.0Hz, 1H), 7.39-7.19 (m, 9H), 6.31 (s, 1H), 4.69 (td, J=7.6, 10.9 Hz, 1H),4.11 (s, 2H), 3.43 (s, 3H), 3.13 (dd, J=12.3, 8.3 Hz, 1H), 1.33 (dd, J=12.5, 11.0 Hz, 1H), 1.16-1.08 (m, 1H), 0.88 (ddd, J=9.3, 5.5, 4.3 Hz, 1H), 0.71 (td, J=5.5, 9.3 Hz, 1H), 0.51-0.42 (m, 1H). LC-MS (Method A): m/z =

402.2 [M+H]⁺, 1.21 min. e.e. >99.5% as determined on a Chiralpak AS-H (25 x 0.46 cm), 5 pm column using a mobile phase of n-hexane/(2-propanol/MeOH 1/1+0.1 % isopropylamine) 60/40 % v/v.

Example 10: 5-benzyI-N-(5,5-difluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)4H-1,2,4-triazole-3-car boxamide

173

Step 3

Step 1: Préparation of tert-butyl (5,5-difluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-l-benzazepin-3yl)carbamate

[0456] A solution of tert-butyl (l-methyl-2,5-dioxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3yl)carbamate (200 mg, 0.658 mmol) in bis(2-methoxyethyl)aminosulfur trifluoride (6 mL) was heated to 65 °C and stirred ovemight. Tire reaction mixture was allowed to cool to ambient température, quenched with water (30 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/hexane, 1/20) to afford the title compound (60 mg, 30%). LC-MS (Method E): m/z = 327 [M+H]⁺, 1.035 min.

Step 2: Préparation of 3-amino-5,5-difluoro-l-methyl-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one

[0457] tert-Butyl (5,5-difluoro-1 -methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)carbamate (40 mg, 0.184 mmol) was added to a solution of (4N) hydrogen chloride in 1,4-dioxane (30 mL). The resulting solution was stirred for 2 hours at ambient température and concentrated under vacuum to afford the title compound (50 mg crude) as a yellow solid. LC-MS (Method N): m/z =227 [M+H]⁺, 0.995 min.

Step 3: Préparation of 5-benzyl-N-(5,5-diftuoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-

3-yl)-4H-1,2,4-triazole-3-carboxamide

[0458] The crude product obtained using Amide Coupling Procedure C was purified by reverse phase chromatography using an Xbridge Prep C18 5 pm, 19 x 150 mm column; Mobile phase: Phase A: aqueous ammonium bicarbonate (0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to afford the title compound. 'H NMR (400 MHz, DMSO-rie) δ 14.25 (s, 1H), 8.59 (s, 1H), 7.63 (m 3H), 7.44 (t, J=

7.5 Hz, 1H), 7.35 - 7.18 (m, 5H), 4.52 (dt, J= 11.8, 7.8 Hz, 1H), 4.10 (s, 2H), 3.26 (s, 3H), 3.15 - 2.81 (m, 2H). LC-MS (Method L): m/z = 412.1 [M+H|\ 1.309 min.

Example 11 and 12: 5-benzyl-N-((3S,5R)-5-fluoro-l-methyI-2-oxo-2,3,4,5-tetrahydro-lHbenzo[b]azepin-3-yl)-4H-l,2,4-triazole-3-carboxamide and 5-benzyI-N-((3R,5S)-5-fluoro-l-methyI2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yI)-4H-l,2,4-triazoIe-3-carboxamide (Example 11) and 5-benzyl-N-((3S,5S)-5-fluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H

174 l,2,4-triazoIe-3-carboxamide and 5-benzyl-N-((3R,5R)-5-fluoro-l-methyl-2-oxo-2,3,4,5-tetrahydrolH-benzo[b]azepin-3-yl)-4H-l,2,4-triazo!e-3-carboxamide (Example 12)

Second eluting isomer

Example 12

[0459] The crude product obtained using Amide Coupling Procedure A was purified by reverse phase column chromatography using an Xbridge Phenyl OBD 5 pm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (25.0% to 55.0% in 7 min) to afford the title compounds:

[0460] Example 11, first eluting isomer: ’H NMR (400 MHz, DMSO-de) δ 14.41 (s, 1H), 8.41 (s, 1H), 7.65-7.49 (m, 2H), 7.45 (dt, J= Ί.Ί, 1.7 Hz, 1H), 7.40 - 7.20 (m, 6H), 5.76 (dd, J= 47.0, 4.8 Hz, 1H), 4.47 (dt, J= 11.4, 7.5 Hz, 1H), 4.12 (s, 2H), 3.27 (s, 3H), 2.94 - 2.56 (m, 2H). LC-MS (Method F): m/z = 394.1 [M+H]⁺, 1.085 min.

[0461] Example 12, second eluting isomer: ’H NMR (400 MHz, DMSO-t/e) δ 14.37 (s, 1H), 8.41 (s, 1H), 7.58 - 7.38 (m, 4H), 7.38 - 7.20 (m, 5H), 5.92 (ddd, J= 46.6, 10.5, 8.1 Hz, 1H), 4.30 (dt, J= 11.4,

7.9 Hz, 1H), 4.12 (s, 2H), 3.31 (s, 3H), 2.96-2.78 (m, 1H), 2.41 - 2.30 (m, 1H). LC-MS (Method F): m/z = 394.1 [M+H]⁺, 1.156 min.

Example 11: Chiral séparation

[0462] This mixture was resolved by chiral HPLC on a Whelk O-l (R,R) (25 x 2.0 cm), 10 pm column using a mobile phase of n-hexane/(ethanol + 0.1% isopropylamine) 30/70% v/v with a flow rate of 18 mL/min to afford the two separated enantiomers.

[0463] First eluting enantiomer (6.8 min), Enantiomer 1: ’H NMR (400 MHz, CDCI3) δ 8.27 (d, J=6.8 Hz, 1H), 7.35 (m, 9H), 5.51 (m, 1H), 4.74 (dt, J=11.0, 7.1 Hz, 1H), 4.15 (s, 2H), 3.41 (s, 3H), 3.07 (m, 1H), 2.44 (m, 1H). LC-MS (Method A): m/z = 394.3 [M+H]⁺, 0.87 min. e.e>99.9% as determined on a Whelk O-l (R,R) (25 x 0.46 cm), 5 pm column using a mobile phase of nhexane/(ethanol + 0.1% isopropylamine) 30/70% v/v with a flow rate of 1 mL/min.

175

[0464] Second eluting enantiomer (8.9 min), Enantiomer 2: ^!H NMR (400 MHz, CDCI3) δ 8.27 (d, J=6.8 Hz, 1H), 7.35 (m, 9H), 5.51 (m, 1H), 4.74 (dt, J=11.0, 7.1 Hz, 1H), 4.15 (s, 2H), 3.41 (s, 3H), 3.07 (m, 1H), 2.44 (m, 1H). LC-MS (Method A): m/z = 394.3 [M+H]⁺, 0.86 min. e.e.>99.9% as determined on a Whelk O-l (R.R) (25 x 0.46 cm), 5 pm column using a mobile phase of nhexane/(ethanol + 0.1% isopropylamine) 30/70% v/v with a flow rate of 1 mL/min.

Example 12: Chiral séparation

[0465] This mixture was resolved by chiral HPLC on a Chiralcel OJ-H (25 x 2.0 cm), 5 pm column using a mobile phase of n-hexanc/(cthanol/mcthanol 1/1 + 0.1% isopropylamine) 30/70% v/v with a flow rate of 18 mL/min to afford the two separated enantiomers.

[0466] First eluting enantiomer (4.8 min), Enantiomer L ^]H NMR (400 MHz, CDCls) δ 8.14 (d, J=6.1 Hz, 1H), 7.62-7.14 (m, 9H), 5.87-5.64 (m, 1H), 4.67-4.54 (m, 1H), 4.17 (s, 2H), 3.44 (s, 3H), 3.03-2.85 (m, 1H), 2.66-2.53 (m, 1H). LC-MS (Method U): m/z = 394.2 [M+HR, 0.75 min. e.e>99.9%as determined on a Chiralcel OJ-H (25 x 0.46 cm), 5 pm column using a mobile phase of nhexane/(ethanol/methanol 1/1 +0.1% isopropylamine) 50/50% v/v with a flow rate of 1 mL/min.

[0467] Second eluting enantiomer (7.0 min), Enantiomer 2: 'H NMR (400 MHz, CDC1₃) δ 8.14 (d, J=6.3 Hz, 1H), 7.62-7.15 (m, 10H), 5.86-5.63 (m, 1H), 4.66-4.53 (m, 1H), 4.12 (s, 2H), 3.42 (s, 3H), 3.00-2.82 (m, 1H), 2.64-2.52 (m, 1H). LC-MS (Method U): m/z = 394.2 [M+H]⁺, 0.74 min. e.e>99.9% as determined on a Chiralcel OJ-H (25 x 0.46 cm), 5 pm column using a mobile phase of nhexane/(ethanol/methanol 1/1 + 0.1% isopropylamine) 50/50% v/v with a flow rate of 1 mL/min.

Example 13: (R)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-4-phenyl5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxamide

o-xylene

125°C, o/n

Step 3

OEt

176

KOH

MeOH, H₂O rt, o/n

HATU, DIEA, DMF rt, 2 h

Step 5

Step 1: Préparation of (2S,3R)-l-nitroso-3-phenylpyrrolidine-2-carboxylic acid

[0468] (2S,3R)-3-phenylpyrrolidine-2-carboxylic acid (1.01 g, 5.23 mmol) was added to a solution of sodium nitrite (800 mg, 11.59 mmol) in water (5 mL). Concentrated hydrochloric acid (5 mL) was added at 0 °C. The reaction mixture was stirred overnight at room température, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (700 mg crude). LC-MS (Method I): m/z = 220.95[M+H]⁺, 0.741 min.

Step 2: Préparation of (R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[l,2c][l,2,3]oxadiazol-7-ium-3aide

[0469] To a solution of (2S,3R)-l-nitroso-3-phenylpyrrolidine-2-carboxylic acid (700 mg, 3.18 mmol) in ether (7 mL) at 0 °C was added trifluoroacetic anhydride (1.01 g, 4.76 mmol) dropwise. The resulting solution was stirred for 2 hours at room température. The reaction mixture was concentrated under vacuum and diluted with water (50 mL). The pH value of the solution was adjusted to 8 with potassium carbonate (0.5 M). The resulting solution was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1:1) to afford the title compound (380 mg, 59%) d. LC-MS (Method I): m/z = 202.9 [M+H]⁺, 0.725 min.

Step 3: Préparation of ethyl (4R)-4-phenyl-4H,5H,6H-pyrrolo[l,2-b]pyrazole-3-carboxylate

[0470] To a solution of (R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[l,2-c][l,2,3]oxadiazol-7-ium3a-ide (380 mg, 1.88 mmol) in o-xylene (6 mL), purged and maintained with an inert atmosphère of nitrogen, was added ethyl prop-2-ynoate (240 mg, 2.45 mmol) dropwise. The resulting solution was stirred overnight at 125 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1:1) to afford the title compound (100 mg, 21%). LC-MS (Method J): m/z = 257.1 [M+H]⁺, 1.367 min.

177

Step 4: Préparation of (4R)-4-phenyl-4H,5H,6H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid

[0471] To a solution of ethyl (4R)-4-phenyl-4H,5H,6H-pyrrolo[l,2-b]pyrazole-2-carboxylate (100 mg, 0.39 mmol) in methanol (2.1 mL) and water (0.7 mL) was added potassium hydroxide (67 mg, 1.19 mmol). The resulting solution was stirred overnight at room température, concentrated under vacuum and the resulting residue was diluted with water. The pH value of the solution was adjusted to 3 with 3N hydrochloric acid. The resulting solid was collected by filtration to afford the title compound (80 mg, 90%). LC-MS (Method I): m/z = 228.9 [M+H]⁺, 0.804 min.

Step 5: Préparation of (R)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4phenyl-5,6-dihydro-4H-pyrrolo[l, 2-b]pyrazole-2-carboxamide

[0472] The crude product obtained using Amide Coupling Procedure B was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 pm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (25.0% to 55.0% in 7 min) to afford the title compound. ’H-NMR (400 MHz, DMSOY) δ 8.12 (d, 7=8.1 Hz, 1H), 7.51 (dd, 7=7.5, 1.9 Hz, 1H), 7.39 - 7.20 (m, 8H), 6.32 (d, 7=0.9 Hz, 1H), 4.84 (dt, J=11.5, 7.9 Hz, 1H), 4.61 - 4.48 (m, 2H), 4.45 - 4.31 (m, 2H), 4.22 (dt, 7=11.0, 7.7 Hz, 1H), 3.32 (s, 3H), 3.09 (dtd, 7=12.7, 8.3, 4.2 Hz, 1H), 2.51 - 2.41 (m, 1H). LC-MS (Method J): m/z = 403.2 [M+H]⁺, 1.499 min.

Example 14: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-5-(2,2,2trifluoroethyI)isoxazoIe-3-carboxamide

Step 1: Préparation of methyl 5-(bromomethyl)isoxazole-3-carboxylate

[0473] To a solution of methyl 5-methylisoxazole-3-carboxylate (4.65 g, 30 mmol) and Nbromosuccinimide in carbon tetrachloride (250 mL) was added benzoyl peroxide (2 mg, 0.1 mol%). The resulting mixture was refhixed at 80 °C for 24 hours. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl

178 acetate/hexane, 1/5) to afford the title compound (1.6 g, 23%) as a white solid. LC-MS (Method C): m/z = 221.7 [M+H]⁺, 0.746 min.

Step 2: Préparation of methyl 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylate

[0474] To a mixture of methyl 5-(bromomethyl)isoxazole-3-carboxylate (350 mg, 1.59 mmol) and cuprous iodide (570 mg, 3.00 mmol) in N,N-dimethylformamide (10 mL) was added methyl 2,2difhioro-2-(fluorosulfonyl)acetate (1.44 g, 7.50 mmol). The resulting mixture was heated at 100 °C for 20 hours. After cooling to room température, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/hexane, 1/5) to afford the title compound (125 mg, 37%) as a yellow solid. LC-MS (Method C): m/z = 209.9 [M+H]⁺, 0.788 min.

Step 3: Préparation of 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylic acid

[0475] To a solution of methyl 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylate (90 mg, 0.43 mmol) in 4:1 ΤΗΓ Η2Ο (2.5 mL) was added lithium hydroxide (72 mg, 3 mmol). The resulting solution was stirred for 40 min at room température. After completion of the reaction the solvent was evaporated under reduced pressure and to the resulting residue was added water (25 mL). This solution was washed with ethyl acetate (3x50 mL). The aqueous layer was acidified with IN hydrochloric acid to pH~3-4, and extracted with ethyl acetate (3 x 20 mL). The combined organic phases from this extraction were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (43 mg crude), which was used directly for the next step without further purification. LC-MS (Method D): m/z = 196.9 [M+H]⁺, 0.290 min.

Step 4: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5-(2,2,2trifluoroethyl)isoxazole-3-carboxamide

[0476] The crude product obtained using Amide Coupling Procedure C was purified by crystallization (ethanol//7-hcxanc) to afford the title compound. ’H NMR (300 MHz, Chloroform-7) δ 7.80 (d, 7= 7.0 Hz, IH), 7.26 - 7.19 (m, 4H), 6.71 (s, IH), 5.04 (dt, 7= 11.1, 7.1 Hz, IH), 4.76 (dd, 7 = 9.8, 7.4 Hz, IH), 4.28 (dd, 7= 11.1, 9.7 Hz, IH), 3.69 (q, 7= 9.7 Hz, 2H), 3.46 (s, 3H). LC-MS (Method E): m/z = 370.2 [M+H]⁺, 2.462 min.

Example 15: 5-benzyI-N-(6,7,8,9-tetrahydro-5H-benzo[7] annulen-7-yl)isoxazole-3-carboxamide

179

[0477] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford the title compound. ’H NMR (300 MHz, DMSO-î/ô) δ 8.63 (d, J = 8.4 Hz, IH), 7.257.14 (m, 5H), 7.15-7.07 (m, 4H), 6.52 (s, IH), 4.19 (s, 2H), 4.17-4.04 (m, IH), 2.89-2.69 (m, 4H), 2.021.97 (m, 2H), 1.43-1.23 (m, 2H). LC-MS (Method F): m/z = 347.1 [M+H]⁺, 1.652 min.

Example 16: (S)-l-benzyI-3-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3yl)-lH-pyrazole-5-carboxamide

Step 3

Step 1: Préparation of ethyl l-benzyl-3-methyl-lH-pyrazole-5-carboxylate

[0478] To a solution of ethyl 2,4-dioxopentanoate (0.5 g, 3.20 mmol) and benzylhydrazine hydrochloride (0.75 g, 3.84 mmol) in éthanol (10 mL) was added N,N-diisopropylethylamine (1.2 g, 9.60 mmol). After stirring ovemight at room température, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound (0.5 g, 65%) as a yellow oil. LC-MS (Method S): m/z = 245.2 [M+H]⁺, 1.070 min.

Step 2: Préparation of l-benzyl-3-methyl-lH-pyrazole-5-carboxylic acid

[0479] A solution of sodium hydroxide (0.25 g, 6.02 mmol) in water (1 mL) was added to a stirred solution of ethvl l-benzyl-3-methyl-lH-pyrazole-5-carboxylate (0.5 g, 2.01 mmol) in éthanol (2 mL). The resuiting mixture was stirred ovemight at 80 °C. After cooling to room température, the reaction mixture was adjusted to pH=3-4 with aqueous hydrochloric acid (1 N, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (0.4 g, 90%) as a

180 white solid, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 217.2 [M+H]⁺, 1.219 min.

Step 3: Préparation of (S)-l-benzyl-3-methyl-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzofb] [l,4]oxazepin-3-yl)-lH-pyrazole-5-carboxamide

[0480] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSO-ûk) δ 8.68 (d, J= 8.4 Hz, 1H), 7.537.47 (m, 1H), 7.35-7.19 (m, 6H), 7.11-7.07 (m, 2H), 6.82 (s, 1H), 5.64-5.51 (m, 2H), 4.88-4.81 (m, 1H), 4.55-4.49 (m, 1H), 4.40-4.35 (m, 1H), 3.30 (s, 3H), 2.20 (s, 3H). LC-MS (Method L): m/z = 391.1 [M+H]⁺, 1.437 min.

Example 17: (R)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-4-phenyl5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-3-carboxamide

Step 1

HATU, DIEA, DMF rt, 2 h

Step 3

Step 1: Préparation of ethyl (4R)-4-phenyl-4H,5H,6H-pyrrolo[l,2-b]pyrazole-3-carboxylate

[0481] To a stirring solution of (R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[l,2-c][l,2,3]oxadiazol7-ium-3a-ide (380 mg, 1.88 mmol) in o-xylene (6 mL) under nitrogen atmosphère was added ethyl prop2-ynoate (240 mg, 2.45 mmol). The resuiting mixture was heated to 125 °C and stirred overnight in an oil bath. The reaction mixture was cooled to rt, concentrated under reduced pressure and the resuiting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound (120 mg, 25%) as a light yellow oil. LC-MS (Method J): m/z = 257.0 [M+H]⁺, 1.323 min.

181

Step 2: Préparation of (4R)-4-phenyl-4H,5H,6H-pyrrolo[l,2-b]pyrazole-3-carboxylic acid

[0482] A solution of potassium hydroxide (67 mg, 1.19 mmol) in water (7 mL) was added to a solution of ethyl (4R)-4-phenyl-4H,5H,6H-pyrrolo[l,2-b]pyrazole-3-carboxylate (100 mg, 0.39 mmol) in methanol (2.1 mL). After stirring ovemight at room température, the reaction mixture was concentrated under reduced pressure and diluted with water. The pH value of the solution was adjusted to 3 with hydrochloric acid (3 N, 20 mL). The precipitate was collected by filtration to afford the title compound (50 mg, 47%) as a yellow solid. LC-MS (Method I): m/z = 228.9 [M+H]¹', 0.738 min.

Step 3: Préparation of (R)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrakydrobenzo[b][l,4]oxazepm-3-yl)-4phenyl-5,6-dihydro-4H-pyrrolo[l, 2-b]pyrazole-3-carboxamide

[0483] The crude product obtained using Amide Coupling Procedure B was purified by préparative HPLC with the following conditions: Column, Xbridge Phenyl OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (25.0% ACN to 55.0% over 7 min); Detector, UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSO-rie) δ 8.02 (s, IH), 7.79 (d, 7= 8.8 Hz, IH), 7.44 (dd, 7= 7.6, 2.0 Hz, IH), 7.34-7.14 (m, 6H), 7.10-7.02 (m, 2H), 4.77-4.58 (m, 2H), 4.35-4.23 (m, IH), 4.22-4.03 (m, 3H), 3.26 (s, 3H), 3.19-3.05 (m, IH), 2.39 (dq, 7= 8.8, 4.3 Hz, IH). LC-MS (Method O): m/z = 403.0 [M+H]⁺, 1.334 min.

Example 18: (S)-N-benzyl-2-((5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3yl)amino)acetamide

[0484] A mixture of (3S)-3-amino-5-methyl-2,3,4,5-tetrahydro-l,5-benzoxazepin-4-one hydrochloride (40 mg, 0.175 mmol, e.e.=90%), N-benzyl-2-chloroacetamide (18 mg, 0.097 mmol), K2CO3 (27 mg, 0.195 mmol), and Kl (32 mg, 0.195 mmol) in DMF (3 mL) was stirred at 30 °C for 16 h. The mixture was diluted with EtOAc and washed twice with sat. NH4CI solution. The aqueous portion was extracted with EtOAc. The combined organic portions were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 80:20 to 0:100) to afford the title compound. ’H NMR (400 MHz, CDCI3) δ 7.46-7.08 (m, 10H), 4.514.37 (m, 2H), 4.33 (dd, 7=10.2, 7.4 Hz, IH), 4.12 (t, 7=10.8 Hz, IH), 3.61-3.43 (m, 3H), 3.41 (s, 3H), 3.06-2.97 (m, IH). LC-MS (Method A): m/z = 340.0 [M+H]⁺, 0.70 min. e.e. = 88% as determined on a Chiralcel OD-H (25 x 0.46 cm), 5 pm column using a mobile phase of n-hexane/(ethanol+0.1% isopropylamine) 35/65% v/v.

182

Example 19: (S)-5-benzyl-N-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)isoxazole3-carboxamide

step 1 step 2

HATU, DMF, DIEA rt, 3h step 3

Step 1: Préparation of tert-butyl N-((3S)-5-ethyl-4-oxo-2,3,4,5-tetrahydro-l,5-benzoxazepin-3yljcarbamate

[0485] Sodium hydride (8.64 mg, 0.22 mmol) was added to a stirring solution of tert-butyl N-((3S)-4oxo-2,3,4,5-tetrahydro-l,5-benzoxazepin-3-yl)carbamate (50 mg, 0.18 mmol) inN,Ndimethylformamide (5 mL). The resulting mixture was stirred for 1 hour at room température. lodoethane (33.7 mg, 0.21 mmol) was added dropwise. After stirring for 3 hours at room température, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (40 mg, 73%) as a yellow solid. LC-MS (Method S): m/z = 307.2 [M+H]⁺, 1.021 min.

Step 2: Préparation of (3S)-3-amino-5-ethyl-2,3,4,5-tetrahydro-l,5-benzoxazepin-4-one hydrochloride

[0486] tert-Butyl N-((3S)-5-ethyl-4-oxo-2,3,4,5-tetrahydro-l,5-benzoxazepin-3-yl)carbamate (40 mg, 0.13 mmol) was added to a solution of hydrogen chloride in dioxane (4M, 10 mL). The reaction mixture was stirred for 3 hours at room température and concentrated under reduced pressure to afford the title compound (30 mg) as a white solid, which was used directly in the next step without further purification. LC-MS (Method D): m/z = 207.1 [M+H]⁺, 0.930 min.

Step 3: Préparation of (S)-5-benzyl-N-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3yl) isoxazole-3-carboxamide

[0487] The crude product obtained using Amide Coupling Procedure B was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm: mobile phase, water (0.05%TFA) and ACN (45.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to

183 afford the title compounds. ’H NMR (300 MHz, DMSO-i/e) δ 8.82 (d, J= 7.8 Hz, 1H), 7.54-7.51 (m,

1H), 7.38-7.21 (m, 8H), 6.54 (s, 1H), 4.84-4.75 (m, 1H), 4.56 (t, J= 11.4 Hz, 1H), 4.39-4.33 (m, 1H),

4.21 (s, 2H), 4.10-4.03 (m, 1H), 3.67-3.60 (m, 1H), 1.02 (t, J= 7.2 Hz, 3H). LC-MS (Method D): m/z =

392.2 [M+H]⁺, 2.181 min.

Example 20: 5-benzyl-N-(l-methyI-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H-l,2,4-triazole-3carboxamide

[0488] Borane tetrahydrofuran complex (IM solution in THF, 570 pL, 0.570 mmol) was added dropwise to a solution of 3-amino-l-methyl-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (50 mg, 0.26 mmol) in THF (1 mL) which had been pre-cooled to 0 °C. Tire reaction was allowed to gradually warm to room température and stirred for 18 h before being quenched with IM HCl solution. The resulting mixture was stirred at room température for 3 h. Volatiles were removed under reduced pressure. The crude product was purified by ion exchange chromatography on an SCX cartridge (MeOH then 7M NH₃in MeOH) to afford the title compound. ’H NMR (400 MHz, DMSO-rfs) δ 7.14-7.02 (m, 2H), 6.93-6.85 (m, 1H), 6.84-6.74 (m, 1H), 3.10-2.85 (m, 2H), 2.84-2.68 (m, 4H), 2.66-2.54 (m, 1H), 2.48-2.36 (m, 1H), 1.89-1.77 (m, 1H), 1.75-1.55 (m, 2H), 1.33-1.06 (m, 1H). LC-MS (Method A): m/z = 177.2 [M+H]⁺, 0.40 min.

[0489] The crude product obtained using Amide Coupling Procedure C was purified by column chromatography (CThCL-McOH, 95:5 to 80:20) and then by reverse phase chromatography (waterCH₃CN, 100:0 to 50:50) to afford the title compound as a mixture of enantiomers. ’H NMR (400 MHz, DMSOX) δ 14.61-14.37 (m, 1H), 8.37-8.25 (m, 1H), 7.35-7.10 (m, 7H), 6.99-6.93 (m, 1H), 6.85 (td, J=7.3, 1.1 Hz, 1H), 4.19-4.11 (m, 1H), 4.08 (s, 2H), 3.05-2.98 (m, 1H), 2.84 (s, 3H), 2.81-2.73 (m, 2H), 2.65-2.58 (m, 1H), 1.89-1.78 (m, 1H), 1.68-1.55 (m, 1H). LC-MS (Method A): m/z = 362.4 [M+H]⁺, 1.02 min.

Example 21: 5-benzyI-N-((4S,9aR)-5-oxohexahydro-lH,3H-pyrrolo[2,l-c][l,4]oxazepin-4yl)isoxazole-3-carboxamide

184

Example 22: 5-benzyI-N-((4S,9aS)-5-oxohexahydro-lH,3H-pyrrolo[2,l-c] [l,4]oxazepin-4yI)isoxazole-3-carboxamide

Example 23: (S)-5-benzyl-N-(l-methyl-2-oxoazepan-3-yl)-4H-l,2,4-triazole-3-carboxamide

HOBt

EDCi

DIPEA

[0490] The crude product obtained using Amide Coupling Procedure C was purified by column chromatography (CtbCb/MeOH 9:1), then by column chromatography on KP-NH modified silica gel (EtOAc/McOH 9:1) and then by reverse phase chromatography (water-CH₃CN, 70:30) to afford the title compound. Ή NMR (400 MHz, DMSO-7₆) δ 14.44 (s, 1H), 8.34 (d, 7=6.2 Hz, 1H), 7.37-7.20 (m, 5H), 4.75-4.65 (m, 1H), 4.11 (s, 2H), 3.68 (dd, 7=15.4, 11.4 Hz, 1H), 3.23 (dd, 7=15.3, 5.2 Hz, 1H), 2.94 (s, 3H), 2.01-1.93 (m, 1H), 1.92-1.82 (m, 1H), 1.81-1.67 (m, 2H), 1.45-1.28 (m, 2H). LC-MS (Method A): m/z = 328.3 [M+H]⁺, 0.74 min.

Example 24: (S)-5-cyano-l-methyl-N-(5-methyI-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3yl)-lH-pyrrole-2-carboxamide

HOBt

EDCi

DIPEA

[0491] The crude product obtained using Amide Coupling Procedure C was purified by column chromatography (cyclohexane-EtOAc, 100:0 to 70:30) to afford the title compound. ’H NMR (400 MHz, CDC1₃) δ 7.32-7.19 (m, 4H), 7.11 (d, 7=6.6 Hz, 1H), 6.77 (d, 7=4.3 Hz, 1H), 6.69 (d, 7=4.3 Hz, 1H), 5.00 (dt, 7=11.2, 6.9 Hz, 1H), 4.77 (dd, 7=9.7, 7.4 Hz, 1H), 4.25 (dd, 7=11.1, 9.7 Hz, 1H), 4.00 (s, 3H), 3.47 (s, 3 H). LC-MS (Method A): m/z = 325.0 [M+H]⁺, 0.93 min.

185

Example 25: (S)-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yI)-4H1,2,4-triazole-3-carboxamide

[0492] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford the title compound. 'H NMR (400 MHz, DMSO-de) δ 14.2 (br. s, 1H), 8.43 (d, J= 6.8 Hz, 1H), 7.54-7.45 (m, 1H), 7.22-7.18 (m, 3H), 4.90-4.75 (m, 1H), 4.58 (t, J= 10.0 Hz, 1H), 4.47-4.35 (m, 1H), 4.39 (s, 3H), 2.39 (s, 3H). LC-MS (Method L): m/z = 302.0 [M+H]⁺, 0.885 min.

Example 26: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)acetamide

Ac₂O, Et₃N, DCM rt, 2 h

[0493] Acetic anhydride (20.5 mg, 0.20 mmol) was added to a solution of (3S)-3-amino-5-methyl2,3,4,5-tetrahydro-l,5-benzoxazepin-4-one hydrochloride (45.6 mg, 0.20 mmol) and triethylamine (40 mg, 0.40 mmol) in dichloromethane (5 mL). After stirring at room température for 2 hours, the reaction mixture was diluted with water (5 mL), and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSO-ri₆) δ 8.25 (d, J= 8.4 Hz, 1H), 7.50-7.45 (m, 1H), 7.36-7.15 (m, 3H), 4.76-4.65 (m, 1H), 4.38-4.15 (m, 2H), 3.29 (s, 3H), 1.84 (s, 3H). LC-MS (Method D): m/z = 235.1 [M+H]⁺, 1.340 min.

186

Example 27: 5-benzyI-N-((4S,9aS)-5-oxohexahydro-lH,3H-pyrroIo[2,l-c] [l,4]oxazepin-4-yl)-4Hl,2,4-triazole-3-carboxamide

Step 1: Préparation of tert-butyl (2S)-2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3oxopropoxy] methyl}pyrrolidine-l -carboxylate

[0494] Boron trifluoride diethyl etherate (0.52 mL, 4.25 mmol) was added to a solution of 1-benzyl 2methyl (2S)-aziridine-l,2-dicarboxylate (2.00 g, 8.50 mmol) and JV-Boc-L-prolinol (6.85 g, 34.03 mmol) in dry CHC1₃ (20 mL) at -30 °C under a nitrogen atmosphère. The solution was left to stir ovemight at room température, then diluted with CH2Q2 (20 mL) and washed with water (3x10 mL) with backextraction. The combined organic extracts were dried over NajSCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-diethyl ether, 50:50) to afford the title product (3.30 g, 89%) as a colorless oil. ’HNMR (400MHz, CDCL) δ 7.47-7.30 (m, 5H), 5.97-5.50 (m, 1H), 5.23-5.08 (m, 2H), 4.49 (br. s., 1H), 4.07-3.21 (m, 10H), 1.97-1.73 (m, 4H), 1.49-1.38 (m, 9H). LC-MS (Method A): m/z = 437.5 [M+H]⁺, 1.18 mm.

Step 2: Préparation of methyi (2S)-2-{[(benzyloxy) carbonyl]amino}-3-[(2S)-pyrrolidin-2ylmethoxy]propanoate

[0495] A solution of tert-butyl (2S)-2-{[(2S)-2-{[(benzyloxy)carbonyl](methyl)amino}-3-methoxy-3oxopropoxy]methyl}pyrrolidine-l-carboxylate (450 mg, 1.03 mmol) in CH2CI2 (5 mL) and TFA (5 mL) was stirred at 0 °C for 3h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column cromatography on ΚΡ-ΝΉ modified silica (cyclohexane-EtOAc, 80:20 to 60:40 then neat MeOH) to afford the title compound (313 mg, 90%) as a colorless oil. ’H NMR (400MHz, CDCL) δ 7.48-7.29 (m, 5H), 6.23 (br. s., 1H), 5.22-5.10 (m, 2H), 4.50 (br. s., 1H), 3.96 (dd,

187

7=9.9, 3.1 Hz, 1H), 3.78 (s, 3H), 3.72 (dd, 7=9.8, 3.3 Hz, 1H), 3.51-3.44 (m, 1H), 3.39-3.32 (m, 1H),

3.25 (dq, 7=4.5, 7.0 Hz, 1H), 3.02-2.93 (m, 1H), 2.91-2.81 (m, 1H), 1.87-1.63 (m, 3H), 1.44-1.32 (m,

1H). LC-MS (Method A): m/z = 337.3 [M+H]⁺, 0.49 min.

Step 3: Préparation of benzyl N-[(4S, 9aS)-5-oxo-octahydropyrrolo[2,1-c][l, 4]oxazepin-4-yl]carbamate

[0496] Trimethylaluminum solution (2M in heptane, 0.56 mL, 1.12 mmol) was added dropwise to a stirred solution of methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(2S)-pyrrolidin-2ylmethoxy]propanoate (313 mg, 0.93 mmol) in CH2CI2 (5 mL) at -30 °C. The solution was left to warm to room température and left to stir at room température for Ih. The reaction was cooled to 0 °C and IN HCl aqueous solution (4.63 mL, 4.63 mmol) and water (5 mL) were added. The phases were separated and the aqueous fraction was extracted twice with CH₂C1₂, filtered through a hydrophobie frit (Phase Separator) and concentrated under reduced pressure. The crude product was purified by column chromatography (CH₂Cl₂-MeOH, 95:5) to give the title compound (217 mg, 77%) as a colorless oil. 'H NMR (400MHz, CDCh) δ 7.45-7.29 (m, 5H), 5.73 (br. s., 1H), 5.14 (br. s., 2H), 4.41 (br. s., 1H), 4.183.89 (m, 3H), 3.82-3.58 (m, 2H), 3.54-3.19 (m, 2H), 2.18-2.04 (m, 1H), 1.97-1.83 (m, 1H), 1.81-1.64 (m, 1H), 1.56 - 1.39 (m, 1H). LC-MS (Method A): m/z = 305.3 [M+H]⁺, 0.74 min.

Step 4: Préparation of (4S,9aS)-4-amino-octahydropyrrolo[2,l-c][l,4]oxazepin-5-one

[0497] Palladium on carbon (10%, 75 mg) was added to a solution of benzyl N-[(4S,9aS)-5-oxooctahydropyrrolo[2,l-c][l,4]oxazepin-4-yl]carbamate (215 mg, 0.71 mmol) in MeOH (5 mL) under a nitrogen atmosphère. The atmosphère of nitrogen was replaced with an atmosphère of hydrogen and the reaction was stirred for 15 h. The reaction was quenched by filtration through a Celite plug, washing with abundant MeOH. The filtrate was concentrated under reduced pressure to give the title compound (116 mg, 96%) which was used directly in the next step. 'H NMR (400MHz, CDCI3) δ 4.23-4.11 (m, 1H), 4.02 (dd, 7=12.5, 1.3 Hz, 1H), 3.93 (dd, 7=12.8, 4.5 Hz, 1H), 3.80-3.68 (m, 2H), 3.64 (dd, 7=4.4, 0.9 Hz, 1H), 3.41 (ddd, 7=11.9, 10.4, 6.8 Hz, 1H), 3.23 (dd, 7=12.7, 9.4 Hz, 1H), 2.18-2.08 (m, 1H), 2.00-1.87 (m, 1H), 1.86-1.68 (m, 1H), 1.57-1.44 (m, 1H). LC-MS (Method B): m/z = 171.1 [M+H]⁺, 0.35 min.

Step 5: Préparation of 5-benzyl-N-((4S,9aS)-5-oxohexahydro-lH,3H-pyrrolo[2,l-c][l,4]oxazepin-4-yl)4H-1,2,4-triazole-3-carboxamide

[0498] To a suspension of 5-benzyl-4H-l,2,4-triazole-3-carboxylic acid (50 mg, 0.246 mmol) and (4S,9aS)-4-amino-octahydropyrrolo[2,l-c][l,4]oxazepin-5-one (42 mg, 0.246 mmol), in CH2CI2 (2 mL) was added N,N-diisopropylethylamine (0.107 mL, 0.49 mmol). The reaction mixture was stirred for 10 minutes, and then T3P solution (50 wt% in EtOAc, 0.22 mL, 0.37 mmol) was added. After 40 minutes the reaction mixture was quenched by adding water, and the two phases were separated. The organic phase was washed with 0.5 N HCl solution, sat. NaHCO, solution, and brine, and concentrated under reduced pressure. The crude product was purified by column chromatography (CH₂Cl₂-MeOH, 90:10 to 70:30) to afford the title compound. 'H NMR (400MHz, CDCI3) δ 8.05 (d, 7=6.3 Hz, 1H), 7.40-7.17 (m.

188

5H), 4.72 (dd, 7=6.9, 4.9 Hz, 1H), 4.33-4.03 (m, 5H), 3.84 (d, 7=12.8 Hz, 1H), 3.75-3.62 (m, 1H), 3.43 (dt, 7=6.8, 11.2 Hz, 1H),3.31 (dd, 7=12.8, 9.5 Hz, 1H), 2.21-2.08 (m, 1H), 1.95-1.83 (m, 1H), 1.81-1.64 (m, 1H), 1.58-1.43 (m, 1H). LC-MS (Method A): m/z = 356.3 [M+H]⁺, 0.67 min.

Example 28 and 29: 5-benzyl-N-((3R,4S)-4-fluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lHbenzo[b]azepin-3-yl)isoxazole-3-carboxamide and 5-benzyl-N-((3S,4R)-4-fluoro-l-methyl-2-oxo2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)isoxazole-3-carboxamide (28); and 5-benzyl-N((3R,4R)-4-fluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yI)isoxazole-3carboxamide and 5-benzyl-N-((3S,4S)-4-fluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lHbenzo[b]azepin-3-yI)isoxazole-3-carboxamide (29)

Example 30: (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[l,2-a]azepin-4-yl)isoxazole-3carboxamide

1) NaN₃, DMF, rt, 1 h

2) PPh₃, THF, H₂O, rt, 3 h

2-hydroxy-5-nitrobenzaldehyde i-propanol, 70°C, 4 days

Step 1 Step 2

CbzCI, K₂CO₃

DCM, H₂O rt, 16 h

NH

Cbz

Lawesson's reagent

THF, rt, 16 h

Step 3

Step 4

189

Step 1: Préparation of 3-amino-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one

[0499] To a solution of 3-iodo-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (4.50 g, 15.7 mmol) in N,Ndimethylformamide (20 mL) was added sodium azide (1.23 g, 18.8 mmol) and the reaction mixture was stirred at room température. Precipitate formed after 30 minutes. The reaction mixture was diluted with water (300 mL). More solids precipitated and the mixture was stirred for an additional 10 minutes. The solid was collected by filtration, washed with water (20 mL), and dried in vacuo. The crude product was dissolved in tetrahydrofuran (30 mL) and water (0.5 mL). Triphenylphosphine (4.50 g, 17.2 mmol) was added and the reaction mixture was stirred at room température for 3 hours. Solids were removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated to afford the title compound (2.00 g, 72%) as a white solid. LC-MS (Method E): m/z= 177.0 [M+H]⁺, 0.413 min.

Step 2: Préparation of (3S)-3-amino-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one

[0500] To a solution of 3-amino-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (1.85 g, 11.0 mmol) in isopropanol (200 mL) at 70 °C was added L-pyroglutamic acid (1.42 g, 11.0 mmol) followed by 2hydroxy-5-nitrobenzaldehyde (0.06 g, 0.33 mmol). The reaction mixture was stirred at 70 °C for 4 days. After cooling to room température, the solid was collected by filtration, rinsed with isopropanol and tire filtrate was basified with ammonium hydroxide (28%, 10 mL). The resulting solution was extracted with dichloromethane (4 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound (0.91 g, 49%) as a white solid. LC-MS (Method E): m/z = 177.0 [M+H]⁺, 0.421 min.

Step 3: Préparation ofbenzyl N-((3S)-2-oxo-2,3,4,5-tetrahydro-lH-l-benzazepin-3-yl)carbamate

[0501] A solution of potassium carbonate (2.00 g, 15 mmol) in water (4 mL) was added to a solution of (3S)-3-amino-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (0.5 g, 3 mmol) in dichloromethane (30 mL)

190 and then benzyl chloroformate (0.77 g, 4.5 mmol) was added. The reaction mixture was stirred at room température for 16 hours. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (0.87 g, 99%) as a white solid. LC-MS (Method E): m/z = 311.0 [M+H]L 0.838 min.

Step 4: Préparation ofbenzyl N-((3S)-2-sulfanylidene-2,3,4,5-tetrahydro-lH-l-benzazepin-3yl)carbamate

[0502] Lawesson’s reagent (1.05 g, 2.6 mmol) was added to a solution of benzyl N-((3S)-2-oxo2,3,4,5-tetrahydro-lH-l-benzazepin-3-yl)carbamate (0.80 g, 2.6 mmol) in tetrahydrofuran (40 mL) and the reaction mixture was stirred under a nitrogen atmosphère for 16 hours at room température. The precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). Tire combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (0.82 g, 98%) as a white solid. LC-MS (Method E): m/z = 349.1 [M+Na]⁺, 0.946 min.

Step 5: Préparation of benzyl N-((3S)-2-((2,2-dimethoxyethyl)amino)-4,5-dihydro-3H-l-benzazepin-3yl)carbamate

[0503] 2,2-Dimethoxyethanamine (1.06 g, 10.1 mmol) was added to a mixture of benzyl N-((3S)-2sulfanylidene-2,3,4,5-tetrahydro-lH-l-benzazepin-3-yl)carbamate (0.81 g, 2.5 mmol) and mercury dichloride (0.89 g, 3.3 mmol) in tetrahydrofuran (25 mL). The resulting mixture was heated for 20 minutes at 55 °C. After cooling to room température, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.89 g, 90%) as a light yellow solid. LC-MS (Method C): m/z = 398.2 [M+H]⁺, 1.182 min.

Step 6: Préparation of (S)-benzyl (5,6-dihydro-4H-benzo[f]imidazo[l,2-a]azepm-4-yl)carbamate [0504] A solution of benzyl N-((3S)-2-((2,2-dimethoxyethyl)amino)-4,5-dihydro-3H-l-benzazepin-3yl)carbamate (0.85 g, 3 mmol) in formic acid (8 mL, 96%) was heated for 2 hours at 100 °C. The black sédiment was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL), basified with aqueous sodium hydroxide (1 N, 30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Tire residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (0.68 g, 95%) as a white solid. LC-MS (Method E): m/z = 334.0 [M+H]⁺, 0.671 min.

191

Step 7: Préparation of (S)-5,6-dihydro-4H-benzo[f]imidazo[l,2-a]azepin-4-amine

[0505] A solution of (S)-benzyl (5,6-dihydro-4H-benzo[f|imidazo[l,2-a]azepin-4-yl)carbamate (0.68 g, 2 mmol) in éthanol (20 mL) was aged ovemight in the presence of palladium on carbon (10%, 0.5 g) under an hydrogen atmosphère (2-3 atm). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford the title compound (0.40 g, 99%) as a yellow oil. LCMS (Method C): m/z = 200.1 [M+H]⁺, 0.915 min.

Step 8: Préparation of (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]iimdazo[l,2-a]azepm-4-yl)isoxazole-3carboxamide

[0506] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (0.1% formic acid) and ACN (45.0% ACN to 70.0% over 7 min); Detector, UV 254/220 nm to afford the title compound. ’H NMR (300 MHz, DMSO-î/ô) δ 9.00 (d, J= 7.8 Hz, 1H), 7.49 (d, J= 1.5 Hz, 1H), 7.46-7.41 (m, 3H), 7.40-7.21 (m, 6H), 6.96 (d, J= 1.5 Hz, 1H), 6.53 (s, 1H), 4.80 (dd, J= 10.2, 7.5 Hz, 1H), 4.18 (s, 2H), 2.72 (dd, J= 11.7, 6.0 Hz, 1H), 2.45-2.27(m, 3H). LC-MS (Method O): m/z = 385.0 [M+H]⁺, 1.587 min.

Example 31 and 34: 5-benzyl-N-((3R,4R)-4-fluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lHbenzo[b]azepin-3-yI)-4H-l,2,4-triazoie-3-carboxamide and 5-benzyI-N-((3S,4S)-4-fluoro-l-methyi2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H-l,2,4-triazole-3-carboxamide (31); and 5benzyl-N-((3R,4S)-4-fluoro-l-methyI-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H-l,2,4triazole-3-carboxamide and 5-benzyl-N-((3S,4R)-4-fluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lHbenzo[b]azepin-3-yl)-4H-l,2,4-triazole-3-carboxamide (34)

192

Example 32: (S)-5-benzyI-N-(9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3yl)-4H-l,2,4-triazole-3-carboxamide

Zn, NH₄CI

THF, MeOH, 25°C, 2 h step 2

Cl step 6

Step 1: Préparation of (2S)-2-(((tert-butoxy)carbonyl)amino)-3-(2-chloro-6-nitrophenoxy)propanoic acid

[0507] Sodium hydride (60%, 0.39 g, 97.6 mmol) was added to a solution of (S)-2-(tertbutoxycarbonylamino)-3-hydroxypropanoic acid (10.0 g, 48.8 mmol) in N,N-dimethylformamide (50 mL) under nitrogen atmosphère. After stirring for 2 hours at 0 °C, l-chloro-2-fluoro-3-nitrobenzene (8.6 g, 48.8 mmol) was added. The reaction mixture was stirred ovemight at room température, quenched with hydrochloric acid (0.5 M, 50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resuiting residue was purified by reverse phase column chromatography using an RP-C18 column (acetonitrile/water, 7/3) to afford the title compound (5.5 g, 31%) as a yellow solid. LC-MS (Method G): m/z = 361.0 [M+H]⁺, 0.665 min.

Step 2: Préparation of (2S)-3-(2-amino-6-chlorophenoxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid

[0508] Zinc (8.13 g, 125 mmol) and ammonium chloride (6.70 g, 125 mmol) were added to a stirred solution of (2S)-2-(((tert-butoxy)carbonyl)amino)-3-(2-chloro-6-nitrophenoxy)propanoic acid (4.5 g, 12.5 mmol) in methanol/tetrahydrofuran (100 mL, 1/1). The resuiting mixture was stirred for 2 hours at 25 °C. Solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford the title compound (4 g crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method G): m/z = 331.0 [M+H]⁺, 0.704 min.

193

Step 3: Préparation of tert-butyl N-((3S)-9-chloro-4-oxo-2,3,4,5-tetrahydro-l,5-benzoxazepin-3yl)carbamate

[0509] 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluroniumhexafluorophosphate (1.1 g, 2.91 mmol) and ethyldiisopropylamine (0.94 g, 7.26 mmol) were added to a stirred solution of (2S)-3-(2amino-6-chlorophenoxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid (0.80 g, 2.42 mmol) inN,Ndimethylformamide (10 mL). After stirring for 2 hours at room température, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to afford the title compound (0.18 g, 24%) as a yellow⁷ solid. LC-MS (Method G): m/z = 313.0 [M+H] ζ 1.006 min.

Step 4: Préparation of tert-butyl N-((3S)-9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydro-l,5-benzoxazepin3-yl) carbamate

[0510] lodomethane (82 mg, 0.58 mmol) was added dropwise to a stirred mixture of tert-butyl N((3S)-9-chloro-4-oxo-2,3,4,5-tetrahydro-l,5-benzoxazepin-3-yl)carbamate (180 mg, 0.58 mmol) and césium carbonate (188 mg, 0.58 mmol) in N,N-dimethylformamide (10 mL). After stirring for 2 hours at room température, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to afford the title compound (120 mg, 64%) as a white solid. LC-MS (Method G): m/z = 327.0 [M+H]⁺, 1.045 min.

Step 5: Préparation of (3S)-3-amino-9-chloro-5-methyl-2,3,4,5-tetrahydro-l,5-benzoxazepin-4-one hydrochloride

[0511] tert-butyl N-((3S)-9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3yl)carbamate (120 mg, 0.37 mmol) was added to a solution of hydrogen chloride in dioxane (4M, 10 mL). The reaction mixture was stirred for 1 hour at room température and concentrated under reduced pressure to afford the title compound (83 mg crude) as a white solid. LC-MS (Method G): m/z = 227.0 [M+H]⁺, 0.772 min.

Step 6: Préparation of (S)-5-benzyl-N-(9-chloro-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide [0512] The crude product obtained using Amide Coupling Procedure C w⁷as purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford the title compound. H NMR (400 MHz, CD3OD) δ 7.44-7.20 (m, 8H), 4.98 (dd, J=

194

15.2, 10.0 Hz, 1H), 4.68 (dd, 7= 13.2, 10.0 Hz, 1H), 4.46 (dd, 7 = 15.2, 13.2 Hz, 1H), 4.17 (s, 2H),3.42 (s, 3H). LC-MS (Method Q): m/z = 412.2 [M+H]⁺, 1.336 min.

Example 33: (S)-l-benzyI-N-(5-methyI-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3yl)azetidine-3-carboxamide

[0513] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN to 60.0% over 7 min); Detector, UV 254 & 220 nm to afford the title compound. *H NMR (300 MHz, CDCI3) δ 7.29 (s, 4H), 7.19 (m, 4H), 7.06 (d, 7 = 6.9 Hz, 1H), 4.95-4.80 (m, 1H), 4.67 (dd, 7= 9.6, 7.5 Hz, 1H), 4.14 (dd, 7= 11.1, 9.6 Hz, 1H), 3.65 (s, 2H), 3.57 (s, 2H), 3.51 (s, 3H), 3.34 (m, 2H), 3.22-3.02 (m, 1H). LC-MS (Method O): m/z = 365.9 [M+H]⁺, 1.215 min.

Example 35: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-5-(lphenylcycIopropyl)-4H-l,2,4-triazole-3-carboxamide

HATU, DIEA, DMF rt, 1h

NH₂NH₂ in THF

EtOH, Et₂O, rt, 2 h step 1 step 2 xylene sealed tube, Microwave 170°C, 10 h step 3

LiOH

THF, H₂O, rt, o/n step 4

EDCI, HOBT, DIEA, DMF rt, 6 h

step 5

195

Step 1: Préparation of 1-phenylcyclopropane-l-carbohydrazide

[0514] A solution of hydrazine in tetraliydrofiiran (1 M, 30 mL) was added to a solution of 1phenylcyclopropane-l-carboxylic acid (0.48 g, 3.00 mmol), 2-(7-aza-l H-bcnzotria.zole-l-yl)-l, 1,3,3tetramethyluronium hexafluorophosphate (1.37 g, 3.60 mmol) and ethyldiisopropylamine (1.16 g, 8.98 mmol) in N,N-dimethylformamide (10 mL). After stirring for 1 hour at room température, the reaction mixture was diluted with water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to afford the title compound (0.53 g, 98%) as a yellow oil. LC-MS (Method R: m/z = 177.2 [M+H]⁺, 0.670 min.

Step 2: Préparation of ethyl 2-ammo-2-(((I-phenylcyclopropyl)formamido)imino)acetate

[0515] Ethyl 2-ethoxy-2-iminoacetate (452 mg, 3.11 mmol) was added to a stirred solution of 1phenylcyclopropane-l-carbohydrazide (528 mg, 3.00 mmol) in ethanol/ether (12 mL, 1/3). The reaction mixture was stirred for 2 hours at room température. The yellow solid was collected by filtration to afford the title compound (300 mg, 36%). LC-MS (Method S: m/z = 276.2 [M+H]⁺, 0.663 min.

Step 3: Préparation of ethyl 5-(l-phenylcyclopropyl)-4H-l,2,4-triazole-3-carboxylate

[0516] A solution of ethyl 2-amino-2-(((l-phenylcyclopropyl)formamido)imino)acetate (275 mg, 1.00 mmol) in xylene (10 mL) was irradiated with microwave radiation for 10 hours at 170 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford tire title compound (100 mg, 39%) as a yellow solid. LC-MS (Method C): m/z = 258.1 [M+H]⁺, 1.641 min.

Step 4: Préparation of 5-(l-phenylcyclopropyl)-4H-l,2,4-triazole-3-carboxylic acid

[0517] A solution of lithium hydroxide (28 mg, 1.17 mmol) in water (1 mL) was added into a solution of ethyl 5-(l-phenylcyclopropyl)-4H-l,2,4-triazole-3-carboxylate (100 mg, 0.39 mmol) in tetrahydrofuran (3 mL) and the resuiting mixture was stirred ovemight at room température. After adjusting the pH to 6-7 with aqueous hydrochloride acid (1 N, 20 mL), the reaction mixture was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (90 mg crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method R): m/z = 230.2 [M+Hf, 0.530 min.

Step 5: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [Ifldoxazepin-B-yty-SfllphenylcyclopropyljAH-l , 2,4-triazole-3-carboxamide

[0518] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD Column, 5 pm, 19 x 150 mm; mobile

196 phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% over 7 min); Detector, UV 254 &

220 nm to afford the title compound. 'H NMR (400 MHz, CD₃OD) δ 7.44-7.20 (m, 9H), 4.99 (dd, 7 =

11.6, 7.6Hz, 1H), 4.58 (dd, 7= 9.6, 7.6Hz, 1H), 4.39(dd,7= 11.6, 10.0Hz, 1H), 3.57 (s, 3H), 1.67-1.56 (m, 2H), 1.46-1.29 (m, 2H). LC-MS (Method D): m/z = 404.1 [M+H]⁺, 1.966 min.

Example 36: 5-benzyl-N-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2a] [1,3] diazepin-3-yl)isoxazole-3-carboxamide

Example 37: (R)-5-benzyl-N-(4,4-difluoro-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3yl)-4H-l,2,4-triazole-3-carboxamide

197

Example 38A and 38B: (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide and (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide

Py, 50°C, 16 h

TMEDA, TMSl, l₂

DCM, 0°C,2h step 5

N

S

1) NaN₃, DMF, rt, 1h

2) PPh₃, THF, H₂O °C, o/n step 6

Step 1 : Préparation ofazepane-2,7-dione

[0519] A stirring solution of azepan-2-one (11.3 g, 100 mmol), 2-hydroxyisoindoline-l,3-dione (1.63 g, 10 mmol), and cobalt acetate (88.5 mg, 0.5 mmol) in acetonitrile (100 mL) was flushed with oxygen (balloon). The reaction mixture was heated overnight at 85 °C under an oxygen atmosphère. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (3.70 g, 29.1%) as a white solid. LC-MS (Method C): m/z = 128.2 [M+H]⁺, 0.683 min.

Step 2: Préparation of 1 -methylazepane-2,7-dione

[0520] lodomethane (1.68 g, 11.8 mmol) was added dropwise to a stirring mixture of azepane-2,7dione (1.50 g, 11.8 mmol) and césium carbonate (3.85 g, 5.0 mmol) in N,N-dimethylformamide (25 mL) at 0 °C. The reaction mixture was stirred overnight at room température, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). Die combined organic layers were washed

198 with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (1.1g, 66.1%) as a yellow oil. LC-MS (Method C): m/z = 142.1 [M+H]⁺, 0.863 min.

Step 3: Préparation of 3-bromo-l-methylazepane-2,7-dione

[0521] Bromine (632 mg, 4.00 mmol) was added to a stirring solution of l-methylazepane-2,7-dione (564 mg, 4.0 mmol) in chloroform (10 mL). The reaction mixture was stirred at 110 °C for 1.5 hours in a sealed tube. The reaction mixture was concentrated under high vacuum to afford the title compound (600 mg crude) as a brown oil. LC-MS (Method C): m/z = 220.1 [M+H]⁺, 0.940 min.

Step 4: Préparation of2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one

[0522] Ethanethioamide (300 mg, 4.0 mmol) was added to a solution of 3-bromo-l-methylazepane2,7-dione (600 mg, 4.0 mmol) in pyridine (10 mL). The reaction mixture was stirred at 50 °C for 16 hours, quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (70 mg, 9%) as a yellow solid. LC-MS (Method C): m/z =197.1 [M+H]⁺, 0.981min.

Step 5: Préparation of 6-iodo-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one

[0523] N¹,N¹,N²,N²-tetramethylethane-l,2-diamine (124 mg, 1.07 mmol) was added to a stirring solution of 2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one (70 mg, 0.36 mmol) in dichloromethane (5 mL) at 0 °C followed by the addition of iodotrimethylsilane (214 mg, 1.07 mmol). The reaction mixture was stirred for 1 hour at 0 °C. After adding iodine (137.2 mg, 0.54 mmol), the reaction mixture was stirred for another 2 hours at 0 °C and quenched with aqueous sodium thiosulfate (5%, 15 mL). The resulting solution was stirred for an additional 15 minutes and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (61 mg crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method R): m/z = 323.2[M+H]⁺, 0.820 min.

Step 6: Préparation of 6-amino-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one

[0524] To a solution of 6-iodo-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one (61 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added sodium azide (37.1 mg, 0.57 mmol). The reaction mixture was stirred for 1 hour at room température and concentrated under reduced pressure. The residue was dissolved in tetrahydrofiiran (3 mL) and water (1 mL) and triphenylphosphine (149.3 mg, 0.57 mmol) was added in one portion. The reaction mixture was stirred at 50 °C overnight, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were

199 washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (33 mg, 83%) as a yellow solid. LC-MS (Method C): m/z = 212.1 [M+Hj⁺, 0.735min.

Step 7: Préparation of 5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6yl)-4H-l,2,4-triazole-3-carboxamide

[0525] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: column: X bridge Prep Cl8, 19 χ 150 mm, 5 pm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: ACN (20% to 80% over 12 min); Detector, UV 220 & 254 nm to afford the title compound. LC-MS (Method R): m/z = 397.1[M+H]⁺, 1.095 min.

Step 8: Préparation of (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin6-yl)-4H-l,2,4-triazole-3-carboxamide (first eluting isomer) and (S)-5-benzyl-N-(2,4-dimethyl-5-oxo5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (second eluting isomer)

[0526] The enantiomers of 5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (24 mg, 0.06 mmol) were separated by Prep-ChiralHPLC with the following conditions: Column: Chiralpak IA, 2 χ 25 cm, 5 pm; Mobile Phase A: hexanes, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B over 17.5 min; UV 220 & 254 nm; RT 1:10.18 min; RT 2: 15.13 min to afford the title compounds:

[0527] Example 38B (first eluting isomer): ’HNMR (400 MHz, Methanol-d/) δ 7.36-7.25 (m, 5H),

4.73- 4.69 (m, 1H), 4.18 (s, 2H), 3.39 (s, 3H), 3.05-2.88 (m, 2H), 2.73-2.64 (m, 4H), 2.36-2.27 (m, 1H). LC-MS (Method D): m/z = 397.1 [M+H]⁺, 1.623 min.

[0528] Example 38A (second eluting isomer): 'H NMR (400 MHz, Methanol- dfi δ 7.36-7.24 (m, 5H),

4.73- 4.68 (m, 1H), 4.18 (s, 2H), 3.39 (s, 3H), 3.06-2.87 (m, 2H), 2.73-2.63 (m, 4H), 2.36-2.27 (m, 1H). LC-MS (Method D): m/z = 397.1 [M+H]⁺, 1.623 min.

Example 39: (S)-5-benzyl-N-(l-methyl-2-oxo-8-(trifluoromethyl)-2,3,4,5-tetrahydro-lHpyrrolo [1,2-a] [1,3] diazepin-3-yl)-4H-l ,2,4-triazole-3-carboxamide

200

Example 40: (S)-5-benzyI-N-(5-methyI-4-oxo-6-(trifluoromethyl)-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)-4H-l,2,4-triazoIe-3-carboxamide

NaH, DMF, rt, o/n

Zn, NH₄CI

25°C, 2h

HATU, DIEA

DMF, rt, o/n

CS2DO3, Mel

DMF, rt, 2h

TMSCF₃,Phl(OAc)₂,

AgF.DMSO rt,o/n

Example 41: (S)-5-benzyl-N-(l-methyI-2-oxo-l,2,3,4-tetrahydropyrido[3,4-b][l,4]oxazepin-3-yI)4H-1,2,4-triazole-3-car boxamide

Boc

NaH, DMF rt, o/n

Pd/C, H₂

MeOH rt, o/n

Step 1

Step 2

HATU, DIEA

DMF rt, 3 h

CS2CO3, Mel

DMF

0°C, 10 min

N HCl dioxane rt, 1 h

Step 3

Step 6

201

Step 1: Préparation of (2S)-2-(((tert-butoxy)carbonyl)amino)-3-((4-nitropyridin-3-yl)oxy)propanoic acid [0529] Sodium hydride (60%, 1.92 g, 80.1 mmol) was added to a stirred solution of (2S)-2-(tertbutoxycarbonylamino)-3-hydroxypropanoic acid (8.21 g, 40.0 mmol) in dimethyl formamide (30 mL) under nitrogen atmosphère at 0 °C. After stirring for 2 hours at 0 °C, a solution of 3-fluoro-4nitropyridine (5.52 g, 40.0 mmol) in dimethyl formamide (10 mL) was added dropwise. The reaction mixture was stirred overnight at room température, quenched by the addition of water (10 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase CombiFlash using a RP-C18 column (acetonitrile/water, 1/4) to afford the title compound (2.41 g, 18%) as a yellow solid. LC-MS (Method S): m/z = 328.1 [M+H]⁺, 0.829 min.

Step 2: Préparation of (2S)-3-((4-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid

[0530] (2S)-2-(((tert-butoxy)carbonyl)amino)-3-((4-nitropyridin-3-yl)oxy)propanoic acid (2.41g, 7.34 mmol) in methanol (20 mL) was aged overnight at room température in the presence of palladium on carbon (10%, 345 mg) under a hydrogen atmosphère (2-3 atm). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford the title compound (1.8 g, 83%) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method S): m/z = 298.1 [M+H]^T, 0.601 min.

Step 3: Préparation of tert-butylN-((3S)-2-oxo-lH,2H,3H,4H-pyrido[3,4-b][l,4]oxazepin-3yl)carbamate

[0531] 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (1.5 g, 4.04 mmol) and ethyldiisopropylamine (1.30 g, 10.1 mmol) were added to a stirred solution of (2S)-3((4-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid (1.01 g, 3.37 mmol) in N,N-dimethylformamide (13 mL). After stirring for 3 hours at room température, the reaction mixture was diluted with water (15 mL), and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Tire resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (0.4 g, 83%) as a yellow solid. LC-MS (Method S): m/z = 280.1 [M+H]⁺, 0.604 min.

Step 4: Préparation of tert-butyl N-((3S)-l-methyl-2-oxo-lH,2H,3H,4H-pyrido[3,4-b][l,4]oxazepin-3yl)carbamate

[0532] lodomethane (203 mg, 1.43 mmol) was added dropwise to a mixture of tert-butyl N-((3S)-2oxo-lH,2H,3H,4H-pyrido[3,4-b][l,4]oxazepin-3-yl)carbamate (400 mg, 1.43 mmol) and césium carbonate (467 mg, 1.43 mmol) in N,N-dimethylformamide (7 mL). After stirring for 10 minutes at 0

202 °C, the reaction mixture was diluted with water (15 mL), and extracted with ethyl acetate (3x15 mL).

The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (300 mg, 72%) as a yellow solid. LC-MS (Method S): m/z = 294.1 [M+H]⁺, 0.650 min.

Step 5: Préparation of (3S)-3-amino-l-methyl-lH,2H,3H,4H-pyrido[3,4-b][l,4]oxazepin-2-one hydrochloride

[0533] A solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL, 20 mmol) was added to a solution of tert-butyl N-((3S)-1 -methyl-2-oxo-lH,2H,3H,4H-pyrido[3,4-b][l,4]oxazepin-3-yl)carbamate (300 mg, 1.02 mmol) in 1,4-dioxane (7 mL). The reaction mixture was stirred for 1 hour at room température and concentrated to afford the title compound (215 mg, 92%) as a white solid. LC-MS (Method S): m/z = 194.1 [M+H]⁺, 0.184 min.

Step 6: Préparation of (S)-5-benzyl-N-(l-methyl-2-oxo-l,2,3,4-tetrahydropyrido[3,4-b][l,4]oxazepin-3yl)-4H-1,2,4-triazole-3-carboxamide

[0534] A solution of (3S)-3-amino-l-methyl-lH,2H,3H,4H-pyrido[3,4-b][l,4]oxazepin-2-one hydrochloride (115 mg, 0.50 mmol) in Ν,Ν-dimethylformamide (1 mL) was added to a stirring solution of 5-benzyl-2H-l,2,4-triazole-3-carboxylic acid (102 mg, 0.50 mmol), ethyldiisopropylamine (129 mg, 1.00 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-l,3-diamine hydrochloride (115 mg, 0.60 mmol) and 1-hydroxybenzotriazole (92 mg, 0.60 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred ovemight at room température and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 χ 150 mm 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 15% B to 45% B over 10 min; 254 nm. The collected fractions were combined and concentrated under reduced pressure to afford the title compound. ’H NMR (400 MHz, CDCI3) δ 12.34 (s, IH), 8.54-8.46 (m, 2H), 8.06 (d, J= Ί3 Hz, IH), 7.36-7.29 (m, 5H), 7.16 (d, J = 5.2 Hz, IH), 5.09 (m, IH), 4.77 (dd, J= 10.0, 3.2 Hz, IH), 4.41 (dd, J= 11.6, 10.0 Hz, IH), 4.20 (s, 2H), 3.46 (s, 3H). LC-MS (Method T): m/z = 379.2 [M+H]⁺, 0.888 min.

203

Example 42: (S)-5-benzyI-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)4H-l,2,4-triazole-3-carboxamide

^HN'Boc /^N<>/^NO2 q Pd/C, H2, MeOH ,/^Na/^NH2 o no₂ ______________ y i u ________* l Y A

NaH, DMF, 0°C to rt, 10 h OH ^rt· ^o/n ^F HN

Step 1 ^Boc Step 2

OH

Hhk

Boc

Step 6

N HCl in dioxane rt, 3 h

Step 5

Step 1: Préparation of (2S)-2-(((tert-biitoxy)carbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid [0535] Sodium hydride (60%, 2 g, 50 mmol) was added into a stirring solution of (2S)-2-(tertbutoxycarbonylamino)-3-hydroxypropanoic acid (5 g, 25.0 mmol) in N,N-dimethylformamide (100 mL). The resuiting mixture was stirred at 0 °C for 2 hours. 3-Fluoro-2-nitropyridine (3.6 g, 25.3 mmol) was added and the reaction mixture was stirred at room température for an additional 8 hours before quenching with hydrochloric acid (3 N, 5 mL). After adjusting the pH to 3-4 with hydrochloric acid (3 N, 20 mL), the resuiting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reversed phase chromatography with a RP-C18 column (acetonitrile/water, 1/2) to afford the title compound (3.2 g, 39%) as a light yellow oil. LC-MS (Method C): m/z = 272.1 [M+H-(/-BuO)]⁺, 1.269 min.

Step 2: Préparation of (2S)-3-((2-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid

[0536] (2S)-2-(((tert-butoxy)carbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid (0.45 g, 1.4 mmol) in methanol (20 mL) was aged overnight at room température in the presence of palladium on carbon (10%, 0.5 g) under hydrogen atmosphère (2-3 atm). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford the title compound (0.32 g, 78%) as a yellow oil. LC-MS (Method C): m/z = 298.1 [M+H]⁺, 0.982 min.

204

Step 3: Préparation of tert-butyl N-((3S)-4-oxo-2H,3H,4H,5PI-pyrido[3,2-b][l,4]oxazepin-3yl)carbamate

[0537] N,N,N’,N’-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophospate (0.73 g, 1.92 mmol) and Ν,Ν-diisopropylethylamine (0.25 g, 1.93 mmol) were added to a stirring solution of (2S)-3((2-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid (0.45 g, 1.51 mmol) inN,Ndimethylformamide (5 mL). After stirring for 6 hours at room température, the reaction mixture was quenched by the addition of water (20 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (0.11 g, 26%) as a white solid. LC-MS (Method C): m/z = 280.1 [M+H]⁺, 1.248 min.

Step 4: Préparation of tert-butyl N-((3S)-5-methyl-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][l,4]oxazepin-3yl)carbamate

[0538] lodomethane (50 mg, 0.35 mmol) was added dropwise to a stirring solution of tert-butyl N((3S)-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][l,4]oxazepin-3-yl)carbamate (100 mg, 0.36 mmol) and césium carbonate (120 mg, 0.36 mmol) in N,N-dimethylformamide (5 mL). After stirring for 3 hours at room température, the reaction mixture was diluted with water (20 mL), and extracted with ethyl acetate (3 x 100 mL) The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (90 mg, 86%) as a white solid. LC-MS (Method C): m/z = 294.1 [M+H]⁺, 1.333 min.

Step 5: Préparation of (3S)-3-amino-5-methyl-2H,3H,4H,5H-pyrido-[3,2-b][l,4]oxazepin-4-one hydrochloride

[0539] tert-butyl N-((3S)-5-methyl-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][l,4]oxazepin-3-yl)carbamate (90 mg, 0.31 mmol) was added to a solution of hydrogen chloride in dioxane (4M, 10 mL). The reaction mixture was stirred for 3 hours at room température and concentrated under reduced pressure to afford the title compound (65 mg, 93%) as a white solid, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 194.1 [M+H]⁺, 0.847 min.

Step 6: Préparation of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3yl)-4H-l, 2,4-triazole-3-carboxamide

[0540] A solution of (3S)-3-amino-5-methyl-2H,3H,4H,5H-pyrido-[3,2-b][l,4]oxazepin-4-one hydrochloride (55 mg, 0.24 mmol) in Ν,Ν-dimethylformamide (1 mL) was added to a stirring solution of 5-benzyl-2H-l,2,4-triazole-3-carboxylic acid (80 mg, 0.40 mmol), 1-hydroxy-benzotrizole (70 mg, 0.53 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) andN,N

205 diisopropylethylamine (160 mg, 1.21 mmol) in N,N-dimethylformamide (2 mL). After stirring for 8 hours at room température, the reaction mixture was quenched by the addition of water (20 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP 18 OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (0.1% formic acid) and ACN (30.0% ACN to 60.0% over 7 min); Detector, UV 254 & 220 nm to afford the title compound. Ή NMR (300 MHz, DMSO-Ts) δ 14.45 (s, 1H), 8.67 (d, J= 7.2 Hz, 1H), 8.37 (dd, J= 4.8, 1.8 Hz, 1H), 7.71 (dd, J= 7.8, 1.5 Hz, 1H), 7.37-7.21 (m, 6H), 4.92-4.82 (m, 1H), 4.73 (dd, 7= 11.4, 9.6 Hz, 1H), 4.53 (dd, 7= 9.6, 7.5 Hz, 1H), 4.14 (s, 2H), 3.37 (s, 3H). LC-MS (Method D): m/z = 379.1 [M+H]⁺, 1.611 min.

Example 43: 3-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3yl)cyclobutane-l-carboxamide

PPh₃CI

O

1) n-BuLi, THF,-60°C, 0.5 h

2) reflux, o/n

Step 1

O

rt, 2h

NaOH, THF, H₂O

Step 4

Step 3

Step 1: Préparation of ethyl 3-(phenylmethylidene)cyclobutane-l-carboxylate

[0541] A solution of n-butyllithium in hexane (2.5 M, 3.4 mL, 8.5 mmol) was added dropwise to a suspension of benzyltriphenylphosphonium chloride (3.3 g, 8.5 mmol) in anhydrous tetrahydrofuran (50 mL) at -60 °C, The resulting mixture was stirred at -60 °C for 0.5 hour and then allowed to warm to room température. Ethyl 3-oxocyclobutanecarboxylate (1.2 g, 8.5 mmol) was added and the reaction mixture was heated at reflux and stirred overnight. After cooling to room température, the reaction mixture was quenched with water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced

206 pressure. The resuiting residue was purified by column chromatography (ethyl acetate/petroleum ether,

1/20) to afford the title compound (0.14 g, 8%) as a light yellow oil. LC-MS (Method S): m/z = 217.2

[M+H]⁺, 1.144 min.

Step 2: Préparation of ethyl 3-benzylcyclobutane-l-carboxylate:

[0542] Ethyl 3-(phenylmethylidene)cyclobutane-l-carboxylate (130 mg, 0.6 mmol) in éthanol (5 mL) was hydrogenated in the presence of palladium on carbon (10%, 15 mg) under a hydrogen atmosphère. After stirring for 2 hours at room température, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford the title compound (100 mg crude) as a yellow oil, which was used directly in the next step without further purification. LC-MS (Method S): m/z = 219.3 [M+H]⁺, 1.160 min.

Step 3: Préparation of 3-benzylcyclobutane-l-carboxylic acid:

[0543] A solution of sodium hydroxide (60 mg, 1.5 mmol) in water (1 mL) was added into a solution of ethyl 3-benzylcyclobutane-l-carboxylate (100 mg, 0.5 mmol) in tetrahydrofiiran (3 mL). After stirring for 2 hours at room température, the reaction mixture was diluted with water (10 mL), adjusted to pH=3 with aqueous hydrochloric acid (3 N, 10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude title compound (85 mg, 97%) as a yellow oil. LC-MS (Method I): m/z = 190.9 [M+H]⁺, 0.954 min.

Step 4: Préparation of 3-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3yl) cyclobutane-1 -carboxamide

[0544] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep Cl8 OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (0.05% NH3H2O), ACN (25% ACN to 55% B over 7 min); detector, UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, CDCI3) δ 7.29-7.13 (m, 9H), 6.41 (d, J = 6.0 Hz, 1H ), 4.93-4.86 (m, 1H), 4.69 (t, J= 7.6 Hz, 1H), 4.12 (t, J= 10.0 Hz, 1H), 3.44 (s, 3H), 2.88-2.69 (m, 3H), 2.48 (q, J= 7.6 Hz, 1H), 2.35-2.24 (m, 2H), 2.09-1.91 (m, 2H). LC-MS (Method O): m/z = 365.0 [M+H]⁺, 1.585 min.

207

Example 44: (S)-5-benzyl-N-(l-methyl-2-oxo-l,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1 ’cyclopropan]-3-yl)-4H-l,2,4-triazole-3-carboxamide

rt, 2 h step 5

Step 1: Préparation of tert-butyl l-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3ylcarbamate

[0545] To a mixture of methyltriphenylphosphonium bromide (4.4 g, 12.3 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 0.30 g, 12.3 mmol). The resulting mixture was stirred for 1 hour at 50 °C under a nitrogen atmosphère. To this mixture a solution of tert-butyl l-methyl-2,5-dioxo2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-ylcarbamate (1.50 g, 4.93 mmol) in tetrahydrofuran (20 mL) was added dropwise at 50 °C. After stirring ovemight at 50 °C, the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL), and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to afford the title compound (600 mg, 40%) as a yellow solid. LC-MS (Method C): m/z = 303.2 [M+H]⁺, 1.531 min.

Step 2: Préparation of tert-butyl N-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2,4]]dodeca-l(8),9,11-trien5-yl]carbamate

[0546] To a solution of potassium hydroxide (2.23 g, 39.7 mmol) in water (3.3 mL) was added a solution of 1 -methyi-1-nitrosourea (2.05 g, 19.7 mmol) in ether (100 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 hour at 0 °C and then the organic phase was separated to get the

208 solution of diazomethane (100 mL). To a solution of tert-butyl l-methyl-5-methylene-2-oxo-2,3,4,5tetrahydro-lH-benzo[b]azepin-3-ylcarbamate (0.6 g, 1.99 mmol) in tetrahydrofuran (5 mL) was added the solution of diazomethane (100 mL) dropwise, followed by adding a mixture of palladium diacetate (45 mg, 0.20 mmol) in tetrahydrofuran (1 mL) dropwise at 0 °C. The reaction mixture was stirred ovemight at room température. The solids were removed by filtration and the fîltrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to afford the title compound (0.15 g, 24%) as a yellow solid. LC-MS (Method C): m/z = 317.2 [M+H]⁺, 1.531 min.

Step 3: Préparation of 3-amino-l-methyl-1,2,3,4-tetrahydrospiro[l -benzazepine-5,1 -cyclopropane]-2one hydrochloride

[0547] A solution of hydrogen chloride in 1,4-dioxane (4 N, 10 mL) was added to a solution of tertbutyl N-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2,4]]dodeca-l(8),9,l l-trien-5-yl]carbamate (150 mg, 0.60 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room température for 2 hours and concentrated under vacuum to afford the title compound (95 mg crude) as a yellow solid. LC-MS (Method K): m/z = 217.2 [M+H]⁺, 0.635 min.

Step 4: Préparation of (3S)-3-amino-l-methyl-l,2,3,4-tetrahydrospiro[l-benzazepine-5,l-cyclopropaneJ2-one (first eluting isomer) and (3R)-3-amino-l-methyl-l,2,3,4-tetrahydrospiro[l-benzazepine-5,lcyclopropane]-2-one (second eluting isomer)

[0548] 3 -Amino-1 -methyl-1,2,3,4-tetrahydrospiro[ 1 -benzazepine-5,1 -cyclopropane]-2-one hydrochloride (90 mg crude) was separated by Prep-Chiral-HPLC with the following conditions: Column: Phenomenex Lux Cellulose-4, AXIA Packed, 2.12 x 25 cm, 5 pm; Mobile Phase A: hexanes (0.1% DEA), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 35% B to 35% B over 17.5 mm; 220/254 nm; RT1 : 11.24 min; RT2: 13.82 min to afford the title compounds.

[0549] First eluting isomer: (36 mg, 38%) as a white solid. LC-MS (Method D): m/z = 217.2 [M+H]⁺, 1.096 min.

[0550] Second eluting isomer: (46 mg, 48%) as a white solid. LC-MS (Method D): m/z = 217.2 [M+H]⁺, 1.089 min.

Step 5: Préparation of (S)-5-benzyl-N-(l-methyl-2-oxo-l,2,3,4-tetrahydrospiro[benzo[b]azepine-5,l ’cyclopropan]-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0551] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% in 7 min); Detector, UV 254 & 220 nm to afford the title compound. 'H NMR (300 MHz, DMSO-fife) δ 8.20 (d, J =7.5 Hz, 1H), 7.457.32 (m, 2H), 7.35-7.20 (m, 7H), 4.46-4.36 (m, 1H), 4.07 (s, 2H), 3.30 (s, 3H), 2.71-2.65 (m, 1H), 1.57

209 (t, J= 12.6 Hz, 1H), 1.10-1.07 (m, 1H), 0.75-0.63 (m, 2H), 0.42-0.37 (m, 1H). LC-MS (Method D):

m/z = 402.2 [M+H]⁺, 1.871 min.

Example 45: (S)-l-benzyl-4-fluoro-5-methyl-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3yI)-lH-pyrazo!e-3-carboxamide

Step 1: Préparation of (3S)-3-amino-2,3,4,5-tetrahydro-l,5-benzoxazepin-4-one hydrochloride

[0552] tert-Butyl N-((3S)-4-oxo-2,3,4,5-tetrahydro-l,5-benzoxazepin-3-yl)carbamate (100 mg, 0.36 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL). The reaction mixture was stirred for 2 hours at room température and concentrated under reduced pressure to afford the title compound (100 mg crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method E): m/z = 178.9 [M+H]⁺, 0.397 min.

Step 2: Préparation of (S)-l-benzyl-4-fluoro-5-methyl-N-(4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0553] The crude product obtained using Amide Coupling Procedure B was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150mm 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 15% B to 45% B in 10 min; 254 nm. The collected fractions were combined and concentrated under reduced pressure to afford the title compound. ^!H NMR (400 MHz, DMSO-fik) δ 10.15 (s, 1H), 8.09 (d, J- 7.6 Hz, 1H), 7.43-7.28 (m, 3H), 7.20-7.09 (m, 6H), 5.39 (s, 2H), 4.80 (dt, J= 10.0, 7.3 Hz, 1H), 4.53-4.39 (m, 2H), 2.17 (d, J= 1.4 Hz, 3H). LC-MS (Method F): m/z =395.0 [M+H]⁺, 2.860 min.

210

Example 46: 5-benzyl-N-((2S)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yI)-4H-l,2,4-triazoIe-3-carboxamide

[0554] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; 254/220 rnnto afford the title compound. LC-MS (Method J): m/z = 388.2 [ M+H] , 1.305 min.

[0555] The enantiomers of 5-benzyl-N-{7-methyl-6-oxo-7-azatricyclo[6.4.0.0^A{2,4}]dodeca1(8),9,1 l-trien-5-yl}-4H-l,2,4-triazole-3-carboxamide were separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IC, 2.0 cm x 25 cm (5 pm); Mobile Phase A: hexanes, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 30 min; 254/220 nm; RT1: 10.478 min; RT2: 13.826 min to afford the title compounds:

[0556] Example 46A (first eluting isomer): ’H NMR (400 MHz, Chloroform-7) δ 8.54 (d, J= 7.1 Hz, 1H), 7.39-7.17 (m, 8H), 7.11 (d, J= 7.5 Hz, 1H), 4.80 (d, J= 7.0 Hz, 1H), 4.22 (s, 2H), 3.35 (s, 3H), 2.28-1.80 (m, 2H), 1.21 (m, 1H), 1.04 (m, 1H). LC-MS (Method J): m/z = 388.2 [M+H]+, 1.302 min.

[0557] Example 46B (second eluting isomer): 'H NMR (400 MHz, Chloroform-7) δ 8.53 (d, J= 7.1 Hz, 1H), 7.39-7.18 (m, 8H), 7.12 (d, J= 7.7 Hz, 1H), 4.80 (d, J= 7.0 Hz, 1H), 4.23 (s, 2H), 3.35 (s, 3H), 2.09 (m, 1H), 2.02 (m, 1H), 1.21 (m, 1H), 1.05 (m, 1H). LC-MS (Method J): m/z = 388.2 [M+H]⁺, 1.306 min.

211

Example 47: (S)-4-fluoro-5-methyl-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-l-(lpheny!cyclopropyl)-lH-pyrazole-3-carboxamide

Example 48: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-5-(3phenyloxetan-3-yl)-4H-l,2,4-triazole-3-carboxamide

NH

212

Example 49: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-5(phenylsulfonyI)thiazole-2-carboxamide

Cul, NMP °C,4 h step 1

m-CPBA, DCM rt, 2 h

LiOH, THF, H₂O rt, 2 h step 3

HATU, DIEA, DMF rt, 1 h step 4

Step 1: Préparation of ethyl b-(phenylthio)thiazole-2-carboxylate

[0558] To a stirring mixture of ethyl 5-iodo-l,3-thiazole-2-carboxylate (300 mg, 1.06 mmol), sodium benzenethiolate (220 mg, 1.66 mmol) in l-methyl-2-pyrrolidinone (10 mL) was added cuprous iodide (40 mg, 0.21 mmol) under an argon atmosphère. The resulting solution was stirred for 4 hours at 70 °C, quenched with water (20 mL) and extracted with ethyl acetate (4 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-TLC (ethyl acetate/petroleum ether, 5/1) to afford the title compound (120 mg, 43%) as a yellow oil. LC-MS (Method S): m/z = 266.0 [M+H]', 1.040 min.

Step 2: Préparation of ethyl 5-(phenylsulfonyl)thiazole-2-carboxylate

[0559] To a stirring mixture of ethyl 5-(phenylthio)thiazole-2-carboxylate (100 mg, 0.38 mmol) in dichloromethane (4 mL) was added 3-chloroperoxybenzoic acid (167 mg, 0.97 mmol). The reaction mixture was stirred for 2 hours at room température and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (100 mg, 88%) as a yellow oil. LC-MS (Method S): m/z = 298.0 [M+H] ', 0.931 min.

Step 3: Préparation of 5-(phenylsulfonyl)thiazole-2-carboxylic acid

[0560] To a stirring mixture of ethyl 5-(phenylsulfonyl)thiazole-2-carboxylate (100 mg, 0.34 mmol) in tetrahydrofuran (3 mL) and water (1 mL) was added lithium hydroxide (12 mg, 0.50 mmol). The resulting mixture was stirred for 2 hours at room température and concentrated under vacuum. The residue was diluted with water (10 mL) and adjusted to pH = 6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was

213 concentrated under vacuum to afford the title compound (90 mg crude) as a white oil, which was used directly in the next step without further purification. LC-MS (Method E): m/z = 270.0 [M+H]⁺, 0.635 min.

Step 4: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5(phenylsulfonyl)thiazole-2-carboxamide

[0561] The crude product obtained using Amide Coupling Procedure B was purified by Prep-HPLC with the following conditions: column: Xbridge Prep Cl 8, 19 * 150 mm, 5 pm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: ACN (20% to 80% over 12 min); Detector, UV 220 & 254 nm to afford the title compound. ’H NMR (300 MHz, DMSO-rie) δ 9.24 (br. s, IH), 8.76 (s, IH), 8.10-8.01 (m, 2H), 7.82-7.63 (m, 3H), 7.52-7.44 (m, IH), 7.38-7.17 (m, 3H), 4.83-4.70 (m, IH), 4.71-4.59 (m, 1 H), 4.45-4.32 (m, IH), 3.30 (s, 3H). LC-MS (Method O): m/z = 443.9 [M+H]⁺, 1.594 min.

Example 50: (lR,2S)-2-benzyl-N-((S)-5-methyI-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3yl)cyclopropane-l-carboxamide

Step 1: Préparation of (±)-trans-2-benzylcyclopropanecarboxylic acid

[0562] Sodium hydroxide (60%, 74 mg, 1.84 mmol) was added to a solution of (±)-trans-ethyl 2benzylcyclopropanecarboxylate (200 mg, 0.74 mmol) in methanol (12 mL) and water (6 mL). The reaction mixture was stirred ovemight at room température. After removal of methanol under reduced pressure, the pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting mixture was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to

214 afford the title compound (95 mg, 73%) as a yellow oil. LC-MS (Method I): m/z = 177.0 | M+H| , 0.877 min.

Step 2: Préparation of trans-2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,3-tetrahydrobenzo[b][l,4]oxazepin-3yl) cyclopropanecarboxamide

[0563] The crude product obtained using Arnide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep Cl8 OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (40.0% ACN to 65.0% over 8 min); Detector, UV 254 nm to afford the title compound. LC-MS (Method J): m/z = 351.1 [M+H]⁺, 2.116 min.

Step 3: Préparation of (IR, 2S)-2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl) cyclopropanecarboxamide and (lS,2R)-2-benzyl-N-((S)-5-methyl4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)cyclopropanecarboxamide

[0564] The diastereomers of trans 2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][L4]oxazepin-3-yl)cyclopropanecarboxamide were separated by Prep-Chiral-HPLC with the following conditions: Column: Phenomenex Lux Cellulose-4, AXIA Packed, 2.12 x 25 cm, 5 pm; Mobile Phase A:hexanes, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 12 min; 254/220 nm; RT1: 7.474 min; RT2: 8.916 min to afford the title compounds:

[0565] Example 50A (first eluting isomer): ’HNMR (400 MHz, Chloroform-ri) δ 7.31-7.23 (m, 2H), 7.24-7.11 (m, 7H), 6.65 (d, J= 6.4 Hz, 1H), 4.94-4.85 (m, 1H), 4.69-4.61 (m, 1H), 4.18-4.09 (m, 1H), 3.44 (s, 3H), 2.79-2.71 (m, 1H), 2.58-2.50 (m, 1H), 1.57 (s, 1H), 1.37-1.33 (m, 1H), 1.20-1.16 (m, 1H), 0.80-0.75 (m, 1H). LC-MS (Method J): m/z = 351.1 [M+H]⁺, 2.116 min.

[0566] Example 50B (second eluting isomer): 'H NMR (400 MHz, Chloroform-i/) δ 7.31-7.26 (m, 2H), 7.21-7.13 (m, 7H), 6.59 (d, J= 6.4 Hz, 1H), 4.95-4.84 (m, 1H), 4.69-4.58 (m, 1H), 4.16-4.09 (m, 1H), 3.43 (s, 3H), 2.79-2.70 (m, 1H), 2.63-2.54 (m, 1H), 1.67-1.57 (m, 1H), 1.37-1.32 (m, 1H), 1.171.13 (m, 1H), 0.78-0.73 (m, 1H). LC-MS (Method J): m/z = 351.1 [M+H]⁺, 1.451 min.

Example 51: 5-(2,3-dihydro-lH-inden-l-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide

NH

step 1 step 2

215

HATU, DIEA, DMF rt, 2 h step 5

Step 1: Préparation of2,3-dihydro-lH-indene-l-carbohydrazide

[0567] A solution of hydrazine in tetrahydrofuran (1 M, 31 mL, 31 mmol) was added to a solution of 2,3-dihydro-lH-indene-l-carboxylic acid (1.0 g, 6.2 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l, 1,3,3tetramethyluronium hexafluorophosphate (2.8 g, 7.4 mmol) and ethyldiisopropylamine (2.4 g, 18.6 mmol) in Ν,Ν-dimethylformamide (20 mL). After stirring for 1 hour at room température, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (0.87 g, 80%) as a white solid. LC-MS (Method E): m/z = 177.0 [M+H]⁺, 0.506 min.

Step 2: Préparation of ethyl 2-amino-2-(2-(2,3-dihydro-lH-indene-l-carbonyl)hydrazono)acetate

[0568] Ethyl 2-ethoxy-2-iminoacetate (412 mg, 2.8 mmol) was added to a solution of 2,3-dihydroIH-indene-l-carbohydrazide (500 mg, 2.8 mmol) in éthanol (5 mL) and diethyl ether (5 mL). The resulting suspension was stirred at room température for 2 hours. The solids were removed by filtration and the filtrate was concentrated under vacuum to afford the title compound (600 mg, 78%) as a yellow solid. LC-MS (Method S): m/z = 276.2 [M+H]⁺, 0.709 min.

Step 3: Préparation of ethyl 5-(2,3-dihydro-lH-inden-l-yl)-4H-l,2,4-triazole-3-carboxylate

[0569] Ethyl 2-amino-2-(2-(2,3-dihydro-lH-indene-l-carbonyl)hydrazono)acetate (600 mg, 2.2 mmol) was added to xylene (10 mL) in a sealed tube. The reaction mixture was heated for 5 hours at 170 °C irradiated by microwave. After concentration under high vacuum, the residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (340 mg, 60%) as a yellow oil. LC-MS (Method I): m/z = 258.1 [M+H]⁺, 0.848 min.

216

Step 4: Préparation of 5-(2,3-dihydro-lH-inden-l-yl)-4PI-l,2,4-triazole-3-carboxy>lic acid

[0570] Lithium hydroxide (95.3 mg, 4.0 mmol) was added to a solution of ethyl 5-(2,3-dihydro-lHinden-l-yl)-4H-l,2,4-triazole-3-carboxylate (340 mg, 1.3 mmol) in tetrahydrofuran (6 mL) and water (3 mL). After stirring at room température for 4 hours and removing tetrahydrofuran under reduced pressure, the reaction mixture was diluted with water (20 mL), the pH was adjusted to 2 with aqueous hydrochloric acid (1 N, 20 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (140 mg, 47%) as a yellow⁷ solid. LC-MS (Method E): m/z = 229.9 [M+H]⁺, 0.642 min.

Step 5: Préparation of 5-(2,3-dihydro-lH-inden-l-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl) -4H-1,2,4-triazole-3-carboxamide

[0571] The crude product obtained using Arnide Coupling Procedure B was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 rnmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 10 min; 254 nm to afford the title compound. ’H NMR (400 MHz, Chloroform-r/) δ 8.12 (d, J= 7.2 Hz, 1H), 7.33 (d, J= 12, 1H), 7.29-7.19 (m, 6H), 5.17-5.06 (m, 1H), 4.77-4.67 (m, 2H), 4.34-4.27 (m, 1H), 3.45 (s, 3H), 3.16-3.01 (m, 2H), 2.68-2.63 (m, 1H), 2.46-2.39 (m, 1H). LC-MS (Method J): m/z = 404.3 [M+H]⁺, 1.332 min.

Example 52: (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f|imidazo[l,2-a]azepin-4-yl)-4H-l,2,4-triazole3-carboxamide

[0572] The crude product obtained using Arnide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP 18 OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (0.05% TFA) and ACN (10.0% ACN to 40.0% over 7 min); Detector, UV 220 & 254 nm to afford the title compound. ’H NMR (300 MHz, DMSO-de) δ 14.43 (s, 1H), 8.67 (s, 1H), 7.56 (d, J= 1.5 Hz, 1H), 7.53-7.47 (m, 3H), 7.46-7.22 (m, 6H), 7.04 (d, J= 1.5 Hz, 1H), 4.87-4.77 (m, 1H), 4.14 (s, 2H), 2.80-2.73 (m, 1H), 2.67-2.56 (m, 1H), 2.46-2.32 (m, 2H). LC-MS (Method O): m/z = 385.0 [M+H]\ 1.229 min.

217

Example 53: 3-benzyl-N-(8-bromo-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-pyrrolo[l,2a][l,3]diazepin-3-yl)-lH-l,2,4-triazole-5-carboxamide

HATU, DIEA, DMF

Example 54A and 54B: 5-((R)-2,3-dihydro-lH-inden-l-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yl)-4H-l,2,4-triazo!e-3-carboxamide and 5-((S)-2,3dihydro-lH-inden-l-yI)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)4H-l,2,4-triazole-3-carboxamide

218

Step 1: Préparation of5-(2,3-dihydro-lH-inden-l-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][l, 4]oxazepin-3-yl)-4H-l ,2,4-triazole-3-carboxamide

[0573] A solution of trimethylaluminum in toluene (2 M, 0.6 mL, 1.2 mmol) was added to a mixture of (S)-3-amino-5-methyl-2,3-dihydropyrido[3,2-b][l,4]oxazepin-4(5H)-one hydrochloride (60 mg, 0.26 mmol) in toluene (2 mL) dropwise at 0 °C. Die resulting solution was warmed to room température and stirred for 30 minutes. A solution of ethyl 5-(2,3-dihydro-lH-inden-l-yl)-4H-l,2,4-triazole-3-carboxylate (108 mg, 0.42 mmol) in toluene (2 mL) was added to the resulting solution dropwise. Die resulting solution was stirred overnight at room température. Die solution was then quenched with water (10 mL) and extracted with ethyl acetate (3x50 mL). Die organic layers were combined and concentrated under vacuum. Die residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column 19 χ 150 mm, 5 mm; Mobile Phase A: water (0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; 254 nm; Rt: 6 min to afford the title compound (25 mg, 23.8%) as a white solid. LC-MS (Method D): m/z = 405.1 [M+H] \ 1.759 min.

Step 2: Préparation of5-((R)-2,3-dihydro-lH-inden-l-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5tetrahydropyridof 3,2-b][1,4]oxazepin-3-yl) -4H-1,2,4-triazole-3-carboxamide and 5-((S) -2,3-dihydroIH-inden-l -yl) -N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl) -4PI-1,2,4triazole-3-carboxamide

[0574] 5-(2,3-dihydro-lH-inden-l-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide (25 mg) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IA, 2 x 25 cm, 5 pm; Mobile Phase A:hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 40 min; 220/254 nm; RT1: 9.716 min; RT2: 29.084 min to afford the title compounds:

[0575] 54A (first eluting isomer): ³H NMR (400 MHz, Methanol-i/4) δ 8.36-8.35 (m, 1H), 7.70-7.68 (m, 1H), 7.34-7.31 (m, 2H), 7.25-7.24 (ni, 1H), 7.22-7.19 (m, 1H), 7.16-7.07 (m, 1H), 5.07-5.02 (m, 1H), 4.72-4.65 (m, 2H), 4.55-4.50 (m, 1H), 3.49 (s, 3H), 3.18-3.15 (m, 1H), 3.07-3.05 (m, 1H), 2.652.62 (m,lH), 2.43-2.38 (m, 1H). LC-MS (Method T): m/z = 405.3 [M+H]⁺, 1.296 min.

[0576] 54B (second eluting isomer): 'H NMR (400 MHz, Methanol-0/4) δ 8.36-8.35 (m, 1H), 7.707.68 (m, 1H), 7.34-7.31 (m, 2H), 7.25-7.24 (m, 1H), 7.22-7.19 (m, 1H), 7.16-7.07 (m, 1H), 5.07-5.02 (m, 1H), 4.72-4.65 (m, 2H), 4.55-4.50 (m, 1H), 3.49 (s, 3H), 3.18-3.15 (m, 1H), 3.07-3.05 (m, 1H), 2.65-2.62 (m,lH), 2.43-2.38 (m, 1H). LC-MS (Method T): m/z = 405.3 [M+H]⁺, 1.301 min.

219

Example 55: (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-l(pyridin-2-ylmethyl)-lH-pyrazole-3-carboxamide

Selectifluor, MeCN

100 °C, 48 h

1) NaH, DMF, 0 °C-rt, 2 h

2) H₂O, rt, 5 h

HOBT, EDCI, DIEA, DMF rt, o/n step 3

step 2

Step 1: Préparation of ethyl 4-fluoro-lH-pyrazole-3-carboxylate

[0577] l-(Chloromethyl)-4-fluoro-l,4-diazonia-bicyclo[2.2.2]octane tetrafluoroborate (14 g, 39.5 mmol) was added to a mixture of ethyl lH-pyrazole-3-carboxylate (5 g, 35.7 mmol) in acetonitrile (50 mL). The resuiting mixture was stirred for 48 hours at 100 °C. After cooling to room température, the solids were removed by filtration and the filtrate was concentrated under vacuum to afford the title compound (2.4 g) as a yellow solid. LC-MS (Method S): m/z = 159.2 [M+H]⁺, 0.639 min.

Step 2: Préparation of 4-fluoro-l-(pyridin-2-ylmethyl)-lH-pyrazole-3-carboxylic acid

[0578] Sodium hydride (60%, 506 mg, 12.7 mmol) was added to a solution of ethyl 4-fluoro-lHpyrazole-3-carboxylate (500 mg, 3.2 mmol) in N,N-dimethylformamide (10 mL) at 0 °C. The resuiting mixture was stirred at room température for 0.5 hour before adding 2-(bromomethyl)pyridine (600 mg, 3.5 mmol). The reaction mixture was stirred at room température for 1.5 hours and quenched by adding water (10 mL). The resuiting solution was stirred at room température for 5 hours. The pH was adjusted to 7 with aqueous hydrochloric acid (1 N, 10 mL). The resuiting solution was extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (360 mg, 72%). LC-MS (Method I): m/z = 221.9 [M+H]⁺, 0.320 min.

Step 3: Préparation of (S)-4fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-l(pyridin-2-ylmethyl)-lPI-pyrazole-3-carboxamide

[0579] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 45% B over 7 min; 254/220 nm to afford the title compound. 'H NMR (400 MHz, DMSO-F) δ

220

8.56-8.55 (m, IH), 8.16-8.15 (d, 7= 4.4 Hz, IH), 8.11-8.09 (m, IH), 7.83-7.82 (m, IH), 7.51-7.49 (m,

IH), 7.34-7.28 (m, 3H), 7.24-7.20 (m, 2H), 5.46 (s, 2H), 4.91-4.78 (m, IH), 4.58-4.53 (m, IH), 4.414.37 (m, IH), 3.33 (s, 3H). LC-MS (Method F): m/z = 396.1 [M+H]⁺, 0.924 mm.

Example 56: (S)-5-benzyl-N-(9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3yl)-2H-l,2,4-triazole-3-carboxamide

CN

Zn(CN)₂, t-BuXPhos, THF, H₂O

3rd Génération t-BuXPhos precatalyst rt, o/n step 1

EDCI, HOBt, DIEA, DMF rt, o/n step 3

N HCl in dioxane rt, 1 h step 2

Step 1 : (S)-tert-butyl 9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate

[0580] To a mixture of (S)-tert-butyl 9-chloro-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-ylcarbamate (200 mg, 0.61 mmol) and zinc cyanide (300 mg, 2.59 mmol) in tetrahydrofuran (2 mL) and water (10 mL) were added 3rd génération t-BuXPhos precatalyst (244 mg, 0.31 mmol) and t-BuXPhos (130 mg, 0.31 mmol) under a nitrogen atmosphère. The reaction mixture was stirred ovemight at room température and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to afford the title compound (150 mg, 78%) as a white solid. LC-MS (Method E): m/z = 262.0 [M+H-56]⁺, 0.853 min.

Step 2: Préparation of (S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-9carbonitrile hydrochloride

[0581] A solution of hydrogen chloride in 1,4-dioxane (4 N, 10 mL) was added to a solution of (S)tert-butyl 9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-ylcarbamate (90 mg, 0.28 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred for 1 hour at room température and concentrated under vacuum to afford the title compound (55 mg) as a white solid. LC-MS (Method E): m/z = 218.0 [M+H]⁺, 0.551 min.

221

Step 3: Préparation of (S)-5-benzyl-N-(9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4] oxazepin-3-yl)-4H-l, 2,4-triazole-3-carboxamide

[0582] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 run to afford the title compound. ^TH NMR (400 MHz, DMSO-TJ δ 14.20 (s, 1H), 8.55 (s, 1H), 7.81 (dd,7=8.2, 1.5 Hz, 1H), 7.72 (dd, 7= 7.8, 1.5 Hz, 1H), 7.44 (t, 7= 8.0 Hz, 1H), 7.35-7.14(m, 5H), 4.944.74 (m, 2H), 4.58-4.47 (m, 1H), 4.10 (s, 2H), 3.30 (s, 3H). LC-MS (Method F): m/z = 403.0 [M+H]⁺, 1.069 min.

Example 57: (S)-l-benzyl-4-fluoro-N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-lHpyrazoIe-3-carboxamide

[0583] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Shield RP 18 OBD Column, 5 pm,19 x 150 mm;

Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 60% B over 7 min; LV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSO-Ts) δ 10.55 (s, 1H), 8.23 (d,7= 7.6 Hz, 1H), 8.17-8.13 (m, 2H), 7.56 (dd,7= 7.6, 1.2 Hz, 1H), 7.41-7.31 (m, 3H), 7.30-7.27 (m, 2H), 7.19-7.15 (m, 1H), 5.35 (s, 2H), 4.83-4.77 (m, 1H), 4.53-4.42 (m, 2H). LC-MS (Method V): m/z = 382.1 [M+H]⁺, 2.321 min.

Example 58: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yI)-5-(lphenylcyclopropyl)-l,3,4-thiadiazole-2-carboxamide

S ηΛ·^νη’

H

POCI3, 70 °C, 6 h

CuBr₂, tert-Butyi nitrite

ACN, rtto60 °C, 16 h

step 1 step 2

100°C, 16 h

CO,Pd(PPh3)₂Cl2,Et₃N, MeOH

N-N o —

LiOH, THF, H₂O rt, 2 h

step 3 step 4

222

step 5

Step 1: Préparation of 5-(l-phenylcyclopropyl)-l,3,4-thiadiazol-2-amine

[0584] A mixture of 1-phenylcyclopropanecarboxylic acid (1.6 g, 10 mmol) and N-aminothiourea (0.91 g, 10 mmol) in phosphoryl trichloride (10 mL) was heated for 1 hour at 70 °C and then cooled to room température. Water (100 mL) was added. The reaction mixture was heated to 70 °C and stirred for 5 hours. The pH value ofthe resulting solution was adjusted to 8 with saturated aqueous sodium hydroxide (30 mL). The solids were collected by filtration to afford the title compound (1.9 g, 87%) as a white solid. LC-MS (Method Q): m/z = 218.1 [M+H]⁺, 0.817 min.

Step 2: Préparation of 2-bromo-5-(l-phenylcyclopropyl)-l,3,4-thiadiazole

[0585] To a mixture of 5-(l-phenylcyclopropyl)-l,3,4-thiadiazol-2-amine (1.1 g, 5.0 mmol) in acetonitrile (20 mL) was added cupric bromide (2.2 g, 10 mmol). The resulting mixture was stirred at room température for 15 minutes before adding tert-butyl nitrite (1.5 mL, 10 mmol) to the mixture dropwise over a period of 15 minutes at room température. The reaction mixture was heated at 60 °C and stirred for 16 hours before adding water (50 mL). The solids were removed by filtration and the filtrate was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to afford the title compound (1.0 g, 70%) as a yellow solid. LC-MS (Method K): m/z = 281.0 [M+H]⁺, 1.107 min.

Step 3: Préparation of ethyl 5-(l-phenylcyclopropyl)-l,3,4-thiadiazole-2-carboxylate

[0586] Bis(triphenylphosphine)palladium(II) chloride (277 mg, 0.395 mmol) was added to a mixture of 2-bromo-5-(l-phenylcyclopropyl)-l,3,4-thiadiazole (1.0 g, 3.57 mmol) and triethylamine (879 mg, 8.70 mmol) in methanol (20 mL). After stirring for 16 hours at 100 °C under a carbon monoxide atmosphère (50 atm), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to afford the title compound (600 mg, 61%) as a yellow solid. LCMS (Method E): m/z = 261.1 [M+H]⁺, 0.923min.

Step 4: Préparation of 5-(l-phenylcyclopropyl)-l,3,4-thiadiazole-2-carboxylic acid

[0587] Lithium hydroxide (5.4 mg, 2.0 mmol) was added to a solution of ethyl 5-(lphenylcyclopropyl)-l,3,4-thiadiazole-2-carboxylate (100 mg, 0.41 mmol) in tetrahydrofiiran (9 mL) and

223 water (3 mL). The resulting mixture was stirred for 2 hours at room température. After removal of tetrahydrofiiran under reduced pressure, the pH value of the solution was adjusted to 3-4 with aqueous hydrochloric acid (1 N, 20 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (80 mg, 76%) as a yellow oil. LC-MS (Method C): m/z = 247.0 [M+H]⁺, 1.288 min.

Step 5: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5-(Iphenylcyclopropyl)-!, 3,4-thiadiazole-2-carboxamide

[0588] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: column: Xbridge Prep C18, 19 x 150 mm 5 pm; Mobile phase: water (10 mmol/L NH4HCO3) and ACN (20% to 80% over 12 min); Detector, UV220 & 254 nm to afford the title compound. Ή NMR (300 MHz, DMSO-ri_ô) δ 9.20 (s, 1H), 7.49-7.18 (m, 9H), 4.77-4.75 (m, 1H), 4.694.62 (m, 1H), 4.41-4.35 (m, 1H), 3.27 (s, 3H), 1.82-1.76 (m, 2H), 1.66-1.57 (m, 2H). LC-MS (Method V): m/z = 421.1 [M+H]⁺, 3.918 min.

Example 59: 5-benzyl-N-[(3S)-l-methyl-2-oxo-l,2,3,4-tetrahydrospiro[l-benzazepine-5,lcyclopropane]-3-yl]-lH-pyrazole-3-carboxamide

[0589] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NHJTCOs) and ACN (50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford the title compound. ’H NMR (300 MHz, DMSO-î/j) δ 13.15 (s, 1H), 7.88 (d, J= 8.1 Hz, 1H), 7.45-7.36 (m, 2H), 7.35-7.18 (m, 7H), 6.34 (s, 1H), 4.46-4.36 (m, 1H), 3.97 (s, 2H), 3.29 (s, 3H), 2.72-2.64 (m, 1H), 1.51 (t, J= 12.0 Hz, 1H), 1.10-1.04 (m, 1H), 0.74-0.66 (m, 2H), 0.43-0.37 (m, 1H). LC-MS (Method D): m/z = 401.2 [M+H]⁺, 1.994 min.

224

Examples 60A and 60B: 5-benzyl-N-((laS,2S,8bR)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-lH-pyrazoIe-3-carboxamide (60A) and 5-benzyl-N((laR,2R,8bS)-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrobenzo[b]cydopropa[d]azepin-2-yI)-lHpyrazole-3-carboxamide (60B)

HO N-

step 1

Step 1: Préparation of 5-benzyl-N-(4-methyl-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-lH-pyrazole-3-carboxamide

[0590] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 prn, 19 x 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; 254/220 nm to afford the title compound. LC-MS (Method I): m/z = 387.2 [M+H]⁺, 1.405 min.

Step 2: Préparation of 5-benzyl-N-((laS,2S,8bR)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-lH-pyrazole-3-carboxamide (first eluting isomer) and 5benzyl-N-((laR,2R,8bS)-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-lHpyrazole-3-carboxamide (second eluting isomer)

[0591] 5-Benzyl-N-{7-methyl-6-oxo-7-azatricyclo[6.4.0.0^A{2,4}]dodeca-l(8),9,l l-trien-5-yl}-lHpyrazole-3-carboxamidc (30 mg, 0.077 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CFHRALPAK IC, 2.0 cm x 25 cm (5 pm); Mobile Phase A: hexanes, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 30 min; 254/220 nm; RT1: 10.478 min; RT2: 13.826 min to afford the title compounds:

[0592] Example 60A (first eluting isomer): ’H NMR (300 MHz, Chloroform-d) δ 8.47 (d, J= 7.7 Hz, 1H), 7.41-7.08 (m, 9H), 6.57 (s, 1H), 4.85 (d, J= 7.6 Hz, 1H), 4.04 (s, 2H), 3.32 (s, 3H), 2.18-1.92 (m, 2H), 1.16-0.88 (m, 2H). LC-MS (Method J): m/z = 387.2 [M+H]⁺, 2.043 min.

225

[0593] Example 60B (second eluting isomer): 'H NMR (300 MHz, Chloroform-ri) δ 8.29 (s, 1H), 7.397.05 (m, 9H), 6.53 (s, 1H), 4.85 (d, J= 7.6 Hz, 1H), 4.04 (s, 2H), 3.31 (s, 3H), 2.18-1.92 (m, 2H), 1.161.07 (m, 1H), 1.02-0.89 (m, 1H). LC-MS (Method J): m/z = 387.2 [M+H]⁺, 1.409 min.

Example 61: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4Joxazepin-3-yI)-2-(lphenylcyclopropyl)oxazole-4-carboxamide

step 3 step 4

Step 1: Préparation of 1-phenylcyclopropanecarboxamide

[0594] To a stirring solution of 1-phenylcyclopropanecarboxylic acid (1.62 g, 10.0 mmol) in dichloromethane (10 mL) was added thionyl chloride (6 g, 50.0 mmol) dropwise at 0 °C. The resulting solution was stirred for 5 hours at room température and the reaction mixture was concentrated under high vacuum. The residue was then added to ammonium hydroxide (28%, 50 mL) dropwise at 0 °C. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (1.50 g, 93%) as a yellow solid. LC-MS (Method I): m/z = 162.1 JM+H] , 0.725 min.

Step 2: Préparation of ethyl 2-(l-phenylcyclopropyl)oxazole-4-carboxylate

[0595] A mixture of ethyl 3-bromo-2-oxopropanoate (970 mg, 5.0 mmol) and 1 -phenylcyclopropanecarboxamide (810 mg, 5.0 mmol) in éthanol (10 mL) was heated for 16 hours at 80 C under a nitrogen atmosphère. After cooling to room température, the reaction mixture was quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium carbonate (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to afford the title compound (420 mg, 33%) as a white solid. LC-MS (Method C): m/z =258.1 [M+H]⁺, 1.527 min.

226

Step 3: Préparation of2-(l-phenylcyclopropyl)oxazole-4-carboxylic acid

[0596] Lithium hydroxide (5.4 mg, 2.02 mmol) was added to a mixture of ethyl 2-(lphenylcyclopropyl) oxazole-4-carboxylate (100 mg, 0.39 mmol) in tetrahydrofuran (9 mL) and water (3 mL). The reaction mixture was stirred for 16 hours at room température. After removal of tetrahydrofuran under reduced pressure, the pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1 N, 5 mL). The resulting mixture was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (67 mg, 76%) as a yellow oil. LC-MS (Method C): m/z =230.1 [M+H]⁺, 1.291 min.

Step 4: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-2-(lphenylcyclopropyl)oxazole-4-carboxamide

[0597] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: column: Xbridge Prep C18, 19 x 150 mm, 5 pm; Mobile phase: Phase A: water (10 mmol/L NH₄HCO,); Phase B: ACN (20% to 80% over 12 min); Detector, UV220 & 254 nm to afford the title compound. ’H NMR (300 MHz, DMSOYe) δ 8.45 (s, 1H), 8.11 (d, J= 7.8 Hz, 1H), 7.497.19 (m, 9H), 4.85-4.76 (m, 1H), 4.57-4.50 (m, 1H), 4.39-4.33 (m, 1H), 3.29 (s, 3H), 1.61-1.58 (m, 2H), 1.42-1.38 (m, 2H). LC-MS (Method D): m/z = 404.2 [M+H]⁺, 2.148 min.

Example 62: (S)-N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yl)-5-(lphenyIcycIopropyl)isoxazole-3-carboxamide

[0598] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Select CSH Prep C18 OBD Column, 5 pm, 19 χ 150 mm;

Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 70% B over 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSO-Y) δ 10.54 (s, 1H), 8.93 (d, J=8.0Hz, 1H), 8.15 (dd, J=4.4, 1.2 Hz, 1H), 7.55 (dd, J= 8.0, 1.2 Hz, 1H), 7.41-7.29 (m, 5H), 7.17 (dd, J= 8.0, 4.8 Hz, 1H), 6.41(s, 1H), 4.85-4.78 (m, 1H), 4.53-4.42 (m, 2H), 1.58-1.43 (m, 4H). LC-MS (Method D): m/z = 391.1 [M+H]⁺, 1.981 min.

227

Example 63: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)thiazole-2-carboxamide

EDCI,HOBT,DIEA,DMF rt,o/n step 7

Step 1: Préparation of (1-phenylcyclopropyl) methanol

[0599] A solution of borane in tetrahydrofuran (1 M, 60 mL, 60 mmol) was slowly added to a solution of 1-phenylcyclopropanecarboxylic acid (6.5 g, 40 mmol) in tetrahydrofuran (40 mL) at 0 °C. The reaction mixture was stirred for 2 hours at room température, quenched with water (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (5.5 g, 93%) as a colorless oil. LC-MS (Method C): m/z =131.2 [M-H₂0+H]⁺, 1.125 min.

Step 2: Préparation of 1-phenylcyclopropanecarbaldehyde

[0600] Dess-Martin periodinane (35.6 g, 84 mmol) was added to a solution of (1phenylcyclopropyl)methanol (5.4 g, 42 mmol) in dichloromethane (40 mL) at 0 C. The resulting mixture was stirred at 0 °C for 1.5 hours. The solids were removed by filtration and the filtrate was concentrated under vacuum. The resulting residue was purified by column chromatography (ethyl

228 acetate/petroleum ether, 1/10) to afford the title compound (4.4 g, 72%) as a colorless oil. LC-MS (Method C): m/z = 147.2 [M+H]⁺, 1.215 min.

Step 3: Préparation of (E)-(l-(2-methoxyvinyl)cyclopropyl)benzene

[0601] To a solution of methoxymethyl)triphenylphosphonium chloride (22.4 g, 65 mmol) in tetrahydrofuran (30 mL) was added a solution of potassium 2-methylpropan-2-olate in tetrahydrofuran (1 M, 65 mL, 65 mmol) at 0 °C. The resuiting mixture was stirred at 0 °C for 0.5 hour followed by the addition of 1-phenylcyclopropanecarbaldehyde (4.2 g, 29 mmol). The reaction mixture was stirred at room température for 1 hour, quenched by the addition of water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tire title compound (20 g crude) as a yellow oil, which was used directly in the next step without further purification.

Step 4: Préparation of 2-bromo-2-(l-phenylcyclopropyl)acetaldehyde

[0602] To a solution of (E)-(l-(2-methoxyvinyl)cyclopropyl)benzene (3.8 g, 22 mmol) in tetrahydrofuran (20 mL) and water (2 mL) was added N-bromosuccinimide (4.3 g, 24 mmol) at -20 °C. The solution was stirred at -20 °C for 1 hour and concentrated to afford the title compound (8 g crude) as a yellow oil, which was used directly in the next step without further purification.

Step 5: Préparation of ethyl 5-(l-phenylcyclopropyl)thiazole-2-carboxylate

[0603] To a solution of 2-bromo-2-(l -phenylcyclopropyl)acetaldehyde (2 g, 8 mmol) in éthanol (20 mL) was added ethyl 2-amino-2-thioxoacetate (1.1 g, 8 mmol). The reaction mixture was stirred at 80 °C for 4 hours and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (310 mg, 14%) as a yellow oil. LC-MS (Method I): m/z - 274.0 [M+H]⁺, 1.034 min.

Step 6: Préparation of 5-(l-phenylcyclopropyl)thiazole-2-carhoxylic acid

[0604] Lithium hydroxide (52.8 mg, 2.2 mmol) was added to a solution of ethyl 5-( 1 phenylcyclopropyl)thiazole-2-carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (2 mL) and water (1 mL). The reaction mixture was stirred at room température overnight, concentrated under reduced pressure and diluted with water (10 mL). The resuiting mixture was adjusted to pH = 5 with aqueous hydrochloric acid (1 N, 10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (49 mg, 56%) as a yellow oil, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 246.1 [M+H]⁺, 1.200 min.

229

Step 7: S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4Joxazepin-3-yl) -5-(1phenylcyclopropyl)thiazole-2-carboxamide

[0605] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: column: Xbridge Prep C18, 19 χ 250 mm, 5 pm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: ACN (45% to 65% over 7 min); Detector, UV220 & 254 nm to afford the title compound. NMR (400 MHz, DMSOU) δ 8.95 (d, J= 7.5 Hz, 1H), 8.36 (dd, J= 4.7, 1.6 Hz, 1H), 7.74 (s, 1H), 7.70 (dd, J= 7.9, 1.6 Hz, 1H), 7.40-7.23 (m, 6H), 4.88-4.71 (m, 2H), 4.52 (dd, J= 9.1, 6.7 Hz, 1H), 3.35 (s, 3H), 1.47 (s, 4H). LC-MS (Method T): m/z = 421.3 [M+H]⁺, 1.729 min.

Example 64: (S)-l-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3yl)-lH-pyrazole-3-carboxamide

HOBT, EDCI, DIEA, DMF rt, o/n step 2

Step 1: Préparation of 1 -benzyl-4-fluoro-lH-pyrazole-3-carboxylic acid

[0606] Sodium hydride (60%, 1 g, 25 mmol) was added to a solution of ethyl 4-fluoro-lH-pyrazole3-carboxylate (1.2 g, 7.6 mmol) in N,N-dimethylformamide (20 mL) at 0 °C. The resulting mixture was stirred for 0.5 hour at room température followed by adding benzyl bromide (1.36 g, 8.0 mmol). The resulting mixture was stirred for 2 hours at room température. Water (20 mL) was added dropwise. The resulting solution was then stirred at room température for 5 hours. The pH value of the solution was adjusted to 7 with aqueous hydrochloric acid (1 N, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was then purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 5 pm, 19 mm x 250 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B over 7 min; 254 nm to afford the title compound (370 mg, 22%) as a white solid. LCMS (Method D): m/z = 221.1 [M+H]⁺, 1.206 min.

230

Step 2: Préparation of (S)-l-benzyl-4fluoro-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4] oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0607] The crude product obtained using Am idc Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Cl8 OBD Column 19 x 150 mm, 5 pm; Mobile Phase A: water (0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; Detector, UV220 & 254 nm to afford the title compound. 'H NMR (400 MHz, Chloroform-ri) δ 7.66 (d, J= 6.8 Hz, 1H), 7.43-7.40 (m, 3H),7.39-7.21 (m, 6H), 5.26 (s, 2H), 5.13-5.07 (m, 1H), 4.83-4.81 (m, 1H), 4.31-4.26 (m, 1H), 3.47 (s, 3H). LC-MS (Method J): m/z = 395.2 [M+H]⁺, 1.474 min.

Example 65: N-[(4S,9aR)-5-oxo-octahydropyrrolo[2,l-c] [l,4]oxazepin-4-yl]-5-benzyl-4H-l,2,4triazole-3-carboxamide

[0608] The title compound was prepared from N-Boc-D-prolinol using the procedure described in Example 27.

[0609] The crude product was purified by column chromatography on KP-NH modifîed silica gel (CH₂C12-MeOH, 97:3 to 90:10) to afford the title compound. 'H NMR (400MHz, CDCL) δ 8.31 (d, <7=6.3 Hz, 1H), 7.37-7.23 (m, 5H), 4.90 (ddd, J=9.3, 6.3, 2.8 Hz, 1H), 4.21 (s, 2H), 4.17 (dd, J=11.7, 2.6 Hz, 1H), 4.09 (q, <7=8.8 Hz, 1H), 3.98 (d, <7=12.5 Hz, 1H), 3.93-3.82 (m, 1H), 3.52-3.39 (m, 2H), 3.24 (dd, <7=12.8, 9.3 Hz, 1H), 2.33-2.17 (m, 1H), 2.01-1.90 (m, 1H), 1.87-1.70 (m, 1H), 1.66-1.51 (m, 1H). LCMS (Method A): m/z = 356.4 [M+H]⁺, 0.71 min.

Example 66: (S)-N-(5-methyI-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yl)-5-(lphenyIcyclopropyl)-l,3,4-oxadiazole-2-carboxamide

O

step 2 step 1

step 3 step 4

231

Step 1: Préparation of 1-phenylcyclopropanecarbohydrazide

[0610] Triethylamine (93.5 g, 925.5 mmol) was added to a stirring mixture of hydrazine dihydrochloride (32.1 g, 308.6 mmol) in N,N-dimethylformamide (300 mL). The resulting mixture was added to a mixture of 1-phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol), O-(7-azabenzotriazol-Iyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (28.2 g, 74.0 mmol) andN,Ndiisopropylethylamine (23.9 g, 185.1 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was stirred at room température for 2 hours, diluted with water (500 mL) and extracted with ethyl acetate (5 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (6 g, 55.2%) as a white solid. LC-MS (Method E): m/z = 177.0 [M+H]⁺, 1.139 min.

Step 2: Préparation of ethyl 2-oxo-2-(2-(l-phenylcyclopropanecarbonyl)hydrazinyl) acetate

[0611] Ethyl 2-chloro-2-oxoacetate (1.56 g, 11.4 mmol) was added to a stirring solution of 1phenylcyclopropane carbohydrazide (2.00 g, 11.4 mmol) and triethylamine (3.44 g, 34.1 mmol) in dichloromethane (40 mL) at room température. The reaction mixture was stirred for 12 hours at room température, quenched by the addition of water (40 mL) and extracted with dichloromethane (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (3 g, 96.7%) as a yellow oil. LC-MS (Method E): m/z = 277.0 [M+H]⁺, 0.676 min.

Step 3: Préparation of ethyl 5-(l-phenylcyclopropyl)-l,3,4-oxadiazole-2-carboxylate

[0612] Tosyl chloride (0.80 g, 3.62 mmol) was added to a stirring solution of ethyl 2-oxo-2-(2-(1phenylcyclopropanecarbonyl)hydrazinyl)acetate (1.0 g, 3.62 mmol) and triethylamine (1.1 g, 6.6 mmol) in dichloromethane (25 mL). The reaction mixture was stirred for 12 hours at room température, quenched by the addition of water (20 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (0.80 g, 85.6%) as a yellow oil. LC-MS (Method C): m/z = 259.0 [M+H]⁺, 1.457 min.

Step 4: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)-!, 3,4-oxadiazole-2-carboxamide

[0613] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3), ACN (40% ACN to 70% B over 7 min); detector, UV 254

232 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSO-t/e) δ 9.49 (s, IH), 8.37-8.35 (m,

IH), 7.71-7.69 (m, IH), 7.42-7.30 (m, 6H), 4.82-4.80 (m, IH), 4.75-4.73 (m, IH), 4.54-4.50 (m, IH),

3.33 (s, 3H), 1.70-1.69 (m, 2H), 1.54-1.50 (m, 2H). LC-MS (Method T): m/z = 406.3 [M+H]⁺, 2.463 min.

Example 67A and 67B: 5-benzyl-N-((laR,2S,8bS)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yI)-4H-l,2,4-triazoIe-3-carboxamide (67A) and 5-benzylN-((laS, 2R,8bR)-4-methyI-3-oxo-l, la, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d] azepin-2-yl)-4Hl,2,4-triazole-3-carboxamide (67B)

Step 3

Step 1: Préparation of tert-butyl (trans-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrobenzo[b] cyclopropa[d]azepin-2-yl)carbamate

[0614] A solution of tert-butyl (cz5-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)carbamate (100 mg, 0.33 mmol) in 1,8diazabicyclo[5.4.0]undec-7-ene was stirred at 90 °C ovemight. The solution was purified by TLC (ethyl acetate/petroleum ether, 1/8) to afford the title compound (60 mg, 60%) as a yellow solid. LC-MS (Method E): m/z = 325.0 [M+Na]⁺, 0.930 min.

Step 2: Préparation oftrans-2-amino-4-methyl-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d] azepin3(4H)-one hydrochloride

[0615] To a solution of tert-butyl (trans-4-methyl-3-oxo-l, la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)carbamate (60 mg, 0.20 mmol) in 1,4-dioxane (2 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL, 20 mmol). The reaction mixture was stirred for 2 hours at room température and concentrated under high vacuum to afford the title compound

233 (40 mg crude) as a yellow solid, which was used directly in the next step without further purification.

LC-MS (Method S): m/z = 203.3 [M+H]⁺, 0.592 min.

Step 3: Préparation of trans-5-benzyl-N-(4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrobenzo[b] cyclopropa[d]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide

[0616] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; 254/220 nm to afford the title compound. LC-MS (Method J): m/z = 388.2 [M+H]⁺, 1.305 min.

Step 7: Préparation of 5-benzyl-N-((1 aR, 2S, 8bS) -4-methyl-3-oxo-l,1a, 2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-l, 2,4-triazole-3-carboxamide (first eluting isomer) and 5-benzyl-N-((laS,2R,8bR)-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrobenzo[b] cyclopropa[d]azepin-2yl)-4H-l,2,4-triazole-3-carboxamide (second eluting isomer)

[0617] The enantiomers of tra«s-5-benzyl-N-(4-methyl-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide (25 mg, 0.065 mmol) were separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak ID-2, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient: 50% B to 50% B over 22 min; UV 254 & 220 nm; RT 1: 11.72 min; RT 2: 18.02 min to afford the title compounds.

[0618] Example 67A (first eluting isomer): ’H NMR (300 MHz, Methanol-i/4) δ 7.56 (d, 7 = 7.5 Hz, 1H), 7.42-7.19 (m, 9H), 4.23-4.13 (m, 3H), 3.43 (s, 3H), 2.25-2.15 (m, 1H), 1.72-1.58 (m, 1H), 1.25-1.13 (m, 1H), 0.79-0.65 (m, 1H). LC-MS (Method D): m/z = 388.2 [M+H]⁺, 1.806 min.

[0619] Example 67B (second eluting isomer): ’H NMR (300 MHz, Methanol-i/4) δ 7.56 (d, 7= 7.5 Hz, 1H), 7.42-7.19 (m, 9H), 4.23-4.13 (m, 3H), 3.43 (s, 3H), 2.25-2.15 (m, 1H), 1.72-1.58 (m, 1H), 1.25-1.13 (m, 1H), 0.79-0.65 (m, 1H). LC-MS (Method D): m/z = 388.2 [M+H]⁺, 1.812 min.

Example 68A: (R)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-yI)-4H-l,2,4triazoIe-3-carboxamide

HOBT, EDCI, DIEA, DMF rt, o/n

[0620] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column 19 χ 150 mm 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B

234 to 55% B over 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (300 MHz, DMSO-t/e) δ

14.42 (s, IH), 8.80 (br. s, IH), 7.70-7.64 (m, 2H), 7.43-7.25 (m, 8H), 7.07 (d, J = 1.2 Hz, IH), 5.40-5.29 (m, IH), 4.64-4.49 (m, 2H), 4.14 (s, 2H). LC-MS (Method D): m/z = 387.1 [M+H]⁺, 1.322 min.

Example 68B: (S)-5-benzyI-N-(4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-yI)-4H-l,2,4triazole-3-carboxamide

HOBT, EDCI, DIEA, DMF o/n

[0621] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column 19 χ 150 mm 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 & 220 nm to afford the title compound ’H NMR (300 MHz, DMSO-Ts) δ 14.39 (s, IH), 8.80 (s, IH), 7.70-7.65 (m, 2H), 7.41-7.22 (m, 8H), 7.07 (d, J= 1.2 Hz, IH), 5.40-5.31 (m, IH), 4.64-4.49 (m, 2H), 4.14 (s, 2H). LC-MS (Method D): m/z = 387.1 [M+H]⁺, 1.325 min.

Example 69A and 69B: (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][l,2,4]triazolo[4,3-a]azepin-4-yl)4H-l,2,4-triazole-3-carboxamide (69A) and (R)-5-benzyI-N-(5,6-dihydro-4Hbenzo[f] [l,2,4]triazolo[4,3-a]azepin-4-yl)-4H-l,2,4-triazole-3-carboxamide (69B)

step 3 step 4

Step 1: Préparation ofbenzyl (5,6-dihydro-4H-benzo[f][l,2,4]triazolo[4,3-a]azepin-4-yl)carbamate [0622] Formylhydrazine (0.54 g, 9 mmol) was added to a stirring solution of (S)-benzyl (2-thioxo2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-ylcarbamate (1.00 g, 3 mmol) in 1-butanol (15 mL). After stirring at 60 °C for 1 hour and at 150 °C for 15 hours, the reaction mixture was concentrated under high vacuum, diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated

235 under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, l/3) to afford the title compound (0.64 g, 63%) as a white solid. LC-MS (Method E): m/z = 335.1 [M+H]⁺,

0.746 min.

Step 2: Préparation of 5,6-dihydro-4H-benzo[ff[1,2,4]triazolo[4,3-a]azepin-4-amine

[0623] Benzyl (5,6-dihydro-4H-benzo[f][l,2,4]triazolo[4,3-a]azepin-4-yl)carbamate (0.63 g, 1.9 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.2 g) under a hydrogen atmosphère (2-3 atm). The reaction mixture was stirred at room température for 6 hours under a hydrogen atmosphère. The solids were removed by filtration and the filtrate was concentrated under high vacuum to afford the title compound (0.36 g, 95%) as a colorless oil. LC-MS (Method C): m/z = 201.1 [M+H]⁺, 0.848 min.

Step 3: Préparation of (S)-5,6-dihydro-4H-benzo[f][l,2,4]triazolo[4,3-a]azepin-4-amine and (R)-5,6dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-amine

[0624] The enantiomers of 5,6-dihydro-4H-benzo[f][l,2,4]triazolo[4,3-a]azepin-4-amine (0.36 g, 1.8 mmol) were separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IC, 2 χ 25 cm, 5 pm; Mobile Phase A: MTBE, Mobile Phase B: EtOH; Llow rate: 15 mL/min; Gradient: 60% B to 60% B over 23 min; 220/254 nm; RT 1: 12.04 min; RT 2: 20.81 min to afford the title compounds.

[0625] (S)-5,6-dihydro-4H-benzo[f| [ 1,2,4]triazolo[4,3-a]azepin-4-amine (first eluting isomer) : 110 mg (62%) as a white solid. LC-MS (Method C): m/z = 201.1 [M+H]⁺, 0.848 min.

[0626] (R)-5,6-dihydro-4H-benzo[f][l,2,4]triazolo[4,3-a]azepin-4-amine (second eluting isomer): 110 mg (62%) as a white solid. LC-MS (Method C): m/z = 201.1 [M+H]⁺, 0.848 min.

Step 4: Préparation of (S)-5-benzyl-Nf5,6-dihydro-4H-benzo[f][l,2,4]triazolo[4,3-a]azepin-4-yl)-4H1,2,4-triazole-3-carboxamide

[0627] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100Â, 5 pm, 19 mm χ 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 40% B over 7 min; UV 254 & 220 nm to afford the title compound. 'HNMR (300 MHz, DMSO-de) δ 14.39 (s, 1H), 8.93 (m, 2H), 7.62-7.59 (m, 1H), 7.56-7.43 (m, 3H), 7.38-7.23 (m, 5H), 5.02-4.92 (m, 1H), 4.14 (s, 2H), 2.84-2.77 (m, 1H), 2.60-2.55 (m, 1H), 2.48-2.40 (m, 2H). LC-MS (Method D): m/z = 386.2 [M+H|⁺, 1.489 min.

236

Exampie 69B: (R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f|[l,2,4]triazolo[4,3-a]azepin-4-yl)-4H-l,2,4triazole-3-carboxamide

HOBT, EDCI, DIEA, DMF rt, o/n

[0628] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge C18 OBD Prep Column, 100Â, 5 pm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/rnin;

Gradient: 20% B to 40% B over 7 min; UV 254 & 220 nm to afford the title compound ’H NMR (300 MHz, DMSO-rie) δ 14.39 (s, IH), 8.93 (m, 2H), 7.62-7.59 (m, IH), 7.56-7.43 (m, 3H), 7.37-7.22 (m, 5H), 5.02-4.92 (m, IH), 4.14 (s, 2H), 2.84-2.73 (m, IH), 2.58-2.54 (m, IH), 2.48-2.41 (m, 2H). LC-MS (Method D): m/z = 386.2 [M+H]⁺, 1.486 min.

Example 70A: (R)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-yl)isoxazole-3carboxamide

CbzCI, K₂CO₃

CH₂CI₂, h₂o rt, 16 h

Lawesson's Reagent

THF, rt, 16 h

step 1 step 2

step 7 step 6

237

Step 1: Préparation of (S)-benzyl (4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

[0629] A solution of potassium carbonate (4.8 g, 35 mmol) in water (9 mL) was added to a solution of (S)-3-amino-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one hydrochloride (1.5 g, 7 mmol) in dichloromethane (70 mL) and then benzyl chloroformate (1.8 g, 10.5 mmol) was added. Tire reaction mixture was stirred at room température for 16 hours. The precipitate was collected by filtration, washed with water (20 mL) and dried under high vacuum to afford the title compound (1.44 g, 66%) as a white solid. LC-MS (Method C): m/z = 313.1 [M+H]⁺, 1.365 min.

Step 2: Préparation of (S)-benzyl 4-thioxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-ylcarbamate

[0630] Lawesson’s reagent (2.43 g, 6 mmol) was added to a solution of (S)-benzyl 4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-ylcarbamate (1.9 g, 6 mmol) in tetrahydrofuran (50 mL) and the reaction mixture was stirred under a nitrogen atmosphère for 16 hours at room température. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.85 g crude) as a light yellow solid. LC-MS (Method E): m/z = 351.0 [M+Na]⁺, 0.946 min.

Step 3: Préparation of (R)-benzyl 4-(2,2-dimethoxyethylamino)-2,3-dihydrobenzo[b][l,4]-oxazepin-3ylcarbamate

[0631] 2,2-Dimethoxyethanamine (2.37 g, 22.6 mmol) was added to a solution of (S)-benzyl 4-thioxo2,3,4,5-tetraliydrobenzo[b][l,4]oxazepin-3-ylcarbamate (1.85 g, 5.65 mmol) and mercury dichloride (2.0 g, 7.35 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 55 °C for 2 hours and cooled to room température. Solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (2.20 g, 98%) as a light yellow oil. LCMS (Method C): m/z = 400.2 [M+H]⁺, 1.157 min.

Step 4: Préparation of benzyl (4,5-dihydrobenzo[b]imidazo[l,2-d][1,4]oxazepin-4-yl)carbamate

[0632] A solution of (R)-benzyl 4-(2,2-dimethoxyethylamino)-2,3-dihydrobenzo[b] [ 1,4]-oxazepin-3ylcarbamate (2.2 g, 5.5 mmol) in formic acid (15 mL, 96%) was stirred at 100°C for 2 hours. The black sédiment was removed by filtration and the filtrate was concentrated under reduced pressure. Tire resulting residue was diluted with water (50 mL), basified with aqueous sodium hydroxide (1 N, 30 mL) to pH = 6 and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue

238 was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (0.45 g, 24%) as a white solid. LC-MS (Method E): m/z = 336.0 [M+H]⁺, 0.655 min.

Step 5.· Préparation of (S)-benzyl (4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-yl)carbamate (first eluting isomer) and (R)-benzyl (4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-yl)carbamate (second eluting isomer)

[0633] The enantiomers of benzyl (4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-yl)carbamate (450 mg, 1.35 mmol) were separated by SFC with the following conditions: Column: CHIRALPAK-ICSFC, 5 cm x 25 cm (5 pm); Mobile Phase A: CO₂ 50%, Mobile Phase B: MeOH: 50%; Flow rate: 150 ml,/min; 220 nm; RT 1: 5.65 min; RT 2: 6.91 min to afford the title compounds:

[0634] (S)-benzyl (4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-yl)carbamate: (250 mg, 56%) as a white solid. LC-MS (Method E): m/z = 336.0 [M+H]⁺, 0.655 min.

[0635] (R)-benzyl (4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-yl)carbamate (second eluting isomer): (200 mg, 45%) as a white solid. LC-MS (Method E): m/z = 336.0 [M+H]⁺, 0.655 min.

Step 6: Préparation of (R)-4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-amine

[0636] (R)-Benzyl (4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-yl)carbamate (0.25 g, 0.75 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.5 g) under a hydrogen atmosphère (2-3 atm). The reaction mixture was stirred for 6 hours at room température under a hydrogen atmosphère. The solids were removed by filtration and the filtrate was concentrated under high vacuum to afford the title compound (0.14 g, 93%) as a white solid. LC-MS (Method C): m/z = 202.1 [M+H]⁺, 0.758 min.

Step 7: Préparation of (R)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[l ,2-d][1,4]oxazepin-4-yl)isoxazole3-carboxamide

[0637] The crude product obtained using Arnide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column, 5 pm, 19 * 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 65% B over 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (300 MHz, DMSO-dâ) δ 9.24 (d, J= 8.7 Hz, 1H), 7.71-7.65 (m, 2H), 7.40-7.28 (m, 8H), 7.07 (d, J=1.2 Hz, 1H), 6.59 (s, 1H), 5.43-5.34 (m, 1H), 4.61-4.46 (m, 2H), 4.24 (s, 2H). LC-MS (Method D): m/z = 387.1 [M+H]⁺, 1.579 min.

239

Example 70B: (S)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[l,2-d] [l,4]oxazepin-4-yI)isoxazole-3carboxamide

Pd/C, H₂, MeOH rt, 6 h

HOBT, EDCi, DIEA, DMF rt, o/n step 2

Step 1: Préparation of (S)-4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-amine

[0638] (S)-Benzyl (4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepin-4-yl)carbamate (0.2 g, 0.6 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.2 g) under a hydrogen atmosphère (2-3 atm). The reaction mixture was stirred at room température for 6 hours under a hydrogen atmosphère. The solids were removed by filtration and the filtrate was concentrated under high vacuum to afford the title compound (0.11 g, 92%) as a white solid. LC-MS (Method C): m/z =

202.1 [M+H]⁺, 0.758 min.

Step 2: Préparation of (S)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[l,2-d][l,4]oxazepm-4-yl)isoxazole3-carboxamide

[0639] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 45% B to 57% B over 7 min; UV 254 & 220 nm to afford the title compound. Ή NMR (300 MHz, DMSO-ri₆) δ 9.24 (d, J= 8.4 Hz, 1H), 7.71-7.65 (m, 2H), 7.42-7.28 (m, 8H), 7.07 (d, J= 1.5 Hz, 1H), 6.59 (s, 1H), 5.43-5.34 (m, 1H), 4.62-4.45 (m, 2H), 4.24 (s, 2H). LC-MS (Method V): m/z = 387.1 [M+H]⁺, 2.491 min.

Example 71 A: (S)-5-benzyI-N-(5,6-dihydro-4H-benzo[f| [l,2,4]triazolo[4,3-a] azepin-4-yl)isoxazole3-carboxamide

HOBT, EDCI, DIEA, DMF rt, o/n

240

[0640] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (lOmmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 58% B over 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (300 MHz, DMSO-dô) δ 9.36 (d, J= 8.4 Hz, 1H), 8.93 (s, 1H), 7.62-7.59 (m, 1H), 7.55-7.43 (m, 3H), 7.40-7.26 (m, 5H), 6.58 (s, 1H), 5.01-4.92 (m, 1H), 4.24 (s, 2H), 2.86-2.77 (m, 1H), 2.49-2.39 (m, 3H). LC-MS (Method D): m/z =

386.2 [M+H]⁺, 1.805 min.

Example 71B: (R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f|[l,2,4]triazolo[4,3-a]azepin-4-yl)isoxazole3-carboxamide

HOBT, EDCI, DIEA, DMF rt, o/n

[0641] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B over 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (300 MHz, DMSO-t/₆) δ 9.36 (d, 7= 8.1 Hz, 1H), 8.93 (s, 1H), 7.63-7.59 (m, 1H), 7.55-7.43 (m, 3H), 7.40-7.26 (m, 5H), 6.58 (s, 1H), 5.01-4.92 (m, 1H), 4.24 (s, 2H), 2.86-2.77 (m, 1H), 2.49-2.38 (m, 3H). LC-MS (Method D): m/z =

386.2 [M+H]⁺, 1.809 min.

241

Example 72: (S)-N-(5-methyI-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-5-(lphenylcyc!opropyl)-lH-pyrazole-3-carboxamide

step 1 step 2

t-BuOK, toluene 0 °C to rt, 4 h

nh₂nh₂ h₂o

step 3 step 4

EtOH, reflux, 1.5 h

Step 1: Préparation ofN-methoxy-N-methyl-l-phenylcyclopropanecarboxamide

[0642] Ν,Ν-diisopropylethylamine (47.2 g, 219.6 mmol) was added to a mixture of 1phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol), Ο,Ν-dimethylhydroxylamine hydrochloride (6.5 g, 67.8 mmol), N-(3-dimethyiaminopropyI))-N’-ethylcarbodiimide hydrochloride (14.2 g, 73.9 mmol) and 1-hydroxybenzotriazole (10.0 g, 73.9 mmol) in Ν,Ν-dimethylformamide (60 mL). The resuiting mixture was stirred ovemight at room température, diluted with water (300 mL) and extracted ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to afford the title compound (11.2 g, 89.6%) as colorless oil. LC-MS (Method K): m/z =206.0 [M+H]⁺, 1.489 min.

Step 2: Préparation of l-(l-phenylcyclopropyl)ethanone

[0643] To a solution of méthylmagnésium bromide (3 M, 14 mL, 42 mmol) in tetrahydrofuran was added a solution ofN-methoxy-N-methyl-l-phenylcyclopropanecarboxamide (11.2 g, 24.4 mmol) in tetrahydrofuran (50 mL) at 0 °C. Tire resuiting mixture was stirred ovemight at room température, quenched with saturated ammonium chloride (50 mL), extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine, dned with sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether,

242

1/20) to afford the title compound (7.4 g, 85%) as a colorless oil. LC-MS (Method E): m/z = 161.0

[M+H]⁺, 0.889 min.

Step 3: Préparation of ethyl 2,4-dioxo-4-(l-phenylcyclopropyl)butanoate

[0644] To a mixture of l-(l-phenylcyclopropyl)ethanone (1.92 g, 12 mmol) and diethyl oxalate (2.1 g, 14.4 mmol) in toluene (8 mL) was added potassium 2-methylpropan-2-olate (1.7 g, 15.6 mmol) at 0 °C. The resulting mixture was stirred at room température for 4 hours and concentrated under vacuum. The residue was diluted with water (20 mL). The resulting mixture was neutralized to pH = 6 with aqueous hydrochloric acid (1 N) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to afford the title compound (1.95 g, 61%) as a yellow solid. LC-MS (Method S): m/z = 261.2 [M+H]⁺, 1.076 min.

Step 4: Préparation of ethyl 5-(l-phenylcyclopropyl)-lH-pyrazole-3-carboxylate

[0645] To a solution of ethyl 2,4-dioxo-4-(l-phenylcyclopropyl)butanoate (800 mg, 3.0 mmol) in éthanol (8 mL) was added hydrazine hydrate (80% aqueous solution, 200 mg, 3.0 mmol). The reaction mixture was stirred at 80 °C for 1.5 hours and concentrated under vacuum. The resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (550 mg, 70%) as a yellow solid. LC-MS (Method K): m/z =256.7 [M+H]⁺, 1.640 min.

Step 5: Préparation of 5-(l-phenylcyclopropyl)-lH-pyrazole-3-carboxylic acid

[0646] To a solution of ethyl 5-(l-phenylcyclopropyl)-lH-pyrazole-3-carboxylate (470 mg, 1.8 mmol) in methanol (4.5 mL) and water (1.5 mL) was added sodium hydroxide (432 mg, 10.8 mmol). The reaction mixture was stirred ovemight at room température and concentrated under vacuum. The residue was diluted with water (20 mL) and adjusted to pH = 5 using aqueous hydrochloric acid (1 N) and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (280 mg crude) as a yellow solid, which -was used directly in the next step without further purification. LC-MS (Method K): m/z =228.7 [M+H]⁺, 1.434 min.

Step 6: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)-lH-pyrazole-3-carboxamide

[0647] The crude product obtained using Arnide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3), ACN (40% ACN to 65% B over 7 min); detector, UV 254 & 220 nm to afford the title compound. 'H NMR (300 MHz, DMSO-rig) 13.16(s, 1H), 8.06 (d, J= 8.1 Hz, 1H),

243

7.55-7.46 (m, 1H), 7.38-7.17 (m, 8H), 6.34 (s, 1H), 4.93-4.75 (m, 1H), 4.60-4.28 (m, 2H), 3.31 (s, 3H),

1.39-1.16 (m, 4H). LC-MS (Method O): m/z = 403.05 [M+H]⁺, 1.511 min.

Example 73: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yI)-5-(lphenylcyclopropyl)-lH-pyrazole-3-carboxamide

[0648] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge C18 OBD Prep Column, 100Â, 5 pm, 19 mm χ 250 mm; Mobile Phase A: water (lOmmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 50% B over 7 min; UV 254 & 220 nm to afford the title compound. ^]H NMR (300 MHz, DMSO-70 δ 13.18 (s, 1H), 8.38-8.35 (m, 1H), 8.24 (d, J= 7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.367.20 (m, 6H), 6.54-6.35 (m, 1H), 4.90-4.80 (m, 1H), 4.70-4.62 (m, 1H), 4.53-4.46 (m, 1H), 3.35 (s, 3H), 1.34-1.30 (m, 4H). LC-MS (Method D): m/z = 404.2 [M+H]⁺, 1.872 min.

Example 74: (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yI)-l(pyridin-2-ylmethyl)-lH-pyrazole-3-carboxamide

[0649] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep Cl8 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 57% B over 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSO-dô) δ 8.56 (d, J= 4.8 Hz, 1H), 8.36 (dd, J= 4.8, 1.6 Hz, 1H), 8.27 (d, J= 7.6 Hz, 1H), 8.16 (d, 7= 4.4 Hz, 1H), 7.87-7.77 (m, 1H), 7.70 (dd, 7= 8.0, 1.6 Hz, 1H), 7.38-7.31 (m, 2H), 7.21 (d, 7= 8.0 Hz, 1H), 5.47 (s, 2H), 4.88-4.80 (m, 1H), 4.71-4.64 (m, 1H), 4.52-4.47 (m, 1H), 3.35 (s, 3H). LC-MS (Method V): m/z = 397.1 [M+H]⁺, 2.159 min.

244

Example 75A and 75B: 5-benzyl-N-((laS,2S,8bR)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocycIopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-l,2,4-triazoIe-3-carboxamide (75A) and 5benzyl-N-((laR,2R,8bS)-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrocycIopropa[d]pyrido[2,3-b]azepin2-yl)-4H-l,2,4-triazole-3-carboxamide (75B)

step 1 chiral seperation

O step 2

Step 1: Préparation of 5-benzyl-N-(cis-4-methyl-3-oxo-1, la, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3b]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide

[0650] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: column: X bridge Prep C18, 19 x 150 mm, 5 pm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: ACN (20% to 80% over 12 min); Detector, UV 220 & 254 nm to afford the title compound (55 mg, 44.3%) as a white solid. LC-MS (Method C): m/z = 389.2 [M+H]⁺, 1.111 min.

Step 2: Préparation of 5-benzyl-N-((laR,2R,8bS)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide (first eluting isomer) and 5-benzyl-N-((laS, 2S, 8bR)-4-methyl-3-oxo-l, la, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3b]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide (second eluting isomer) ,O ,O

[0651] The enantiomers of 5-benzyl-N-(cZy-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2₅3-b]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide (55 mg, 0.14 mmol) were separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IC, 2 x 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 19 mL/min; Gradient: 35% B to 35% B over 18.5 min; UV 220 & 254 nm; RT 1: 13.00 min; RT 2: 15.67 min to afford the title compounds:

245

[0652] Example 75B (first eluting isomer): 'H NMR (400 MHz, DMSOU) δ 14.37 (s, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.40-8.38 (m, 1H), 8.02-7.98 (m, 1H), 7.35-7.25 (m, 6H), 4.46 (d, J= 7.2 Hz, 1H), 4.16 (s,

2H), 3.30 (s, 3H), 2.33-2.26 (m, 1H), 2.05-1.99 (m, 1H), 1.21-1.14 (m, 1H), 1.11-1.04 (m, 1H). LC-MS (Method D). m/z = 389.2 [M+H]⁺, 1.651 min.

[0653] Example 75A (second eluting isomer): ^JH NMR (400 MHz, DMSOU) δ 8.54 (d, J= 7.2 Hz, 1H), 8.40-8.38 (m, 1H), 8.02-7.98 (m, 1H), 7.38-7.23 (m, 6H), 4.46 (d, J= 7.2 Hz, 1H), 4.14 (s, 2H), 3.30 (s, 3H), 2.32-2.26 (m, 1H), 2.06-1.99 (m, 1H), 1.20-1.15 (m, 1H), 1.10-1.04 (m, 1H). LC-MS (Method D): m/z = 389.2 [M+H]⁺, 1.656 min.

Example 76: (S)-l-benzyI-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2bj [l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

HOBT, EDCI, DIEA, DMF rt, o/n

[0654] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 32% B to 54% B over 7 min; UV 254 & 220 nm to afford the title compound. 'H NMR (300 MHz, DMSO-Ts) δ 8.37 (dd, 7= 4.5, 1.5 Hz, 1H), 8.26 (d, 7= 7.5 Hz, 1H), 8.15 (d, 7= 4.5 Hz, 1H), 7.71 (dd,7=8.1, 1.8 Hz, 1H), 7.43-7.27 (m, 6H), 5.36 (s, 2H), 4.90-4.80 (m, 1H), 4.73-4.65 (m, 1H), 4.55-4.48 (m, 1H), 3.36 (s, 3H). LC-MS (Method D): m/z = 396.1 [M+H]⁺, 1.893 min.

Example 77: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)isoxazole-3-carboxamide

NaOH, MeOH, H₂O rt, o/n step 2

step 1

HOBT, EDCI, DIEA, DMF rt, o/n step 3

246

Step 1: Préparation of ethyl 5-(l-phenylcyclopropyl)isoxazole-3-carboxylate

[0655] To a mixture of ethyl 2,4-dioxo-4-(l-phenylcyclopropyl)butanoate (970 mg, 3.7 mmol) in éthanol (10 mL) was added hydroxylamine hydrochloride (255 mg, 3.7 mmol). The reaction mixture was heated at reflux and stirred for 4 hours. Upon concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (260 mg, 27%) as a yellow solid. LC-MS (Method K): m/z = 258.1 [M]⁺, 1.603 min.

Step 2: Préparation of 5-(l-phenylcyclopropyl)isoxazole-3-carboxylic acid

[0656] To a solution of ethyl 5-(l-phenylcyclopropyl)isoxazole-3-carboxylate (100 mg, 0.39 mmol) in methanol (3 mL) and water (1 mL) was added sodium hydroxide (93 mg, 2.33 mmol). The resulting mixture was stirred at room température ovemight, concentrated to dryncss and diluted with water (10 mL). The reaction mixture was adjusted to pH = 5 with aqueous hydrochloric acid (1 N, 10 mL), and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (80 mg crude) as a yellow solid. LC-MS (Method E): m/z = 229.9 [M+H]⁺, 0.840 min.

Step 3: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)isoxazole-3-carboxamide

[0657] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 75% B over 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (300 MHz, DMSO-î/ô) δ 8.95 (d, J= 8.1 Hz, 1H), 8.37 (dd, J= 4.8, 1.5 Hz, 1H), 7.70 (dd, J= 7.8, 1.5 Hz, 1H), 7.43-7.29 (m, 6H), 6.38 (s, 1H), 4.90-4.80 (m, 1H), 4.70-4.62 (m, 1H), 4.55-4.48 (m, 1H), 3.35 (s, 3H), 1.58-1.51 (m, 2H), 1.50-1.42 (m, 2H). LC-MS (Method D): m/z = 405.1 [M+H]⁺, 2.134 min.

247

Example 78: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)-lH-imidazole-2-carboxamide

Step 1: Préparation of2-bromo-l-(l-phenylcyclopropyl)ethanone

[0658] To a solution of l-(l-phenylcyclopropyl)ethanone (4.0 g, 25.0 mmol) and triethylamine (5.0 g, 50 mmol) in dichloromethane (100 mL) was added trimethylsilyl trifluoromethanesulfonate (5.55 g, 25.0 mmol) at 0 °C. After stirring for 0.5 hour, l-bromopyrrolidine-2,5-dione (4.9 g, 27.5 mmol) was added in portions at 0 °C. The reaction mixture was stirred for another 2 hours, quenched with 100 mL of water and extracted with dichloromethane (3 x 80 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to afford the title compound (3.4 g, 57%) as a yellow oil. LC-MS (Method E): m/z =238.8 [M+H]⁺, 0.971 min.

Step 2: Préparation of ethyl 5-(l-phenylcyclopropyl)-lPI-imidazole-2-carboxylate

[0659] A solution of 2-bromo-l-(l-phenylcyclopropyl)ethanone (3.4 g, 14.2 mmol), ethyl 2-amino-2iminoacetate (1.65 g, 14.2 mmol) and triethylamine (4.3 g, 42.6 mmol) in éthanol (50 mL) was heated at reflux for 5 hours. Upon concentration under reduced pressure the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (520 mg, 14%) as a yellow solid. LC-MS (Method C): m/z = 257.0 [M+H]⁺, 1.000 min.

Step 3: Préparation of 5-(l-phenylcyclopropyl)-lH-imidazole-2-carboxylic acid

[0660] To a solution of ethyl 5-(l-phenylcyclopropyl)-lH-imidazole-2-carboxylate (300 mg, 1.2 mmol) in methanol (9 mL) and water (3 mL) was added sodium hydroxide (288 mg, 7.2 mmol). The mixture was stirred at room température overnight. Tire solution was adjusted to pH = 5, and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (130 mg crude) as a yellow solid. LC-MS (Method C): m/z = 229.1 [M+H]⁺, 0.906 min.

248

Step 4: Préparation of (S)-Nf5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)-lH-imidazole-2-carboxamide

[0661] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 χ 150 mm; mobile phase, water (10 mmol/L NH4HCO3), ACN (40% ACN to 70% B over 7 min); detector, UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSO-Ts) δ 13.11-12.79 (m, IH), 8.32-8.17 (m, IH), 7.51 (dd, J= 7.6, 1.9 Hz, IH), 7.37-7.16 (m, 8H), 6.85-6.44 (m, IH), 4.88-4.74 (m, IH), 4.66-4.50 (m, IH), 4.45-4.35 (m, IH), 3.32 (s, 3H), 1.38-1.27 (m, 2H), 1.25-1.12 (m, 2H). LC-MS (Method Q): m/z = 403.3 [M+H]⁺, 1.533 min.

Example 79: (S)-7-(2-fluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3yl)benzo [d] thiazole-2-carboxamide

Pd(dppf)CI₂, K₂CO₃dioxane, H₂O °C, o/n step 2

Step 1: Préparation of (S)-7-bromo-N-(5-methyl-4-oxo-2,3,4,t>-tetrahydrobenzo[b][l,4] oxazepin-3yl) benzo[d]thiazole-2-carboxamide

[0662] Utilizing the procedure described in Example 54 provided title compound (370 mg) as a yellow solid that was used in the next step without purification. LC-MS (Method S): m/z = 432.2 [M+H]⁺, 1.102 min.

Step 2: Préparation of7-(2-fluorophenyl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4] oxazepin-3-yl)benzo[d]thiazole-2-carboxamide

[0663] [1,1 ’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.04mmol) was added to a mixture of (S)-7-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxaz-epin-3yl)benzo[d]thiazole-2-carboxamide (170 mg, 0.39 mmol), 2-fluorophenylboronic acid (85 mg, 0.59 mmol) and potassium carbonate (109 mg, 0.79 mmol) in dioxane (2 mL) and water (0.5 mL) under an

249 atmosphère of nitrogen. The resulting mixture was stirred overnight at 80 °C. Solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by PrepHPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow⁷ rate: 20 mL/min; Gradient: 3% B to 38% B over 7 min; 254 & 220 nm; Rt: 6.33 min to afford the title compound. ’H NMR (300 MHz, DMSO-r/e) δ 9.31-9.29 (d, J= 7.5 Hz, 1H), 8.29-8.26 (d, J = 8.1 Hz, 1H), 7.79-7.77 (m, 1H), 7.68-7.60 (m, 2H), 7.60-7.51 (m, 2H), 7.43-7.26 (m, 5H), 4.89-4.72 (m, 2H), 4.50-4.44 (m, 1H), 3.33 (s, 3H). LCMS (Method T): m/z = 448.3 [M+H]⁺, 1.884 min.

Example 80A and 80B: 5-benzyl-N-((laS,2S,8bR)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yI)-lH-pyrazole-3-carboxamide (80A) and 5-benzylN-((laR,2R,8bS)-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)lH-pyrazole-3-carboxamide (80B)

step 1

step 2

Step 1: Préparation of 5-benzyl-N-(cis-4-methyl-3-oxo-l,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3b]azepin-2-yl) -lH-pyrazole-3-carboxamide

[0664] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge C18 OBD Prep Column, 100Â, 5 pm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 50% B over 7 min; UV 254 & 220 mn to afford the title compound. LC-MS (Method D): m/z = 388.2 [M+H]⁺, 1.757 min.

Step 2: Préparation of 5-benzyl-N-((laS,2S,8bR)-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydro cyclopropa[d]pyrido[2,3-b]azepin-2-yl)-lH-pyrazole-3-carboxamide (first eluting isomer) and 5-benzylN-((laR, 2R, 8bS)-4-methyl-3-oxo-l, la, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1Hpyrazole-3-carboxamide (second eluting isomer)

[0665] The racemate of 5-benzyl-N-(cis-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-lH-pyrazole-3-carboxamide (60 mg, 0.16 mmol) was

250 separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL IC, 2 χ 25 cm, 5 pm;

Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 60% B to 60% B over

16.5 min; UV 254 & 220 nm; RT 1: 8.27 min; RT 2: 13.00 min to afford the title compounds:

[0666] Example 80A (first eluting isomer): ’H NMR (300 MHz, Methanol-A) δ 8.38 (dd, J = 4.8, 1.8 Hz, 1H), 7.94 (dd, J= 7.8, 1.8 Hz, 1H), 7.35-7.21 (m, 6H), 6.52 (s, 1H), 4.65 (s, 1H), 4.05 (s, 2H), 3.40 (s, 3H), 2.31-2.23 (m, 1H), 2.12-2.03 (m, 1H), 1.32-1.26 (m, 1H), 1.22-1.13 (m, 1H). LC-MS (Method D): m/z = 388.2 [M+H]⁺, 1.757 min.

[0667] Example 80B (second eluting isomer); ’H NMR (300 MHz, Methanol-tri) δ 8.38 (dd, J= 4.5, 1.8 Hz, 1H), 7.94 (dd, J= 7.8, 1.5 Hz, 1H), 7.35-7.21 (m, 6H), 6.52 (s, 1H), 4.65 (s, 1H), 4.06 (s, 2H), 3.40 (s, 3H), 2.31-2.23 (m, 1H), 2.12-2.04 (m, 1H), 1.33-1.26 (m, 1H), 1.22-1.13 (m, 1H). LC-MS (Method D): m/z = 388.2 [M+H]⁺, 1.757 min.

Example 81A and 81B: 5-benzyl-N-((laS,2S,8bR)-4-methyI-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)isoxazole-3-carboxamide (81 A) and 5-benzyl-N((laR, 2R,8bS)-4-methyl-3-oxo-l,la, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2yl)isoxazole-3-carboxamide (81B)

step 1

step 2

Step 1 : Préparation of5-benzyl-N-(cis-4-methyl-3-oxo-l, la, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3b]azepin-2-yl)isoxazole-3-carboxamide

[0668] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min: Gradient; 25% B to 55% B over 7 min; UV 254 & 220 nm to afford the title compound. LC-MS (Method D); m/z = 389.1 [M+H]⁺, 2.036 min.

251

Step 2: Préparation of 5-benzyl-N-((laR,2R,8bS)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)isoxazole-3-carboxamide (first eluting isomer) and 5henzyl-N-((laS, 2S, 8bR)-4-methyl-3-oxo-l, la, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2yl)isoxazole-3-carboxamide (second eluting isomer)

[0669] The racemate of 5-benzyl-N-(cis-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)isoxazole-3-carboxamide (60 mg, 0.15 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IC, 2 x 25 cm, 5 pm; Mobile Phase A: hexanes, Mobile Phase B: EtOH; Flow rate: 18 mL/min; Gradient: 50% B to 50% B over 17 min; UV 254 & 220 nm; RT 1:12.098 min; RT 2: 14.358 min to afford the title compounds:

[0670] Example 81B (first eluting isomer): ’HNMR (300 MHz, DMSO-r/ô) δ 8.98 (d, 7 = 7.5 Hz, 1H), 8.40 (dd, 7= 4.5, 1.8 Hz, 1H), 7.98 (dd, 7= 7.5, 1.8 Hz, 1H), 7.40-7.26 (m, 6H), 6.62 (s, 1H), 4.45 (d, 7= 7.2 Hz, 1H), 4.24 (s, 2H), 3.29 (s, 3H), 2.34-2.25 (m, 1H), 2.02-1.94 (m, 1H), 1.25-1.06 (m, 2H). LC-MS (Method D): m/z = 389.1 [M+H]⁺, 2.036 min.

[0671] Example 81A (second eluting isomer): 'H NMR (300 MHz, DMSO-Ts) δ 8.98 (d, J= 7.2 Hz, 1H), 8.40 (dd, 7= 4.5, 1.8 Hz, 1H), 7.98 (dd, 7= 7.5, 1.8 Hz, 1H), 7.40-7.26 (m, 6H), 6.62 (s, 1H), 4.45 (d, 7= 7.2 Hz, 1H), 4.24 (s, 2H), 3.29 (s, 3H), 2.34-2.25 (m, 1H), 2.02-1.94 (m, 1H), 1.22-1.06 (m, 2H). LC-MS (Method D): m/z = 389.1 [M+H]⁺, 2.027 min.

Example 82A and 82B: l-benzyl-4-fluoro-N-((laS,2S,8bR)-4-methyl-3-oxo-l,la?2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yI)-lH-pyrazole-3-carboxamide (82A) and 1-benzyl4-fluoro-N-((laR,2R,8bS)-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrocycIopropa[d]pyrido[2,3

b] azepin-2-yl)-lH-pyrazole-3-carboxamide (82B) .0

HO

HOBT, EDC1, DIEA, DMF rt, o/n step 1 step 2

252

Step 1: Préparation of l-benzyl-4-fluoro-N-(cis-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-lH-pyrazole-3-carboxamide

[0672] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge C18 OBD Prep Column, 100Â, 5 pm, 19 mm χ 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; UV 254 & 220 nm to afford the title compound (58 mg, 50%) as a white solid. LC-MS (Method V): m/z = 406.1 [M+H]⁺, 2.852 min.

Step 2: Préparation of l-benzyl-4-fluoro-N-((laR,2R,8bS)-4-methyl-3-oxo-l, la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-lH-pyrazole-3-carboxamide (first eluting isomer) and l-benzyl-4-fluoro-N-((laS, 2S, 8bR)-4-methyl-3-oxo-l, la, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3b]azepin-2-yl)-lH-pyrazole-3-carboxamide (second eluting isomer)

[0673] The racemate of l-benzyl-4-fhioro-N-(cis-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-lH-pyrazole-3-carboxamide (58 mg, 0.15 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IC, 2 χ 25 cm, 5 pm;

Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 18 mL/min; Gradient: 50% B to 50% B over 23 min; UV 254 & 220 nm; RT 1: 10.936 min; RT 2: 16.976 min to afford the title compounds:

[0674] Example 82B (first eluting isomer): ’H NMR (300 MHz, DMSOA) δ 8.39 (dd, J= 4.8, 1.8 Hz, IH), 8.17-8.12 (m, 2H), 8.00 (dd, J= 7.8, 1.8 Hz, 1H), 7.44-7.28 (m, 6H), 5.36 (s, 2H), 4.46 (d, J= 6.9 Hz, 1H), 3.30 (s, 3H), 2.33-2.24 (m, 1H), 2.06-1.98 (m, 1H), 1.26-1.14 (m, 1H), 1.12-1.03 (m, 1H). LCMS (Method V): m/z = 406.1 [M+HR, 2.852 min.

[0675] Example 82A (second eluting isomer): ’H NMR (300 MHz, Methanol-c/4) δ 8.38 (dd, J= 4.8, 1.8 Hz, 1H), 7.94 (dd, J= 7.5, 1.8 Hz, 1H), 7.77 (d, J= 4.5 Hz, 1H), 7.44-7.27 (m, 6H), 5.35 (s, 2H), 4.66 (s, 1H), 3.41 (s, 3H), 2.32-2.23 (m, 1H), 2.15-2.03 (m, 1H), 1.33-1.26 (m, 1H), 1.22-1.14 (m, 1H). LC-MS (Method D): m/z = 406.1 [M+HR, 1.932 min.

253

Example 83A: 5-benzyI-N-((laS,2S,8bR)-5,7-difluoro-3-oxo-l,la,2,3,4,8bhexahydrobenzo [b] cyclopropafd] azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide

Pd(PPh₃)₄, DMF _F °C, 16 h

NH₂

7^ QH

SOCI₂, DCM rt, 3 h

step 1 step 2

Grubbs catalyst 2^nd génération toluene °C, 16 h step 3

1) KOH, Et₂O, 0°C, 1h

2) Pd(OAc)₂, THF, rt, o/n step 4

TMSI, TMEDA, l₂

DCM, 0 °C, 3 h

step 5

step 9

Step 1: Préparation of2,4-difluoro-6-vinylbenzenamine

[0676] To a solution of 2-bromo-4,6-difluoroaniline (10.0 g, 48.0 mmol) in N,N-dimethylformamide (50 mL) was added tributyl(ethenyl)stannane (18.0 g, 56.7 mmol) and tetrakis(triphenylphosphine)palladium (2.2 g, 1.90 mmol) under a nitrogen atmosphère. The resulting mixture was stirred for 16 hours at 80 °C. After cooling to room température, the reaction mixture was quenched by the addition of water (200 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/17) to afford the title compound (6.0 g, 80%) as a yellow oil. LC-MS (Method C): m/z = 156.0 [M+H] , 1.216 min.

Step 2: Préparation ofN-(2,4-difluoro-6-vinylphenyl)but-3-enamide

[0677] Thionyl chloride (9.3 g, 46.46 mmol) was added to a solution of but-3-enoic acid (4.0 g, 46.46 mmol) in dichloromethane (20 mL) dropwise. After stirring for 1 hour at room température, the

254 resulting mixture was added to a solution of triethylamine (11.8 g, 116.6 mmol) and 2-ethenyl-4,6difluoroaniline (6.0 g, 38.67 mmol) in dichloromethane (20 mL). The reaction mixture was stirred for 3 hours at room température, quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filteredand concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/17) to afford tire title compound (5.7 g, 66%) as a yellow oil. LC-MS (Method C): m/z = 224.0 [M+HT, 1.145 min.

Step 3: Préparation of (Z)-7,9-difluoro-lH-benzo[b]azepin-2(3H)-one

[0678] [l,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro(phenylmethylidene) ruthénium tricyclohexylphosphine (3.4 g, 4.0 mmol) was added to a solution of N-(5-ethenyl-2,4difluorophenyl)but-3-enamide (4.4 g, 19.9 mmol) in toluene (150 mL). The resulting solution was stirred for 16 hours at 80 °C and then concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (2.8 g, 69%) as a yellow oil. LC-MS (Method S): m/z = 196.0 [M+H]⁺, 0.754 min.

Step 4: Préparation of 5,7-difluoro-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

[0679] To a solution of potassium hydroxide (40 g, 714 mmol) in water (60 mL) was added a solution of 1 -methyl-1-nitrosourea (20.6 g, 199.8 mmol) in ether (150 mL) dropwise at 0 °C under nitrogen atmosphère. The resulting mixture was stirred for 1 hour at 0 °C and then the organic phase was separated to get a solution of diazomethane (150 mL). To a solution of 7,9-difluoro-2,3-dihydro-lH-l-benza-zepin2-one (2.0 g, 10.25 mmol) in tetrahydrofuran (60 mL) was added the solution of diazomethane (150 mL) dropwise, followed by adding a mixture of palladium diacetate (224.5 mg, 1.00 mmol) in tetrahydrofuran (10 mL) dropwise at 0 °C. The reaction mixture was stirred ovemight at room température. The solids were removed by filtration and the filtrate was concentrated under vacuum to afford the title compound (1.2 g crude) as a yellow oil. LC-MS (Method C): m/z = 210.0 [M+H]⁺, 1.117 min.

Step 5: Préparation of trans-5,7-difluoro-2-iodo-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d] azepin3(4H)-one

[0680] To amixture of 5,7-difluoro-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (1.2 g, 6.0 mmol) in dichloromethane (60 mL) was added Ν,Ν,Ν’,Ν’-tetramethylethylenediamine (2.1g, 18.0 mmol) followed by the addition of iodotrimethylsilane (3.6 g, 18.0 mmol) at 0 °C. After stirring for 2 hours at 0 °C, iodine (2.3 g, 9.0 mmol) was added. The reaction mixture was stirred for 1 hour at 0 °C, quenched with aqueous sodium thiosulfate (5%, 40 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (1.32 g crude) as a yellow oil. LC-MS (Method C): m/z = 336.0 [M+H] , 1.213 min.

255

Step 6: Préparation of cis-2-azido-5,7-difluoro-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d] azepin3(4H)-one

[0681] Sodium azide (250 mg, 3.84 mmol) was added to a solution of traws-5,7-difluoro-2-iodol,la,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (860 mg, 2.56 mmol) in N,Ndimethylformamide (40 mL). The resulting mixture was stirred for 16 hours at room température, quenched by adding water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford tire title compound (520 mg crude) as a yellow oil. LC-MS (Method C): m/z = 251.0 [M+H]⁺, 1.176 mm.

Step 7: Préparation of cis-2-amino-5,7-difluoro-l,la,2,8b-tetrahydrobenzo[b] cyclopropa[d]azepin3(4H)-one

[0682] Triphenylphosphine (629 mg, 2.40 mmol) was added to a solution of c/5-2-azido-5,7-difluorol,la,2,8b-tetraliydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (400 mg, 1.60 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The resulting mixture was stirred for 16 hours at room température, diluted with water (50 mL) and extracted with dichloromethane (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (methanol/ dichloromethane, 3/97) to afford the title compound (310 mg, 86%) as a yellow oil. LC-MS (Method C): m/z = 225.0 [M+H]+, 0.776 min.

Step 8: Préparation of (laR,2R8bS)-2-amino-5,7-diftuoro-l,la,2,8btetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (first eluting i s orner) and (laS,2S,8bR)-2-amino5,7-difluoro-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (second eluting isomer) [0683] The racemate of cA-2-amino-5,7-difluoro-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d] azepin3(4H)-one (310 mg, 1.38 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IA, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B over 28 min; 254/220 nm; RTL 10.247 min; RT2: 20.789 min to afford the title compounds :

[0684] (laR,2R,8bS)-2-amino-5,7-difluoro-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d] azepin3(4H)-one (first eluting isomer): (150 mg, 48%) as a white solid. LC-MS (Method C): m/z = 225.0 [M+H]⁺, 0.776 min.

[0685] (laS,2S,8bR)-2-amino-5,7-difluoro-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d] azepin-3(4H)one (second eluting isomer): (140 mg, 45%) as a white solid. LC-MS (Method C): m/z = 225.0 [M+H] , 0.776 min.

256

Step 9: 5-benzyl-N-((laS,2S,8bR)-5,7-difluoro-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepm-2-yl)-4H-l,2,4-triazole-3-carboxamide

[0686] N,N-diisopropylethylamine (50 mg, 0.39 mmol) was added to a mixture of (laS,2S,8bR)-2ammo-5,7-difluoro-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (30 mg, 0.13 mmol), 5-benzyl-4H-l,2,4-triazole-3-carboxyIic acid (32 mg, 0.16 mmol), N-(3-dimethylaminopropyl)-N’ethylcarbodimide hydrochloride (31 mg, 0.16 mmol) and 1-hydroxybenzotriazole (22 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL). The resuiting mixture was stirred for 2 hours at room température, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, XBridge C18 OBD Prep Column, 5 pm, 19 mm χ 250 mm; mobile phase, water (10 mmoL/L NH4HCO3) and ACN (30.0% ACN to 60.0% over 7 min); Detector, UV 254 nm to afford the title compound. 'H NMR (400 MHz, DM S 0-7.) δ 14.30 (br. s, IH), 9.96 (br. s, IH), 8.43 (d, J= 6.8 Hz, IH), 7.36-7.19 (m, 7H), 4.61 (d, J= 6.8 Hz, IH), 4.14 (s, 2 H), 2.32-2.26 (m, IH), 2.07-2.01 (m, IH), 1.43-1.39 (m, IH), 1.12-1.07 (m, IH). LC-MS (Method Q): m/z = 410.3 [M+H]⁺, 1.144 min.

Example 83B: 5-benzyI-N-((laR,2R,8bS)-5,7-difluoro-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide

[0687] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, XBridge C18 OBD Prep Column, 5 pm, 19 mm x 250 mm; mobile phase, water (10 mmoL/L NH4HCO3) and ACN (30.0% ACN up to 60.0% in 7 min); Detector, UV 254 nm to afford the title compound. ’H NMR (400 MHz, DMSO-7) δ 14.41 (s, IH), 9.95 (s, IH), 8.42 (d, J= 6.8 Hz, IH), 7.35-7.19 (m, 7H), 4.61 (d, J= 6.8 Hz, IH), 4.14 (s, 2H), 2.32-2.26 (m, IH), 2.07-2.01 (m, IH), 1.43-1.39 (m, IH), 1.12-1.07 (m, IH). LC-MS (Method Q): m/z = 410.30 [M+H]⁺, 1.143 min.

257

Example 84: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-7phenylbenzo[d]thiazole-2-carboxamide

[0688] [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg, 0.05 mmol) was added to a mixture of (S)-7-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxaz-epin-3yl)benzo[d]thiazole-2-carboxamide (200 mg, 0.47 mmol), phenylboronic acid (85 mg, 0.70 mmol) and potassium carbonate (128 mg, 0.93 mmol) in dioxane (2 mL) and water (0.5 mL) under a nitrogen atmosphère. The resulting mixture was stirred overnight at 80 °C. Solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 3% B to 38% B over 7 min; 254 & 220 nm; Rt: 6.33 min to afford the title compound. 'H NMR (300 MHz, OMSOY) δ 9.30 (d, J= 7.8 Hz, 1H), 8.23 (d, J= 7.8 Hz, 1H), 7.79-7.60 (m, 4H), 7.60-7.49 (m, 4H), 7.34-7.26 (m, 3H), 4.964.68 (m, 2H), 4.50-4.45 (m, 1H), 3.33 (s, 3H). LC-MS (Method T): m/z = 430.3 [M+H]⁺, 1.906 min.

Example 85: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yl)1,3,4-thiadiazole-2-carboxamide

O

step 1 step 2

step 3 step 4

Step 1: Préparation of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate

[0689] To a stirring solution of 2-phenylacetohydrazide (2 g, 13.3 mmol) and triethylamine (4.04 g,

39.9 mmol) in dichloromethane (30 mL) was added ethyl 2-chloro-2-oxoacetate (1.8 g, 13.4 mmol)

258 dropwise at 0 °C. The resulting solution was stirred for 12 hours at room température, diluted with water (20 mL) and extracted with dichloromethane (5 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (1.2 g, 36%) as a white solid. LC-MS (Method I): m/z = 251.0[M+H]⁺, 0.944 min.

Step 2: Préparation of ethyl 5-benzyl-l, 3,4-thiadiazole-2-carboxylate

[0690] To a mixture of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate (0.65 g, 2.6 mmol) in tetrahydrofuran (8 mL) was added Lawesson’s reagent (1.89 g, 4.7 mmol). The resulting mixture was stirred for 3 hours at 70 °C. After cooling to room température, the reaction mixture was diluted with ethyl acetate (30 mL). The phases were separated and the organic layer was washed with aqueous sodium bicarbonate (10%, 3 x 20 mL) and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (500 mg, 78%) as a yellow oil. LC-MS (Method I): m/z = 249.0 [M+H]⁺, 0.991 min.

Step 3: Préparation of 5-benzyl-l, 3,4-thiadiazole-2-carboxylic acid

[0691] To a mixture of ethyl 5-benzyl-l,3,4-thiadiazole-2-carboxylate (500 mg, 2.01 mmol) in tetrahydrofuran (6 mL) and water (2 mL) was added lithium hydroxide (97 mg, 4.04 mmol). The resulting solution was stirred for 12 hours at room température and concentrated under vacuum. The residue was diluted with water (10 mL) and the pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting solution was extracted with ethyl acetate (3x15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (250 mg crude) as a white solid. LC-MS (Method I): m/z = 221.0 [M+H]⁺, 0.574 min.

Step 4: Préparation of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3yl)-l, 3,4-thiadiazole-2-carboxamide

[0692] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep Cl8 OBD Column, 5 pm, 19 ^x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 38% B to 70% B over 7 min; UV 254 & 220 nm to afford the title compound. ‘H NMR (300 MHz, DMSO<7)5 9.46 (d, 7= 6.6 Hz, 1H), 8.37 (dd, 7= 4.8, 1.8 Hz, 1H), 7.71 (dd, 7= 7.8, 1.5 Hz, 1H), 7.38-7.26 (m, 6H), 4.91-4.75 (m, 2H), 4.58-4.52 (m, 3H), 3.36 (s, 3H). LC-MS (Method D): m/z = 396.1 [M+H]⁺, 1.912 min.

259

Example 86: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3yl)thiazole-2-carboxamide

ΗΟΒΤ, EDCI, DIEA, DMF rt, o/n

[0693] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column, 5 pm, 19 * 150 mm; Mobile Phase A: water (10 mrnol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 38% B to 70% B over 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (300 MHz, DMSOÆ.) δ 8.95 (d, 7 = 7.2 Hz, 1H), 8.37 (dd, J= 4.8, 1.5 Hz, 1H), 7.88 (s, 1H), 7.71 (dd, J= 8.1, 1.5 Hz, 1H), 7.37-7.23 (m, 6H), 4.89-4.72 (m, 2H), 4.56-4.50 (m, 1H), 4.28 (s, 2H), 3.36 (s, 3H). LC-MS (Method D): m/z = 395.1 [M+H]⁺, 2.096 min.

Example 87: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[bJ [l,4]oxazepin-3-yl)-l-(lphenylcyclopropyl)-lH-l,2,3-triazole-4-carboxamide

1) DPPA, Et₃N, toluene

100 °C, 5 h

2) t-BuOH, rt, o/n

rt, 3 h

N HCl in dioxane

NH₂ HCl step 2

1) MeMgBr, THF, -60 °C, 30 min

2) TsN₃, THF, -60 °C to rt, 1 h

Cu(OAc)₂neat, rt, o/n step 4

step 3

Step 1: Préparation of tert-butyl 1-phenylcyclopropylcarbamate

[0694] To a stirring mixture of 1-phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol) and diphenyl phosphorazidate (17.0 g, 61.7 mmol) in toluene (100 mL) was added triethylamine (18.6 g, 185 mmol) The reaction mixture was stirred for 5 hours at 100 °C, cooled to room température and then 2-methylpropan-2-ol (33.7 mg, 0.216 mmol) was added. The reaction mixture was stirred

260 ovemight at room température and concentrated under high vacuum. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (4.00 g, 28%) as a yellow solid. LC-MS (Method C): m/z = 234.2 [M+H]⁺, 1.345 min.

Step 2: Préparation of 1-phenylcyclopropanamine hydrochloride

[0695] Tert-butyl 1-phenylcyclopropylcarbamate (4.0 g, 17.2 mmol) was added to a solution of hydrogen chloride in dioxane (4 N, 50 mL, 200 mmol). The reaction mixture was stirred for 3 hours at room température and concentrated under high vacuum to afford the title compound (2.00 g, 88%) as a white solid. LC-MS (Method C): m/z =134.2 [M+H]⁺, 0.775 min.

Step 3: Préparation of (l-azidocyclopropyl)benzene

[0696] To a stirring solution of 1-phenylcyclopropanamine hydrochloride (320 mg, 1.89 mmol) in ether (10 mL) was added a solution of méthylmagnésium bromide in ether (3 M, 1.89 mL, 5.67 mmol) at -60 °C under an argon atmosphère. After stirring for 30 minutes at -60 °C, 4-methylbenzenesulfonyl azide (745 mg, 3.78 mmol) was added. The reaction mixture was stirred for 1 hour at -60 °C, quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (500 mg crude) as a yellow solid.

Step 4: Préparation of ethyl l-(l-phenylcyclopropyl)-lH-l,2,3-triazole-4-carboxylate

[0697] Cupric acetate (468 mg, 3.14 mmol) was added to a solution of (l-azidocyclopropyl)benzene in ethyl propiolate (5 mL). The reaction mixture was stirred ovemight at room température and concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (100 mg, 12%) as a yellow oil. LC-MS (Method C): m/z = 258.1 [M+H]⁺, 1.250 min.

Step 5: Préparation of l-(l-phenylcyclopropyl)-lH-l,2,3-triazole-4-carboxylic acid

[0698] Lithium hydroxide (18.7 mg, 0.78 mmol) was added to a solution of ethyl 1-(1phenylcyclopropyl)-lH-l,2,3-triazole-4-carboxylate (100 mg, 0.39 mmol) in tetrahydrofuran (3 mL) and water (1 mL). The resulting solution was stirred ovemight at room température, concentrated under vacuum and diluted with water (5 mL). The pH of the solution was adjusted to 5 with aqueous hydrochloric acid (1 N, 5 mL). The resulting solution was extracted with ethyl acetate (3x5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (30 mg crude) as a white solid. LC-MS (Method D): m/z = 230.2 [M+H]⁺, 0.532 min.

261

Step 6: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-l-(lphenylcyclopropyl)-lH-l, 2,3-triazole-4-carboxamide

[0699] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; 220 nm; Rt: 6 min to afford the title compound. ^!H NMR (300 MHz, DMSO-ris) δ 8.88 (s, 1H), 8.58 (d, 7= 8.1 Hz, 1H), 7.53-7.49 (m, 1H), 7.39-7.20 (m, 5H), 7.07-7.04 (m, 2H), 4.89-4.81 (m, 1H), 4.65-4.55 (m, 1H), 4.43-4.30 (m, 1H), 3.32 (s, 3H), 1.79-1.78 (m, 2H), 1.731.64 (m, 2H). LC-MS (Method D): m/z = 404.1 [M+H]⁺, 1.992 min.

Example 88: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-2-(lphenyicyciopropyl)-lH-imidazoIe-5-carboxamide

Step 1: Préparation of (Z)-N’-hydroxy-l-phenylcyclopropanecarboximidamide

[0700] Hydroxylamine hydrochloride (1.4 g, 20.3 mmol) was added to a mixutre of 1phenylcyclopropanecarbonitrile (1.5 g, 10.5 mmol) and sodium carbonate (2.2 g, 20.7 mmol) in éthanol (20 mL) and water (10 mL). The resulting mixture was stirred at 80 °C for 18 hours. After cooling to room température, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to afford the title compound (1.2 g, 68%) as a white solid. LC-MS (Method E): m/z = 176.8 [M+H]⁺, 0.371 min.

Step 2: Préparation of ethyl 2-(l-phenylcyclopropyl)-lH-imidazole-5-carboxylate

[0701] A solution of (Z)-N’-hydroxy-1-phenylcyclopropanecarboximidamide (1.2 g, 6.8 mmol) and ethyl propiolate (1.0 g, 10.2 mmol) in éthanol (50 mL) was stirred at 80 °C overnight and concentrated

262 under vacuum. The residue was dissolved in oxydibenzene (20 mL) and the mixture was stirred at 200 °C for 2 hours. The resulting mixture was concentrated and purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (0.7 g, 40%) as a yellow solid. LC-MS (Method C): m/z = 257.0 [M+H]⁺, 1.200 min.

Step 3: Préparation of2-(l-phenylcyclopropyl)-lH-imidazole-5-carboxylic acid

[0702] Lithium hydroxide (288 mg, 7.2 mmol) was added to a solution of 2-(l-phenylcyclopropyl)lH-imidazole-5-carboxylate (300 mg, 1.2 mmol) in tetrahydrofuran (9 mL) and water (3 mL). The reaction mixture was stirred ovemight at room température, diluted with water (20 mL), adjusted pH to5 with aqueous hydrochloric acid (1 N, 10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (130 mg crude) as a yellow solid. LC-MS (Method C): m/z = 229.1 [M+H]⁺, 0.906 min.

Step 4: Préparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-2-(lphenytcyclopropyl)-IH-imidazole-5-carboxamide

[0703] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 60% B over 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (300 MHz, DMSO-i/e) δ 12.28 (s, 1H), 7.86 (d, J= 8.1 Hz, 1H), 7.52-7.49 (m, 2H), 7.37-7.19 (m, 8H), 4.89-4.79 (m, 1H), 4.544.38 (m, 2H), 3.33 (s, 3H), 1.48-1.40 (m, 2H), 1.28-1.20 (m, 2H). LC-MS (Method O): m/z = 403.1 [M+H]⁺, 1.389 min.

Example 89A: 5-benzyl-N-((laR,2R,8bS)-5,7-difluoro-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yI)-l,3,4°^xadiazole-2-carboxamide

O

step 3 step 4

263

Step 1 : Préparation of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate

[0704] Ethyl 2-chloro-2-oxoacetate (603 mg, 4.4mmol) was added to a stirring solution of 2phenylacetohydrazide (660 mg, 4.4 mmol) and triethylamine (1.33 g, 13.2 mmol) in dichloromethane (20 mL). The réaction mixture was stirred at room température for 5 hours, quenched by the addition of water (20 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (550 mg, 50%) as a yellow oil. LC-MS (Method S): m/z = 251.0 [M+H]⁺, 0.679 min.

Step 2: Préparation of ethyl 5-benzyl-l, 3,4-oxadiazole-2-carboxylate

[0705] Tosyl chloride (840 mg, 4.4 mmol) was added to a stirring solution of ethyl 2-oxo-2-(2-(2phenylacetyl)hydrazinyl)acetate (666 mg, 6.6 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred overnight at room température, quenched by the addition of water (20 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (500 mg, 98%) as a yellow oil. LC-MS (Method C): m/z = 233.0 [M+H]⁺, 1.200 min.

Step 3: Préparation of 5-benzyl-l, 3,4-oxadiazole-2-carboxylic acid

[0706] Lithium hydroxide (103 mg, 4.3 mmol) was added to a stirring solution of ethyl 5-benzyl-l,3,4oxadiazole-2-carboxylate (500 mg, 2.15 mmol) in tetrahydrofuran (5 mL) and water (2 mL). The reaction mixture was stirred overnight at room température, concentrated under vacuum and diluted with water (20 mL). The pH value ofthe mixture was adjusted to pH=6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (250 mg crude) as a yellow semi-solid. LC-MS (Method I): m/z = 205.0 [M+H]⁺, 0.058 min.

Step 4: Préparation of 5-benzyl-N-((laR,2R,8bS)-5,7-difluoro-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-l,3,4-oxadiazole-2-carboxamide

[0707] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, XBridge C18 OBD Prep Column, 5 μηι, 19 mm χ 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN up to 60.0% over 7 min); Detector, UV 254 nm to afford the title compound. ’H NMR (400 MHz, CD3OD) δ 7.38-7.29 (m, 5H), 7.12-7.08 (m, 1H), 6.98-6.93 (m, 1 H), 4.82 (d, J= 0.8 Hz, 1H), 4.36 (s, 2H), 2.31-2.25 (m, 1H), 2.12-2.07 (m, 1H), 1.67-1.63 (m, 1H), 1.23-1.17 (m, 1 H). LC-MS (Method V): m/z = 411.05 [M+H]⁺, 2.915 min.

264

Example 89B: 5-benzyl-N-((laS,2S,8bR)-5,7-difluoro-3-oxo-l,la,2,3A8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-l,3,4-oxadiazole-2-carboxamide

[0708] The crude product obtained using Arnide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, XBridge C18 OBD Prep Column, 5 pm, 19 mm * 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN to 60.0% over 7 min); Detector, UV 254 nm to afford the title compound. Ή NMR (400 MHz, CD₃OD) δ 7.39-7.28 (m, 5H), 7.11-7.08 (m, 1H), 6.98-6.93 (m, 1 H), 4.81 (d, J= 0.8 Hz, 1H), 4.36 (s, 2H), 2.31-2.25 (m, 1H), 2.12-2.07 (m, 1H), 1.67-1.63 (m, 1H), 1.23-1.17 (ni, 1 H). LC-MS (Method Q): m/z = 411.30 [M+H]⁺, 0.965 min.

Example 90A : l-benzyl-N-((l aR,2R,8bS)-5,7-difluoro-3-oxo-l ,1 a,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-lH-l,2,3-triazole-4-carboxamide

EDCI, HOBT, DIEA, DMF rt, 2 h

[0709] The crude product obtained using Arnide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, XBridge C18 OBD Prep Column, 5 pm, 19 mm x 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN up to 60.0% over 7 min); Detector, UV 254 nm to afford the title compound. ’H NMR (400 MHz, DMSO-0/5) δ 9.90 (br. s, 1H), 8.77 (s, 1H), 8.51 (d, J= 7.0 Hz, 1H), 7.43-7.33 (m, 5H), 7.32-7.26 (m, 1H), 7.24-7.19 (m, 1H), 5.67 (s, 2H), 4.63 (d, J= 6.9 Hz, 1H), 2.32-2.26 (m, 1H), 2.06-2.00 (m, 1H), 1.44-1.40 (m, 1H), 1.14-1.08 (m, 1H). LC-MS (Method D): m/z = 410.10 [M+H]⁺, 1.876 min.

Example 90B : l-benzyl-N-((l aS,2S,8bR)-5,7-difluoro-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cycIopropa[d]azepin-2-yl)-lH-l,2,3-triazole-4-carboxamide

EDCI, HOBT, DIEA, DMF rt, 2 h

[0710] The crude product obtained using Arnide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, XBridge C18 OBD Prep Column, 5 pm, 19 mm χ 250 mm;

265 mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN to 60.0% over 7 min); Detector, UV

254 nm to afford the title compound. ^JH NMR (400 MHz, DMSO-rie) δ 9.90 (s, 1H), 8.77 (s, 1H), 8.51 (d, J= 7.0 Hz, 1H), 7.46-7.33 (m, 5H), 7.30-7.26 (m, 1H), 7.24-7.19 (m, 1H), 5.67 (s, 2H), 4.63 (d, J=

6.9 Hz, 1H), 2.32-2.26 (m, 1H), 2.05-2.00 (m, 1H), 1.45-1.40 (m, 1H), 1.14-1.08 (m, 1H). LC-MS (Method J): m/z = 410.15 [M+H| , 1.269 min.

Example 91: (S)-N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)-lH-pyrazole-3-carboxamide

[0711] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep Phenyl OBD Column, 5 pm, 19 χ 150 mm ; Mobile Phase A:water (0.1% formic acid), Mobile Phase B: ACN; Llow rate: 20 mL/min; Gradient: 25% B to 60% B over 7 min; UV 254 &220 nm to afford the title compound. ^JH NMR (400 MHz, DMSO-fie) δ 13.18 (s, 1H), 10.53 (s, 1H), 8.24-8.14 (m, 2H), 7.56 (dd, J= 8.0, 1.6 Hz, 1H), 7.34-7.15 (m, 6H), 6.38 (s, 1H), 4.84-4.77 (m, 1H), 4.52-4.41 (m, 2H), 1.35-1.30 (m, 4H). LC-MS (Method D): m/z = 390.1 [M+H]⁺, 1.537 mm.

266

Example 92: l-benzyI-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yI)-4-fluoro-lH-pyrazole-3-carboxamide

no₂

F

OH O

NaH, DMF 0°C to rt, 3 h

OH

HN_ Boc

Pd/C, H₂, MeOH rt, 6 ti step 2

step 1

step 6 step 3

Step 1: Préparation of (2S,3R)-2-(tert-butoxycarbonylamino)-3-(2-nitropyridin-3-yloxy)- butanoic acid [0712] Sodium hydride (60%. 9.2 g, 230 mmol) was added to a stirring solution of (2S,3R)-2-(tertbutoxycarbonylamino)-3-hydroxybutanoic acid (25 g, 115 mmol) in N,N-dimethylformamide (500 mL) and the reaction mixture was stirred at 0 °C for 1 hour. After addition of 3-fluoro-2-nitropyridine (16.4 g, 115 mmol), the reaction mixture was stirred at room température for another 2 hours and then quenched by the addition of hydrochloride acid (3 N, 20 mL). The pH value of the reaction solution was adjusted to 3-4 with hydrogen chloride (3 N, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (acetonitrile/water, 1/2) to afford the title compound (3.8 g, 10%) as a light yellow oil. LC-MS (Method C): m/z = 286.1 [M+H-56]⁺, 1.167 min.

Step 2: Préparation of (2S,3R)-3-(2-aminopyridin-3-yloxy)-2-(tert-butoxycarbonylammo)- butanoic acid [0713] (2S,3R)-2-(tert-butoxycarbonylamino)-3-(2-nitropyridin-3-yloxy)butanoic acid (3.77 g, 11 mmol) in methanol (30 mL) was hydrogenated in the presence of palladium carbon (10%, 1.0 g) under a hydrogen atmosphère (2-3 atm). The reaction mixture was stirred for 6 hours at room température. The solids were removed by filtration and the filtrate was concentrated under vacuum to afford the title compound (3.12 g, 91%) as a colorless oil. LC-MS (Method C): m/z = 312.1 [M+H] , 0.887 min.

267

Step 3: Préparation of tert-butyl (2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] oxazepin3-ylcarbamate

[0714] Ν,Ν-diisopropylethylamine (1.43 g, 11 mmol) was added to a stirring solution of (2S,3R)-3-(2ammopyridin-3-yloxy)-2-(tert-butoxycarbonylamino)butanoic acid (3.0 g, 10 mmol) and Ν,Ν,Ν’,Ν’tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophospate (4.18 g, 11 mmol) ίηΝ,Νdimethylformamide (50 mL). The reaction mixture was stirred for 5 hours at room température, quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 100 mL). Tire combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to afford the title compound (2.2 g, 78%) as a white solid. LC-MS (Method C): m/z = 294.1 [M+H]⁺, 1.136 min.

Step 4: Préparation of tert-butyl (2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [1,4] oxazepin-3-ylcarbamate

[0715] lodomethane (388 mg, 2.73 mmol) was added dropwise to a stirring solution of tert-butyl (2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-ylcarbamate (800 mg, 2.73 mmol) and césium carbonate (890 mg, 2.73 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred for 1 hour at 0 °C and 3 hours at room température, diluted with water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (670 mg, 80%) as a white solid. LC-MS (Method C): m/z = 308.2 [M+H]⁺, 1.250 min.

Step 5: Préparation of (2R3S)-3-amino-2,5-dimethyl-2,3-dihydropyrido[3,2-b][l,4]oxazepin-4(5H)-one hydrochloride

[0716] Tert-butyl (2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3ylcarbamate (670 mg, 2.18 mmol) was added to a solution of hydrogen chloride in dioxane (4M, 10 mL, 40 mmol). The reaction mixture was stirred for 5 hours at room température and concentrated under reduced pressure to afford the title compound (460 mg crude) as a white solid. LC-MS (Method E): m/z = 207.90 [M+H]⁺, 0.432 min.

Step 6: Préparation of l-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [1,4]oxazepin-3-yl)-4-fluoro-lH-pyrazole-3-carboxamide

[0717] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Cl8 OBD Prep Column, 5 pm, 19 mm x 250 mm; Mobile Phase A: water (lOmmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B in 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSOJ₆) δ 8.36 (dd, 7=4.4, 1.6 Hz, 1H), 8.15 (d, 7= 4.4 Hz, 1H), 7.76 (dd,7=8.0, 1.6 Hz, 1H), 7.61 (d,7 =

268

6.4 Hz, 1H), 7.42-7.31 (m, 4H), 7.31-7.27 (m, 2H), 5.37 (s, 2H), 5.00-4.93 (m, 1H), 4.92-4.88 (m, 1H),

3.40 (s, 3H), 1.32 (d, J= 6.0 Hz, 3H). LC-MS (Method F): m/z = 409.9 [M+H]⁺, 1.336 min.

Example 93: l-benzyl-N-((2S,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin3-yl)-4-fluoro-lH-pyrazole-3-carboxamide

OH O

OH

HN, Boc

NaH, DMF 0°C to rt, 12 h

Pd/C, H₂, MeOH rt, 3 h step 2

HATU, DIEA, DMF rt, 3 h step 3 step 1

step 6

[0718] The title compound was prepared from (2S,3S)-2-(tert-butoxycarbonylamino)-3hydroxybutanoic acid using the procedure described in Example 92.

[0719] The crude product obtained was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column 19 x 150 mm, 5 pm: Mobile Phase A: water (10 mmol/L NHHCOj), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 & 220 nm to afford the title compound. 'H NMR (400 MHz, DMSO-i/e) δ 8.46 (d, J= 8.4 Hz, 1H), 8.38 (dd, J= 4.8, 1.2 Hz, 1H), 8.14 (d, J= 4.4 Hz, 1H), 7.63 (dd, J= 8.0, 1.6 Hz, 1H), ΊΑ2-Ί2Ί (m, 6H), 5.36 (s, 2H), 5.10-5.01 (m, 1H), 4.45-4.40 (m, 1H), 3.34 (s, 3H), 1.26 (d, J= 6.0 Hz, 3H). LC-MS (Method D): m/z = 410.1 [M+H]^T, 1.923 min.

Example 94: 5-benzyI-N-((2R,3S)-2,5-dimethyI-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepin3-yl)-4H-l,2,4-triazole-3-carboxamide

269

[0720] Ν,Ν-diisopropylethylamine (95 mg, 0.73 mmol) was added to a mixture of 5-benzyl-4H-l,2,4triazole-3-carboxylic acid (50 mg, 0.24 mmol), (2R,3S)-3-amino-2,5-dimethyl-2,3-dihydropyrido[3,2b][l,4]oxazepin-4(5H)-one hydrochloride (50 mg, 0.24 mmol), N-(3-dimethylaminopropyl))-N’ethylcarbodiimide hydrochloride (60 mg, 0.32 mmol) and 1-hydroxybenzotriazole (43 mg, 0.32 mmol) in N,N-dimethylfomiamide (2 mL). The reaction mixture was stirred overnight at room température, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge Shield RP18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 5% B over 4 min; UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSO-de) δ 14.46 (s, 1H), 8.36 (dd, J= 4.8, 1.6 Hz, 1H), 7.98 (d, J= 6.0 Hz, 1H), 7.76 (dd, J= 8.0, 1.6 Hz, 1H), 7.38-7.23 (m, 6H), 5.01-4.94 (m, 1H), 4.93-4.89 (m, 1H), 4.14 (s, 2H), 3.40 (s, 3H), 1.31 (d, J=6.0Hz, 3H). LC-MS (Method D): m/z = 393.1 [M+H]⁺, 1.725 min.

Example 95: 5-benzyI-N-((2S,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin3-yl)-4H-l,2,4-triazole-3-carboxamide

Example 96: 5-benzyl-N-((2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [l,4]oxazepin-3yl)-4H-l,2,4-triazole-3-carboxamide

270

Step 1: Préparation of (2R,3S)-3-amino-2-methyl-2,3-dihydropyrido[3,2-b][l,4]oxazepin-4(5H)-one hydrochloride

[0721] Tert-butyl (2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3ylcarbamate (100 mg, 0.34 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 5 ml ) The reaction mixture was stirred for 2 hours at room température and concentrated under reduced pressure to afford the title compound (100 mg crude) as a white solid. LC-MS (Method E): m/z = 194.0 [M+H]⁺, 0.432 min.

Step 2: Préparation of5-benzyl-N-((2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b]

[1,4]oxazepin-3-yl)-4PI-l,2,4-triazole-3-carboxamide

[0722] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Bridge C18 OBD Prep Column, 10 pm, 19 mm x 250 mm;

Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 35% B over 7 min UV 254 & 220 nm to afford the title compound. ’H NMR (300 MHz, DMSO-Js) δ 14.41 (s, IH), 10.84 (s, IH), 8.19-8.08 (m, 2H), 7.62 (dd, J= 8.1, 1.2 Hz, IH), 7.37-7.20 (m, 6H), 4.984.86 (m, 2H), 4.15 (s, 2H), 1.30 (d, J= 6.0 Hz, 3H). LC-MS (Method D): m/z = 379.1 [M+H]⁺, 1.546 min.

Example 97: 5-benzyl-N-((2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3yl)-4H-l,2,4-triazole-3-carboxamide

Step 1: Préparation of (2S,3S)-3-amino-2-methyl-2,3-dihydropyrido[3,2-b][l,4]oxazepin-4(5H)-one hydrochloride

[0723] Tert-butyl (2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl carbamate (50 mg, 0.17 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 5 mL, 20 mmol). The reaction mixture was stirred for 2 hours at room température and concentrated under vacuum to afford the title compound (35 mg crude) as a white solid. LC-MS (Method E): m/z = 194.0 [M+H] , 0.432 min.

271

Step 2: Préparation of5-benzyl-N-((2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4] oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0724] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X Select CSH prep Cl8 OBD Prep Column, 5 pm, 19 mm χ 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 ml,/min; Gradient: 15% B to 60% B over 7 min; UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, DMSO-ùfc) δ 14.36 (s, 1H), 10.56 (s, 1H), 8.68 (d, J= 8.8 Hz, 1H), 8.23-8.20 (m, 1H), 7.56 (d, J= 8.8 Hz, 1H), 7.39-7.17 (m, 6H), 5.11-4.90 (m, 1H), 4.44 (m, 1H), 4.16 (s, 2H), 1.32 (d, J= 6.0 Hz, 3H). LCMS (Method F): m/z = 378.95 [M+H]⁺, 0.932 min.

Example 98A and 98B: (R)-5-benzyl-N-(8’-oxo-6’,7’,8’,9’-tetrahydrospiro[cyclopropane-l,5’pyrido[2,3-bJazepin]-7’-yi)-4H-l,2,4-triazoie-3-carboxamide (98A) and (S)-5-benzyI-N-(8’-oxo6’,7’,8’,9’-tetrahydrospiro[cyclopropane-l,5’-pyrido[2,3-b]azepin]-7’-yl)-4H-l,2,4-triazole-3carboxamide (98B)

Step 1: Préparation of 7 ’-amino-ô 7 ’-dihydrospiro[cyclopropane-l,5 ’-pyrido[2,3-b]azepin]-8 ’(9 ’H)one hydrochloride

[0725] A solution of hydrogen chloride in 1,4-dioxane (4 N, 10 mL, 40 mmol) was added to a solution of tert-butyl (8’-oxo-6’,7’,8’,9’-tetrahydrospiro[cyclopropane-l,5’-pyrido[2,3-b]azepin]-7’-yl)carbamate (100 mg, 0.34 mmol) in 1,4-dioxane (4 mL). The reaction mixture was stirred for 2 hours at room température and concentrated under high vacuum to afford the title compound (80 mg crude) as a white solid. LC-MS (Method C): m/z = 204.1 [M+H]⁺, 0.677 mm.

272

Step 2: Préparation of 5-benzyl-N-(8 ’-oxo-6’,7’,8’,9’-tetrahydrospiro[cyclopropane-l,5’-pyrido[2,3b]azepin]- 7 ’-yl) -4H-1,2,4-triazole-3-carboxamide

[0726] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: waters (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; 254/220 nm to afford the title compound (50 mg, 56%) as a white solid. LC-MS (Method V): m/z = 389.2 [M+H]⁺, 0.982 min.

Step 2: Préparation of (R)-5-benzyl-N-(8’-oxo-6’,7’,8’,9’-tetrahydrospiro[cyclopropane-l,5’-pyrido[2,3b]azepin]-7’-yl)-4H-l,2,4-triazole-3-carboxamide (first eluting isomer) and (S)-5-benzyl-N-(8’-oxo6’, 7’, 8’, 9 ’-tetrahydrospiro [cyclopropane-1,5 ’-pyrido[2,3-bJazepin/- 7 ’-yl)-4H-l, 2,4-triazole-3carboxamide (second eluting isomer)

[0727] The racemate of 5-benzyl-N-(8’-oxo-6’,7’,8’,9’-tetrahydrospiro[cyclopropane-l,5’-pyrido[2,3b]azepin]-7’-yl)-4H-l,2,4-triazole-3-carboxamide (50 mg, 0.128 mmol) was separated by Prep-ChiralHPLC with the following conditions: Column: Chiralpak ID-2, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane/DCM 4.5:1, Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient: 50% B to 50% B over 22 min; UV 254 & 220 nm; RT 1:11.72 min; RT 2: 18.02 min to afford the title compounds:

[0728] Example 98A (first eluting isomer): ’H NMR (300 MHz, DMSO-rie) δ 14.28 (s, IH), 10.37 (s, IH), 8.27 (dd, 7= 4.8, 1.8 Hz, IH), 7.69 (dd, 7= 7.6, 1.8 Hz, IH), 7.34-7.08 (m, 6H), 4.42-4.33 (m, IH), 3.30 (s, 3H), 2.82-2.68 (m, IH), 1.72 (s, IH), 1.23-1.05 (m, IH), 0.88-0.78 (m, IH), 0.70-0.65 (m, IH), 0.40-0.25 (m, IH). LC-MS (Method D): m/z = 389.2 [M+H]\ 1.499 min.

[0729] Example 98B (second eluting isomer): ’H NMR (300 MHz, DMSO-Ts) δ 10.38 (d, 7= 2.8 Hz, IH), 8.37-8.22 (m, 2H), 7.71-7.67 (m, IH), 7.44-7.08 (m, 6H), 4.43-4.34 (m, IH), 4.06 (s, 2H), 2.78-2.71 (m, IH), 1.73 (t, 7= 12.3 Hz, IH), 1.23-1.05 (m, 2H), 0.86-0.79 (m, IH), 0.71-0.64 (m, IH), 0.27 (s, IH). LC-MS (Method D): m/z = 389.2 [M+H]⁺, 1.503 min.

Example 99: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yl)-5-(lphenyIcyclopropyl)-lH-imidazole-2-carboxamide

[0730] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: column: X bridge Prep C18, 19 χ 150 mm, 5 pm; Mobile phase: Phase A: water (10 mmol/L NFUHCOs); Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7

273 min; Detector, UV 220 & 254 nm; Rt: 6.32 min to afford the title compound. ’H NMR (300 MHz,

DMSO-TO δ 12.80 (s, 1H), 8.50-8.32 (m, 2H), 7.72-7.70 (m, 1H), 7.39-7.15 (m, 6H), 6.78-6.65 (m, 1H),

4.92-4.63 (m, 2H), 4.52-4.48 (m, 1H), 3.36 (s, 3H), 1.35-1.30 (m, 2H), 1.28-1.11 (m, 2H). LC-MS (Method O): m/z = 404.0 [M+H|⁺, 1.412 min.

Example 100A and 100B: 4-(2-fluorophenoxy)-N-((laS,2S,8bR)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide (100A) and 4-(2-fluorophenoxy)-N((laR,2R,8bS)-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2yl)picolinamide (100B)

Step 1: Préparation of 4-(2-fluorophenoxy)-N-(cis-4-methyl--3-oxo-l, la,2,3,4,8b-hexahydro cyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide

[0731] Tire crude product obtained using Amide Coupling Procedure C was purified by prep-TLC (ethyl acetate/petroleum ether, 1/3) to afford the title racemic compound. LC-MS (Method J): m/z = 419.1 [M+H]⁺, 1.330 min.

Step 2: Préparation of 4-(2-fluorophenoxy)-N-((laS,2S,8bR)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide (first eluting isomer) and 4-(2fluorophenoxy) -N-((laR, 2R, 8bS)-4-methyl-3-oxo-l ,1a,2,3,4,8b-hexahydrocyclopropa [d]pyrido[2,3b]azepin-2-yl)picolinamide (second eluting isomer)

[0732] Tire racemate of 4-(2-fluorophenoxy)-N-(cis-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydro cyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide (25 mg, 0.096 mmol) was separated by Prep-ChiralHPLC with the following conditions: Column: Chiralpak IA, 2 x 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 19 min; 220/254 nm; RT1: 13.609 min; RT2: 15.738 min to afford the title compounds:

274

[0733] Example 100A (first eluting isomer): Ή NMR (300 MHz, Methanol-X) δ 8.59 (d, J= 5.6 Hz,

1H), 8.39 (dd, J= 4.7, 1.8 Hz, 1H), 7.95 (dd, J= 7.7, 1.8 Hz, 1H), 7.55 (d, J= 2.5 Hz, 1H), 7.42 -7.27 (m, 5H), 7.15 (dd, J= 5.6, 2.6 Hz, 1H), 4.66 (s, 1H), 3.42 (s, 3H), 2.32-2.26 (m, 1H), 2.17-2.06 (m, 1H),

1.36- 1.32 (m, 1H), 1.23-1.14 (m, 1H). LC-MS (Method J): m/z = 419.2 [M+H]⁺, 1.467 min.

[0734] Example 100B (second eluting isomer): Ή NMR (300 MHz, Methanol-X) δ 8.58 (d, J =5.6 Hz, 1H), 8.38 (dd, J= 4.7, 1.8 Hz, 1H), 7.95 (dd, J=7.7, 1.8 Hz, 1H), 7.55 (d, J= 2.6 Hz, 1H), 7.41-7.28 (m, 5H), 7.14 (dd, J= 5.6, 2.6 Hz, 1H), 4.65 (s, 1H), 3.42 (s, 3H), 2.35-2.25 (m, 1H), 2.15-2.03 (m, 1H),

1.37- 1.25 (m, 1H), 1.24-1.16 (m, 1H). LC-MS (Method T): m/z = 419.3 [M+H]⁺, 2.774 min.

Example 101A and 101B: (R)-5-benzyl-N-(l,4-dimethyl-5-oxo-l,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (101A) and (S)-5-benzyI-N-(l,4-dimethyl-5-oxo1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (101B) ^no2 BrZn

Ό'

NO₂

N

rt, 2 h nh₂

O'

O Pd/c, H₂, MeOH

step 2

Pd(OAc)₂, sphos, THF ¹ 40 °C, o/n step 1

Step 1: Préparation of ethyl 4-(l-methyl-4-nitro-lPI-pyrazol-5-yl)butanoate

[0735] To a stirring solution of 5-bromo-l-methyl-4-nitro-lH-pyrazole (2.0 g, 9.76 mmol), (4-ethoxy4-oxobutyl)zinc(II) bromide (0.5 M in tetrahydrofuran) (29.2 mL, 14.6 mmol) and dicyclohexyl(2’,6’dimethoxybiphenyl-2-yl)phosphine (402.3 mg, 0.98 mmol) in tetrahydrofuran (100 mL) was added a

275 solution of palladium diacetate (109.8 mg, 0.49 mmol) in tetrahydrofuran dropwise with stirring under a nitrogen atmosphère. The resulting mixture was heated overnight at 40 °C. The reaction mixture was concentrated under high vacuum and the residue was purified by column chromatography (methanol/dichloromethane, 1/99) to afford the title compound (445 mg, 18.9%) as a yellow oil. LC-MS (Method C): m/z = 242.1 [M+H]⁺, 1.156 min.

Step 2: Préparation of ethyl 4-(4-amino-l-methyl-lH-pyrazol-5-yl)butanoate

[0736] Ethyl 4-(l-methyl-4-nitro-lH-pyrazol-5-yl)butanoate (405 mg, 1.68 mmol) was hydrogenated in the presence of palladium on carbon (10%, 41mg) under a hydrogen atmosphère (2-3 atm) in methanol (20 mL). The reaction mixture was stirred for 2 hours at room température. Then the solids were removed by filtration and the solvents were evaporated under vacuum to afford the title compound (320 mg crude) as a yellow solid. LC-MS (Method C): m/z = 212.2 [M+H]⁺, 0.768 min

Step 3: Préparation of 4-(4-amino-l-methyl-lH-pyrazol-5-yl)butanoic acid

[0737] A solution of ethyl 4-(4-amino-l-methyl-lH-pyrazol-5-yl)butanoate (320 mg, 1.51 mmol) and lithium hydroxide (108.9 mg, 4.53 mmol) in tetrahydrofuran/water = 3/1 (4 mL) was stirred for 3 hours at room température. The pH value of the solution was adjusted to 6-7 with hydrochloride acid (1 N). The resulting solution was concentrated under vacuum to afford the title compound (220 mg crude) as a yellow solid. LC-MS (Method C): m/z = 184.1 [M+H]⁺, 0.318 min.

Step 4: Préparation of l-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(lH,4H,6H)-one

[0738] N,N-diisopropylethylamine (465.2 mg, 3.6 mmol) was added to a stirring solution of 4-(4amino-1-methyl-lH-pyrazol-5-yl)butanoic acid (220 mg, 1.2 mmol) andN,N,N’,N’-tetramethyl-O-(7azabenzotriazol-l-yl)uronium hexafluorophospate (548.2 mg, 1.44 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred for 2 hours at room température, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (160 mg, 80.8%) as a yellow solid. LC-MS (Method C): m/z = 166.2 [M+H]⁺, 0.751min.

Step 5: Préparation of l,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(lH,4H,6H)-one

[0739] lodomethane (150.5 mg, 1.06 mmol) was added dropwise to a stirred solution of l-methyl-7,8dihydropyrazolo[4,3-b]azepin-5(lH,4H,6H)-one (160 mg, 0.96 mmol) and sodium hydride (60%) (42.4 mg, 1.06 mmol) in N,N-dimethylformamide (5 mL) with stirring. The reaction mixture was stirred for 2 hours at room température, quenched by water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate, 3/1) to

276 afford the title compound (140 mg, 81.5%) as a yellow solid. LC-MS (Method C): m/z = 180.2 [M+H]⁺,

0.816 min.

Step 6: Préparation of 6-iodo-l,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(lH,4H,6H)-one

[0740] N¹,N¹,N²,N²-tetramethylethane-l,2-diamine (271.4 mg, 2.34 mmol) was added to a stirring solution of l,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(lH,4H,6H)-one (140 mg, 0.78 mmol) in dichloromethane (5 mL) at 0 °C followed by the addition of iodotrimethylsilane (468 mg, 2.34 mmol). The reaction mixture was stirred for 1 hour at 0 °C. After adding iodine (137.2 mg, 0.54 mmol), the reaction mixture was stirred for another 1 hour at 0 °C and quenched with aqueous sodium thiosulfate (5%, 15 mL). The reaction mixture was stirred for another 15 minutes and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (214 mg crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 306.0 [M+H]⁺, 0.953 min.

Step 7: Préparation of 6-amino-l,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(lH,4H,6H)-one

[0741] To a solution of 6-iodo-l,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(lH,4H,6H)-one (214 mg, 0.70 mmol) in N,N-dimethylformamide (4 mL) was added sodium azide (136.9 mg, 2.1 mmol). The reaction mixture was stirred for 2 hours at room température and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL) and water (2 mL) and triphenylphosphine (551.8 mg, 2.1 mmol) was added in one portion. The reaction mixture was stirred at 50 °C ovemight, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (100 mg, 73.6%) as a yellow solid. LC-MS (Method C): m/z = 195.1 [M+H|⁺, 0.386 min.

Step 8: Préparation of 5-benzyl-N-(l,4-dimethyl-5-oxo-l,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6yl) -4H-1,2,4-triazole-3-carboxamide

[0742] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: column: X bridge Prep C18, 19 χ 150 mm, 5 pm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: ACN (20% to 80% over 12 min); Detector, UV 220 & 254 nm to afford the title compound. LC-MS (Method C): m/z = 380.2 [M+H]⁺, 1.290 min.

277

Step 9: Préparation of (R)-5-benzyl-N-(l,4-dimethyl-5-oxo-l,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4H-l,2,4-triazole-3-carboxamide (first eluting isomer) and (S)-5-benzyl-N-(l,4-dimethyl-5-oxo1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (second eluting isomer)

[0743] The racemate of 5-benzyl-N-(l,4-dimethyl-5-oxo-l,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4H-l,2,4-triazole-3-carboxamide (50 mg, 0.13 mmol) were separated by Prep-Chiral-HPLC with the following conditions.· Column: Chiralpak IA, 2 x 25 cm, 5 pm ;Mobile Phase A: Hex, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 60% B to 60% B over 21 min: 220/254 nm; RT1: 12.12 min; RT2: 18.44 mm.

[0744] Example 101A (first eluting isomer): ’H NMR (400 MHz, Methanol-tL) δ 7.51 (s, 1H), 7.347.22 (m, 5H), 4.60 (dd, J= 2.0, 10.0 Hz, 1H), 4.17 (s, 2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.20-3.11 (m, 1H), 2.99-2.91 (m, 1H), 2.48-2.41 (m, 1H), 2.25-2.14 (m, 1H). LC-MS (Method V): m/z = 380.1 [M+H]⁺, 2.240 min.

[0745] Example 101B (second eluting isomer): ’H NMR (400 MHz, Methanol-tL) δ 7.51 (s, 1H), 7.357.22 (m, 5H), 4.60 (dd, J= 2.4, 10.4 Hz, 1H), 4.17 (s, 2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.20-3.11 (m, 1H), 2.99-2.91 (m, 1H), 2.49-2.41 (m, 1H), 2.25-2.14 (m, 1H). LC-MS (Method D): m/z = 380.2 [M+H]⁺, 1.471 min.

Example 102A & 102B: 5-((R)-2,3-dihydro-lH-inden-l-yI)-N-((S)-4-oxo-2,3,4,5tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide and 5-((S)-2,3dihydro-lH-inden-l-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-4H-l,2,4triazole-3-carboxamide

278

Step 1: Préparation of 5-(2,3-dihydro-lH-inden-l-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido [3,2b][1,4]oxazepin-3-yl)-4H-l, 2,4-triazole-3-carboxamide

[0746] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 5 pm, 19 mm χ 250 mm; Mobile Phase A: water (10 rnmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 ml./min: Gradient: 20% B to 36% B over 7 min; 254 nm; Rt: 7 min to afford the title compound. LC-MS (Method D): m/z = 391.1 [M+H]⁺, 1.593 min.

Step 2: Préparation of 5-((R)-2,3-dihydro-lH-inden-l-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-4PI-1,2,4-triazole-3-carboxamide and 5-((S)-2,3-dihydro-lH-inden-l-yl)-N-((S)-4oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide

[0747] The racemate of5-(2,3-dihydro-lH-inden-I-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide (10 mg) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA 2.12 x 15 cm, 5 pm; Mobile Phase A: Hex:DCM 4.5:1, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 17.5 min; 220/254 nm; RT1: 10.95 min; RT2: 15.02 min to afford the the title compounds.

[0748] Example 102A (First eluting isomer): ’H NMR (400 MHz, Methanol-ta) δ 8.14-8.13 (m, 1H), 7.57-7.55 (m, 1H), 7.33-7.31 (m, 1H), 7.31-7.10 (m, 3H), 7.09-7.07 (m, 1H), 5.04-4.91 (m, 1H), 4.694.61 (m, 2H), 4.47-4.42 (m, 1H), 3.18-3.15 (m, 1H), 3.07-3.03 (m, 1H), 2.65-2.63 (m, 1H), 2.44-2.39 (m, 1H). LC-MS (Method T): m/z = 391.3 [M+H]⁺, 1.133 min.

[0749] Example 102B (Second eluting isomer): 'H NMR (400 MHz, MethanolX) δ 8.14-8.13 (m, 1H), 7.57-7.55 (m, 1H), 7.33-7.31 (m, 1H), 7.31-7.10 (m, 3H), 7.09-7.07 (m, 1H), 5.04-4.91 (m, 1H), 4.694.61 (m, 2H), 4.47-4.42 (m, 1H), 3.18-3.15 (m, 1H), 3.07-3.03 (m, 1H), 2.65-2.63 (m, 1H), 2.44-2.39 (m, 1H). LC-MS (Method T): m/z = 391.3 [M+H]⁺, 1.135 min.

Example 103A and 103B: (R)-5-benzyl-N-(7,9-difluoro-2-oxo-l,2,3,4tetrahydrospiro[benzo[b]azepine-5,l’-cyclopropan]-3-yl)-4H-l,2,4-triazole-3-carboxamide and (S)5-benzyI-N-(7,9-difluoro-2-oxo-l,2,3,4-tetrahydrospiro[benzo[b]azepine-5,l’-cyclopropan]-3-yl)4H-l,2,4-triazole-3-carboxamide

K₂CO₃, DMF °C, o/n step 1

279

step 4

Dess-Martin reagent

DCM, 0°C, 2h step 5

THF, 50 °C, o/n step 6

Pd/C, H₂

MeOH, rt, o/n step 7

step 8

Step 1: Préparation of dimethyl 2-(3,5-difluoro-2-nitrophenyl)malonate

[0750] Dimethyl malonate (15 g, 114 mmol) was added dropwise to a stirring mixture of 1,3,5trifluoro-2-nitrobenzene (10 g, 56 mmol) and potassium carbonate (23 g, 168 mmol) in N,Ndimethylformamide (150 mL). The reaction mixture was stirred ovemight at 70 °C and quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to afford the title compound (15 g, 92%) as yellow oil. LC-MS (Method C): m/z = 290.0 [M+H]⁺, 1.235 min.

Step 2: Préparation of methyi 2-(3,5-difluoro-2-nitrophenyl) acetate

[0751] A solution of lithium chloride (6.3 g, 150 mmol) in water (20 mL) was added to a solution of dimethyl 2-(3,5-difhioro-2-nitrophenyl)malonate (15 g, 52 mmol) in dimethyl sulfoxide (50 mL). The reaction mixture was stirred ovemight at 100 °C and quenched by the addition of water (250 mL). The

280 resulting solution was extracted with ethyl acetate (3x150 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (11g crude) as a yellow oil, which was used direct!y in the next step without fürther purification.

Step 3: Préparation of methyl l-(3,5-difluoro-2-nitrophenyl)cyclopropanecarboxylate

[0752] 1,2-Dibromoethane (13 g, 70 mmol) was added dropwise to a stirring solution of methyl 2(3,5-difluoro-2-nitrophenyl)acetate (11 g, 48 mmol) and potassium carbonate (20 g, 145 mmol) in N,Ndimethylformamide (50 mL). The reaction mixture was stirred overnight at 70 °C and quenched by the addition of water (250 mL). The resulting solution was extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to afford the title compound (1.1g, 9%) as a yellow oil. LC-MS (Method C): m/z = 258.1 [M+H]⁺, 1.291 min.

Step 4: Préparation of (l-(3,5-difluoro-2-nitrophenyl)cyclopropyl)methanol

[0753] A solution of diisobutylaluminium hydride in toluene (1 M, 9.4 mL, 9.4 mmol) was added dropwise to a stirring solution of methyl l-(3,5-difluoro-2-nitrophenyl)cyclopropanecar- boxylate (1.1g, 4.3 mmol) in toluene (30 mL) at -78 °C under nitrogen atmosphère. The reaction mixture was stirred at 78 °C for 2 hours, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to afford the title compound (0.92 g, 94%) as a yellow oil. LC-MS (Method C): m/z = 230.1 [M+H]⁺, 1.192 min.

Step 5: Préparation of l-(3,5-difluoro-2-nitrophenyl)cyclopropanecarbaldehyde

[0754] Dess-Martin periodinane (3.4 g, 8 mmol) was added to a stirring solution of (1-(3,5-difluoro-2nitrophenyl)cyclopropyl)methanol (0.92 g, 4 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at 0 °C for 2 hours, quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to afford the title compound (0.85 mg, 92%) as yellow oil.

Step 6: Préparation of (E)-ethyl 3-(l-(3,5-difluoro-2-mtrophenyl)cyclopropyl)acrylate

[0755] Ethyl (triphenylphosphoranylidene) acetate (1.5 g, 4.3 mmol) was added to a stirring solution of l-(3,5-difluoro-2-nitrophenyl)cyclopropanecarbaldehyde (800 mg, 3.5 mmol) in tetrahydrofiiran (50 mL). The reaction mixture was stirred overnight at 50 °C, quenched by the addition of water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine,

281 dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to afford the title compound (0.64 g,

61%) as a yellow oil, LC-MS (Method C): m/z = 298.0 [M+H]⁺, 1.382 min.

Step 7: Préparation of ethyl 3-(l-(2-amino-3,5-difluorophenyl)cyclopropyl)propanoate

[0756] (£)-ethyl 3-(1-(3,5-difluoro-2-nitrophenyl)cyclopropyl)acrylate (640 mg, 2.2 mmol) in methanol (30 mL) was hydrogenated in presence of palladium on carbon (10%, 65 mg) under a hydrogen atmosphère (2-3 atm). After stirring overnight at room température under a hydrogen atmosphère, the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum to afford the title compound (400 mg crude) as a yellow oil. LC-MS (Method C): m/z = 270.1 [M+H]⁺, 1.361 min.

Step 8: Préparation of 3-(l-(2-amino-3,5-difluorophenyl)cyclopropyl)propanoic acid

[0757] Lithium hydroxide (180 mg, 7.5 mmol) was added to a solution of ethyl 3-(l-(2-amino-3,5difluorophenyl)cyclopropyl)propanoate (400 mg, 1.5 mmol) in tetrahydroforan (30 mL) and water (10 mL). The reaction mixture was stirred at room température overnight. After removal of tetrahydroforan under reduced pressure, the resulting solution was adjusted to pH = 7 with aqueous hydrochloric acid (1 N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (320 mg crude) as a yellow oil. LC-MS (Method C): m/z =242.1 [M+H]⁺, 1.143 min.

Step 9: Préparation of7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,l ’-cyclopropan]-2(1 H) -one

[0758] N,N-diisopropylethylamine (515 mg, 4.0 mmol) was added to a mixture of 3-(l-(2-amino-3,5difluorophenyl)cyclopropyl)propanoic acid (320 mg, 1.3 mmol) and N,N,N’,N’-tetramethyl-O-(7azabenzotriazol-l-yl)uronium hexafluorophospate (608 mg, 1.6 mmol ) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room température for 2 hours and quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to afford the title compound (270 mg, 91%) as a yellow oil. LC-MS (Method C): m/z = 224.1 [M+H]⁺, 1.303 min.

Step 10: Préparation of7,9-difluoro-3-iodo-3,4-dihydrospiro[benzo[b]azepine-5,l ’-cyclopropan]-2(1H)one

[0759] Ν,Ν,Ν’,Ν’-tetramethylethylenediamine (418 mg, 3.6 mmol) was added into a solution of 7,9difluoro-3,4-dihydrospiro[benzo[b]azepine-5,l’-cyclopropan]-2(lH)-one (270 mg, 1.2 mmol) in dichloromethane (40 mL) at 0 °C followed by addition of iodotrimethylsilane (720 mg, 3.6 mmol) dropwise over 20 min. The mixture was stirred for 1 hour at 0 °C and then iodine (457 mg, 1.8 mmol)

282 was added into the mixture. After stirring for an additional 1 hour at 0 °C, the reaction mixture was quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (410 mg crude) as yellow oil. LC-MS (Method C): m/z = 350.1 [M+H]⁺, 1.262 min.

Step 11: Préparation of 3-azido-7,9-diftuoro-3,4-dihydrospiro[benzo[b]azepine-5,l ’-cyclopropan]2(lH)-one

[0760] Sodium azide (117 mg, 1.8 mmol) was added to a solution of 7,9-difluoro-3-iodo-3,4dihydrospiro[benzo[b]azepine-5,l’-cyclopropan]-2(lH)-one (410 mg, 1.2 mmol) inN,Ndimethylformamide (20 mL). The resulting mixture was stirred ovemight at room température and quenched by the addition of water (40 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (260 mg crade) as a yellow oil. LC-MS (Method E): m/z = 265.1 [M+H]⁺, 0.875 min.

Step 12: Préparation of 3-amino-7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,l ’-cyclopropan]2(lH)-one

[0761] Triphenylphosphine (393 mg, 1.5 mmol) was added to a solution of 3-azido-7,9-difluoro-3,4dihydrospiro[benzo[b]azepine-5,l’-cyclopropan]-2(lH)-one (260 mg, 1.0 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The resulting mixture was stirred ovemight at room température, diluted with water (20 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 5/1) to afford the title compound (210 mg, 90%) as a yellow oil. LC-MS (Method C): m/z = 239.1 [M+H]⁺, 0.814 min.

Step 13: Préparation of 5-benzyl-N-(7,9-difluoro-2-oxo-l,2,3,4-tetrahydrospiro[benzo[b]azepine-5,l cyclopropanJ-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0762] Tire crade product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm, 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 & 220 nm to afford the title compound (30 mg, 26%) as a white solid. LCMS (Method O): m/z = 423.9 [M+H]⁺, 1.204 min.

283

Step 14: Préparation of(R)-5-benzyl-N-(7,9-difluoro-2-oxo-l,2,3,4-tetrahydrospiro[benzo[b] azepine5,1 ’-cyclopropan]-3-yl)-4H-l,2,4-triazole-3-carboxamide (example 103A) and (S)-5-benzyl-N-(7,9difluoro-2-oxo-l, 2,3,4-tetrahydrospiro[benzo[b]azepine-5,1 ’-cyclopropanJ-3-yl)-4H-l, 2,4-triazole-3carboxamide (example 103B)

[0763] The racemate of 5-benzyl-N-(7,9-difluoro-2-oxo-l,2,3,4-tetrahydrospiro[benzo[b] azepine-5,1 ’cyclopropan]-3-yl)-4H-l,2,4-triazole-3-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IA, 2 χ 25 cm, 5 pm; Mobile Phase A: hexanes, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 55% B to 55% B over 27 min; UV 220 & 254 nm; Rtl: 13.94 min; Rt2: 21.44 min to afford the two title compounds.

[0764] Example 103A (first eluting isomer): 'H NMR (400 MHz, Methanol-Y) δ 7.33-7.26 (m, 5H), 7.10-6.99 (m, 2H), 4.72-4.62 (m, 1H), 4.17 (s, 2H), 3.08-2.99 (m, 1H), 1.63-1.57 (m, 1H), 1.25-1.18 (m, 1H), 1.07-1.01 (m, 1H), 0.85-0.77 (m, 1H), 0.59-0.52 (m, 1H). LC-MS (Method O): m/z = 423.9 [M+H]⁺, 1.204 min.

[0765] Example 103B (second eluting isomer): ’H NMR (400 MHz, MethanolY) δ 7.36-7.23 (m, 5H), 7.07-6.98 (m, 2H), 4.73-4.64 (m, 1H), 4.23 (s, 2H), 3.07-2.96 (m, 1H), 1.68-1.53 (m, 1H), 1.25-1.18 (m, IH), 1.06-0.99 (m, 1H), 0.84-0.77 (m, 1H), 0.59-0.52 (m, 1H). LC-MS (Method V): m/z = 424.2 [M+H]⁺, 2.031 min.

Example 104A and 104B: (R)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide and (S)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide

Pd(OAc)_2> Sphos, THF rt, o/n step 1

step 2

Pd/C, H₂, MeOH rt, 5 h step 3

TMEDA, TMSI, l₂, DCM

0°C, 2 h step 5

284

NaN₃, DMF °C, o/n

PPh₃, THF, H₂O rt, 16 h

step 7

HOBT, EDCI, DIEA, DMF rt, o/n step 8

Step 1: Préparation of ethyl 4-(l-methyl-4-nitro-lH-pyrazol-3-yl)butanoate

[0766] A solution of (4-ethoxy-4-oxobutyl)zinc(II) bromide in tetrahydrofuran (0.5 M, 41.5 mL, 20.7 mmol) was added to a stirring mixture of 3-iodo-l-methyl-4-nitro-lH-pyrazoie (4.32 g, 17.1 mmol) and dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yI)phospliine (864 mg, 2.1 mmol) in tetrahydrofuran (50 mL) under nitrogen atmosphère, followed by the addition of a mixture of palladium diacetate (432 mg, 1.9 mmol) in tetrahydrofuran dropwise. The resulting mixture was stirred ovemight at room température and concentrated under high vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/99) to afford the title compound (1.7 g, 41.3%) as a yellow oil. LC-MS (Method E): m/z = 242.1 [M+H]⁺, 0.852 min.

Step 2: Préparation of 4-(l-methyl-4-nitro-lH-pyrazol-3-yl)butanoic acid

[0767] Lithium hydroxide (339 mg, 14.1 mmol) was added to a mixture of ethyl 4-( 1-methyl-4-nitrolH-pyrazol-3-yl)butanoate (1.7 g, 7.05 mmol) in tetrahydrofuran (30 mL) and water (10 mL). The reaction mixture was stirred for 2 hours at room température. After removal of tetrahydrofuran under reduced pressure, the pH value of the solution was adjusted to 6-7 with aqueous hydrochloride acid (1 N, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under high vacuum to afford the title compound (1.2 g crade) as a yellow solid. LC-MS (Method E): m/z = 213.9 [M+H]⁺, 0.617 min.

285

Step 3: Préparation of 4-(4-amino-l-methyl-lH-pyrazol-3-yl)butanoic acid

[0768] A solution of 4-(l-methyl-4-nitro-lH-pyrazol-3-yl)butanoic acid (1.2 g, 5.61 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium on carbon (10%, 120 mg) under a hydrogen atmosphère (2-3 atm). After stirring for 5 hours at room température under a hydrogen atmosphère, the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum to afford the title compound (1 g crude) as a yellow solid. LC-MS (Method C): m/z = 184.1 [M+H]⁷, 0.304 min.

Step 4: Préparation of2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

[0769] N,N-diisopropylethylamine (2.2 g, 17.05 mmol) was added to a stirred mixture of 4-(4-aminol-methyl-lH-pyrazol-3-yl)butanoic acid (1.0 g, 5.46 mmol) and N,N,N’,N’-tetramethyl-O-(7azabenzotriazol-l-yl)uronium hexafluorophospate (2.5 g, 6.58 mmol) inN,N-dimethylformamide (20 mL). The reaction mixture was stirred for 3 hours at room température and diluted with water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (560 mg, 62.1%) as a yellow solid. LC-MS (Method C): m/z = 166.2 [M+H], 0.331 min.

Step 5: Préparation of 6-iodo-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

[0770] N¹,N¹,N²,N²-tetramethylethane-l,2-diamine (1.01 g, 8.73 mmol) was added to a stirring mixture of 2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one (0.48 g, 2.91 mmol) in dichloromethane (30 mL) at 0 °C followed by adding iodotrimethylsilane (1.16 g, 5.82 mmol) dropwise over 20 min. The reaction mixture was stirred for 1 hour at 0 °C. lodine (1.11g, 4.37 mmol) was added to the mixture. The reaction mixture was stirred for an additional 1 hour at 0 °C and quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL). The resulting solution was stirred for 15 minutes and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (550 mg crude) as a yellow solid. LC-MS (Method I): m/z = 291.9 [M+H]⁺, 0.522 min.

Step 6: Préparation of 6-azido-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

[0771] Sodium azide (246 mg, 3.78 mmol) was added to a solution of 6-iodo-2-methyl-7,8dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one (550 mg, 1.89 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was stirred ovemight at 40 °C, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (480 mg crude) as a brown solid, which was used directly in the next step without further purification. LC-MS (Method I): m/z = 207.0 [M+H]⁺, 0.481 min.

286

Step7: Préparation of 6-amino-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H, 6H)-one

[0772] Triphenylphosphine (1.5 g, 7.28 mmol) was added to a solution of 6-azido-2-methyl-7,8dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one (0.48 g, 2.18 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The resuiting mixture was stirred for 16 hours at room température, diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). Dre combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to afford the title compound (300 mg, 70.9%) as a yellow oil. LC-MS (Method R): m/z = 181.3 [M+H]⁺, 0.655 min.

Step 8: Préparation of 5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)4H-1,2,4-triazole-3-carboxamide

[0773] Tire crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 47% B over 7 min; UV 254 & 220 nm; Rt: 6.22 min to afford the title compound (50 mg, 26.8%) as a white solid. LC-MS (Method Y): m/z = 366.0 [M+H]⁺, 0.779 min.

Step 9: Préparation of (R)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6, 7,8-hexahydropyrazolo[4,3-b]azepin-6yl)-4H-l,2,4-triazole-3-carboxamide (example 104A) and (S)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-l, 2,4-triazole-3-carboxamide (example 104B)

[0774] The racemate of 5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6yl)-4H-l,2,4-triazole-3-carboxamide (50 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: i-PrOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 21 min; UV 254 & 220 nm; Rtl: 9.68 min; Rt2: 14.84 min to afford the title compounds:

[0775] Example 104A (first eluting isomer): ’HNMR (400 MHz, DMS0-7î) δ 14.37 (br. s, IH), 9.86 (s, IH), 8.39 (br. s, IH), 7.40 (s, IH), 7.34-7.22 (m, 5H), 4.40-4.35 (m, IH), 4.11 (s, 2H), 3.74 (s, 3H), 2.90-2.81 (m, 2H), 2.26-2.20 (m, IH), 2.11-1.97 (m, IH). LC-MS (Method X): m/z = 366.2 [M+H]⁺, 2.165 min.

[0776] Example 104B (second eluting isomer): ’H NMR (400 MHz, DMSO-d₆) δ 14.37 (br. s, IH), 9.86 (s, IH), 8.39 (br. s, IH), 7.40 (s, IH), 7.34-7.22 (m, 5H), 4.40-4.35 (m, IH), 4.11 (s, 2H), 3.74 (s, 3H), 2.89-2.84 (m, 2H), 2.25-2.21 (m, IH), 2.11-1.97 (m, IH). LC-MS (Method T): m/z = 366.3 [M+H]⁺, 0.858 min.

287

Example 105A and 105B: (S)-5-benzyl-N-(2,4-dimethyI-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yI)-4H-l,2,4-triazole-3-carboxamide and (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide

step 1 step 2

Step 1: Préparation of 6-azido-2,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

[0777] lodomethane (664 mg, 4.68 mmol) was added dropwise to a stirred mixture of 6-azido-2methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one (480 mg, 2.33 mmol) and césium carbonate (1.5 g, 4.66 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 2 hours at room température and quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (480 mg crude) as a brown solid. LC-MS (Method I): m/z = 221.0^+14^, 0.565 min.

Step 2: Préparation of 6-amino-2,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

[0778] Triphenylphosphine (2.44 g, 9.31 mmol) was added to a solution of 6-azido-2,4-dimethyl-7,8dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one (480 mg, 2.18 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The resulting mixture was stirred for 16 hours at room température, diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to afford the title compound (300 mg, 71%) as a yellow oil. LC-MS (Method I): m/z = 195.0 [M+H]⁺, 0.168 min.

288

Step 3: Préparation of 5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b] azepin-6yl)-4H-1,2,4-triazole-3-carboxamide

[0779] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge CI8 OBD Prep Column, 100 Â, 5 pm, 19 mm χ 250 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 30% B over 10 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound (50 mg, 26.8%) as a white solid. LC-MS (Method Q): m/z = 380.4 [M+H]/ 0.786 min.

Step 4: Préparation of (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4H-l,2,4-triazole-3-carboxamide (example 105A) and (R)-5-benzyl-N-(2,4-dimethyl-5-oxo2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (example 105B)

[0780] The racemate of 5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4H-l,2,4-triazole-3-carboxamide (50 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IC, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane:DCM=4.5:l, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 21 min; UV 220 & 254 nm; Rtl: 8.88 min; Rt2: 16.76 min to afford the title compounds:

[0781] Example 105A (first eluting isomer): ’HNMR (400 MHz, DMSO-ds) δ 14.35 (br. s, 1H), 8.32 (br. s, 1H), 7.83 (s, 1H), 7.34-7.22 (m, 5H), 4.53-4.45 (m, 1H), 4.11 (s, 2H), 3.79 (s, 3H), 3.19 (s, 3H), 2.85-2.66 (m, 2H), 2.35-2.31 (m, 1H), 2.30-2.26 (m, 1H). LC-MS (Method T): m/z = 380.2 [M+H]/ 0.958 min.

[0782] Example 105B (second eluting isomer): 'HNMR (400 MHz, DMSO-de) δ 14.29 (br. s, 1H), 8.30 (br. s, 1H), 7.83 (s, 1H), 7.34-7.22 (m, 5H), 4.52-4.46 (m, 1H), 4.11 (s, 2H), 3.79 (s, 3H), 3.19 (s, 3H), 2.85-2.68 (m, 2H), 2.35-2.31 (m, 1H), 2.30-2.27 (m, 1H). LC-MS (Method T): m/z = 380.2 [M+H]/ 0.953 min.

Example 106: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)-4H-l,2,4-triazole-3-carboxamide

[0783] Tire crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (0.1% formic acid); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B over 7 min; Detector, UV 254 & 220 nm; Rt: 5.47 min to afford the title compound. ^!H

289

NMR (400 MHz, DMSO-7₆) δ 14.11 (s, 1H), 8.49 (d, J= 7.9 Hz, 1H), 8.37 (dd, J= 4.8, 1.5 Hz, 1H),

7.71 (dd, 7= 8.0, 1.5 Hz, 1H), 7.40-7.22 (m, 6H), 4.92-4.66 (m, 2H), 4.56-4.55 (m, 1H), 3.36 (s, 3H),

1.52-1.27 (m, 4H). LC-MS (Method O): m/z = 405.0 [M+H]⁺, 1.126 min. .

Example 107A and 107B: (R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)-4H-l,2,4-triazole-3-carboxamide and (S)-5-benzyl-N-(9-methyI-8-oxo-6,7,8,9tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4H-l,2,4-triazole-3-carboxamide

step 4 step 5 step 6

step 7 step 8

Step 1: Préparation of (E)-6,7-dihydroquinolin-8(5H)-one oxime

[0784] Hydroxylamine hydrochloride (1.4 g, 20.3 mmol) was added to a solution of 6,7dihydroquinolin-8(5H)-one (1.5 g, 10.2 mmol) and sodium hydroxide (1.2 g, 30.0 mmol) in éthanol (20 mL) and water (10 mL). The resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to afford the title compound (1.4 g, 86.4%) as a white solid. LC-MS (Method E): m/z =163.1 [M+H]', 0.362 min.

290

Step 2: Préparation of (E)-6,7-dihydroquinolin-8(5H)-one O-methylsulfonyl oxime

[0785] Triethylamine (3.5 g, 30.6 mmol) and methanesulfonyl chloride (0.74 g, 6.4 mmol) were added to a solution of (E)-6,7-dihydroquinolin-8(5H)-one oxime (1.4 g, 8.64 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room température for 2 hours, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (1.7 g, 82%) as a yellow solid. LC-MS (Method C): m/z = 241.0 [M+H]⁺, 0.810 min.

Step 3: Préparation of 6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

[0786] Potassium acetate (5 g, 51 mmol) was added to a solution of (£)-6,7-dihydroquinolin-8(5H)one O-methylsulfonyl oxime (1.7 g, 7 mmol) in éthanol (40 mL) and water (20 mL). The reaction mixture was stirred ovemight at 110 °C and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to afford the title compound (1.0 g, 87%) as a yellow solid. LC-MS (Method C): m/z = 162.8 [M+H]⁺, 0.612 min.

Step 4: Préparation of 9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9PI)-one

[0787] lodomethane (1.0 g, 0.70 mmol) was added dropwise to a stirring mixture of 6,7-dihydro-5Hpyrido[2,3-b]azepin-8(9H)-one (1.0 g, 0.60 mmol) and césium carbonate (3.0 g, 0.92 mmol) inN,Ndimethylformamide (20 mL). The reaction mixture was stirred at room température ovemight, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/30) to afford the title compound (0.97 g, 89.8%) as a yellow solid. LC-MS (Method C): m/z = 177.1 [M+H]⁺, 1.192 min.

Step5: Préparation of7-iodo-9-mefhyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

[0788] N¹,N¹,N²,N²-tetramethylethane-l,2-diamine (1.9 g, 16.4 mmol) was added to a stirring mixture of 9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (0.97 g, 5.5 mmol) in dichloromethane (100 mL) at 0 °C followed by the addition of iodotrimethylsilane (3.3 g, 16.5 mmol) over 20 minutes. The reaction mixture was stirred for 1 hour at 0 °C. After adding iodine (4.2 g, 16.5 mmol), the reaction mixture was stirred for an additional 4 hours at room température before quenching by the addition of aqueous sodium thiosulfate (5%, 30 mL). The resulting solution was stirred for 15 minutes and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was

291 purified by column chromatography (ethyl acetate/petroleum ether, 1/30) to afford the title compound (1.5 g, 89.8%) as a white solid, LC-MS (Method C): m/z = 303.0 [M+H]⁺, 1.350 min.

Step 6: Préparation of7-azido-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

[0789] Sodium azide (650 mg, 10.0 mmol) was added to a solution of 7-iodo-9-methyl-6,7-dihydro5H-pyrido[2,3-b]azepin-8(9H)-one (1.5 g, 4.9 mmol) in N,N-dimethylformamide (10 mL). Tire reaction mixture was stirred for 5 hours at room température, diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (900 mg, 84%) as a white solid. LC-MS (Method C): m/z = 218.2 [M+H]⁺, 0.586 min.

Step 7: Préparation of7-amino-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

[0790] Triphenylphosphine (1.6 g, 6,1 mmol) was added to a solution of 7-azido-9-methyl-6,7dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (0.9 g, 4.1 mmol) in tetrahydrofuran (10 mL) and water (10 mL). The réaction mixture was stirred at room température ovemight, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (0.65 g, 82%) as a white solid. LC-MS (Method C): m/z = 192.1 [M+H]⁺, 0.386 min.

Step 8: Préparation of 5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4H-

1.2.4- triazole-3-carboxamide

[0791] N,N-diisopropylethylamine (201.2 mg, 1.56 mmol) was added to a mixture of 5-benzyl-4H-

1.2.4- triazole-3-carboxylic acid (104.6 mg, 0.52 mmol), 7-amino-9-methyl-6,7-dihydro-5H-pyrido[2,3b]azepin-8(9H)-one (100 mg, 0.52 mmol), N-(3-dimethylaminopropyl))-N’-ethylcarbodiimide hydrochloride (119.6 mg, 0.62 mmol) and 1-hydroxybenzotriazole (84.2 mg, 0.62 mmol) inN,Ndimethylformamide (4 mL). The reaction mixture was stirred ovemight at room température, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 10% B to 35% B over 11 min; UV 254 & 220 nm; Rt: 10 min to afford tire title compound (50 mg, 25%) as a white solid. LC-MS (Method D): m/z = 377.2 [M+H] , 1.551 min.

292

Step 9: Préparation of (R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)4PI-1,2,4-triazole-3-carboxamide (example 107A) and (S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9tetrahydro-5PI-pyrido[2,3-b]azepin-7-yl)-4PI-l,2,4-triazole-3-carboxamide (example 107B)

[0792] The racemate of 5-benzyi-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yi)4H-l,2,4-triazole-3-carboxamide (50 mg, 0.14 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak ID-2, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: MeOH:EtOH=l:l; Flow rate: 17 mL/min; Gradient: 60% B to 60% B over 23 min; UV 220 & 254 nm; Rtl: 8.53 min; Rt2: 18.27 min to afford the title compounds:

[0793] Example 107A (first eluting isomer): ’HNMR (300 MHz, DMSO-X) δ 14.35 (br. s, 1H), 8.528.42 (m, 2H), 7.82-7.79 (m, 1H), 7.34-7.21 (m, 6H), 4.35-4.26 (m, 1H), 4.10 (s, 2H), 3.34 (s, 3H), 2.752.62 (m, 2H), 2.41-2.16 (m, 2H). LC-MS (Method D): m/z = 377.2 [M+H]⁺, 1.551 min.

[0794] Example 107B (second eluting isomer): ’HNMR (300 MHz, DMSO-X) δ 14.35 (br. s, 1H), 8.45-8.41 (m, 2H), 7.83-7.79 (m, 1H), 7.35-7.15 (m, 6H), 4.35-4.23 (m, 1H), 4.10 (s, 2H), 3.34 (s, 3H), 2.75-2.61 (m, 2H), 2.50-2.20 (m, 2H). LC-MS (Method D): m/z = 377.2 [M+Hf, 1.546 min.

Example 108: (S)-2-benzyî-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4] oxazepin-3-yl)lH-imidazole-5-carboxamide

CN

step 3

Step P. Préparation of (Z)-N'-hydro:c\’-2-phenylaceiimidamide

[0795] Sodium bicarbonate (1.44 g, 17.1 mmol) was added to a mixture of 2-phenylacetonitrile (1.0 g, 8.54 mmol) and hydroxylamine hydrochloride (1.19 g, 17.1 mmol) in éthanol (15 mL) and water (5.0 mL). The reaction mixture was stirred at 80 °C ovemight, diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography

293 (methanol/dichloromethane, 5/95) to afford the title compound (1.15 g, 90%) as a white solid. MS (Method I): m/z = 151.1 [M+H]⁺, 0.194 min.

Step 2: Préparation of ethyl 2-benzyl-lH-imidazole-5-carboxylate

[0796] A reaction mixture of (Z)-N’-hydroxy-2-phenylacetimidamide (1.0 g, 6.67 mmol) and ethyl propiolate (1.96 g, 20 mmol) in éthanol (20 mL) was stirred at 80 °C ovemight. Diphenylether (50 mL) was added to the mixture and stirred at 130 °C for 2 hours. The reaction mixture was quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/99) to afford the title compound (650 mg, 43%) as agray solid. LC-MS (Method L): m/z = 231.1 [M+H]⁺, 1.197 min.

Step 3: Préparation of (S)-2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3yl)-lH-imidazole-5-carboxamide

[0797] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 45% B over 7 min; UV 254 & 220 nm; Rt: 6 min to afford the title compound. 'H NMR (400 MHz, DMSO-i/e) δ 12.41 (s, 1H), 8.36 (dd, J= 4.8, 1.6Hz, 1H), 8.01 (d, J=8.0Hz, 1H), 7.71 (dd, 7 = 8.0, 1.6 Hz, 1H), 7.57 (d, 7 = 2.1 Hz, 1H), 7.38-7.17 (m, 6H), 4.90-4.76 (m, 1H), 4.64 (dd, 7= 11.5, 9.8 Hz, 1H), 4.54-4.45 (m, 1H), 4.02 (s, 2H), 3.36 (s, 3H). LC-MS (Method O): m/z = 378.0 [M+H]⁺, 1.047 mm.

Example 109A and 109B: (S)-l-benzyI-N-(2,4-dimethyI-5-oxo-2,4,5,6,7,8-hexahydropyrazoIo[4,3b]azepin-6-yl)-4-fluoro-lH-pyrazole-3-carboxamide and (R)-l-benzyI-N-(2,4-dimethyl-5-oxo2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-lH-pyrazole-3-carboxamide

HO —N

HOBT, EDCI, DIEA, DMF rt, o/n step 1 —N chiral seperation step 2

294

Step 1: Préparation of l-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6yl)-4-fluoro-lH-pyrazole-3-carboxamide

[0798] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 50% B over 7 min; UV 254 & 220 nm; Rt: 6 min to afford the title compound (80 mg, 55.6%) as a white solid. LC-MS (Method Q): m/z = 397.4 [M+Hf, 1.115 min.

Step 2: Préparation of (S)-l-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4-fluoro-lH-pyrazole-3-carboxamide (example 109A) and (R)-l-benzyl-N-(2,4-dimethyl-5-oxo2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-lH-pyrazole-3-carboxamide (example 109B).

[0799] The racemate of l-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4-fluoro-lH-pyrazole-3-carboxamide (80 mg, 0.20 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Lux 5u Cellulose-3, AXIA Packed, 2.12 χ 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 40% B to 40% B over 15 min; UV 254 & 220 nm; Rtl: 9.89 min; Rt2: 12.58 min to afford the title compounds:

[0800] Example 109A (first eluting isomer): ’HNMR (400 MHz, DMSO-ri_e) δ 8.13 (d, J=4.4 Hz, 1H), 7.92 (d, <7=7.2 Hz, 1H), 7.83 (s, 1H), 7.40-7.31 (m, 3H), 7.31-7.28 (m, 2H), 5.33 (s, 2H), 4.50-4.44 (m, 1H), 3.78 (s, 3H), 3.18 (s, 3H), 2.84-2.77 (m, 1H), 2.75-2.67 (m, 1H), 2.33-2.24 (m, 1H), 2.16-2.04 (m, 1H). LC-MS (Method T): m/z = 397.2 |M+H| , 1.155 min.

[0801] Example 109B (second eluting isomer): ’H NMR (400 MHz, DMSO-ris) δ 8.13 (d, J= 4.4 Hz, 1H), 7.93 (d, J= 7.2 Hz, 1H), 7.83 (s, 1H), 7.40-7.31 (m, 3H), 7.31-7.26 (m, 2H), 5.33 (s, 2H), 4.51-4.42 (m, 1H), 3.78 (s, 3H), 3.18 (s, 3H), 2.87-2.63 (m, 2H), 2.35-2.21 (m, 1H), 2.18-2.03 (m, 1H). LC-MS (Method T): m/z = 397.2 [M+H]⁺, 1.154 min.

295

Exampie 110A and 110B: 5-benzyl-N-((laR,2R,8bS)-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide and 5-benzylN-((laS,2S,8bR)-3-oxo-l,la,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yI)-4H-l,2,4triazole-3-carboxamide

Step 1: Préparation of 3-benzyl-N-(cis-3-oxo-l,la,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2, 3b]azepin-2-yl)-4PI-l, 2,4-triazole-3-carboxamide

[0802] The crude product obtained using Amide Coupling Procedure C was purified by Prep-TLC (ethyl acetate/petroleum ether, 1/3) to afford the title compound (20 mg, 26.7%) as a yellow solid. LCMS (Method I): m/z = 375.2 [M+H]⁺, 1.007 min.

Step 2: Préparation of 5-benzyl-N-((laR,2R,8bS)-3-oxo-l, la,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide (example 110A) and 5-ben-zyl-N((laS, 2S, 8bR)-3-oxo-l, la, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-l, 2,4-triazole3-carboxamide (example 110B)

[0803] The racemate of 5-benzyl-N-(cis-3-oxo-l,la,2,3,4,8b-hexahydrocyclopropa[d]pyrido [2,3b]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide (20 mg, 0.053 mmol) was separated by Prep-ChiralHPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 20 min; UV 254 & 220 nm; Rtl: 12.8 min; Rt2: 16.08 min to afford the title compounds:

[0804] Example 110A (first eluting isomer): *H NMR (400 MHz, CDjOD-îL) δ 8.24 (dd, J= 4.8, 1.6 Hz, 1H), 7.91 (dd, J= 7.6, 1.6 Hz, 1H), 7.38-7.16 (m, 6H), 4.84 (s, 1H), 4.17 (s, 2H), 2.25-2.21 (m, 1H), 2.15-2.09 (m, 1H), 1.62-1.57 (m, 1H), 1.16-1.12 (m, 1H). LC-MS (Method J): m/z = 375.2 [M+H]⁺, 1.007 min.

296

[0805] Example 110B (second eluting isomer): ’H NMR (300 MHz, CDsOD-îL) δ 8.23 (dd, J= 4.8,

1.8 Hz, IH), 7.90 (dd, J= 7.5, 1.8 Hz, IH), 7.39-7.13 (m, 6H), 4.84 (s, IH), 4.18 (s, 2H), 2.19-2.09 (m,

2H), 1.64-1.55 (m, IH), 1.17-1.10 (m, IH). LC-MS (Method F): m/z = 374.9 [M+H]⁺, 0.919 mm.

Example 111A and 111B: (R)-l-benzyI-4-fluoro-N-(9-methyI-8-oxo-6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepin-7-yI)-lH-pyrazole-3-carboxamide and (S)-l-benzyl-4-fluoro-N-(9-methyI-8oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-lH-pyrazole-3-carboxamide

rt, o/n

step 1

Step 1 Préparation of l-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin7-yl)-lH-pyrazole-3-carboxamide

[0806] N,N-diisopropylethylamine (201.2 mg, 1.56 mmol) was added to a mixture of l-benzyl-4fluoro-lH-pyrazole-3-carboxylic acid (104.6 mg, 0.52 mmol), 7-amino-9-methyl-6,7-dihydro-5Hpyrido[2,3-b]azepin-8(9H)-one (100 mg, 0.52 mmol), N-(3-dimethylaminopropyl))-N’-ethylcarbodiimide hydrochloride (119.6 mg, 0.62 mmol) and 1-hydroxybenzotriazole (84.2 mg, 0.62 mmol) in N,Ndimethylformamide (3 mL). The reaction mixture was stirred ovemight at room température, diluted with water (10 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crade product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 55% B over 7 min; UV 254 & 220 nm; Rt: 5.6 min to afford the title compound (32 mg, 25.4%) as a white solid. LCMS (Method D): m/z = 394.2[M+H]⁺, 1.571 min.

297

Step 2: Préparation of (R)-l-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)-lH-pyrazole-3-carboxamide (example 111A) and (S)-l-benzyl-4fluoro-N-(9-methyl-8oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-lH-pyrazole-3-carboxamide (example 111B)

[0807] The racemate of l-benzyl-4-fiuoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)-lH-pyrazole-3-carboxamide (32 mg, 0.081 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 15 min; UV 254 &. 220 nm; Rtl: 11.47 min; Rt2: 13.24 min to afford the title compounds:

[0808] Example 11 IA (first eluting isomer): Ή NMR (300 MHz, DMSO-ri₆) δ 8.42-8.40 (m, 1H), 8.10-8.02 (m, 2H), 7.80-7.77 (m, 1H), 7.39-7.24 (m, 6H), 5.31 (s, 2H), 4.32-4.23 (m, 1H), 3.33 (s, 3H), 2.78-2.60 (m, 2H), 2.38-2.25 (m, 2H). LC-MS (Method D): m/z = 394.2 [M+H]⁺, 1.571 min.

[0809] Example 11 IB (second eluting isomer): ’H NMR (300 MHz, DMSO-c/ô) δ 8.42-8.40 (m, 1H), 8.10-8.02 (m, 2H), 7.80-7.77 (m, 1H), 7.39-7.24 (m, 6H), 5.31 (s, 2H), 4.32-4.23 (m, 1H), 3.32 (s, 3H), 2.72-2.66 (m, 2H), 2.39-2.26 (m, 2H). LC-MS (Method D): m/z = 394.2 [M+H]⁺, 1.570 min.

Example 112: 5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yI)isoxazole-3-carboxamide

[0810] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 5 pm, 19 χ 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B in 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound. ’H NMR (400 MHz, DMSO-rie) δ 8.35 (dd, J= 4.7, 1.5 Hz, 1H), 8.27 (d, J= 7.0 Hz, IH), 7.73 (dd, J= 7.9, 1.5 Hz, 1H), 7.397.23 (m, 6H), 6.61 (s, IH), 4.99-4.87 (m, 2H), 4.22 (s, 2H), 3.39 (s, 3H), 1.36 (d, J= 6.2 Hz, 3H). LCMS (Method X): m/z = 393.2 [M+H]⁺, 3.187 min.

298

Example 113: (S)-N-(l-methyl-2-oxo-l,2,3,4-tetrahydropyrido[3,4-b] [l,4]oxazepin-3-yl)-5-(lphenylcyclopropyl)-4H-l,2,4-triazole-3-carboxamide

[0811] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 10% B to 40% B over 7 min; UV 254 & 220 nm; Rt: 6 min to afford the title compound.¹H NMR (400 MHz, DMSO-ds) δ 14.11 (s, 1H), 8.91-8.36 (m, 3H), 7.53 (d, J= 5.3 Hz, 1H), 7.33 (m, 5H), 4.94-4.82 (m, 1H), 4.82-4.70 (m, 1H), 4.51 (dd, J= 9.6, 7.2 Hz, 1H), 3.32 (s, 3H), 1.59-1.20 (m, 4H). LC-MS (Method O): m/z = 405.0 [M+H]⁺, 1.127 min.

Example 114A and 114B: (S)-l-benzyI-N-(l,4-dimethyl-5-oxo-l,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)-4-fluoro-lH-pyrazole-3-carboxamide and (R)-l-benzyl-N-(l,4-dimethyl-5-oxol,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-lH-pyrazole-3-carboxamide

step 2

Step 1: Préparation of l-benzyl-N-(l,4-dimethyl-5-oxo-l,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6yl)-4fluoro-lH-pyrazole-3-carboxamide

[0812] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column 19 x 150 mm 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B

299 to 50% B over 7 min; UV 254 & 220 nm; Rt: 6 min to afford the title compound (50 mg, 48.6%) as a white solid. LC-MS (Method C): m/z = 397.2 [M+H]⁺, 1.512 min.

Step 2: Préparation of (S)-l-benzyl-N-(l,4-dimethyl-5-oxo-l,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4fluoro-lH-pyrazole-3-carboxamide (example 114A) and (R)-l-benzyl-N-(l,4-dimethyl-5-oxo1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-lH-pyrazole-3-carboxamide (example 114B).

[0813] The racemate of l-benzyl-N-(l,4-dimethyl-5-oxo-l,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yI)-4-fluoro-lH-pyrazole-3-carboxamide (50 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 18 min; UV 254 & 220 nm; Rtl: 12.54 min; Rt2: 15.41 min. to afford the title compounds:

[0814] Example 114A (first eluting isomer): ’H NMR (400 MHz, DMSO-t/e) δ 8.14 (d, J-4.0 Hz, 1H), 8.07 (d, J= 6.4 Hz, 1H), 7.50 (s, 1H), 7.41-7.27 (m, 5H), 5.34 (s, 2H), 4.43-4.37 (m, 1H), 3.74 (s, 3H), 3.24 (s, 3H), 3.06-2.96 (m, 1H), 2.91-2.84 (m, 1H), 2.30-2.23 (m, 1H), 2.10-1.99 (m, 1H). LC-MS (Method D): m/z = 397.1 [M+H]⁺, 1.500 min.

[0815] Example 114B (second eluting isomer): ’H NMR (400 MHz, DMSO-r/e) δ 8.14 (d, J= 4.4 Hz, 1H), 8.07 (d, J= 6.8 Hz, 1H), 7.50 (s, 1H), 7.41-7.26 (m, 5H), 5.34 (s, 2H), 4.43-4.37 (m, 1H), 3.74 (s, 3H), 3.24 (s, 3H), 3.06-2.96 (m, 1H), 2.91-2.83 (m, 1H), 2.30-2.22 (m, 1H), 2.10-1.99 (m, 1H). LC-MS (Method D): m/z = 397.1 [M+H]⁺, 1.514 min.

Example 115: (S)-4-fluoro-l-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2b] [l,4]oxazepin-3-yI)-lH-pyrazole-3-carboxamide

1) NaH, DMF, 0 °C-rt, 2 h

2) H₂O, rt, 5 h step 1

Br

HOBT, EDCI, DIEA, DMF rt, o/n step 2

NH₂ HCl

Step 1: Préparation of 4-fluoro-l-(4-fluorobenzyl)-lH-pyrazole-3-carboxylic acid

[0816] Sodium hydride (60%, 152 mg, 3.8 mmol) was added to a solution of methyl 4-fluoro-lHpyrazole-3-carboxylate (200 mg, 1.27 mmol) in N,N-dimethylformamide (10 mL) at 0 °C. The resulting mixture was stirred at room température for 0.5 hour followed by addition of l-(bromomethyl)-4

300 fluorobenzene (264 mg, 1.40 mmol). The reaction mixture was stirred at room température for another

1.5 hours and quenched by addition of water (20 mL). The resulting solution was then stirred at room température for 5 hours. The pH value of the solution was adjusted to 7 with aqueous hydrochloric acid (1 N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Â, 5 pm, 19 mm χ 250 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B over 9 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound (100 mg, 33.2%). LC-MS (Method S): m/z = 239.2 [M+H]⁺, 1.093 min.

Step 2: Préparation of (S)-4-fluoro-l-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0817] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 χ 150 mm 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 & 220 nm; Rt: 6.32 min to afford the title compound.¹H NMR (400 MHz, DMSO-i/e) δ 8.37-8.35 (m, 1H), 8.27 (d, .7= 8 Hz, 1H), 8.14 (d, J= 4.4 Hz, 1H), 7.71-7.69 (m, 1H), 7.367.32 (m, 3H), 7.25-7.20 (m, 2H), 5.33 (s, 2H), 4.87-4.81 (m, 1H), 4.70-4.65 (m, 1H), 4.52-4.48 (m, 1H), 3.35 (s, 3H). LC-MS (Method X): m/z = 414.2 [M+H]⁺, 2.606 min.

Example 116: (S)-N-(5,6-dihydro-4H-benzo[f|imidazo[l,2-a]azepin-4-yl)-5-(2fluorophenoxy)pyridazine-3-carboxamide

301

Step 1: Préparation of 3-chloro-5-(2-fluorophenoxy)pyridazine

[0818] 2-Fluorophenol (2 g, 17.8 mmol) was added dropwise to a stirring mixture of 3,5dichloropyridazine (3.17 g, 21.4mmol) and césium carbonate(8.7 g, 26.9 mmol)in acetonitrile (40 mL). The reaction mixture was stirred at room température for 1 hour under a nitrogen atmosphère. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether) to afford the title compound (2.8 g, 70%) as a white solid. LCMS (Method X): m/z = 225.1 [M+H]⁺, 0.919 mm.

Step 2: Préparation of ethyl 5-(2fluorophenoxy)pyridazine-3-carboxylate

[0819] 1,1’ -Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.95 g, 1.16 mmol) was added to a mixture of 3-chloro-5-(2-fluorophenoxy)pyridazine (2.6 g, 11.6 mmol) and sodium acetate (1.9 g, 23.2 mmol) in éthanol (125 mL) and N,N-dimethylformamide (25 mL). The reaction mixture was stirred overnight at 90 °C under a carbon monooxide atmosphère (1 MPa). After cooling to room température, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to afford the title compound (2.4 g, 79%) as a colorless oil. LC-MS (Method X): m/z =263.1 [M+H]⁺, 0.905 min.

Step 3: Préparation of 5-(2-fluorophenoxy)pyridazine-3-carboxylic acid

[0820] Lithium hydroxide (48 mg, 2 mmol) was added to a stirring solution of ethyl 5-(2fluorophenoxy)pyridazine-3-carboxylate (131 mg, 0.5 mmol) in tetrahydrofuran (8 mL) and water (2 mL). The reaction mixture was stirred for 1 hour at room température. After removal of tetrahydrofuran under reduced pressure, the residue was diluted with water (20 mL). The pH ofthe resulting solution was adjusted to 4 with aqueous hydrochloride acid (2 N, 5 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (100 mg crude) as a white solid. LC-MS (Method R): m/z = 235.2 [M+H]⁺, 0.507 min.

Step 4: Préparation of (S)-N-(5,6-dihydro-4H-benzo[f]imidazo[l,2-a]azepin-4-yl)-5-(2fluorophenoxy)pyridazine-3-carboxamide

[0821] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 * 150 mm 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN, Flow rate: 30 mL/min; Gradient: 45% B to 50% B over 5 min; UV 254 & 220 nm to afford the title compound. ’H NMR (400 MHz, Methanol-iL) 5 9.25 (d, 7= 2.8 Hz, 1H), 7.51-7.32 (m, 10H), 7.08 (d, 7= 1.2 Hz, 1H), 5.11-5.06 (m, 1H), 2.88-2.81 (m, 1H), 2.80-2.71 (m, 1H), 2.66-2.57 (m, 1H), 2.51-2.42 (m, 1H). LC-MS (Method D): m/z = 416.1 [M+H]⁺, 1.337 min.

302

Example 117: N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepin-3-yl)-4(2-fluorophenoxy)picoIinamide

[0822] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 85% B over 7 min; UV 254 & 220 nm; Rt: 6.35 min to afford the title compound. ’H NMR (400 MHz, DMSOYô) δ 8.75 (d, J= 6.8 Hz, 1H), 8.64 (d, J= 5.6 Hz, 1H), 8.36 (dd, J= 4.8, 1.6 Hz, 1H), 7.76 (dd, J= 8.0, 1.6 Hz, 1H), 7.54-7.39 (m, 3H), 7.38-7.33 (m, 3H), 7.27-7.29 (m, 1H), 5.02-4.95 (m, 1H), 4.94-4.89 (_m, 1H), 3.41 (s, 3H), 1.32 (d, J= 6.0 Hz, 3H). LC-MS (Method Q): m/z = 423.0 [M+H]⁺, 2.885 min.

Example 118A & 118B: (R)-5-benzyl-N-(l-methyl-5-oxo-l,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide and (S)-5-benzyl-N-(l-methyl-5-oxo-l,4,5,6,7,8hexahydropyrazolo[4,3-b]azepin-6-yI)-4H-l,2,4-triazoIe-3-carboxamide

Step 1: Préparation of 5-benzyl-N-(l-methyl-5-oxo-l ,4,5,6,7,8-hexahydropyrazolo[4,3-b] azepm-6-yl)4H-1,2,4-triazole-3-carboxamide

[0823] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column 19 χ 150 mm 5 pm; Mobile

303

Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to

35% B over 10 min; UV 254 & 220 nm; Rt: 9 min to afford the title compound (50 mg, 38.1%) as a white solid. LC-MS (Method C): m/z = 366.2 [M+H]⁺, 1.174 min.

Step 2: (R)-5-benzyl-N-(l-methyl-5-oxo-l, 4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-l, 2,4triazole-3-carboxamide (example 118A) and (S)-5-benzyl-N-(l-methyl-5-oxo-l,4,5,6,7,8hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (example 118B)

[0824] The racemate of 5-benzyl-N-(l-methyl-5-oxo-l,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6yl)-4H-l,2,4-triazole-3-carboxamide (50 mg, 0.14 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 * 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 12 min; 254/220 nm; Rtl : 8.84 min; Rt2: 10.81 min to afford the title compounds:

[0825] Example 118A (first eluting isomer): Ή NMR (400 MHz, DMSO-7₆) δ 10.00 (s, 1H), 8.53 (d, J=5.6Hz, 1H), 7.41-7.29 (m, 5H), 7.17 (s, 1H), 4.41-4.37 (m, 1H), 4.18 (s, 2H), 3.76 (s, 3H), 3.05-3.00 (m, 2H), 2.34-2.30 (m, 1H), 2.10-2.05 (m, IH). LC-MS (Method D): m/z = 366.1 [M+H]⁺, 1.180 min.

[0826] Example 118B (second eluting isomer): 'H NMR (400 MHz, DMSO-ûfc) δ 9.94 (s, 1H), 8.46 (d, J= 6.0 Hz, 1H), 7.35-7.10 (m, 5H), 7.10 (s, 1H), 4.35-4.30 (m, 1H), 4.12 (s, 2H), 3.69 (s, 3H), 3.00-2.92 (m, 2H), 2.27-2.23 (m, 1H), 2.04-1.98 (m, 1H). LC-MS (Method D): m/z = 366.1 [M+H]⁺, 1.177 min.

Example 119A & 119B: 5-benzyl-N-((7R,7aR,8aS)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-4H-l,2,4-triazole-3-carboxamide and 5-benzyl-N((7S,7aS,8aR)-5-methyI-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)4H-l,2,4-triazole-3-carboxamide

M''SnBu₃

Pd(PPh₃)₄, DMF °C, 16 h step 1

step 2

Cs₂CO₃, CH₃I

DMF, rt, 4 h step 4

1) KOH, Et₂O, 0°C, 1 h

2) Pd(OAc)₂, THF °C to rt, o/n step S

304

PPh₃, THF, H₂O rt, 16 h

step 9

Step 1 : Préparation of 3-vinylpyrazm-2-amine

[0827] To a solution of 3-bromopyrazin-2-amine (10 g, 57 mmol) in N,N-dimethylformamide (50 mL) was added tributyl(ethenyl)stannane (20 g, 63 mmol) and tetrakis(triphenylphosphine)palladium (2.7 g, 2.3 mmol) under a nitrogen atmosphère. The resulting mixture was stirred for 16 hours at 80 °C, quenched by the addition of water (200 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to afford the title compound (6.0 g, 86%) as a yellow solid. LC-MS (Method C): m/z = 122.1 [M+H]⁺, 0.658 min.

Step 2: Préparation ofN-(3-vinylpyrazin-2-yl)hui-3-enamide

[0828] Thionyl chloride (9.3 g, 46.5 mmol) was added to a solution of but-3-enoic acid (4.0 g, 46.5 mmol) in dichloromethane (20 mL) dropwise. After stirring for 1 hour at room température, the resulting mixture was added to a solution of triethylamine (11.8 g, 116.6 mmol) and 3-vinylpyrazin-2amine (4.7 g, 38.7 mmol) in dichloromethane (20 mL). The reaction mixture was stirred for 2 hours at room température, quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/1) to afford the title compound (5.7 g, 78%) as a yellow oil. LC-MS (Method C): m/z = 190.1 [M+H]⁺, 0.881 min.

Step 3: Préparation of (Z)-5H-pyrazino[2,3-b]azepin-6(7H)-one

[0829] [l,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro(phenylmethylidene) ruthénium tricyclohexylphosphine (340 mg, 0.4 mmol) was added to a solution of N-(3-vinylpyrazin-2305 yl)but-3-enamide (380 mg, 2 mmol) in toluene (50 mL). The resulting solution was stirred for 16 hours at 80 °C and then concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 5/1) to afford the title compound (210 mg, 65%) as a yellow oil. LC-MS (Method C): m/z = 162.1 [M+H]⁺, 0.762 min.

Step 4: Préparation of (Z)-5-methyl-5H-pyrazino[2,3-b]azepin-6(7H)-one

[0830] lodomethane (180 mg, 1.3 mmol) was added dropwise to a stirring solution of (Z)-5Hpyrazino[2,3-b]azepin-6(7H)-one (210 mg, 1.3 mmol) and césium carbonate (1.3 g, 3.9 mmol) in N,Ndimethylformamide (30 mL). The reaction mixture was stirred for 4 hours at room température, diluted with water (60 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 4/1) to afford the title compound (200 mg, 88%) as a yellow solid. LC-MS (Method E): m/z = 176.1 [M+H]⁺, 0.776 min.

Step 5: Préparation of 5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin- 6(5H)-one

[0831] To a solution of potassium hydroxide (4 g, 71.4 mmol) in water (6 mL) was added a solution of 1-methyl-1-nitrosourea (2.1 g, 20 mmol) in ether (30 mL) dropwise at 0 °C under a nitrogen atmosphère. The resulting mixture was stirred for 1 hour at 0 °C and then the organic phase was separated to provide a solution of diazomethane (30 mL). To a solution of (Z)-5-methyl-5H-pyrazino[2,3-b]azepin-6(7H)-one (200 mg, 1.1 mmol) in tetrahydrofuran (10 mL) was added the solution of diazomethane (30 mL) dropwise, followed by adding a mixture of palladium diacetate (25 mg, 0.11 mmol) in tetrahydrofuran (5 mL) dropwise at 0 °C. The reaction mixture was stirred ovemight at room température. The solids were removed by filtration and the filtrate was concentrated under vacuum to afford the title compound (110 mg crude) as a yellow oil. LC-MS (Method E): m/z = 190.1 [M+H]⁺, 0.825 min.

Step 6: Préparation of trans-7-iodo-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b] azepin6(5H)-one

[0832] To a mixture of 5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one (110 mg, 0.6 mmol) in dichloromethane (20 mL) was addedN,N,N’,N’-tetramethylethylene-diamine (210 mg, 1.8 mmol) followed by the addition of iodotrimethylsilane (360 mg, 1.8 mmol) at 0 °C. After stirring for 2 hours at 0 °C, iodine (230 mg, 0.9 mmol) was added. The reaction mixture was stirred for 1 hour at 0 °C, quenched with aqueous sodium thiosulfate (5%, 40 mL) and extracted with dichloromethane (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (132 mg crude) as a yellow oil. LC-MS (Method E): m/z = 316.1 [M+H]⁺, 0.840 min.

306

Step 7: Préparation of cis-7-azido-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b] azepin6(5H)-one

[0833] Sodium azide (39 mg, 0.6 mmol) was added to a mixture of trans-7-iodo-5-methyl- 7,7a,8,8atetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one (132 mg, 0.4 mmol) inN,Ndimethylformamide (10 mL). The resulting mixture was stirred for 16 hours at room température, quenched by the addition of water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (60 mg crude) as a yellow oil. LC-MS (Method C): m/z = 231.1 [M+H]⁺, 1.036 min.

Step 8: Préparation of cis-7-amino-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin6(5H)-one

[0834] Triphenylphosphine (102 mg, 0.39 mmol) was added to a mixture of cis-7-azido-5-methyl7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one (60 mg, 0.26 mmol) in tetrahydrofuran (10 mL) and water (1 mL), The resulting mixture was stirred for 16 hours at room température, diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/19) to afford the title compound (40 mg, 75%) as a yellow oil. LC-MS (Method E): m/z = 205.1 [M+H]⁺, 0.406 min.

Step 9: Préparation of 5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d] pyrazino[2,3-b]azepin-7-yl)-4H-l ,2,4-triazole-3-carboxamide

[0835] N,N-diisopropylethylamine (93 mg, 0.72 mmol) was added to a mixture of 5-benzyl-4H-l,2,4triazole-3-carboxylic acid (51 mg, 0.24 mmol), cis-7-amino-5-methyl-7,7a,8,8atetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one (40 mg, 0.20 mmol), N-(3-dimethylaminopropyl))-N’-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was stirred ovemight at room température, diluted with water (20 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 χ 150 mm, 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 & 220 nm to afford the title compound (20 mg, 26%) as a white solid. LC-MS (Method D): m/z = 390.2 [M+H]⁺, 1.386 min.

307

Step 10: Préparation of 5-benzyl-N-((7R, 7aR,8aS)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-4P[-l,2,4-triazole-3-carboxamide (example 119A) and5benzyl-N-((7S, 7aS, 8aR) -5-methyl-6-oxo-5,6,7,7a, 8,8a-hexahydrocyclopropa[d]-pyrazino[2,3-b]azepin- 7yl)-4H-l,2,4-triazole-3-carboxamide (example 119B)

[0836] The racemate of 5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-4H-l,2,4-triazole-3-carboxamide (20 mg, 0.05 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IA, 2 x 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 55% B to 55% B over 27 min; 220/254 nm ; Rtl: 13.94 min; Rt2: 21.44 min to afford the title compounds:

[0837] Example 119A (first eluting isomer): ’H NMR (400 MHz, MethanolA) δ 8.44-8.40 (m, 2H), 7.36-7.21 (m, 5H), 4.81 (s, 1H), 4.18 (s, 2H), 3.42 (s, 3H), 2.66-2.58 (m, 1H), 2.29-2.18 (m, 1H), 1.571.48 (m, 1H), 1.36-1.25 (m, 1H). LC-MS (Method D): m/z = 390.1 [M+H]⁺, 1.389 min.

[0838] Example 119B (second eluting isomer): ’HNMR (400 MHz, Methanol-dk) δ 8.46-8.38 (m,

2H), 7.39-7.21 (m, 5H), 4.81 (s, 1H), 4.18 (s, 2H), 3.42 (s, 3H), 2.66-2.58 (m, 1H), 2.30-2.22 (m, 1H),

1.57-1.50 (m, 1H), 1.35-1.26 (m, 1H). LC-MS (Method D): m/z = 390.2 [M+H]⁺, 1.384 min.

Example 120A and 120B: 5-benzyl-N-((laS,2S,8bR)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-l,3,4-thiadiazole-2-carboxamide and 5-benzylN-((laR, 2R,8bS)-4-methyl-3-oxo-l, la, 2,3,4,8b-hexahydrocyclopropa-[d]pyrido[2,3-b]azepin-2-yI)1,3,4-thiadiazoIe-2-carboxamide

nh₂

step 1 chiral seperation

NH NO S

step 2

Step 1: Préparation of 5-benzyl-N-(cis-4-methyl-3-oxo-l, la,2,3,4,8b-hexahydrocyclopropa[d] pyrido[2,3-b]azepin-2-yl)-l, 3,4-thiadiazole-2-carboxamide

[0839] The crude product obtained using Arnide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B

308 to 55% B over 7 min; UV 254 & 220 nm; Rt: 6.32 min to afford the title compound (20 mg, 32.9%) as a white solid. LC-MS (Method I): m/z = 406.2 [M+H]⁺, 1.001 min.

Step 2: Préparation of 5-benzyl-N-((laS,2S,8bR)-4-methyl-3-oxo-l, la,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-l,3,4-thiadiazole-2-carboxamide (example 120A) and 5-benzyl-N((1 aR, 2R, 8b S)-4-methyl-3-oxo-l ,1a, 2,3,4,8b-hexahydrocyclopropa-[d]pyrido[2,3-b]azepin-2-yl) -1,3,4thiadiazole-2-carboxamide (example 120B)

[0840] The racemate of 5-benzyl-N-(cis-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrocyclopropa- [d]pyrido[2,3-b]azepin-2-yl)-l,3,4-thiadiazole-2-carboxamide (20 mg, 0.049 mmol) was separated by Prepchiral-separation with following conditions: Column: Lux Cellulose-4, 0.46 χ 5 cm, 3 pm; Mobile Phase A: hexane; Mobile Phase B: EtOH; Flow rate: LO mL/min; Gradient: 50% B to 50% B over 8 min; UV 254 & 220 nm; Rtl : 4.09 min; Rt2: 6.43 min to afford the title compounds:

[0841] Example 120A (first eluting isomer): ’H NMR (400 MHz, Methanol-X) δ 8.38 (dd, J= 4.8, 2.0 Hz, 1H), 7.94 (dd, J= 7.6, 2.0 Hz, 1H), 7.41-7.26 (m, 6H), 4.64 (s, 1H), 4.53 (s, 2H), 3.41 (s, 3H), 2.332.25 (m, 1H), 2.15-2.06 (m, 1H), 1.34-1.28 (m, 1H), 1.21-1.12 (m, 1H). LC-MS (Method D): m/z = 406.1 [M+H]⁺, 1.703 min.

[0842] Example 120B (second eluting isomer): ’H NMR (400 MHz, Methanol-X) δ 8.36 (dd, J= 4.8, 2.0 Hz, 1H), 7.91 (dd, J= 7.6, 2.0 Hz, 1H), 7.38-7.24 (m, 6H), 4.62 (s, 1H), 4.50 (s, 2H), 3.38 (s, 3H), 2.29-2.24 (m, 1H), 2.12-2.06 (m, 1H), 1.32-1.26 (m, 1H), 1.22-1.14 (m, 1H). LC-MS (Method V): m/z = 406.1 [M+H]⁺, 2.915 min.

Example 121A & 121B: (R)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepin-7-yl)picolinamide and (S)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)picolinamide

309

Step 1: Préparation of methyl 4-(2,4-difluorophenoxy)picolinate

[0843] To a sealed tube were added methyl 4-chloropicolinate (1 g, 5.85 mmol), 2,4-difluorophenol (1.14 g, 8.77 mmol), césium carbonate (5.7 g, 17.5 mmol), copper powder (0.38 g, 5.94 mmol) and N,Ndimethylformamide (10 mL). The resulting mixture was heated at 100 °C by micro wave irradiation and stirred for 3 hours, diluted with water (20 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (0.5 g crude) as a white solid. LCMS (Method I): m/z = 265.9 [M+H]⁺, 0.926 min.

Step 2: Préparation of 4-(2,4-difluorophenoxy)picolinic acid

[0844] Lithium hydroxide (260 mg, 10.8 mmol) was added to a stirring mixture of methyl 4phenoxypicolinate (500 mg, 1.89 mmol) in tetrahydrofuran (10 mL) and water (5 mL). The resulting solution was stirred overnight at room température. After removal of tetrahydrofuran under reduced pressure, the pH of the aqueous solution was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (200 mg crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method X): m/z = 252.2 [M+H]⁺, 0.639 min.

Step 3: Préparation of 4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3bJazepin- 7-yl)picolinamide

[0845] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 19 χ 150 mm 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 70% B over 7 min; 254 & 220 nm; Rt: 5.590 min to afford the title compound (80 mg, 40.1%) as a white solid. LC-MS (Method R): m/z = 425.3 [M+H]⁺, 1.442 min.

310

Step 4: Préparation of (R)-4-(2,4-difliiorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepin-7-yl)picolinamide (example 121A) and (S)-4-(2,4-difluorophenoxy)-N-(9-methyl-8oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)picolinamide (example 121B)

[0846] The racemate of 4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepin-7-yl)picolinamide (80 mg, 0.19 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak ID-2, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 55% B to 55% B over 23 min; UV 220 & 254 nm; Rtl: 14.83 min; Rt2: 18.87 min to afford the title compounds:

[0847] Example 121A (first eluting isomer): ’H NMR (400 MHz, DMSO-r/s) δ 8.88 (d, J= 8.0 Hz, IH), 8.60 (d, J= 5.6 Hz, IH), 8.44-8.43 (m, IH), 7.84-7.81 (m, IH), 7.65-7.48 (m, 2H), 7.36-7.22 (m, 4H), 4.36-4.29 (m, IH), 3.36 (s, 3H), 2.81-2.70 (m, 2H), 2.50-2.44 (m, IH), 2.35-2.21 (m, IH). LC-MS (Method T): m/z = 425.25 [M+H]⁺, 1.432 min.

[0848] Example 121B (second eluting isomer): ’H NMR (400 MHz, DMSO-r/g) δ 8.88 (d, J= 7.6 Hz, IH), 8.60 (d, J= 5.6 Hz, IH), 8.44-8.43 (ni, IH), 7.84-7.81 (m, IH), 7.61-7.50 (m, 2H), 7.34-7.24 (m, 4H), 4.34-4.31 (m, IH), 3.36 (s, 3H), 2.77-2.73 (m, 2H), 2.51-2.50 (m, IH), 2.31-2.21 (m, IH). LC-MS (Method X): m/z = 425.25 [M+H]⁺, 1.437 min.

Example 122: 3-benzy l-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b]

[l,4]oxazepin-3-yl)isoxazole-5-carboxamide

EtOH, H₂O rt, 5 h

HONH₂ HCl, NaOH

O

°C, 5 h step 2 step 1

AIMe₃, toluene rt, o/n

step 3

Step 1: Préparation of (E)-2-phenylacetaldehyde oxime

[0849] Sodium hydroxide (1.2 g, 30.0 mmol) was added to a mixture of 2-phenylacetaldehyde (1.2 g, 10.0 mmol) and hydroxylamine hydrochloride (1.4 g, 20.3 mmol) in éthanol (40 mL) and water (20 mL). The resuiting mixture was stirred at room température for 5 hours, diluted with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine, dried

311 over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to afford the title compound (400 mg, 29.6%) as a white solid. LC-MS (Method E): m/z = 136.0 [M+H]⁺, 0.371 min.

Step 2: Préparation of ethyl 3-benzylisoxazole-5-carboxylate

[0850] Ethyl propiolate (2.7 g, 27.5 mmol) was added to a mixture of (E)-2-phenylacetaldehyde oxime (400 mg, 2.9 mmol) and chromium oxide (2.5 g, 29.7 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 80 °C for 5 hours. Solids were removed by filtration and the filtrate was evaporated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to afford the title compound (200 mg, 40%) as a yellow solid. LC-MS (Method C): m/z = 232.0 [M+H]⁺, 1.200 min.

Step 3: Préparation of 3-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrîdo[3,2-b]

[1,4] oxazepin-3-yl) isoxazole-5-carboxamide

[0851] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Â, 19 x 250 mm 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 55% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound. ’H NMR (400 MHz, DMSO-i/e) δ 8.73 (d, J= 7.6 Hz, 1H), 8.34-8.33 (m, 1H), 7.71-7.69 (m, 1H), 7.36-7.24 (m, 6H), 7.18 (s, 1H), 5.03-4.99 (m, 1H), 4.84-4.78 (m, 1H), 4.06 (s, 2H), 3.40 (s, 3H), 1.37 (d, J= 6.4 Hz, 3H). LC-MS (Method D): m/z = 393.1 [M+H]⁺, 1.787 min.

Example 123: (S)-5-benzyl-N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)thiazole-2carboxamide

[0852] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Â, 5 pm, 19 mm χ 250 mm; Mobile Phase A: water (lOmmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 40% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound. ’H NMR (300 MHz, DMSO-7₆) δ 10.56 (s, 1H), 8.92 (d, J= 7.9 Hz, 1H), 8.15 (dd, J= 4.7, 1.5 Hz, 1H), 7.88 (s, 1H), 7.56 (dd, J= 8.0, 1.5 Hz, 1H), 7.41-7.12 (m, 6H), 4.88-4.74 (m, 1H), 4.62-4.41 (m, 2H), 4.28 (s, 2H). LC-MS (Method O): m/z = 381.0 [M+H]⁺, 1.290 min.

312

Example 124: 5-benzyI-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)thiazole-2-carboxamide

[0853] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 19 χ 150 mm, 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B over 7 min; UV 254 & 220 nm to afford the title compound (18.8 mg, 9%) as a white semisolid. 'HNMR (400 MHz, Methanol</₄) δ 8.36-8.30 (m, 1H), 7.76-7.65 (m, 2H), 7.37-7.22 (m, 6H), 5.04-4.96 (m, 2H), 4.26 (s, 2H), 3.50 (s, 3H), 1.42 (d, J= 6.0 Hz, 3H). LC-MS (Method D): m/z = 409.2 [M+H]⁺, 1.638 min.

Example 125A & 125B: (R)-5-benzyl-N-(9’-methyl-8’-oxo-6’,7’,8’,9’tetrahydrospiro[cydopropane-l,5’-pyrido[2,3-b]azepin]-7’-yl)-4H-l,2,4-triazole-3-carboxamide (125A) and (S)-5-benzyl-N-(9’-methyI-8’-oxo-6’,7’,8’,9’-tetrahydrospiro[cyclopropane-l,5’pyrido[2,3-b]azepin]-7’-yl)-4H-l,2,4-triazole-3-carboxamide (125B)

step 4 step 5

Pd/C, H₂

MeOH, rt, o/n step 7

LiOH, THF, H₂O rt. o/n step 8

313

^Boc step 9

Step 1: Préparation ofdimethyl 2-(2-nitropyridin-3-yl)malonate

[0854] Dimethyl malonate (14 g, 105.6 mmol) was added dropwise to a stirring mixture of 3-fluoro-2nitropyridine (10 g, 70.4 mmol) and potassium carbonate (19.5 g, 140.8 mmol) in N,Ndimethylformamide (25 mL) at room température. The reaction mixture was stirred ovemight at 70 °C, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (18 g, 89.8%) as abrown oil. LC-MS (Method R): m/z = 255.1 [M+H]⁺, 0.762 min.

Step 2: Préparation of methyl 2-(2-nitropyridin-3-yl)acetate

[0855] A solution of lithium chloride (8 g, 189 mmol) in water (10 mL) was added to a mixture of dimethyl 2-(2-nitropyridin-3-yl)malonate (16 g, 63 mmol) in dimethyl sulfoxide (50 mL). The reaction mixture was stirred at 100 °C ovemight, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (12 g crude) as a brown oil. LC-MS (Method R): m/z = 197.1 [M+H]⁺, 0.673 min.

Step 3: Préparation of methyl l-(2-nitropyridin-3-yl)cyclopropanecarboxylate

[0856] 1,2-Dibromoethane ( 17 g, 91.8 mmol) was added dropwise to a stirring mixture of 3 -fluoro-2nitropyridine (12 g, 61.2 mmol) and potassium carbonate (25.3 g, 183.6 mmol) in N,Ndimethylformamide (25 mL) at room température. The reaction mixture was stirred ovemight at 70 °C, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined

314 organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (5 g, 36.8%) as a red oil. LC-MS (Method R): m/z = 223.1 [M+H]⁺, 0.802 min.

Step 4: Préparation of (l-(2-nitropyridin-3-yl)cyclopropyl)methanol

[0857] A solution of diisobutylaluminium hydride in toluene (1 M, 45 mL, 45 mmol) was added dropwise to a stirring solution of methyl l-(2-nitropyridin-3-yl)cyclopropanecarboxylate (5 g, 22.5 mmol) in toluene (50 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours, quenched by the addition of water (2 mL) and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (3 g, 68.6%) as a yellow solid. LC-MS (Method C): m/z = 195.1 [M+H]⁺, 0.975 min.

Step 5: Préparation of l-(2-nitropyridin-3-yl)cyclopropanecarbaldehyde

[0858] Dess-Martin periodinane (13 g, 30.9 mmol) was added to a stirring solution of (1-(2nitropyridin-3-yl)cyclopropyl)methanol (3 g, 15.5 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at 0 °C for 2 hours, quenched by the addition of water (50 mL) and extracted with dichloromethane (3x50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (2.5 g, 84.2%) as a yellow oil. LC-MS (Method C): m/z =193.0 [M+H]⁺, 1.002 min.

Step 6: Préparation of (Z)-methyl 2-(tert-butoxycarbonylamino)-3-(l-(2-nitropyridin-3yl) cyclopropyl) acrylate

[0859] l,8-Diazabicyclo[5.4.0]undec-7-ene (4 g, 26 mmol) was added to a stirring solution of methyl 2-{[(tert-butoxy)carbonyl]amino}-2-(dimethoxyphosphoryl)acetate (7.7 g, 26 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 70 °C for 1 hour followed by the addition of a solution of 1(2-nitropyridin-3-yl)cyclopropanecarbaldehyde (2.5 g, 13 mmol) in tetrahydrofuran (50 mL). Then the reaction mixture was stirred overnight at 70 °C, quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (3 g, 63.5%) as a yellow solid. LC-MS (Method E): m/z = 364.0 [M+H]⁺, 0.860 min.

Step 7: Préparation of methyl 3-(l-(2-aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbonylamino)propanoate

[0860] (Z)-methyl2-(tert-butoxycarbonylamino)-3-( 1 -(2-nitropyridin-3-yl)cyclopropyl)acrylate (3 g, 8.26 mmol) in methanol (50 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.3 g)

315 under a hydrogen atmosphère (2-3 atm). The reaction mixture was stirred ovemight at room température under a hydrogen atmosphère. The solids were removed by filtration and the filtrate was concentrated under high vacuum to afford the title compound (2.5 g crude) as a white solid. LC-MS (Method C): m/z = 336.1 [M+H]⁺, 0.926 min.

Step 8: Préparation of 3-(l-(2-aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbonylamino) propanoic acid

[0861] Lithium hydroxide (358 mg, 14.9 mmol) was added to a solution of methyl 3-(1-(2aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbony lamino)propanoate (2.5 g, 7.46 mmol) in tetrahydrofuran (15 mL) and water (5 mL). The reaction mixture was stirred at room température ovemight and concentrated under vacuum. The residue was diluted with water (20 mL) and adjusted to pH=7 with aqueous hydrochloride acid (1 N, 10 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (1 g crade) as a white solid. LC-MS (Method R): m/z =322.1 [M+H]⁺, 0.580 mm.

Step 9: Préparation of tert-butyl (8’-oxo-6’,7’,8’,9’-tetrahydrospiro[cyclopropane-l,5’-pyrido[2,3b]azepin]-7’-yl)carbamate

[0862] N,N-diisopropylethylamine (1.2 g, 9.34 mmol) was added to a mixture of 3-(1-(2aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbonylamino)propanoic acid (1 g, 3.11 mmol), 2-(7-azalH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (1.59 g, 3.73mmol ) inN,Ndimethylformamide (20 mL). The reaction mixture was stirred for 2 hours at room température, quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (500 mg, 53%) as a yellow solid. LC-MS (Method R): m/z = 304.0 [M+H]⁺, 0.842 min.

Step 10: Préparation of tert-butyl (9 ’-methyl-8 ’-oxo-6 ’,7’,8 ’,9’-tetrahydrospiro[cyclopropane-l,5’pyrido[2,3-b]azepin]-7’-yl)carbamate

[0863] lodomethane (52 mg, 0.36 mmol) was added dropwise to a stirring solution of tert-butyl(8’oxo-6’,7’,8’,9’-tetrahydrospiro[cyclopropane-l,5’-pyrido[2,3-b]azepin]-7’-yl)carbamate (110 mg, 0.36 mmol) and césium carbonate (119 mg, 0.36 mmol) in N,N-dimethylformamide (5 mL) at 0 °C. The reaction mixture was stirred 2 hours at room température, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (110 mg, 95.6%) as a white solid. LC-MS (Method C): m/z = 218.1 [M+H-100]⁺, 1.613 min.

316

Step 11 : Préparation of 7 '-amino-9 ’-methyl-6 7 ’-dihydrospiro [cyclopropane-1,5 ’-pyrido[2,3-b]azepin]~ ’(9 ’H)-one hydrochloride

[0864] A solution of hydrogen chloride in 1,4-dioxane (4M, 10 mL, 40 mmol) was added to a solution oftert-butyl (O’-methyl-S’-oxo-ô’^JS’^’-tetrahydrospirotcyclopropane-LS’-pyridop^-bjazepin]-?’yl)carbamate (110 mg, 0.34 mmol) in 1,4-dioxane (4 mL). The reaction mixture was stirred for 2 hours at room température and concentrated under high vacuum to afford the title compound (80 mg crude) as a white solid. LC-MS (Method C): m/z = 218.1 [M+H]⁺, 0.777 mm.

Step 12: Préparation of 5-benzyl-N-(9 ’-methyl-8 ’-oxo-6 ’,7’,8 ’, 9’-tetrahydro spiro-[cyclopropane-1,5 pyrido[2,3-b]azepin]-7 ’-yl)-4H-l, 2,4-triazole-3-carboxamide

[0865] N,N-diisopropylethylamine (107 mg, 0.828 mmol) was added to a mixture of 5-benzyl-4Hl,2,4-triazole-3-carboxylic acid (62 mg, 0.304 mmol), 7’-amino-9’-methyl-6’,7’dihydrospiro[cyclopropane-l,5’-pyrido[2,3-b]azepin]-8’(9’H)-one hydrochloride (60 mg, 0.276 mmol), N-(3-dimethylaminopropyl))-N’-ethylcarbodiimide hydrochloride (69 mg, 0.359 mmol) and 1hydroxybenzotriazole (49 mg, 0.359 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was stirred overnight at room température, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column 19 * 150 mm, 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 & 220 nm to afford the title compound. LC-MS (Method D): m/z = 403.1 [M+H], 1.460 min.

Step 13: Préparation of (R)-5-benzyl-N-(9’-methyl-8’-oxo-6’,7’,8’,9 ’-tetrahydrospiro- [cyclopropane1,5 ’-pyrido[2,3-b]azepin]- 7 ’-yl) -4H-1,2,4-triazole-3-carboxamide (first eluting isomer) and (S) -5benzyl-N-(9 ’-methyl-8 ’-oxo-6 ’,7’,8’,9 ’-tetrahydrospiro[cyclopropane-l,5 ’-pyrido[2,3-b]azepin]-7 ’-yl)4H-1,2,4-triazole-3-carboxamide (second eluting isomer)

[0866] The racemate of 5-benzyl-N-(9’-methyl-8’-oxo-6’,7’,8’,9’-tetrahydrospiro-[cyclopropane-l,5 pyndo|2,3-b]azcpin|-7’-yl)-4H-l,2,4-triazole-3-carboxamide (60 mg, 0.149 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak ID-2, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane/DCM (4.5/1), Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient: 50% B to 50% B over 22 min; UV 254 & 220 nm; RT 1: 11.72 min; RT 2: 18.02 minto afford the title compounds: [0867] Example 125A (first eluting isomer): ’HNMR (300 MHz, DMSO-riô) δ 14.27 (s, IH), 8.41 (dd, J= 4.8, 1.8 Hz, 2H), 7.75 (dd, J= 7.6, 1.8 Hz, IH), 7.34-7.18 (m, 6H), 4.42-4.33 (m, IH), 4.09 (s, 2H), 3.31 (s, 3H), 2.73-2.63 (m, IH), 1.73-1.62 (m, IH), 1.09-1.05 (m, IH), 0.70 (d, J= 5.4 Hz, 2H), 0.36 (d, J= 10.0 Hz, IH). LC-MS (Method D): m/z = 403.1 [M+H]⁺, 1.661 min.

317

[0868] Example 125B (second eluting isomer): 'H NMR (300 MHz, DMSO-rig) δ 14.27 (s, 1H), 8.41 (dd, <7= 4.8, 1.8 Hz, 2H), 7.75 (dd, J= 7.6, 1.8 Hz, 1H), 7.35- 7.18 (m, 6H), 4.40-4.33 (m, 1H), 4.09 (s,

2H), 3.30 (s, 3H), 2.69 (t, J= 10.6 Hz, 1H), 1.68 (t, J= 12.3 Hz, 1H), 1.07 (d, J= 10.0 Hz, 1H), 0.70 (d,

J= 5.5 Hz, 2H), 0.36 (d, J = 9.9 Hz, 1H). LC-MS (Method D): m/z = 403.1 [M+H]⁺, 1.673 min.

Example 126: (S)-5-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [1,4] oxazepin-3-yl)thiazole-2-carboxamide

Selectfluor, MeCN reflux, o/n

NBS, BPO, CCI₄ °C, o/n

step 1 step 2

Step 1: Préparation of methyl 4-fluoro-5-methylthiazole-2-carboxylate

[0869] l-Chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (7.0 g, 19.8 mmol) was added to a mixture of methyl 4-fluoro-5-methylthiazole-2-carboxylate (1.6 g, 10.2 mmol) in acetonitrile (50 mL) under a nitrogen atmosphère. The reaction mixture was heated to reflux and stirred ovemight, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (600 mg, 33.7%) as a white solid. LC-MS (Method C): m/z = 176.1 [M+H]⁺, 1.240 min.

Step 2: Préparation of methyl 5-(bromomethyl)-4-ftuorothiazole-2-carboxylate

[0870] Benzoyl peroxide (10 mg, 0.04 mmol) was added to a mixture of N-bromosuccinimide (650 mg, 3.6 mmol) and methyl 4-fluoro-5-methylthiazole-2-carboxylate (600 mg, 3.4 mmol) in carbon tetrachloride (20 mL). The reaction mixture was stirred ovemight at 75 °C. Solids were removed by filtration. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium bicarbonate (20 mL) and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to afford the title compound (600 mg, 68.9%) as a yellow solid. LC-MS (Method F): m/z = 254 [M+H]⁺, 1.490 min.

318

Step 3: Préparation of methyl 5-benzyl-4-fluorothiazole-2-carboxylate

[0871] Tetrakis(triphenylphosphine)palladium (147 mg, 0.13 mmol) was added to a mixture of methyl 5-(bromomethyl)-4-fluorothiazole-2-carboxylate (582 mg, 2.3 mmol), phenylboronic acid (402 mg, 3.3 mmol) and sodium carbonate (1 g, 9.4 mmol) in toluene (20 mL) and éthanol (10 mL) under a nitrogen atmosphère. The reaction mixture was stirred at 80 °C overnight, quenched by the addition of water (20 mL) and extracted with cthy! acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to afford the title compound (400 mg, 66.6%) as a yellow solid. LC-MS (Method C): m/z = 252.2 [M+Hj\ 1.971 min.

Step 4 : (S)-5-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4Joxazepin- 3yl) thiazole-2-carboxamide

[0872] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 19 χ 150 mm, 5 pm; Mobile phase A: water (10 mmol/L NH4HCO3), Mobile phase B: ACN; 40% ACN up to 70% B over 7 min; UV 254 & 220 nm to afford the title compound. *H NMR (400 MHz, DMSO-t/e) δ 9.14 (d, J= 7.6 Hz, 1H), 8.36 (dd, J= 4.8, 1.6 Hz, 1H), 7.70 (dd, J= 8.0, 1.6 Hz, 1H), 7.39-7.21 (m, 6H), 4.88-4.71 (m, 2H), 4.51 (t, J= 5.6 Hz, 1H), 4.17 (s, 2H), 3.34 (s, 3H). LC-MS (Method V): m/z = 413.00 [M+H]⁺, 2.480 min.

Example 127: l-(4-Cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [l,4]oxazepin-3-yl)-4-fluoro-lH-pyrazole-3-carboxamide

step 2

Step 1: Préparation of l-(4-cyanobenzyl)-4-fluoro-lH-pyrazole-3-carboxylic acid

[0873] Sodium hydride (60%, 144 mg, 6 mmol) was added to a stirring mixture of ethyl 4-fluoro-lHpyrazole-3-carboxylate (474 mg, 3 mmol) inN,N-dimethylformamide (20 mL). The resulting mixture

319 was stirred for 2 hours at room température, followed by the addition of 4-(bromomethyl)benzonitrile (585 mg, 3 mmol). The resulting mixture was stirred for 2 hours at room température. After the addition of water (20 mL), the reaction mixture was stirred overnight at room température, the pH was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Â, 5 pm, 19 mm x 250 mm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 50% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound (250 mg, 34%) as a white solid. LC-MS (Method C): m/z =246.1 [M+H]⁺, 0.969 min.

Step 2: Préparation of l-(4-cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5 tetrahydropyrido[3,2b][l >4] oxazepin-3-yl) -4-fluoro-lH-pyrazole-3-carboxamide

[0874] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Â, 5 pm, 19 mm x 250 mm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow? rate: 20 mL/min; Gradient: 25% B to 48% B over 12 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound. 'H NMR (400 MHz, DMSOY) δ 8.35 (dd, 7= 4.8, 1.6 Hz, 1H), 8.20 (d, 7= 4.4 Hz, 1H), 7.88-7.85 (m, 2H), 7.75 (dd, 7= 8.0, 1.6 Hz, 1H), 7.61 (d, 7= 6.4 Hz, 1H), 7.44-7.41 (m, 2H), 7.36 (dd, 7= 8.0, 4.8 Hz, 1H), 5.50 (s, 2H), 4.99-4.88 (m, 2H), 3.39 (s, 3H), 1.31 (d, 7= 6.4 Hz, 3H). LC-MS (Method X): m/z = 435.2 [M+H]⁺, 1.355 min.

Example 128: l-(3-Cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [1,4] oxazepin-3-yl)-4-fluoro-l H-pyrazole-3-carboxamide

320

Step 1: Préparation of l-(3-cyanobenzyl)-4-fluoro-lH-pyrazole-3-carboxylic acid

[0875] Sodium hydride (60%, 144 mg, 6 mmol) was added to a stirring mixture of ethyl 4-fhioro-lHpyrazole-3-carboxylate (474 mg, 3 mmol) in N,N-dimethylformamide (20 mL) at 0 °C. The resulting mixture was stirred for 2 hours at room température, followed by addition of 4(bromomethyl)benzonitrile (585 mg, 3 mmol). The reaction mixture was stirred for another 2 hours at room température. After addition of water (20 mL), the resulting mixture was stirred overnight at room température. The pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 * 150 mm, 5 pm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 50% B over 7 min; UV 254 &. 220 nm; Rt: 6 min to afford the title compound (230 mg, 31%) as a white solid. LC-MS (Method C): m/z = 246.1 [M+H]⁺, 1.236 min.

Step 2: Préparation of l-(3-cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5- tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-4fluoro-lH-pyrazole-3-carboxamide

[0876] The crude product obtained using Arnide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Â, 5 pm, 19 mm * 250 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 48% B over 12 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound. 'H NMR (400 MHz, DMSOtee) δ 8.36 (dd, J= 4.8, 1.6 Hz, 1H), 8.19 (d, J= 4.4 Hz, 1H), 7.86-7.79 (m, 2H), 7.75 (dd, J= 8.0, 1.6 Hz, 1H), 7.62-7.60 (m, 3H), 7.36 (dd, 7= 8.0, 4.4 Hz, 1H), 5.45 (s, 2H), 4.994.88 (m, 2H), 3.40 (s, 3H), 1.32 (d, J= 6.0 Hz, 3H). LC-MS (Method D): m/z = 435.1 [M+H]⁺, 1.659 mm.

Example 129A and 129B: (S)-5-Benzyl-N-(2,4-dimethyI-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[l,5a][l,3]diazepin-6-yl)-4H-l,2,4-triazole-3-carboxamide and (R)-5-Benzyl-N-(2,4-dimethyl-5-oxo5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,3]diazepin-6-yl)-4H-l,2,4-triazoIe-3-carboxamide

O step 1 step 2 ,O

rt, 3 h step 5 step 3 step 4

321

NaN₃, DMF rt, 2 h step 6

PPh₃, THF, H₂O rt, o/n

step 7

EDCI, HOBT, DIEA, DMF rt, o/n step 8

Step 1: Préparation of methyl 4-(3-methyl-5-nitro-lH-pyrazol-l-yl)butanoate

[0877] Sodium hydride (60%, 2.5 g, 63 mmol) was added to a mixture of 3-methyl-5-nitro-lHpyrazole (8 g, 63 mmol) in tetrahydrofuran (80 mL) at 0 °C. The resulting mixture was stirred for 0.5 hour at 0 °C followed by the addition of methyl 4-bromobutanoate (11.2 g, 63 mmol). The reaction mixture was stirred for 1 hour at 0 °C, quenched by the addition of water (40 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to afford the title compound (2.2 g, 15%) as a colorless oil. LC-MS (Method C): m/z = 228.1 [M+H]⁺, 1.180 min.

Step 2: Préparation of methyl 4-(5-amino-3-methyl-lH-pyrazol-l-yl)butanoate

[0878] A mixture of methyl 4-(3-methyl-5-nitro-lH-pyrazol-l-yl)butanoate (2.2 g, 9.7 mmol) in methanol (50 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.2 g) under a hydrogen atmosphère (2-3 atm). After stirring for 2 hours at room température under hydrogen atmosphère, the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum to afford the title compound (1.8 g, 94%) as a yellow solid. LC-MS (Method C): m/z = 198.1 [M+H]^-, 0.733 min.

Step 3: Préparation of2-methyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin-5(6H)-one

[0879] The crude product obtained using the procedure described in Example 54 was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (1.0 g, 66%) as a yellow solid. LC-MS (Method C): m/z = 166.1 [M+H]⁺, 0.755 min.

322

Step 4: Préparation of2,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin-5(6H)-one

[0880] lodomethane (0.74 g, 5.4 mmol) was added dropwise to a stirring mixture of 2-methyl-7,8dihydro-4H-pyrazolo[l,5-a][l,3]diazepin-5(6H)-one (0.90 g, 5.4 mmol) and césium carbonate (5.28 g, 16.2 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred for 3 hours at room température, diluted with water (20 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to afford the title compound (0.72 g, 74%) as a yellow solid. LC-MS (Method C): m/z = 180.1 [M+H]⁺, 0.865 min.

Step 5: Préparation of 6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][I,3]diazepin- 5(6H)-one [0881] N¹,N¹,N²,N²-tetramethylethane-l,2-diamine (1.2 g, 12.0 mmol) was added to a stirring mixture of 2,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin-5(6H)-one (720 mg, 4.0 mmol) in dichloromethane (10 mL) at 0 °C followed by addition of iodotrimethylsilane (2.4 g, 12.0 mmol) dropwise over 20 min. The reaction mixture was stirred for 1 hour at 0 °C. After addition of iodine (2.0 g, 8.0 mmol), the reaction mixture was stirred for another 1 hour at 0 °C. Then the mixture was quenched by tire addition of aqueous sodium thiosulfate (5%, 20 mL), stirred for another 15 minutes and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane) to afford the title compound (500 mg, 41%) as a yellow solid. LCMS (Method C): m/z = 306.0 [M+H]⁺, 1.033 min.

Step 6: Préparation of 6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin- 5(6H)-one

[0882] Sodium azide (137 mg, 2.10 mmol) was added to a mixture of 6-iodo-2,4-dimethyl-7,8dihydro-4H-pyrazolo[l,5-a][l,3]diazepin-5(6H)-one (500 mg, 1.64 mmol) in N,N-dimethylformamide (10 mL). The resulting mixture was stirred for 2 hours at room température, quenched by the addition of water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (280 mg crude) as a yellow oil. LC-MS (Method S): m/z = 221.3 [M+H]⁺, 0.763 min.

Step 7: Préparation of6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin- 5(6H)-one [0883] Triphenylphosphine (734 mg, 2.80 mmol) was added to a stirring mixture of 6-azido-2,4dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin-5(6H)-one in tetrahydrofuran (10 mL) and water (2 mL). The reaction mixture was stirred ovemight at room température, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by

323 column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (200 mg, 62%) as a yellow oil. LC-MS (Method I): m/z = 195.0 [M+H]⁺, 0.263min.

Step 8: Préparation of 5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a]

[1,3[diazepin-6-yl)-4H-l, 2,4-trîazole-3-carboxamide

[0884] N,N-diisopropylethylamine (140 mg, 1.13 mmol) was added to a mixture of 5-benzyl-4H-1,2,4triazole-3-carboxylic acid (73 mg, 0.36 mmol), 6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5a][l,3]diazepin-5(6H)-one (70 mg, 0.36 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (65 mg, 0.39 mmol) in N,Ndimethylformamide (2 mL). The reaction mixture was stirred ovemight at room température, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 χ 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min- Gradient: 15% B to 45% B over 7 min; UV 254 & 220 nm; Rt: 6 min to afford the title compound (50 mg, 36%) as a white solid. LC-MS (Method Y): m/z = 380.2 [M+H] , 0.750 min.

Step 9: Préparation of (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4PI-pyrazolo [1,5a][l ,3]diazepin-6-yl)-4H-l ,2,4-triazole-3-carboxamide (129A) and (R)-5-benzyl-N-(2,4-dimethyl-5-oxo5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,3]diazepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (129B) [0885] The racemate of 5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo [1,5a][l,3]diazepin-6-yl)-4H-l,2,4-triazole-3-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IC, 2 χ 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 22 min; UV 254 & 220 nm; Rt 1: 10.04 min; Rt 2: 18.12 min to afford the title compounds:

[0886] Example 129A (first eluting isomer): ’HNMR (300 MHz, DMSO-t/β) δ 14.31 (s, IH), 8.55 (s, IH), 7.40-7.18 (m, 5H), 6.13 (s, IH), 4.41-4.20 (m, 2H), 4.20-4.02 (m, 3H), 3.23 (s, 3H), 2.65-2.26 (m, 2H), 2.18 (s, 3 H). LC-MS (Method D): m/z = 380.2 [M+H]⁺, 1.298 min.

[0887] Example 129B (second eluting isomer): ’H NMR (300 MHz, DMSO-rZs) δ 14.30 (s, IH), 8.46 (s, IH), 7.38-7.20 (m, 5H), 6.13 (s, IH), 4.41-4.20 (m, 2H), 4.20-4.02 (m, 3H), 3.23 (s, 3H), 2.61-2.37 (m, 2H), 2.17 (s, 3H). LC-MS (Method D): m/z = 380.2 [M+H]⁺, 1.300 min.

324

Example 130: (S)-l-(3-Cyano-5-fluorobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][l,4]o^xazepiⁿ-3-yl)-lH-pyrazole-3-carboxamide

step 3

Stepl: Préparation of 3-fluoro-5-(hydroxymethyl)benzonitrile

[0888] Sodium borohydride (1.0 g, 6.71 mmol) was added to a stirring mixture of 3-fluoro-5formylbenzonitrile (306 mg, 8.05 mmol) in éthanol (10 mL) and tetrahydrofuran (10 mL) at 0 °C under nitrogen atmosphère. After stirring at 0 °C for 1 hour, the reaction mixture was concentrated under vacuum, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (980 mg crude) as a yellow solid. LC-MS (Method T): m/z = 152.3 [M+H]⁺, 0.671 min.

Step 2: Préparation of 3-(bromomethyl)-5-fluorobenzonitrile

[0889] Tribromophosphine (2.9 g, 10.7 mmol) was added to a stirring mixture of 3-fluoro-5(hydroxymethyl)benzonitrile (0.8 g, 5.30 mmol) in dichloromethane (10 mL). After stirring ovemight at room température, the reaction mixture was concentrated under vacuum to afford the title compound (0.8 g crude) as a yellow solid, which was used directly in the next step without further purification.

Step 3: Préparation of (S)-l-(3-cyano-5-fluorobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0890] Potassium carbonate (55 mg, 0.40 mmol) was added to a stirring mixture of (S)-4-fluoro-N(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide (40 mg, 0.13 mmol) and 3-(bromomethyl)-5-fluorobenzonitrile (34 mg, 0.16 mmol) inN,Ndimethylformamide (2 mL). After stirring at room température for 2 hours, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.

325

The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN: Flow rate: 30 mL/min; Gradient: 35% B to 65% B over 5 min; UV 254 & 220 nm; Rt: 3.75 min to afford the title compound. 'H NMR (400 MHz, DMSO-î/ê) δ 8.37 (dd, J = 4.8, 1.6 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.18 (d, J= 4.4 Hz, 1H), 7.90-7.86 (m, 1H), 7.71 (dd, J= 7.6, 1.2 Hz, 1H), 7.66 (s, 1H), 7.56-7.52 (m, 1H), 7.36-7.32 (m, 1H), 5.44 (s, 2H), 4.89-4.81 (m, 1H), 4.70-4.64 (m, 1H), 4.54-4.49 (m, 1H), 3.36 (s, 3H). LC-MS (Method X): m/z = 439.2 [M+H]⁺, 1.291 min.

Example 131A and 131B: (S)-5-Benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[l,5a][l,3]diazepin-6-yl)-4H-l,2,4-triazole-3-carboxamide and (R)-5-Benzyl-N-(3,4-dimethyI-5-oxo5,6,7,8-tetrahydro-4H-pyrazoIo[l,5-a][l,3]diazepin-6-yl)-4H-l,2,4-triazoIe-3-carboxamide

DIAD, PPh₃, THF rt, o/n step 1

Pd/C,H₂, MeOH rt, 2 h

step 2

AIMe₃,toluene

O°C-rt, 4 h step 3

step 4 step 5 step 6

PPh₃, THF, H₂O rt, o/n step 7

EDCI, HOBT, DIEA, DMF rt, o/n step 8

Step 1: Préparation of methyl 4-(4-methyl-5-nitro-lH-pyrazol-l-yl)butanoate

[0891] Diisopropyl azodicarboxylate (3.4 g, 16.9 mmol) was slowly added to a stirring mixture of methyl 4-hydroxybutanoate (2 g, 16.9 mmol), 4-methyl-5-nitro-lH-pyrazole (1 g, 7.8 mmol) and triphenylphosphine (4.44 g, 16.9 mmol) in tetrahydrofuran (40 mL) at 0 °C under nitrogen atmosphère.

326

After stirring overnight at room température, the reaction mixture was quenched by the addition of water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to afford the title compound (1.0 g, 56%) as a colorless oil. LC-MS (Method C): m/z = 228.1 [M+H]\ 1.130 min.

Step 2: Préparation of methyl 4-(5-amino-4-methyl-lH-pyrazol-l-yl)butanoate

[0892] A solution of methyl 4-(4-methyl-5-nitro-lH-pyrazol-l-yl)butanoate (1.0 g, 4.4 mmol) in methanol (30 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.1 g) under a hydrogen atmosphère (2-3 atm). After stirring for 2 hours at room température under hydrogen atmosphère, the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum to afford the title compound (0.85 mg, 97%) as a yellow solid. LC-MS (Method I): m/z = 197.9 [M+H]⁺, 1.013 min.

Step 3: Préparation of 3-methyl-7,8-dihydro-4H-pyrazolo[l,5-a][1,3]diazepin-5(6H)-one

[0893] The crude product obtained using the procedure described in Example 54 was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (600 mg, 84%) as a yellow solid. LC-MS (Method C): m/z = 166.1 [M+H]⁺, 0.782 min.

Step 4: Préparation of 3,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin-5(6H)-one

[0894] lodomethane (511 mg, 3.6 mmol) was added to a stirring mixture of 3-methyl-7,8-dihydro-4Hpyrazolo[l,5-a][l,3]diazepin-5(6H)-one (600 mg, 3.6 mmol) and césium carbonate (3.52 g, 10.8 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred for 3 hours at room température, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to afford the title compound (480 mg, 78%) as a yellow solid. LC-MS (Method C): m/z = 180.1 [M+Et] ', 0.876 min.

Step 5: Préparation of 6-iodo-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin- 5(6H)-one [0895] N¹,N¹,N²,N²-tetramethylethane-l,2-diamine (0.82 mg, 8.02 mmol) was added to a stirring mixture of 3,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin-5(6H)-one (0.48 mg, 2.67 mmol) in dichloromethane (10 mL) at 0 °C followed by the addition of iodotrimethylsilane (1.6 g, 8.01 mmol). After stirring for 1 hour at 0 °C, iodine (1.36 g, 5.35 mmol) was added. The reaction mixture was stirred for another 1 hour at 0 °C and quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL). The resulting mixture was stirred for another 15 minutes and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane) to

327 afford the title compound (0.427 g, 52%) as a yellow solid. LC-MS (Method I): m/z = 305.9 [M+H]⁺,

0.756 min.

Step 6: Préparation of 6-azido-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin- 5(6H)-one

[0896] Sodium azide (137 mg, 2.1 mmol) was added to a stirring mixture of 6-iodo-3,4-dimethyl-7,8dihydro-4H-pyrazolo[l,5-a][l,3]diazepin-5(6H)-one (427 mg, 1.39 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 2 hours at room température, quenched with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (400 mg crude) as a yellow oil. LC-MS (Method C): m/z = 220.7 [M+H]⁺, 1.383 min.

Step 7: Préparation of 6-amino-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin- 5(6P4)-one

[0897] Triphenylphosphine (734 mg, 2.80 mmol) was added to a stirring mixture of 6-azido-3,4dimethyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,3]diazepin-5(6H)-one (400 mg, 1.80 mmol) in tetrahydrofuran (10 mL) and water (2 mL). After stirring ovemight at room température, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford tire title compound (232 mg, 86%) as a yellow oil. LC-MS (Method C): m/z = 194.7 [M+H]⁺, 0.378 min.

Step 8: Préparation of 5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a]

[1,3]diazepin-6-yl) -4H-1,2,4-triazole-3-carboxamide

[0898] N,N-diisopropylethylamine (140 mg, 1.13 mmol) was added to a mixture of 5-benzyl-4H-l,2,4triazole-3-carboxylic acid (73 mg, 0.36 mmol), 6-amino-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[l,5a][l,3]diazepin-5(6H)-one (70 mg, 0.36 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (65 mg, 0.39 mmol) inN,Ndimethylformamide (2 mL). After stirring ovemight at room température, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column 100 Â, 10 pm, 19 mm x 250 mm; Mobile Phase A: water (0.05% formic acid), Mobile Phase B. ACN; Flow rate: 20 mL/min; Gradient: 22% B to 43% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound (50 mg, 36%) as a white solid. LC-MS (Method T): m/z = 380.3 [M+H] , 1.041 min.

328

Step 9: Préparation of (S)-5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7.8-iet.rahydro-4H-pyrazolo [1,5a][l,3]diazepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (131 A) and (R)-5-benzyl-N-(3,4-dimethyl-5-oxo5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,3]diazepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (131B)

[0899] The racemate of 5-bcnzyl-N-(3,4-dimcthyl-5-oxo-5,6,7,8-tctrahydro-4H-pyrazolo|1.5-a] [l,3]diazepin-6-yl)-4H-l,2,4-triazole-3-carboxamide (50 mg, 0.13 mmol) was separated by Prep-ChiralHPLC with the following conditions: Column: Chiralpak IF, 2 x 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient: 40% B to 40% B over 24 min; UV 254 & 220 nm; Rt 1: 7.35 min; Rt 2: 8.28 min to afford the title compounds:

[0900] Example 13 IA (first eluting isomer): ’H NMR (300 MHz, DMSO-î/ô) δ 14.31 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 7.40-7.18 (m, 6H), 4.36-4.09 (m, 5H), 3.22 (s, 3H), 2.61-2.23 (m, 2H), 2.02 (s, 3H). LCMS (Method D): m/z = 380.2 [M+H]⁺, 1.312 min.

[0901] Example 13 IB (second eluting isomer): ’H NMR (300 MHz, DMSO-fifc) δ 14.31 (s, 1H), 8.34 (d, J= 7.6 Hz, 1H), 7.38-7.20 (m, 6H), 4.30-4.14 (m, 5H), 3.22 (s, 3H), 2.60-2.27 (m, 2H), 2.02 (s, 3H). LC-MS (Method D): m/z = 380.2 [M+H]⁺, 1.312 min.

Example 132: l-Benzyl-4-chloro-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

NOS, DMF rt, o/n

K₂CO₃, DMF rt, o/n step 2

step 1

AIMe₃ in toluene, rt, o/n

step 3

Step 1: Préparation of ethyl 4-chloro-lH-pyrazole-3-carboxylate

[0902] l-Chloropyrrolidine-2,5-dione (5.75 g, 42.9 mmol) was added to a stirring mixture of ethyl 1Hpyrazole-3-carboxylate (5.00 g, 35.7 mmol) in N,N-dimethylformamide (40 mL). The reaction mixture was stirred ovemight at room température and diluted with water (100 mL). The solids were removed by filtration and the filtrate was concentrated under vacuum to afford the title compound (6.0 g crude) as a yellow oil. LC-MS (Method S): m/z = 175.2 [M+H]⁺, 0.695 min.

329

Step 2: Préparation of ethyl l-benzyl-4-chloro-lH-pyrazole-3-carboxylate

[0903] Potassium carbonate (7.1 g, 51.4 mmol) was added to a stirring mixture of (ethyl 4-chloro-1Hpyrazole-3-carboxylate (3.0 g, 17.1 mmol) and (bromomethyl)benzene (3.6 g, 21.1 mmol) in N,Ndimethylformamide (10 mL). The reaction mixture was stirred at room température overnight, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (2.0 g, 44%) as a colorless oil. LC-MS (Method S): m/z = 265.2 [M+H]⁺, 1.040 min.

Step 3: Préparation of l-benzyl-4-chloro-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0904] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100Â, 5 pm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 65% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound. Ή NMR (400 MHz, DMSO-de) δ 8.36 (dd, 4.8, 1.6 Hz, 1H), 8.26 (s, 1H), 7.76-7.71 (m, 2H), 7.42-7.29 (m, 6H), 5.42 (s, 2H), 4.99-4.88 (m, 2H), 3.40 (s, 3H), 1.32 (d, J= 6.0 Hz, 3H). LC-MS (Method T): m/z = 426.2 [M+H]⁺, 1.518 min.

Example 133: (S)-4-Fluoro-l-(2-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [1,4] oxazepin-3-yI)-lH-pyrazole-3-carboxamide

[0905] Potassium carbonate (34 mg, 0.25 mmol) was added to a mixture of (S)-4-fluoro-N-(5-methyl4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide (25 mg, 0.08 mmol) and l-(bromomethyl)-2-fluorobenzene (19 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL). After stirring at room température for 3 hours, the reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 35% B to 65% B over 5 min; UV 254 & 220 nm; Rt: 3.75 min to afford the title

330 compound. Ή NMR (400 MHz, DMSO-ûfc) δ 8.37 (dd, J= 4.8, 1.6 Hz, IH), 8.24 (d, 7= 7.6 Hz, IH),

8.12 (d, J= 4.4 Hz, IH), 7.71 (dd, 7=8.0, 1.6 Hz, IH), 7.46-7.40 (m, IH), 7.35-7.21 (m, 4H), 5.43 (s,

2H), 4.88-4.80 (m, IH), 4.70-4.64 (m, IH), 4.53-4.48 (m, IH), 3.35 (s, 3H). LC-MS (Method T): m/z =

414.2 [M+H]⁺, 1.346 min.

Example 134: 5-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yI)-l,3,4-oxadiazole-2-carboxamide

[0906] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 60% B over 15 min; UV 254 & 220 nm; Rt: 14.5 min to afford the title compound (13.3 mg, 17%) as awhite solid. ’HNMR (400 MHz, Methanol-tri) δ 8.33-8.31 (m, IH), 7.71-7.67 (m, IH), 7.377.28 (m, 6H), 5.07-4.97 (m, 2H), 4.34 (s, 2H), 3.50 (s, 3H), 1.44 (d, 7= 6.0 Hz, 3H). LC-MS (Method J): m/z = 394.15 [M+H]⁺, 2.483 min.

Example 135: (S)-4-Fluoro-l-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

NaOH, MeOH, H₂O °C, o/n

Step 2

K₂CO₃, DMF, rt, 3h

Step 3

Step 1: Préparation of 4fluoro-lH-pyrazole-3-carboxylic acid

[0907] Sodium hydroxide (253 mg, 6.33 mmol) was added to a mixture of ethyl 4-fluoro-lH-pyrazole3-carboxylate (500 mg, 3.16 mmol) in methanol (10 mL) and water (4 mL). The resulting solution was heated to 40 °C and stirred ovemight. After removal of methanol under reduced pressure, the resulting

331 solution was adjusted to pH = 6 with aqueous hydrochloric acid (1 N, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (400 mg,

97.2%) as a white solide. LC-MS (Method T): m/z = 131.4 [M+H]⁺, 0.567 min.

Step 2: Préparation of (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3yl) -lPI-pyrazole-3-carboxamide

[0908] N,N-diisopropylethylamine (993 mg, 7.70 mmol) was added to a mixture of (S)-3-amino-5methyl-2,3-dihydropyrido[3,2-b][l,4]oxazepin-4(5H)-one hydrochloride (354 mg, 1.54 mmol), 4-fluorolH-pyrazole-3-carboxylic acid (200 mg, 1.54 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (355 mg, 1.85 mmol) and 1-hydroxybenzotriazole (250 mg, 1.85 mmol) inN,Ndimethylformamide (10 mL). After stirring ovemight at room température, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-TLC (ethyl acetate) to afford the title compound (200 mg, 42.6%) as a white solid. LC-MS (Method T): m/z = 306.3 [M+H]⁺, 0.696 min.

Step 3: Préparation of (S)-4-fluoro-l-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido- [3,2b] [1,4] oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0909] Potassium carbonate (68 mg, 0.49 mmol) was added to a mixture of (S)-4-fluoro-N-(5-methyl4-oxo-2,3,4,5-tctrahydropyrido[3.2-b]| l,4]oxazcpin-3-yl)-IH-pyrazole-3-carboxamide (50 mg, 0.16 mmol) and l-(bromomethyl)-3-fhiorobenzene (38 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL). After stirring at room température for 3 hours, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 78% B over 7 min; UV 254 & 220 nm; Rt: 6.5 min to afford the title compound. ’H NMR (400 MHz, DMSOA) δ 8.36 (d, J= 4.0 Hz, 1H), 8.27 (d, J= 8.0 Hz, 1H), 8.16 (d, J= 4.4 Hz, 1H), 7.70 (d, J= 7.6 Hz, 1H), 7.49-7.38 (m, 1H), 7.38-7.28 (m, 1H), 7.22-6.98 (m, 3H), 5.38 (s, 2H), 4.92-4.78 (m, 1H), 4.78-4.61 (m, 1H), 4.61-4.41 (m, 1H), 3.36 (s, 3H). LC-MS (Method T): m/z = 414.2 [M+H]⁺, 1.347 min.

332

Example 136: l-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide

step 3

Step 1: Préparation of methyl 1-benzyl-lH-l,2,4-triazole-3-carboxylate

[0910] Sodium hydride (60%, 192 mg, 8 mmol) was added to a stirring mixture of methyl 1H-1,2,4triazole-3-carboxylate (508 mg, 4 mmol) in N,N-dimethylformamide (10 mL). The resulting mixture was stirred at room température for 2 hours followed by the addition of (bromomethyl)benzene (680 mg, 4 mmol) under a nitrogen atmosphère. After stirring for another 2 hours, the reaction mixture was quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 50 mL). Tire combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to afford the title compound (400 mg, 46%) as a white solid. LC-MS (Method E): m/z = 217.9 [M+H]⁺, 0.661 min.

Step 2: Préparation of l-benzyl-lPI-l,2,4-triazole-3-carboxylic acid

[0911] Lithium hydroxide (48 mg, 2 mmol) was added to a stirring mixture of methyl 1-benzyl-lHl,2,4-triazole-3-carboxylate (108 mg, 0.5 mmol) in tetrahydrofuran (3 mL) and water (1 mL). After stirring at 0 °C for 2 hours, the pH of the reaction mixture was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (80 mg, 79%) as a white solid. LC-MS (Method E): m/z = 203.9 [M+Hf, 0.560 mm.

333

Step 3: Préparation of l-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido [3,2b][l,4]oxazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide

[0912] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100Â, 5 μηι. 19 mm ^x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 75% B over 7 min; UV 254 & 220 nm; Rt: 6.3 min to afford the title compound (31.5 mg, 40%) as a white solid. ’H NMR (400 MHz, DMSCM) δ 8.86 (s, 1H), 8.36 (dd, J = 4.4, 1.2 Hz, 1H), 8.01 (d, J=6.4Hz, 1H), 7.76 (dd, J= 8.0, 1.6 Hz, 1H), 7.41-7.31 (m, 6H), 5.50 (s, 2H), 5.00-4.88 (m, 2H), 3.40 (s, 3H), 1.31 (d, J= 6.4 Hz, 3H). LC-MS (Method D): m/z = 393.15 [M+H]⁺, 1.553 min.

Example 137: (S)-4-FIuoro-l-((5-fluoropyridin-3-yl)methyI)-N-(5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

step 1 step 2

Stepl: Préparation of3-(bromomethyl)-5-fluoropyridine

[0913] Tribromophosphine (853 mg, 3.15 mmol) was added to a solution of (5-fluoropyridin-3yl)methanol (200 mg, 1.57 mmol) in dichloromethane (2 mL). The reaction mixture was stirred overnight at room température. The solvent was evaporated under vacuum to afford the title compound (150 mg crude). LC-MS (Method S); m/z = 190.1 [M+H]⁺, 0.787 min.

Step 2: Préparation of (S)-4-fluoro-l-((5-fluoropyridin-3-yl)methyl)-N-(5-methyl-4-oxo- 2,3,4,5tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl) -lH-pyrazole-3-carboxamide

[0914] Potassium carbonate (181 mg, 1.31 mmol) was added to a mixture of (S)-4-fluoro-N-(5methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide (80 mg, 0.26 mmol) and 3-(bromomethyl)-5-fluoropyridine (107 mg, 0.39 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was stirred at room température for 3 hours, diluted with water (2 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was

334 purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column,

100Â, 5 pm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3); Mobile Phase B: ACN;

Flow rate: 20 mL/min; Gradient: 15% B to 35% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound. ’H NMR (400 MHz, DMSO-î/s) δ 8.59 (d, J= 2.8 Hz, 1H), 8.46 (s, 1H), 8.37 (dd, J = 4.8, 1.6 Hz, 1H), 8.30 (d, J= 8.0 Hz, 1H), 8.20 (d, J= 4.4 Hz, 1H), 7.72-7.67 (m, 2H), 7.36-7.32 (m, 1H), 5.46 (s, 2H), 4.88-4.81 (m, 1H), 4.70-4.64 (m, 1H), 4.54-4.49 (m, 1H), 3.36 (s, 3H). LC-MS (Method T): m/z = 415.2 [M+H]⁺, 1.057 min.

Example 138: N-((2R,3S)-2,5-dimethyI-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-5(l-phenylcyclopropyl)-l,3,4-oxadiazole-2-carboxamide

[0915] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100Â, 5 pm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient' 40% B to 60% B in 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound. 'H NMR (300 MHz, DMSOK) δ 8.58 (s, 1H), 8.36 (dd, J= 4.5, 1.5 Hz, 1H), 7.74 (dd, J= 8.1, 1.5 Hz, 1H), 7.447.29 (m, 6H), 4.96-4.90 (m, 2H), 3.40 (s, 3H), 1.72-1.68 (m, 2H), 1.56-1.52 (m, 2H), 1.39-1.36 (m, 3H). LC-MS (Method D): m/z = 420.15 [M+H]⁺, 1.777 min.

Example 139: N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-5(2-fluorophenoxy)pyridazine-3-carboxamide

AIMe₃, toluene, rt, o/n

[0916] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 5 mm, 19 x 150 mm, Mobile Phase A: water (10 mmol/L NH4HCO3); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; UV 254 & 220 nm; Rt: 6.5 min to afford the title compound. Ή NMR (300 MHz, DMSO-I) δ 9.48 (d, J= 3.0 Hz, 1H), 8.89 (d, J= 6.3 Hz, 1H), 8.36 (dd, J= 4.8, 1.8 Hz, 1H), 7.77

335 (dd, J= 7.8, 1.5 Hz, 1H), 7.58-7.34 (m, 5H), 7.27 (dd, J= 3.0, 0.9 Hz, 1H), 5.05-4.93 (m, 2H), 3.42 (s,

3H), 1.35 (d, J= 5.7 Hz, 3H). LC-MS (Method D): m/z = 424.1 [M+H]⁺, 1.747 min.

Example 140: l-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [1,4] oxazepin-3-yl)-lH-imidazole-4-car boxamide

step 1 step 2

Step 1: Préparation of ethyl l-benzyl-lH-imidazole-4-carboxylate

[0917] Sodium hydride (60%, 0.51 g, 21.3 mmol) was added to a stirring solution of ethyl 1Himidazole-4-carboxylate (2.0 g, 14.3 mmol) in N,N-dimethylformamide (15 mL). The resulting mixture was stirred for 30 minutes at 0°C followed by the addition of (bromomethyl)benzene (2.93 g, 17.13 mmol). After stirring at room température for 1.5 hours, the reaction mixture was quenched by the addition of water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound (1.0 g, 30%) as a yellow oil. LC-MS (Method C): m/z = 231.1 [M+H]⁺, 0.985 min.

Step 2: Préparation of l-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2b][1,4[oxazepin-3-yl) -lH-imidazole-4-carboxamide

[0918] Tire crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column, XBridge Shield RP18 OBD, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 55% B over 7 min; Detector: UV 254 & 220 nm to afford the title compound. 'H NMR (400 MHz, DMSOY) δ 8.33 (dd, J = 4.4, 1.2 Hz, 1H), 7.89 (d, J= 1.2 Hz, 1H), 7.78-7.71 (m, 3H), Ί.3Ί-Ί2Ί (m, 6H), 5.21 (s, 2H), 4.92-4.84 (m, 2H), 3.37 (s, 3H), 1.28 (d, J= 6.0 Hz, 3H). LC-MS (Method F): m/z = 392.0 [M+H]⁺, 1.029 min.

336

Example 141A and 141B: (S)-5-Benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2-b][l,4]oxazepin-7yl)-4H-l,2,4-triazoie-3-carboxamide and (R)-5-benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2b] [1,4] oxazepin-7-yl)-4H-l ,2,4-triazole-3-carboxamide

Ph

Ph—Ph

n-BuLi, THF, -78°C to rt, 3 h

step 1

K₂CO₃, MeCN reflux, 2 h step 2

AcOH, MeOH

60°C, 2 h step 3

Cul, K₂CO₃, DMF

100°C, o/n step 4

NH₄OAc, NaBH₃CN

MeOH, rt, o/n

EDCI, HOBT, DIEA, DMF rt, o/n step 6

Step 1: Préparation of2-chloro-l-(l-trityl-lH-imidazol-2-yl)ethanone

[0919] A solution of zz-butyllithium in hexane (2.5 M, 13.2 mL, 33.0 mmol) was added to a stirred mixture of 1-trityl-lH-imidazole (9.3 g, 30.0 mmol) in tetrahydrofuran (190 mL) dropwise at -78 °C under a nitrogen atmosphère. After the addition was complété, the reaction mixture was warmed to -10 °C slowly and stirred for 1 hour. Then the mixture was cooled to -78 °C again and a solution of tert-butyl 2-chloroacetate (5.4 g, 36.0 mol) in tetrahydrofuran (10 mL) was added in one portion. The resulting mixture was warmed to room température with stirring over 2-3 hours, quenched with ice-water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with

337 brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (900 mg, 7.8%) as a yellow solid.

Step 2: Préparation of2-(2-bromopyridin-3-yloxy)-l-(l-trityl-lH-imidazol-2-yl)ethanone

[0920] 2-Chloro-l-(l-trityl-lH-imidazol-2-yl)ethanone (772.0 mg, 2.0 mmol) was added to a stirred mixture of 2-bromopyridin-3-ol (346.0 mg, 2.0 mmol) and potassium carbonate (414.0 mg, 3.0 mmol) in acetonitrile (10 mL) under a nitrogen atmosphère. The resulting mixture was heated to reflux and stirred for 2 hours. After cooling to room température, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (700 mg, 66.9%) as a yellow⁷ solid. LC-MS (Method C): m/z = 524.1 [M+H]⁺, 1.490 min.

Step 3: Préparation of2-(2-bromopyridin-3-yloxy)-l-(lH-imidazol-2-yl)ethanone

[0921] A mixture of 2-(2-bromopyridin-3-yloxy)-l-(l-trityl-lH-imidazol-2-yl)ethanone (700 mg, 1.34 mmol) in methanol/acetic acid (5 mL/Ι mL) was heated at reflux and stirred ovemight. After cooling to room température, the resulting mixture was concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound (300 mg, 79.7%) as a yellow solid. LC-MS (Method R): m/z = 282.2 [M+H| , 0.628 min.

Step 4: Préparation ofimidazo[l,2-d]pyrido[3,2-b][l,4]oxazepin-7(6H)-one

[0922] Cuprous iodide ( 19 mg, 0.1 mmol) was added to a mixture of 2-(2-bromopyridin-3-yloxy)-1 (lH-imidazol-2-yl)ethanone (281 mg, 1.0 mmol), L-proline (23.1 mg, 0.2 mmol) and potassium carbonate (345 mg, 2.50 mmol) in toluene (10 mL) under a nitrogen atmosphère. The resulting mixture was stirred ovemight at 100 °C. After cooling to room température, the reaction mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with dichloromethane/methanol (10/1) (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/40) to afford the title compound (70 mg, 34.8%) as a yellow solid. LC-MS (Method R): m/z = 202.3 [M+H]⁺, 0.540 min.

Step 5: Préparation of 6,7-dihydroimidazo[l,2-d]pyrido[3,2-b][l,4]oxazepin-7-amine

[0923] Sodium cyanoborohydride (11.0 mg, 0.17 mmol) was added to a stirring mixture of imidazo[l,2-d]pyrido[3,2-b][l,4]oxazepin-7(6H)-one (50.0 mg, 0.29 mmol) and ammonium acetate (383.0 mg, 4.98 mmol) in methanol (5 mL). The resulting mixture was stirred ovemight at room température. The reaction mixture was concentrated under vacuum. The residue was purified by column

338 chromatography (methanol/dichloromethane, 1/15) to afford the title compound (30 mg, 59.4%) as a yellow solid. LC-MS (Method C): m/z = 203.1 [M+H]⁺, 0.778 min.

Step 7: Préparation of 5-benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2-b][l,4]oxazepin-7-yl)-4H-

1,2,4-triazole-3-carboxamide

[0924] The crude product obtained using Amide Coupling Procedure C was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the title compound (16 mg, 27.6%) as a white solid. LC-MS (Method C): m/z = 388.1 [M+H]⁺, 0.921 min.

Step 7: Préparation of (S)-5-benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2-b][l,4]oxazepin-7-yl)-4H-

1.2.4- triazole-3-carboxamide (141A) and (R)-5-benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2b][l,4]oxazepin-7-yl)-4H-l,2,4-triazole-3-carboxamide (141B).

[0925] The racemate of 5-benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2-b][l,4]oxazepin-7-yl)-4H-

1.2.4- triazole-3-carboxamide (16 mg, 0.041 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IC, 2 x 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 30 min; UV254 & 220 nm; Rt 1: 16.881; Rt 2: 24.391 to afford the title compounds:

[0926] Example 141A (first eluting isomer): ’H NMR (400 MHz, CDsOD-rL) δ 8.43 (s, 1H), 8.31 (dd, J= 4.4, 1.2 Hz, 1H), 7.70 (dd, J= 8.0, 1.2 Hz, 1H), 7.42 (dd, J= 8.0, 4.4 Hz, 1H), 7.33-7.22 (m, 6H), 5.86 (s, 1H), 4.59-4.48 (m, 2H), 4.15 (s, 2H). LC-MS (Method D): m/z = 388.1 [M+H]⁺, 1.139 min.

[0927] Example 141B (second eluting isomer): ’H NMR (400 MHz, CD3OD-J4) δ 8.37 (s, 1H), 8.29 (dd, J= 4.4, 1.6 Hz, 1H), 7.67 (dd, J= 8.0, 1.2 Hz, 1H), 7.38 (dd, J= 8.0, 4.4 Hz, 1H), 7.32-7.20 (m, 6H), 5.83 (s, 1H), 4.57-4.47 (m, 2H), 4.10 (s, 2H). LC-MS (Method D): m/z = 388.1 [M+H]⁺, 1.139 min.

Example 142: (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [l,4]oxazepin-3yl)isoxazole-3-carboxamide

[0928] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; UV 254 & 220 nm; Rt: 5.6 min to afford the title compound. ’H NMR (300 MHz, DMSO-Y) δ 8.94 (d, J= 7.8 Hz, 1H), 8.33 (dd, J= 4.8, 1.5 Hz, 1H), 7.66 (dd, J= 7.8, 1.5 Hz, 1H), 7.35-7.21 (m, 6H), 6.52 (s, 1H), 4.86-4.77 (m, 1H), 4.67-4.59 (m, 1H), 4.51-4.44 (m, 1H), 4.19 (s, 2H), 3.31 (s, 3H). LC-MS (Method D): m/z =379.1 [M+H]⁺, 1.719 min.

339

Example 143: N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-4fluoro-l-(4-fluorobenzyl)-lH-pyrazole-3-carboxamide

[0929] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 65% B over 7 min; UV 254 & 220 nm; Rt: 5 min to afford the title compound (26.2 mg, 28%) as a white solid. Ή NMR (300 MHz, DMSO-î/₆) δ 8.32 (dd, J= 4.8, 1.5 Hz, 1H), 8.10 (d, J= 4.5 Hz, 1H), 7.71 (dd, J= 7.8, 1.5 Hz, 1H), 7.56 (d, J= 6.6 Hz, 1H), 7.35-7.29 (m, 3H), 7.22-7.14 (m, 2H), 5.31 (s, 2H), 4.94-4.83 (m, 2H), 3.36 (s, 3H), 1.27 (d, J= 6.3 Hz, 3H). LC-MS (Method D): m/z =428.1 [M+H]⁺, 1.771 min.

Example 144: (S)-l-(3-cyanobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

HOBT, EDCI, DIEA, DMF rt, o/n

[0930] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; UV 254 & 220 nm; Rt: 5.5 min to afford the title compound. *H NMR (300 MHz, DMSOtes) δ 8.32 (dd, J= 4.8, 1.5 Hz, 1H), 8.22 (d, J= 7.8 Hz, 1H), 8.14 (d, J= 4.2 Hz, 1H), 7.81-7.74 (m, 2H), 7.68-7.64 (m, 1H), 7.61-7.55 (m, 2H), 7.32-7.27 (m, 1H), 5.39 (s, 2H), 4.85-4.76 (m, 1H), 4.67-4.59 (m, 1H), 4.50-4.44 (m, 1H), 3.32 (s, 3H). LC-MS (Method D): m/z =421.1 [M+H]⁺, 1.550 min.

340

Example 145A and 145B: (S)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yI)-5(l-phenylcyclopropyl)-l,3,4-oxadiazo!e-2-carboxamide and (R)-N-(9-methyl-8-oxo-6,7,8,9tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(l-phenylcyclopropyl)-l,3,4-oxadiazole-2-carboxamide

Step 1: Préparation ofN-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(lphenylcyclopropyl)-!, 3,4-oxadiazole-2-carboxamide

[0931] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC: Column: XBridge Shield RP 18 OBD, 19 x 150 mm, 5 pm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: ACN (35.0% ACN to 41.0% over 7 min); Detector, UV220 & 254 nm; Rt: 5.88 min to afford the title compound (45 mg, 25.4%) as a white solid. LC-MS (Method E): m/z = 404.00 [M+H]⁺, 0.833 min.

Step 2: Préparation of (S)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(lphenylcyclopropyl)-l,3,4-oxadiazole-2-carboxamide (first eluting isomer) and (R)-N-(9-methyl-8-oxo6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(l-phenylcyclopropyl)-!,3,4-oxadiazole-2carboxamide (second eluting isomer).

[0932] The racemate of N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-( 1 phenylcyclopropyl)-!,3,4-oxadiazole-2-carboxamide (45 mg, 0.11 mmol) was separated by Prep-ChiralHPLC with the following conditions: Column: ChiralpakIA, 5 pm, 2.12 x 15 cm; Mobile Phase A: hexane, Mobile Phase B: IP A; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 13.5 min; UV 220 & 254 nm; Rt 1: 8.78; Rt 2: 11.03 to afford the title compounds:

[0933] Example 145A (first eluting isomer): 'H NMR (400 MHz, Methanol-tL) δ 8.41 (dd, J = 4.9, 1.8 Hz, 1H), 7.78 (dd, J = 7.5, 1.8 Hz, 1H), 7.45-7.42 (m, 2H), 7.38-7.25 (m, 4H), 4.48-4.44 (m, 1H), 3.45 (s, 3H), 2.91-2.76 (m, 2H), 2.60-2.49 (m, 1H), 2.37-2.28 (m, 1H), 1.77-1.74 (m, 2H), 1.55-1.53 (m, 2H). LC-MS (Method X): m/z = 404.10 [M+H]⁺, 1.180 min.

341

[0934] Example 145B (second eluting isomer): ’H NMR (400 MHz, Methanol-<7) δ 8.41 (dd, J= 4.9,

1.8 Hz, 1H), 7.79 (dd, J= 7.6, 1.8 Hz, 1H), 7.46-7.42 (m, 2H), 7.38-7.25 (m, 4H), 4.49-4.44 (m, 1H),

3.45 (s, 3H), 2.90-2.77 (m, 2H), 2.60-2.49 (m, 1H), 2.37-2.28 (m, 1H), 1.77-1.74 (m, 2H), 1.55-1.53 (m,

2H). LC-MS (Method X): m/z = 404.00 [M+H]⁺, 1.179 min.

Example 146: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)l,3,4-oxadiazole-2-carboxamide

[0935] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 5 mm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; UV 254 & 220 nm; Rt: 5 min to afford the title compound. ’H NMR (300 MHz, DMSOU) δ 9.50 (s, 1H), 8.33 (dd, J= 4.8, 1.5 Hz, 1H), 7.69-7.65 (m, 1H), 7.38-7.24 (m, 6H), 4.84-4.65 (m, 2H), 4.53-4.47 (m, 1H), 4.34 (s, 2H), 3.31 (s, 3H). LC-MS (Method D): m/z = 380.1 [M+H]⁺, 1.531min.

Example 147: 5-benzyI-N-((2R,3S)-2,5-dimethyI-8-(methylsulfonyl)-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide

Br₂, DMF

step 1 step 2

step 5

342

Step 1: Préparation of tert-butyl (2R,3S)-8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2b][l,4]oxazepin-3-ylcarbamate

[0936] Bromine (1.63 g, 10.2 mmol) was added to a stirring mixture of tert-butyl (2R,3S)-2-methyl-4oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-ylcarbamate (1.0 g, 3.4 mmol) in N,Ndimethylformamide (30 mL). The reaction mixture was stirred at room température for 4 hours and quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL). The resulting solution was extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (900 mg, 71%) as a white solid. LC-MS (Method C): m/z = 372.0 [M+H]⁺, 1.283 min.

Step 2: Préparation of tert-butyl (2R,3S)-8-bromo-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro- pyrido[3,2b][1,4]oxazepin-3-ylcarbamate

[0937] lodomethane (306 mg, 2.2 mmol) was added to a stirring mixture of tert-butyl (2R,3S)-8bromo-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-ylcarbamate (800 mg, 2.2 mmol) and césium carbonate (703 mg, 2.2 mmol) inN,N-dimethylformamide (20 mL). The reaction mixture was stirred for 2 hours at room température, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to afford the title compound (650 mg, 79%) as a white solid. LC-MS (Method C): m/z = 330.0 [M+H-56]⁺, 1.408 min.

Step 3: Préparation of tert-butyl (2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5tetrahydropyrido[3,2-b] [1,4]oxazepin-3-ylcarbamate

[0938] A solution of isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 0.52 mL, 1.04 mmol) was added to a stirring mixture of tert-butyl (2R,3S)-8-bromo-2,5-dimethyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][l,4]oxazepin-3-ylcarbamate (200 mg, 0.52 mmol) in tetrahydrofuran (5 mL) at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C followed by the addition of methanesulfonyl chloride (60 mg, 0.52 mmol). The reaction mixture was stirred for another 2 hours at room température, diluted with water (15 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (55 mg, 28%) as a white solid. LC-MS (Method C): m/z = 330.1 [M+H-56]⁺, 1.208 min.

343

Step 4: Préparation of (2R,3S)-3-amino-2,5-dimethyl-8-(methylsulfonyl)-2,3-dthydropyrido- [3,2b][1,4]oxazepin-4(5H)-one hydrochloride

[0939] To a stirring mixture of tert-butyl (2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][l,4]oxazepin-3-ylcarbamate (55 mg, 0.15 mmol) in 1,4-dioxane (5 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 2 mL, 8 mmol). The reaction mixture was stirred for 2 hours at room température and concentrated under high vacuum to afford the title compound (46 mg crude) as a white solid, which was used directly in the next step without further purification. LCMS (Method C): m/z = 286.1 [M+H]⁺, 0.783 min.

Step 5: Préparation of 5-benzyl-N-((2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-4H-l, 2,4-triazole-3-carboxamide

[0940] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Â, 5 pm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound. ^!H NMR (400 MHz, DMSO-d₆) δ 14.40 (s, IH), 8.81 (d, J= 2.0 Hz, IH), 8.22 (d, J= 2.0 Hz, IH), 8.01 (br s, IH), 7.36-7.21 (m, 5H), 5.15-5.04 (m, 2H), 4.16 (s, 2H), 3.45 (s, 3H), 3.39 (s, 3H), 1.35 (d, J= 6.4 Hz, 3H). LC-MS (Method D): m/z =471.1 [M+H]⁺, 1.519 min.

Example 148A and 148B: (S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)-l,3,4-oxadiazole-2-carboxamide and (R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9tetrahydro-5H-pyrido[2,3-b]azepin-7-yI)-l,3,4-oxadiazole-2-carboxamide

Step 1 : Préparation of 5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin- 7-yl)-

1,3,4-oxadiazole-2-carboxamide

[0941] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 5 mm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient:

344

40% B to 52% B over 4 min; UV 254 & 220 nm; Rt: 4 min to afford the title compound (20 mg, 14.2%) as a white solid. LC-MS (Method D): m/z = 378.1 [M+H]⁺, 1.492 min.

Step 2: Préparation of (S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-

1.3.4- oxadïazole-2-carboxamide (first eluting isomer) and (R)-5-benzyl-N-(9-methyl-8-oxo-6, 7,8,9tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-l,3,4-oxadiazole-2-carboxamide (second eluting isomer)

[0942] The racemate of 5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-

1.3.4- oxadiazole-2-carboxamide (20 mg) was separated by Prep-Chiral-HPLC with the following conditions: Column: CFHRALPAK IA, 2.12 x 15 cm, 5 pm; Mobile Phase A: hexane; Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 12 min; UV 254 & 220 nm; Rt 1: 7.106; Rt 2: 9.363 min to afford the title compounds:

[0943] Example 148A (first eluting isomer): 'H NMR (300 MHz, CD3OD -dfi δ 8.44 (dd, 7= 5.1, 1.8 Hz, 1H), 7.81 (dd, 7= 7.5, 1.5 Hz, 1H), 7.38-7.26 (m, 6H), 4.54-4.46 (m, 1H), 4.34 (s, 2H), 3.48 (s, 3H), 2.90-2.78 (m, 2H), 2.65-2.51 (m, 1H), 2.41-2.97 (m, 1H). LC-MS (Method D): m/z = 378.1 [M+H]⁺, 1.492 min.

[0944] Example 148B (second eluting isomer): 'H NMR (300 MHz, CD3OD -dp δ 8.41 (dd, 7= 4.8, 1.8 Hz, 1H), 7.78 (dd, 7= 7.2, 1.5 Hz, 1H), 7.39-7.21 (m, 6H), 4.52-4.41 (m, 1H), 4.31 (s, 2H), 3.45 (s, 3H), 2.91-2.75 (m, 2H), 2.64-2.45 (m, 1H), 2.41-2.25 (m, 1H). LC-MS (Method D): m/z = 378.1 [M+H]⁺, 1.496 min.

Example 149: (S)-5-(2-fluorophenoxy)-N-(5-methyI-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)pyridazine-3-carboxamide

[0945] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Â, 5 mm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B over 7 min; UV 254 & 220 nm; Rt: 6.5 min to afford the title compound. Ή NMR (300 MHz, DMSO-Y) δ 9.45-9.42 (m, 2H), 8.34-8.31 (m, 1H), 7.69-7.65 (m, 1H), 7.53-7.38 (m, 3H), 7.37-7.27 (m, 2H), 7.22 (d, 7= 3.6 Hz, 1H), 4.91-4.74 (m, 2H), 4.56-4.50 (m, 1H), 3.32 (s, 3H). LCMS (Method V): m/z = 410.1 [M+H]⁺, 2.765 min.

345

Example 150: 5-benzyI-N-((2R,3S)-8-cyano-2,5-dimethyI-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yI)-4H-l,2,4-triazole-3-carboxamide

Br

N HCl in dioxane rt, 2 h step 2

step 3

Step 1: Préparation of tert-butyl (2R,3S)-8-cyano-2.5-dimethyl-4-oxo-2,3,4.5-telrahydropyrido- [3,2b][1,4Joxazepin-3-ylcarbamate

[0946] Tetrakis(triphenylphosphanyl)palladium (60 mg, 0.052 mmol) was added to a suspension of zinc cyanide (80 mg, 0.68 mmol) and tert-butyl (2R,3S)-8-bromo-2,5-dimethyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][l,4]oxazepin-3-ylcarbamate (200 mg, 0.52 mmol) in Ν,Ν-dimethylformamide (2 mL) under a nitrogen atmosphère. The reaction mixture was heated at 140 °C under microwave and stirred for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (110 mg, 64%) as a white solid. LC-MS (Method C): m/z = 277.1 [M+H-56]⁺, 1.300 min.

Step 2: Préparation of (2R,3S)-3-amino-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepine-8-carbonitrile hydrochloride

[0947] To a solution of tert-butyl (2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro- pyrido[3,2b][l,4]oxazepin-3-ylcarbamate (68 mg, 0.21 mmol) in 1,4-dioxane (5 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 2 mL, 8 mmol). The resulting mixture was stirred for 2 hours at room température and concentrated under high vacuum to afford the title compound (55 mg crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 233.1 [M+H]⁺, 0.825 min.

Step 3: Préparation of 5-benzyl-N-((2R, 3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro- pyrido[3,2b][1,4[oxazepin-3-yl) -4H-1,2,4-triazole-3-carboxamide

[0948] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30%

346

B to 65% B over 7 min; UV 254 & 220 nm; Rt: 6 min to afford tire title compound. 'H NMR (400 MHz,

DMSO-î/ô) δ 14.43 (s, 1H), 8.82 (d, J= 1.6 Hz, 1H), 8.31 (d, J= 2.0 Hz, 1H), 8.00 (br s, 1H), 7.36-7.23 (m, 5H), 5.08-5.01 (m, 2H), 4.15 (s, 2H), 3.42 (s, 3H), 1.33 (d, J= 6.0 Hz, 3H). LC-MS (Method F): m/z = 418.0 [M+H]/ 1.187 min.

Example 151: (S)-5-benzyl-4-cyano-N-(5-methyl-4-oxo-2,3,4,5- tetrahydropyrido[3,2b] [1,4] oxazepin-3-yI)thiazo!e-2-carboxamide

[0949] The crude product obtained using the procedure described in Example 54 was purified by PrepHPLC with the following conditions: Column: XBridge Prep C18 OBD Column 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; 254 nm; Rt: 6.32 min to afford the title compound. ^]H NMR (400 MHz, CD3OD-A) δ 8.35 (dd, J= 4.8, 1.6 Hz, 1H), 7.67 (dd, J= 8.0, 1.6 Hz, 1H), 7.43- 7.26 (m, 6H), 4.98 (dd, J= 11.5, 7.4 Hz, 1H), 4.70-4.55 (m, 2H), 4.42 (s, 2H), 3.48 (s, 3H). LC-MS (Method Q): m/z = 420.3 [M+H]/ 1.503 min.

Example 152A and 152B: (R)-l-(3-cyanobenzyl)-4-fluoro-N-(9-methyI-8-oxo-6,7,8,9-tetrahydro5H-pyrido[2,3-b] azepin-7-yl)-lH-pyrazo!e-3-carboxamide and (S)-l-(3-cyanobenzyI)-4-fluoro-N-(9methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yI)-lH-pyrazole-3-carboxamide

Step 1: Préparation of l-(3-cyanobenzyl)-4-fluoro-N-(9-mefhyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)-lH-pyrazole-3-carboxamide

[0950] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, lOOA, 5 pm, 19 mm x 250

347 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min;

Gradient: 20% B to 50% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound (65 mg, 60%) as a white solid. LC-MS (Method D): m/z = 419.1 [M+H]⁺, 1.508 min.

Step 2: Préparation of (R)-l-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepin-7-yl)-lH-pyrazole-3-carboxamide (first eluting isomer) and (S)-l-(3-cyanobenzyl)~ 4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-lH-pyrazole-3carboxamide (second eluting isomer)

[0951] The racemate of l-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepin-7-yl)-lH-pyrazole-3-carboxamide (65 mg, 0.16 mmol) was separated by PrepChiral-HPLC with the following conditions: Column: Chiralpak ID-2, 5 pm, 2 x 25 cm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 60% B to 60 B% over 20 min; UV 254 & 220 nm; Rt 1: 12.92 min; Rt 2: 16.60 min to afford the title compounds:

[0952] Example 152A (first eluting isomer): ’H NMR (400 MHz, DMSO-dô) δ 8.44 (dd, J= 4.8, 1.6 Hz, 1H), 8.16 (d, J=4.4Hz, 1H), 8.08 (d, J=7.6Hz, 1H), 7.85-7.78 (m, 3H), 7.64-7.58 (m, 2H), 7.307.26 (m, 1H), 5.42 (s, 2H), 4.34-4.26 (m, 1H), 3.35 (s, 3H), 2.78-2.65 (m, 2H), 2.43-2.25 (m, 2H). LCMS (Method F): m/z = 419.0 [M+H]⁺, 1.070 min.

[0953] Example 152B (second eluting isomer): ’H NMR (400 MHz, DMSO-de) Ô 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (d, J= 4.4 Hz, 1H), 8.08 (d, J= 7.6 Hz, 1H), 7.85-7.78 (m, 3H), 7.64-7.58 (m, 2H), 7.307.26 (m, 1H), 5.42 (s, 2H), 4.34-4.26 (m, 1H), 3.35 (s, 3H), 2.78-2.64 (m, 2H), 2.43-2.24 (m, 2H). LCMS (Method F): m/z = 419.1 [M+H]⁺, 1.071 min.

Example 153: (S)-l-(2-cyanobenzyl)-4-fluoro-N-(5-methyI-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

NC

[0954] 2-(Bromomethyl) benzonitrile (39 mg, 0.20 mmol) was added to a stirring mixture of (S)-4fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-lH-pyrazole-3carboxamide (50 mg, 0.16 mmol) and potassium carbonate (68 mg, 0.49 mmol) in N,Ndimethylformamide (4 mL). The resulting mixture was stirred at room température for 3 hours, diluted with water (5 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dry’ under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Cl8 OBD

348

Column 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; 254 nm; Rt: 6.32 min to afford the title compound. ’H NMR (400 MHz, CD₃OD-î/₄) δ 8.35 (dd, J= 4.8, 1.6 Hz, 1H), 7.88 (d, 7= 4.5 Hz, 1H), 7.83 (dd, 7= 7.7, 1.3 Hz, 1H), 7.73-7.66 (m, 2H), 7.56 (td, 7= 7.6, 1.1 Hz, 1H), 7.38 (d, 7= 7.9 Hz, 1H), 7.32 (dd, 7= 8.0, 4.8 Hz, 1H), 5.59 (s, 2H), 5.01 (dd, J= 11.5, 7.2 Hz, 1H), 4.68 (dd, 7= 9.8, 7.2 Hz, 1H), 4.50 (dd, 7= 11.5, 9.9 Hz, 1H), 3.49 (s, 3H). LC-MS (Method Q): m/z = 421.3 [M+H]⁺, 1.201 min.

Example 154A and 154B: (R)-l-benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2-b][l,4]oxazepin-7yI)-4-fluoro-lH-pyrazole-3-carboxamide and (S)-l-benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2b] [l,4]oxazepin-7-yl)-4-fluoro-lH-pyrazole-3-carboxamide

step 1

Step 1: Préparation of 1 -benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2-b] [l,4]oxazepin-7-yl)-4-fluorolH-pyrazole-3-carboxamide

[0955] The crude product obtained using Amide Coupling Procedure C was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the title compound (16 mg, 33.0%) as a white solid. LC-MS (Method S): m/z = 405.2 [M+H]⁺, 0.954 min.

Step 2: Préparation of (S)-l-benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2-b][l,4]oxazepin-7-yl)-4fluoro-lH-pyrazole-3-carboxamide (first eluting isomer) and (R)-l-benzyl-N-(6,7-dihydroimidazo[l,2d]pyrido[3,2-b][l,4]oxazepin-7-yl)-4-fluoro-lH-pyrazole-3-carboxamide (second eluting isomer)

[0956] The racemate of l-benzyl-N-(6,7-dihydroimidazo[l,2-d]pyrido[3,2-b][l,4]oxazepin-7-yl)-4fluoro-lH-pyrazole-3-carboxamide (16 mg, 0.039 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IC, 5 pm, 2 x 25 cm; Mobile Phase A: hexane: DCM = 5:1, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 26 min; UV 254 & 220 nm; Rt 1: 3.96 min; Rt 2: 6.18 min to afford the title compounds:

349

[0957] Example 154A (first eluting isomer): *HNMR (300 MHz, MethanolY) δ 8.25-8.22 (m, 2H),

7.70 (d, J= 4.5 Hz, 1H), 7.61 (dd, J= 8.1, 1.5 Hz, 1H), 7.34-7.22 (m, 6H), 7.07 (d, J= 1.5 Hz, 1H), 5.735.69 (m, 1H), 5.25 (s, 2H), 4.47-4.44 (m, 2H). LC-MS (Method T): m/z = 405.2 [M+H]⁺, 1.063 min.

[0958] Example 154B (second eluting isomer): 'H NMR (300 MHz, MethanolY) δ 8.25-8.22 (m, 2H), 7.70 (d, J= 4.5 Hz, 1H), 7.61 (dd, J= 8.1, 1.5 Hz, 1H), 7.34-7.22 (m, 6H), 7.07 (d, J= 1.5 Hz, 1H), 5.73-5.69 (m, 1H), 5.25 (s, 2H), 4.47-4.44 (m, 2H). LC-MS (Method T): m/z = 405.2 [M+H]⁺, 1.069 min.

Example 155: l-Benzyl-N-((2R,3S)-2,5-dimethyI-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yI)-lH-pyrazo!e-3-carboxamide

Br

1) NaH, DMF, rt, 4 h

2) LiOH, H₂O, rt, o/n step 1

Step J: Préparation of l-benzyl-lH-pyrazole-3-carboxylic acid

[0959] Sodium hydride (96 mg, 4 mmol) was added to a stirring mixture of ethyl lH-pyrazole-3carboxylate (280 mg, 2 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred at room température for 2 hours followed by the addition of (bromomethyl)benzene (340 mg, 2 mmol). After stirring for another 2 hours, the reaction mixture was diluted with water (5 mL). Lithium hydroxide (96 mg, 4 mmol) was added and the resulting mixture was stirred overnight at room température, tire pH was adjusted to 6 with hydrochloric acid (2 N, 20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 55% B over 7 min; UV 254 & 220 nm; Rt: 4.9 min to afford the title compound (220 mg, 54.4%) as a white solid. LC-MS (Method E): m/z = 202.9 [M+H]⁺, 0.855 min.

350

Step 2: Préparation of l-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0960] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 pm, 19 x 150 mm;

Mobile Phase A: w'ater (0.1% formic acid). Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 75% B over 7 min; UV 254 & 220 nm; Rt: 3.3 min to afford the title compound. ’HNMR (400 MHz, DMSO</₆) δ 8.36 (dd, J= 4.8, 1.6 Hz, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.76 (dd, J= 8.0, 1.6 Hz, 1H), 7.70 (d, J= 6.4 Hz, 1H), 7.42-7.25 (m, 6H), 6.70 (d, J= 2.0 Hz, 1H), 5.46 (s, 2H), 4.99-4.89 (m, 2H), 3.40 (s, 3H), 1.32 (d, J= 6.0 Hz, 3H). LC-MS (Method V): m/z = 392.1 [M+H]⁺, 2.961 min.

Example 156A and 156B: 4-fluoro-l-(4-fluorobenzyl)-N-((laR,2R,8bS)-4-methyl-3-oxol,la,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-lH-pyrazoie-3-carboxamide and 4fluoro-l-(4-fluorobenzyl)-N-((laS,2S,8bR)-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yI)-lH-pyrazole-3-carboxamide

[0961] The crude product obtained using Amide Coupling Procedure C was purified by Prep-TLC (methanol/dichloromethane, 1/20) to afford the title compound as a white solid.

[0962] The racemate was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IC, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 19 mL/min; Gradient: 35% B to 35% B over 18.5 min; UV 220 & 254 nm; Rtl: 13.00; Rt2: 15.67 to afford the title compounds:

[0963] Example 156A (first eluting isomer): ^!H NMR (400 MHz, CDsOD-rift δ 8.35 (dd, J= 4.8, 2.0 Hz, 1H), 7.92 (dd, J= 7.6, 1.6 Hz, 1H), 7.77 (d, J= 4.4 Hz, 1H), 7.38-7.35 (m, 2H), 7.27 (dd, J= 8.0, 4.8 Hz, 1H), 7.14-7.07 (m, 2H), 5.31 (s, 2H), 4.63 (s, 1H), 3.39 (s, 3H), 2.28-2.22 (m, 1H), 2.10-2.05 (m, 1H), 1.27-1.20 (m, 1H), 1.18-1.12 (m, 1H). LC-MS (Method D): m/z = 424.1 [M+H]⁴, 1.658 min.

351

[0964] Example 156B (second eluting isomer): 'H NMR (400 MHz, CD/OD-c/ff δ 8.35 (dd, J= 4.8,

2.0 Hz. 1H), 7.92 (dd, J= 8.0, 2.0 Hz, 1H), 7.76 (d, J= 4.4 Hz, 1H), 7.49 -7.35 (m, 2H), 7.26 (dd, J =

7.6, 4.8 Hz, 1H), 7.12-7.08 (m, 2H), 5.31 (s, 2H), 4.63 (s, 1H), 3.39 (s, 3H), 2.28-2.22 (m, 1H), 2.10-2.04 (m, 1H), 1.26-1.19 (m, 1H), 1.18-1.27 (m, 1H). LC-MS (Method D): m/z = 424.1 [M+H]⁺, 1.664 min.

Example 157A and 157B: 5-benzyl-N-((laR,2R,8bS)-4-methyI-3-oxo-l,la,2,3,4,8bhexahydrocyciopropa[d]pyrido[2,3-b]azepin-2-yl)-l,3,4-oxadiazole-2-carboxamide and 5-benzyl-N((laS,2S,8bR)-4-methyl-3-oxo-l,la,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)1,3,4-oxadiazole-2-car boxamide

[0965] The crude product obtained using the procedure described in Example 54was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound as a white solid.

[0966] The racemate was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK AS-H, 2.0 cm I.D x 25 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 16 min; UV 220 & 254 nm; Rtl: 8.212; Rt2: 10.554 to afford the title compounds:

[0967] Example 157A (fïrst eluting isomer): 'HNMR (300 MHz, DMSO-ri₆) δ 9.48 (d, J= 6.6 Hz,

1H), 8.39 (dd, J= 4.8, 1.8 Hz, 1H), 7.99 (dd, J= 7.5, 1.8 Hz, 1H), Ί.3Ί-Ί2Ί (m, 6H), 4.42 (d, J= 6.3 Hz, 1H), 4.38 (s, 2H), 3.34 (s, 3H), 2.31-2.26 (m, 1H), 2.07-1.96 (m, 1H), 1.23-1.08 (m, 2H). LC-MS (Method X): m/z = 390.1 [M+H]⁺, 2.745 min.

[0968] Example 157B (second eluting isomer): ’H NMR (300 MHz, DMSO-rie) δ 9.47 (d, J= 6.0 Hz, 1H), 8.39 (dd, J= 6.6, 1.8 Hz, 1H), 7.97 (dd, 7.5, 1.8 Hz, 1H), 7.37-7.21 (m, 6H), 4.43 (d, J= 6.3 Hz, 1H), 4.39 (s, 2H), 3.33 (s, 3H), 2.32-2.26 (m, 1H), 2.03-1.99 (m, 1H), 1.23-1.08 (m, 2H). LC-MS (Method D). m/z = 390.1 [M+H]⁺, 1.533 min.

352

Example 158: (S)-l-benzyl-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

O

HCl H₂N

1) NaNO₂, CHCI₃/H₂O, rt, 12 h

2) 60 °C, 6 h step 1

CN

Y^NH

NaOH, EtOH, H₂O rt, 4 h step 2

Stepl : Préparation of ethyl 5-cyano-lH-pyrazole-3-carboxylate

[0969] Sodium nitrite (10.56 g, 153 mmol) was added to a mixture of ethyl propiolate (5.00 g, 51.1 mmol) and 2-aminoacetonitrile hydrochloride (9.44 g, 102 mmol) in chloroform (150 mL) and water (5 mL). The reaction mixture was stirred for 12 hours at room température, then heated to 60 °C and stirred for another 6 hours. After cooling to room température, the resuiting mixture was filtered. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/9) to afford the title compound (2.90 g, 35%) as a yellow solid. LC-MS (Method C): m/z =166.1[M+H]⁺, 1.032 min.

Step2: Préparation of 5-cyano-lPI-pyrazole-3-carboxylic acid

[0970] A solution of sodium hydroxide in water (2 M, 30 mL, 60 mmol) was added to a mixture of ethyl 5-cyano-lH-pyrazole-3-carboxylate (1.5 g, 9.09 mmol) in éthanol (25 mL). The reaction mixture was stirred for 4 hours at room température. After removal of éthanol under reduced pressure, the pH value of the solution was adjusted to 3-4 with aqueous hydrochloric acid (1 M, 100 ml, 100 mmol). The resuiting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under high vacuum to afford the title compound (400 mg crude) as a yellow solid. ’H NMR (400 MHz, DMSO-î/ô) δ 14.89 (s, IH), 7.43 (s, IH), 3.15 (s, IH).

Step3: Préparation of (S)-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] oxazepin-3yl)-lH-pyrazole-3-carboxamide

353

[0971] The crude product obtained using Amide Coupling Procedure C was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound (180 mg, 53%) as a yellow solid. LC-MS (Method S): m/z =313.2[M+H]⁺, 0.749 min.

Step 4: Préparation of((S)-l-benzyl-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]bxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0972] Césium carbonate (80 mg, 0.25 mmol) was added to a mixture of (S)-5-cyano-N-(5-methyl-4oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide (60 mg, 0.19 mmol) and (bromomethyl)benzene (39 mg, 0.23 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred for 0.5 hour at room température, diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP 18 OBD, 5 pm, 19 x 150 mm; Mobile Phase A: Water (0.1% formic acid); Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 20% B to 45% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound: ’H NMR (400 MHz, DMSO-Ts) δ 8.67 (d, J= 7.9 Hz, IH), 8.35 (dd, J= 4.7, 1.6 Hz, IH), 7.69 (dd, 7= 8.0, 1.6 Hz, IH), 7.58 (s, IH), 7.44-7.29 (m, 4H), 7.28-7.22 (m, 2H), 5.65 (s, 2H), 4.90-4.84 (m, IH), 4.73-4.67 (m, IH), 4.54-4.50 (m, IH), 3.35 (s, 3H). LC-MS (Method T): m/z = 403.2 [M+H]⁺, 1.412 min.

Example 159: (S)-5-cyano-l-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[0973] The crude product obtained using the procedure described in Example 158, Step 4 was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD, 5 pm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3); Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 60% B over 12 min; UV 254 & 220 nm; Rt: 6.5 min to afford the title compound: ’H NMR (400 MHz, DMSO-7.) δ 8.67 (d, 7= 7.9 Hz, IH), 8.36 (dd, 7= 4.8, 1.6 Hz, IH), 7.70 (dd, 7= 7.9, 1.6 Hz, IH), 7.59 (s, IH), 7.36-7.29 (m, 3H), Ί2Ί-Ί.20 (m, 2H), 5.64 (s, 2H), 4.90-4.84 (m, IH), 4.72-4.67 (m, IH), 4.544.50 (m, IH), 3.36 (s, 3H). LC-MS (Method T): m/z = 421.1 [M+H]⁺, 1.433 min.

354

Example 160A and 160B: (S)-5-benzyl-N-(5’-methyl-4’-oxo-4’,5’-dihydro-3’H-spiro[cyclopropanel,2’-pyrido[3,2-b] [l,4]oxazepin]-3’-yl)-l,3,4-oxadiazole-2-carboxamide and (R)-S-benzyl-N-(S’methyl-4’-oxo-4’,5’-dihydro-3’H-spiro[cyclopropane-l,2’-pyrido[3,2-b][l,4]oxazepin]-3’-yl)-l,3,4oxadiazole-2-carboxamide

PtK

Ph'

Ph O

OTMS benzoic acid, toluene °C, o/n

DMA, 4 A MS

130°C, o/n

step 1 step 2

Pd/C, H₂, MeOH rt, 2h step 3

AIMe₃, toluene rt, o/n step 4

CH₃I, Cs₂CO₃

DMF, 0°C, 2 h step 5

TMEDA, TMSI, l₂

DCM, 0°C, 2 h step 6

NaN₃

DMF, rt, 2 h step 7

step 10

Pd/C, H₂, MeOH rt, 30 min step 8

AIMe₃, toluene, rt, o/n step 9 chiral séparation

Step 1 : Préparation of ethyl 2-cyclopropylideneacetate

[0974] Ethyl 2-(triphenylphosphoranylidene)acetate (52 g, 149.42 mmol) was added to a mixture of (1ethoxycyclopropoxy)trimethylsilane (20 g, 114.94 mmol) and benzoic acid (1.83 g, 14.95 mmol) in toluene (150 mL). The reaction mixture was stirred at 80 °C ovemight under nitrogen atmosphère. After cooling to room température, the reaction mixture was concentrated under reduced pressure. The residue was purified

355 by column chromatography (dichloromethane/petroleum ether, 1/1) to afford the title compound (2.1 g,

14%) as a colorless oil. LC-MS (Method S): m/z = 127.2 [M+H]⁺, 0.886 min.

Step 2: Préparation of ethyl 2-(l-((2-nitropyridin-3-yl)oxy)cyclopropyl)acetate

[0975] 2-Nitropyridin-3-ol (3.36 g, 24.00 mmol) was added to a mixture of ethyl 2cyclopropylideneacetate (1.00 g, 7.93 mmol) and molecular sieves 4Â (2.80 g) in dimethylacetamide (40 mL). The reaction mixture was stirred at 130 °C overnight under nitrogen atmosphère. After cooling to room température, the mixture was diluted with diethyl ether (150 mL) and washed with aqueous sodium hydroxide (0.2 M, 3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane /petroleum ether, 2/1) to afford the title compound (450 mg, 21%) as a yellow oil. LCMS (Method S): m/z = 267.2 [M+H]⁺, 0.935 min.

Step 3: Préparation of ethyl 2-(l-((2-aminopyridin-3-yl)oxy)cyclopropyl)acetate

[0976] A mixture of ethyl 2-(l-((2-nitropyridin-3-yl)oxy)cyclopropyl)acetate (800 mg, 3.00 mmol) in methanol (30 mL) was hydrogenated in the presence of palladium on carbon (10%, 80 mg) under hydrogen atmosphère (2-3 atm). The reaction mixture was stirred for 2 hours at room température. The mixture was filtered through Celite and the filtrate was concentrated under high vacuum to afford the title compound (650 mg, 92%) as a yellow oil. LC-MS (Method S): m/z = 237.1 [M+H]⁺, 0.587 min.

Step 4: Préparation of 3 ’H-spiro[cyclopropane-l,2’-pyrido[3,2-b] [l,4]oxazepin]-4 ’(5 ’H)-one

[0977] A solution of trimethylaluminum in toluene (2 M, 5.3 mL, 10.55 mmol) was added dropwise to a stirring mixture of ethyl 2-(1-((2-aminopyridin-3-yl)oxy)cyclopropyl)acetate (500 mg, 2.11 mmol) in toluene (50 mL). The resulting mixture was stirred overnight at room température, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to afford the title compound (290 mg, 72%) as a yellow oil. LC-MS (Method S): m/z = 191.1 [M+H]⁺, 0.704 min.

Step 5: Préparation of 5 '-methyl-3 ’H-spiro[cyclopropane-l,2’-pyrido[3,2-b][l,4]oxazepin]-4 ’(5’H)-one

[0978] lodomethane (178 mg, 1.26 mmol) was added dropwise to a stirring mixture of 3Ήspiro[cyclopropane-l,2’-pyrido[3,2-b][l,4]oxazepin]-4’(5’H)-one (200 mg, 1.05 mmol) and césium carbonate (341 mg, 1.05 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 2 hours at 0 °C, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/17) to afford the title compound (150 mg, 69%) as a white solid. LC-MS (Method S): m/z = 205.1 [M+H] , 0.767 min.

356

Step 6: Préparation of 3’-iodo-5’-methyl-3’PI-splro[cyclopropane-l,2’-pyrido[3,2-b][l,4] oxazepin]4 ’(5 ’Hfone

[0979] Ν,Ν,Ν’,Ν’-tetramethylethylenediamine (0.49 g, 4.25 mmol) was added to a mixture of 5’methyl-3’H-spiro[cyclopropane-l,2’-pyrido[3,2-b][l,4]oxazepin]-4’(5’H)-one (0.18 g, 0.85 mmol) in dichloromethane (40 mL) at 0 °C followed by addition of iodotrimethylsilane (1.70 g, 8.50 mmol) dropwise over 20 minutes. The mixture was stirred for 1 hour at 0 °C and then a solution of iodine (0.32 g, 1.25 mmol) in dichloromethane (100 mL) was added to the mixture. The reaction mixture was stirred for another 1 hour at 0 °C, quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (280 mg crude) as a yellow oil. LC-MS (Method C): m/z = 330.8 [M+H]⁺, 0.946 min.

Step 7: Préparation of 3’-azido-5^,-methyl-3’H-spiro[cyclopropane-l,2’-pyrido[3,2-b][1,4] oxazepin]4 ’(5 ’Hj-one

[0980] Sodium azide (109 mg, 1.68 mmol) was added to a mixture of 3 '-iodo-5 ’-methyl-3 ’Hspiro[cyclopropane-l,2’-pyrido[3,2-b][l,4]oxazepin]-4’(5’H)-one (280 mg, 0.84 mmol) in N,Ndimethylformamide (5 mL). The resuiting mixture was stirred for 2 hours at room température, quenched by the addition of water (40 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-TLC (ethyl acetate/petroleum ether, 1/2) to afford the title compound (70 mg, 33%) as a yellow solid. LC-MS (Method C): m/z = 246.0 [M+H]⁺, 0.925 min.

Step 8: Préparation of 3’-amino-5’-methyl-3’H-spiro[cyclopropane-l,2’-pyrido[3,2-b][l,4] oxazepin]4’(5’Hfone

[0981] A mixture of 3’-Azido-5’-methyl-3’H-spiro[cyclopropane-l,2’-pyrido[3,2-b][l,4]oxaze pin]4’(5’H)-one (70 mg, 0.28 mmol) in methanol (10 mL) was hydrogenated in the presence of palladium on carbon (10%, 10 mg) under hydrogen atmosphère (2-3 atm). After stirring for 30 minutes at room température the reaction mixture was filtered through Celite and the filtrate was concentrated under vacuum to afford the title compound (50 mg, 78%) as a white solid. LC-MS (Method S): m/z = 220.2 [M+H]⁺, 0.690 min.

Step 9: Préparation of 5-benzyl-N-(5 ’-methyl-4 ’-oxo-4 ’, 5 ’-dihydro-3 ’H-spiro[cyclopropane-1,2 ’pyrido[3,2-b][1,4]oxazepin]-3 ’-yl)-l, 3,4-oxadiazole-2-carboxamide

[0982] The crude product obtained using the procedure described in Example 54was purified by PrepTLC (ethyl acetate/petroleum ether, 1/1) to afford the title compound (42 mg, 45%) as a white solid. LCMS (Method S): m/z = 406.0 [M+H]⁺, 1.024 min.

357

Step 10: Préparation of (S)-5-benzyl-N-(5’-methyl-4’-oxo-4’,5’-dihydro-3’H-spiro[cyclopropane-l,2’pyrido[3,2-b][1,4]oxazepin]-3 ’-yl)-l, 3,4-oxadiazole-2-carboxamide and (R)-5-benzyl-N-(5 ’-methyl-4 oxo-4 ’,5 ’-dihydro-3 Ή-spiro[cyclopropane-1,2 ’-pyrido[3,2-b][l,4]oxazepin]-3 ’-yl)-l,3,4-oxadiazole-2carboxamide

[0983] The racemate of 5-benzyl-N-(5’-methyl-4’-oxo-4’,5’-dihydro-3’H-spiro[cyclopropane-l,2’pyrido[3,2-b][l,4]oxazepin]-3’-yl)-l,3,4-oxadiazole-2-carboxamide (42 mg, 0.10 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2.12 x 15 cm, 5 pm;

Mobile Phase A: Hexane, Mobile Phase B: IP A; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 14 min; UV 254 & 220 nm; Rt 1: 12.359; Rt 2: 20.087 to afford the title compounds:

[0984] Example 160A (first eluting isomer): ’H NMR (300 MHz, DMSO-40 δ 9.01 (d, J= 8.7 Hz, 1H), 8.39 (dd, J= 4.8, 1.5 Hz, 1H), 7.74 (dd, J = 8.1, 1.5 Hz, 1H), 7.39-7.27 (m, 6H), 5.20 (d, J= 8.4 Hz, 1H), 4.35 (s, 2H), 3.40 (s, 3H), 1.36-1.28 (m, 1H), 1.16-1.02 (m, 1H), 1.00-0.94 (m, 1H), 0.58-0.50 (m, 1H). LC-MS (Method V): m/z = 406.1 [M+H]⁺, 2.745 min.

[0985] Example 160B (second eluting isomer): 'H NMR (300 MHz, DMSO-i/e) δ 9.01 (d, J= 8.4 Hz, 1H), 8.39 (dd, J= 4.8, 1.5 Hz, 1H), 7.74 (dd, J= 8.1, 1.5 Hz, 1H), 7.39-7.27 (m, 6H), 5.20 (d, J= 8.4 Hz, 1H), 4.35 (s, 2H), 3.40 (s, 3H), 1.36-1.31 (m, 1H), 1.16-1.03 (m, 1H), 1.00-0.94 (m, 1H), 0.58-0.50 (m, 1H). LC-MS (Method D): m/z = 406.1 [M+H]⁺, 1.652 min.

Example 161: (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide

H₂SO₄, MeOH rt, 3 h step 1

NH₂NH₂ H₂O, MeOH °C, o/n

step 2

step 6

Step 1: Préparation of methyl 2-(3-cyanophenyl)acetate

[0986] Sulfiiric acid (98%, 2.0 mL) was added to a mixture of 2-(3-cyanophenyl)acetic acid (3.5 g, 22.0 mmol) in methanol (80 mL). The resulting mixture was stirred at room température for 3 hours and

358 concentrated under vacuum. The residue was diluted with water (40 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (3.30 g, 87%) as a colorless oil. LCMS (Method S): m/z = 176.2 [M+H]⁺, 0.504 min.

Step 2: Préparation of 2-(3-cyanophenyl)acetohydrazide

[0987] Hydrazine hydrate (80%, 3.3 mL, 85.0 mmol) was added to a mixture of methyl 2-(3cyanophenyl)acetate in methanol (50 mL). The reaction mixture was stirred at 65 °C ovemight and then concentrated under reduced pressure. Tire residue was diluted with water (40 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the crude title compound (2.4 g, 80%) as a white solid. LC-MS (Method S): m/z = 176.2 [M+H]⁺, 0.506 min.

Step 3: Préparation of ethyl 2-(2-(2-(3-cyanophenyl)acetyl)hydrazinyl)-2-iminoacetate

[0988] Ethyl 2-ethoxy-2-iminoacetate (1.82 g, 12.6 mmol) was added to a stirring mixture of 2-(3cyanophenyl)acetohydrazide (2.0 g, 11.5 mmol) in éthanol (20 mL) and diethyl ether (60 mL). The reaction mixture was stirred at room température ovemight. The white solid was collected by filtration and rinsed with diethyl ether to afford the title compound (2.88 g, 92%) as a white solid. LC-MS (Method C): m/z = 275.1 [M+H]⁺, 0.913 min.

Step 4: Préparation of ethyl 5-(3-cyanobenzyl)-4H-l,2,4-triazole-3-carboxylate

[0989] Molecular sieves 4Â (50 mg) was added to a mixture of ethyl 2-(2-(2-(3-cyanophenyl)acetyl)hydrazinyl)-2-iminoacetate (1.0 g, 3.65 mmol) in xylene (10 mL). The reaction mixture was stirred at 160 °C ovemight in a sealed tube and concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound (500 mg, 54%) as a white solid. LC-MS (Method S): m/z = 257.2 [M+H]⁺, 0.767 min.

Step 5: Préparation of 5-(3-cyanobenzyl)-4H-l,2,4-triazole-3-carboxylic acid

[0990] A solution of lithium hydroxide (94 mg, 4.0 mmol) in water (5 mL) was added to a solution of ethyl 5-(3-cyanobenzyl)-4H-l,2,4-triazole-3-carboxylate (500 mg, 2.0 mmol) in tetrahydrofuran (15 mL). The resulting mixture was stirred at room température ovemight. After removal of tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 7 with aqueous hydrochloric acid (1 N, 10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (430 mg crude) as a white solid. LC-MS (Method C): m/z = 229.1 [M+H] , 0.816 min.

Step 6: Préparation of (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-4H-l, 2,4-triazole-3-carboxamide

359

[0991] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Â, 5 pm, 19 mm x 250 mm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 45% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound: ’H NMR (400 MHz, DMSOY) δ 14.53 (br s, 1H), 8.68 (s, 1H), 8.37 (dd, J= 4.4, 1.2 Hz, 1H), 7.79-7.69 (m, 3 H), 7.64-7.61 (m, 1H), 7.58-7.53 (m, 1H), 7.36-7.32 (m, 1H), 4.90-4.82 (m, 1H), 4.75-4.69 (m, 1H), 4.55.4.49 (m₅ 1H), 4.22 (s, 2H), 3.36 (s, 3H). LC-MS (Method T): m/z = 404.2 [M+H]⁺, 1.095 min.

Example 162: (S)-5-(3-cyano-5-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide

nh₂nh₂ h₂o, ch₃oh reflux, 3 h

EtOH, ether, rt, 4 h step 4

F

Zn(CN)₂, Pd(PPh₃)₄, DMF „ A.

----------- î f J microwave, 140 °C, 3 h step 2

step 3

EDCI, HOBT, DIEA, DMF rt, o/n xylenes, MS 4A sealed tube, 160 °C, 4 h step 5

step 7

Step 1: Préparation of methyl 2-(3-bromo-5-fluorophenyl) acetate

[0992] Thionyl chloride (4.26 g, 35.8 mmol) was added to a stirring mixture of methyl 2-(3-bromo-5fluorophenyl)acetic acid (2.6 g, 11.93 mmol) in methanol (30 mL) dropwise, followed by the addition of Ν,Ν-dimethylformamide (two drops). The reaction mixture was stirred for 2 hours at room température and concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to afford the title compound (2.79 g, 92.2%) as a yellow solid. LC-MS (Method S): m/z = 247.1 [M+H]”, 1.079 min.

Step 2: Préparation of methyl 2-(3-cyano-5-fluorophenyl)acetate

360

[0993] Tetrakis(triphenylphosphanyl)palladium (1.2 g, 1.05 mmol) was added to a mixture of methyl 2-(3-bromo-5-fluorophenyl)acetate (2.6 g, 10.5 mmol) and dicyanozinc (1.64 g, 14.17 mmol) inN,Ndimethylformamide (30 mL) under nitrogen atmosphère. The reaction mixture was heated at 140 °C by micro wave and stirred for 3 hours. After cooling to room température, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to afford the title compound (1.12 g, 54%) as a yellow solid. LC-MS (Method C): m/z = 194 [M+H]⁺, 0.914 mm.

Step 3: Préparation of2-(3-cyano-5-fluorophenyl)acetohydrazide

[0994] Hydrazine hydrate (1.45 g, 29 mmol) was added to a mixture of methyl 2-(3-cyano-5fluorophenyl)acetate (1.12 g, 5.80 mmol) in methanol (20 mL). The resulting mixture was heated at reflux, stirred for 3 hours and concentrated under high vacuum. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/1) to afford the title compound (0.92 g, 82.2%) as a white solid. LC-MS (Method S): m/z = 194 [M+H]⁺, 0.30 min.

Step 4: Préparation of ethyl 2-(2-(2-(3-cyano-5-fluorophenyl)acetyl)hydrazinyl)-2-iminoacetate

[0995] Ethyl 2-ethoxy-2-iminoacetate (692 mg, 4.ΊΊ mmol) was added to a stirred mixture of 2-(3cyano-5-fluorophenyl)acetohydrazide (910 mg, 4.77 mmol) in éthanol (5 mL) and diethyl ether (15 mL). The reaction mixture was stirred for 4 hours at room température. The solid was collected by filtration and dried under high vacuum to afford the title compound (160 mg, 80.8%) as a white solid. LC-MS (Method C): m/z = 293 [M+H]⁺, 0.727 min.

Step 5: Préparation of ethyl 5-(3-cyano-5-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylate

[0996] A mixture of ethyl 2-(2-(2-(3-cyano-5-fluorophenyl)acetyl)hydrazinyl)-2-iminoacetate (1 g, 3.42 mmol) and 4Â molecular sieves in xylenes (20 mL) was stirred for 4 hours at 160 °C. After cooling to room température, the reaction mixture was concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to afford the title compound (0.75 g, 79.5 %) as a white solid. LC-MS (Method C): m/z = 275.0 [M+H]⁺, 0.811 min.

Step 6: Préparation of 5-(3-cyano-5-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylic acid

[0997] Lithium hydroxide (79.2 mg, 3.3 mmol) was added to a stirring mixture of ethyl 5-(3-cyano-5fluorobenzyl)-4H-l,2,4-triazole-3-carboxylate (140 mg, 0.78 mmol) in tetrahydrofuran (10 mL) and water (3 mL). The reaction mixture was stirred ovemight at room température. After removal of tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH—6 with aqueous hydrochloric acid (1 M, 20 mL, 20 mmol), and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dned over anhydrous sodium sulfate, filtered and concentrated

361 under vacuum to afford the title compound (250 mg crude) as a yellow solid. LC-MS (Method C): m/z =

247.0 [M+H]⁺, 0.633 min.

Step 7: Préparation of (S)-5-(3-cyano-5-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1> 4]oxazepin-3-yl)-4H-l, 2,4-triazole-3-carboxamlde

[0998] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: X bridge Prep C18, 19 x 150 mm, 5 pm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: MeCN (20% to 80% over 12 min); Detector, UV 220 & 254 nm to afford the title compound: 'H NMR (300 MHz, DMSO-r/g) δ 14.37 (s, 1H), 8.56 (s, 1H), 8.37 (dd, J= 4.8, 1.5 Hz, 1H), Ί.ΊΊ-Ί.6Ί (m, 3H), 7.59-7.55 (m, 1H), 7.33 (dd, J= 8.1, 4.8 Hz, 1H), 4.91-4.71 (m, 2H), 4.45.4.48 (m_; 1H), 4.26 (s, 2H), 3.36 (s, 3H). LC-MS (Method D): m/z = 422.1 [M+H]⁺, 1.367 min.

Example 163: (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3yI)-4H-l,2,4-triazole-3-carboxamide

[0999] Tire crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD Column 19 x 150 mm 5 pm 10 nm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min;

Gradient: 25% B to 75% B in 7 min; UV 254 & 220 nm; Rt: 6.34 min.: Ή NMR (400 MHz, DMSO-de) δ 8.48 (s, 1H), 7.78-7.73 (m, 2H), 7.64-7.61 (m, 1H), 7.57-7.49 (m, 2H), 7.36-7.22 (m, 3H), 4.87-4.79 (m, 1H), 4.62-4.56 (m, 1H), 4.44-4.38 (m, 1H), 4.20 (s, 2H), 3.32 (s, 3H). LCMS (Method D): m/z = 403.1 [M+H]⁺, 1.367 min.

362

Example 164: (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3yl)thiazole-2-carboxamide

step 3

Pd(PPh₃)₄, K₂CO₃, EtOH, toluene °C, 2 h step 2

HO

B

HO

CN

Step 1: Préparation of ethyl 5-(bromomethyl)thiazole-2carboxylate

[1000] Benzoyl peroxide (6 mg, 0.02 mmol) was added to a mixture of ethyl 5-methylthiazole-2carboxylate (420 mg, 2.45 mmol) and N-bromosuccinimide (459 mg, 2.58 mmol) in carbon tetrachloride (6 mL). The resuiting mixture was stirred overnight at 75 °C under nitrogen atmosphère, quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to afford the title compound (300 mg, 48.8%) as a yellow solid. LC-MS (Method S): m/z = 252.3 [M+H]⁺, 0.928 min.

Step 2: Préparation of 5-(3-cyanohenzyl)thiazole2-carboxylic acid

[1001] Tetrakis(triphenylphosphine)palladium (28 mg, 0.02 mmol) was added to a mixture of ethyl 5(bromomethyl)thiazole-2carboxylate (300 mg, 1.20 mmol), (3-cyanophenyl)boronic acid (194 mg, 1.32 mmol) and potassium carbonate (190 mg, 1.37 mmol) in toluene/ethanol (5 mL/5 mL) under nitrogen atmosphère. The resuiting mixture was stirred for 2 hours at 90 °C. After cooling to room température, the reaction mixture was concentrated under vacuum. The residue was diluted with water (30 mL), the pH value ofthe resuiting solution was adjusted to 3 with aqueous hydrochloric acid (1 M, 50 mL, 50 mmol) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (100 mg, 34.1%) as a yellow oil. LC-MS (Method C): m/z = 245.2 [M+H]⁺, 1.208 min.

363

Step 3: Préparation of (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b]

[1,4]oxazepin-3-yl) thiazole-2-carboxamide

[1002] The crude product obtained using Amide Coupling Procedure B was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 65% B over 7 min; UV 254 & 220 nm; Rt: 6.5 min to afford the title compound: ‘H NMR (300 MHz, DMSO-î/₆) δ 8.82 (d, J= 8.0 Hz, IH), 7.93-7.90 (m, IH), 7.84-7.80 (m, IH), 7.78-7.71 (m, IH), 7.70-7.63 (m, IH), 7.62-7.44 (m, 2H), 7.40-7.20 (m, 3H), 4.88-4.75 (m, IH), 4.73-4.60 (m, IH), 4.48-4.37 (m, IH), 4.34 (s, 2H), 3.30 (s, 3H). LC-MS (Method V): m/z = 419.2 [M+H]⁺, 3.361 min.

Example 165: (S)-l-benzyI-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yI)-lH-pyrazoîe-3-carboxamide

2M aq.NaOH

MeOH.rt, o/n

K₂CO₃, DMF rt, 0.5 h

step 3

Step 1: Préparation of 5fluoro-lH-pyrazole-3-carboxylic acid

[1003] A solution of sodium hydroxide (2 M, 0.63 mL, 1.26 mmol) was added to a stirring mixture of ethyl 5-fluoro-lH-pyrazole-3-carboxylate (100 mg, 0.63 mmol) in methanol (5 mL). The reaction mixture was stirred at room température overnight. After removal of methanol under reduced pressure, the resulting solution was adjusted to pH = 5 with aqueous hydrochloric acid (1 N, 2 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The fîltrate was concentrated under vacuum to afford the title compound (80 mg, 97%) as a white solid. ’H NMR (300 MHz, DMSO-rie) δ 13.67 (s, IH), δ 13.49 (s, IH), δ 6.47 (dd, J= 6.3, 2.2 Hz, IH).

364

Step 2: Préparation of (S)-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] oxazepin3-yl)-lH-pyrazole-3-carboxamide

[1004] The crude product obtained using Amide Coupling Procedure C was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (100 mg, 56.8%) as a white solid. LC-MS (Method E): m/z = 306.1 [M+H]⁺, 0.898 min.

Step 3: Préparation of (S)~l-benzyl-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[1005] The crude product obtained using the procedure described in Example 158, Step 4 was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Cl8 OBD Column, 5 pm, 19 x 150 mm; Mobile phase: Phase A: Water (0.05% TFA), Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B in 7 min; Detector, UV 254 & 220 nm to afford the title compound: ’H NMR (300 MHz, CD₃OD-d₄) δ 8.30 (dd, J= 4.7, 1.6 Hz, 1H), 7.63 (dd, J= 8.0, 1.6 Hz, 1H), 7.40-7.20 (m, 6H), 6.27 (d, J= 5.6 Hz, 1H), 5.30 (s, 2H), 4.96 (dd, J= 11.6, 7.2 Hz, 1H), 4.62 (dd, J= 9.8, 7.2 Hz, 1H), 4.46 (dd, J= 11.6, 9.8 Hz, 1H), 3.44 (s, 3H). LC-MS (Method D): m/z = 396.1 [M+H]⁺, 1.659 min.

Example 166: (S)-5-fluoro-l-(4-fIuorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yI)-lH-pyrazole-3-carboxamide

CS2CO3, DMF rt, 0.5 h

[1006] The crude product obtained using the procedure described in Example 158, Step 4 was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5pm, 19 x 150mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 5% B to 55% B over 7 min; Detector, UV 254 & 220 nm to afford the title compound: 'H NMR (300 MHz, CD₃OD-d₄) δ 8.30 (dd, J= 4.8, 1.6 Hz, 1H), 7.63 (dd, J= 8.0, 1.6 Hz, 1H), 7.33-7.25 (m, 3H), 7.14-7.01 (m, 2H), 6.27 (d, J= 5.6 Hz, 1H), 5.29 (s, 2H), 4.96 (dd, J= 11.5, 7.2 Hz, 1H), 4.62 (dd, J= 9.8, 7.2 Hz, 1H), 4.46 (dd, J= 11.5, 9.8 Hz, 1H), 3.44 (s, 3H). LC-MS (Method D): m/z = 414.1 [M+H]⁺, 1.667 min.

Example 167: (S)-5-cyano-l-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]o^xazepin-3-yl)-lH-pyrazole-3-carboxamide

365

[1007] The crude product obtained using the procedure described in Example 158, Step 4 was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD, 5 pm, 19 x 150 mm;

Mobile Phase A: Water (10 mmol/L NH4HCO3); Mobile Phase B: MeCN; Flow rate: 20 mL/min;

Gradient: 25% B to 55% B over 7 min; UV 254 & 220 nm; Rt: 6.32 min to afford the title compound: Ή NMR (400 MHz, DMSO-7₆) δ 8.67 (d, J= 7.9 Hz, 1H), 8.36 (dd, J= 4.7, 1.6 Hz, 1H), 7.87-7.82 (m, 1H), 7.80-7.75 (m, 1H), 7.69 (dd, J= 8.0, 1.6 Hz, 1H), 7.65-7.58 (m, 2H), 7.52-7.58 (m, 1H), 7.35-7.28 (m, 1H), 5.73 (s, 2H), 4.90-4.81 (m, 1H), 4.72-4.63 (m, 1H), 4.54-4.47 (m, 1H), 3.35 (s, 3H). LC-MS (Method T): m/z = 428.1 [M+H]⁺, 1.320 min.

Example 168: (S)-l-((5-cyanopyridin-3-yl)methyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

K₂CO₃, DMF rt, 3 h

[1008] 5-(Bromomethyl)nicotinonitrile (35 mg, 0.18 mmol) was added into a stirring mixture of (S)-4fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-lH-pyrazole-3carboxamide (45 mg, 0.15 mmol) and potassium carbonate (62 mg, 0.45 mmol) inN,Ndimethylformamide (4 mL). The resulting mixture was stirred at room température for 3 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product obtained using the procedure described in Example 158, Step 4 was purified by PrepHPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 50% B over 7 min; UV 254 & 220 nm; Rt: 6.5 min to afford the title compound : 'H NMR (400 MHz, CD₃OD-7₄) δ 8.91 (d, J= 1.9 Hz, 1H), 8.82 (d, J= 2.1 Hz, 1H), 8.35 (dd, J= 4.8, 1.6 Hz, 1H), 8.19 (t, 7= 2.0 Hz, 1H), 7.92 (d, 7= 4.4 Hz, 1H), 7.68 (dd, 7= 8.0, 1.6 Hz, 1H), 7.32 (dd, 7 = 8.0, 4.8 Hz, 1H), 5.48 (s, 2H), 5.02 (dd, 7= 11.5, 7.2 Hz, 1H), 4.69 (dd, 7= 9.9, 7.2 Hz, 1H), 4.51 (dd, J = 11.5, 9.9 Hz, 1H), 3.50 (s, 3H). LC-MS (Method D): m/z = 422.0 [M+H]⁺, 1.328 min.

366

Example 169: (S)-5-benzyl-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yI)-4H-l,2,4-triazole-3-carboxamide

Step 1: Préparation of (S)-tert-butyl (5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2b][1,4]oxazepin-3-yl)carbamate

[1009] Trideuterated iodomethane (233.5 mg, 1.61 mmol) was added to a stirring mixture of (S)-tertbutyl 4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-ylcarbamate (450 mg, 1.61 mmol) and césium carbonate (629.2 mg, 1.93 mmol) in N,N-dimethylformamide (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (360 mg, 75.5%) as a white solid. LC-MS (Method E): m/z = 297.2 [M+H]⁺, 0.903 min.

Step 2: Préparation of (S)-3-amino-5-trideuteriomethyl-2,3-dihydropyrido[3,2-b][l,4]oxazepin4(5H)-one hydrochloride

[1010] (S)-tert-butyl (5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3yl)carbamate (200 mg, 0.68 mmol) was added to a solution of hydrochloride in 1,4-dioxane (4 M, 5 mL, 20 mmol). The reaction mixture was stirred at room température for 2 hours and concentrated under vacuum to afford the title compound (140 mg crude) as a white solid. LC-MS (Method E): m/z = 197.1 [M+H]⁺, 0.761 min.

Step 3: Préparation of (S)-5-benzyl-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2b] [l,4]oxazepin-3-yl)-4H-l, 2,4-triazole-3-carboxamide

[1011] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4CO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; Detector, UV 254 & 220 nm to afford the title compound: ¹H NMR (400 MHz, CD₃OD-i/₄) δ 8.33 (dd, J= 4.8, 1.6 Hz, IH), 7.66 (dd, J= 8.0, 1.6 Hz, IH), 7.38-7.22 (m, 6H), 5.02 (dd, J

367 = 11.6, 7.2 Hz, 1H), 4.67 (dd, 7= 9.9, 7.2 Hz, 1H),4.51 (dd, J= 11.5, 9.9 Hz, 1H), 4.16 (s, 2H). LC-MS (Method D): m/z = 382.1 [M+H]⁺, 1.371 min.

Example 170A and 170B: l-(3-cyanobenzyl)-N-((laS,2S,8bR)-5,7-difluoro-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyciopropa[d]azepin-2-yl)-4-fluoro-lH-pyrazole-3-carboxamide and l-(3cyanobenzyl)-N-((laR,2R,8bS)-5,7-difluoro-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4-fluoro-lH-pyrazole-3-carboxamide

[1012] The crude product obtained using Amide Coupling Procedure C was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the title compound as a white solid.

[1013] The racemate was separated by Prep-Chiral-HPLC with the following conditions: Column: (R,R)WHELK-01 5/100 Kromasil, 2.11 cm x 25 cm (5 pm); Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 60% B to 60% B over 22 min; UV 254 & 220 nm; Rtl: 14.06; Rt2: 18.79 to afford the the title compounds:

[1014] Example 170A (first eluting isomer): 'H NMR (400 MHz, CD3OD-Î/4) δ 7.88 (d, J = 4.4, Hz, 1H), 7.75-7.72 (m, 2H), 7.66-7.63 (m, 1H), 7.61-7.56 (m, 1H), 7.13-7.09 (m, 1H), 6.99-6.92 (m, 1H), 5.23 (s, 2H), 4.82 (s, 1H), 2.31-2.24 (m, 1H), 2.15-2.09 (m, 1H), 1.66-1.61 (m, 1H), 1.22-1.17 (m, 1H). LC-MS (Method D): m/z = 452.1 [M+H]⁺, 1.627 min.

[1015] Example 170B (second eluting isomer): ’H NMR (400 MHz, CD3OD-J4) δ 7.88 (d, 7= 4.4 Hz, 1H), 7.74-7.72 (m, 2H), 7.67-7.63 (m, 1H), 7.61-7.56 (m, 1H), 7.13-7.09 (m, 1H), 6.99-6.92 (m, 1H), 5.43 (s, 2H), 4.82 (s, 1H), 2.29-2.25 (m, 1H), 2.15-2.11 (m, 1H), 1.66-1.60 (m, 1H), 1.22-1.15 (m, 1H). LC-MS (Method V): m/z = 452.1 [M+H]⁺, 2.781 min.

368

Example 171 : (S)-l-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [l,4]oxazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide

step 3

Step 1: Préparation o/methyl l-(3-cyanobenzyl)-lH-l,2,4-triazole-3-carboxylate

[1016] Sodium hydride (60%, 0.38 g, 9.5 mmol) was added to a stirring mixture of methyl 1H-1,2,4triazole-3-carboxylate (1.0 g, 7.87 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred for 1 hour at room température, followed by the addition of 3-(bromomethyl)benzonitrile (1.69 g, 8.67 mmol). The resulting mixture was stirred for another 1 hour at room température, diluted with water (30 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (600 mg, 31.5%) as a white solid. LC-MS (Method C): m/z =243.1 [M+H]⁺, 0.925 min.

Step 2: Préparation of l-(3-cyanobenzyl)-lH-l,2,4-triazole-3-carboxylic acid

[1017] A solution of lithium hydroxide (360 mg, 15.0 mmol) in water (10 ml) was added to a stirring mixture of l-(3-cyanobenzyl)-lH-l,2,4-triazole-3-carboxylate (600mg, 2.48 mmol) in tetrahydrofuran (20 ml). The reaction mixture was stirred at room température for 2 hours. After removal of tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 7 with aqueous hydrochloric acid (1 N, 10 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (250 mg, 17.7%) as a white solid. LC-MS (Method X): m/z =229.1 [M+H]⁺, 1.227 min.

Step 3: Préparation of (S)-l-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

[1018] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm 5 μηι; Mobile

369

Phase A: Water (10 mmol/L NFLHCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 20%

B to 45% B over 7 min; 254 nm; Rt: 6 min to afford the title compound: ’H NMR (400 MHz, CD3OD-CZ4) δ 8.64 (s, IH), 8.33 (dd, 7=4.8, 1.6 Hz, IH), 7.77-7.64 (m, 4H), 7.57 (t, 7= 7.7 Hz, IH), 7.30 (dd, 7=

8.0, 4.8 Hz, IH), 5.55 (s, 2H), 5.03 (dd, 7= 11.7, 7.3 Hz, IH), 4.69 (dd, 7= 9.9, 7.1 Hz, IH), 4.52 (dd, 7 = 11.2, 9.6 Hz, IH), 3.47 (s, 3H). LC-MS (Method D): m/z = 404.2 [M+H]⁺, 1.371 min.

Example 172: l-(3-cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yI)-lH-l,2,4-triazole-3-carboxamide

[1019] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 75% B over 7 min; 254 nm; Rt: 6.25 min to afford the title compound: ’H NMR (300 MHz, CD3OD ri₄) δ 8.66 (s, IH), 8.33 (dd, 7= 4.8, 1.6 Hz, IH), 7.78-7.65 (m, 4H), 7.57 (t, 7= 7.8 Hz, IH), 7.32 (dd, J = 8.0, 4.8 Hz, IH), 5.56 (s, 2H), 5.07-5.01 (m, 2H), 3.49 (s, 3H), 1.38 (d, 7= 5.9 Hz, 3H). LC-MS (Method D): m/z = 418.2 [M+H]⁺, 1.477 min.

Example 173: (S)-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)5-(l-phenylcyclopropyI)-l,3,4-oxadiazoIe-2-carboxamide

[1020] The crude product obtained using the procedure described in Example 54was purified by PrepHPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5 pm, 19 x 150 mm; Mobile phase: Phase A: Water (10 mmol/L NH4HCO3), Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; Detector, UV 254 nm to afford the title compound: ’H NMR (300 MHz, DMSO-7,) δ 9.49 (d, 7= 7.6 Hz, IH), 8.36 (dd, 7= 4.7, 1.6 Hz, IH), 7.70 (dd, 7= 8.0, 1.6 Hz, IH), 7.50-7.28 (m, 6H), 4.87-4.62 (m, 2H), 4.50 (dd, 7= 9.3, 7.1 Hz, IH), 1.72-1.62 (m, 2H), 1.55-1.44 (m, 2H). LC-MS (Method D): m/z = 409.1 [M+H]⁺, 1.624 min.

370

Example 174: 5-benzyI-N-((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5tetrahydropyrido [3,2-b] [1,4] oxazepin-3-y I)-1,3,4-oxadiazole-2-car boxamide

step 3

Step 1: Préparation of tert-butyl ((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate

[1021] Trideuterated iodomethane (124 mg, 0.85 mmol) was added to a stirring mixture of tert-butyl (2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-ylcarbamate (250 mg, 0.85 mmol) and césium carbonate (278 mg, 0.85 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred at room température for 5 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to afford the title compound (230 mg, 87.1%) as a white solid. LC-MS (Method C): m/z = 311.1 [M+H]⁺, 1.260 min.

Step 2: Préparation of (2R,3S)-3-amino-2-imethyl-5-trideuterated methyl-2,3-dihydropyrido[3,2b][l,4]oxazepin-4(5H)-one hydrochloride

[1022] Tert-butyl((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)carbamate (100 mg, 0.32 mmol) was added to a solution of hydrogen chloride in 1.4-dioxane (4 N, 6.0 mL, 24 mmol). The reaction mixture was stirred at room température for 3 hours and concentrated under vacuum to afford the title compound (80 mg, 99%) as a white solid. LC-MS (Method C): m/z = 211.1 [M+H]⁺, 0.757 min.

Step 3: Préparation of 5-benzyl-N-((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5tetrahydropyrido [3,2-bJ[l, 4]oxazepin-3-yl)-l, 3,4-oxadiazole-2-carboxamide

[1023] The crude product obtained using the procedure described in Example 54was purified by PrepHPLC with the following conditions: Column: XBridge Prep OBD C18 Column 19 x 250 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min;

371

Gradient: 25% B to 75% B over 7 min; UV 254 & 220 nm; Rt: 6.85 min to afford the title compound : 'H

NMR (400 MHz, DMSO-î/₆) δ 8.58 (s, 1H), 8.36 (dd, J= 4.8, 1.6 Hz, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H),

7.40-7.28 (m, 6H), 4.98-4.90 (m, 2H), 4.38 (s, 2H), 1.37 (d, J= 6.4 Hz, 3H). LC-MS (Method D): m/z =

397.2 [M+H]⁺, 1.680 min.

Example 175: (S)-l-benzyl-4-fluoro-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

[1024] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5 pm, 19x150 mm; Mobile phase: Phase A: Water (10 mmol/L NH4HCO3), Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 65% B over 7 min; Detector, UV 254 nm to afford the title compound: ’H NMR (300 MHz, DMSOri₆) δ 8.32 (dd, <7= 4.7, 1.6 Hz, 1H), 8.21 (d, J= 7.8 Hz, 1H), 8.10 (d, J= 4.5 Hz, 1H), 7.66 (dd, J= 8.0, 1.6 Hz, 1H), 7.42-7.19 (m, 6H), 5.31 (s, 2H), 4.85-4.76 (m, 1H), 4.64 (dd, J= 11.5, 9.7 Hz, 1H), 4.47 (dd, J= 9.6, 7.4 Hz, 1H). LC-MS (Method J): m/z = 399.3 [M+H]⁺, 1.331 min.

Example 176: 5-benzyl-N-((laR,2S,8bS)-5,7-difluoro-3-oxo-l,la,2,3,4,8bhexahy drobenzo [b] cyclopropafd] azepin-2-yI)-4H-l ,2,4-triazoIe-3-car boxamide

[1025] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: Column: XBridge Prep OBD C18 Column 30 x 150 mm 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 25% B to 55% B over 7 min; 254 nm; Rt: 6.32 min to afford the title compound: ’H NMR (400 MHz, DMSO-rie) δ 14.34 (br s, 1H), 9.72 (s, 1H), 8.62 (s, 1H), 7.35-7.18 (m, 7H), 4.12 (s, 2H), 3.98 (dd,

372

J= 10.5, 7.5 Hz, 1H), 2.26-2.17 (m, 1H), 1.87-1.77 (m, 1H), 1.13-1.04 (m, 1H), 0.60-0.57 (m, 1H). LCMS (Method Q): m/z = 410.5 [M+H]⁺, 1.773 min.

Example 177A and 177B: 5-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8ahexahydrocyciopropa[d]pyrazino[2,3-b]azepin-7-yl)-l,3,4-oxadiazole-2-carboxamide and 5-benzylN-((7R,7aR,8aS)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)l,3,4-oxadiazoIe-2-carboxamide

[1026] The crude product obtained using the procedure described in Example 54 was purified by PrepTLC (ethyl acetate/petroleum ether, 3/1) to afford the title compound as a white solid.

[1027] The racemate of 5-benzyl-N-(cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d]pyrazino[2,3-b]azepin-7-yl)-l,3,4-oxadiazole-2-carboxamide (40 mg, 0.10 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB S-5 pm, 250 x 20 mm, 5 pm; Mobile Phase A:Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 26 min; 220/254 nm; Rtl: 19.32; Rt 2: 23.55 to afford the the title compounds:

[1028] Example 177A (first eluting isomer): 'H NMR (400 MHz, CDsODU) δ 8.42-8.37 (m, 2H), 7.37-7.25 (m, 5H), 4.77 (s, 1H), 4.33 (s, 2H), 3.40 (s, 3H), 2.65-2.57 (m, 1H), 2.25-2.17 (m, 1H), 1.551.48 (m, 1H), 1.35-1.30 (m, 1H). LCMS (Method D): m/z = 391.1 [M+H]⁺, 1.231 min.

[1029] Example 177B (second eluting isomer): ’H NMR (400 MHz, CD₃OD-<7) δ 8.42-8.37 (m, 2H), 7.36-7.25 (m, 5H), 4.77 (s, 1H), 4.33 (s, 2H), 3.39 (s, 3H), 2.64-2.56 (m, 1H), 2.24-2.16 (m, 1H), 1.541.46 (m, 1H), 1.34-1.28 (m, 1H). LC-MS (Method D): m/z = 391.1 [M+H]⁺, 1.225 mm.

373

Example 178A and 178B: (S)-4-fluoro-l-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5Hpyrazino[2,3-b]azepin-7-yl)-lH-pyrazole-3-carboxamide and (R)-4-fluoro-l-(2-fluorobenzyl)-N-(5methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yI)-lH-pyrazole-3-carboxamide

Mel, CS2CO3

DMF, rt, o/n

step 3 step 4 step 5

Pd/C, H₂

MeOH, rt, 5 h step 6

F

EDCI, HOBT, DIEA, DMF rt, o/n step 7

Step 1: Préparation of ethyl 4-(3-aminopyrazin-2-yl)butanoate

[1030] A solution of (4-ethoxy-4-oxobutyl)zinc(II) bromide in tetrahydrofuran (0.5 M, 26.0 mL, 13.0 mmol) was added to a mixture of 3-bromopyrazin-2-amine (1.0 g, 5.8 mmol) and tetrakis(triphenylphosphanyl)palladium (0.67 g, 0.58 mmol) in tetrahydrofùran (60 mL) under a nitrogen atmosphère. The resulting mixture was stirred ovemight at 70 °C. After cooling to room température, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (0.45 g, 37.0%) as a light yellow oil. LC-MS (Method S): m/z = 210.2 [M+H]⁺, 0.592 min.

Step 2: Préparation of8,9-dihydro-5PI-pyrazino[2,3-b]azepm-6(7H)-one

[1031] A solution of trimethylaluminum in toluene (2 M, 6.0 mL, 12.0 mmol) was added to a stirring mixture of ethyl 4-(3-aminopyrazin-2-yl)butanoate (450 mg, 2.2 mmol) in toluene (20 mL). After stirring ovemight at room température, the reaction mixture was quenched by the addition of water (50 mL) and

374 extracted with dichloromethane (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, l/10) to afiford the title compound (0.32 g, 91.0%) as a light yellow solid. LC-MS (Method S): m/z = 164.2 [M+H]⁴, 0.473 min.

Step 3: Préparation of 5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one

[1032] lodomethane (313 mg, 2.2 mmol) was added dropwise to a stirring mixture of 8,9-dihydro-5Hpyrazino[2,3-b]azepin-6(7H)-one (320 mg, 2.0 mmol) and césium carbonate (717 mg, 2.2 mmol) inN,Ndimethylformamide (15 mL). After stirring ovemight at room température, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (300 mg, 87.0%) as a light yellow solid. LC-MS (Method S): m/z = 178.1 [M+H]⁴, 0.570 min.

Step 4: Préparation of7-iodo-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin- 6(7H)-one

[1033] To a mixture of 5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one (300 mg, 1.70 mmol) and Ν,Ν,Ν’,Ν’-tetramethylethylenediamine (1.97 g, 17.0 mmol) in dichloromethane (80 mL) at 0 °C was added iodotrimethylsilane (2.38 g, 17.0 mmol) dropwise over 30 minutes. The resulting mixture was stirred for 2 hours at 0 °C, followed by the addition of a solution of iodine (0.65 g, 2.6 mmol) in dichloromethane (100 mL) dropwise over 30 minutes. After stirring for 1 hour at room température, the reaction mixture was quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (450 mg crude, 87.7%) as a yellow oil. LC-MS (Method S): m/z = 304.1 [M+H]⁴, 0.610 min.

Step 5: Préparation of7-azido-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin- 6(7H)-one

[1034] Sodium azide (290 mg, 4.47 mmol) was added to a stirring mixture of 7-iodo-5-methyl-8,9dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one (450 mg, 1.49 mmol) in N,N-dimethylformamide (50 mL). After stirred at room température for 3 hours, the reaction mixture was quenched by the addition of water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (260 mg crude) as a yellow oil. LC-MS (Method S): m/z = 219.1 [M+H]⁴, 0.600 min.

Step 6: Préparation of7-amino-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin- 6(7H)-one

[1035] 7-Azido-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one (260 mg, 1.2 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium on carbon (10%, 26 mg) under a hydrogen atmosphère (2-3 atm). After stirring for 5 hours at room température under a hydrogen

375 atmosphère, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and dried under high vacuum to afford the title compound (200 mg, 88%) as a colorless oil. LCMS (Method S): m/z = 193.1 [M+H]⁺, 0.356 min.

Step 7: Préparation of 4-fluoro-l-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9- letrahydro-SHpyrazino[2,3-b]azepin- 7-yl)-lH-pyrazole-3-carboxamide

[1036] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield C18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NFLHCO;), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 35% B to 50% B in 8 min; UV 254 & 220 nm; Rt: 6.82 min to afford the title compound (30 mg, 28%) as a white solid. LC-MS (Method O): m/z = 413.1 [M+H]⁺, 1.396 min.

Step 8: Préparation of (S)-4-fliioro-l-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9- tetrahydro-5Hpyrazino[2,3-b]azepin- 7-yl)-lH-pyrazole-3-carboxamide and (R)-4- fluoro-l-(2-fluorobenzyl)-N-(5methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-lH-pyrazole-3-carboxamide

[1037] Tire racemate of 4-fluoro-l-(2-fïuorobenzyl)-N-(5-methyl-6-oxo- 6,7,8,9-tetrahydro-5Hpyrazino[2,3-b]azepin-7-yl)-lH-pyrazole-3-carboxamide (30.0 mg, 0.07 mmol) was separated by PrepChiral-HPLC with the following conditions: Column: CFHRALPAK IF, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B in 30 min; UV 254 & 220 nm; Rtl : 17.00 min; Rt2: 24.16 min to afford the title compounds:

[1038] Example 178A (first eluting isomer): ’H NMR (400 MHz, CD3OD-Î/4) δ 8.48 (d, J = 2.8 Hz, IH), 8.39 (d, J= 2.8 Hz, IH), 7.77 (d, 4.4 Hz, IH), 7.45-7.38 (m, IH), 7.34-7.29 (m, IH), 7.24-7.15 (m, 2H), 5.41 (s, 2H), 4.58-4.52 (m, IH), 3.50 (s, 3H), 3.18-3.08 (m, IH), 3.04-2.98 (m, IH), 2.80-2.69 (m, IH), 2.41-2.31 (m, IH). LC-MS (Method T): m/z = 413.1 [M+H]⁺, 1.198 min.

[1039] Example 178B (second eluting isomer): ’H NMR (400 MHz, CD3OD-Î/4) δ 8.47 (d, J— 2.8 Hz, IH), 8.38 (d, J= 2.8 Hz, IH), 7.78 (d, J= 4.4 Hz, IH), 7.45-7.38 (m, IH), 7.34-7.29 (m, IH), 7.25-7.15 (m, 2H), 5.41 (s, 2H), 4.58-4.52 (m, IH), 3.50 (s, 3H), 3.19-3.08 (m, IH), 3.05-2.98 (m, IH), 2.81-2.69 (m, IH), 2.41-2.32 (m, IH). LC-MS (Method X): m/z = 413.1 [M+H]⁺, 2.354 min.

376

Example 179A and 179B: 4-fluoro-l-(2-fluorobenzyl)-N-((7S,7aS,8aR)-5-methyl-6-oxo5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yI)-lH-pyrazole-3-carboxamide and

4-fIuoro-l-(2-fluorobenzyl)-N-((7R,7aR,8aS)-5-methyI-6-oxo-5,6,7,7a,8,8ahexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-lH-pyrazole-3-carboxamide

[1040] The crude product obtained using Amide Coupling Procedure C was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the title compound as a white solid.

[1041] The racemate was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IF, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B in 38 min; UV 254 & 220 nm; Rtl: 22.995; Rt2: 30.882 to afford the tire title compounds:

[1042] Example 179A (first eluting isomer): ’H NMR (400 MHz, CDsOD-üL) δ 8.30 (dd, J= 2.4, 6.4 Hz, 2H), 7.68 (d, J = 4.4 Hz, 1H), 7.34-7.27 (m, 1H), 7.25-7.20 (m, 1H), 7.13-7.04 (m, 2H), 5.23 (s, 2H), 4.66 (s, 1H), 3.31 (s, 3H), 2.54-2.47 (m, 1H), 2.17-2.10 (m, 1H), 1.43-1.37 (m, 1H), 1.22-1.15 (m, 1H). LC-MS (Method D): m/z = 425.0 [M+H]⁺, 1.679 min.

[1043] Example 179B (second eluting isomer): 'H NMR (400 MHz, CD3OD-0/4) δ 8.42 (dd, J= 3.2, 6.8 Hz, 2H), 7.80 (d, J= 4.4 Hz, 1H), 7.45-7.39 (m, 1H), 7.37-7.32 (m, 1H), 7.25-7.16 (m, 2H), 5.44 (s, 2H), 4.78 (s, 1H), 3.42 (s, 3H), 2.65-2.58 (m, 1H), 2.28-2.22 (m, 1H), 1.54-1.49 (m, 1H), 1.33-1.27 (m, 1H). LC-MS (Method D): m/z = 425.0 [M+H]⁺, 1.684 min.

377

Example 180A and 180B: (S)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7yl)-5-(l-phenylcyclopropyl)-l,3,4-oxadiazole-2-carboxamide and (R)-N-(5-methyl-6-oxo-6,7,8,9tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-5-(l-phenylcyclopropyl)-l,3,4-oxadiazole-2carboxamide

[1044] The crude product obtained using Amide Coupling Procedure C was purified by Prep-TLC (ethyl acetate/petroleum ether, 1/1) to afford the title compound.

[1045] The racemate of N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-5-(lphenylcyclopropyl)-l,3,4-oxadiazole-2-carboxamide (30 mg, 0.08mmol) was separated by Prep-ChiralHPLC with the following conditions: Column: CHIRALPAKIE, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: MeOH; Flow rate: 20 mL/min; Gradient: 100% B to 100% B over 16 min; UV 254 & 220 nm; Rt 1: 10.459 min; Rt 2: 12.463 min to afford the title compounds:

[1046] Example 180A (first eluting isomer): H NMR (400 MHz, CD3ODY) δ 8.49 (d, 7= 2.4 Hz, 1H), 8.40 (d, 7= 2.8 Hz, 1H), 7.48-7.46 (m, 2H), 7.41-7.31 (m, 3H), 4.57-4.51 (m, 1H), 3.49 (s, 3H), 3.18-3.09 (m, 1H), 3.05-2.99 (m, 1H), 2.74-2.63 (m, 1H), 2.50-2.41 (m, 1H), 1.80-1.77 (m, 2H), 1.591.55 (m, 2H). LC-MS (Method D): m/z = 405.0 [M+H]⁺, 1.260 min.

[1047] Example 180B (second eluting isomer): ‘H NMR (400 MHz, CDsODY) δ 8.49 (d, 7= 2.4 Hz, 1H), 8.40 (d, 7= 2.8 Hz, 1H), 7.49-7.46 (m, 2H), 7.42-7.31 (m,3H), 4.57-4.50 (m, 1H), 3.50 (s, 3H), 3.18-3.09 (m, 1H), 3.06-2.99 (m, 1H), 2.74-2.63 (m, 1H), 2.50-2.40 (m, 1H), 1.81-1.77 (m, 2H), 1.601.55 (m, 2H). LC-MS (Method D): m/z = 405.0 [M+H]⁺, 1.261 min.

378

Example 181A and 181B: 5-(3-cyanobenzyl)-N-((laR,2R,8bS)-5,7-difluoro-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide and 5-(3cyanobenzyI)-N-((l aS,2S,8bR)-5,7-difluoro-3-oxo-l,l a,2,3,4,8bhexahydrobenzo[b]cycIopropa[d]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide

[1048] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield C18 OBD Column, 5 pm,19 x 150 mm; Mobile Phase A/Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 30% B to 53% B over 8 min; 254 & 220 nm Rt: 7.43 min to afford the title compound as a white solid.

[1049] The racemate was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane:DCM=5:l, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 23 min; 254 & 220 nm; Rtl: 9.885; Rt2: 16.633 to afford tire the title compounds:

[1050] Example 181A (first eluting isomer): 'HNMR (400 MHz, CD3OD-J4) δ 7.71 (s, 1H), 7.65-7.61 (m, 2H), 7.54-7.48 (m, 1H), 7.18-7.05 (m, 1H), 6.99-6.90 (m, 1H), 4.81 (s, 1H), 4.24 (s, 2H), 2.31-2.22 (m, 1H), 2.15-2.07 (m, 1H), 1.74-1.63 (m, 1H), 1.24-1.14 (m, 1H). LC-MS (Method J): m/z = 435.4 [M+Hf, 1.200 min.

[1051] Example 181B (second eluting isomer): ’HNMR (400 MHz, CD3OD-Î/4) δ 7.70 (s, 1H), 7.667.62 (m, 2H), 7.55-7.49 (m, 1H), 7.19-7.07 (m, 1H), 6.98-6.91 (m, 1H), 4.81 (s, 1H), 4.24 (s, 2H), 2.322.23 (m, 1H), 2.16-2.07 (m, 1H), 1.67-1.59 (m, 1H), 1.23-1.14 (m, 1H). LC-MS (Method V): m/z = 435.1 [M+H]⁺, 3.354 min.

379

Example 182A and 182B: (R)-4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3b]azepin-7-yl)-l-((2-methylpyridin-3-yl)methyI)-lH-pyrazole-3-carboxamide and (S)-4-fluoro-N-(5methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-l-((2-methyIpyridin-3-yl)methyl)lH-pyrazoIe-3-carboxamide

Step 1: Préparation of ethyl 4-fluoro-l-((2-methylpyridin-3-yl)methyl)-lH-pyrazole-3-carboxylate

[1052] 3-(Bromomethyl)-2-methylpyridine (283 mg, 1.52 mmol) was added to a stirring mixture of ethyl 4-fluoro-lH-pyrazole-3-carboxylate (200 mg, 1.27 mmol) and césium carbonate (1.24 g, 3.80 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred at room température for 3 hours, quenched by the addition of water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to afford the title compound (300 mg, 90.9%) as a white solid. LC-MS (Method C): m/z = 264.1 [M+H]⁺, 1.291 min.

Step 2: Préparation of 4-fluoro-l-((2-methylpyridin-3-yl)methyl)-lPI-pyrazole-3-carboxylic acid

[1053] Lithium hydroxide (82 mg, 3.42 mmol) was added to a mixture of ethyl 4-fluoro-l-((2-methyl pyridin-3-yl)methyl)-lH-pyrazole-3-carboxylate (300 mg, 1.14 mmol) in tetrahydrofuran (12 mL) and water (4 mL). The reaction mixture was stirred at room température ovemight. After removal of tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 6 with aqueous hydrochloric acid (1 N, 10 mL), and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under

380 vacuum to afford the title compound (220 mg crude) as a white solid. LC-MS (Method C): m/z = 236.0

[M+H]/ 0.365 min.

Step 3: Préparation of 4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-l((2-methylpyridin-3-yl) methyl)-lH-pyrazole-3-carboxamide

[1054] Tire crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield C18 OBD Column, 5 pm, 19x150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 20% B to 33% B over 8 min; UV 254 & 220 nm; Rt: 7.28 min to afford the title compound. LC-MS (Method Y): m/z = 410.2 [M+H]/ 0.841 min.

Step 4: Préparation of (R)-4fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7yl)-l-((2-methylpyridin-3-yl)methyl)-lH-pyrazole-3-carboxamide and (S)-4-fluoro-N-(5-methyl-6-oxo6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-l-((2-methylpyridin-3-yl)methyl)-lH-pyrazole-3carboxamide

[1055] The racemate of 4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7yl)-l-((2-methylpyridin-3-yI)mcthyl)-lH-pyrazole-3-carboxamidc (40 mg, 0.10 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50 B% to 50 B% over 13 min; UV 254 & 220 nm; Rt 1: 9.428 min; Rt 2: 11.106 min to afford the the title compounds:

[1056] Example 182A (first eluting isomer): ^!H NMR (400 MHz, CD3OD-Î/4) δ 8.49 (d, J= 2.8 Hz, 1H), 8.42-8.39 (m, 2H), 7.80 (d, J= 4.4 Hz, 1H), 7.51-7.48 (m, 1H), 7.33-7.29 (m, 1H), 5.45 (s, 2H), 4.58-4.53 (m, 1H), 3.50 (s, 3H), 3.18-3.08 (m, 1H), 3.04-2.98 (m, 1H), 2.81-2.70 (m, 1H), 2.58 (s, 3H),

2.42- 2.31 (m, 1H). LC-MS (Method D): m/z = 410.0 [M+H]/ 0.715 min.

[1057] Example 182B (second eluting isomer): 'H NMR (400 MHz, CDsOD-û/) δ 8.49 (d, J= 2.8 Hz, 1H), 8.42-8.39 (m, 2H), 7.80 (d, J= 4.4 Hz, 1H), 7.52-7.48 (m, 1H), 7.34-7.29 (m, 1H), 5.45 (s, 2H), 4.58-4.53 (m, 1H), 3.50 (s, 3H), 3.18-3.07 (m, 1H), 3.05-2.98 (m, 1H), 2.81-2.70 (m, 1H), 2.58 (s, 3H),

2.42- 2.30 (m, 1H). LC-MS (Method D): m/z = 410.0 [M+H]/ 0.720 min.

381

Example 183A and 183B: l-benzyl-4-fluoro-N-((laR,2R,8bS)-4-trideuteriomethyl-7(methylsulfonyl)-3-oxo-l,la,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-lH-pyrazole-3carboxamide and l-benzyl-4-fluoro-N-((laS,2S,8bR)-4-trideuteriomethyl-7-(metliylsulfonyl)-3-oxol,la,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-lH-pyrazole-3-carboxamide

Br₂, H₂SO₄₍ AcOH rt, o/n step 1

NaOH, DMSO

120 °C, o/n step 3

O

II ,S.

ONa

Cul, L-proline

step 5

Step 1: Préparation of7-bromo-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one

[1058] A solution of bromine (8 mL, 155 mmol) in acetic acid (100 mL) was added to a solution of 4,5-Dihydro-lH-benzo[b]azepin-2(3H)-one (10 g, 62 mmol) and sulfone acid (5 mL) in acetic acid (100 mL) dropwise at 0 °C. After stirring ovemight at room température, the reaction mixture was poured into

382 ice water (200 mL), neutralized with ammonium hydroxide (28%, 100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 99/1) to afford the title compound (11.5 g, 77%) as a colorless oil. LC-MS (Method C): m/z =240.0 [M+H]⁺, 1.152 min.

Step 2: Préparation of7-bromo-l-trideuteriomethyl-4, 5-dihydro-lH-benzo[b]azepin-2(3H)-one

[1059] Trideuterated iodomethane (5.9 g, 41 mmol) was added dropwise to a stirring mixture of 7bromo-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one (9 g, 38 mmol) and césium carbonate (13.4 g, 41 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred for 2 hours at room température, diluted with water (60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to afford the title compound (7.2 g, 75%) as a yellow solid. LC-MS (Method C): m/z =257.1 [M+H]⁺, 1.234 min.

Step 3: Préparation of l-trideuteriomethyl-7-(methylsulfonyl)-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one

[1060] Cuprous iodide (304 mg, 1.6 mmol) was added to a mixture of 7-bromo-1 -trideuteriomethyl4,5-dihydro-lH-benzo[b]azepin-2(3H)-one (4.1 g, 16 mmol), L-proline (368 mg, 3.2 mmol), sodium hydroxide (64 mg, 1.6 mmol) and sodium methanesuiphinate (8.16 g, 80 mmol) in dimethyl sulfoxide (20 mL) under nitrogen atmosphère. The reaction mixture was stirred ovemight at 120 °C. After cooling to room température, the reaction mixture was diluted with saturated aqueous ammonium chloride (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to afford the title compound (2.7 g, 66%) as a yellow solid. LC-MS (Method C): m/z =257.1 [M+H]⁺, 0.907 min.

Step 4: Préparation of 3-iodo-l-trldeuteriomethyl-7-(rnethylsulfonyl)-4,5-dihydro-lH-benzo[b]azepin2(3H)-one

[1061] N¹,N¹,N²,N²-tetramethylethane-l,2-diamine (3.8 g, 33 mmol) was added to a stirring mixture of l-trideuteriomethyl-7-(methylsulfonyl)-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one (2.7 g, 11 mmol) in dichloromethane (40 mL) at 0 °C, followed by the addition of iodotrimethylsilane (6.6 g, 33 mmol) dropwise over 30 minutes. After stirring for 1 hour at 0 °C, a solution of iodine (4.2 g, 16.5 mmol) in dichloromethane (100 mL) was added. The reaction mixture was stirred for 2 hours at 0 °C, quenched by the addition of aqueous sodium thiosulfate (5%, 60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane) to

383 afford the title compound (3.5 g, 88%) as a yellow solid. LC-MS (Method S): m/z = 382.9 [M+H]⁺, 0.826 min.

Step 5: Préparation of 1-trideuterated methyl-7-(methylsulfonyl)-lH-benzo[b]azepin-2(3H)-one

[1062] l,8-Diazabicyclo[5.4.0]undec-7-ene (3.8 g, 25.2 mmol) was added to a stirring mixture of 3iodo-1-trideuterated methyl-7-(methylsulfonyl)-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one (3.2 g, 8.4 mmol) in N,N-dimethylformamide (10 mL) at room température. The reaction mixture was stirred overnight at 80 °C, quenched by the addition of water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane) to afford the title compound (1.8 g, 85%) as a yellow solid. LC-MS (Method T): m/z = 255.2 [M+H]⁺, 0.698 min.

Step 6: Préparation of 4-trideuteriomethyl-7-(methylsulfonyl)-l,la,2,8btetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

[1063] 1-Methyl-1-nitrosourea (7.4 g, 70 mmol) was added to a solution of potassium hydroxide (14 g,

350 mmol) in water (21 mL) and ether (100 mL) at 0 °C. The resulting mixture was stirred for 1 hour at 0 °C and then the organic phase was separated to provide a solution of diazomethane in ether (100 mL). The solution of diazomethane (100 ml) was added to the mixture of l-trideuteriomethyl-7(methylsulfonyl)-lH-benzo[b]azepin-2(3H)-one (1.8 g, 7 mmol) in tetrahydrofuran (30 mL) dropwise, followed by addition of a mixture of palladium diacetate (158 mg, 0.7 mmol) in tetrahydrofuran (10 mL) dropwise at 0 °C. The reaction mixture was stirred overnight at room température. The solids were removed by filtration and the filtrate was concentrated under vacuum to afford the title compound (1.5 g crude) as a yellow oil. LC-MS (Method E): m/z = 268.9 [M+H]⁺, 0.757 min.

Step 7: Préparation of trans-2-iodo-4-trideuteriomethyl-7-(methylsulfonyl)-l,la,2,8btetrahydrobenzo [b]cyclopropa[d]azepin-3 (4H) -one

[1064] N¹.N¹,N²,N²-tctramethylcthanc-L2-diamine (1.95 g, 16.8 mmol) was added to a stirring mixture of 4-trideuteriomethyl-7-(methylsulfonyl)-l,la,2,8b-tetrahydrobenzo[b]cyclopropa [d]azepin3(4H)-one (1.5 g, 5.6 mmol) in dichloromethane (30 mL) at 0 °C, followed by the addition of iodotrimethylsilane (3.4 g, 16.8 mmol) dropwise over 30 minutes. After stirring for 1 hour at 0 °C, a solution of iodine (2.1 g, 8.4 mmol) in dichloromethane (50 mL) was added. The reaction mixture was stirred for 2 hours at 0 °C, quenched by the addition of aqueous sodium thiosulfate (5%, 40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (1.6 g crude) as a yellow oil. LC-MS (Method S): m/z = 394.9 [M+H]⁺, 0.892 min.

384

Step 8: Préparation of cis-2-azido-4-trideuteriomethyl-7-(methylsulfonyl)-l,la,2,8btetrahydrobenzofb]cyclopropa[d]azepin-3 (4H) -one

[1065] Sodium azide (390 mg, 6 mmol) was added to a stirring mixture of trans-2-iodo-4trideuteriometliyi-7-(methylsulfonyI)-l,la,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepm-3(4H)-one (1.6 g, 4 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred ovemight at room température, quenched with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the title compound (800 mg crude) as a yellow oil. LC-MS (Method S): m/z = 309.9 [M+H]⁺, 0.855 min.

Step 9: Préparation of cis-2-amino-4-trideuteriomethyl-7-(methylsulfonyl)-l,la,2,8btetrahydrobenzo [b]cyclopropa[d]azepin-3 (4H) -one

[1066] A solution of cis-2-azido-4-trideuteriomethyl-7-(methylsulfonyl)-l, la,2,8btetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (800 mg, 2.59 mmol) in methanol (30 mL) was hydrogenated in the presence of palladium on carbon (10%, 100 mg) under hydrogen atmosphère (2-3 atm). After stirring for 2 hours at room température under hydrogen atmosphère, the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum and the resulting residue was purified by column chromatography (dichloromethane) to afford the title compound (500 mg, 68%) as a yellow solid. LC-MS (Method F): m/z = 283.9 [M+H]⁺, 0.715 min.

Step 10: Préparation of l-benzyl-4-fluoro-N-(cis-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo1, la, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-lPl-pyrazole-3-carboxamide

[1067] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5 pm, 19 x 150 mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: MeCNFlow rate; 20 mL/min; Gradient: 32% B to 55% B over 8 min;

254 & 220 nm; Rt: 7.38 min to afford the title compound. LC-MS (Method E): m/z = 486.1 [M+H]⁺, 1.037 min.

Step 11: Préparation of l-benzyl-4-fluoro-N-((laR,2R,8bS)-4-trideuteriomethyl-7-(methylsulfonyl)-3oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl) -lH-pyrazole-3-carboxamide and 1 benzyl-4-fluoro-N-((laS,2S,8bR)-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-lH-pyrazole-3-carboxamide

[1068] The racemate of l-benzyl-4-fluoro-N-(cis-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo1, la,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-lH-pyrazole-3-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2.12 x 15 cm, 5 pm;

Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 22 min; 254 & 220 nm; Rtl: 10.61; Rt2: 16.166 to afford the title compounds:

385

[1069] Example 183A (first eluting isomer): ’HNMR (400 MHz, CD3OD-Î/4) δ 8.05 (d, J= 2.3 Hz,

1H), 7.86 (dd, J= 8.5, 2.3 Hz, 1H), 7.75 (d, J= 4.5 Hz, 1H), 7.53 (d, J= 8.5 Hz, 1H), 7.42-7.31 (m, 5H),

5.33 (s, 2H), 4.66 (s, 1H), 3.17 (s, 3H), 2.47-2.37 (m, 1H), 2.15-2.06 (m, 1H), 1.38-1.30 (m, 1H), 1.261.17 (m, 1H). LC-MS (Method V): m/z = 486.1 [M+H]⁺, 3.132 min.

[1070] Example 183B (second eluting isomer): ’H NMR (400 MHz, CD3OD-0/4) δ 8.05 (d, J= 2.3 Hz, 1H), 7.86 (dd, J= 8.5, 2.3 Hz, 1H), 7.76 (d, J= 4.5 Hz, 1H), 7.53 (d, J= 8.5 Hz, 1H), 7.43-7.30 (m, 5H), 5.33 (s, 2H), 4.66 (s, 1H), 3.17 (s, 3H), 2.47-2.37 (m, 1H), 2.15-2.07 (m, 1H), 1.37-1.31 (m, 1H), 1.281.17 (m, 1H). LC-MS (Method D): m/z = 486.1 [M+H]⁺, 1.390 min.

Example 184: (S)-4-fluoro-l-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

Cs₂CO₃, DMF, rt, 3h

[1071] Césium carbonate (453 mg, 1.39 mmol) was added to a stirring mixture of (S)-4-fluoro-N-(5methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [ 1,4]oxazepin-3 -yl)-1 H-pyrazole-3-carboxamide (100 mg, 0.33 mmol) and 4-(bromomethyl)-l-methyl-lH-pyrazole hydrochloride (208 mg, 0.82 mmol) inN.Ndimethylformamide (7 mL). After stirring for 3 hours at room température, the reaction mixture was quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column; Xbridge Prep C18, 5 pm, 19 x 150 mm; Mobile Phase A; Water (0.1 mmol/L NH4HCO3), Mobile Phase B; MeCN; Flow rate: 20 ml./min; Gradient: 15% B to 36% B over 10 min; UV 254 & 220 nm to afford the title compound: Ή NMR (300 MHz, DMSO4) δ 8.37 (dd, J= 4.8, 1.5 Hz, 1H), 8.22 (d, J= 7.5 Hz, 1H), 8.01 (d, J= 4.2 Hz, 1H), 7.75 (s, 1H), 7.71 (dd, J= 8.1, 1.5 Hz, 1H), 7.49 (s, 1H), 7.34 (dd, J= 8.1, 4.8 Hz, 1H), 5.19 (s, 2H), 4.91-4.81 (m, 1H), 4.69 (dd, J= 11.1, 9.6 Hz, 1H), 4.53 (dd, J= 9.6, 7.5 Hz, 1H), 3.82 (s, 3H), 3.37 (s, 3H). LC-MS (Method D): m/z = 400.0 [M+H]⁺, 1.357 min.

386

Example 188: (S)-5-benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7yl)isoxazole-3-carboxamide

step 1

[1072] The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1) to afford the racemate. LC-MS (Method E): m/z = 378.2 [M+H]⁺, 0.998min. The racemate of 5-benzyl-N-(5-methyl-6-oxo6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)isoxazole-3-carboxamide was separated by PrepChiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane: DCM = 5:1, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 20 min; UV 254 & 220 nm; Rtl: 11.1; Rt2: 15.01 to afford the title compound as the first eluting isomer: ’H NMR (400 MHz, CD₃OD-d₄) δ 8.48-8.35 (m, 2H), 7.35-7.23 (m, 5H), 6.38 (s, 1H), 4.48 (dd, J= 8.0, 12.0 Hz, 1H), 4.16 (s, 2H), 3.47 (s, 3H), 3.15-3.05 (m, 1H), 3.02-2.95 (m, 1H), 2.72-2.61 (m, 1H), 2.432.34 (m, 1H). LC-MS (Method D): m/z = 378.0 [M+H]⁺, 1.645 min.

Example 190: (S)-5-benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino]2,3b]azepin-7-yl)-l,3,4-oxadiazole-2-carboxamide

step 1

[1073] The residue was purified by Prep-TLC (ethyl acetate/hexane, 3/1) to afford the racemate. LCMS (Method C): m/z = 378.1 [M+H]⁺, 1.141min. The racemate of 5-benzyl-N-(5-methyl-6-oxo-6,7,8,9tetrahydro-5H- pyrazino[2,3-b]azepin-7-yl)-l,3,4-oxadiazole-2-carboxamide was separated by Prep

387

Chiral-HPLC with the following conditions: Column: CHIRALPAK IA 2 x 25 cm, 5 pm; Mobile Phase A: Hexane: DCM=5: 1, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 20 min; UV254 &220nm; Rtl: ll.l;Rt2: 15.01 toaffordthetitlecompoundasthefirst eluting isomer: ’H NMR (400 MHz, CD₃OD-7₄) δ 8.46 (d, J= 2.8 Hz, IH), 8.37 (d, J= 2.4 Hz, IH), 7.37-7.26 (m, 5H), 4.53 (dd, J= 12.0, 7.6 Hz, IH), 4.32 (s, 2H), 3.48 (s, 3H), 3.18-3.06 (m, IH), 3.03-2.97 (m, IH), 2.732.62 (m, IH), 2.49-2.39 (m, IH). LC-MS (Method J): m/z = 379.1 [M+H]⁺, 1.072 min.

Example 192: 5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)oxazoIe-2-carboxamide

[1074] The crude product obtained was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5 pm, 19 x 150 mm; Mobile Phase A: Water (O.I%NFLHC03), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 35% B to 66% B over 8 min; UV 254 & 220 nm; Rt: 6.98 min to afford the title compound. ’HNMR (400 MHz, CD3OD -dÀ) δ 8.34 (dd, 7= 4.8, 1.6 Hz, IH), 7.69 (dd, 7= 8.0, 1.6 Hz, IH), 7.38-7.22 (m, 6H), 7.04 (s, IH), 5.07-4.96 (m, 2H), 4.13 (s, 2H), 3.50 (s, 3H), 1.42 (d, J= 5.9 Hz, 3H). LC-MS (Method D): m/z = 393.1 [M+H]⁺, 1.524 min.

Example 193: 5-benzyl-N-((3S,4R)-l,4-dimethyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3b][l,4]oxazepin-3-yl)-l,3,4-oxadiazole-2-carboxamide

NH₂ HCl step 3

[1075] The crude product was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the title compound: ’HNMR (400 MHz, CDsOD-ôL) δ 8.22-8.19 (m, IH), 7.94-7.90 (m, IH), 7.43-7.39 (m, IH), 7.35-7.26 (m, 5H), 5.14-5.07 (m, 2H), 4.31 (s, 2H), 3.44 (s, 3H), 1.45 (d, 7= 6.0 Hz, 3H). LC-MS (Method T): m/z = 394.1 [M+H]⁺, 1.202 min.

388

Example 194: 5-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8ahexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)oxazole-2-carboxamide

step 1 chiral séparation step 2

[1076] The crude product was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the racemate. LC-MS (Method E): m/z = 390.2 [M+H]⁺, 1.018 min. The racemate of 5-benzyl-N-cis-5methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-oxazole-2-carboxamide (50 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 pm; Mobile Phase A: MTBE, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30 B to 30 B in 15 min; UV 254 & 220 nm; Rtl: 7.635; Rt2: 9.685 to afford the title compound as the first eluting isomer: ^TH NMR (400 MHz, CD3OD-Î/4) δ 8.45-8.40 (m, 2H), 7.397.23 (m, 5H), 7.04 (s, IH), 4.77 (s, IH), 4.14 (s, 2H), 3.42 (s, 3H), 2.67-2.59 (m, IH), 2.28-2.20 (m, IH), 1.57-1.50 (m, IH), 1.37-1.28 (m, IH). LC-MS (Method D): m/z = 390.1 [M+H]⁺, 1.361 min.

Example 195: l-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8ahexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-lH-l,2,3-triazole-4-carboxamide

[1077] The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1) to afford the racemate. LC-MS (Method E). m/z = 390.2 [M+H]⁺, 0.932min. The racemate of 5-benzyl-N-cis-5-methyl-6-oxo5,6,7,7a, 8,8a-hexahydro-cyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1 H-1,2,3-triazole-2-carboxamide (5 0

389 mg, 0.129 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column:

CHIRALPAK IA, 2.12 x 15 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: IP A; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 20 min; UV 254 & 220 nm; Rtl: 11.273; Rt2: 15.609 to afford the title compound as the first eluting isomer: ’H NMR (400 MHz, CD3OD-Î/4) δ 8.42-8.38 (m, 3H), 7.417.32 (m, 5H), 5.65 (s, 2H), 4.79 (s, 1H), 3.40 (s, 3H), 2.64-2.57 (m, 1H), 2.26-2.20 (m, 1H), 1.54-1.49 (m, 1H), 1.33-1.26 (m, 1H). LC-MS (Method J): m/z = 390.1 [M+H]⁺, 1.162 min.

Example 197: 5-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8ahexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)isoxazole-3-carboxamide

[1078] The crade product was purified by Prep-TLC (ethyl acetate/hexane, 3/1) to afford the racemate. LC-MS (Method E): m/z = 390.2 [M+H]⁺, 1.072min. The racemate of 5-benzyl-N-cis-5-methyl-6-oxo5,6,7,7a,8,8a-hexahydro-cyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-isoxazole-2-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane : DCM= 5: 1, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 24 min; UV 254 & 220 nm; Rtl: 15.4 ; Rt2: 19.4 to afford the title compound as the first eluting isomer: ’HNMR (400 MHz, CD3OD-Î/4) δ 8.42-8.38 (m, 2H), 7.36-7.24 (m, 5H), 6.44 (s, 1H), 4.76 (s, 1H), 4.18 (s, 2H), 3.57 (s, 3H), 2.64-2.57 (m, 1H), 2.24-2.17 (m, 1H), 1.53-1.48 (m, 1H), 1.32-1.26 (m, 1H). LC-MS (Method D): m/z = 390.0 [M+H]⁺, 1.747 min.

390

Example 198: 5-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8ahexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-l,3,4-thiadiazole-2-carboxamide

[1079] The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1) to afford tire racemate. LC-MS (Method E): m/z = 407.1 [M+H]⁺, 1.017min.

[1080] The racemate of 5-benzyl-N-(cis-5-methyl-6-oxo-5,6,7,7a,8,8ahexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-l,3,4-thiadiazole-2-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak ID-2,2 x25 cm. 5 pm; Mobile Phase A: MTBE, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 26 min; UV 254 & 220 nm; Rtl: 19.418; Rt2: 22.874 to afford the title compound as the first eluting isomer: ’H NMR (400 MHz, CD3OD-Û4) δ 8.41-8.37 (m, 2H), 7.38-7.26 (m, 5H), 4.77 (s, IH), 4.51 (s, 2H), 3.48 (s, 3H), 2.65-2.58 (m, IH), 2.28-2.22 (m, IH), 1.56-1.50 (m, IH), 1.34-1.27 (m, IH). LC-MS (Method D): m/z = 407.1 [M+H]⁺, 1.680 min.

Example 200: (S)-5-benzyl-N-(2,4-dimethyI-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6yl)-l,3,4-oxadiazole-2-carboxamide

step 1 step 2 chiral seperation

391

[1081] The crude product was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the racemate. LC-MS (Method D): m/z = 398.10 [M+H]⁺, 1.284 min. The racemate of 5-benzyl-N-(2,4dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-l,3,4-oxadiazole-2-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CFHRALPAK IA, 2.12 x 15 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 13 min; UV 220 & 254 nm; Rtl: 7.88; Rt2: 10.109 to afford the title compound as the first eluting isomer: Ή NMR (400 MHz, CD₃OD-ri₄) δ 7.41-7.24 (m, 5H), 4.65 (dd, J= 11.5, 6.7 Hz, 1H), 4.33 (s, 2H), 3.36 (s, 3H), 3.06-2.84 (m, 2H), 2.72-2.54 (m, 4H), 2.46-2.33 (m, 1H). LC-MS (Method D): m/z = 398.10 [M+H]⁺, 1.283min.

Example 201 : (S)-l-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-lH-l,2,3-triazole-4-carboxamide

EDCI, HOBT, DIEA

DMF, rt, 2 h

[1082] The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 2/1) to afford tire title compound: Ή NMR (400 MHz, CD₃OD -d₄) δ 8.41-8.33 (m, 2H), 7.68 (dd, J= 8.1, 1.6 Hz, 1H), 7.45-7.28 (m, 6H), 5.66 (s, 2H), 5.04 (dd, J =11.6, 7.2 Hz, 1H), 4.69 (dd, J= 9.9, 7.2 Hz, 1H), 4.54 (dd, J= 11.6, 9.8 Hz, 1H), 3.49 (s, 3H). LC-MS (Method D): m/z = 379.1 [M+H]⁺, 1.239 mm.

Example 203: l-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-lH-l,2,3-triazole-4-carboxamide

[1083] The crude product was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5 pm, 19 x 150 mm; Mobile Phase A: Water (0.1%ΝΗΤΚΌ₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 66% B over 8 min; UV 254 & 220 nm; Rt: 6.68 min to afford the title compound. Ή NMR (300 MHz, CD₃OD-ri₄) δ 8.27 (s, 1H), 8.23-8.20 (m, 1H), 7.56 (dd, J= 8.0, 1.6 Hz, 1H), 7.29-7.17 (m, 6H), 5.54 (s, 2H), 4.97-4.85 (m, 2H), 3.38 (s, 3H), 1.31 (d, J= 6.2 Hz, 3H). LCMS (Method Q): m/z = 393.2 [M+H]⁺, 1.354 min.

392

Example 204: 2-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [l,4]oxazepin-3-yl)-2H-l,2,3-triazoIe-4-carboxamide

[1084] The crude product was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5 pm, 19 x 150 mm; Mobile Phase A: Water (OJkiNHHCCL). Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 35 % B to 72 % B over 8 min; UV 254 & 220 nm; Rt: 5.95 min to afford the title compound. Ή NMR (300 MHz, CD₃OD-J₄) δ 8.32 (dd, J= 4.7, 1.5 Hz, 1H), 8.06 (s, 1H), 7.68 (dd, J= 8.0, 1.6 Hz, 1H), 7.40-7.27 (m, 6H), 5.70 (s, 2H), 5.09-4.97 (m, 2H), 3.49 (s, 3H), 1.41 (d, J= 6.1 Hz, 3H). LC-MS (Method D): m/z = 393.10 [M+H]⁺, 1.479 min.

Example 205: l-benzyl-N-((3S,4R)-l-trideuteriomethyI-4-methyi-2-oxo-l,2,3,4tetrahydropyrido [2,3-b] [1,4] oxazepin-3-yl)-4-fluoro-l H-pyrazoIe-3-carboxamide

Pd/C, H₂

MeOH, rt, o/n

step 2

SOCI₂(1 eq.) DMF

MeOH, rt, 5 h step 3

AIMe₃ in toluene

60°C, o/n step 4

Cs₂CO₃, CD₃I, DMF

0°C to rt, o/n step 5

393

EDCI, HOBT, DIEA, DMF rt, o/n

step 7

[1085] The crude product was purified by Prep-HPLC with the following conditions: Column: Kinetex 5 pm EVO C18 OBD Column, 21.2 x 150 mm, 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 30% B to 60% B over 8 min; UV 254 & 220 nm; Rt: 7.52 min to afford the title compound: 'H NMR (400 MHz, CD3OD-Î/4) δ 8.23 (dd, J= 4.8, 1.6 Hz, 1H), 7.94 (dd, J= 8.0, 2.0 Hz, 1H), 7.77 (d, J= 4.4 Hz, 1H), 7.46-7.32 (m, 6H), 5.35 (s, 2H), 5.185.07 (m, 2H), 1.45 (d, J= 6.0 Hz, 3H). LC-MS (Method O): m/z = 413.2 [M+H]⁺, 1.472 min.

Example 206: l-benzyl-N-((laS,2S,8bR)-7-cyano-4-trideuteriomethyl-3-oxo-l,la,2,3,4,8bhexahydrobenzo[b]cydopropa[d]azepin-2-yl)-4-fluoro-lH-pyrazole-3-carboxamide

d₃ç 0 zP Zn(CN)₂, Pd(PPh₃)₄	D₃Ç	zP TMEDA, TMSI, l₂
	J / DMF, MW, 140°C, 3 h II		/ 0°C, 3 h
Br	—J NC
	step 1		step 2

DBU °C, o/n step 3

1) KOH(40% aq.), Et₂O, 0°C, 1h

2) Pd(OAc)₂, THF, 0°C, 1h

TMEDA, TMSI, l₂

0°C, 3 h step 5 step 4

394

[1086] The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1) to afford the racemate. LC-MS (Method C): m/z = 433.1 [M+H]⁺, 1.078 min. The racemate of l-benzyl-N-(cis-7-cyano-4trideuteriomethyl-3-oxo-l,la,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4-fluoro-lHpyrazole-3-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CH IRA LP AK IA, 2.12 x 15 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 18 min; UV 254 & 220 nm; Rtl: 8.283; Rt2: 14.011 to afford the title compound as the second eluting isomer: ’H NMR (400 MHz, OMSOA) δ 8.15 (d, J= 4.4 Hz, 1H), 8.09 (d, J= 6.8 Hz, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.77 (dd, J= 8.4, 2.0 Hz, 1H), 7.45 (d, J= 8.4 Hz, 1H), 7.41-7.28 (m, 5H), 5.35 (s, 2H), 4.46 (d, J= 6.8 Hz, 1H ), 2.39-2.32 (m, 1H), 2.03-1.96 (m, 1H), 1.19-1.14 (m, 1H), 1.12-1.08 (m, 1H). LC-MS (Method D): m/z = 433.2 [M+H]⁺, 1.321 min.

Example 209: (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,S-tetrahydropyrido[3,2-b] [l,4]oxazepin3-yl)-l-(oxazol-4-ylmethyI)-lH-pyrazole-3-carboxamide

PBr₃, DCM rt,o/n step 1

Cs₂CO₃, DMF, rt, 3 h step 2

[1087] The crude product was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18; 19 x 150 mm; 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/ min; Gradient: 21% B to 25 % B over 10 min; UV 254 & 220 nm to afford the title compound: ’H NMR (300 MHz, DMSO-t/β) δ 8.40 (d, J= 0.6 Hz, 1H), 8.36 (dd, J= 4.8,1.5 Hz, 1H), 8.23 (d, J= 7.8 Hz, 1H), 8.19 (d, J= 0.9 Ηζ,ΙΗ), 8.04 (d, J= 4.5 Ηζ,ΙΗ), 7.70 (dd, J= 7.8, 1.5 Hz, 1H), 7.33 (dd, J= 8.1, 4.8 Hz, 1H), 5.28 (s, 2H), 4.89-4.78 (m, 1H), 4.67 (dd, J= 11.4, 9.9 Hz, 1H), 4.50 (dd, J= 9.6, 7.5 Hz, 1H), 3.35 (s, 3H). LC-MS (Method T): m/z = 387.2 [M+H]⁺, 0.973 min.

395

Example 213: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-5-(pyridin2-ylmethyl)thiazole-2-carboxamide

EDCI, HOBT, DIEA

DMF, rt, 16 h step 2

[1088] The title compound was prepared according to the methods described herein using the appropriate starting material. The crude product was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the title compound: ’H NMR (400 MHz, CD3OD-0/4) δ 8.51-8.48 (m, IH), 8.33 (dd, J = 4.8, 1.6 Hz, IH), 7.84-7.77 (m, 2H), 7.66 (dd, J= 8.0, 1.6 Hz, IH), 7.44-7.38 (m, IH), 7.34-7.27 (m, 2H), 4.97 (dd, J= 11.5, 7.2 Hz, IH), 4.67 (dd, J= 9.9, 7.2 Hz, IH), 4.52 (dd, 7= 11.5, 9.9 Hz, IH), 4.40 (s, 2H), 3.47 (s, 3H). LC-MS (Method D): m/z = 396.0 [M+H]⁺, 1.786 min.

Example 214: (S)-4-fluoro-l-((5-fluoropyridin-2-yl)methyl)-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yI)-lH-pyrazole-3-carboxamide

[1089] The crude product was purified by Prep-HPLC with the following conditions: Column. Gemini-NX/5u, C18 150 x 21.2 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 45% B to 50% B over 8 min; UV 254 & 220 nm; Rt: 7.33 to afford the title compound: ’H NMR (300 MHz, CD3OD-Î/4) δ 8.45 (d, 7= 3.0 Hz, IH), 7.84 (d, 7= 4.5 Hz, IH), 7.65-7.58 (m, IH), 7.44-7.20 (m, 5H), 5.43 (s, 2H), 4.97 (dd, 7= 11.4, 7.5 Hz, IH), 4.56 (dd, 7

396 = 9.9, 7.5 Hz, 1H), 4.37 (dd, J= 11.4, 9.9 Hz, 1H), 3.41 (s, 3H). LC-MS (Method D): m/z = 414.1

[M+H]⁺, 1.579 min.

Example 215: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)l,2,4-oxadiazole-3-carboxamide

[1090] The residue was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5 pm, 19 x 150 mm; Mobile Phase A: Water (O.^NHjHCOs), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 30 % B to 60 % B over 8 min; UV 254 & 220 nm; Rt: 6.65 min to afford the title compound: ’H NMR (300 MHz, CD₃OD-7fr δ 8.36-8.31 (m, 1H), 7.69-7.63 (m, 1H), 7.40-7.26 (m, 6H), 5.07-4.97 (m, 1H), 4.71-4.62 (m, 1H), 4.60-4.49 (s, 1H), 4.38 (s, 2H), 3.47 (s, 3H). LC-MS (Method D): m/z = 380.1 [M+H]⁺, 1.322 min.

Example 216: (S)-l-((5-chIoropyridin-2-yI)methyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

EDCI, HOBT, D1EA, DMF rt, o/n step 1

step 2 step 3

397

[1091] The residue was purified by Prep-HPLC with the following conditions: Column: GeminiNX/5u, C18 150 x 21.2 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN;

Flow rate: 20 mL/min; Gradient: 40% B to 55% B over 8 min; UV 254 & 220 nm; Rt: 6.73 min to afford the title compound: Ή NMR (300 MHz, CD3ODY) δ 8.51 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.4, 3.6 Hz, 2H), 7.42-7.35 (m, 1H), 7.32-7.17 (m, 4H), 5.40 (s, 2H), 4.94 (dd, 7= 11.4, 7.5 Hz, 1H), 4.54 (dd, 7 = 9.9, 7.5 Hz, 1H), 4.34 (dd, 7= 11.7, 10.2 Hz, 1H), 3.37 (s, 3H). LC-MS (Method D): m/z = 430.1 [M+H]⁺, 1.673 min.

Example 217: 5-benzyI-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yI)-l,3,4-thiadiazole-2-carboxamide

[1092] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: Gemini-NX/5u, C18 150 x 21.2 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 55% B to 80% B over 6 min; UV 254 & 220 nm; Rt: 4.60 min to afford the title compound. ^!H NMR (300 MHz, CD3ODY) δ 8.34-8.25 (m, 1H), 7.70-7.66 (m, 1H), 7.39-7.25 (m, 6H), 5.11-4.96 (m, 2H), 4.51 (s, 2H), 3.50 (s, 3H), 1.42 (d, 7= 6.0 Hz, 3H). LC-MS (Method D): m/z = 410.0 [M+H]⁺, 1.725 min.

Example 218: 5-benzyl-N-((laS,2S,8bR)-7-cyano-4-methyl-3-oxo-l,la,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-l,2,4-triazole-3-carboxamide

398

step 11

[1093] The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1) to afford the racemate. LC-MS (Method D): m/z = 414.1 [M+H]/ 1.222 min. The racemate of 5-benzyl-N-(cis-7-cyano-4methyl-3-oxo-1, la, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-l,2,4-triazole-3carboxamide was separated was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 pm; Mobile Phase A: MTBE, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 20% B to 20% B over 16 min; UV 254 & 220 nm; Rtl: 7.89: Rt2: 8.598 to afford the title compound as the second eluting isomer: ³H NMR (400 MHz, CDsOD-dft δ 8.71 ( d, J= 2.4 Hz, 1H), 8.32 (d, J= 2.0 Hz, 1H), 7.37-7.25 (m, 5H), 4.73 (s, 1H), 4.20 (s, 2H), 3.44 (s, 3H), 2.402.33 (m, 1H), 2.21-2.14 (m, 1H), 1.46-1.41 (m, 1H), 1.34-1.26 (m, 1H). LC-MS (Method D): m/z = 414.1 [M+H]/ 1.221 min.

Example 219: (S)-5-(3-cyanobenzyi)-N-(9-methyI-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)thiazole-2-carboxamide

step 1

399

[1094] The crude product obtained using Amide Coupling Procedure C was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the racemate. LC-MS (Method S): m/z = 418.1 [M+H]⁺, 1.025 min. The racemate of 5-(3-cyanobenzyl)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)thiazole-2-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: (R,R)Whelk-01, 21.1 x 250 mm, 5 pm; Mobile Phase A: Hexane: Dichloromethane = 4.5: 1, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 70% B to 70% B over 23 min; UV 254 & 220 nm; Rtl: 12.88; Rt2: 18.81 to afford the title compound as the first eluting isomer: ^JH NMR (400 MHz, CD3OD-J4) δ 8.44 (dd, J= 4.8, 1.6 Hz, 1H), 7.81 (dd, J= 7.6, 1.6 Hz, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.66-7.61 (m, 2H), 7.55-7.51 (m, 1H), 7.31-7.27 (m, 1H), 4.52-4.46 (m, 1H), 4.35 (s, 2H), 3.48 (s, 3H), 2.94-2.79 (m, 2H) 2.69-2.58 (m, 1H), 2.34-2.24 (m, 1H). LC-MS (Method D): m/z = 418.0 [M+H]⁺, 1.716 min.

Example 220: (S)-4-fluoro-l-((6-methoxypyridin-2-yI)methyl)-N-(5-methyI-4-oxo-2,3,4,5tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-pyrazole-3-carboxamide

rt, o/n

PBr₃, DCM

K₂CO₃ , DMF, 25 °C, 3 h step 1 step 2

[1095] The crude product was purified by Prep-HPLC with the following conditions: Column: Gemini-NX/5u, C18 150 x 21.2 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 40% B to 50% B over 8 min; UV 254 & 220 nm; Rt: 8.07 min to afford the title compound. 'H NMR (300 MHz, CD3OD-Î/4) δ 7.85 (d, / = 4.5 Hz, 1H), 7.63 (dd, J= 8.1,7.2 Hz, 1H), 7.43-7.40 (m, 1H), 7.39-7.20 (m, 3H), 6.78 (d, J= 7.2, 1H), 6.71 (d,J=8.4, 1H), 5.32 (s, 2H), 4.98 (dd, J= 11.4, 7.5 Hz, 1H), 4.58 (dd, J = 9.9, 7.5 Hz, 1H), 4.37 (dd, J= 11.4, 9.9 Hz, 1H), 3.86 (s, 3H), 3.40 (s, 3H). LC-MS (Method D): m/z = 426.2 [M+H]⁺, 1.755 min.

400

Example 221: 5-(difluoro(phenyI)methyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b] [l,4]oxazepin-3-yI)-l,3,4-oxadiazole-2-carboxamide

CrO₃, AcOH °C, 2 h step 1

BAST °C, o/n step 2

AIMe₃ in toluene, 50 °C, o/n

step 3

[1096] The crude product was purified by Prep-HPLC with the following conditions: Column: Gemini-NX/5u, C18 150 x 21.2 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 47% B to 60% B over 10 min; UV 254 & 220 nm; Rt: 8.82 min to afford the title compound. ’HNMR (300 MHz, CD₃OD-î/₄) δ 8.33 (dd, J = 4.8, 1.8 Hz, 1H), 7.69-7.66 (m, 3H), 7.62-7.53 (m, 3H), 7.32 (dd, 8.1, 4.8 Hz, 1H), 5.08-4.93 (m, 2H), 3.50 (s, 3H), 1.44 (d, J = 6.3 Hz, 3 H). LC-MS (Method O): m/z = 430.1 [M+H]⁺, 1.679 min.

Example 222: 5-benzyl-N-((2R,3S)-2,5-dimethyI-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][l,4]oxazepin-3-yl)-l,2,4-oxadiazole-3-carboxamide

[1097] The crude product was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5 pm, 19 x 150 mm; Mobile Phase A: Water (0.1 % NH4HCO3), Mobile Phase B: MeCN;

Flow rate: 20 mL/min; Gradient: 40 % B to 70 % B over 8 min; UV 254 & 220 nm; Rt: 5.87 min to afford the title compound. Ή NMR (300 MHz, CD₃ODte₄) δ 8.35-8.31 (m, 1H), 7.71-7.66 (m, 1H), 7.417.27 (m, 6H), 5.10-4.97 (m, 2H) 4.39 (s, 2H), 3.49 (s, 3H), 1.40 (d, J= 6.2 Hz, 3H). LC-MS (Method D). m/z = 394.1 [M+H]⁺, 2.709 min.

401

Example 223: 5-(4-fluorobenzyI)-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8ahexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-l,3,4-oxadiazoIe-2-carboxamide

H,N„ „Boc r- ² N H T	H H
EDCI, HOBT, DIEA	îX A -/ N Boc
DMF, rt, o/n	H

step 1

	η o
4 N HCl in dioxane y	AA ,nh₂hci N H
rt, 2 h
step 2

step 6 chiral séparation step 7

[1098] The crude product was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the racemate. LC-MS (Method D): m/z = 409.05 [M+H]⁺, 1.255min. The racemate of 5-(4-fluorobenzyl)-Ncis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazmo[2,3-b]azepin-7-yl)-l,3,4-oxadiazole2-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2 x 25 cm, 5 pm; Mobile Phase A: MTBE, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 16 min; UV 254 & 220 nm; Rtl: 10.514 ; Rt2: 13.482 to afford the title compound as the first eluting isomer: *H NMR (400 MHz, CDCL-ri) δ 8.49-8.32 (m, 3H), 7.397.28 (m, 2H), 7.14-6.94 (m, 2H), 4.85 (d, J= 7.0 Hz, 1H), 4.25 (s, 2H), 3.45 (s, 3H), 2.71-2.62 (m, 1H), 2.30-2.21 (m, 1H), 1.57-1.50 (m, 1H), 1.30-1.22 (m, 1H). LC-MS (Method AQ: m/z = 409.05 [M+H]⁺, 2.450 min.

402

Example 224: (S)-4-fluoro-N-(5-methyI-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-l(pyrimidin-2-y!methyl)-lH-pyrazole-3-carboxamide

[1099] The crude product was purified by the Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5 pm, 19 x 150 mm; Mobile Phase A: Water (0.1% NFLHCCL), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 16 % B to 43% B over 8 min; UV 254 & 220 nm; Rt: 7.47 min to afford the title compound. ’HNMR (300 MHz, CD3OD-0/4) δ 8.81-8.77 (m, 2H), 7.91-7.87 (m, IH), 7.48-7.41 (m, 2H), 7.38-7.21 (m, 3H), 5.58 (s, 2H), 5.03-4.95 (m, IH), 4.62-4.56 (m, IH), 4.43-4.34 (m, IH), 3.42 (s, 3H). LC-MS (Method D): m/z = 397.0 [M+H]⁺, 2.334 min.

Example 225: (S)-5-benzyl-N-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] azepin-3-yl)l,3,4-oxadiazole-2-carboxamide

[1100] ’H NMR (300 MHz, CD3OD -ri₄) δ 7.47-7.18 (m, 9H), 4.47 (dd, 7= 11.7, 7.9 Hz, IH), 4.31 (s, 2H), 3.40 (s, 3H), 2.93-2.82 (m, IH), 2.73 (dd, J= 13.6, 6.8 Hz, IH), 2.52-2.43 (m, IH), 2.33-2.21 (m, IH). LC-MS (Method D): m/z = 377.0 [M+H]⁺, 1.732 min.

[1101] The other compounds of Table 1 were, or can be, prepared according to the Examples above and/or general procedures described herein using the approporiate starting materials.

Biological Assays

[1102] Compounds were tested for binding and cellular kinase activity according to the following protocols. proGST-hRIPKl (8-327) enzyme was generated by Proteros GmbH by Baculovirus expression System.

[1103] The cellular necroptosis assay (Cell IC50 in Tables 5-7) évaluâtes the ability of compounds to reverse the necrosis induced by human TNFa. Ten concentrations of the test compounds were assessed in duplicate in two different test occasions. FADD-deficient Jurkat cells were purchased from ATCC (ATCC-CRL-2572) and cultured in suspension in RPMI medium supplemented with 10% heat inactivated of FBS and 1% Pen-Strep. The day of the experiment cells were diluted to a density of

403

0.12xl0⁵ cells/mL (5,000 cells/well) with culture medium and added (40 pL) into the 384-well plate containing 0.2 pL/well of test compounds and reference compounds (CRCs) (200x). Cell plates were then incubated at 37°C -5% CO₂. After 30 min, necroptotic cell death was induced with human TNFa (10 ng/mL) and cell viability was evaluated 48h later by measuring cellular ATP levels using CellTiter-Glo® kit (Promega). Luminescence was read by using Victor V (Perkin Elmer) multilabel plate reader. Data were expressed as % of max viability calculated comparing the values to TNFa untreated control cells which represents 100% of cell viability. CRCs were analyscd by Dotmatics and IC50 values were calculated by non-linear régression using 4 parameter-logistic équation.

[1104] Fluorescent Polarization Binding (FP Binding) assay (Berger S.B. et al. (2015) Cell Death Discovery, 1: 15009; Maki J.L. et al. (2012) Anal Biochem., 427(2): 164-174) was performed in polystyrène low volume 384-weil black plate, at Room Température (RT) in a final volume of 10.1 μΙ/well using 10 nM of GST-hRIPKl (8-327) enzyme and 5 nM of fluorescent-labeled ligand (14-(2-{[3({2-{[4-(cyanomethyl)phenyl]amino}-6-[(5-cyclopropyl-lH-pyrazol-3-yl)amino]-4-pyrimidinyl}amino) propyl]amino} -2-oxoethyI)-16,16,18,18-tetramethyl-6,7,7a,8a,9,10,16,18-octahydrobenzo [2”,3”]indolizino[8”,7”:5',6']pyrano [3',2':3,4]pyrido[l,2-a]indol-5-ium-2-sulfonate.

[1105] Test Compounds were serially diluted in DMSO at 100 fold final concentrations in the assay (1% DMSO final). In each well of a 384-well Plate were dispensed 0.1 pL of compound solution (or DMSO for contrais) followed by 5 pL of GST-hRIPKl (8-327) at twice the final concentrations in assay buffer (50 mM HEPES pH 7.5, 10 mM NaCI, 50 mM MgCl₂, 0.02% CHAPS, 0.5 mM DIT and 0.01% Pluronic F127). For négative control the enzyme addition was replaced by assay buffer only.

[1106] After addition of 5 pL of fluorescent-labeled ligand at twice the final concentrations in assay buffer, the plate was incubated at RT for 30 min. At the end, the binding was measured as FP value with the Envision (PerkinElmer) plate reader using fîlter for an excitation λ = 531 nm FP and an émission λ = 595 nm FP (S & P-pol).

[1107] GST-hRIPKl (8-327) enzyme was generated by Proteros GmbH by Baculovirus expression system.

[1108] Test compounds were diluted in DMSO and 0.1 pL of solution was dispensed to each well of a 384-well white solid microplate. The assay buffer was 50 mM HEPES pH 7.5, 50 mM NaCI, 30 mM MgCl₂. The buffer was supplemented with 0.02% CHAPS, 0.01% of Pluronic F127, 0.1 mg/mL BSA and 1 mM DTT. MnCl₂, 5 mM, was included in tire assay buffer on the day of the experiment. The enzymatic reaction comprised 1.5 pg/mL GST-hRIPKl (8-327) and 50 pM ATP for receptor interacting protein kinase 1 and 15 pM ATP. 5 pL of enzyme and 5 pL of ATP were added to the plate at twice the final assay concentration and incubated at room température for 3 hours. Following this reaction, 10 pL of ADP-Glo reagent (Promega) was added to each well and incubated for 40 min at room température. This stops the kinase reaction and depletes any remaining ATP. 20 pL of ADP-Glo

404 détection reagent was then added to each well and incubated at room température for at least 15 minutes. The détection reagent couverts ADP to ATP and introduces luciferase and luciferin to detect ATP. The luminescence is then measured with the Envision (PerkinElmer) plate reader. Test compound inhibition was expressed as percent inhibition of internai assay controls. For concentration response curves, normalized data is fit and IC50 determined using XL-fit (IDBS) for Excel. The IC50 were averaged to détermine a mean value, for a minimum of two independent experiments.

[1109] Test compound inhibition was expressed as percent inhibition of internai assay controls. For concentration response curves, normalized data is fit and IC50 determined using XL-fit (IDBS) for Excel. The IC50 were averaged to détermine a mean value, for a minimum of two independent experiments.

[1110] receptor-interacting protein kinase 1 cellular activity and binding of exemplary compounds was determined according to the above general procedure. Results are summarized in Table 5. In the table below, activity is provided as follows: +++ = 0.0001 pM < IC50 < 1 pM; ++ = 1 pM < IC50 < 10 pM; + = 10 pM < IC50; ++* = 3 pM < IC50.

Table 5

Compound	FP IC₅₀ (pM)	ADP IC₅₀ (μΜ)	Cell IC₅₀ (μΜ)
IA	+++		+++
IB	+++
2	+++	+++	+++
2A	+++		+++
2B	+++		+++
3	+++		1 ! ί
4	+++		+++
5	+++		+++
6	++-h		+++
7	+++		+++
7A	+++		+++
7B	+		++
8	+++		i 1 1
9	+++		+++
10	+++		+++
11	+++		+++
HA	+++		+++

Compound	FP IC50 (μΜ)	ADP IC₅₀(μΜ)	Cell IC₅₀ (μΜ)
11B	++		+++
12	+++		+++
12A	+++		+++
12B	+++		+++
13	+++
14	+++
15		+
16		+
17		+
18		+
19		++
20		++
21		+
22		+
23		+
24		+
25		+

405

Compound	FP IC₅o (μΜ)	ADP IC₅₀(μΜ)	Cell IC₅₀ (μΜ)
26		+
27		+
30	+++		+++
32	+++		+++
33	+
35	+++		+++
38A	+++		+++
38B	++*
41	+++		+++
42	+++		+++
43	++
44	+++		+++
45	+++		+++
46A	+++		+++
46B	++*
49	++
50A	+++
50B	++
51	+++		+++
52	+++		+++
54A	+++		+++
54B	+++		+++
55	+++		+++
56	+++		+++
57	+++		+++
58	+++		+++
59	+++		1 ++
60
60A	+++		+++
60B	++*
61	+++		+++
62	+++		+++
63	+++		+++

Compound	FP ICso (μΜ)	ADP IC₅₀(μΜ)	Cell IC₅o (μΜ)
64	+++		+++
65		+
66	+++		+++
67A	+++
67B	++*
68A	+++		+++
68B	++*
69A	+++		+++
69B	++*
70A	+++		+++
70B	++*
71A	+++		+++
71B	++*
72	+++		+++
73	+++		+++
74	+++		+++
75A	+++		+++
75B	++*
76	+++		+++
77	+++		[ } \|
78	+++		+++
79	+++		+++
80A	+++		+++
80B	++*
81A	+++		+++
81B	++*
82A	+++		+++
82B	++*
83A	+++		+++
83B	++
84	+++		+++
85	+++		+++
86	+++		+++

406

Compound	FP ICso (μΜ)	ADP IC₅₀(μΜ)	Cell IC_S0 (μΜ)
87	+++
88	++*		++
89A	++
89B	+++		+++
90A	++
90B	+++		+++
91	_\|—[—j-
92	+++		+++
93	+++
94	+++		+++
95	++*
96	+++		+++
98A	++*
98B	+++
99	++		+++
100A	+++		+++
100B	+++
101A	++*
101B	+++		+++
102A	++
102B	+++
103A	++*
103B	+++		+++
104 A	++*
104B	+++
105A	+++		+++
105B	++*
106	+++
107A	++*
107B	+++		+++
108	+++
109A	+++		+++
109B	\| \| *

Compound	FP IC₅o (μΜ)	ADP IC₅₀(μΜ)	Cell ICso (μΜ)
110A	++*
110B	+++		+++
111A	++
111B	+++		+++
112	+++		+++
113	+++
114A	+++		+++
114B	\| \| &
115	+++		+++
116	+++		+++
117	+++		+++
118A	++*
118B	++
119A	++*
119B	+++		+++
120A	+++		+++
120B	++*
121A	++*
121B	+++
122	+++		1 1 \|
123	+++		H—H-
124	+++		+++
125A	++*
125B	+++		+++
126	+++		+++
127	+++
128	+++		+++
129A	+++
129B	++*
130	+++		+++
131A	-H—h
131B	++*
132	+++		1--1--+

407

Compound	FP ICso (μΜ)	ADP IC_S#(μΜ)	Cell ICso (pM)
133	-HH-		+++
134	-H-+		+++
135	+++		+++
136	+++		+++
137	+++		+++
138	+++		+++
139	-H-+		1 \| ·\|
140	+++		+++
141A	++*
141B	+++
142	+++		+++
143	+++		+++
144	+++		+++
145A	+++		+-H-
145B	++*
146	+++		+-H-
147	+++		+++
148A	+++		+++
148B	++
149	+++		-H-H-
150	+++		+++
151	+++		+++
152A	++*
152B	+++		-H-+
153	+++		-HH-
154A	++*
154B	+++		1 I 1·
155	+++
156A	++*
156B	+++		+-H-
157A	++*
157B	+++		H—H-
158	+++		1 1 1

Compound	FP ICso (μΜ)	ADP ICso (pM)	Cell IC₅₀ (pM)
159	+++
160A	+++		+++
160B	++*
161	+++		+++
162	+++		+++
163	+++		+++
164	i \| \|		+-H-
165	+++		+++
166	-H-+		+++
167	-H-H		+++
168	+++		+++
169	+++		+++
170A	+++		+++
170B	++*
171	+++		+++
172	+++		+++
173	+++		+++
174	+++		+++
175	+++		+++
176	+++
177A	+++		-HH-
177B	++*
178A	+++		+++
178B	++*
179A	+++		+++
179B	++*
180A	+++		+++
180B	++*
181A	++*
181B	+++		+++
182A	++*
182B	+++		+++
183A	++*

408

Compound	FP ICso (μΜ)	ADP IC₅₀(μΜ)	Cell IC_S0 (μΜ)
183B	+++		H—1—H
184	+++
188	+++		H—!—r
190	1 \| !
192	+++		+++
193	+++		+++
194	-H—h
195	+++		+++
197	+++		1 \| \|
198	+++		+++
200	+++		+++
201	+++		+++
203	+++		+++
204	+++
205	+++		+++
206	+++		-H-+
207	++*

Compound	FP IC₅o (μΜ)	ADP IC₅0 (μΜ)	Cell IC₅₀ (μΜ)
208	+++
209	+++		+++
213	+++
214	-H—H		H-H-
215	+++		+++
216	+++		+++
217	+++		+++
218	+++		+++
219	+++		+++
220	+++		+++
221	+++		+++
222	+++		+++
223	+++		+++
224	4—H-		+++
225	+++		+++
226	+++
227	+++

Table 6

Compound	Cell IC₅₀(μΜ)	Human hépatocyte CLhep Avg (mL/min/kg)	ER MDR1	Rat unbound CL (mL/min/kg)	Dog unbound CL (mL/min/kg)	Cyno unbound CL (mL/min/kg)
119B	0.002	0	18	20		26
161	0.002	0
163	0.001	0
42	0.0006	0.8	19	22	64	42
83A	0.002	1.0	29	116		82
170A	0.003	3.1
177A	0.002	4.2	1.4	55		58
146	0.0007	4.2	1.0	61		39
94	0.006	4.9	14	44		40
171	0.0007	5.1	19	32

409

Compound	Cell IC₅₀(μΜ)	Human hépatocyte CLhep Avg (mL/min/kg)	ER MDR1	Rat unbound CL (mL/min/kg)	Dog unbound CL (mL/min/kg)	Cyno unbound CL (mL/min/kg)
172	0.001	5.3		65
183B	0.0008	5.3	36
66	0.012	6.3	1.6	113	36	116
195	0.016	7.1
198	0.020	8.5
134	0.003	9.0	1.1	100		140
75A	0.003	9.1	24	91		93
205	0.021	11
148A	0.0007	12
197	0.003	13
46A	0.002	16	16	188
142	0.0007	16
77	0.001	19	0.6	595
8	0.004	19	0.8	3700
9	0.008	19
92	0.0007		1.4	420
193	0.21

Table 7 Comparative Compounds

	Structure	Cell ICso (μΜ)	Human hépatocyte CLhep Avg (mL/min/k g)	ER MDR1	Rat unbound CL (mL/ min/kg)	Dog unbound CL (mL/min /kg)	Cyno unbound CL (ml/min/ kg)
A	\ o χ n H	0.0005	6.8	6.4	77	240	117
B	\ O o o'VxX	0.0003	14	1.0
C	\ o ΟΥ/ΐ Hi	0.001	19	0.9

410

The comparative compounds in Table 7 were prepared as described in Examples 12, 146, and 77, respectively, of WO 2014/125444.

[1112] The in vivo efficacy of compounds can be determined in mice using a TNF-driven systemic inflammatory response syndrome model as described by Duprez et. al. (2011, Immunity 35(6), 908-918) and Berger et. al. (2015, Cell Death Disc. 1, 15009). In this model system TNF/zVAD (tumor necrosis factor/Z-Val-Ala-DL-Asp-fluoromethylketone, a caspase inhibitor) treatment results in température loss and the production of several inflammatory cytokines. The ability of a test compound to inhibit these inflammatory effects can be measured in this model by dosing mice with test compound 15 minutes before administration of TNF/zVAD and measuring the inflammatory response. The dose required to inhibit the inflammatory response is a measure of the compounds efficacy at that dose. Using this model, Compound 42 was orally pre-dosed at 5 mg/kg 15 minutes before intraveneous administration of TNF/zVAD and température loss in the mice was measured by an implanted température chip. Treatment of mice with 5 mg/kg of Compound 42 resulted in 96% inhibition of température loss when compared to TNF/zVAD vehicle treated animais. In comparison, WO 2014/125444 discloses in Table 2 that Example 12, corresponding to Example A of Table 7 above, required a dose of 30 mg/kg to achieve 93% inhibition. The decrease in dosing has a number of important potential advantages, including requiring less frequent administration to a patient, increased patient compliance, and improved safety profile such as lower toxicities while achieving similar efficacy.

[1113] Based on the known crystal structure of comparative Example C and receptor-interacting protein kinase 1 (Harris et al. J. Med. Chem., 2016, 59 (5), pg. 2163-2178), the phenyl carbon atom adjacent to the azepinone moiety (i.e., X⁹ of the formulas disclosed herein) interacts with a lipophilie pocket of receptor-interacting protein kinase 1.

[1114] Certain compounds were found to hâve significantly improved metabolic stability when X⁹ of the formulas disclosed herein is a N atom as compared to a carbon atom. For instance, Compound 42, in comparison to comparative Example A, when tested according to the assay described below, was found to hâve an average human hépatocyte clearance of 0.8 mL/min/kg versus 6.8 mL/min/kg for comparative Example A. As described in the metabolic stability section below, a CLhep of 6.8 mL/min/kg corresponds to a clearance of approximately 32% of liver blood flow, whereas for Compound 42, a CLhep value of 0.8 mL/min/kg corresponds to a clearance of less than 4% of liver blood flow, demonstrating the significant improvement in stability for compounds when X⁹ is a N atom. From the data presented above, it will be apparent to those skilled in the art that compounds with lower human CLhep values should allow for lower human clinical doses, less frequent administration to a patient, increased patient compliance, and improved safety profile such as lower toxicities.

411

MDCK1I-MDR1 Permeability

[1115] The blood brain barrier (BBB) séparâtes circulating blood from the extracellular fluid of the central nervous System (CNS). The passive membrane permeability (Papp) and the P-gp (Pglycoprotein) substrate efflux potential were determined using the MDCKII-MDR1 cell line as an in vitro model of the effective permeability of a compound through the BBB. A bidirectional assay (Apical to Basolateral (A-->B) and Basolateral to Apical (B-+A)), in the absence and in the presence of GF 120918 (a P-gp inhibitor) was conducted using pre-plated MDCKII-MDR1 cells (Corning HTS Transwell-96) obtained from SOLVO Biotechnology. The assay was run at 3 μΜ for 90 min (minutes) in triplicate using a HBSS + 12.5 mM HEPES pH 7.4 transport buffer. Following incubation of samples from donor and receiver, wells were removed and measured by LC-MS/MS. Samples were extracted by protein précipitation with acetonitrile containing an appropriate internai standard (IS) having a known mass and molecular weight. The precipitate was centrifuged for 10 min at 3000 rpm (révolutions per minute). The supematants were then collected, diluted if necessary, and injected on to the LC-MS/MS System. Spécifie parent / daughter ion pairs for the test article and IS were used to selectively measure the test articles. Papp (apparent permeability expressed in nm/sec [nanometer/second]) values were calculated according to the following équation:

„ . f dQ\ [ 1 j |

Papptnml = \ — W — M

A)

[1116] Where dQ/dt is the permeability rate, Co is the initial concentration in the donor solution (expressed as IS ratio), A and B are the surface areas of the filter (the surface area of the cell monolayer).

[1117] Monolayer efflux ratios (ER) were derived using the following équation:

EffluxRatio = t

B - APappfnm / sec)

A - BPapp(nm / sec)

[1118] Compounds with a MDCKII-MDR1 efflux ratio of less than or equal to 2.5 are likely to demonstrate ability to cross the blood-brain-barrier.

Metabolic Stability (Hépatocytes)

[1H9] The metabolic stability of compounds was evaluated in human cryopreserved hépatocytes (BioreclamationIVT, NY, USA) in duplicate. Test articles (or controls) were added to a 24-well incubation plate (Becton Dickinson Labware, USA) containing 0.5 xlO⁶ hepatocytes/mL in suspension. The plate was held at 37 °C and agitated with constant orbital shaking (orbital speed at 350 rpm). At each time point (0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150 and 180 min) a Tecan Evo robot aspirated 50 pT. ofthe incubation mixture and 100 pL of acetonitrile containing internai standard to quenchthe reaction. The quenched mixtures were dispensed into a 96-well plate along with 120 pL of aqueous

412 solution to equilibrate the solvent content at 37%. Samples were centrifuger! (3000 rpm for 10 minutes) and the plate sealed prior to injection onto an LC-MS/MS system.

[1120] The appropriate parent / daughter ions were monitored for the test article and IS with the LCMS/MS system. The intrinsic clearance (Clint; expressed pL/min/million cells) was determined from the first order élimination constant (k, min ^!) of test article decay and the volume of the incubation. These values were sealed to intrinsic organ clearance (CL_mt) using human spécifie sealing factors (139 X 10⁶hepatocytes/g liver and 25.7 g liver/kg body weight). The intrinsic organ CL was then converted to the hepatic clearance (CLhep) using the well-stirred model as shown below, where Qh is human hepatic blood flow.

Qh * ^C^int ^h’^r «?» + CW

[1121] Hepatic clearance is expressed as mL/min/kg. The hepatic clearance relates to the flow of blood through the liver that is completely cleared of the compound. A human CLhep of 20.9 mL/min/kg corresponds to approximately complété compound clearance by the liver or 100% of liver blood flow. Accordingly, a human CLh_ep of 6 mL/min/kg corresponds to a clearance of approximately 29% of liver blood flow. A human CLhep value of 2 mL/min/kg corresponds to a clearance of approximately 10% of liver blood flow. A human CLh_ep value of 1 mL/min/kg or less corresponds to a clearance of approximately 5% of liver blood flow or less. A human CLhep value of 0 mL/min/kg corresponds to undetectable compound clearance by the liver.

[1122] In certain embodiments provided are compounds having a CLhep of less than 5, 4, 3, 2, or mL/min/kg when tested according to the above human hepatic stability assay. In certain embodiments such compounds do not readily cross the blood brain barrier. In certain embodiments such compounds hâve a MDCKII-MDR1 efflux ratio of greater than 2.5.

[1123] In certain embodiments provided are compounds having a CLhep of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mL/min/kg when tested according to the above human hepatic stability assay. In certain embodiments such compounds are able to cross the blood brain barrier. In certain embodiments such compounds hâve a MDCKII-MDR1 efflux ratio of 2.5 or less.

Protein Binding

[1124] The protein binding in plasma was determined using a Rapid Equilibrium Dialysis Device (Thermo Scientific RED Device) or 96-well dialyzer apparatus (HTDialysis LLC). Plasma was spiked with test / control compounds to give a final concentration of 0.5 μΜ (plasma). If required, plasma samples were pre-incubated (2 hours at 37 °C) with diisopropyl fluorophosphate (DFP) at the final concentration of 100 μΜ to prevent compound dégradation due to amide hydrolysis. Appropriate volumes of spiked samples along with blank phosphate buflèr were added to either device and incubated at 37 °C for a total of 5 hours with agitation at 500 rpm. Following incubation, an equal aliquot of

413 dialysed matrix (plasma or buffer) is added to an equal volume of the opposite blank matrix such that the volume of buffer to plasma are equal. Mixed matrix samples were extracted by protein précipitation using acetonitrile containing the appropriate IS. Samples were then centrifuged for 10 min at 2800 rpm. Supematants were collected and diluted and then injected on to an HPLC-MS/MS or UPLC-MS/MS System. Samples were analyzed by monitoring the appropriate parent / daughter ion transitions for the test and control compounds. The peak area ratios were used to measure test item concentrations. The fraction unbound (Afu) was determined as the ratio of the peak area ratio in buffer divided by the peak area ratio in plasma.

In Vivo Pharmacokinetic (PK) Studies

[1125] The PK properties of test articles were determined in male Sprague-Dawley Crl:CD(SD) rats, male Beagle dogs and male cynomolgus monkeys. Studies were conducted to the highest standards of animal welfare in accordance with national législation and under approval of the internai animal care and use committees.

[1126] Compounds were administered by IV bolus to animais following an overnight fast. Compounds for IV administration were formulated as solutions using either 1% DMSO (dimethyl sulfoxide):20% PEG400 (polyethylene glycol 400):79% saline, or 5-50% NMP in D5W (5% dextrose in water). The formulations were administered at dose volumes ranging from 0.5-2 mL/kg. The IV dose ranged from 0.5-1 mg/kg.

[1127] Following dose administration, 8-9 serial blood samples were collected over 24 hours. Samples were mixed with anticoagulant and placed on wet ice prior to processing. Plasma was harvested following centrifugation, extracted using protein précipitation with acetonitrile containing IS. The processed supematant was analyzed using UPLC or LC-MS/MS using spécifie parent / daughter ion pairs for the test article and IS. Plasma concentrations were determined using a calibration curve prepared using known concentrations of analyte. Pharmacokinetic parameters utilizing measured concentrations were calculated using Phoenix WinNonlin. The unbound plasma clearance was calculated as the ratio of the total body clearance divided by the fraction unbound in plasma.

[1128] Unless otherwise defined, ail technical and scientific tenus used herein hâve the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[1129] The inventions illustratively described herein may suitably be practiced in the absence of any element or éléments, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein hâve been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any

414 équivalents of the features shown and described or portions thereof, but it is recognized that varions modifications are possible within the scope of the invention claimed.

[1130] Ail publications, patent applications, patents, and other référencés mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the présent spécification, including définitions, will control.

[1131] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

1. A compound of Formula (Ile) :

or a tautomer, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutically acceptable sait thereof, wherein:

q is 0, 1, or 2;

R¹ is H or Ci-Cô alkyl optionally substituted with halo, hydroxy, or cyano;

Y² is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR⁵- or -C(R⁶)2-;

R⁵ is H or optionally substituted Ci-Cf, alkyl;

R³ and R⁴ are independently H, halo, or optionally substituted Ci-Ce alkyl, or R³ and R⁴, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or R³ and R⁶ together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring, optionally substituted aryl, or optionally substituted heteroaiyl ring;

L is absent, -O-, -S-, -S(O)-, -S(O)₂-, -NR⁷-, or -C(R⁸)₂-;

R⁷ is H or optionally substituted Ci-Ce alkyl;

each R⁸ is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R⁸, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and

R⁹ is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R¹⁰ is independently cyano, halo, optionally substituted Ci-Ce alkyl, or -S(O)₂-Ci-Cé alkyl.

415

2. The compound of claim 1, wherein the compound of Formula (Ile) is represented by

Formula Va:

R³ O

Va or a tautomer, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutically acceptable sait thereof, wherein:

q is 0, 1, or 2;

X⁶ is CR¹⁴;

R¹ is H or optionally substituted Ci-Cô alkyl;

Y² is -O- or -C(R⁶)₂-;

each R⁶ is independently H, halo, optionally substituted Ci-Cô alkyl;

R³ is H, halo, optionally substituted Ci-Cô alkyl, or R³ and R⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

L is -C(R⁸)₂-;

R⁹ is optionally substituted aryl or optionally substituted heteroaryl;

each R¹⁰ is independently cyano, halo, optionally substituted Ci-Cô alkyl, or -S(O)2-Ci-Cô alkyl; and

R¹⁴ is hydrogen.

416

3. The compound of claim 1, wherein the compound of Formula (Ile) is a compound of

Formula VI:

R¹

q is 0, 1, or 2;

X⁶ is CR¹⁴;

R¹ is H or optionally substituted Ci-Cô alkyl;

Y² is -O- or -C(R⁶)₂-;

each R⁶ is independently H, halo, optionally substituted Ci-Cô alkyl;

L is -C(R⁸)₂-;

R⁹ is optionally substituted aryl;

each R¹⁰ is independently halo, or optionally substituted Ci-Cô alkyl; and

R¹⁴ is hydrogen.

4. The compound of any preceding claim, wherein R¹ is methyl.

5. The compound of any preceding claim, wherein Y² is O.

6. The compound of any preceding claim, wherein R³ is hydrogen or fluoro.

417

7. The compound of claim 1, wherein A is phenyl, phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl, oxadiazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.

8. The compound of any one of claims 1 or 4-7, wherein L is absent, -S(O)₂-, or -C(R⁸)₂-,

9. The compound of any preceding claim, wherein two R⁸ together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

10. The compound of any one of claims 1 -8, wherein L is -C(R⁸)2- and each R⁸ is independently H, halo, or optionally substituted Ci-C6 alkyl.

11 The compound of any one of claims 1 or 4-10, wherein R⁹ is optionally substituted pyridyl, phenyl, or 2,3-dihydro-lH-indenyl.

12. A compound of claim 1, wherein the compound is selected from the compounds in Table 1, Table 2, Table 3 or Table 4, or a tautomer, stereoisomer, or mixture of stéréo isomers thereof, or a pharmaceutically acceptable sait thereof.

13. The compound of claim 12, having the structure:

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable sait thereof.

14. The compound of claim 12, having the structure:

418

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable sait thereof

15. A pharmaceutical composition comprising a compound from any preceding claim and an excipient.

16. Use of the compound according to any one of claims 1 -14 or the pharmaceutical composition of claim 15 in the manufacture of a médicament for treating a receptor-interacting protein kinase 1-mediated disease or disorder.