EA044271B1 - RECEPTOR INTERACTING PROTEIN KINASE 1 INHIBITORS - Google Patents

Description

Cross reference to related applications

This application claims priority under 35 USC § 119(e), based on US Provisional Application Nos. 62/292202, filed February 5, 2016, 62/341019, filed May 24, 2016, 62/363775, filed 18 July 2016, 62/385217 filed September 8, 2016, and 62/417219 filed November 3, 2016. The contents of said applications are incorporated herein in their entirety by reference.

Field of technology

In general, the present invention relates to kinase inhibitors, pharmaceutical compositions containing them, as well as therapeutic methods for using these inhibitors.

State of the art

Although inflammation can be a protective mechanism in response to noxious insults such as pathogen invasion and tissue damage, chronic inflammation is a significant factor underlying many human diseases such as neurodegeneration, rheumatoid arthritis, autoimmune and inflammatory diseases, and also cancer. Similarly, activation of cell death pathways such as necrosis and apoptosis, which are required to eliminate infected or damaged cells, is also a significant underlying mechanism of human diseases, including acute and chronic neurodegenerative diseases.

Receptor-interacting protein kinase 1 is a key regulator of inflammation, apoptosis, and necroptosis. Receptor-interacting protein kinase 1 plays an important role in modulating inflammatory responses mediated by nuclear factor kappa-light chain enhancer of activated B cells (NF-kB). In a more recent study, its kinase activity was shown to control necroptosis, a form of necrotic cell death that has traditionally been considered passive and unregulated, and is also characterized by a unique morphology. In addition, receptor-interacting protein kinase 1 is part of the pro-apoptotic complex, indicating its activity in regulating apoptosis.

Receptor-interacting protein kinase 1 is regulated by complex and complex regulatory mechanisms, including ubiquitination, deubiquitination, and phosphorylation. These regulatory events together determine whether the cell survives and activates an inflammatory response or dies through apoptosis or necroptosis. Dysregulation of receptor-interacting protein kinase 1 signaling can lead to widespread inflammation or cell death, and conversely, studies have shown that inhibition of receptor-interacting protein kinase 1 may represent an effective therapy for diseases involving inflammation or cell death.

Description

Provided herein are compounds suitable for use as inhibitors of receptor-interacting protein kinase 1. Also provided herein are pharmaceutical compositions that contain such compounds, as well as methods of using (or administering) such compounds, particularly in a method of treating a disease or disorder. mediated by receptor-interacting protein kinase 1.

In specific embodiments, a compound of formula II is provided:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof. where q is 0, 1 or 2;

X ⁶ , X ⁷ , X ⁸ and X ⁹ are each N or CH;

R ¹ represents H or C ₁ -C ₆ -alkyl, optionally substituted with halogen, hydroxy or cyano;

Y ² represents -O- or -C(R ⁶ ) ₂ -;

each R ⁶ independently represents H, halogen or C1-C6-alkyl, or two R ⁶ together with the carbon atom to which they are attached form a C1-C ₅ -alken-1-yl or cycloalkyl ring;

R ³ and R ⁴ independently represent H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁴ together with the carbon atoms to which they are attached form a cycloalkyl ring, or R ³ and R ⁶ together with the carbon atoms , to which they are attached form a cycloalkyl ring;

A is a cycloalkyl ring, a heterocyclyl ring or a heteroaryl ring, optionally substituted with halogen, C ₁ -C ₆ alkyl or cyano;

L is absent or represents -O-, -S(O) ₂ - or -C(R ⁸ ) ₂ -;

each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

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R ⁹ represents cycloalkyl, aryl, optionally substituted with halogen or cyano, or heteroaryl, optionally substituted with halogen, C ₁ -C6 alkyl, cyano or C ₁ -C6 alkoxy;

each R ¹⁰ independently represents cyano, halogen or C ₁ -C ₆ -alkyl; provided that at least one of the following occurs:

(1) at least one of R ³ and R ⁴ is halogen or C ₁ -C ₆ alkyl, or R ³ and R ⁴ together with the carbon atoms to which they are attached form a cycloalkyl ring, or R ³ and R ^6, together with the carbon atoms to which they are attached, form a cycloalkyl ring;

(2) L is absent or is -C(R ⁸ )2-, and each R ⁸ is C1-C ₆ -alkyl or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

(3) Y ² is -C(R ⁶ )2-, and one R ⁶ is H, halogen or C1-C ₆ alkyl, and the other R ⁶ is halogen or C1-C6 alkyl; or two R ⁶ together with the carbon atom to which they are attached form a C1-C5-alken-1-yl or cycloalkyl ring;

(4) Y ² represents -O-, and A represents a heteroaryl ring substituted with halogen or cyano, or A represents a thiazolyl or a 3- or 4-membered ring; one of X ⁷ and X ⁹ represents a nitrogen atom, and A is not an isoxazole;

(5) R ¹ represents C ₂ -C ₆ -alkyl; or (6) when X ⁹ and X ⁶ are both CH, forming an optionally substituted phenyl ring, as in the fragment

at least one substituent is at position 1 or 4 and is (a) not fluorine, chlorine or methyl at position 1 and/or (b) not fluorine or methyl at position 4;

and with the further condition that said compound is not: 5-(difluoro(phenyl)methyl)-N(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) isoxazole-3-carboxamide; 5(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3carboxamide;

2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-metrahydrobenzo[b][1,4]oxazenin-3 yl)thiazol-4-carboxamide or 2-benzyl -N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)thiazol-4-carboxamide;

wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 carbon atoms in the ring, having a single ring or multiple rings, where the cycloalkyl may be fused, bridged or spiro;

each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo (C=O) or N-oxide (N-O-) moieties and/or single ring or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In specific embodiments, the compound is a compound of formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf):

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or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. In specific embodiments, a compound of formula IIe is provided:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof. In specific embodiments, a compound of formula V is provided:

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

X ⁶ and X ⁹ are independently N or CR ¹⁴ ;

R ¹ represents H or C ₁ -C ₆ -alkyl;

Y ² represents -O- or -C(R ⁶ )2-;

each R ⁶ independently represents H, halogen or C ₁ -C ₆ -alkyl;

R ³ represents H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl ring;

L represents -C(R ⁸ ) ₂ -;

each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

R ⁹ is aryl, optionally substituted with halogen or cyano, or heteroaryl, optionally substituted with halogen, C1- _C6 alkyl, cyano or _C1 - _C6 alkoxy;

each R ¹⁰ independently represents cyano, halogen or C ₁ -C ₆ -alkyl; and each R ¹⁴ independently represents hydrogen, cyano, halogen, C ₁ -C ₃ alkyl, optionally substituted with halogen, or C ₁ -C ₃ alkoxy, optionally substituted with halogen;

provided that when both of X ⁶ and X ⁹ are CR ¹⁴ , one or more of (i), (ii), (iii), (iv) and (v) are true: (i) R ³ and R ⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, (ii) L is -C(R ⁸ )2-, and each R ⁸ is combined with the carbon atom to which they are attached with formation of cyclopropyl, (iii) R ⁹ is substituted with at least one cyano, (iv) X ⁹ is not CH, CF, C-Cl or C-CH3 and/or (v) X ⁶ is not CH, CF or C-CH ₃ ; and additionally where:

each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 carbon atoms in the ring, having a single ring or multiple rings, where the cycloalkyl may be fused, bridged or spiro;

each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo (C=O) or N-oxide (N-O-) moieties and/or single ring or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In specific embodiments, a compound of formula V is represented by formula Va:

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

X ⁶ represents N or CR ¹⁴ ;

R ¹ represents H or C ₁ -C ₆ -alkyl;

Y ² represents -O- or -C(R ⁶ ) ₂ -;

each R ⁶ independently represents H, halogen or C ₁ -C ₆ -αalkyl;

R ³ represents H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl ring;

L represents -C(R ⁸ ) ₂ -;

each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

R ⁹ is aryl, optionally substituted with halogen or cyano, or heteroaryl, optionally substituted with halogen, C ₁ -C ₆ -alkyl, cyano or C ₁ -C ₆ -alkoxy;

each R ¹⁰ independently represents cyano, halogen or C ₁ -C ₆ -alkyl; And

R ¹⁴ represents hydrogen, cyano, halogen, C ₁ -C ₃ -alkyl, optionally substituted with halogen, or C ₁ -C ₃ -alkoxy, optionally substituted with halogen; and further wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 ring carbon atoms, having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged or spiro;

each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo (C=O) or N-oxide (N-O-) moieties and/or single ring or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In specific embodiments, a compound of formula VI is provided:

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where q is 0, 1 or 2;

X ⁶ represents N or CR ¹⁴ ;

R ¹ represents H or C ₁ -C ₆ -alkyl;

Y ² represents -O- or -C(R ⁶ ) ₂ -;

each R ⁶ independently represents H, halogen or C ₁ -C ₆ -alkyl;

R ³ represents H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl ring;

L represents -C(R ⁸ ) ₂ -;

each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

R ⁹ is aryl, optionally substituted with halogen or cyano; each R ¹⁰ independently represents halogen or C ₁ -C ₆ -alkyl; And

R ¹⁴ represents hydrogen, cyano, halogen, C ₁ -C ₃ alkyl, optionally substituted with halogen, or C ₁ -C ₃ alkoxy, optionally substituted with halogen; and further wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 ring carbon atoms, having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged or spiro;

each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo (C=O) or N-oxide (N-O-) moieties and/or single ring or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In specific embodiments, a specific connection is proposed, presented in table. 14, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof.

Provided herein is a pharmaceutical composition containing a compound of any formula described herein and an excipient.

Provided herein is a method of treating a disease or disorder mediated by receptor-interacting protein kinase 1, the method comprising administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof.

In specific embodiments, said disease or disorder is an inflammatory disease or disorder, necrotizing cell disease, neurodegenerative disease, central nervous system disease, eye disease, malignancy, immune-mediated disease, allergic disease, autoimmune disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, retinal detachment, retinal pigmentary degeneration, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic arthritis with systemic onset, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis , autoimmune hepatitis, autoimmune diseases of the liver and biliary tract, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune idiopathic thrombocytopenic purpura (ITP), transplant rejection, ischemic and reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, acute cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1-converting enzyme-related fever, chronic obstructive pulmonary disease, periodic syndrome associated with tumor necrosis factor, periodontitis, trauma, ischemia, stroke, myocardial infarction, infection, lysosomal storage disease, Gaucher disease, Krabbe disease, Niemann-Pick disease, amyotrophic lateral sclerosis (ABS/Lou Gehrig's disease), HIV-related dementia, degenerative retinal disease, glaucoma, age-related macular degeneration, psoriasis, psoriatic arthritis, brain damage, spinal cord injury, dementia, Huntington's disease, diabetic neuropathy, poly- 5 044271 glutamine (polyQ) diseases, Fahr's disease, Menkes' disease, Wilson's disease, cerebral ischemia, Friedreich's ataxia, rheumatoid arthritis, Lewy body disease or prion disorder.

1. Definitions.

The following description sets forth examples of embodiments of the present invention. However, it should be understood that such description is not intended to limit the scope of the present invention, but is presented as a description of exemplary embodiments.

As used herein, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

A dash (-) that is not between two letters or symbols is used to indicate where a substituent is added. For example, -C(O)NH2 is attached via a carbon atom. A dash at the beginning or end of a chemical group is a matter of convenience; chemical groups may be represented with or without one or more dashes without losing their normal meaning. A wavy line drawn through a line in the structure indicates where the group is attached. Unless required chemically or structurally, directionality or stereochemistry is not indicated or implied by the order in which a chemical group is written or named.

The prefix C _u - _v indicates that the following group contains from and to v carbon atoms. For example, C ₁ . ₆ alkyl means that the alkyl group contains from 1 to 6 carbon atoms.

Reference to an exemplary value or parameter herein includes (and describes) implementations that relate directly to such value or parameter. In specific embodiments, the term approximately includes the indicated amount ±10%. In specific embodiments, the term approximately includes the indicated amount of ±5%. In specific embodiments, the term approximately includes the indicated amount of ±1%. Also, the term about X includes a description of X. Also, indefinite and definite singular forms include references to the plural unless the context clearly indicates otherwise. Thus, for example, a reference to a compound includes a plurality of such compounds, and a reference to an assay includes a reference to one or more assays and their equivalents known to those skilled in the art, and so on.

Alkyl refers to a straight or branched saturated hydrocarbon chain. As used herein _{, alkyl has 1-20 carbon atoms (i.e. C1.20 alkyl )} , 1-8 carbon atoms (i.e. _C1.8 αalkyl), 1-6 carbon atoms (i.e. C _1.6 alkyl) or _{1-4 carbon atoms (i.e. C 1.4 αalkyl )} . In certain embodiments, alkyl has 1-12 carbon atoms (ie, C ₁ . ₁₂ alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl moiety having a specific number of carbon atoms is named according to a chemical name or defined by a molecular formula, all positional isomers having that number of carbon atoms may be included; thus, for example, butyl includes n-butyl (i.e. -(CH ₂ ) ₃ CH ₃ ), sec-butyl (i.e. -CH(CH ₃ )CH ₂ CH ₃ ), isobutyl (i.e. -CH ₂ CH(CH ₃ ) ₂ ) and tert-butyl (i.e. -C(CH ₃ ) ₃ ); and propyl includes n-propyl (ie -(CH ₂ ) ₂ CH ₃ ) and isopropyl (ie -CH(CH ₃ ) ₂ ).

Alkenyl refers to an alkyl group containing at least one carbon-carbon double bond and having 2-20 carbon atoms (i.e. C ₂ - ₂₀ alkenyl), 2-8 carbon atoms (i.e. C ₂ - ₈ alkenyl ₎ , 2-6 carbon atoms (i.e. _{C2_6} alkenyl) or 2-4 carbon atoms ( _{i.e. C2_4} alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butanedienyl (including 1,2-butanedienyl and 1,3-butanedienyl).

Alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond _{and having 2-20 carbon atoms (i.e. C2_20 alkynyl )} , 2-8 carbon atoms (i.e. _{C2_8} alkynyl ), 2-6 carbon atoms ( _i.e. C _{2_6} alkynyl) or 2-4 carbon atoms ₍ i.e. C _{2_4} alkynyl). The term alkynyl also includes groups having one triple bond and one double bond.

Alkoxy belongs to the alkyl-O- group. Examples of alkoxy groups include methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2dimethylbutoxy.

Alkylthio belongs to the alkyl-S- group.

Acyl refers to the group -C(O)R, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl and benzoyl.

Amido refers to both the C-amido group, which refers to the -C(O)NR ^y R ^z group, and the N-amido group, which refers to the -NR ^y C(O)R ^z group, where R ^y and R ^z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may optionally be substituted.

Amino refers to the group -NR ^y R ^z 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 not be necessarily replaced.

Amidino refers to -C(NH)(NH2). In specific 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 optionally be substituted as defined herein.

Aryl refers to an aromatic carbocyclic group containing a single ring (eg, monocyclic) or multiple rings (eg, bicyclic or tricyclic), including fused systems. As used herein, aryl has 6-20 ring carbons (i.e., _C6-20 aryl), 6-12 ring carbons (i.e., _C6-12 aryl) _, or 6-10 ring carbons (t i.e. C ₆ - ₁₀ aryl). In certain embodiments _, aryl has 6-18 carbon atoms (ie, _C6-18 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl and anthryl. However, aryl does not include or overlap in any way with heteroaryl, as defined below. If one or more aryl groups are fused to a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl.

Azido refers to -N ₃ .

Arilalkyl or aralkyl belongs to the arylalkyl- group.

Carbamoyl refers to both the O-carbamoyl group, which refers to the -OC(O)NR ^y R ^z group, and the N-carbamoyl group, which refers to the -NR ^y C(O)OR ^z group, where R ^y and R ^z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may optionally be substituted.

Carboxyl refers to -C(O)OH.

Carboxylic acid ester or ester refers to -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

Cyano or carbonitrile belongs to the -CN group.

Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged and spiro ring systems. The term cycloalkyl includes cycloalkenyl groups (ie, a cyclic group having at least one double bond). As used herein _, cycloalkyl _{has 3-20 ring carbons (i.e., C3_20 cycloalkyl} ), 3-12 ring carbons (i.e., _{C3_12} cycloalkyl), 3-10 ring carbons (ie C ₃ - ₁₀ cycloalkyl), 3-8 carbon atoms in the ring (ie C ₃ - ₈ cycloalkyl) or 3-6 carbon atoms in the ring (ie C ₃ - ₆ cycloalkyl). In certain embodiments, the cycloalkyl has 3-15 carbon atoms in the ring (ie, C ₃ - ₁₅ cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In addition, the term cycloalkyl is intended to include any non-aromatic ring that can be fused to an aryl ring, regardless of attachment to the moiety of the molecule.

In specific embodiments, cycloalkyl also includes spirocycloalkyl 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, norbornyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl and the like.

Guanidino belongs to -NHC(NH)(NH2). In specific embodiments, guanidino refers to -NRC(NR)(NR2), wherein each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

Cycloalkylalkyl belongs to the cycloalkylalkyl- group. Hydrazino belongs to -NHNH2.

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

Imido refers to the group -C(O)NRC(O)R, where each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

Halogen or halo includes fluorine, chlorine, bromine and iodine.

Haloalkyl refers to a straight or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by halogen. For example, when a residue is substituted with more than one halogen atom, it may be named using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (di) or three (tri) halogen groups, which may, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3). In specific embodiments, examples of haloalkyl include difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

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Haloalkoxy refers to an alkoxy group, as defined above, in which one or more hydrogen atoms are replaced by halogen.

Haloalkoxy refers to an alkoxy group, as defined above, in which one or more hydrogen atoms are replaced by halogen.

Heteroalkyl refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently substituted by the same or a different heteroatom group. The term heteroalkyl includes a straight or branched saturated chain containing carbon and heteroatoms. As an example, 1, 2 or 3 carbon atoms may be independently substituted by the same or different heteroatom group. Heteroatoms 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 cycloheterocyclyl, 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 optionally be substituted. In specific embodiments, examples of heteroalkyl groups include -CH ₂ OCH ₃ , -CH ₂ SCH _{3 ,} and -CH2NRCH ₃ , wherein 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 1-10 carbon atoms, 1-8 carbon atoms, or 1-4 carbon atoms; and 1-3 heteroatoms, 1-2 heteroatoms or 1 heteroatom. In specific embodiments, the term heteroalkyl requires that the site of attachment of the moiety of the molecule be on a carbon atom.

Heteroaryl refers to an aromatic group having a single ring, multiple rings or multiple fused rings, as well as one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein _{, heteroaryl contains 1-20 ring carbons (i.e., C1.20 heteroaryl} ), 3-12 ring carbons (i.e., _C3.12 heteroaryl) _, or 3-8 ring carbons (ie C ₃ - ₈ heteroaryl); and 1-5 heteroatoms, 1-4 heteroatoms, 1-3 heteroatoms, 1-2 heteroatoms or 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In specific embodiments, the term heteroaryl refers to a 5-14 membered ring system. In particular embodiments, heteroaryl contains 1-13 carbon atoms in the ring (ie, C ₃ . ₁₂ heteroaryl). In specific embodiments, heteroaryl contains 1-6 heteroatoms. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl and pyrazolyl. Examples of fused rings containing heteroatoms include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[ 1,5a]pyridinyl, where said heteroaryl can be linked to any ring of the fused system. In specific embodiments, examples of heteroaryl groups include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzodolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl , benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-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, 1- phenyl-1H- pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazole yl, triazolyl, tetrazolyl, triazinyl and thiophenyl ( those. thienyl). Any aromatic ring that has single or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of whether it is attached to the moiety of the molecule (ie, through any of the fused rings). Heteroaryl does not include or overlaps with aryl as defined above.

Heteroarylalkyl belongs to the heteroarylalkyl- group.

Heterocyclyl refers to a saturated or unsaturated cyclic alkyl group with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term heterocyclyl includes heterocycloalkenyl groups (ie, a heterocyclyl group having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. The heterocyclyl may be a single ring or multiple rings, which multiple rings may be fused, bridged, or spiro. In particular embodiments, the heterocyclyl may contain one or more oxo (C=O) or N-oxide (N-O-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (ie, it can be attached via a carbon atom or a heteroatom). In addition, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom that can be fused to an aryl or heteroaryl ring, regardless of

- 8 044271 addition to the remainder of the molecule. As used herein _, a heterocyclyl contains 2-20 ring carbons (i.e., _C2-20 heterocyclyl), 2-12 ring carbons _{(i.e., C2-12 heterocyclyl} ), 2-10 ring carbons (i.e. _{C2_10} heterocyclyl) _{, 2-8 carbon atoms in the ring (i.e. C2_8 heterocyclyl} ), _3-12 carbon atoms in the ring ( _{i.e. C3_12} heterocyclyl), 3-8 carbon atoms in _the ring (i.e. C _{3_8} heterocyclyl) or 3-6 carbon atoms in the ring (i.e. C _{3_6} heterocyclyl) _; and 1-5 heteroatoms, 1-4 heteroatoms, 1-3 heteroatoms, 1-2 heteroatoms, or 1 heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl and morpholinyl. In specific embodiments, examples of heterocyclyl groups include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrroles dinyl, oxazolidinyl, piperidinyl, piperazinil, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl and 1,1dioxothiomorpholinyl. Also used herein, the term spiroheterocyclyl refers to a ring system in which a 3-10 membered heterocyclyl has one or more additional rings, wherein said one or more additional rings is a 3-10 membered cycloalkyl or a 3-10 membered heterocyclyl, wherein one atom one or more of said additional rings is also an atom of said 3-10 membered heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, wherein said heterocyclyl may be linked to any ring condensed system.

Hydroxy or hydroxyl refers to the -OH group.

Oxo belongs to the group (=O) or (O).

Nitro belongs to the -NO2 group.

Heterocyclylalkyl belongs to the heterocyclylalkyl- group.

Oxime refers to the group -CR(=NOH), where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

Sulfonyl refers to the group -S(O) ₂ R, where R represents alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

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 optionally be substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

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 optionally be substituted as defined herein.

Alkylsulfonyl refers to the group -S(O) ₂ R, where R represents alkyl. Alkylsulfinyl refers to the group -S(O)R, where R represents alkyl. Thiocyanate belongs to the -SCN group.

The thiol belongs to the -SH group.

Thioxo or thione belongs to the group (=S) or (S).

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

In specific embodiments of any of the terms defined above, R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Specific common 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 alkylenyl group, an arylene group or an arylenyl group, respectively. Also, unless specifically stated otherwise, when combinations of groups are referred to herein as a single moiety, for example, arylalkyl, the last mentioned group contains the atom by which said moiety is attached to the remainder of the molecule.

The terms optional or optional mean that the event or circumstance described below may or may not occur, and that such description includes cases in which the specified event or circumstance occurs and cases in which it does not occur. Also, the term optionally substituted refers to any one or more carbon atoms on the specified atom or group may or may not be replaced by a moiety other than hydrogen.

- 9 044271

The term substituted means that one or more hydrogen atoms on the designated atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valence of the designated atom is not exceeded. Said one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylic acid ester, cyano, guanidino, halogen, haloalkyl, haloalkoxy , heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.

In specific embodiments, the term substituted herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and/or heteroalkyl), wherein at least one atom hydrogen is substituted 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, carboxylic acid ester . alkylsulfinyl , thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo, N-oxide or -Si(R ¹⁰⁰ ) ₃ , where each R ¹⁰⁰ independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.

In specific embodiments, the term substituted herein means any of the foregoing groups (i.e., alkyl, alkylene, alkoxy, haloalkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl, heteroaryl, hydroxyalkyl, and/or alkoxyalkyl), wherein at least one atom hydrogen is replaced by a bond with 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; alkenyl, haloalkenyl group, alkynyl group, haloalkynyl group, cyclic group such as aryl, heteroaryl, cycloalkyl or heterocyclyl group, oxygen atom in groups such as hydroxy groups, alkoxy groups and ester groups; sulfur atom in groups such as thiol groups, thioalkyl groups, thiohaloalkyl groups, sulfone groups, sulfonyl groups and sulfoxide groups; 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 various other groups. Substituted also means any of the above groups where one or more hydrogen atoms are replaced by a higher order bond (eg, a double or triple bond) with a heteroatom such as oxygen in the oxo, carbonyl, formyl, carboxyl, carbonate and ester groups; and nitrogen in groups such as imines, oximes, hydrazones and nitriles.

In specific embodiments, substituted includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, wherein one or more hydrogen atoms are independently substituted with deuterium, halogen, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^g R ^h , -NR ^g C(=O)R ^h , -NR ^g C(=O)NR ^g R ^h , -NR ^g C(=O)OR ^h , -NR ^g S(=O)1-2R ^h , -C(=O)R ^g , -C(=O)OR ^g , -OC(=O)OR ^g , -OC(=O)R ^g , -C(=O)NR ^g R ^h , -OC(=O)NR ^g R ^h , -OR ^g , -SR ^g , -S(=O)R ^g , -SiOrir -OS(=O)1-2R ^g , -S(=O)i-2OR ^g , -NR ^g S(=O)i_2NR ^g R ^h , =NSO2R ^g , =NOR ^g , -S(=O)1-2NR ^g R ^h , -SF5, -SCF3 or -OCF3. In specific embodiments, substituted means any of the above groups wherein one or more hydrogen atoms are substituted -C(=O)R ^g , -C(=O)OR ^g , -C(=O)NR ^g R ^h , -CH2SO2R ^g , -CH2SO2NR ^g R ^h . In specific embodiments, substituted means any of the above groups wherein one or more hydrogen atoms are substituted -NR ^g S(O)1_2NR ^g R ^h , -CH2S(O)R ^g , -CH2S(O)NR ^g R ^h , -OC (=O)OR ^g , -SF ₅ , -SCF ₃ or -OCF ₃ . In specific embodiments, substituted further refers to any of the above groups wherein one or more hydrogen atoms are replaced by an amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl bond , cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl and/or heteroarylalkyl group. As used herein, R ^g and R ^h and Ri are the same or different and are independently halogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and/or heteroarylalkyl , or two of R ^g and R ^h and Ri combine with the atoms to which they are attached to form a heterocyclyl ring, optionally substituted with oxo, halogen or alkyl, optionally substituted with oxo, halogen, amino, hydroxy or alkoxy. In one embodiment, each of said alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heteroaryl and/or heteroarylalkyl is independently optionally substituted with one or more oxo, alkyl, halogen, amino, hydroxy or alkoxy. In addition, each of the above-mentioned substituents may also optionally be replaced by one or more of the above-mentioned substituents.

- 10 044271

Polymers or similar unspecified structures obtained by attaching other substituents with additional substituents added ad infinitum (eg, a substituted aryl containing a substituted alkyl that is itself substituted by a substituted aryl group that is further substituted by a substituted heteroalkyl group, etc.) are not contemplated. for inclusion in this document. Unless otherwise stated, the maximum number of serial substitutions in the 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. Likewise, the above definitions are not intended to include unacceptable substitution patterns (eg, methyl substituted with 5 fluorine atoms or heteroaryl groups containing two adjacent ring oxygen atoms). Such unacceptable substitution patterns are well known to one skilled in the art. When used to change a chemical group, the term substituted may describe other chemical groups as defined herein. Unless otherwise indicated, when a group is described as optionally substituted, any substituents on such group are themselves unsubstituted. For example, in certain embodiments, the term substituted alkyl refers to an alkyl group containing one or more substituents, including hydroxy, halogen, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, said one or more substituents may be further substituted with halogen, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, said substituents may be further substituted with halogen, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

In many cases, the compounds of the present invention are capable of forming acid and/or base addition salts due to the presence of amino and/or carboxyl groups or groups similar thereto.

Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, stereoisomers and prodrugs of the compounds described herein. Pharmaceutically acceptable or physiologically acceptable refers to compounds, salts, compositions, dosage forms and other substances that are suitable for use in the preparation of a pharmaceutical composition suitable for pharmaceutical use in animals or humans.

The term pharmaceutically acceptable salt of a particular compound refers to salts that retain the biological effectiveness and properties of the specified compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts or physiologically acceptable salts include, for example, inorganic acid salts and organic acid salts. In addition, if the compounds described herein are obtained in the form of an acid addition salt, the free base can be prepared by making a solution of such acid salt alkalizing. Conversely, if the product is a free base, the addition salt, specifically a pharmaceutically acceptable addition salt, can be prepared by dissolving said free base in a suitable organic solvent and treating said solution with an acid, in accordance with standard techniques for preparing acid addition salts from basic compounds . Those skilled in the art will recognize various synthetic techniques that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric 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, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic 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 magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines such as alkylamines (i.e. NH ₂ (alkyl)), dialkylamines (i.e. IN (alkyl) ₂ ), trialkylamines (i.e. K(alkyl)z), substituted alkylamines (i.e. NH ₂ (substituted alkyl)), di(substituted alkyl)amines (i.e. IN(substituted alkyl) ₂ ), tri(substituted alkyl)amines (i.e. K(substituted alkyl) ₃ ), alkenyl amines (i.e. NH ₂ (alkenyl)), dialkenyl amines (i.e. IN(alkenyl) ₂ ), trialkenyl amines (i.e. K( alkenyl) ₃ ), substituted alkenyl amines (i.e. NH ₂ (substituted alkenyl)), di(substituted alkenyl) amines (i.e. IN(substituted alkenyl) ₂ ), tri(substituted alkenyl) amines (i.e. K(substituted alkenyl) ₃ , mono-, di- or tri-cycloalkylamines (i.e. NH ₂ (cycloalkyl), HN(cycloalkyl) ₂ , K(cycloalkyl) ₃ ),

- 11 044271 mono-, di- or tri-arylamines (i.e. NH ₂ (aryl), HN (aryl) ₂ , N (aryl) ₃ ) or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanoamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

Some of the compounds exist in the form of tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imido acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between tautomers, one of ordinary skill in the art will understand that these compounds include both amide and imido acid tautomers. Thus, it is understood that amide-containing compounds include their imido-acid tautomers. Thus, it is understood that compounds containing imido acids include their amide-containing tautomers.

The compounds disclosed herein, or their pharmaceutically acceptable salts, include a center of asymmetricity and may thus promote the formation of enantiomers, diastereomers and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or as (D)- or (L)- for amino acids. All such possible isomers, as well as their racemic and optically pure forms, are intended to be included in the present invention. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolution using standard techniques, e.g. chromatography or fractional crystallization. Standard techniques for preparing/isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or racemate salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, the compounds are intended to include both E- and Z-geometric isomers. Likewise, all tautomeric forms are intended to be included.

Stereoisomers are isomers that differ only in how their atoms are organized in space and include enantiomers and diastereomers. In specific embodiments, a stereoisomer refers to a compound composed of the same atoms connected by the same bonds, but having different three-dimensional structures that are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes enantiomers, which refer to two stereoisomers whose molecules are non-overlapping mirror images of each other.

Enantiomers are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture.

Diastereoisomers are stereoisomers that contain at least two asymmetric atoms, but which are not mirror images of each other.

Absolute stereochemistry was determined according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon atom can be determined using R or S. Separated compounds whose absolute configuration is unknown are designated as (+) or (-) depending on the direction (dextro- or levorotatory), in which they rotate the plane of polarized light at the wavelength of the sodium D line.

As used herein, a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient or excipient includes all possible solvents, dispersants, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any standard vehicle or agent is compatible with the active ingredient, it is intended for use in therapeutic compositions. Additional active ingredients may also be included in the compositions.

2. List of abbreviations and abbreviations.

Abbreviation Meaning Abbreviation Meaning VOD. Water d Doublet VOS tert-butyloxycarbonyl DAD Diode array detector br Wide DAST Diethylaminosulfur trifluoride

- 12 044271

dd doublet of doublets MeCN Acetonitrile ddd doublet of doublets of doublets MeOH Methanol dddd doublet of doublets of doublets m Multiplet (at doublets use with J) dt Doublet of triplets m/z Mass to charge ratio DIPEA/DIEA Diisopropylethylamine [M+N] ⁺ Mass Spectrum Maximum Plus DMF Dimethyl formamide hydrogen DMSO Dimethyl sulfoxide min Minute(s) ee/e.e. Enantiomeric purity MS Mass spectrometry ER Electrospray N Normal IER Electrospray source NCS A-Chlorosuccinimide ions NMR Nuclear magnetic resonance Et Ethyl in current nights During the night EtOH Ethanol FDA Photodiode no-matrix EtOAc Ethyl acetate detector HATU 1- quin Quintuplet [Bis(dimethylamino)methylene] CT Room temperature - 1H-1,2,3-triazolo [4,5- S Singlet (when using 7] pyridinium 3- with J) hexafluorophosphate oxide sec Second(s) HBTU Ν,Ν,Ν Ν -Tstramstil-C-(1Hbenzotriazol-1-yl)uronium sat. Saturated Triplet T hexafluorophosphate HOBt 1-hydroxybenzotriazole THF Tetrahydrofuran HPLC Highly efficient TFU Trifluoroacetic acid liquid chromatography Pete Total ion current hour/hour Hours those Thin layer chromatography Hz Hertz TMEDA Ν,Ν,Ν’,Ν’,- J Interaction constant Tetramethylethylenediamine (MHz) TMIS Iodotrimethylsilane zhms/zhh- Liquid chromatography - v/v Volume/Volume ms mass spectrometry δ Chemical shift (ppm) M Mole

3. Connections.

Provided herein are compounds suitable for use as inhibitors of receptor-interacting protein kinase 1. In specific embodiments, a compound of formula II is provided:

R ¹

II or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, where

- 13 044271 q is equal to 0, 1 or 2;

X ⁶ , X ⁷ , X ⁸ and X ⁹ are each N or CH;

R ¹ represents H or C ₁ -C ₆ -alkyl, optionally substituted with halogen, hydroxy or cyano;

Y ² represents -O- or -C(R ⁶ ) ₂ -;

each R ⁶ independently represents H, halogen or C1-C6 alkyl, or two R ⁶ together with the carbon atom to which they are attached form a C1-C ₅ alken-1-yl or cycloalkyl ring;

R ³ and R ⁴ independently represent H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁴ together with the carbon atoms to which they are attached form a cycloalkyl ring, or R ³ and R ⁶ together with the carbon atoms , to which they are attached form a cycloalkyl ring;

A represents a cycloalkyl ring, a heterocyclyl ring or a heteroaryl ring, optionally substituted with halogen, C ₁ -C ₆ alkyl or cyano;

L is absent or represents -O-, -S(O) ₂ - or -C(R ⁸ ) ₂ -;

each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

R ⁹ represents cycloalkyl, aryl, optionally substituted with halogen or cyano, or heteroaryl, optionally substituted with halogen, C ₁ -C ₆ -alkyl, cyano or C ₁ -C ₆ -alkoxy;

each R ¹⁰ independently represents cyano, halogen or C ₁ -C ₆ -alkyl;

provided that at least one of the following occurs:

(1) at least one of R ³ and R ⁴ is halogen or C ₁ -C ₆ alkyl, or R ³ and R ⁴ together with the carbon atoms to which they are attached form a cycloalkyl ring, or R ³ and R ^6, together with the carbon atoms to which they are attached, form a cycloalkyl ring;

(2) L is absent or is -C(R ⁸ )2-, and each R ⁸ is C1-C ₆ -alkyl or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

(3) Y ² is -C(R ⁶ )2-, and one R ⁶ is H, halogen or C1-C ₆ alkyl, and the other R ⁶ is halogen or C1-C6 alkyl; or two R ⁶ together with the carbon atom to which they are attached form a C1-C ₅ -alken-1-yl or cycloalkyl ring;

(4) Y ² represents -O-, and A represents a heteroaryl ring substituted with halogen or cyano, or A represents a thiazolyl or a 3- or 4-membered ring; one of X ⁷ and X ⁹ represents a nitrogen atom, and A is not an isoxazole;

(5) R ¹ represents C ₂ -C ₆ -alkyl; or (6) when X ⁹ and X ⁶ are both CH, forming an optionally substituted phenyl ring, as in fragment , at least one substituent is at position 1 or 4 and is (a) not fluorine, chlorine or methyl at position 1 and/or (b) not fluorine or methyl at position 4;

and with the further condition that said compound is not: 5-(difluoro(phenyl)methyl)-N-(4oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole -3-carboxamide; 5-(difluoro(phenyl)methyl)-N(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3-carboxamide; 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide or 2- benzylN-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide;

wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 carbon atoms in the ring, having a single ring or multiple rings, where the cycloalkyl may be fused, bridged or spiro;

each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo (C=O) or N-oxide (N-O-) moieties and/or single ring or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In specific embodiments, the compound is a compound of formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf):

- 14 044271

or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. In specific embodiments, the compound is a compound of formula IIe:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof. In specific embodiments, a compound of formula V is provided:

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

X ⁶ and X ⁹ are independently N or CR ¹⁴ ;

R ¹ represents H or C ₁ -C ₆ -alkyl;

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Y ² represents -O- or -C(R ⁶ ) ₂ -;

each R ⁶ independently represents H, halogen or C ₁ -C ₆ -alkyl;

R ³ represents H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl ring;

L represents -C(R ⁸ ) ₂ -;

each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

R ⁹ is aryl, optionally substituted with halogen or cyano, or heteroaryl, optionally substituted with halogen, C ₁ -C ₆ -alkyl, cyano or C ₁ -C ₆ -alkoxy;

each R ¹⁰ independently represents cyano, halogen or C ₁ -C ₆ -alkyl; and each R ¹⁴ independently represents hydrogen, cyano, halogen, C ₁ -C ₃ alkyl, optionally substituted with halogen, or C ₁ -C ₃ alkoxy, optionally substituted with halogen;

provided that when both of X ⁶ and X ⁹ are CR ¹⁴ , one or more of (i), (ii), (iii), (iv) and (v) are true: (i) R ³ and R ⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, (ii) L is -C(R ⁸ )2-, and each R ⁸ is combined with the carbon atom to which they are attached with formation of cyclopropyl, (iii) R ⁹ is substituted with at least one cyano, (iv) X ⁹ is not CH, CF, C-Cl or C-CH3 and/or (v) X ⁶ is not CH, CF or C-CH3; and further wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 ring carbon atoms, having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged or spiro;

each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo (C=O) or N-oxide (N-O-) moieties and/or single ring or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In specific implementations, when the fragment is

q is 0 or

R ¹⁰ is halogen or C1-C ₆ -alkyl, and L is absent, then ring A is a 3-, 4- or 5-membered monocyclic ring. In specific embodiments, a compound of formula V is represented by formula Va:

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

X ⁶ represents N or CR ¹⁴ ;

R ¹ represents H or C ₁ -C ₆ -alkyl;

Y ² represents -O- or -C(R ⁶ ) ₂ -;

each R ⁶ independently represents H, halogen or C ₁ -C ₆ -alkyl;

R ³ represents H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl ring;

L represents -C(R ⁸ ) ₂ -;

each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

R ⁹ is aryl, optionally substituted with halogen or cyano, or heteroaryl, optionally substituted with halogen, C ₁ -C ₆ -alkyl, cyano or C ₁ -C ₆ -alkoxy;

each R ¹⁰ independently represents cyano, halogen or C ₁ -C ₆ -alkyl; And

R ¹⁴ represents hydrogen, cyano, halogen, C ₁ -C ₃ alkyl, optionally substituted with halogen, or C 1 -C3 alkoxy, optionally substituted with halogen; and further wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 ring carbon atoms, having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged or spiro;

each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo (C=O) or N-oxide (N-O-) moieties and/or single ring or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In specific embodiments, the compound has Formula VI:

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

X ⁶ represents N or CR ¹⁴ ;

R ¹ represents H or C ₁ -C ₆ -alkyl;

Y ² represents -O- or -C(R ⁶ ) ₂ -;

each R ⁶ independently represents H, halogen or C ₁ -C ₆ -alkyl;

R ³ represents H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl ring;

L represents -C(R ⁸ ) ₂ -;

each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

R ⁹ is aryl, optionally substituted with halogen or cyano;

each R ¹⁰ independently represents halogen or C ₁ -C ₆ -alkyl; And

R ¹⁴ represents hydrogen, cyano, halogen, C ₁ -C ₃ alkyl, optionally substituted with halogen, or C ₁ -C ₃ alkoxy, optionally substituted with halogen; and further wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 ring carbon atoms, having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged or spiro;

each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo (C=O) or N-oxide (NO-) moieties and/or single ring or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In specific embodiments of compounds of formulas Va and VI, R ⁶ is CR ¹⁴ . In particular embodiments of compounds of formulas Va and VI, R ⁶ is N. In particular embodiments of compounds of formulas Va and VI, R ¹⁴ is hydrogen.

In specific embodiments of compounds of Formula II (or subformulas thereof), R ¹ is C ₁ -C ₆ alkyl. In specific embodiments of the compounds of Formula II (or subformulas thereof), R ¹ is methyl.

In specific embodiments of compounds of Formula II (or subformulas thereof), R ³ is hydrogen.

In specific embodiments of the compounds of Formula II (or subformulas thereof), R ³ and R ⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl. In certain embodiments, R ³ and R ⁶ together with the carbon atoms to which they are attached form cyclopropyl.

In specific embodiments of compounds of formula II (or subformulas thereof), L is absent or is -S(O) ₂ -or -C(R ⁸ ) ₂ -.

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In specific embodiments of compounds of formula II (or subformulas thereof), the two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring. In particular embodiments, L is -C(R ⁸ ) ₂ - and two R ⁸ are taken together with the carbon atom to which they are attached to form cyclopropyl.

In specific embodiments of the compounds of Formula II (or subformulas thereof), R ⁹ is optionally substituted pyridyl, phenyl, or 2,3-dihydro-1H-indenyl.

It is understood that the specific features described herein, which for clarity are described in the context of individual embodiments, may also be presented in combination in a single embodiment. Conversely, various features described herein, which for brevity are described in the context of a single embodiment, may also be presented separately or in any suitable subcombination. All combinations of embodiments relating to the chemical groups represented by the variables contained in Formula II (and all other formulas described herein) are specifically included in the present invention as if all possible combinations were mentioned separately and directly, provided that that such combinations cover compounds that provide stable compounds (ie, compounds that can be isolated, characterized and tested for biological activity). In addition, all subcombinations of chemical groups listed in the embodiments describing such variables, as well as all subcombinations of uses and medical indications described herein, such as pathological conditions or disorders mediated by receptor-interacting protein kinase 1, are also specifically included in the present invention as if all possible subcombinations of chemical groups and subcombinations of uses and medical indications were mentioned herein separately and directly. In addition, some embodiments include each combination of one or more additional agents described herein as if all possible combinations were mentioned separately and directly.

In specific embodiments, the compound may be selected from the compounds in Table 1. 1, 2, 3 or 4. Also included in the present invention are tautomers, stereoisomers and mixtures of stereoisomers of these compounds. Also included in the present invention is a compound selected from Table. 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof.

Table 1

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- 19 044271

- 20 044271

- 21 044271

- 22 044271

67V \ 0 CX /'TLX ΧΧΌ 174 D СХ Α ^Ν ν_Χ'Ν 1^4 Χζ J^Q 175 D dA ^D AAw 176 DAho 177A \ .O Ajo 177V CCC ⁿ hi η 178A F 178V F 179A F 179V F 72 QC A ⁿ l/' ^nh χί o 180A (XJC ⁿ a? ⁿ ' ⁿ 73 (D Stl™ x>o 180V (χΑ'Τ-Λ - ^J l G p 74 -Λ...- 181A T ⁿ /° Ase: ΛΑ /Τ^ ^ν 'ν '-' o νΆΑΧΙ n \ ^Χ Ν 75A \ 0 ΙΑ ΛΆ ^Х -^47 v~7 Jf G |) U 0 181V f ⁿ /O Ar ^N A La ^F ^^47 X 1) ° ^X N 75V ^nAn-A IX/'Tih xx --M /—JI f l) -- about 5AJ 182A sDa η 76 182V (Yes p o Idum 77 QΑ ^Ν Α{χ 183A D >C:Aw 78 Af L-MN χά _β \ο 183V D >A/Aw

-23 044271

-24044271

92 203 93 OYyu 204 'TD; 94 >o n 205 ^D D 95 (X Arch yu N 206 AAw 96 OS Χκα-ν ο A ₀ Ahl) 207 ^D D 4 0 < ⁿ V ^N ^C Uah'? ⁿ =\ 208 AHdso 98A AND ABOUT Av^X □ A L'm Λ ν' A 1 II Oh 209 98V I O Αν ^Ν Χ O A\ ⁿ z^'n ^4 Λ ν' D 1 /) ^Α ο νΆΑ> Η 99 \ Ρ Αν ^Ν Χ 1 /-“ΝΗ ^Ν Α YuA Η1 π ⁰ 100A Ατχ „ F 100V \p/ ^N _V M CU'''h^O ⁷ /=\°-yJ F 213 °Xhw 214 April 215 Ss _o 5~RTd n 102A Cc Xpx r\ A/A ° J^A 216 Apor 102V An-) 217 OS A) Λ ^Ν cA A oAaХ) SW f H p AA MX H w 218 \ .0 ί 3 А\ ⁿ / ^ν 'ν А“\ ii Г /1 Ν \ о nXAJ 103V H p A ^N v A ^nh n ^f M/ _o hw 219 \ .о ί 1 /^ ^{ΝΗ ν} α 220 ^α 7¼. Ν X

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table 2

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Table 3

Table 4

- 27 044271

Second eluting isomer

Diastereomer 1

Diastereomer 2

F

-28044271

- 29 044271

- 30 044271

- 31 044271

- 32 044271

- 33 044271

- 34 044271

- 35 044271

In specific implementations, the connection may be:

- 36 044271

- 37 044271

α a

- 38 044271

- 39 044271

- 40 044271

- 41 044271

- 42 044271

or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. In specific embodiments, the connection is

or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. In specific embodiments, the connection is

or a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

4. Methods of treatment and application.

Treatment is an approach to obtaining favorable or desired results, including clinical results. Favorable or desirable clinical results may

- 43 044271 include one or more of the following: a) inhibiting a disease or pathological condition (for example, reducing one or more symptoms caused by the specified disease or pathological condition, and/or reducing the severity of the specified disease or pathological condition); b) slowing or stopping the development of one or more clinical symptoms associated with a disease or condition (for example, stabilizing the specified disease or condition, preventing or slowing the worsening or progression of the specified disease or condition, and/or preventing or slowing the spread (for example, metastasis) of the specified disease or pathological condition); and/or c) alleviation of the specified disease, that is, causing regression of clinical symptoms (for example, alleviating the condition of the disease, providing partial or complete remission of the specified disease or pathological condition, enhancing the effect of another drug, delaying the progression of the specified disease, improving the quality of life and/ or increased survival).

Prevention refers to any treatment of a disease or condition that prevents the development of clinical symptoms of said disease or condition. In some embodiments, the compounds can be administered to a subject (including a human) with an increased risk or family history of a disease or condition.

Subject refers to an animal, such as a mammal (including a human), that is or will be the subject of treatment, observation or experiment. The methods described herein may be suitable for use in human and/or veterinary medicine. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

The term "therapeutically effective amount" or effective amount of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue thereof, means an amount sufficient to effect a treatment when administered to a subject to provide a therapeutic effect, such as relief. symptoms or slowing the progression of the disease. For example, a therapeutically effective amount may be an amount sufficient to alleviate a symptom of a disease or condition described herein. The therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the body weight and age of the subject, the severity of the disease or condition, and the route of administration, which can be readily determined by one of ordinary skill in the art.

The term trauma in the context of this document refers to any physical damage to the body caused by an attack, accident, fracture, etc. The term ischemia refers to a cardiovascular disorder characterized by a low-oxygen state, usually associated with obstructed arterial supply or inadequate blood flow, which leads to tissue hypoxia. The term stroke refers to a cardiovascular disorder caused by a blood clot or bleeding in the brain, most commonly caused by a temporary interruption of blood flow to the brain when a blood vessel is blocked by the clot, and in specific embodiments of the present invention, the term stroke refers to an ischemic stroke or hemorrhagic stroke. The term myocardial infarction refers to a cardiovascular disorder characterized by localized necrosis resulting from obstruction of the blood supply.

The methods described herein can be applied to cell populations in vivo or ex vivo. In vivo means in a living individual, that is, in an animal or a human being. In this context, the methods described herein can be used in an individual for therapeutic purposes. Ex vivo means outside the 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 can be obtained using methods well known in the art. Examples of body fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine the optimal regimen and/or dosages for administration of a compound of the present invention for a particular purpose, cell type, individual, and other parameters. The carefully selected information from this application can be used for experimental purposes or in clinical practice to establish in vivo treatment protocols. Other ex vivo applications for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to study their safe or tolerable dosages in human and non-human subjects. Such properties can be studied using methods known to those skilled in the art.

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Experiments with gene knockout animal models and Necrostatin 1, an inhibitor of receptor-interacting protein kinase 1, have shown the effectiveness of inhibition of receptor-interacting protein kinase 1 in protecting tissues from inflammatory bowel diseases (eg, ulcerative colitis and Crohn's disease), psoriasis, photoreceptor necrosis caused by retinal detachment, retinal pigmentary dystrophy, acute pancreatitis caused by caerulein, as well as sepsis/systemic inflammatory response syndrome (SIRS), and ischemic brain injury with improvement, ischemic and reperfusion injury of the retina, Huntington's disease, ischemic and reperfusion kidney injury, cisplatin-induced kidney injury, traumatic brain injury, hematologic and solid organ malignancies, bacterial and viral infections (eg, tuberculosis and influenza), and lysosomal storage diseases.

The receptor-interacting protein kinase 1 inhibitors of the present invention are therefore suitable for use in the treatment of diseases and disorders mediated by receptor-interacting protein kinase 1, including, but not limited to, inflammatory diseases or disorders, necrotic cell diseases, neurodegenerative diseases, central nervous diseases systems (CNS), eye diseases, infections and malignant neoplasms. In specific embodiments, the receptor-interacting protein kinase 1 inhibitors described herein can inhibit inflammation, protect tissue or cell from damage or unwanted cell death (e.g., necrosis or apoptosis), relieve symptoms, and improve immune response or neural function in a patient. suffering from any of the previously mentioned diseases or pathological conditions. Moreover, these compounds may be suitable for the treatment of immune-mediated disease such as, but not limited to, allergic diseases, autoimmune diseases and the prevention of transplant rejection.

Provided herein are compounds and compositions that are intended for use in treating a disease or disorder mediated by receptor-interacting protein kinase 1. Also provided is a method of treating a disease or disorder mediated by receptor-interacting protein kinase 1, the method comprising administering a therapeutically effective amount of a compound or pharmaceutical compositions described herein to a subject in need thereof. In specific embodiments, the disease or disorder is an inflammatory disease associated with the A20 SNP.

Various specific diseases and disorders are described below. In specific embodiments, said disease or disorder is an inflammatory disease or disorder, necrotizing cell disease, neurodegenerative disease, central nervous system disease, eye disease, malignancy, immune-mediated disease, allergic disease, autoimmune disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, retinal detachment, retinal pigmentary degeneration, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic arthritis with systemic onset, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis , autoimmune hepatitis, autoimmune diseases of the liver and biliary tract, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune idiopathic thrombocytopenic purpura (ITP), transplant rejection, ischemic and reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, acute cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1-converting enzyme-related fever, chronic obstructive pulmonary disease, periodic syndrome associated with tumor necrosis factor, periodontitis, trauma, ischemia, stroke, myocardial infarction, infection, lysosomal storage disease, Gaucher disease, Krabbe disease, Niemann-Pick disease, amyotrophic lateral sclerosis (ABS/Lou Gehrig's disease), HIV-related dementia, degenerative retinal disease, glaucoma, age-related macular degeneration, psoriasis, psoriatic arthritis, brain injury, spinal cord injury, dementia, Huntington's disease, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr's disease, Menkes' disease, Wilson's disease, cerebral ischemia, Friedreich's ataxia, rheumatoid arthritis, Lewy body disease, or prion disorder. In specific embodiments, the disease or disorder is trauma, ischemia, stroke, myocardial infarction, infection, lysosomal storage disease, Niemann-Pick disease, Gaucher disease, Krabbe disease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS). Lou Gehrig's disease), Huntington's disease, HIV-related dementia, encephalopathy, degenerative retinal disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease. In specific embodiments, said disease or disorder is Alzheimer's disease, ABS, Friedreich's hereditary ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, Huntington's disease, MS

- 45 044271 multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr's disease, Menkes' disease, Wilson's disease, cerebral ischemia, lysosomal storage disease or prion disorder. In specific embodiments, said disease is ABS. In specific embodiments, said disease is Alzheimer's disease. In specific embodiments, the disease is a lysosomal storage disease. In specific embodiments, said disease is Parkinson's disease. In specific embodiments, the disorder is an ischemic disease of organs including, but not limited to, the brain, heart, kidney, and liver. In some different embodiments, the disorder is an eye disease, such as degenerative retinal disease, glaucoma, or age-related macular degeneration. In some different embodiments, the disorder is a disease of the central nervous system (CNS).

In specific embodiments, the compounds and compositions are suitable for the treatment of psoriasis.

In specific embodiments, the disorder is an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis (both of which are collectively known as inflammatory bowel disease). In particular embodiments, the mammal is a primate, canine or feline subject. In particular embodiments, the mammal is a human subject. Without wishing to be bound by theory, it is believed that inhibition of receptor-interacting protein kinase 1 by the compounds disclosed herein is responsible, at least in part, for their anti-inflammatory activity. Accordingly, embodiments of the present invention also include methods of inhibiting receptor-interacting protein kinase 1, in vitro or in a subject in need thereof, such method comprising contacting receptor-interacting protein kinase 1 and a compound disclosed herein. In some of these embodiments, inhibition of receptor-interacting protein kinase 1 is effective in blocking (partial or complete) the release of inflammatory mediators such as TNF and/or IL6.

In specific embodiments, a method of treating a disease or disorder selected from the group consisting of rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SoJIA), spondyloarthritis, osteoarthritis, psoriasis, Crohn's disease, ulcerative colitis, and multiple sclerosis is provided, the method comprising administering a therapeutically effective amount of a compound provided herein to a subject in need thereof. In specific embodiments, a method is provided for treating a disease or disorder selected from the group consisting of autoimmune hepatitis, atherosclerosis, neutrophilic dermatoses, or a rare disease caused by A20, NEMO, or LUBAC mutations, the method comprising administering a therapeutically effective amount of a compound provided herein , to the subject in need. In specific embodiments, the compound has formula II (or any formula described herein or a tautomer thereof), wherein A is a triazole. In specific embodiments, the compound has formula V or Va. In specific embodiments, the method includes administering compound 42 or a tautomer thereof.

Inflammatory diseases or disorders.

The receptor-interacting protein kinase 1 inhibitors described herein are suitable for use in the treatment of inflammatory diseases and disorders. Inflammatory diseases and disorders typically involve high levels of inflammation in connective tissues or degeneration of such tissues.

Non-limiting examples of inflammatory diseases and disorders include Alzheimer's disease, 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 erythematosus (SLE), nephritis, Parkinson's disease and ulcerative colitis.

In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of rheumatoid arthritis (RA). In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of ulcerative colitis. In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of psoriasis. In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of psoriasis or psoriatic arthritis. In specific embodiments, said disease is spondyloarthritis.

Necrotic cell diseases.

The compounds described herein are suitable for use in the treatment of diseases/disorders caused by or otherwise associated with necrosis. The term necrotizing cell disease refers to diseases associated with or caused by cell necrosis, such as trauma, ischemia, stroke, myocardial infarction, infection, Gaucher disease, Krabbe disease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's, HIV-related dementia, degenerative retinal disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis, or inflammatory bowel disease.

Necrotizing cell diseases can be acute diseases such as trauma, ischemia, stroke, myocardial infarction, septic shock caused by lethal anthrax toxin, sepsis, cellular injury caused by LPS, and T cell death caused by HIV leading to immunodeficiency. Necrotizing cell diseases also include chronic neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, infectious encephalopathies and dementias such as HIV-associated dementia.

Neurodegenerative diseases and diseases of the central nervous system.

The receptor-interacting protein kinase 1 inhibitors described herein are also suitable for use in the treatment of neurodegenerative diseases. Neurodegenerative diseases can negatively impact many activities of the body, such as balance, movement, speech, breathing and cardiac function. Neurodegenerative diseases can be genetic or caused by disorders such as alcoholism, tumors, strokes, toxins, chemicals and viruses.

Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease and spinal muscular atrophy. In specific embodiments, neurodegenerative and CNS diseases include Niemann-Pick disease type C1 (NPC1), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.

In specific embodiments, the receptor-interacting protein kinase 1 inhibitors described herein are suitable for use in treating NPC1 by inhibiting necroptosis, which leads to neuronal loss. In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of Alzheimer's disease. In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of Parkinson's disease. In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of amyotrophic lateral sclerosis (ALS).

More broadly, the receptor-interacting protein kinase 1 inhibitors described herein can be used to preserve neuronal viability and promote axonal growth and neural function in the central nervous system (CNS). Accordingly, the compounds of the present invention can be used to reduce or even reverse the loss of cognitive, motor and sensory functions associated with a disease or disorder in the CNS by preserving neuronal viability and/or promoting axonal regeneration and/or neural functions.

The receptor-interacting protein kinase 1 inhibitors described herein can be used in a method of promoting axon regeneration 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 receptor-interacting protein kinase 1 inhibitors described herein can be used in a method for stimulating neural function or preserving viability after damage to a CNS neuron. In other embodiments, the compounds may be used to stimulate regeneration of the axon of a CNS neuron that has undergone degeneration due to a disease or disorder in the CNS. RIP (receptor interacting protein kinase 1) inhibitors can be administered by any standard methods, for example locally into the neuron, or applied ex vivo before engraftment.

Accordingly, according to one aspect of the present invention, there is provided a method of treating a CNS disorder in a subject in need thereof, wherein the symptom of the CNS disorder is axon degeneration or damage in a CNS neuron. The method involves administering to a subject an effective amount of a compound or composition described in the present invention so as to stimulate axon regeneration in a CNS neuron affected by a disorder in the CNS. After administration, nerve function can be assessed, for example as an indicator of axon regeneration. It is also believed that after administration of the specified compound or composition, the function of the CNS neuron is maintained or improved compared to the function of the neuron before administration.

Non-limiting examples of diseases or disorders in the central nervous system include brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Farah disease, Menkes disease, Wilson disease, cerebral ischemia and prion disorder.

In example embodiments, the CNS disorder is a traumatic brain injury or a spinal cord injury.

This document also provides methods for stimulating neuronal survival and axonal regeneration in the CNS. CNS disorders characterized by impaired or reduced axonal growth or axonal degeneration may result from injury to CNS neurons (eg, trauma, surgery, nerve compression, nerve contusion, nerve transection, neurotoxicity, or other physical injury to the brain or spinal cord) or neurodegenerative disease CNS in which axonal degeneration is a symptom of the specified disease (eg, Alzheimer's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, prion disorder (e.g., Creutzfeldt-Jakob disease) In specific embodiments, the CNS disorder is a brain injury (e.g., traumatic brain injury) or a spinal cord injury (e.g., chronic, acute, or traumatic spinal cord injury. In specific embodiments, said disturbance in the CNS affects the subject's basic vital functions, such as breathing, heart rate, and blood pressure, such as a lesion or aneurysm in the brain stem.

In specific embodiments, said disturbance in the central nervous system affects the cognitive abilities of the subject. In specific embodiments, said disturbance in the CNS affects the movement and/or strength of the subject. In specific embodiments, said disturbance in the central nervous system affects the subject's coordination.

In specific embodiments, said disorder in the CNS affects the cognitive abilities of the subject, wherein the disorder is, for example, a cortical lesion or a neurodegenerative disease of the CNS, such as Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration , progressive supranuclear palsy and prion disorders.

In specific embodiments, said CNS disorder affects the subject's movement and/or strength, wherein said disorder is, for example, a brain or spinal cord injury or a neurodegenerative CNS disease such as Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, corticosteroids. basal degeneration, progressive supranuclear palsy, Huntington's disease, multiple system atrophy, amyotrophic lateral sclerosis and hereditary spastic paresis.

In specific embodiments, said CNS disorder affects the subject's coordination, wherein the disorder is, for example, cerebellar damage or a neurodegenerative CNS disease such as spinocerebellar atphoria, Friedreich's ataxia, and prion disorders.

In each of the following methods, said CNS disorder includes, but is not limited to, brain injury, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Farah disease, Menkes disease, Wilson disease, cerebral ischemia, prion disorder (eg, Creutzfeldt-Jakob disease), corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy, hereditary spastic paresis and spinocerebellar atphoria.

Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, lysosomal storage diseases, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease and spinal muscular atrophy.

In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of Alzheimer's disease. In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of Parkinson's disease. In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of amyotrophic lateral sclerosis (ALS). In specific embodiments, the compounds and compositions of the present invention are suitable for the treatment of lysosomal storage diseases.

In specific embodiments, said disorders are brain disorders such as, but not limited to, Alzheimer's disease, ABS, frontotemporal dementia, vascular dementia, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy, multiple sclerosis, neuromyelitis optica, ischemic brain injury (stroke), hypoxic brain injury, traumatic brain injury, spinal cord injury, sepsis-induced brain injury, CNS infections, CNS abscesses, glioblastoma multiforme, epilepsy, neuropathic pain, major depression, bipolar depression, schizophrenia, autism, Niemann-Pick disease, Behcet's neurodisease.

In specific embodiments, a method of treating a disease or disorder in the CNS is provided, comprising administering a therapeutically effective amount of a compound provided herein to a subject in need thereof. In specific embodiments, said disease or disorder is Alzheimer's disease or amyotrophic lateral sclerosis (ALS). In specific embodiments, the compound has formula I (or any formula described herein) wherein A is not a triazole. In specific embodiments, said compound has formula VI.

Eye diseases.

The receptor-interacting protein kinase 1 inhibitors described herein are also suitable for use in the treatment of ocular diseases, for example, to reduce or prevent the loss of viability of photoreceptor cells or retinal pigment epithelial cells.

In particular embodiments, the present invention provides a method of preserving the visual function of the eye of a subject with an eye disease, wherein a symptom of the eye disease is loss of viability of photoreceptor cells in the retina of the eye affected by the disease. The method includes administering to the eye of a subject an effective amount of a compound or composition described in the present invention so as to maintain the viability of photoreceptor cells located in the retina of the eye. After administration, visual function (eg, visual acuity) of the eye may be maintained or improved compared to visual function of the eye before administration.

The eye disease may be a disease selected from the group consisting of age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, diabetic retinopathy, central areolar choroid dystrophy, Best's disease, adult vitelline macular degeneration, patterned degeneration, myopic dystrophy, central serous retinopathy, Stargardt disease, rod-cone dystrophy, North Carolina macular degeneration, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity. AMD can be a neovascular or dry form of AMD. Retinal detachment can be rhegmatogenous, serous, or tractional retinal detachment. In specific embodiments, said eye disease may be a disease selected from the group consisting of geographic retinal atrophy, glaucoma, and other ischemic eye diseases.

In specific embodiments, the present invention provides a method of maintaining the viability of retinal pigment epithelial cells (RPE) in the retina of a subject with an eye disease by administering a compound of the present invention. The subject being treated may have loss of retinal pigment epithelial cells in the retina of the eye due to a disease, and the eye disease may be selected from the group consisting of age-related macular degeneration (AMD), Best disease, myopic dystrophy, Stargardt disease, uveitis, vitelline adult macular degeneration, yellow spot fundus, multiple transient white dot syndrome, serpiginous choroidopathy, acute multifocal posterior placoid pigment epitheliopathy (AMPPE) and other uveitic diseases. In specific embodiments, the method comprises administering to the eye of a subject an effective amount of a compound or composition described herein to maintain the viability of retinal pigment epithelial cells.

In another embodiment, a method is provided for preserving the viability of photoreceptor cells located in the retina of a subject with an eye disease selected from the group consisting of age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, diabetic retinopathy, central areolar choroid degeneration, Best disease, adult vitelline macular degeneration, patterned dystrophy, myopic dystrophy, central serous retinopathy, Stargardt disease, rod-cone dystrophy, North Carolina macular degeneration, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity. Therefore, in specific embodiments, the method comprises administering to the eye an effective amount of a compound or composition described herein to maintain the viability of photoreceptor cells located in the retina of the eye of a subject with the disease.

In another embodiment, a method is provided for maintaining the viability of photoreceptor cells located in the retina of a mammal after retinal detachment. Retinal detachment can be a rhegmatogenous retinal detachment, tractional retinal detachment, or serous retinal detachment. In other embodiments, retinal detachment may result from a retinal tear, retinoblastoma, melanoma or other cancers, diabetic retinopathy, uveitis, choroidal neovascularization, retinal ischemia, pathological myopia, or trauma. In specific embodiments, the method comprises administering an effective amount of a compound or composition described herein to an eye in which a portion of the retinal detachment is sufficient to maintain the viability of photoreceptor cells located in that portion of the detached retina.

In another embodiment, a method is provided for preserving the visual function of the eye of a subject with an eye disease selected from the group consisting of age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, central areolar choroidal dystrophy, retinal detachment, diabetic retinopathy, Best's disease , vitelline macular degeneration in adults,

- 49 044271 patterned dystrophy, myopic dystrophy, central serous retinopathy, Stargardt disease, rod-cone dystrophy, North Carolina macular degeneration, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity, where the symptom of said eye disease is loss of photoreceptor viability retinal cells, the method comprising treating a subject with a compound or composition described herein.

According to another aspect of the present invention, there is provided a method of preserving the visual function of the eye of a subject with an eye disease, wherein the symptom of the eye disease is loss of photoreceptor cell viability and/or viability of RPE cells in the retina of the eye, the method comprising treating the subject with a compound or composition described herein.

In specific embodiments, a method is provided for preserving the visual function of the eye of a subject with eye diseases, wherein a symptom of the eye disease is loss of viability of retinal ganglion cells in the retina of the eye affected by such diseases. The method includes administering to the eye of a subject an effective amount of a compound or composition described in the present invention so as to maintain the viability of retinal ganglion cells located in the retina of the eye. After administration of the specified compound or composition, the visual function of the eye can be maintained or improved compared to the visual function of the eye before administration. In addition, once injected, the preserved retinal ganglion cell is able to support axonal regeneration.

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

The compounds described herein are also suitable for use in the treatment of optic neuropathies such as ischemic optic neuropathy (eg, arteritis-related and non-arteritic anterior ischemic optic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrating optic neuropathy, traumatic optic neuropathy , mitochondrial optic neuropathy (eg, Leber optic neuropathy), trophic optic neuropathy, toxic optic neuropathy, and hereditary optic neuropathy (eg, Leber optic neuropathy, dominant optic atrophy, Beer macular degeneration).

Also disclosed is a method for preserving the visual function of the eye of a subject with an eye disease selected from the group consisting of glaucoma, optic nerve damage, optic neuropathies, diabetic retinopathy, central retinal artery occlusion and central retinal vein occlusion. The method includes administering to the eye of a subject an effective amount of a compound or composition described in the present invention so as to preserve the viability of retinal ganglion cells located in the retina of the eye, as well as the visual function of the eye.

According to another aspect of the present invention, a method of preserving the viability of retinal ganglion cells located in the retina of a mammal affected by, for example, glaucoma, optic nerve damage, optic neuropathies, diabetic retinopathy, central retinal artery occlusion and central retinal vein occlusion is disclosed. The method involves administering an effective amount of a compound or composition described herein to an eye in which a portion of the retina has been affected to a degree sufficient to preserve the viability of retinal ganglion cells located in that portion of the affected retina. The preserved retinal ganglion cell is capable of supporting axonal regeneration.

Also disclosed is a method for promoting axonal regeneration in the eye of a subject with an eye disease, wherein a symptom of the eye disease is loss of retinal ganglion cell viability in the retina of the eye affected by such disease. The method includes administering to the eye of a subject an effective amount of a compound or composition described in the present invention so as to stimulate the regeneration of axons of retinal ganglion cells located in the retina of the eye.

It is understood that in each of the preceding embodiments, the methods and compositions described herein can be used to maintain the viability and/or promote axonal regeneration of retinal ganglion cells during the treatment of underlying diseases, including, but not limited to, glaucoma, optic nerve damage , optic neuritis, optic neuropathies, diabetic retinopathy, central retinal artery occlusion and central retinal vein occlusion.

Injury or tissue damage.

The ability of the compounds described herein to inhibit inflammation and cell death makes them suitable for alleviating injury or tissue damage. Injury or tissue damage can result from any of the diseases or conditions described above. For example, the compounds can be used to alleviate injury or damage to brain tissue following ischemic brain injury, or to alleviate injury or damage to tissue

- 50 044271 heart after myocardial infarction, or for the relief of injury or damage to brain tissue associated with Huntington's disease, Alzheimer's disease or Parkinson's disease, or for the relief of injury or damage to liver tissue associated with nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, liver disease and biliary tract or primary sclerosing cholangitis, or to relieve injury or damage to liver tissue associated with acetaminophen overdose, or to relieve injury or damage to kidney tissue associated with kidney transplantation or the administration of nephrotoxic drugs or substances. In specific embodiments, for example, the compounds can be used to alleviate injury or damage to brain tissue following injury or lung injury.

Non-limiting examples of trauma or damage to brain tissue include stroke (eg, hemorrhagic and nonhemorrhagic), traumatic brain injury (TBI), cerebral hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage secondary to cerebral arterial malformation, cerebral infarction, perinatal injury brain, non-traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, intracerebral hemorrhage, brain infections, brain tumor, silent brain injury, spinal cord injury, hypoxic-ischemic brain injury , focal cerebral ischemia, global cerebral ischemia and hypoxic hypoxia.

In one embodiment, the compounds and compositions of the present invention can be used to treat peritoneal tissue injury. Non-limiting examples of peritoneal tissue damage include peritoneal wasting, peritoneal sclerosis, and peritoneal cancer. For example, the receptor-interacting protein kinase 1 inhibitors described herein are suitable for use in the treatment of peritoneal injury caused by peritoneal dialysis fluid (PDF) and PD side effects.

Liver damage and diseases.

In one embodiment, the compounds and compositions of the present invention can be used to treat liver injury or disease. Non-limiting examples of liver injury or damage include not only degeneration or necrosis of liver parenchymal cells that result from injury caused by a specific factor, but also adverse events caused by biological responses to injury, such as mobilization, infiltration, activation of Kupffer cells, leukocytes and the like , fibrosis of liver tissue, etc., and these reactions can occur individually or in combination. In specific embodiments, the receptor-interacting protein kinase 1 inhibitors described herein are suitable for use in the treatment of steatohepatitis and hepatocellular carcinoma by inhibiting receptor-interacting protein kinase 1-dependent hepatocyte apoptosis and hepatocarcinogenesis. In one embodiment, the receptor-interacting protein kinase 1 inhibitors described herein are suitable for use in the treatment of alcoholic hepatitis, autoimmune hepatitis, fulminant liver failure, acute cholestasis, and liver injury.

Kidney damage and disease.

In one embodiment, the compounds and compositions of the present invention can be used to treat kidney injury or disease. Non-limiting examples of kidney diseases include chronic kidney disease (CKD) (eg, glomerular diseases, tubulointerstitial diseases, obstruction, polycystic kidney disease), acute kidney injury (AKI), diabetic nephropathy, fibrosis, glomerulonephritis, focal glomerulosclerosis, immune complex nephropathy, crystalline nephropathy, or lupus nephritis. Kidney disease can be caused by drug-induced kidney damage or kidney transplant rejection. Kidney disease may be characterized as nephrotic syndrome or kidney failure. In one embodiment, the receptor-interacting protein kinase 1 inhibitors described herein are suitable for use in the treatment of kidney diseases (eg, AKI) by inhibiting the cell death pathway in kidney diseases. In one embodiment, the receptor-interacting protein kinase 1 inhibitors described herein are suitable for use in treating a patient with kidney stones and preventing crystal-induced cytotoxicity and acute kidney injury by inhibiting receptor-interacting protein kinase 3-MLKL-mediated necroptosis.

Skin diseases.

In one embodiment, the compounds and compositions of the present invention can be used to treat skin diseases, including, but not limited to, inflammatory skin diseases or neutrophilic dermatosis.

Malignant neoplasms.

In one embodiment, the compounds and compositions of the present invention are suitable for the treatment of malignancies/cancers such as carcinoma, sarcoma, melanoma, lymphoma or leukemia. Non-limiting examples of malignancies, for

- 51 044271 treatments for which 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, genitourinary cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, stomach cancer, endometrial cancer, esophageal cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (eg, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusions, malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblastic tumors , hemangiopericytomas, Kaposi's sarcomas, myxoid sarcomas, round cell carcinomas, squamous cell carcinomas, squamous cell carcinomas of the esophagus, oral cancer, vulvar cancer, cancers of the adrenal cortex, ACTH-producing tumors, lymphoma and leukemia.

Infectious diseases.

In one embodiment, the compounds and compositions of the present invention are suitable for the treatment of infectious 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 infectious diseases for which the receptor-interacting protein kinase 1 inhibitors described herein are suitable for treatment include viral infectious diseases and bacterial infectious diseases. The viral infectious disease is not particularly limited and includes, for example, infectious diseases with respiratory infectious viruses (for example, infectious diseases caused by respiratory infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, adenovirus, reovirus and the like ), pneumonia caused by Staphylococcus aureus (MRSA), hemorrhagic pneumonia caused by Serratia marcescens, herpes zoster caused by the herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS and the like. The bacterial infectious disease is not particularly limited and includes, for example, infectious diseases caused by Bacillus cereus, Vibrio parahaemolyticus, Enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRSA, Salmonella, Botulinus, Candida and the like.

Bone diseases.

In one embodiment, the compounds and compositions of the present invention are suitable for the treatment of bone diseases that may result from a bone remodeling disorder in which the balance between bone formation and bone resorption is disrupted. Non-limiting examples of bone remodeling disorders include osteoporosis, Paget's disease, osteoarthritis, rheumatoid arthritis, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, congenital hypophosphatasia, fibromatous focal lesions, fibrous dysplasia, multiple myeloma, abnormal bone turnover, osteolytic bone disease, and periodontitis. Additional examples of bone diseases for which the receptor-interacting protein kinase 1 inhibitors described herein are suitable include bone fracture, bone trauma, or bone deficiency conditions associated with post-traumatic bone surgery, post-prosthetic joint surgery, post-plastic bone surgery, post- dental surgery, chemotherapy for bone, or radiotherapy for bone. Additional examples of diseases affecting bones or bone joints for which receptor-interacting protein kinase 1 inhibitors described herein are suitable for treatment include metastatic bone cancer, rheumatoid diseases such as rheumatoid arthritis, osteoarthritis and other inflammatory arthropathies. In one embodiment, the receptor-interacting protein kinase 1 inhibitors described herein are suitable for use in the treatment of postmenopausal osteoporosis by inhibiting osteocyte necroptosis and cancellous bone breakdown.

Cardiovascular diseases.

In one embodiment, the compounds and compositions of the present invention are suitable for the treatment of cardiovascular diseases, which may include platelet-depleted cardiovascular disease, occlusive disorder and stenosis. Non-limiting examples of cardiovascular diseases include coronary artery and peripheral artery disease, including, but not limited to, atherosclerosis, arterial occlusion, aneurysm formation, thrombosis, post-traumatic aneurysm formation, restenosis and post-surgical implant occlusion. Atherosclerosis is believed to be a consequence of inflammation due to insufficient adaptation, caused primarily by macrophages. Thus, the compounds and compositions of the present invention can be used to treat atherosclerosis by inhibiting macrophage necroptosis.

Transplantation.

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In one embodiment, the compounds and compositions of the present invention are suitable for treating transplant patients. Non-limiting examples of transplant patients for whom the receptor-interacting protein kinase 1 inhibitors described herein are suitable include patients with solid and non-solid organ and tissue transplants, and grafts such as liver, heart, kidney, and heterogeneous and autologous transplants. /bone marrow transplants. Immunosuppressive therapy is commonly used to prevent graft rejection in solid organ transplant recipients. Bone marrow transplant recipients typically undergo extensive radiation and chemotherapy before transplantation. Receptor-interacting protein kinase 1 and NF-κB signaling in dying cells are thought to determine cross-priming of CD8+ T cells. Thus, the receptor-interacting protein kinase 1 inhibitors described herein are suitable for use in treating a transplant patient and preventing graft rejection by modulating CD8+ T cell cross-priming.

Other diseases and pathological conditions.

Additional examples of diseases and disorders for which the receptor-interacting protein kinase 1 inhibitors described herein are suitable include pancreatitis, atopic dermatitis, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), systemic red lupus (SLE), Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, primary sclerosing cholangitis (PSC), acetaminophen toxicity, kidney damage/trauma (nephritis, transplantation, surgery, administration of nephrotoxic drugs, e.g. cisplatin, acute kidney injury (AKI), celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), acute cerebrovascular accident (cerebral infarction, stroke), myocardial infarction (MI), allergic diseases (including asthma), diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-converting enzyme 1 (ICE/caspase-1) fever, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO deficiency syndrome ( F-kappa B essential modulator gene deficiency (also known as IKK-gamma or IKKG) deficiency, HOIL-1 deficiency ((also known as RBCK1 heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain binding complex deficiency syndrome ( linear ubiquitin chain assembly complex, LUBAC), hematologic and solid organ malignancies, bacterial and viral infections (eg, tuberculosis and influenza), and lysosomal storage diseases. Additional examples of diseases and disorders for which receptor-interacting protein kinase 1 inhibitors described herein are suitable include Gaucher disease or organ failure.

Non-limiting examples of lysosomal storage diseases include Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartyl glucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, storage disease free sialic acid in children, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, disease sialic acid accumulation, Tay-Sachs disease and Wolman disease.

5. Pharmaceutical compositions and methods of administration.

The compounds provided herein are typically administered in the form of pharmaceutical compositions. Thus, also provided herein are pharmaceutical compositions that contain one or more of the compounds described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue thereof, as well as one or more pharmaceutically acceptable bases thereof, selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable carriers include, for example, inert solid diluents and excipients, diluents including sterile aqueous solution and various organic solvents, penetration enhancers, solubilizers and adjuvants. Such compositions are prepared by a method well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions can be administered in a single dose or in multiple doses. The pharmaceutical composition can be administered using various methods, including, for example, rectal, buccal, intranasal and transdermal routes. In specific embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or in the form of an inhalant.

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One route of administration is parenteral, for example by injection. Forms in which the pharmaceutical compositions described herein may be formulated for injection include, for example, aqueous or oleaginous suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solution and similar pharmaceutical carriers.

Oral administration may be another route of administration for the compounds described herein. Administration can be carried out, for example, using enteric-coated capsules or tablets. In the preparation of pharmaceutical compositions that contain at least one compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue thereof, the active ingredient is typically diluted with an excipient and/or placed in a carrier that may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid or liquid material that acts as a base, carrier or vehicle for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, starch capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid form), ointments containing, for example, more than 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions and sterile packaged powders.

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, sterile water, syrup and methylcellulose. The compositions may further include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavors.

Compositions that include at least one compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue thereof, can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or polymer matrix formulations containing the drug. Another formulation for use in the methods described herein utilizes transdermal delivery devices (patches). Such transdermal patches can be used for continuous or intermittent infusion of the compounds described herein in controlled amounts and can be configured to deliver pharmaceutical agents continuously, pulsed or as needed.

To prepare solid compositions, such as tablets, the main active ingredient can be mixed with a pharmaceutical excipient to form a solid composition into a dosage form containing a homogeneous mixture of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture thereof stereoisomers, prodrugs or deuterated analogues. Where composition data is referred to as homogeneous before dosage form, the active ingredient may be uniformly distributed throughout the composition so that the composition can be readily divided into equally effective unit dosage forms such as tablets, pills and capsules.

Tablets or pills containing the compounds described herein may be coated or otherwise formulated to provide a dosage form that provides the benefit of prolonged release, or to protect against acidic conditions of the stomach. For example, a tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being contained as a coating over the former. The two components may be separated by an enteric layer, which serves to prevent disintegration in the stomach and allows the inner component to enter the duodenum intact or be delayed for release. A variety of materials can be used for such enteric layers or coatings, including a number of polymer acids and mixtures of polymer acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid and solid compositions may contain suitable pharmaceutically acceptable excipients described herein. In specific embodiments, the compositions are administered by the oral or nasal route to achieve a local or systemic effect. In other embodiments, the compositions in pharmaceutically acceptable solvents can be nebulized using inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or said nebulizing device can be attached to an inhalation mask or intermittent positive pressure ventilator. The compositions in the form of a solution, suspension or powder can be administered, preferably orally or nasally, using devices that provide delivery of the composition in a suitable manner.

6. Dosed administration.

The specific dosage level of a compound of the present invention for any particular subject will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration and rate of elimination, combination of drugs and the severity of the particular disease in the subject being treated. For example, a dose may be expressed as the number of milligrams of a compound described herein per kilogram of subject body weight (mg/kg). Dosages from about 0.1 to 150 mg/kg may be suitable. In particular embodiments, dosages from about 0.1 to 100 mg/kg may be suitable. In other embodiments, a dose of from about 0.5 to 60 mg/kg may be suitable. Normalization according to the subject's body weight is particularly useful when adjusting dosages for subjects of widely varying body sizes, for example, when a drug is used in both children and adults, or when the effective dose for a non-human subject, such as a dog, is translated at a dose appropriate for a human subject.

The daily dose can also be expressed as the total amount of a compound described herein administered in one dose or once daily. The daily dosage of a compound described herein may range from about 1 mg to 4000 mg, from about 2000 to 4000 mg/day, from about 1 to 2000 mg/day, from about 1 to 1000 mg/day, from about 10 to 500 mg/day, about 20 to 500 mg/day, about 50 to 300 mg/day, about 75 to 200 mg/day, or about 15 to 150 mg/day.

When administered orally, the total daily dose for a human subject may range from 1 to 1000 mg, from about 1000 to 2000 mg/day, from about 10 to 500 mg/day, from about 50 to 300 mg/day, from about 75 up to 200 mg/day or from about 100 to 150 mg/day.

The compounds of the present invention or compositions thereof can be administered once, twice, three or four times daily using any suitable route of administration described above. Also, administration or treatment with these compounds can be continued for a number of days; for example, treatment is typically continued for at least 7 days, 14 days, or 28 days per course of treatment. Courses of treatment are well known for cancer chemotherapy and are often alternated with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between courses. In other embodiments, courses of treatment may also be continuous.

In specific embodiments, the method includes administering to a subject an initial daily dose of from about 1 to 800 mg of a compound described herein and increasing such dose in steps until clinical effectiveness is achieved. To increase the dose, steps of approximately 5, 10, 25, 50 or 100 mg can be used. The dose can be increased daily, every other day, twice a week or once a week.

7. Synthesis of compounds.

The compounds can be prepared using the methods described herein and standard modifications thereof, which will be apparent from the present description and methods well known in the art. Standard and well known synthetic methods may be used in addition to those presented herein. Synthesis of exemplary compounds described herein can be carried out as described in the following examples. When available, reagents can be purchased from commercial sources, such as Sigma Aldrich or other chemical suppliers.

The compounds of the present invention can be prepared using the methods described herein and standard modifications thereof, which will be apparent from the present description and methods well known in the art. Standard and well known synthetic methods may be used in addition to those presented herein. Synthesis of exemplary compounds described herein, for example, compounds having structures described by one or more of the formulas or compounds described herein, can be accomplished as described in the following examples. When available, reagents can be purchased from commercial sources, such as Sigma Aldrich or other chemical suppliers.

The compounds of the present invention can be prepared from readily available starting materials using, for example, the following general methods and techniques. It should be understood that where conventional or preferred process conditions are given (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressure, etc.), other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reagents or solvent used, but such conditions can be determined by one of ordinary skill in the art using standard optimization techniques.

In addition, as will be apparent to those skilled in the art, standard protecting groups may be needed to prevent specific functional groups from engaging in undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for the installation and removal of specific functional groups are well known in the art. For example, a variety of 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 references cited therein.

Moreover, the compounds of the present invention 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 stereoisomerically enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present invention unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.

The starting materials for the following reactions are generally known compounds or can be prepared using known techniques or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, WI, USA), Bachem (Torrance, CA, USA), Emka-Chemce or Sigma (St. Louis, MO, USA). Others can be prepared using procedures or obvious modifications thereof described in standard references such as Fieser and Fieser, Reagents in Organic Synthesis, volumes 1-15 (John Wiley, and Sons, 1991), Rodd, Chemistry of Carbon Compounds , volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, volumes 1-40 (John Wiley, and Sons, 1991), March, Advanced Organic Chemistry, (John Wiley, and Sons, ^5th Edition, 2001 ), and Larock, Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

The terms solvent, inert organic solvent, or inert solvent refer to a solvent that is inert under the reaction conditions described in conjunction with it (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like). Unless specifically stated otherwise, the solvents used in the reactions of the present invention are inert organic solvents and the reactions are carried out under an inert gas, preferably nitrogen.

The term as needed refers to the addition of an amount sufficient to achieve a specified function, for example, to bring a solution to the required volume (i.e. 100%).

Scheme 1 shows the synthesis of compounds of formula I, where LG represents a leaving group, and X ¹ , X ² , Y ¹ , Y ² , A, L, R ² , R ³ , R ⁴ and R ⁹ are as defined herein document.

Scheme 1.

As shown in Scheme 1, compounds of formula I can be prepared by contacting suitably substituted 1-a with compound 1-b under standard amide bond-forming reaction conditions. An activating agent may be used to facilitate the reaction, as is typical for peptide coupling reactions. Suitable coupling agents (or activating agents) are known in the art and include, for example, carbodiimides (e.g. N,N'-dicyclohexylcarbodiimide (DCC), N,N'-dicyclopentylcarbodiimide, N,N'diisopropylcarbodiimide (DIC), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-tert-butyl-Nmethylcarbodiimide (BMC), N-tert-butyl-N-ethylcarbodiimide (BEC), 1,3-bis(2,2-dimethyl -1,3-dioxolan4-ylmethyl)carbodiimide (BDDC), etc.), anhydrides (e.g. symmetrical, mixed or cyclic anhydrides), activated esters (e.g. phenyl activated ester, p-activated ester) hydroxam, hexafluoroacetone (HFA), etc.), acylazoles (acimidazoles using CDI, acylbenzotriazoles, etc.), acylazides, acyl halides, phosphonium salts (HOBt, PyBOP, HOAt, etc.), amino salts/ uronium (for example, tetramethylaminium salts, salts

- 56 044271 bispyrrolidinoamine, bispiperidinoamine salts, imidazolium uronium salts, pyrimidinium uronium salts, uronium salts obtained from N-trimethyl-N-phenylurea, amino/uronium combination reagents based on morpholine, uronium antimonium salts, etc.), organophosphorus reagents (e.g. phosphinic and phosphoric acid derivatives), organosulfur reagents (e.g. sulfonic acid derivatives), triazine coupling reagents (e.g. 2chloro-4,6-dimethoxy-1,3,5-triazine chloride, 4-( 4,6-dimethoxy-1,3,5-triazin-2-yl-4 methylmorpholinium, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholinium tetrafluoroborate, etc. .), pridinium coupling reagents (e.g., Mikaiyama reagent, pyridinium tetrafluoroborate coupling reagents, etc.), polymer-supported reagents (e.g., polymer-bound carbodiimide, polymer-bound TBTU, polymer-bound 2,4,6-trichloro -1,3,5-triazine, polymer-bound HOBt, polymer-bound HOSu, polymer-bound IIDQ, polymer-bound EEDQ, etc.), and the like (see, for example, El-Faham, et al. Chem. Rev., 2011, 111(11): 6557-6602; Han, et al. Tetrahedron, 2004, 60:2447-2467). The compounds of formula 1-a and 1-b for use in Scheme 1 can be prepared as described in the Schemes and Examples provided herein or by standard synthetic methods known in the art using suitable starting materials.

Scheme 2 shows an example of the synthesis of compounds that contain a 6,7-fused ring, and in which Y ¹ represents O. In Scheme 2, PG represents a protecting group (eg, BOC), and X ⁶ , X ⁷ , X ⁸ , X ⁹ , Y ² , q , R ¹ , R ³ , R ⁴ and R ¹⁰ are as defined herein.

Scheme 2.

In Scheme 2, suitably substituted 2-a can be cyclized under standard amide bond formation conditions (eg, as described above). The compounds of Formula 2-a can be obtained from commercial sources or prepared as described in the Examples provided herein or by standard synthetic methods known in the art using suitable starting materials. In addition, desired functional groups at Y ² , R ¹ , R ³ , R ⁴ and R ¹⁰ can be introduced before or after cyclization using standard synthetic methods known in the art (eg, halogenation, reduction, oxidation, olefination, alkylation etc.).

Scheme 3 shows an example of the synthesis of compounds that contain a 5,7-fused ring, and in which Y ¹ represents O. In Scheme 3, Z represents halogen, and X ¹ , X ² , X ³ , X ⁴ , X ⁵ , Y ² , q, R ¹ , R ³ , R ⁴ and R ¹⁰ are as defined herein.

Scheme 3.

In Scheme 3, suitably substituted 3-a can be contacted with hydroxylamine hydrochloride under reaction conditions suitable to produce 3-b. Ring expansion of 3-bc to produce lactam 3-c can be accomplished by contacting the oxime 3-b with phosphorus pentoxide. As an alternative to lactams, 3-c can be prepared 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 azapanon nitrogen with a compound of formula

- 57 044271

R1-LG, where LG is a suitable leaving group (eg halogen), produces 3-d. Bringing 3-d into contact with sodium azide produces 3-d. Reduction of the azide to 3-e (eg hydrogenation, triphenylphosphine, etc.) produces 3-f. The compounds of Formula 3-a can be obtained from commercial sources or prepared as described in the Examples provided herein or by standard synthetic methods known in the art using suitable starting materials. Additionally, alternative functional groups may be introduced before, during, or after the steps shown in Scheme 3 using standard synthetic methods known in the art (e.g., halogenation, reduction, oxidation, olefination, alkylation, etc.) .

Also provided herein is a method for preparing a compound of formula II:

or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, comprising giving a compound of formula XVI or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof:

it and bringing a compound of formula XVI or isomers into contact with a compound of formula XVII:

salt, tautomer, stereoisomer or mixture of stereo-

under reaction conditions suitable for the preparation of a compound of formula II or a salt, tautomer, stereoisomer or mixture of stereoisomers, wherein

Y ² represents -O-, -S-, or -NR ⁵ -;

R ⁵ represents H or optionally substituted C ₁ -C ₆ alkyl; And

L, ring A, q, R ¹ , R ³ , R ⁴ , R ⁹ , R ¹⁰ , X ⁶ , X ⁷ , X ⁸ and X ⁹ are as defined herein.

In specific embodiments, a method for preparing a compound of Formula II is provided:

or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, comprising (a) bringing a compound of formula X

or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof into contact with a compound of formula XI

under reaction conditions suitable for the preparation of a compound of formula XII or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof

- 58 044271 (b) contacting a compound of formula XII or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof under reaction conditions suitable for the preparation of a compound of formula (XIII) or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof

(c) contacting a compound of formula XIII or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof under reaction conditions suitable to produce a compound of formula XIV or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof

(d) optionally, contacting a compound of formula XIV or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof with an alkylating agent under reaction conditions suitable to produce a compound of formula XV or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof

(e) deprotecting a compound of formula XV or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof under reaction conditions suitable for preparing a compound of formula XVI or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof

and contacting a compound of formula XVI or isomers thereof with a compound of formula XVII:

salt, tautomer, stereoisomer or mixture of stereo-

under reaction conditions suitable for the preparation of a compound of formula II or a salt, tautomer, stereoisomer or mixture of stereoisomers, wherein

P represents a protecting group;

Y ² represents -O-, -S-, or -NR ⁵ -;

R ⁵ represents H or optionally substituted C ₁ -C ₆ -alkyl; And

L, ring A, q, R ¹ , R ³ , R ⁴ , R ⁹ , R ¹⁰ , X ⁶ , X ⁷ , X ⁸ and X ⁹ are as defined herein.

In specific embodiments of the methods described above, at least one of X ⁷ or X ⁹ is N. In specific embodiments of the methods described above, X ⁷ is N and X ⁶ , X ⁸ and X ⁹ are CH. In specific embodiments of the methods described above, X ⁹ represents N and X ⁶ , X ⁷ and X ⁸ represent CH. In specific embodiments of the methods described above, R ¹ represents methyl. In specific embodiments of the methods described above, Y ² represents -O-.

In specific embodiments of the methods described above, P is tert-butoxycarbonyl. In specific embodiments of the methods described above, the reaction conditions in step (b) include hydrogen gas. In specific embodiments of the methods described above, the reaction conditions in step (c) include a peptide coupling reagent. In specific embodiments of the methods described above, the alkylating agent in step (d) is methyl iodide.

It should also be understood that in any of the above diagrams, the addition of any substituent

- 59 044271 can give rise to a number of isomeric products (including, but not limited to, enantiomers or one or more diastereomers), any or all of which can be isolated and purified using standard techniques. In cases where enantiomerically pure or enriched compounds are desired, chiral chromatography and/or enantiomerically pure or enriched starting materials commonly used in the art or as described in the Examples may be used.

Examples

The following examples are included to demonstrate specific embodiments of the present invention. It will be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques for normal operation in the practice of the present invention, and thus may be considered to constitute specific preferred methods for practicing it. However, those skilled in the art will, in light of the present disclosure, understand that many changes can be made to the specific embodiments disclosed and still achieve the same or analogous results without departing from the spirit and scope of the present invention.

General techniques.

Liquid chromatography - mass spectrometry, method A.

Total ion current (TIC) and UV chromatographic traces of DMD, together with MS and UV spectra associated with the peaks, were measured using an Acquity™ UPLC/MS system equipped with a photodiode array (PDA) detector and coupled with a Waters single quadrupole mass spectrometer operating in a modified mode of positive and negative electrospray ionization. (LC/MS-ES (±) analyzes were performed using an Acquity™ CSH UPLC column, C18 (50x2.1 mm, 1.7 µm particle size), column temperature 40°C, mobile phase: A-water+ 0.1% HCOOH/B-CH ₃ CN+0.1 ^o /o HCOOH, flow rate: 1.0 µl/min, analysis time=2.0 min, gradient: t=0 min 3% B, t= 1.5 min 99.9% V, t=1.9 min 99.9% V, t=2.0 min 3% V, stop time 2.0 min Positive ER 100-1000, Negative ER 100-1000 , UV detection of DMD 210-350 nm.

Liquid chromatography - mass spectrometry, method B.

Total ion current and UV chromatographic traces of DMD along with MS and UV spectra associated with the peaks were measured using an Acquity™ UPLC/MS system equipped with a photodiode array (PDA) detector coupled to a Waters single quadrupole mass spectrometer , operating in a modified mode of positive and negative ionization by electrospray. [LC/MS-ES (+/-) analyzes were performed using an Acquity™ BEN UPLC column, C18 (50x2.1 mm, particle size 1.7 µm), column temperature 40°C, mobile phase: A - 0.1% v/v aqueous ammonium solution pH 10/B - CH3CN, flow rate: 1.0 µl/min, analysis time=2.0 min, gradient: t=0 min 3% B, t=1.5 min 99.9% B, t=1.9 min 99.9% V, t=2.0 min 3% V, stop time 2.0 min. Positive ER 100-1000, Negative ER 100-1000, UV detection DMD 210-350 nm.

Liquid chromatography - mass spectrometry, method C.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Shim-pack XRODS, 2.2 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 2.2 min with a total analysis time of 2.6 min . The column temperature was 40°C and the flow rate was 1.0 mL/min.

Liquid chromatography - mass spectrometry, method D.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Shim-pack XRODS, 2.2 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 3.2 min with a total analysis time of 3.6 min . The column temperature was 40°C and the flow rate was 1.0 mL/min.

Liquid chromatography - mass spectrometry, method E.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between the ratio of mass to

- 60 044271 charge (m/z) 90 and 900 with scanning time from 0.5 to 1.0 s. Used Ascentis Express column

C18, 2.7 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 1.8 min with a total analysis time of 2.0 min . The column temperature was 45°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method F.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Ascentis Express C18, 2.7 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 2.8 min with a total analysis time of 3.0 min . The column temperature was 45°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method G.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Kinetex EVO, 2.6 µm, 3.0x50 mm. A linear gradient was applied starting at 90% A (A: 0.05% NH4HCO3 in water) to 95% B (B: MeCN) in 1.7 min for a total analysis time of 2.0 min. The column temperature was 40°C and the flow rate was 1.3 mL/min.

Liquid chromatography - mass spectrometry, method N.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Kinetex EVO, 2.6 µm, 3.0x50 mm. A linear gradient was applied starting at 90% A (A: 0.05% NH4HCO3 in water) to 95% B (B: MeCN) in 2.7 min for a total analysis time of 3.0 min. The column temperature was 40°C and the flow rate was 1.3 mL/min.

Liquid chromatography - mass spectrometry, method I.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Ascentis Express C18, 2.7 µm, 2.1x50 mm. A linear gradient was applied starting from 90% A (A: 0.10% formic acid in water) to 100% B (B: 0.10% formic acid in MeCN) in 1.70 min with a total analysis time of 2. 0 min. The column temperature was 45°C and the flow rate was 1.0 mL/min.

Liquid chromatography - mass spectrometry, method J.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Ascentis Express C18, 2.7 µm, 2.1x50 mm. A linear gradient was applied starting from 90% A (A: 0.10% formic acid in water) to 95% B (B: 0.10% formic acid in MeCN) in 2.70 min with a total analysis time of 3. 0 min. The column temperature was 45°C and the flow rate was 1.0 mL/min.

Liquid chromatography - mass spectrometry, method K.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Ascentis Express C18, 2.7 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 1.6 min with a total analysis time of 2.0 min . The column temperature was 40°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method L.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an LCMS 2020 MS detector. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an ion electrospray source (ESI), operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Ascentis Express C18, 2.7 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 2.6 min with a total analysis time of 3.0 min . The column temperature was 40°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method M.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Kinetex XB-C18, 2.6 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 2.8 min with a total analysis time of 3.0 min . The column temperature was 40°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method N.

LCMS analyzes were carried out on an LCMS instrument from SHIMADZU, consisting of an UHPLC 20AD and an 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) operating in positive or negative mode. The mass spectrometer was scanned between mass-to-charge ratio (m/z) 90 and 900 with scan times ranging from 0.5 to 1.0 s. The column used was Ascentis Express C18, 2.7 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 1.7 min with a total analysis time of 2.0 min . The column temperature was 40°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method O.

The column used was Agilent Poroshell HPH-C18, 2.7 µm, 3.0 x 50 mm. A linear gradient was applied starting at 95% A (A: 0.05% NH ₄ HCO ₃ in water) and ending at 95% B (B: 0.05% NH ₄ HCO ₃ in MeCN) in 2.7 min with a total analysis time 3 min. The column temperature was 45°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method R.

The column used was Ascentis Express C18, 3.5 µm, 4.6x50 mm. A linear gradient was applied starting from 90% A (A: 0.05% NH4HCO3 in water) to 95% B (B: 0.05% NH4HCO3 in MeCN) in 5.2 min with a total analysis time of 5.6 min . The column temperature was 40°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method Q.

The column used was Agilent Poroshell HPH-C18, 2.7 µm, 3.0 x 50 mm. A linear gradient was applied starting from 95% A (A: 0.05% NH4HCO3 in water) to 95% B (B: 0.05% NH4HCO3 in MeCN) in 4.7 min with a total analysis time of 5.0 min . The column temperature was 40°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method R.

The column used was Agilent Poroshell HPH-C18, 2.7 µm, 3.0 x 50 mm. A linear gradient was applied starting from 95% A (A: 0.05% NH4HCO3 in water) to 95% B (B: 0.05% NH4HCO3 in MeCN) in 1.8 min with a total analysis time of 2.0 min . The column temperature was 40°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method S.

The column used was Ascentis Express C18, 2.7 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 1.8 min with a total analysis time of 2.0 min . The column temperature was 40°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, T. method.

The column used was Ascentis Express C18, 2.7 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 2.7 min with a total analysis time of 3.0 min . The column temperature was 40°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method U.

We used an Acquity UPLCTM BEN column, C18 (50x2.1 mm, particle size 1.7 µm), column temperature 40°C, mobile phase: A - 10 mM solution of aqueous ammonium bicarbonate, adjusted to pH 10 with an aqueous solution of ammonium/B - CH3CN, flow rate: 1.0 µl/min, analysis time = 2.0 min, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99 .9% V, t=2.0 min 3% V, stop time 2.0 min. Positive ER 100-1000, Negative ER 100-1000, UV detection DMD 210-350 nm.

Liquid chromatography - mass spectrometry, method V.

- 62 044271

The column used was Shim-pack XR-ODS, 2.2 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 4.2 min with a total analysis time of 5.3 min . The column temperature was 40°C and the flow rate was 1.0 mL/min.

Liquid chromatography - mass spectrometry, method W.

The column used was Shim-pack XR-ODS, 2.2 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in MeCN) in 4.2 min with a total analysis time of 5.3 min . The column temperature was 40°C and the flow rate was 1.0 mL/min.

Liquid chromatography-mass spectrometry, method X.

The column used was Ascentis Express C18, 2.7 µm, 3.0x50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 95% B (B: 0.05% TFA in MeCN) in 4.1 min with a total analysis time of 5.3 min . The column temperature was 40°C and the flow rate was 1.5 mL/min.

Liquid chromatography - mass spectrometry, method Y.

The column used was Poroshell HPH-C18, 2.7 µm, 3.0 x 50 mm. A linear gradient was applied starting from 95% A (A: 0.05% _NH4HCO3 in water) to 95% B (B: 0.05% NH4HCO3 in MeCN) in 1.8 _min with a total analysis time of 2 min. The column temperature was 45°C and the flow rate was 1.5 mL/min.

HPLC analyzes were performed on a SHIMADZU UHPLC with two LC20 AD pumps and an SPD-M20A diode array detector. The column used was XBridge C18, 3.5 µm, 4.6 x 100 mm. A linear gradient was applied starting at 90% A (A: 0.05% TFA in water) to 95% B (B: 0.05% TFA in MeCN) over 10 min with a total analysis time of 15 min. The column temperature was 40°C and the flow rate was 1.5 mL/min. The diode array detector was scanned from 200-400 nm.

Thin layer chromatography (TLC) was performed on Alugram® (Silica Gel 60 F254) from Mancherey-Nagel and typically used UV to visualize the spots. In some cases, additional imaging techniques were used. In these cases, the TLC plate was coated with iodine (prepared by adding about 1 g of I2 to 10 g of silica gel and stirring thoroughly), ninhydrin (commercially available from Aldrich) or Magic Stain (prepared by thoroughly stirring 25 g of (NH ₄ ) ₆ Mo ₇ O ₂₄ .4H ₂ O, 5 g (NH ₄ ) ₂ Ce(IV)(NO ₃ ) ₆ in 450 ml water and 50 ml concentrated H2SO4) to visualize the compound. Flash chromatography was performed using 40-63 μm (230-400 mesh) silica gel from Silicycle according to procedures similar to those described in Still, WC; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923. Standard solvents used for flash or thin layer chromatography were mixtures of chloroform/methanol, dichloromethane/methanol, ethyl acetate/methanol, and hexanes/ethyl acetate.

Analytical methods.

^l H-nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Avance III instrument equipped with a 300 MHz BBFO probe operating at 300 MHz, or one of the following instruments: a Bruker Avance 400 instrument equipped with a 400 MHz UAL S1 probe, Bruker Avance 400 instrument equipped with 6 S1 400 MHz 5 mm 1H- ¹³ C ID probe, Bruker Avance III 400 nanobar instrument equipped with 5 mm Broadband BBFO direct probe, Bruker Mercury Plus 400 NMR spectrometer equipped with Bruker 400 BBO probe, all of which operate at a frequency of 400 MHz. Spectra were obtained in the established solvent at approximately room temperature unless otherwise stated. In all cases, the NMR data coincided with the proposed structures. Flash chromatography was performed using 40-63 μm (230-400 mesh) silica gel from Silicycle according to procedures similar to those described in Still, WC; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923.

Receiving connections.

Where preparation of starting materials is not described, they are available from commercial sources, known from the literature, or can be easily obtained by those skilled in the art using standard techniques. Where compounds are stated to have been prepared analogously to earlier examples or intermediates, one skilled in the art will appreciate that reaction times, reagent equivalents, and temperatures may vary for each particular reaction, and that it may be necessary or desirable to employ others. extraction or purification techniques. Where reactions are carried out using microwave radiation, a Biotage Initiator microwave reactor is used.

The actual power supplied varies during the reaction to ensure a constant temperature.

- 63 044271

Example 1. 5-Benzyl-N-(2-chloro-4-methyl-5-oxo-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-6-yl)-1,2 -oxazole3-carboxamide.

Step 1. Preparation of N-[4,5,6,7-Tetrahydro-1-benzothiophene-4-ylidene]hydroxylamine.

A solution of hydroxylamine hydrochloride (4.56 g, 65.7 mmol) in 5N. sodium acetate solution (120 ml) was added to a solution of 6,7-dihydro-1-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 hours. Volatile compounds 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 Na ₂ SO ₄ , 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 (1.10 g, 51%). ¹ H NMR (400 MHz, CDCl3) 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.

Stage 2. Preparation of 4H,5H,6H,7H,8H-Thieno[3,2-b]azepin-5-one.

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 hours. N-[4,5,6,7-Tetrahydro- 1-Benzothiophen-4-ylidene]hydroxylamine (1.10 g, 6.58 mmol) was then added with stirring to the above solution, which had previously been heated to 100°C. After stirring for 4 hours at 110°C, the reaction mixture was cooled and carefully quenched by adding sat. NaHCO ₃ solution. The mixture was extracted with chloroform. The combined organic parts were washed with sat. a solution of NaHCO ₃ and water, dried over Na ₂ SO ₄ , 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%). 1H NMR (400 MHz, CDCl ₃ ) δ 7.90-7.69 (m, 1H), 7.08 (d, J=5.3 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 3.00 (t, J=6.9 Hz, 2H), 2.67-2.60 (m, 2H), 2.26-2.14 (m, 2H).

Stage 3. Preparation of 2-Chloro-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one.

N-Chlorosuccinimide (356 mg, 2.68 mmol) was added to a solution of 4H,5H,6H,7H,8H-thieno[3,2-b]azepin5-one (450 mg, 2.69 mmol) in DMF (10 ml ). The reaction mixture was heated to 50°C and stirred at this temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed twice with sat. NH ₄ Cl solution, dried over Na ₂ SO ₄ , 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%). 1H NMR (400 MHz, CDCl ₃ ) δ 7.73 (br.s, 1H), 6.50 (s, 1H), 2.89 (t, J=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. Preparation of 2-Chloro-6-iodo-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one.

Iodotrimethylsilane (264 μL, 0.189 mmol) was added to a solution of 2-chloro-4H,5H,6H,7H,8H-thieno[3,2b]azepin-5-one (190 mg, 0.945 mmol) and TMEDA (430 μL, 22 .8 mmol) in CH ₂ Cl ₂ (3 ml), which was pre-cooled to -10°C. The reaction mixture was stirred at -10°C for 30 minutes. Powdered iodine (360 mg, 1.42 mmol) was added. The mixture was stirred at -10°C for 1 hour, left to reach room temperature for 1.5 hours, stirred for another 30 minutes and quenched with 1 M Na2S2O3 solution. The layers were separated and the aqueous portion was extracted twice with CH2Cl2. The combined organic parts were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was triturated with CH ₂ Cl ₂ to obtain the title compound (135 mg, 44%). 1H NMR (400

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MHz, DMSO-d6) δ 10.03 (s, 1H), 6.69 (s, 1H), 4.99-4.91 (m, 1H), 3.15-3.06 (m, 1H) , 2.95 (ddd, J=17.4, 11.9,

5.5 Hz, 1H), 2.19-208 (m, 1H), 1.88 (dddd, J=14.9, 11.9, 5.1, 2.0 Hz, 1H).

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

Iodomethane (29 µl, 0.460 mmol) was added to a mixture of 2-chloro-6-iodo-4H,5H,6H,7H,8H-thieno[3,2b]azepin-5-one (135 mg, 0.418 mmol) and Cs ₂ CO ₃ (205 mg, 0.627 mmol) in DMF (6 ml). The reaction mixture was stirred at room temperature for 4 hours, cooled to 4°C and stirred at this temperature for 36 hours. Additional iodomethane (29 μl, 0.460 mmol) was added and the mixture was stirred at room temperature for 5 hours. EtOAc, and the organic part were washed twice with 0.5 M HCl, 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%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.28 (s, 1H), 4.82 (dd, J=9.2, 6.7 Hz, 1H), 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. Preparation of 6-Azido-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one.

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 NaN ₃ (20 mg, 0.307 mmol) in DMF (2 ml) was stirred at 33°C for 2 hours. EtOAc was added and the organic part was washed twice with 0.5 M HCl solution, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the title compound (52 mg), which was immediately used in the next step. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.28 (s, 1H), 4.11 (dd, J=11.7, 7.4 Hz, 1H), 3.20 (s, 3H), 2.88-2.77 (m, 2H), 2.53-2.40 (m, 1H), 2.28-2.13 (m, 1H). LC-MS (Method A): m/z=257.1 [M+H] ⁺ , 1.04 min.

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

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 temperature for 18 hours. The reaction mixture was diluted with EtOAc and washed twice with water. The organic part was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane/EtOAc, 60:40) to give the title compound (37 mg, 85% purity). 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 (s, 1H), 3.37-3.28 (m, 1H), 3.16 (s, 3H), 2.71-2.64 (m, 2H), 2.37-2.26 (m, 1H), 1.90-1.77 (m, 1H), 1.66 (br. s, 2H). LC-MS (Method A): m/z=231.1 [M+H]+, 0.41 min.

Method of combining amides A.

Step 8. Preparation and separation of 5-Benzyl-N-(2-chloro-4-methyl-5-oxo-4H,5H,6H,7H,8H-thieno[3,2b]azepin-6-yl)-1, 2-oxazole-3-carboxamide.

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 µl, 0.261 mmol) and 5-benzyl-1,2-oxazole-3-carboxylic acid (19 mg, 0.092 mmol) in DMF (3.5 ml) was stirred at room temperature for 4 hours. EtOAc was added and the organic portion was washed twice with sat. NH4Cl 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. The mixture was separated by chiral HPLC on a Whelk O-1 (R,R) column (25x2.0 cm), 10 μm, using a mobile phase of n-hexane/(EtOH/MeOH/CH ₂ Cl ₂ 45/45 /10+0.1% isopropylamine) 20/80% v/v yielding the two title compounds as separated enantiomers.

First eluting enantiomer, enantiomer 1: 1H NMR (400 MHz, CDCl ₃ ) δ 7.76 (d, J=7.5 Hz, 1H), 7.42-7.20 (m, 5H), 6.80 ( s, 1H), 6.34 (s, 1H), 4.81 (dt, J=11.2, 7.2 Hz, 1H), 4.13 (s, 2H), 3.31 (s, 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. enantiomeric purity >99.5% as determined using a Whelk O-1 (R,R) column (25 x 2.0 cm), 10 µm, using n-hexane/(EtOH/MeOH/CH ₂ Cl) mobile phase ₂ 45/45/10+0.1% isopropylamine) 20/80% v/v

Second eluting enantiomer, enantiomer 2: 1H NMR (400 MHz, CDCl ₃ ) δ 7.82-7.71 (m, 1H), 7.39-7.23 (m, 5H), 6.80 (s, 1H ), 6.34 (s, 1H), 4.81 (dt, J=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. enantiomeric purity = 98.4%, as determined using a Whelk O-1 (R,R) column (25x2.0 cm), 10 µm, using n-hexane/(EtOH/MeOH/CH ₂ Cl) mobile phase ₂ 45/45/10+0.1% isopropylamine) 20/80% v/v

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Example 2. 5-Benzyl-N-(5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole3-carboxamide.

Step 1. Preparation of (2R)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid.

Ditert-butyl dicarbonate (7.19 g, 32.9 mmol) was added to a solution of (2R)-2-amino-4-(2aminophenyl)-4-oxobutanoic acid sulfate (9.18 g, 29.9 mmol) and triethylamine ( 12.1 g, 119.6 mmol) in dioxane (50 ml) under nitrogen with stirring. The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to give the title compound (9.18 g, crude). LC-MS (method C): m/z=309.1 [M+H]+, 1.307 min.

Step 2. Preparation of (R)-tert-butyl-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) carbamate.

2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (13.6 g, 35.9 mmol) and ethyldiisopropylamine (11.6 g, 89.7 mmol) was added to a stirred solution of (2R)-4-(2aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid (9.21 g, 29.8 mmol) in N,Ndimethylformamide (50 ml ). The resulting solution was stirred for 2 hours at room temperature. The reaction mixture was diluted with water (50 ml), and extracted with ethyl acetate (3x40 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to give the title compound (2.2 g, 25%). LC-MS (method C): m/z=291.1 [M+H] ⁺ , 1.298 min.

Step 3. Preparation of tert-butyl-(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) carbamate.

Pometane (1.08 g, 7.60 mmol) was added dropwise to the stirred solution of (R)-tert-butyl(2,5-dioxo-2,3,4,5-tetraαhydro-1H-benzo[b]azepine- 3-yl)carbamate (2.01 g, 6.89 mmol) and cesium 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 temperature. Water (10 ml) was added to quench the reaction mixture. The reaction mixture was extracted with ethyl acetate (3x50 ml). The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give the title compound (1.20 g, 57%). LC-MS (method G): m/z=305.0 [M+H] ⁺ , 1.004 min.

Step 4. Preparation of tert-butyl-(5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetraαhydro-1H-benzo[b]azepin3-yl)carbamate.

Tert-butyl-(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (506.0 mg, 1.66 mmol) in methanol (20 ml) was hydrogenated in the presence of 10% palladium catalyst on a carbon carrier (50.0 mg) in an atmosphere of hydrogen (2-3 atmospheres). The resulting solution was stirred overnight at room temperature. Solids were removed by filtration and the filtrate was evaporated in vacuo to give the title compound (0.5 g, crude). LC-MS (method C): m/z=307.2 [M+H] ⁺ , 1.273 min.

Step 5. Preparation of tert-butyl-N-[5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3

- 66 044271 il]carbamate.

Diethylaminosulfur trifluoride (40.3 mg, 0.25 mmol) was added to the solution of tert-butyl-(5-hydroxy-1methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3 -yl)carbamate (30.6 mg, 0.10 mmol) in dichloromethane (2 ml) under nitrogen at 0°C. The resulting solution was stirred for 3 hours at 0°C. The reaction mixture 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 sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give the title compound (25 mg, 81%). LC-MS (Method K): m/z=208.9 [M-Boc+H]+, 0.946 min.

Step 6. Preparation of 3-amino-5-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one hydrochloride.

Tert-Butyl-N-[5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate solution (25.0 mg, 0.08 mmol) in 4n. hydrogen chloride in dioxane (2 ml) was stirred for 0.5 h at room temperature. The resulting mixture was concentrated in vacuo to give the title compound (20 mg, crude). LC-MS (Method K): m/z=208.9 [M+H] ⁺ , 0.555 min.

Step 7. Preparation of 5-benzyl-N-(5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3yl)isoxazole-3-carboxamide.

A solution of 5-benzyl-1,2-oxazole-3-carboxylic acid (16.0 mg, 0.08 mmol) in N,N-dimethylformamide (2 ml) was added to the stirred solution of 2-(7-aza-1H- benzotriazol-1-yl)-1,1,3,3tetramethyluronium (45.6 mg, 0.12 mmol), ethyldiisopropylamine (38.7 mg, 0.30 mmol), 3-amino-5-fluoro-1-methyl hydrochloride 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (20.0 mg, 0.08 mmol) in N,Ndimethylformamide (10 ml). The resulting solution was stirred for 2 hours at room temperature and then diluted with water (10 ml). The reaction mixture was extracted with ethyl acetate (3x20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 µm, 19x150 mm column; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (50.0% ACN to 70.0% in 7 min) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) 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.

Method of combining amides B.

Step 8. Preparation of 5-benzyl-N-(5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3yl)isoxazole-3-carboxamide (first eluting isomer, example 2A) and 5-benzyl-N-(5-fluoro-1-methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazol-3- carboxamide (second eluting isomer, example 2B).

3-Amino-5-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (30 mg, 0.140 mmol) was added to the stirred solution of 5-benzyl-1,2- oxazole-3-carboxylic acid (32.3 mg, 0.159 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (65.7 mg, 0.173 mmol) and N,Ndiisopropylethylamine (55.7 mg, 0.432 mmol) in N,N-dimethylformamide (5 ml). After stirring for 3 hours at room temperature, 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 under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase, water (0.05% TFA) and ACN (from 45.0% ACN to 70.0% in 7 min); detector, UV 254/220 nm to obtain title compounds:

Example 2A, first eluting isomer. ^1H NMR (300 MHz, CD3OD) δ 8.53 (d, J=6.9 Hz, 1H), 7.557.50 (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.

Example 2B, second eluting isomer: 1H NMR (300 MHz, DMSO-d 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.

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Example 3. (S)-5-benzyl-N-(1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3yl)isoxazol-3- carboxamide

Stage 6

Step 1. Preparation of (2S)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid.

Ditert-butyl dicarbonate (0.96 g, 4.39 mmol) was added to a solution of (2S)-2-amino-4-(2aminophenyl)-4-oxobutanoic acid sulfate (1.22 g, 4.00 mmol) and triethylamine ( 1.21 g, 11.98 mmol) in dioxane (10 ml) under nitrogen with stirring. The resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated in vacuo to give the title compound (1.22 g crude). LC-MS (Method K): m/z = 309.1 [M+H]+, 1.549 min.

Step 2. Preparation of tert-butyl-N-[(3S)-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3yl]carbamate.

2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.82 g, 4.80 mmol) and ethyldiisopropylamine (1.55 g, 11.99 mmol) was added to a stirred solution of (2S)-4-(2aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid (1.23 g, 4.00 mmol) in N,Ndimethylformamide (10 ml ). The resulting solution was stirred for 2 hours at room temperature. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic parts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (850 mg). LC-MS (Method K): m/z=291.1 [M+H] ⁺ , 0.850 min.

Step 3. Preparation of tert-butyl-N-[(3S)-1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3yl]carbamate.

Sweep (118 mg, 0.83 mmol) was added dropwise to the stirred mixture of tert-butyl-N-[(3S)2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3- yl]carbamate (220.0 mg, 0.76 mmol) and cesium carbonate (272 mg, 0.83 mmol) in N,N-dimethylformamide (20 ml). The resulting mixture was stirred for 6 hours at room temperature, after which water (10 ml) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (3x20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give the title compound (130 mg, 56%). LC-MS (Method K): m/z=305.0 [M+H] ⁺ , 0.907 min.

Step 4. Preparation of tert-butyl-N-[(3S)-1-methyl-5-methylidene-2-oxo-2,3,4,5-tetrahydro-1H-1benzazepin-3-yl]carbamate.

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 a nitrogen atmosphere. Then a solution of tert-butyl-N-[(3S)-1-methyl-2,5-dioxo-2,3,4,5tetrahydro-1H-1-benzazepin-3-yl]carbamate (101 .0 mg, 0.33 mmol) in tetrahydrofuran (2 ml) with stirring. The resulting solution was stirred overnight at room temperature. The reaction mixture was then quenched by adding saturated aqueous ammonium chloride (5 ml). The resulting solution was extracted with ethyl acetate (3 x 10 ml) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give the title compound (75 mg, 75%). LC-MS (method C): m/z=303.2 [M+H] ⁺ , 1.531 min.

Step 5. Preparation of (S)-3-amino-1-methyl-5-methylene-4,5-dihydro-1H-benzo[b]azepin2(3H)-one hydrochloride.

A solution of tert-butyl-N-[(3S)-1-methyl-5-methylidene-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-68 044271 yl]carbamate (40, 0 mg, 0.13 mmol) in hydrogen chloride in dioxane (4N, 6 ml) was stirred for an hour at room temperature. The reaction mixture was concentrated in vacuo to give the title compound (25.2 mg, crude). LC-MS (method C): m/z=203.2 [M+H]+, 0.635 min.

Method of combining amides C.

Step 6. Preparation of (S)-5-benzyl-N-(1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3yl)isoxazole-3 -carboxamide.

(S)-3-Amino-1-methyl-5-methylene-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one hydrochloride solution (25.4 mg, 0.10 mmol ) in N,N-dimethylformamide (2 ml) was added to a stirred solution of 5-benzyl1,2-oxazole-3-carboxylic acid (20 mg, 0.10 mmol), 1-hydroxybenzotriazole (16 mg, 0.12 mmol), 1-(3dimethylaminopropyl)-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 temperature. 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 in vacuo. The crude product was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 µm, 19x150 mm column; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (50.0% ACN to 70.0% in 7 min) to give the title compound (17.8 mg, 44%) as a white solid . The compound was further purified by chiral HPLC on a Chiralpak AS-H (25x2.0 cm) 5 µm column using n-hexane/(2-propanol/MeOH 1/1+0.1% isopropylamine) mobile phase 60 /40% v/v with obtaining title connection. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (d, J=6.8 Hz, 1H), 7.44-7.22 (m, 8H), 7.18 (d, J=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, J=12.0, 15.6 Hz, 1H). LC-MS (Method A): m/z=388.1 [M+H] ⁺ , 1.21 min. enantiomeric purity >99.5% as determined using a Chiralpak AS-H column (25x0.46 cm), 5 µm column using n-hexane/(2-propanol/MeOH 1/1+0.1%) mobile phase isopropylamine) 60/40% v/v

Example 4 (S)-1-Benzyl-4-chloro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]ohazepin3-yl )-1H-pyrazole-3-carboxamide.

_m MSB.DMF N^ _M u 1) NaH, ΤΓΦ,, 0 °C, 1h.

A/N-nh ---:--- VA G ----------* ft CT, incl. nights q' 2) BnBl, CT, 2 hours.

θ CI

Stage 1 Stage 2 /CHO

CI Stage 3\O

OS G ' /°

HATU, O1EA, DMF

Stage 4 31

Step 1. Preparation of ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate.

N-Chlorosuccinimide (0.81 g, 5.99 mmol) was added to a solution of ethyl 5-methyl-1H-pyrazole-3carboxylate (1.01 g, 6.49 mmol) in N,N-dimethylformamide (5 ml). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give the title compound (0.81 g, 65%). LCMS (method C): m/z=230.1 [M+CH ₃ CN+H]+, 1.240 min.

Step 2. Preparation of ethyl 1-benzyl-4-chloro-5-methyl-1H-pyrazole-3-carboxylate.

Sodium hydride (108 mg, 4.50 mmol) was added to a solution of ethyl 4-chloro-5-methyl-1H-pyrazole-3carboxylate (600 mg, 3.18 mmol) in tetrahydrofuran (3 ml). After stirring for 1 hour at 0°C, benzyl bromide (550 mg, 3.22 mmol) was added. The resulting mixture was stirred for 2 hours at room temperature. 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to give the title compound (500 mg, 56%). LC-MS (method E):

- 69 044271 m/z=278.9 [M+H]+, 0.986 min.

Step 3. Preparation of 1-benzyl-4-chloro-5-methyl-1H-pyrazole-3-carboxylic acid.

Potassium hydroxide (80 mg, 1.43 mmol) was added to a solution of ethyl 1-benzyl-4-chloro-5-methyl-1Hpyrazole-3-carboxylate (120 mg, 0.43 mmol) in methanol (1.5 ml) and water (0.5 ml). The resulting solution was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and diluted with water (5 ml). Added 3n. hydrochloric acid to adjust the pH to 3. The resulting solid was collected by filtration to give the title compound (110 mg). LC-MS (method F): m/z=251.0 [M+H] ⁺ , 1.323 min.

Step 4. Preparation of (S)-1-benzyl-4-chloro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine- 3-yl)-1 H-pyrazole-3-carboxamide.

The crude material obtained by amide coupling procedure B was purified by reverse phase chromatography using an Xbridge Prep C18 5 µm, 19 x 150 mm column.

Mobile phase. phase A: aqueous ammonium bicarbonate (0.05%). phase B: acetonitrile; (from 20 to 80% in 12 min) to obtain the title compound. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (d, J=7.9 Hz, 1H), 7.50 (dd, J=7.6, 1.9 Hz, 1H), 7.43-7.14 (m, 8H), 5.46 (s, 2H), 4.83 (dt, J=11.5, 7.8 Hz, 1H), 4.56 (dd, J= 11.5, 9.8 Hz, 1H), 4.42 (dd, J=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][1,4]oxazepin-3-yl)thiazol-2carboxamide.

Step 1. Preparation of ethyl 5-methylthiazole-2-carboxylate.

Oxalyl chloride (5 mL, 50.0 mmol) was added to a stirred 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 temperature and concentrated in vacuo. The precipitate was quenched by adding ethanol (50 ml) and concentrated in vacuo. The precipitate was diluted with water (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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. Preparation of ethyl 5-(bromomethyl)thiazole-2-carboxylate.

N-Bromosuccinimide (900 mg, 5.0 mmol) was added to a solution of ethyl 5-methylthiazole-2-carboxylate (850 mg, 5.0 mmol) in carbon tetrachloride (20 ml). The reaction was initiated with benzoyl peroxide (1 mg) and then heated at 75°C and 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 (3x20 ml). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane, 1/20) to give the title compound (1.0 g, 80%). LC-MS (method F): m/z=250, 252 [M+H]+, 1.490 min.

Step 3. Preparation of ethyl 5-benzylthiazole-2-carboxylate.

Ethyl 5-(bromomethyl)thiazole-2-carboxylate (300 mg, 1.38 mmol), toluene (10 ml), ethanol (5 ml), phenylboronic acid (100 mg, 2.00) were placed in a 50 ml round bottom flask. mmol) and sodium carbonate (372 mg, 5.52 mmol). The reaction mixture was placed under a nitrogen atmosphere and tetrakis(triphenylphosphine)palladium (147 mg, 0.13 mmol) was added.

The resulting solution was stirred at 85°C overnight under nitrogen and then quenched by adding water (20 ml). The resulting solution was extracted with ethyl acetate (3x40 ml). United

- 70 044271 the organic layers were washed with saturated aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane, 1/15) to give the title compound (250 mg, 56%). LC-MS (method C): m/z=248 [M+H]+, 1.971 min.

Step 4. Preparation of 5-benzylthiazole-2-carboxylic acid.

A solution of lithium hydroxide (5.4 mg, 2.02 mmol) in water (3 ml) was added to a solution of ethyl 5benzylthiazole-2-carboxylate (100 mg, 0.405 mmol) in tetrahydrofuran (9 ml). The resulting solution was stirred for 2 hours at room temperature and diluted with water (10 ml). The pH value of the solution was adjusted to 3-4 using 1N. aqueous solution of hydrogen chloride. The resulting solution was extracted with ethyl acetate (3x20 ml) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (80 mg, 76%). LC-MS (method F): m/z =220 [M+H]+, 0.790 min.

Step 5. Preparation of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)thiazol-2-carboxamide.

The crude material obtained by the amide C coupling procedure was purified by reverse phase chromatography using an Xbridge Prep C18 5 µm, 19 x 150 mm column. Mobile phase. phase A: aqueous ammonium bicarbonate (0.05%). phase B: acetonitrile; (from 20% to 80% in 12 min) to obtain the title compound. 1H NMR (300 MHz, Chloroform-d) 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)-1-Benzyl-4-fluoro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepineSelectfluor__/ / ^Ν ΝΗ 1) NaH, ΤΓΦ·, o°C, 1 hour.

MeCN, 65°C overnight O DH 2) VpVg, CT, 2h.

Stage 1 ^F Stage 2

3-yl)-1H-pyrazole-3-carboxamide.

Step 1. Preparation of ethyl 4-fluoro-5-methyl-1H-pyrazole-3-carboxylate.

Selectfluor (3.5 g, 9.9 mmol) was added to a solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (1.01 g, 6.49 mmol) in acetonitrile (10 ml). The resulting solution was stirred overnight at 65°C in an oil bath. The reaction mixture was cooled to room temperature and concentrated in vacuo. The precipitate was diluted with water (10 ml) and extracted with ethyl acetate (2x10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to give the title compound (660 mg, 59%). LC-MS (method E): m/z=172.9 [M+H]+, 0.607 min.

Step 2. Preparation of ethyl 1-benzyl-4-fluoro-5-methyl-1H-pyrazole-3-carboxylate.

Sodium hydride (118 mg, 4.92 mmol) was added to a solution of ethyl 4-fluoro-5-methyl-1H-pyrazole-3carboxylate (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 temperature. The reaction mixture was then quenched with water (20 ml) and extracted with ethyl acetate (2x20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to give the title compound (240 mg, 26%). LC-MS (method C): m/z=263.1 [M+H]+, 1.490 min.

Step 3. Preparation of 1-benzyl-4-fluoro-5-methyl-1H-pyrazole-3-carboxylic acid.

Potassium hydroxide (80 mg, 1.43 mmol) was added to a solution of ethyl 1-benzyl-4-fluoro-5-methyl-1Hpyrazole-3-carboxylate (113 mg, 0.43 mmol) in methanol (1.5 ml) and water (0.5 ml). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated in vacuo 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 give the title compound (110 mg). LC

- 71 044271

MS (method E): m/z=235.1 [M+H]+, 1.257 min.

Step 4. Preparation of (S)-1-benzyl-4-fluoro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-teIragidrobenzo[b][1,4]oxazepine- 3 -yl)-1 H-pyrazol-3-carboxamide.

The crude material obtained by amide coupling procedure B was purified by reverse phase chromatography using an Xbridge Prep C18 5 µm 19x150 mm column. Mobile phase. phase A: aqueous ammonium bicarbonate (0.05%). phase B: acetonitrile; (from 20 to 80% in 12 min) to obtain the title compound. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (d, J=8.0 Hz, 1H), 7.50 (dd, J=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, J=11.4, 7.8 Hz, 1H), 4.56 (dd, J=11.5, 9.8 Hz, 1H), 4.42 (dd, J=9.8, 7.7 Hz, 1H), 3.32 (s , 3H), 2.16 (d, J=1.4 Hz, 3H). LC-MS (method F): m/z=409.1 [M+H] ⁺ .1.412 min.

Example 7. 5-Benzyl-N-((2S)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepine-2-

1) KOH, Et ₂ O, O°c, 11h

2) Pd(OAc) ₂ , o °C to RT, V

Stage 4

Step 1. Preparation of (Z)-mret-butyl-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepin-3-yl)carbamate.

To a solution of tert-butyl-(5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3yl)carbamate (918.0 mg, 3.00 mmol ) and triethylamine (909.0 mg, 9.00 mmol) in dichloromethane (20 ml), a solution of methanesulfonyl chloride (687 mg, 6.00 mmol) in dichloromethane (2 ml) was added dropwise at 0°C. After stirring overnight at room temperature, the reaction mixture was quenched by adding water (10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. 1,8-Diazabicyclo[5.4.0]undec7-ene was added to the crude solid with stirring. The resulting 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 (3x40 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.3 g, crude). LC-MS (method C): m/z=289.0 [M+H] ⁺ , 1.494 min.

Step 2. Preparation of tert-butyl-N-[7-methyl-6-oxo-7-azatricyclo[6,4.0,O-[2,4]]dodeca-1(8),9,11trien-5-yl] carbamate.

A solution of 1-methyl-1-nitrosourea (1.073 g, 10.41 mmol) in ester (10 ml) was added dropwise to a solution of potassium hydroxide (1.166 g, 20.78 mmol) in water (1.75 ml) with stirring at 0°C. After stirring for 1 hour at 0°C, the organic phase was separated to obtain a diazomethane solution (10 ml). To a solution of (Z)-tert-butyl-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepin-3yl)carbamate (300.0 mg, 1.04 mmol) in tetrahydrofuran ( 4 ml) diazomethane solution (10 ml) was added with stirring at 0°C. A solution of palladium diacetate (23.3 mg, 0.10 mmol) in tetrahydrofuran (1 ml) was added dropwise to this mixture with stirring at 0°C. The resulting mixture was stirred overnight at room temperature. Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give the title compound (50 mg, 16%). LC-MS (Method N): m/z=303.1 [M+H] ⁺ , 1.043 min.

Step 3. Preparation of 5-amino-7-methyl-7-azatricyclo[6,4.0,0-[2,4]]dodeca-1(8),9,11trien-6-one hydrochloride.

A solution of tert-butyl-N-[7-methyl-6-oxo-7-azatricyclo[6,4.0,0-[2,4]]dodeca-1(8),9,11-trien-5yl]carbamate (151 .0 mg, 0.50 mmol) were exposed to 4N. hydrogen chloride in dioxane (10 ml) for 1 hour at room temperature. The reaction mixture was concentrated in vacuo to give the title compound (50 mg, crude). LC-MS (method C): m/z=203.1 [M+H]+, 1.043 min.

Step 4. Preparation of 5-benzyl-N-((2S)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)isoxazole -3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 µm, 19x150 mm column; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (50.0% ACN to 70.0% in 7 min) to obtain the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.82 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.397.20 (m, 8H), 6.60 (s, 1H), 4.45 (d, J=7.5 Hz, 1H), 4.22 (s, 2H), 3.22 (s, 3H), 2.30- 2.21 (m, 1H), 1.92-1.84 (m, 1H), 1.08-1.01 (m, 2H). LC-MS (Method H): m/z=388.1 [M+H]+, 1.700 min.

The mixture was separated by chiral HPLC on a Chiralpak IB column (25x2.0 cm), 5 µm using a mobile phase of n-hexane/(ethanol/methanol/dichloromethane 45/45/10 + 0.1% isopropylamine) 60/ 40% v/v at a flow rate of 18 ml/min to obtain two separated enantiomers.

First eluting enantiomer (6.3 min), enantiomer 1: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J=7.0 Hz, 1H), 7.40-7.16 (m, 8H), 7.10 (dd, J=7.8, 1.4 Hz, 1H), 6.35 (s, 1H), 4.76 (d, J=7.2 Hz, 1H), 4, 12 (s, 2H), 3.35 (s, 3H), 2.17-2.08 (m, 1H), 2.02 (td, J=8.7, 4.9 Hz, 1H), 1 .22 (q, J=5.3 Hz, 1H), 1.05 (td, J=8.5, 6.5 Hz, 1H). LC-MS (Method A): m/z=388.3 [M+H] ⁺ , 1.17 min. enantiomeric purity >99.9% as determined using a Chiralpak IB column (25x0.46 cm), 5 µm using nhexane/(ethanol/methanol/dichloromethane 45/45/10 + 0.1% isopropylamine) mobile phase 60/40% v/v with a flow rate of 1 ml/min.

Second eluting enantiomer (7.9 min), enantiomer 2: 1H NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, J=7.3 Hz, 1H), 7.41-7.17 (m, 8H ), 7.12 (dd, J=7.7, 1.6 Hz, 1H), 6.37 (s, 1H), 4.78 (d, J=7.0 Hz, 1H), 4.14 (s, 2H), 3.36 (s, 3H), 2.14 (td, J=9.2, 5.4 Hz, 1H), 2.03 (td, J=8.7, 5.0 Hz, 1H), 1.23 (q, J=5.3 Hz, 1H), 1.07 (td, J=8.5, 6.3 Hz, 1H). LC-MS (Method A): m/z=388.3 [M+H] ⁺ , 1.17 min. enantiomeric purity >99.9% as determined using a Chiralpak IB column (25x0.46 cm), 5 µm using nhexane/(ethanol/methanol/dichloromethane 45/45/10+0.1% isopropylamine) mobile phase 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][1,4]oxazepin-3-yl)-5-(1phenylcyclopropyl)isoxazole-3 -carboxamide.

Stage 3

Step 1. Preparation of methyl 5-(1-phenylcyclopropyl)-1,2-oxazole-3-carboxylate.

A solution of 1-methyl-1-nitrosourea (449.8 mg, 4.36 mmol) in ester (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 h at 0°C, the organic phase was separated to obtain a diazomethane solution (10 ml). To a solution of ethyl 5-(1-phenylethenyl)-1,2-oxazole-3-carboxylate (50.0 mg, 0.21 mmol) in tetrahydrofuran (3 ml) was added a solution of diazomethane (10 ml) with stirring at 0° C followed by adding a solution of palladium diacetate (4.7 mg, 0.02 mmol) in tetrahydrofuran (1 ml) dropwise with stirring at 0°C. The resulting solution was stirred overnight at room temperature. Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give the title compound (30 mg, 57%) as a yellow solid. LC-MS (method C): m/z=244.0 [M+H] ⁺ , 1.519 min.

Step 2. Preparation of 5-(1-phenylcyclopropyl)-1,2-oxazole-3-carboxylic acid.

A solution of methyl 5-(1-phenylcyclopropyl)-1,2-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 temperature. The pH value of the solution was adjusted to 6-7 using 1N. 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 in vacuo to give

- 73 044271 title compound (20 mg, crude). LC-MS (Method G): m/z=230 [M+H]+, 0.700 min.

Step 3. Preparation of (S)-N-(5-methyl-4-oxCO-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1phenylcyclopropyl)isoxazol- 3-carboxamide.

The crude product obtained by the amine coupling procedure B was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 µm, 19x150 mm column; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (50.0% ACN to 70.0% in 7 min) to obtain the title compound. ¹ H NMR (300 MHz, DMSO-d^ 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-(1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1'-cyclopropane]-3 yl)isoxazole -3-carboxamide.

Step 1. Preparation of tert-butyl-N-[(3S)-1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1cyclopropan]-3-yl]carbamate.

A solution of 1-methyl-1-nitrosourea (255.8 mg, 2.48 mmol) in ester (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 h at 0°C, the organic phase was separated to obtain a diazomethane solution (10 ml). To a solution of tert-butyl-N-[(3R)-1-methyl-2-oxo-2,3-dihydro-1H-1-benzazenin-3yl]carbamate (75.0 mg, 0.25 mmol) in tetrahydrofuran ( 1.5 ml), a solution of diazomethane (10 ml) was added dropwise, followed by a solution of palladium diacetate (5.5 mg, 0.02 mmol) in tetrahydrofuran (0.5 ml) was added dropwise with stirring at 0°C. The resulting solution was stirred overnight at room temperature. Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give the title compound (55 mg, 70%). LC-MS (method C): m/z=317.2 [M+H] ⁺ , 1.531 min.

Step 2. Preparation of (3S)-3-amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine5,1-cyclopropan]-2-one hydrochloride.

Tert-butyl-N-[(3S)-1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-3 yl]carbamate (40.0 mg , 0.13 mmol) were exposed to 4N. hydrogen chloride in dioxane (6 ml) for 1 hour at room temperature. The resulting mixture was concentrated in vacuo to give 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. Preparation of (S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydrosniro[benzo[b]azepin-5,1'cyclopropan]-3-yl) isoxazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 µm, 19x150 mm column; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (50 to 70% in 7 min) to give the title compound (17.8 mg, 44%) as a white solid. The compound was further purified by chiral HPLC on a Chiralpak AS-H (25x2.0 cm) 5 µm column using n-hexane/(2-propanol/MeOH 1/1+0.1% isopropylamine) mobile phase 60 /40% v/v with obtaining title connection. 1H NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, J=7.0 Hz, 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), 0.510.42 (m, 1H). LC-MS (Method A): m/z=402.2 [M+H] ⁺ , 1.21 min. Enantiomeric purity >99.5% as determined using a Chiralpak AS-H column (25 x 0.46 cm), 5 µm using n-hexane/(2-propanol/MeOH 1/1+0.1%) mobile phase isopropylamine) 60/40% v/v

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Example 10. 5-Benzyl-N-(5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetraαhydro-1H-benzo[b]azenin-3-yl)-4H1,2 ,4-triazole-3-carboxamide.

Stage 3

Step 1. Preparation of tert-butyl-(5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3yl)carbamate.

A solution of tert-butyl-(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (200 mg, 0.658 mmol) in bis trifluoride (2-methoxyethyl)aminosulfur (6 ml) was heated to 65°C and stirred overnight. The reaction mixture was left to warm to air temperature, quenched with water (30 ml) and extracted with ethyl acetate (3x40 ml). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane, 1/20) to give the title compound (60 mg, 30%). LC-MS (method E): m/z=327 [M+H]+, 1.035 min.

Step 2. Preparation of 3-amino-5,5-difluoro-1-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one.

Tert-butyl-(5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (40 mg, 0.184 mmol) was added to a solution (4N) of hydrogen chloride in 1,4-dioxane (30 ml). The resulting solution was stirred for 2 hours at air temperature and concentrated in vacuo to give the title compound (50 mg, crude) as a yellow solid. LC-MS (Method N): m/z=227 [M+H] ⁺ , 0.995 min.

Step 3. Preparation of 5-benzyl-N-(5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin3-yl)-4H-1, 2,4-triazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by reverse phase chromatography using an Xbridge Prep C18 5 µm, 19 x 150 mm column. Mobile phase: phase A: aqueous ammonium bicarbonate (0.05%); phase B: acetonitrile; (from 20 to 80% in 12 min) to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) 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), 3.152.81 (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-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin3-yl) -4H-1,2,4-triazole-3-carboxamide and 5-benzyl-N-((3R,5S)-5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro1H- benzo[b]αzepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (example 11) and 5-benzyl-N-((3S,5S)-5-fluoro-1methyl-2- oxo-2,3,4,5-tetrahydro-1H-benzo[b]αzepin-3-yl)-4H-1,2,4-triazole-3-carboxamide and 5-benzyl-N((3R,5R) -5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]αzepin-3-yl)-4H-1,2,4-triazole-3carboxamide (example 12 ).

Second eluting isomer

Example 12

The crude product obtained by the amine coupling procedure A was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 µm, 19x150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 25.0% to 55.0% in 7 min) to obtain the title compounds.

Example 11, first eluting isomer: 1H NMR (400 MHz, DMSO-d ₆ ) δ 14.41 (s, 1H), 8.41 (s, 1H), 7.65-7.49 (m, 2H), 7.45 (dt, J=1.1, 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.

Example 12, second eluting isomer: 1H NMR (400 MHz, DMSO-d ₆ ) 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 separation.

The mixture was separated by chiral HPLC on a Whelk O-1 (R,R) (25 x 2.0 cm), 10 µm column using n-hexane/(ethanol + 0.1% isopropylamine) 30/70% mobile phase. v/v at a flow rate of 18 ml/min to obtain two separated enantiomers.

First eluting enantiomer (6.8 min), enantiomer 1: 1H NMR (400 MHz, CDCl ₃ ) 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. enantiomeric purity >99.9% as determined by Whelk O-1 (R,R) column (25 x 0.46 cm), 5 µm using n-hexane/(ethanol + 0.1% isopropylamine) mobile phase 30/70% v/v with a flow rate of 1 ml/min.

Second eluting enantiomer (8.9 min), enantiomer 2: 1H NMR (400 MHz, CDCl ₃ ) 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. enantiomeric purity >99.9% as determined by Whelk O-1 (R,R) column (25 x 0.46 cm), 5 µm using n-hexane/(ethanol + 0.1% isopropylamine) mobile phase 30/70% v/v with a flow rate of 1 ml/min.

Example 12: Chiral separation.

The mixture was separated by chiral HPLC on a Chiralcel OJ-H column (25x2.0 cm), 5 µm using a mobile phase of n-hexane/(ethanol/methanol 1/1+0.1% isopropylamine) 30/70% v/v at a flow rate of 18 ml/min to obtain two separated enantiomers.

First eluting enantiomer (4.8 min), enantiomer 1: 1H NMR (400 MHz, CDCl ₃ ) 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+H] ⁺ , 0.75 min. enantiomeric purity >99.9% as determined using a Chiralcel OJ-H column (25 x 0.46 cm), 5 µm using n-hexane/(ethanol/methanol 1/1 + 0.1% isopropylamine) mobile phase 50/50% v/v with a flow rate of 1 ml/min.

Second eluting enantiomer (7.0 min), enantiomer 2: 1H NMR (400 MHz, CDCl ₃ ) 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. enantiomeric purity >99.9% as determined using a Chiralcel OJ-H column (25 x 0.46 cm), 5 µm using mobile phase n-hexane/(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][1,4]oxazepin-3-yl)-4-phenyl- 5,6dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide.

Stage 4 Stage 5

Step 1. Preparation of (2S,3R)-1-nitroso-3-phenylpyrrolidine-2-carboxylic acid.

- 76 044271 (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 temperature, diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (700 mg, crude). LC-MS (method I): m/z=220.95 [M+H]+, 0.741 min.

Step 2. Preparation of (R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[1,2c][1,2,3]oxadiazol-7ia-3a-ide.

To a solution of (2S,3R)-1-nitroso-3-phenylpyrrolidine-2-carboxylic acid (700 mg, 3.18 mmol) in ester (7 ml) at 0°C, trifluoroacetic anhydride (1.01 g) was added dropwise , 4.76 mmol). The resulting solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water (50 ml). The pH of the solution was adjusted to 8 using potassium carbonate (0.5 M). The resulting solution was extracted with dichloromethane (3x50 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1:1) to give the title compound (380 mg, 59%). LC-MS (method I): m/z=202.9 [M+H] ⁺ , 0.725 min.

Step 3. Preparation of ethyl-(4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carboxylate.

To a solution of (R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxαdiazol-7-ium-3a-ideα (380 mg, 1.88 mmol) in o-xylene (6 ml), purged and under an inert nitrogen atmosphere, ethylprop-2-inoate (240 mg, 2.45 mmol) was added 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 give the title compound (100 mg, 21%). LC-MS (method J): m/ 257.1 [M+H] ⁺ , 1.367 min.

Step 4. Preparation of (4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid.

To a solution of ethyl-(4R)-4-phenyl-4H,5H,6H-nirrolo[1,2-b]pyrazole-2-carboxylate (100 mg, 0.39 mmol) in methanol (2.1 ml) and water (0.7 ml) potassium hydroxide (67 mg, 1.19 mmol) was added. The resulting solution was stirred overnight at room temperature, concentrated in vacuo and the resulting precipitate was diluted with water. The pH value of the solution was adjusted to 3 using 3N. hydrochloric acid. The resulting solid was collected by filtration to give the title compound (80 mg, 90%). LC-MS (method I): m/z=228.9 [M+H] ⁺ , 0.804 min.

Step 5. Preparation of (R)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxαzepin-3-yl)-4phenyl-5 ,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide.

The crude product obtained by the amine coupling procedure B was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 µm, 19x150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (25.0 to 55.0% in 7 min) to obtain the title compound. ¹ H-NMR (400 MHz, DMSO-06) δ 8.12 (d, J=8.1 Hz, 1H), 7.51 (dd, J=7.5, 1.9 Hz, 1H), 7 ,39-7.20 (m, 8H), 6.32 (d, J=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, J=11.0, 7.7 Hz, 1H), 3.32 (s, 3H), 3.09 (dtd, J=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][1,4]oxazepin-3-yl)-5-(2,2,2trifluoroethyl) )isoxazole-3-carboxamide.

Stage 3

Step 1. Preparation of methyl 5-(bromomethyl)isoxazole-3-carboxylate.

To a solution of methyl 5-methylisoxazole-3-carboxylate (4.65 g, 30 mmol) and N-bromosuccinimide in carbon tetrachloride (250 ml) was added benzoyl peroxide (2 mg, 0.1 mol%). The resulting mixture was refluxed at 80°C for 24 hours. Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (1.6 g, 23%) as a white solid. LC-MS (method c): m/z=221.7 [M+H] ⁺ , 0.746 min.

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Step 2. Preparation of methyl 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylate.

To a mixture of methyl 5-(bromomethyl)isoxazole-3-carboxylate (350 mg, 1.59 mmol) and copper iodide (570 mg, 3.00 mmol) in N,N-dimethylformamide (10 ml) was added methyl-2,2 -difluoro-2-(fluorosulfonyl)acetate (1.44 g, 7.50 mmol). The resulting mixture was heated at 100°C for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (3x25 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 give 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. Preparation of 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylic acid.

To a solution of methyl 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylate (90 mg, 0.43 mmol) in 4:1 THF:H ₂ O (2.5 ml) was added lithium hydroxide (72 mg , 3 mmol). The resulting solution was stirred for 40 minutes at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure, and water (25 ml) was added to the resulting residue. This solution was washed with ethyl acetate (3x50 ml). The aqueous layer was acidified with 1N. hydrochloric acid to pH~3-4 and extracted with ethyl acetate (3x20 ml). The combined organic phases from this extract were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 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. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxαzepin-3-yl)-5-(2,2, 2trifluoroethyl)isoxazole-3-carboxamide.

The crude product obtained by the amine coupling procedure C was purified by crystallization (ethanol/n-hexane) to give the title compound. 1H NMR (300 MHz, Chloroformd) δ 7.80 (d, J=7.0 Hz, 1H), 7.26-7.19 (m, 4H), 6.71 (s, 1H), 5.04 (dt, J=11.1, 7.1 Hz, 1H), 4.76 (dd, J=9.8, 7.4 Hz, 1H), 4.28 (dd, J=11.1, 9 .7 Hz, 1H), 3.69 (q, J=9.7 Hz, 2H), 3.46 (s, 3H). LC-MS (method E): m/z=370.2 [M+H] ⁺ , 2.462 min.

Example 15 5-Benzyl-N-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)isoxazole-3-carboxamide.

The crude product obtained by the Amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Phenyl OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 50.0% ACN to 70.0% in 7 min); detector, UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (d, J=8.4 Hz, 1H), 7.25-7.14 (m, 5H), 7.15-7.07 (m , 4H), 6.52 (s, 1H), 4.19 (s, 2H), 4.17-4.04 (m, 1H), 2.89-2.69 (m, 4H), 2, 02-1.97 (m, 2H), 1.43-1.23 (m, 2H). LC-MS (method F): m/z=347.1 [M+H] ⁺ , 1.652 min.

Example 16. (S)-1-Benzyl-3-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)-1 H -pyrazole-5-carboxamide.

NaOH, EUN, H ₂ O

80°C, overnight

Stage 2

Step 1. Preparation of ethyl 1-benzyl-3-methyl-1H-pyrazole-5-carboxylate.

N,N-diisopropylethylamine (1.2 g, 9.60 mmol). After stirring overnight at room temperature, the reaction mixture was 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 reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to give the title compound (0.5 g, 65%) as a yellow oil. LC-MS (method S): m/z=245.2

- 78 044271

[M+H]+, 1.070 min.

Step 2. Preparation of 1-benzyl-3-methyl-1H-pyrazole-5-carboxylic acid.

A solution of sodium hydroxide (0.25 g, 6.02 mmol) in water (1 ml) was added to a stirred solution of ethyl 1-benzyl-3-methyl-1H-pyrazole-5-carboxylate (0.5 g, 2.01 mmol) in ethanol (2 ml). The resulting mixture was stirred overnight at 80°C. After cooling to room temperature, the reaction mixture was adjusted to pH=3-4 with aqueous hydrochloric acid (1N, 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 reduced pressure to give the title compound (0.4 g, 90%) as a 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. Preparation of (S)-1-benzyl-3-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxαzepin3-yl)-1H -pyrazole-5-carboxamide.

The crude product obtained from the Amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Phenyl OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (from 50.0% ACN to 70.0% in 7 min); Detector, UV 254 & 220 nm, producing the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (d, J=8.4 Hz, 1H), 7.53-7.47 (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][1,4]oxazepin-3-yl)-4-phenyl- 5,6dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide.

Step 1. Preparation of ethyl (4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carboxylate.

To a stirred solution of (K)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxadiazol-7ia-3a-ide (380 mg, 1 .88 mmol) in o-xylene (6 ml) under nitrogen atmosphere was added ethylprop-2-inoate (240 mg, 2.45 mmol). The resulting 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 resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to give the title compound (120 mg, 25%) as a light yellow oil. LC-MS (method J): m/z=257.0 [M+H] ⁺ , 1.323 min.

Step 2. Preparation of (4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid.

A solution of potassium hydroxide (67 mg, 1.19 mmol) in water (7 ml) was added to a solution of ethyl (4R)-4phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carboxylate (100 mg, 0.39 mmol) in methanol (2.1 ml). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure and diluted with water. The pH of the solution was adjusted to 3 using hydrochloric acid (3N, 20 ml). The precipitate was collected by filtration to obtain the title compound (50 mg, 47%) as a yellow solid. LC-MS (method I): m/z=228.9 [M+H] ⁺ , 0.738 min.

Step 3. Preparation 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[1,2-b]pyrazole-3-carboxamide.

The crude product obtained from the amine coupling procedure B was purified by preparative HPLC under the following conditions: column, Xbridge Phenyl OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 25.0% ACN to 55.0% in 7 min); detector, UV 254 & 220 nm, to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.44 (dd, J=7.6, 2 ,0 Hz, 1H), 7.34-7.14 (m, 6H), 7.10-7.02 (m, 2H), 4.77-4.58 (m, 2H), 4.35- 4.23 (m, 1H), 4.22-4.03 (m, 3H), 3.26 (s, 3H), 3.19-3.05 (m, 1H), 2.39 (dq, J=8.8, 4.3 Hz, 1H). LC-MS (method O):

- 79 044271 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][1,4]oxazepin-3yl)amino)acetamide.

Mixture of (3S)-3-amino-5-methyl-2,3,4,5-tetrahydro-1,5-benzochazepin-4-one hydrochloride (40 mg, 0.175 mmol, enantiomeric purity=90%), N-benzyl -2-chloroacetamide (18 mg, 0.097 mmol), K ₂ CO ₃ (27 mg, 0.195 mmol) and KI (32 mg, 0.195 mmol) in DMF (3 ml) were stirred at 30°C for 16 hours. The mixture was diluted EtOAc and washed twice with sat. NH ₄ Cl solution. The aqueous portion was extracted with EtOAc. The combined organic parts were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 80:20 to 0:100) to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.08 (m, 10H), 4.51-4.37 (m, 2H), 4.33 (dd, J=10.2, 7 .4 Hz, 1H), 4.12 (t, J=10.8 Hz, 1H), 3.61-3.43 (m, 3H), 3.41 (s, 3H), 3.062.97 (m , 1H). LC-MS (Method A): m/z=340.0 [M+H] ⁺ , 0.70 min enantiomeric purity = 88% as determined using a Chiralcel OD-H column (25x0.46 cm), 5 µm using a mobile phase in the form of n-hexane/(ethanol+0.1% isopropylamine) 35/65% v/v.

Example 19 (S)-5-benzyl-N-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole3-carboxamide.

Stage 1 Stage 2

Step 1. Preparation of tert-butyl-N-((3S)-5-ethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazenin-3-yl) carbamate.

Sodium hydride (8.64 mg, 0.22 mmol) was added to the stirred solution of tert-butyl-N-((3S)-4oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl) carbamate (50 mg, 0.18 mmol) in N,N-dimethylformamide (5 ml). The resulting mixture was stirred for 1 hour at room temperature. Iodoethane (33.7 mg, 0.21 mmol) was added dropwise. After stirring for 3 hours at room temperature, 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 give 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. Preparation of (3S)-3-amino-5-ethyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one hydrochloride.

Tert-butyl-N-((3S)-5-ethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate (40 mg, 0.13 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 10 ml). The reaction mixture was stirred for 3 hours at room temperature and concentrated under reduced pressure to give 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. Preparation of (S)-5-benzyl-N-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) isoxazol-3- carboxamide.

The crude product obtained by amine coupling procedure B was purified by Prep-HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase, water (0.05% TFA) and ACN (from 45.0% ACN to 70.0% in 7 min); Detector, UV 254 & 220 nm, producing title compounds. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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- 80 044271

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-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3carboxamide.

Borane-tetrahydrofuran complex (1 M solution in THF, 570 μl, 0.570 mmol) was added dropwise to a solution of 3-amino-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one ( 50 mg, 0.26 mmol) in THF (1 ml), which was pre-cooled to 0°C. The reaction mixture was left to gradually warm to room temperature and stirred for 18 hours, after which it was quenched with a 1 M HCl solution. The resulting mixture was stirred at room temperature for 3 hours. Volatile compounds were removed under reduced pressure. The crude product was purified by SCX cartridge ion exchange chromatography (MeOH then 7 M NH3 in MeOH) to give the title compound. 1H NMR (400 MHz, DMSO-d6) 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.

The crude product obtained by the amine coupling procedure C was purified by column chromatography (CH ₂ Cl ₂ -MeOH, 95:5 to 80:20) and then by reverse phase chromatography (water-CH ₃ CN, 100:0 up to 50:50) to obtain the title compound as a mixture of enantiomers. 1H NMR (400 MHz, DMSO-d ₆ ) 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-Benzyl-N-((4S,9aR)-5-oxohexahydro-1 H,3H-pyrrolo[2,1 -c][1,4]oxazepin-4yl)isoxazole-3 - carboxamide.

CW

Example 22. 5-Benzyl-N-((4S,9aS)-5-oxohexahydro-1H,3H-pyrrolo[2,1-c][1,4]oxazepin-4yl)isoxazole-3 - carboxamide.

Example 23. (S)-5-Benzyl-N-(1-methyl-2-oxoazepan-3-yl)-4H-1,2,4-triazole-3-carboxamide.

The crude product obtained by the C-amine coupling procedure was purified by column chromatography (CH ₂ Cl ₂ /MeOH 9:1), then by KP-NH-modified silica gel column chromatography (EtOAc/MeOH 9:1), and then by reverse phase chromatography (water-CH ₃ CN, 70:30) to give the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 14.44 (s, 1H), 8.34 (d, J=6.2 Hz, 1H), 7.37-7.20 (m, 5H), 4.75-4.65 (m, 1H), 4.11 (s, 2H), 3.68 (dd, J=15.4, 11.4 Hz, 1H), 3.23 (dd, J= 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-1-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)1 N-pyrrole-2-carboxamide.

The crude product obtained by the amine coupling procedure C was purified by column chromatography (cyclohexane-EtOAc, 100:0 to 70:30) to give the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.19 (m, 4H), 7.11 (d, J=6.6 Hz, 1H), 6.77 (d, J=4.3 Hz, 1H), 6.69 (d, J=4.3 Hz, 1H), 5.00 (dt, J=11.2, 6.9 Hz, 1H), 4.77 (dd, J=9 ,7, 7.4 Hz, 1H), 4.25 (dd, J=11.1, 9.7 Hz, 1h), 4.00 (s, 3H), 3.47 (s, 3H). LC-MS (Method A): m/z=325.0 [M+H]+, 0.93 min.

Example 25. (S)-5-Methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H1,2, 4-triazole-3-carboxamide.

The crude product obtained from the Amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Phenyl OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 50.0% ACN to 70.0% in 7 min); Detector, UV 254 & 220 nm, producing the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) 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][1,4]oxazepin-3-yl)acetamide.

Acetic anhydride (20.5 mg, 0.20 mmol) was added to a solution of (3S)-3-amino-5methyl-2,3,4,5-tetrahydro-1,5-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 temperature for 2 hours, the reaction mixture was diluted with water (5 ml) and extracted with dichloromethane (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The precipitate was purified using Prep-HPLC under the following conditions: column, Xbridge Phenyl OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 50.0% ACN to 70.0% in 7 min); Detector, UV 254 & 220 nm, producing the title compound. 1H NMR (400 MHz, DMSO^) 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.

Example 27. 5-Benzyl-N-((4S,9aS)-5-oxohexahydro-1H,3H-pyrrolo[2, 1-c][1,4]oxazepin-4-yl)-4H1,2,4 -triazole-3-carboxamide.

tert-butyl-(2S)-2-{[(2S)-2-{ [(benzyloxy)carbonyl] amino}-3-methoxy-3 Step 1. Preparation of oxopropoxy]methyl}pyrrolidine-1-carboxylate.

Boron trifluoride diethyletherate (0.52 mL, 4.25 mmol) was added to a solution of 1-benzyl-2-methyl (2S)-aziridine-1,2-dicarboxylate (2.00 g, 8.50 mmol) and N-Boc -L-prolinol (6.85 g, 34.03 mmol) in dry CHCl ₃ (20 ml) at -30°C under nitrogen atmosphere. The solution was left to stir overnight at room temperature, then diluted with CH ₂ Cl ₂ (20 ml) and washed with water (3x10 ml) with back extraction. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-diethyl ether, 50:50) to give the title product (3.30 g, 89%) as a colorless oil. 1H NMR (400 MHz, CDCl ₃ ) δ 7.47-7.30 (m, 5H), 5.97-5.50 (m, 1H), 5.23-5.08 (m,

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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 min.

Step 2. Preparation of methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(2S)-pyrrolidin-2ylmethoxy]propanoate.

Solution of tert-butyl-(2S)-2-{[(2S)-2-{[(benzyloxy)carbonyl](methyl)amino}-3-methoxy-3oxopropoxy]methyl}pyrrolidine-1-carboxylate (450 mg, 1 .03 mmol) in CH ₂ Cl ₂ (5 ml) and TFA (5 ml) were stirred at 0°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified using KP-NH-modified column chromatography silica gel (cyclohexane-EtOAc, 80:20 to 60:40, then pure MeOH) to give the title compound (313 mg, 90%) as a colorless oil. 1H NMR (400 MHz, CDCl ₃ ) 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, J=9.9, 3.1 Hz, 1H), 3.78 (s, 3H), 3.72 (dd, J=9.8 , 3.3 Hz, 1H), 3.51-3.44 (m, 1H), 3.39-3.32 (m, 1H), 3.25 (dq, J=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. Preparation of benzyl-N-[(4S,9aS)-5-oxooctahydropyrrolo[2,1-c][1,4]oxazepin-4yl]carbamate.

A solution of trimethylaluminum (2 M in heptane, 0.56 ml, 1.12 mmol) was added dropwise to the stirred solution of methyl (2S)-2-{[(benzuloxy)carbonyl]amino}-3-[(2S)-pyrrolidine -2-ulmethoxy]propanoate (313 mg, 0.93 mmol) in CH ₂ Cl ₂ (5 ml) at -30°C. The solution was left to warm to room temperature and left to stir at room temperature for 1 hour. The reaction mixture was cooled to 0°C and 1N was added. aqueous HCl solution (4.63 ml, 4.63 mmol) and water (5 ml). The phases were separated and the aqueous fraction was extracted twice with CH ₂ Cl ₂ , filtered through a hydrophobic inlet column filter (phase separator) and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ Cl ₂ -MeOH, 95:5) to give the title compound (217 mg, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.29 (m, 5H), 5.73 (br. s., 1H), 5.14 (br. s., 2H), 4.41 (br. s., 1H), 4.18-3.89 (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. Preparation of (4S,9aS)-4-aminooctahydropyrrolo[2,1-c][1,4]oxazepin-5-one.

Carbon-supported palladium catalyst (10%, 75 mg) was added to a solution of benzyl-N[(4S,9aS)-5-oxooctahydropyrrolo[2,1-c][1,4]oxazepin-4-yl]carbamate (215 mg , 0.71 mmol) in MeOH (5 ml) under nitrogen. The nitrogen atmosphere was replaced by a hydrogen atmosphere and the reaction mixture was stirred for 15 hours. The reaction mixture was quenched by filtration through a pad of Celite, washing with excess MeOH. The filtrate was concentrated under reduced pressure to obtain the title compound (116 mg, 96%), which was used directly in the next step. 1H NMR (400 MHz, CDCl ₃ ) δ 4.234.11 (m, 1H), 4.02 (dd, J=12.5, 1.3 Hz, 1H), 3.93 (dd, J=12.8 , 4.5 Hz, 1H), 3.80-3.68 (m, 2H), 3.64 (dd, J=4.4, 0.9 Hz, 1H), 3.41 (ddd, J= 11.9, 10.4, 6.8 Hz, 1H), 3.23 (dd, J=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. Preparation of 5-benzyl-N-((4S,9aS)-5-oxohexahydro-1H,3H-pyrrolo[2,1-c][1,4]oxazepin-4yl)-4H-1,2,4 -triazole-3-carboxamide.

To a suspension of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (50 mg, 0.246 mmol) and (4S,9aS)-4amino-octahydropyrrolo[2,1-c][1,4]oxazepine -5-one (42 mg, 0.246 mmol), N,Ndiisopropylethylamine (0.107 ml, 0.49 mmol) was added to CH2Cl2 (2 ml). The reaction mixture was stirred for 10 min, and then a solution of T3P (50 wt.% in EtOAc, 0.22 ml, 0.37 mmol) was added. After 40 min, the reaction mixture was quenched by adding water and the two phases were separated. The organic phase was washed with 0.5N. HCl solution, sat. NaHCO ₃ solution and brine, and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ Cl ₂ -MeOH, 90:10 to 70:30) to give the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, J=6.3 Hz, 1H), 7.40-7.17 (m, 5H), 4.72 (dd, J=6.9 , 4.9 Hz, 1H), 4.33-4.03 (m, 5H), 3.84 (d, J=12.8 Hz, 1H), 3.75-3.62 (m, 1H) , 3.43 (dt, J=6.8, 11.2 Hz, 1H), 3.31 (dd, J=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.

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Example 28 and 29. 5-Benzyl-N-((3R,4S)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin3-yl) isoxazole-3-carboxamide and 5-benzyl-N-((3S,4R)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1Hbenzo[b]azepin-3-yl )isoxazole-3-carboxamide (28); and 5-benzyl-N-((3R,4R)-4-fluoro-1-methyl-2-oxo-2,3,4,5tetrahydro-1H-benzo[b]azepin-3-yl)isoxazol-3- carboxamide and 5-benzyl-N-((3S,4S)-4-fluoro-1-methyl-2oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazol-3 -carboxamide (29).

28

Example 30. (S)-5-Benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)isoxazole-3carboxamide.

Stage 1. Preparation of 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one.

Sodium azide (1, 23 g, 18.8 mmol), and the reaction mixture was stirred at room temperature. A precipitate formed after 30 minutes. The reaction mixture was diluted with water (300 ml). More solids precipitated and the mixture was stirred for another 10 minutes. The solid was collected by filtration, washed with water (20 ml), and dried under vacuum. 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 temperature for 3 hours. Solids were removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated to give 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. Preparation of (3S)-3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one.

To a solution of 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (1.85 g, 11.0 mmol) in isopropanol (200 ml) at 70°C was added acid (1.42 g, 11.0 mmol) and then 2-hydroxy-5nitrobenzaldehyde (0.06 g, 0.33 mmol). The reaction mixture was stirred at 70°C for 4 days.

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After cooling to room temperature, the solid was collected by filtration, washed with isopropanol, and the filtrate was made basic with ammonium hydroxide (28%, 10 ml). The resulting solution was extracted with dichloromethane (4x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 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. Preparation of benzyl-N-((3S)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate.

A solution of potassium carbonate (2.00 g, 15 mmol) in water (4 ml) was added to a solution of (3S)-3-amino-2,3,4,5tetrahydro-1H-1-benzazepin-2-one (0.5 g, 3 mmol) in dichloromethane (30 ml), and then benzyl chloroformate (0.77 g, 4.5 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.87 g, 99%) as a white solid. LC-MS (method E): m/z = 311.0 [M+H] ⁺ , 0.838 min.

Step 4. Preparation of benzyl-N-((3S)-2-sulfanylidene-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl) carbamate.

Lawson's reagent (1.05 g, 2.6 mmol) was added to a solution of benzyl-N-((3S)-2-oxo-2,3,4,5-tetrahydro1H-1-benzazepin-3-yl)carbamate (0 .80 g, 2.6 mmol) in tetrahydrofuran (40 ml), and the reaction mixture was stirred under nitrogen atmosphere for 16 hours at room temperature. The precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting precipitate was diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The 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. Preparation of benzyl-N-((3S)-2-((2,2-dimethoxyethyl)amino)-4,5-dihydro-3H-1-benzazepin-3yl) carbamate.

2,2-Dimethoxyethanamine (1.06 g, 10.1 mmol) was added to the mixture of benzyl-N-((3S)-2-sulfanylidene2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl) carbamate (0.81 g, 2.5 mmol) and mercuric dichloride (0.89 g, 3.3 mmol) in tetrahydrofuran (25 ml). The resulting mixture was heated for 20 min at 55°C. After cooling to room temperature, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The resulting precipitate was diluted with water (20 ml) and extracted with dichloromethane (3x100 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. Preparation of (S)-benzyl-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)carbamate.

A solution of benzyl-N-((3S)-2-((2,2-dimethoxyethyl)amino)-4,5-dihydro-3H-1-benzazepin-3-yl)carbamate (0.85 g, 3 mmol) in formic acid (8 ml, 96%) was heated for 2 hours at 100°C. The black precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting precipitate was diluted with water (50 ml), made basic with aqueous sodium hydroxide (1N, 30 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 reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give the title compound (0.68 g, 95%) as a white solid. LC-MS (method E): m/z=334.0 [M+H] ⁺ , 0.671 min.

Step 7. Preparation of (S)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepine-4-amine.

A solution of (S)-benzyl-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)carbamate (0.68 g, 2 mmol) in ethanol (20 ml) kept overnight in the presence of a palladium catalyst on a carbon support (10%, 0.5 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give the title compound (0.40 g, 99%) as a yellow oil. LC-MS (method C): m/z=200.1 [M+H] ⁺ , 0.915 min.

Step 8. Preparation of (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)isoxazole3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase, water (0.1% formic acid) and ACN (from 45.0% ACN to 70.0% in 7 min); Detector, UV 254/220 nm, producing the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) 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-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin3-yl) -4H-1,2,4-triazole-3-carboxamide and 5-benzyl-N-((3S,4S)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro1H- benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (31); and 5-benzyl-N-((3R,4S)-4-fluoro-1-methyl-2-85 044271 oxo-2,3,4,5-tetrahydro-N-benzo[L]azepin-3-yl) -4H-1,2,4-triazole-3-carboxamide and 5-benzyl-N-((3S,4R)4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 N-benzo[b]azepin-3-yl)-4H-1,2,4-triazol-3-carboxamide (3 4).

Example 32. (S)-5-Benzyl-N-(9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)4H -1,2,4-triazole-3-carboxamide.

Stage 6

Step 1. Preparation of (2S)-2-(((tert-butoxy)carbonyl)amino)-3-(2-chloro-6-nitrophenoxy)propanoic acid.

Sodium hydride (60%, 0.39 g, 97.6 mmol) was added to a solution of (S)-2-(tert-butoxycarbonylamino)3-hydroxypropanoic acid (10.0 g, 48.8 mmol) in N,N- dimethylformamide (50 ml) under nitrogen atmosphere. After stirring for 2 hours at 0°C, 1-chloro-2-fluoro-3-nitrobenzene (8.6 g, 48.8 mmol) was added. The reaction mixture was stirred overnight at room temperature, quenched with hydrochloric acid (0.5 M, 50 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 reduced pressure. The resulting residue was purified by reverse phase chromatography using an RP-C18 column (acetonitrile/water, 7/3) to give 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. Preparation of (28)-3-(2-amino-6-chlorophenoxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid.

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 resulting mixture was stirred for 2 hours at 25°C. Solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 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.

Step 3. Preparation of tert-butyl-N-((3S)-9-chloro-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl) carbamate.

2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 g, 2.91 mmol) and ethyldiisopropylamine (0.94 g, 7.26 mmol) was added to a stirred solution of (28)-3-(2-amino-6chlorophenoxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid (0.80 g, 2.42 mmol) in N,Ndimethylformamide (10 ml). After stirring for 2 hours at room temperature, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3x40 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 give the title compound (0.18 g, 24%) as a yellow solid. LC-MS (Method G): m/z=313.0 [M+H]+, 1.006 min.

Step 4. Preparation of tert-butyl-N-((3S)-9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxαzepin-3yl)carbamate.

Iodomethane (82 mg, 0.58 mmol) was added dropwise to the stirred mixture of tert-butyl-N-((3S)-9chloro-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-3 -yl)carbamate (180 mg, 0.58 mmol) and cesium carbonate (188 mg, 0.58 mmol) in N,N-dimethylformamide (10 ml). After stirring for 2 hours at room temperature, the reaction mixture was quenched with water (50 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 reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to give 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. Preparation of (3S)-3-amino-9-chloro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxαzepin4-one hydrochloride.

Tert-butyl-N-((3S)-9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate (120 mg, 0. 37 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 10 ml). The reaction mixture was stirred for 1 hour at room temperature and concentrated under reduced pressure to give 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. Preparation of (S)-5-benzyl-N-(9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3yl)-4H -1,2,4-triazole-3-carboxamide

The crude product obtained from the Amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Phenyl OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 50.0% ACN to 70.0% in 7 min); Detector, UV 254 & 220 nm, producing the title compound. 1H NMR (400 MHz, CD3OD) δ 7.44-7.20 (m, 8H), 4.98 (dd, J=15.2, 10.0 Hz, 1H), 4.68 (dd, J= 13.2, 10.0 Hz, 1H), 4.46 (dd, J=15.2, 13.2 Hz, 1H), 4.17 (s, 2H), 3.42 (s, 3H). LC-MS (Q method): m/z=412.2 [M+H] ⁺ , 1.336 min.

Example 33. (S)-1-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)azetidin-3carboxamide.

O

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 30.0% ACN to 60.0% in 7 min); Detector, UV 254 & 220 nm, producing the title compound. 1H NMR (300 MHz, CDCl ₃ ) δ 7.29 (s, 4H), 7.19 (m, 4H), 7.06 (d, J=6.9 Hz, 1H), 4.95-4, 80 (m, 1H), 4.67 (dd, J=9.6, 7.5 Hz, 1H), 4.14 (dd, J=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][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl) 4H-1,2,4-triazole-3-carboxamide.

N.H.

Stage 3

Stage 4

Stage 5

Step 1. Preparation of 1-phenylcyclopropane-1-carbohydrazide.

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A solution of hydrazine in tetrahydrofuran (1 M, 30 ml) was added to a solution of 1-phenylcyclopropane-1-carboxylic acid (0.48 g, 3.00 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1 hexafluorophosphate ,1,3,3tetramethyluronium (1.37 g, 3.60 mmol) and ethyldiisopropylamine (1.16 g, 8.98 mmol) in N,Ndimethylformamide (10 ml). After stirring for 1 hour at room temperature, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3x20 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 give 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. Preparation of ethyl 2-amino-2-(((1-phenylcyclopropyl)formamido)imino)acetate.

Ethyl 2-ethoxy-2-iminoacetate (452 mg, 3.11 mmol) was added to a stirred solution of 1-phenylcyclopropane-1-carbohydrazide (528 mg, 3.00 mmol) in ethanol/ester (12 mL, 1/3). The reaction mixture was stirred for 2 hours at room temperature. The yellow solid was collected by filtration to give the title compound (300 mg, 36%). LC-MS (Method S: m/z=276.2 [M+H] ⁺ , 0.663 min.

Step 3. Preparation of ethyl 5-(1-phenylcyclopropyl)-4H-1,2,4-triazole-3-carboxylate.

A solution of ethyl 2-amino-2-(((1-phenylcyclopropyl)formamido)imino)acetate (275 mg, 1.00 mmol) in xylene (10 ml) was microwaved for 10 h 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 give the title compound (100 mg, 39%) as a yellow solid. LC-MS (method C): m/z=258.1 [M+H] ⁺ , 1.641 min.

Step 4. Preparation of 5-(1-phenylcyclopropyl)-4H-1,2,4-triazole-3-carboxylic acid.

A solution of lithium hydroxide (28 mg, 1.17 mmol) in water (1 ml) was added to a solution of ethyl 5-(1phenylcyclopropyl)-4H-1,2,4-triazole-3-carboxylate (100 mg, 0.39 mmol ) in tetrahydrofuran (3 ml), and the resulting mixture was stirred overnight at room temperature. After adjusting the pH to 67 with aqueous hydrochloric acid (1N, 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 give 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+H] ⁺ , 0.530 min.

Step 5. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1phenylcyclopropyl)-4H -1,2,4-triazole-3-carboxamide.

The crude product obtained from the Amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Phenyl OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 50.0% ACN to 70.0% in 7 min); detector, UV 254 & 220 nm, to obtain the title compound. 1H NMR (400 MHz, CD3OD) δ 7.44-7.20 (m, 9H), 4.99 (dd, J=11.6, 7.6 Hz, 1H), 4.58 (dd, J= 9.6, 7.6 Hz, 1H), 4.39 (dd, J=11.6, 10.0 Hz, 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-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,3]diazepine3 -yl)isoxazole-3-carboxamide.

°

Example 37 (R)-5-benzyl-N-(4,4-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) 4H-1,2,4-triazole-3-carboxamide.

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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-1, 2,4-triazole-3-carboxamide and (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro4H-thiazolo[4,5-b]azepine -6-yl)-4H-1,2,4-triazol-3-carboxamide.

Stage 1. Preparation of azepane-2,7-dione.

Stirred solution of azepan-2-one (11.3 g, 100 mmol), 2-hydroxyisoindoline-1,3-dione (1.63 g, 10 mmol) and cobalt acetate (88.5 mg, 0.5 mmol) in acetonitrile (100 ml) was purged with oxygen (balloon). The reaction mixture was heated overnight at 85°C under an oxygen atmosphere. Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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.

Stage 2. Preparation of 1-methylazepane-2,7-dione.

Iodomethane (1.68 g, 11.8 mmol) was added dropwise to a stirred mixture of azepane-2,7-dione (1.50 g, 11.8 mmol) and cesium carbonate (3.85 g, 5.0 mmol) in N,N-dimethylformamide (25 ml) at 0°C. The reaction mixture was stirred overnight at room temperature, quenched by adding water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give the title compound (1.1 g, 66.1%) as a yellow oil. LC-MS (method C): m/z=142.1 [M+H]+, 0.863 min.

Step 3. Preparation of 3-bromo-1-methylazepane-2,7-dione.

Bromine (632 mg, 4.00 mmol) was added to a stirred solution of 1-methylazepane-2,7-dione (564 mg, 4.0 mmol) in chloroform (10 ml). The reaction mixture was stirred at 110°C for 1.5 h in a sealed tube. The reaction mixture was concentrated under high vacuum to give the title compound (600 mg, crude) as a brown oil. LC-MS (method C): m/z=220.1 [M+H]+,

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0.940 min.

Step 4. Preparation of 2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one.

Ethanthioamide (300 mg, 4.0 mmol) was added to a solution of 3-bromo-1-methylazepane-2,7-dione (600 mg, 4.0 mmol) in pyridine (10 ml). The reaction mixture was stirred at 50°C for 16 hours, quenched by adding 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give the title compound (70 mg, 9%) as a yellow solid. LC-MS (method C): m/z=197.1 [M+H]+, 0.981 min.

Step 5. Preparation of 6-iodo-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one.

N ¹ ,N ¹ ,N ² ,N ² -tetramethylethane-1,2-diamine (124 mg, 1.07 mmol) was added to a stirred 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 a further 15 min and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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. Preparation of 6-amino-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one.

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 temperature and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 ml) and water (1 ml) and triphenylphosphine (149.3 mg, 0.57 mmol) were added in one portion. The reaction mixture was stirred at 50°C overnight, diluted with water (10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give the title compound (33 mg, 83%) as a yellow solid. LC-MS (method C): m/z=212.1 [M+H] ⁺ , 0.735 min.

Step 7. Preparation of 5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin6-yl)-4H-1, 2,4-triazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: Xbridge Prep C18, 19x150 mm, 5 µm; Mobile phase: phase A: water (10 mmol/l NH4HCO ₃ ); phase B: ACN (20 to 80% in 12 min); detector, UV 220 & 254 nm, to obtain the title compound. LC-MS (method R): m/z=397.1[M+H] ⁺ , 1.095 min.

Step 8. Preparation of (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5b]azepin-6-yl)- 4H-1,2,4-triazole-3-carboxamide (first eluting isomer) and (S)-5-benzyl-N-(2,4dimethyl-5-oxo-5,6,7,8-tetrahydro-4H- thiazolo[4,5-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (second eluting isomer).

Enantiomers of 5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)4H-1,2, 4-triazole-3-carboxamide (24 mg, 0.06 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IA, 2x25 cm, 5 µm; mobile phase A: hexanes, mobile phase B: EtOH; flow rate: 15 ml/min; gradient: from 50% B to 50% B in 17.5 minutes; UV 220 & 254 nm; RT 1:10.18 min; RT 2: 15.13 min, obtaining title compounds:

Example 38B (first eluting isomer): 1H NMR (400 MHz, Methanol- _d4 ) 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.

Example 38A (second eluting isomer): 1H NMR (400 MHz, Methanol- _d4 ) 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-(1-methyl-2-oxo-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2a] [1,3 ]diazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide.

Example 40 4H-1,2,4-triazole-3-carboxamide.

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Example 41. (S)-5-Benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)4H -1,2,4-triazole-3-carboxamide. O

Step 1. Preparation of (2S)-2-(((tert-butoxy)carbonyl)amino)-3-((4-nitropyridin-3-yl)oxy)propanoic acid.

Sodium hydride (60%, 1.92 g, 80.1 mmol) was added to a stirred solution of (2S)-2-(m-tertbutoxycarbonylamino)-3-hydroxypropanoic acid (8.21 g, 40.0 mmol) in dimethylformamide (30 ml ) in a nitrogen atmosphere at 0°C. After stirring for 2 hours at 0°C, a solution of 3fluoro-4-nitropyridine (5.52 g, 40.0 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature, quenched by adding water (10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The precipitate was purified by reverse phase CombiFlash using an RP-C18 column (acetonitrile/water, 1/4) to give the title compound (2.41 g, 18%) as a yellow solid. LCMS (method S): m/z=328.1 [M+H]+, 0.829 min.

Step 2. Preparation of (2S)-3-((4-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid.

(2S)-2-(((tert-butoxy)carbonyl)amino)-3-((4-nitropyridin-3-yl)oxy)propanoic acid (2.41 g, 7.34 mmol) in methanol (20 ml ) were kept overnight at room temperature in the presence of a palladium catalyst on a carbon support (10%, 345 mg) in a hydrogen atmosphere (2-3 atm). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give 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]+, 0.601 min.

Step 3. Preparation of tert-butyl-N-((3S)-2-oxo-1H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin-3yl)carbamate.

2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.5 g, 4.04 mmol) and ethyldiisopropylamine (1.30 g, 10.1 mmol) was added to a stirred solution of (2S)-3-((4aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid (1.01 g, 3.37 mmol) in

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N,N-dimethylformamide (13 ml). After stirring for 3 hours at room temperature, 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 resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give 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. Preparation of tert-butyl-N-((3S)-1-methyl-2-oxo-1H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin3-yl)carbamate.

Iodomethane (203 mg, 1.43 mmol) was added dropwise to the mixture of tert-butyl-N-((3S)-2-oxo-1H,2H,3H,4Hpyrido[3,4-b][1,4]oxazepine -3-yl)carbamate (400 mg, 1.43 mmol) and cesium carbonate (467 mg, 1.43 mmol) in N,N-dimethylformamide (7 ml). After stirring for 10 min at 0°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 give 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. Preparation of (3S)-3-amino-1-methyl-1H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin2-one hydrochloride.

A solution of hydrogen chloride in 1,4-dioxane (4 M, 5 ml, 20 mmol) was added to a solution of tert-butylN-((3S)-1-methyl-2-oxo-1H,2H,3H,4H-pyrido[3 ,4-b][1,4]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 temperature and concentrated to give the title compound (215 mg, 92%) as a white solid. LCMS (method S): m/z=194.1 [M+H] ⁺ , 0.184 min.

Step 6. Preparation of (S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin3 -yl)-4H -1,2,4-triazole-3-carboxamide.

A solution of (3S)-3-amino-1-methyl-1H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin-2-one hydrochloride (115 mg, 0.50 mmol) in N,N-dimethylformamide (1 ml) was added to a stirred solution of 5-benzyl-2H-1,2,4triazole-3-carboxylic acid (102 mg, 0.50 mmol), ethyldiisopropylamine (129 mg, 1.00 mmol), N ¹ -((ethylimino)methylene)-N ³ ,N ³ -dimethylpropane-1,3-diamine hydrochloride (115 mg, 0.60 mmol) and 1hydroxybenzotriazole (92 mg, 0.60 mmol) in N,N-dimethylformamide (5 ml). The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19x150 mm 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 30 ml/min; gradient: from 15% B to 45% B in 10 minutes; 254 nm. The collected fractions were combined and concentrated under reduced pressure to give the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 12.34 (s, 1H), 8.54-8.46 (m, 2H), 8.06 (d, J=7.3 Hz, 1H), 7, 36-7.29 (m, 5H), 7.16 (d, J=5.2 Hz, 1H), 5.09 (m, 1H), 4.77 (dd, J=10.0, 3, 2 Hz, 1H), 4.41 (dd, J=11.6, 10.0 Hz, 1H), 4.20 (s, 2H), 3.46 (s, 3H). LC-MS (method T): m/z=379.2 [M+H]+, 0.888 min.

Example 42. (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)4H -1,2,4-triazole-3-carboxamide.

Stage 6

Step 1. Preparation of (28)-2-(((tert-butoxy)carbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid.

Sodium hydride (60%, 2 g, 50 mmol) was added to the stirred solution of (2S)-2-(tert

- 92 044271 butoxycarbonylamino)-3-hydroxypropanoic acid (5 g, 25.0 mmol) in N,N-dimethylformamide (100 ml). The resulting 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 temperature for an additional 8 hours before quenching with hydrochloric acid (3n., 5 ml). After adjusting the pH to 3-4 with hydrochloric acid (3N, 20 ml), the resulting mixture was extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography using an RP-C18 column (acetonitrile/water, 1/2) to give the title compound (3.2 g, 39%) as a light yellow oil. LC-MS (method C): m/z=272.1 [M+H-(tBuO)] ⁺ , 1.269 min.

Step 2. Preparation of (2S)-3-((2-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid.

(2S)-2-(((tert-Butoxy)carbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid (0.45 g, 1.4 mmol) in methanol (20 ml ) were kept overnight at room temperature in the presence of a palladium catalyst on a carbon support (10%, 0.5 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give the title compound (0.32 g, 78%) as a yellow oil. LC-MS (method C): m/z=298.1 [M+H] ⁺ , 0.982 min.

Step 3. Preparation of tert-butyl-N-((3S)-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3yl)carbamate.

N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.73 g, 1.92 mmol) and N,N-diisopropylethylamine (0.25 g, 1. 93 mmol) was added to a stirred solution of (2S)-3-((2aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid (0.45 g, 1.51 mmol) in N,N-dimethylformamide (5 ml). After stirring for 6 hours at room temperature, the reaction mixture was quenched by adding water (20 ml) and extracted with ethyl acetate (3x100 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 give 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. Preparation of tert-butyl-N-((3S)-5-methyl-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin3-yl)carbamate.

Pometan (50 mg, 0.35 mmol) was added dropwise to the stirred solution of tert-butyl-N((3S)-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4 ]oxazepin-3-yl)carbamate (100 mg, 0.36 mmol) and cesium carbonate (120 mg, 0.36 mmol) in N,N-dimethylformamide (5 ml). After stirring for 3 hours at room temperature, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3x100 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 give 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. Preparation of (3S)-3-amino-5-methyl-2H,3H,4H,5H-pyrido-[3,2-b][1,4]oxazepin4-one hydrochloride.

Tert-butyl-N-((3S)-5-methyl-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (90 mg , 0.31 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 10 ml). The reaction mixture was stirred for 3 hours at room temperature and concentrated under reduced pressure to give 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. Preparation of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin3-yl)-4H -1,2,4-triazole-3-carboxamide.

(3S)-3-Amino-5-methyl-2H,3H,4H,5H-pyrido-[3,2-b][1,4]oxazepin-4-one hydrochloride solution (55 mg, 0.24 mmol) in N,N-dimethylformamide (1 ml) was added to a stirred solution of 5-benzyl-2H1,2,4-triazole-3-carboxylic acid (80 mg, 0.40 mmol), 1-hydroxy-benzotriazole (70 mg, 0 .53 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and N,Ndiisopropylethylamine (160 mg, 1.21 mmol) in N,N-dimethylformamide (2 ml) . After stirring for 8 hours at room temperature, the reaction mixture was quenched by adding 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 reduced pressure. The resulting precipitate was purified using Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase, water (0.1% formic acid) and ACN (from 30.0% ACN to 60.0% in 7 min); Detector, UV 254 & 220 nm, producing the title compound. 1H NMR (300 MHz, DMSO-d6) 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,

- 93 044271

1H), 7.37-7.21 (m, 6H), 4.92-4.82 (m, 1H), 4.73 (dd, J=11.4, 9.6 Hz, 1H), 4 .53 (dd, J=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][1,4]oxazepin-3-yl)cyclobutane1-carboxamide.

Step 1. Preparation of ethyl 3-(phenylmethylidene)cyclobutane-1-carboxylate.

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 h and then left to warm to room temperature. Ethyl 3-oxocyclobutanecarboxylate (1.2 g, 8.5 mmol) was added and the reaction mixture was refluxed and stirred overnight. After cooling to room temperature, the reaction mixture was quenched with water (50 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 reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to give 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.

Stage 2. Preparation of ethyl 3-benzylcyclobutane-1-carboxylate.

Ethyl 3-(phenylmethylidene)cyclobutane-1-carboxylate (130 mg, 0.6 mmol) in ethanol (5 ml) was hydrogenated in the presence of a carbon-supported palladium catalyst (10%, 15 mg) under a hydrogen atmosphere. After stirring for 2 hours at room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give 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. Preparation of 3-benzylcyclobutane-1-carboxylic acid.

A solution of sodium hydroxide (60 mg, 1.5 mmol) in water (1 ml) was added to a solution of ethyl 3benzylcyclobutane-1-carboxylate (100 mg, 0.5 mmol) in tetrahydrofuran (3 ml). After stirring for 2 hours at room temperature, the reaction mixture was diluted with water (10 ml), adjusted to pH=3 with aqueous hydrochloric acid (3N, 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 reduced pressure to give 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. Preparation of 3-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)cyclobutane-1-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase, water (0.05% NH ₃ H ₂ O), ACN (from 25% ACN to 55% B in 7 min); detector, UV 254 & 220 nm, to obtain the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) 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.

- 94 044271

Example 44 4H-1,2,4-triazole-3-carboxamide.

Step 1. Preparation of tert-butyl-1-methyl-5-methylene-2-oxo-2,3,4,5'-tetraαhydro-1H-benzo[b]azepin3-ylcarbamate.

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 atmosphere. A solution of tert-butyl-1-methyl-2,5-dioxo-2,3,4,5tetrahydro-1H-benzo[b]azepin-3-ylcarbamate (1.50 g, 4.93 mmol) was added dropwise to this mixture ) in tetrahydrofuran (20 ml) at 50°C. After stirring overnight at 50°C, the reaction mixture was quenched with saturated aqueous ammonium chloride (30 ml) and extracted with ethyl acetate (3x40 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give 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. Preparation of tert-butyl-N-[7-methyl-6-oxo-7-azatricyclo[6,4.0,0-[2,4]]dodecα-1(8),9,11trien-5-yl] carbamate.

To a solution of potassium hydroxide (2.23 g, 39.7 mmol) in water (3.3 ml) was added dropwise a solution of 1methyl-1-nitrosourea (2.05 g, 19.7 mmol) in ester (100 ml) at 0°C. The resulting mixture was stirred for 1 hour at 0°C and then the organic phase was separated to obtain a diazomethane solution (100 ml). To a solution of tert-butyl-1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin3-ylcarbamate (0.6 g, 1.99 mmol) in tetrahydrofuran (5 ml) a solution of diazomethane (100 ml) was added dropwise, followed by a mixture of palladium diacetate (45 mg, 0.20 mmol) in tetrahydrofuran (1 ml) dropwise at 0°C. The reaction mixture was stirred overnight at room temperature. Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give 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. Preparation of 3-amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepin-5,1cyclopropan]-2-one hydrochloride.

A solution of hydrogen chloride in 1,4-dioxane (4N, 10 ml) was added to a solution of tert-butyl-N-[7methyl-6-oxo-7-azatricyclo[6,4.0,0-[2,4]]dodeca- 1(8),9,11-trien-5-yl]carbamate (150 mg, 0.60 mmol) in 1,4-dioxane (2 ml). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo to give 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. Preparation of (3S)-3-amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropan]2-one (first eluting isomer) and (3R)-3 -amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1cyclopropan]-2-one (second eluting isomer).

3-Aamino-1 methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropan]-2-one hydrochloride (90 mg, crude) was separated using rep. chiral HPLC under the following conditions: column: Phenomenex Lux Cellulose-4, AXIA Packed, 2.12x25 cm, 5 µm; mobile phase A: hexanes (0.1% DEA), mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 35% B to 35% B in 17.5 minutes; 220/254 nm; RT 1: 11.24 min; RT 2: 13.82 min, producing title compounds.

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First eluting isomer: (36 mg, 38%) as a white solid. LC-MS (method D):

m/z=217.2 [M+H]+, 1.096 min.

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. Preparation of (S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1'cyclopropan]-3-yl) -4H-1,2,4-triazole-3-carboxamide.

The crude product obtained from the Amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Phenyl OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (from 50.0% ACN to 70.0% in 7 min); Detector, UV 254 & 220 nm, producing the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.20 (d, J=7.5 Hz, 1H), 7.45-7.32 (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 (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)-1-Benzyl-4-fluoro-5-methyl-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)1H -pyrazole-3-carboxamide.

CT, 2 hours

Stage 1 Stage 2

Step 1. Preparation of (3S)-3-amino-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one hydrochloride.

Tert-butyl-N-((3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate (100 mg, 0.36 mmol) was added to the hydrogen chloride solution in 1,4-dioxane (4 M, 5 ml). The reaction mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure to give 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. Preparation of (S)-1-benzyl-4-fluoro-5-methyl-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin3-yl)-1H -pyrazole-3-carboxamide.

The crude product obtained by amine coupling procedure B was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19x150 mm 5 µm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 30 ml/min; gradient: from 15% B to 45% B in 10 minutes; 254 nm. The collected fractions were combined and concentrated under reduced pressure to give the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) 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.

Example 46 5-Benzyl-N-((2S)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin2-yl)-4H-1 ,2,4-triazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 65% B in 7 minutes; 254/220 nm, producing the title compound. LC-MS (method J): m/z=388.2 [M+H] ⁺ , 1.305 min.

Enantiomers of 5-benzyl-N-{7-methyl-6-oxo-7-azatricyclo[6,4.0,0 ^Λ {2,4}]dodeca-1(8),9,11-trien-5yl}-4H- 1,2,4-triazole-3-carboxamide was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAK IC, 2.0 cm x 25 cm (5 µm); mobile phase A: hexanes, mobile phase

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B: EtOH; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 30 minutes; 254/220 nm; RT 1: 10.478 min; RT 2: 13.826 min, obtaining title compounds:

Example 46A (first eluting isomer): 1H NMR (400 MHz, Chloroform-d) 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.

Example 46B (second eluting isomer): 1H NMR (400 MHz, Chloroform-d) δ 8.53 (d, J=7.1 Hz, 1H), 7.39-7.18 (m, 8H), 7, 12 (d, J=1.1 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.

Example 47 )-1H-pyrazole-3-carboxamide.

F

Example 48 )-4H-1,2,4-triazole-3-carboxamide.

Example 49 -carboxamide.

O

Stage 1 Stage 2

Step 1. Preparation of ethyl 5-(phenylthio)thiazole-2-carboxylate.

To a stirred mixture of ethyl 5-iodo-1,3-thiazol-2-carboxylate (300 mg, 1.06 mmol), sodium besolthiolate (220 mg, 1.66 mmol) in 1-methyl-2-pyrrolidinone (10 ml ) copper iodide (40 mg, 0.21 mmol) was added under argon. The resulting solution was stirred for 4 hours at 70°C, quenched

- 97 044271 with water (20 ml) and extracted with ethyl acetate (4x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using St. TLC (ethyl acetate/petroleum ether, 5/1) gave 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. Preparation of ethyl 5-(phenylsulfonyl)thiazole-2-carboxylate.

To a stirred 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 temperature and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give 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. Preparation of 5-(phenylsulfonyl)thiazole-2-carboxylic acid.

Lithium hydroxide (12 mg, 0.50 mmol) was added to a stirred mixture of ethyl 5-(phenylsulfonyl)thiazole-2-carboxylate (100 mg, 0.34 mmol) in tetrahydrofuran (3 mL) and water (1 mL). The resulting mixture was stirred for 2 hours at room temperature and concentrated in vacuo. The precipitate was diluted with water (10 ml) and adjusted to pH=6 using an aqueous solution of hydrochloric acid (1N, 10 ml). The resulting solution was extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (90 mg, crude) as a white oil, which was used directly in the next step without further purification. LCMS (method E): m/z=270.0 [M+H] ⁺ , 0.635 min.

Step 4. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5(phenylsulfonyl)thiazol-2 -carboxamide.

The crude product obtained by amine coupling procedure B was purified by Prep-HPLC under the following conditions: column: Xbridge Prep C18, 19x150 mm, 5 µm; Mobile phase: phase A: water (10 mmol/l NH4HCO3); phase B: ACN (20% to 80% in 12 min); Detector, UV 220 & 254 nm, producing the title compound. 1H NMR (300 MHz, DMSO- _d6 ) δ 9.24 (br. s, 1H), 8.76 (s, 1H), 8.10-8.01 (m, 2H), 7.82-7 .63 (m, 3H), 7.52-7.44 (m, 1H), 7.38-7.17 (m, 3H), 4.83-4.70 (m, 1H), 4.71 -4.59 (m, 1H), 4.45-4.32 (m, 1H), 3.30 (s, 3H). LC-MS (method O): m/z=443.9 [M+H] ⁺ , 1.594 min.

Example 50 -1-carboxamide.

Stage 1. Preparation of (±)-trans-2-benzylcyclopropanecarboxylic acid.

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 overnight at room temperature. After removing the methanol under reduced pressure, the pH of the solution was adjusted to 6 using an aqueous solution of hydrochloric acid (1N, 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 in vacuo to give 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. Preparation of trans-2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin3-yl)cyclopropanecarboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 40.0% ACN to 65.0% in 8 min); Detector, UV 254

- 98 044271 nm, producing the title compound. LC-MS (method J): m/z=351.1 [M+H]+, 2.116 min.

Step 3. Preparation of (1R,2S)-2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin3-yl) cyclopropanecarboxamide and (1S,2R)-2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) cyclopropanecarboxamide.

Diastereomers of trans-2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazenin-3yl)cyclopropanecarboxamide were separated using Rev. chiral HPLC under the following conditions: column: Phenomenex Lux Cellulose-4, AXIA Packed, 2.12x25 cm, 5 µm; mobile phase A: hexanes, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 30% B to 30% B in 12 minutes; 254/220 nm; RT 1: 7.474 min; RT 2: 8.916 min, obtaining title compounds:

Example 50A (first eluting isomer): ¹ H NMR (400 MHz, Chloroform-d) 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.

Example 50B (second eluting isomer): ^1H NMR (400 MHz, Chloroform-d) 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), 1.17-1.13 (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-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]oxazepin-3 -yl)-4H-1,2,4-triazol-3 - carboxamide.

Step 1. Preparation of 2,3-dihydro-1H-indene-1-carbohydrazide.

A solution of hydrazine in tetrahydrofuran (1 M, 31 ml, 31 mmol) was added to a solution of 2,3-dihydro1H-indene-1-carboxylic acid (1.0 g, 6.2 mmol), 2-(7-aza-1H) hexafluorophosphate -benzotriazol-1-yl)1,1,3,3-tetramethyluronium (2.8 g, 7.4 mmol) and ethyldiisopropylamine (2.4 g, 18.6 mmol) in N,Ndimethylformamide (20 ml). After stirring for 1 hour at room temperature, the reaction mixture was 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 in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give 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. Preparation of ethyl 2-amino-2-(2-(2,3-dihydro-1H-inden-1-carbonyl)hydrazono)acetate.

Ethyl 2-ethoxy-2-iminoacetate (412 mg, 2.8 mmol) was added to a solution of 2,3-dihydro-1H-indene-1carbohydrazide (500 mg, 2.8 mmol) in ethanol (5 ml) and diethyl ether (5 ml). The resulting suspension was stirred at room temperature for 2 hours. Solids were removed by filtration and the filtrate was concentrated in vacuo to give 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. Preparation of ethyl 5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazole-3-carboxylate.

Ethyl 2-amino-2-(2-(2,3-dihydro-1H-indene-1-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 under microwave irradiation. After concentration under high vacuum, the residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give the title compound (340 mg, 60%) as a yellow oil. LC-MS (method I): m/z=258.1 [M+H] ⁺ , 0.848 min.

Step 4. Preparation of 5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazole-3-carboxylic acid.

- 99 044271

Lithium hydroxide (95.3 mg, 4.0 mmol) was added to a solution of ethyl 5-(2,3-dihydro-1H-inden-1-yl)-4H1,2,4-triazole-3-carboxylate (340 mg , 1.3 mmol) in tetrahydrofuran (6 ml) and water (3 ml). After stirring at room temperature for 4 hours and removing the tetrahydrofuran under reduced pressure, the reaction mixture was diluted with water (20 ml), the pH was adjusted to 2 with aqueous hydrochloric acid (1N, 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 in vacuo to give the title compound (140 mg, 47%) as a yellow solid. LC-MS (method E): m/z=229.9 [M+H]+, 0.642 min.

Step 5. Preparation of 5-(2,3-dihydro-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [ 1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide.

The crude product obtained by amine coupling procedure B was purified by Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 50% B in 10 minutes; 254 nm, producing the title compound. 1H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J=7.2 Hz, 1H), 7.33 (d, J=7.2, 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[1,2-a]azepin-4-yl)-4H-1,2,4-triazole -3carboxamide.

He

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase, water (0.05% TFA) and ACN (from 10.0% ACN to 40.0% in 7 min); detector, UV 220 & 254 nm, to obtain the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) 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.

Example 53 yl)-1H-1,2,4-triazole-5-carboxamide.

-----------* ( „ / DMSO KON N R V g D' on O 1 G ° J 1 4n HCI _ D N ^N y Br TMEDA, TMSI, 1 ₂ XJ ' ^E n but n - _n DBP £ Ϊ /= O N-^lDD - _Br -^ HATU, DIEA, DMF G ° J KOH, 60°C J ^U DPPA, Et ₃ N 9 MeOH,H ₂ O G O THF ^: , p-ViON Dx DxDx 80°C, during. /o < OH nights V G 0 HATU, DIEA bg— ^CS2C ° ³ ' ^Me1 \ O J, U NH ₃ in MeOH DD \ ^{ir 1} heating ^{Br NH2} \ O < ^Ν Λ_ n 1 DMN N-m -K o

- 100 044271

Example 54A and 54B. 5-((R)-2,3-Dihydro-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropurido[3,2 -b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide and 5-((S)-2,3-dihydro-1H-inden-1-yl) -N((S)-5-methyl-4-oxo-2,3,4,5-tetraαhydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4 -triazole-3-carboxamide.

Step 1. Preparation of 5-(2,3-dihydro-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2 -b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide.

A solution of trimethylaluminum in toluene (2 M, 0.6 ml, 1.2 mmol) was added dropwise to a mixture of (S)-3-amino-5-methyl-2,3-dihydropyrido[3,2-b][1] hydrochloride ,4]oxazepin-4(5H)-one (60 mg, 0.26 mmol) in toluene (2 ml) at 0°C. The resulting solution was warmed to room temperature and stirred for 30 minutes. A solution of ethyl 5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazole-3-carboxylate (108 mg, 0.42 mmol) in toluene (2 ml) at drops were added to the resulting solution. The resulting solution was stirred overnight at room temperature. The solution was then quenched with water (10 ml) and extracted with ethyl acetate (3x50 ml). The organic layers were combined and concentrated in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Prep Phenyl OBD 19x150 mm, 5 mm; mobile phase A: water (0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 50% B in 7 minutes; 254 nm; Rt: 6 min to obtain 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. Preparation of 5-((R)-2,3-dihydro-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide and 5-((8)-2,3-dihydro-1H-indene -1 yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxαzepin-3-yl)-4H- 1,2,4-triazole3-carboxamide.

5-(2,3-Dihydro-1H-unden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][ 1,4]oxazepin3-yl)-4H-1,2,4-triazole-3-carboxamide (25 mg) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IA, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 50% B to 50% B in 40 minutes; 220/254 nm; RT 1: 9.716 min; RT 2: 29.084 min, obtaining title compounds:

54A (first eluting isomer): ^1H NMR (400 MHz, Methanol^ ₄ ) δ 8.36-8.35 (m, 1H), 7.70-7.68 (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), 4.724.65 (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, 1H), 2.432.38 (m, 1H). LC-MS (method T): m/z=405.3 [M+H]+, 1.296 min.

54B (second eluting isomer): 1H NMR (400 MHz, Methanol-b ₄ ) δ 8.36-8.35 (m, 1H), 7.70-7.68 (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, 1H), 2.43-2.38 (m, 1H). LC-MS (method T): m/z=405.3 [M+H]+, 1.301 min.

Example 55 -ylmethyl)-1 H-pyrazol-3-carboxamide.

- 101 044271

Step 1. Preparation of ethyl 4-fluoro-1H-pyrazole-3-carboxylate.

1-(Chloromethyl)-4-fluoro-1,4-diazonium-bicyclo[2,2.2]octane tetrafluoroborate (14 g, 39.5 mmol) was added to a mixture of ethyl 1H-pyrazole-3-carboxylate (5 g, 35 .7 mmol) in acetonitrile (50 ml). The resulting mixture was stirred for 48 hours at 100°C. After cooling to room temperature, solids were removed by filtration and the filtrate was concentrated in vacuo to give 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. Preparation of 4-fluoro-1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxylic acid.

Sodium hydride (60%, 506 mg, 12.7 mmol) was added to a solution of ethyl 4-fluoro-1H-pyrazole-3carboxylate (500 mg, 3.2 mmol) in N,N-dimethylformamide (10 ml) at 0° C. The resulting mixture was stirred at room temperature for 0.5 h, after which 2-(bromomethyl)pyridine (600 mg, 3.5 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h and quenched by adding water (10 ml). The resulting solution was stirred at room temperature for 5 hours. The pH was adjusted to 7 using an aqueous solution of hydrochloric acid (1N, 10 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 in vacuo to give the title compound (360 mg, 72%). LC-MS (method I): m/z=221.9 [M+H] ⁺ , 0.320 min.

Step 3. Preparation of (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)1-(pyridine -2-ylmethyl)-1H-pyrazol-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 45% B in 7 minutes; 254/220 nm, producing the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.56-8.55 (m, 1H), 8.16-8.15 (d, J=4.4 Hz, 1H), 8.11-8 .09 (m, 1H), 7.83-7.82 (m, 1H), 7.51-7.49 (m, 1H), 7.34-7.28 (m, 3H), 7.24 -7.20 (m, 2H), 5.46 (s, 2H), 4.91-4.78 (m, 1H), 4.58-4.53 (m, 1H), 4.41-4 .37 (m, 1H), 3.33 (s, 3H). LC-MS (method F): m/z=396.1 [M+H] ⁺ , 0.924 min.

Example 56. (S)-5-Benzyl-N-(9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)2H -1,2,4-triazole-3-carboxamide.

Step 1. (S)-tert-butyl-9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3ylcarbamate.

To a mixture of (S)-tert-butyl-9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3ylcarbamate (200 mg, 0.61 mmol ) and zinc cyanide (300 mg, 2.59 mmol) in tetrahydrofuran (2 ml) and water (10 ml), the third generation precatalyst t-BuXPhos (244 mg, 0.31 mmol) and t-BuXPhos (130 mg, 0 .31 mmol) in a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and diluted with water (50 ml). The resulting mixture was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to give 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. Preparation of (S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carbonitrile hydrochloride.

A solution of hydrogen chloride in 1,4-dioxane (4N, 10 ml) was added to a solution of (S)-tert-butyl-9cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-ylcarbamate (90 mg, 0.28 mmol) in 1,4dioxane (2 ml). The reaction mixture was stirred for 1 hour at room temperature and concentrated in vacuo to give the title compound (55 mg) as a white solid. LC-MS (method E): m/z=218.0 [M+H] ⁺ , 0.551 min.

Step 3. Preparation of (S)-5-benzyl-N-(9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa

- 102 044271 zepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

The crude product obtained from the Amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Phenyl OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (from 50.0% ACN to 70.0% in 7 min); Detector, UV 254 & 220 nm, producing the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 14.20 (s, 1H), 8.55 (s, 1H), 7.81 (dd, J=8.2, 1.5 Hz, 1H), 7.72 (dd, J=7.8, 1.5 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.35-7.14 (m, 5H), 4 .94-4.74 (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 1Hpyrazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19 x 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 60% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. ^1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.23 (d, J=7.6 Hz, 1H), 8.17-8.13 (m, 2H), 7.56 (dd, J=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][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)- 1,3,4-thiadiazole-2-carboxamide.

Stage 3 Stage 4

EDCI, NOVT, DIEA DMF

CT scan, during nights Stage 5

Step 1. Preparation of 5-(1-phenylcyclopropyl)-1,3,4-thiadiazol-2-amine.

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 h at 70°C and then cooled to room temperature. Water (100 ml) was added. The reaction mixture was heated to 70°C and stirred for 5 hours. The pH of the resulting solution was adjusted to 8 using saturated aqueous sodium hydroxide solution (30 ml). The solids were collected by filtration to obtain 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. Preparation of 2-bromo-5-(1-phenylcyclopropyl)-1,3,4-thiadiazole.

Copper bromide (2.2 g, 10 mmol) was added to a mixture of 5-(1-phenylcyclopropyl)-1,3,4-thiadiazol-2-amine (1.1 g, 5.0 mmol) in acetonitrile (20 ml) . The resulting mixture was stirred at room temperature for 15 min, after which tert-butyl nitrite (1.5 mL, 10 mmol) was added dropwise to the mixture over 15 min at room temperature. The reaction mixture was heated at 60°C and stirred for 16 hours, after which water (50 ml) was added. Solids were removed by filtration and the filtrate was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give 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. Preparation of ethyl 5-(1-phenylcyclopropyl)-1,3,4-thiadiazole-2-carboxylate.

Bis(triphenylphosphine)palladium(P) chloride (277 mg, 0.395 mmol) was added to the mixture of 2-bromo-5-(1

- 103 044271 phenylcyclopropyl)-1,3,4-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 carbon monoxide (50 atm), the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to give the title compound (600 mg, 61%) as a yellow solid. LC-MS (method E): m/z=261.1 [M+H]+, 0.923 min.

Step 4. Preparation of 5-(1-phenylcyclopropyl)-1,3,4-thiadiazole-2-carboxylic acid.

Lithium hydroxide (5.4 mg, 2.0 mmol) was added to a solution of ethyl 5-(1-phenylcyclopropyl)-1,3,4thiadiazole-2-carboxylate (100 mg, 0.41 mmol) in tetrahydrofuran (9 ml) and water (3 ml). The resulting mixture was stirred for 2 hours at room temperature. After removing tetrahydrofuran under reduced pressure, the pH of the solution was adjusted to 3-4 using an aqueous solution of hydrochloric acid (1N, 20 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 in vacuo to give 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. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1phenylcyclopropyl)-1 ,3,4-thiadiazole-2-carboxamide.

The crude product obtained using the amine coupling procedure C was purified using Prep-HPLC under the following conditions: column: Xbridge Prep C18, 19x150 mm 5 µm; mobile phase: water (10 mmol/l NH4HCO ₃ ) and ACN (from 20% to 80% in 12 min); detector, UV220 & 254 nm, producing the title compound. ^1H NMR (300 MHz, DMSO^) δ 9.20 (s, 1H), 7.49-7.18 (m, 9H), 4.77-4.75 (m, 1H), 4.69- 4.62 (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 -pyrazole-3-carboxamide.

CT, 2 hours

The crude product obtained from the Amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, Xbridge Phenyl OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (from 50.0% ACN to 70.0% in 7 min); detector, UV 254 & 220 nm, to obtain the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) 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.

Examples 60A and 60B. 5-Benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclonprona[d]azenin-2-yl)- 1H-pyrazole-3-carboxamide (60A) and 5-benzyl-N-((1aR,2R,8bS)-methyl-3-oxo1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d] azepin-2-yl)-1H-pyrazol-3-carboxamide (60B).

Stage 1

Step 1. Preparation of 5-benzyl-N-(4-methyl-3-oxo-1,1 a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin2-yl)-1 H-nirazol- 3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 65% B in 7 minutes; 254/220 nm, producing the title compound. LC-MS (method I): m/z=387.2 [M+H] ⁺ , 1.405 min.

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Step 2. Preparation of 5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepine-2 -yl)-1H-pyrazol-3-carboxamide (first eluting isomer) and 5-benzyl-N((1 aR,2R,8bS)-4-methyl-3-oxo-1,1 a,2,3,4 ,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1 H-pyrazol-3carboxamide (second eluting isomer).

5-Benzyl-N-{7-methyl-6-oxo-7-azatricyclo[6,4.0,0 ^Λ {2,4}]dodeca-1(8),9,11-trien-5-yl}-1H -pyrazole3-carboxamide (30 mg, 0.077 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAK IC, 2.0 cm x 25 cm (5 µm); mobile phase A: hexanes, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 30 minutes; 254/220 nm; RT 1: 10.478 min; RT 2: 13.826 min, obtaining title compounds:

example 60A (first eluting isomer): 1H 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), 1.160.88 (m, 2H). LC-MS (method J): m/z=387.2 [M+H]+, 2.043 min.

example 60B (second eluting isomer): 1H NMR (300 MHz, Chloroform-d) 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), 1.16-1.07 (m, 1H), 1.02-0.89 (m, 1H). LC-MS (method J): m/z=387.2 [M+H]+, 1.409 min.

Example 61 -4-carboxamide.

O

Stage 1 Stage 2

Stage 1. Preparation of 1-phenylcyclopropanecarboxamide.

To a stirred solution of 1-phenylcyclopropanecarboxylic acid (1.62 g, 10.0 mmol) in dichloromethane (10 mL), thionyl chloride (6 g, 50.0 mmol) was added dropwise at 0°C. The resulting solution was stirred for 5 hours at room temperature, and the reaction mixture was concentrated under high vacuum. The precipitate was then added dropwise to ammonium hydroxide (28%, 50 ml) at 0°C. The resulting solution was diluted with water (50 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.50 g, 93%) as a yellow solid. LC-MS (method I): m/z=162.1 [M+H] ⁺ , 0.725 min.

Step 2. Preparation of ethyl 2-(1-phenylcyclopropyl)oxazole-4-carboxylate.

A mixture of ethyl 3-bromo-2-oxopropanoate (970 mg, 5.0 mmol) and 1-phenylcyclopropanecarboxamide (810 mg, 5.0 mmol) in ethanol (10 ml) was heated for 16 h at 80 °C under nitrogen atmosphere . After cooling to room temperature, the reaction mixture was quenched by adding water (50 ml) and extracted with ethyl acetate (3x50 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give the title compound (420 mg, 33%) as a white solid. LC-MS (method C): m/z=258.1 [M+H] ⁺ , 1.527 min.

Step 3. Preparation of 2-(1-phenylcyclopropyl)oxazole-4-carboxylic acid.

Lithium hydroxide (5.4 mg, 2.02 mmol) was added to a mixture of ethyl 2-(1-phenylcyclopropyl)oxazole-4carboxylate (100 mg, 0.39 mmol) in tetrahydrofuran (9 ml) and water (3 ml). The reaction mixture was stirred for 16 hours at room temperature. After removing the tetrahydrofuran under reduced pressure, the pH of the solution was adjusted to 6 using an aqueous solution of hydrochloric acid (1e., 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 in vacuo to give 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. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(1phenylcyclopropyl)oxazol- 4-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: Xbridge Prep C18, 19x150 mm, 5 µm; Mobile phase: phase A: water (10 mmol/l NH4HCO3); phase B: ACN (20% to 80% in 12 min); Detector, UV220 & 254 nm, producing the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.11 (d, J=7.8

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Hz, 1H), 7.49-7.19 (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 -3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: X Select CSH Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 70% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H), 8.93 (d, J=8.0 Hz, 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.

Example 63 )thiazole-2-carboxamide.

Stage 7

Stage 1. Preparation of (1-phenylcyclopropyl)methanol.

A solution of borohydride 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 temperature, quenched with water (50 ml) and extracted with ethyl acetate (3x60 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (5.5 g, 93%) as a colorless oil. LC-MS (method C): m/z=131.2 [M-H ₂ O+H] ⁺ , 1.125 min.

Stage 2. Preparation of 1-phenylcyclopropanecarbaldehyde.

Dess-Martin reagent (35.6 g, 84 mmol) was added to a solution of (1-phenylcyclopropyl)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. Solids were removed by filtration and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give 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. Preparation of (E)-(1-(2-methoxyvinyl)cyclopropyl)benzene.

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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 resulting mixture was stirred at 0°C for 0.5 h followed by the addition of 1phenylcyclopropanecarbaldehyde (4.2 g, 29 mmol). The reaction mixture was stirred at room temperature for 1 hour, quenched by adding water (100 ml) and extracted with ethyl acetate (3x100 ml). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (20 g, crude) as a yellow oil, which was used directly in the next step without further purification.

Step 4. Preparation of 2-bromo-2-(1-phenylcyclopropyl)acetaldehyde.

To a solution of (E)-(1-(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. This solution was stirred at -20°C for 1 hour and concentrated to give the title compound (8 g, crude) as a yellow oil, which was used directly in the next step without further purification.

Step 5. Preparation of ethyl 5-(1-phenylcyclopropyl)thiazole-2-carboxylate.

Ethyl 2-amino-2-thioxoacetate (1.1 g, 8 mmol) was added to a solution of 2-bromo-2-(1-phenylcyclopropyl)acetaldehyde (2 g, 8 mmol) in ethanol (20 ml). The reaction mixture was stirred at 80°C for 4 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give 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. Preparation of 5-(1-phenylcyclopropyl)thiazole-2-carboxylic acid.

Lithium hydroxide (52.8 mg, 2.2 mmol) was added to a solution of ethyl 5-(1-phenylcyclopropyl)thiazole-2carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (2 ml) and water (1 ml). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and diluted with water (10 ml). The resulting mixture was adjusted to pH=5 with aqueous hydrochloric acid (1N, 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 in vacuo to give 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.

Step 7. (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxαzepin-3-yl)-5-(1 -phenylcyclopropyl)thiazole-2-carboxamide.

The crude product obtained using the amine coupling procedure C was purified using Prep-HPLC under the following conditions: column: Xbridge Prep C18, 19x250 mm, 5 µm; mobile phase: phase A: water (10 mmol/l NH4HCO3); phase B: ACN (45% to 65% in 7 min); Detector, UV220 & 254 nm, producing the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) 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 -pyrazole-3-carboxamide.

NOVT, EDCI, O1EA, DMF KT, incl. nights Stage 2

Step 1. Preparation of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid.

Sodium hydride (60%, 1 g, 25 mmol) was added to a solution of ethyl 4-fluoro-1H-pyrazole-3-carboxylate (1.2 g, 7.6 mmol) in N,N-dimethylformamide (20 ml) at 0°C. The resulting mixture was stirred for 0.5 h at room temperature followed by the addition of benzyl bromide (1.36 g, 8.0 mmol). The resulting mixture was stirred for 2 hours at room temperature. Water (20 ml) was added dropwise. The resulting solution was then stirred at room temperature for 5 hours. The pH of the solution was adjusted to 7 using an aqueous solution of hydrochloric acid (1N, 20 ml). Semi

- 107 044271 the prepared solution was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was then purified by Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 60% B in 7 minutes; 254 nm to give the title compound (370 mg, 22%) as a white solid. LC-MS (method D): m/z=221.1 [M+H] ⁺ , 1.206 min.

Step 2. Preparation of (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H -pyrazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19 x150 mm, 5 µm; mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 55% B in 7 minutes; Detector, UV220 & 254 nm, producing the title compound. 1H NMR (400 MHz, Chloroform-d) 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 carboxamide

The title compound was prepared from N-Boc-D-prolinol using the procedure described in Example 27.

The crude product was purified by column chromatography on KP-NH modified silica gel (CH ₂ Cl ₂ -MeOH, 97:3 to 90:10) to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J=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, J =8.8 Hz, 1H), 3.98 (d, J=12.5 Hz, 1H), 3.93-3.82 (m, 1H), 3.523.39 (m, 2H), 3.24 (dd, J=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). LC-MS (Method A): m/z=356.4 [M+H] ⁺ , 0.71 min.

Example 66 )-1,3,4-oxadiazole-2-carboxamide.

Step 1. Preparation of 1-phenylcyclopropanecarbohydrazide.

Triethylamine (93.5 g, 925.5 mmol) was added to a stirred 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 1phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol), O-(7-azabenzotriazol-1yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28.2 g, 74.0 mmol) and N,N-diisopropylethylamine (23.9 g, 185.1 mmol) in N,N-dimethylformamide (100 ml). The reaction mixture was stirred at room temperature for 2 hours, diluted with water (500 ml) and extracted with ethyl acetate (5x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of ethyl 2-oxo-2-(2-(1-phenylcyclopropanecarbonyl)hydrazinyl)acetate.

Ethyl 2-chloro-2-oxoacetate (1.56 g, 11.4 mmol) was added to a stirred solution of 1-phenylcyclopropane carbohydrazide (2.00 g, 11.4 mmol) and triethylamine (3.44 g, 34.1 mmol) in dichloromethane (40 ml) at room temperature. The reaction mixture was stirred for 12 hours at room temperature, quenched by adding 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of ethyl 5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxylate.

Tosyl chloride (0.80 g, 3.62 mmol) was added to a stirred 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 temperature, quenched by adding water (20 ml) and extracted with dichloromethane (3x 25 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5(1 -phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3), ACN (from 40% ACN to 70% B in 7 min); detector, UV 254 & 220 nm, to obtain the title compound. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.49 (s, 1H), 8.37-8.35 (m, 1H), 7.71-7.69 (m, 1H), 7, 42-7.30 (m, 6H), 4.82-4.80 (m, 1H), 4.75-4.73 (m, 1H), 4.54-4.50 (m, 1H), 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-((1aR,2S,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)- 4H-1,2,4-triazole-3-carboxamide (67A) and 5-benzyl-N-((1aS,2R,8bR)-4-methyl-3okso-1,1a,2,3,4,8b- hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide (67B).

Stage 3

Stage 1. Preparation of tert-butyl-(trans-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[y]azepin-2-yl)carbamate.

Tert-butyl-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2yl)carbamate solution (100 mg, 0.33 mmol) in 1,8-diazabicyclo[5,4.0]undec-7-ene was stirred at 90°C overnight. This solution was purified by TLC (ethyl acetate/petroleum ether, 1/8) to give the title compound (60 mg, 60%) as a yellow solid. LC-MS (method E): m/z=325.0 [M+Na] ⁺ , 0.930 min.

Stage 2. Preparation of trans-2-amino-4-methyl-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3 (4H)-one hydrochloride.

To a solution of tert-butyl-(trans-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin2-yl)carbamate (60 mg, 0.20 mmol ) in 1,4-dioxane (2 ml), a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 ml, 20 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature and concentrated under high vacuum to give the title compound (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. Preparation of trans-5-benzyl-N-(4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[y]azepin-2-yl)-4H- 1,2,4-triazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 65% B in 7 minutes; 254/220 nm, producing the title compound. LC-MS (method J): m/z=388.2 [M+H] ⁺ , 1.305 min.

Step 7. Preparation of 5-benzyl-N-((1aR,2S,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclo- 109 044271 propa[d ]azepin-2-ul)-4H-1,2,4-Ίriazole-3-carboxamide (the first eluting isomer) and 5-benzyl-N((1aS,2R,8bR)-4-methyl-3-oxo-1 ,1α,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3carboxamide (second eluting isomer).

Enantiomers of trans-5-benzyl-N-(4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2 ,4-triazole-3-carboxamide (25 mg, 0.065 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak ID-2, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 17 ml/min; gradient: from 50% B to 50% B in 22 min; UV 254 & 220 nm; RT 1: 11.72 min; RT 2: 18.02 min, producing title compounds.

Example 67A (first eluting isomer): 1H NMR (300 MHz, Methanol-d ₄ ) δ 7.56 (d, J=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.

Example 67B (second eluting isomer): 1H NMR (300 MHz, Methanol-d ₄ ) δ 7.56 (d, J=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[1,2-d][1,4]oxazepin-4-yl)-4H-1,2,4triazol-3-carboxamide .

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19 x150 mm 5 µm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 30 ml/min; gradient: from 25% B to 55% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ 14.42 (s, 1H), 8.80 (br. s, 1H), 7.70-7.64 (m, 2H), 7.43-7, 25 (m, 8H), 7.07 (d, J=1.2 Hz, 1H), 5.40-5.29 (m, 1H), 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-Benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-4H1,2,4-triazole-3-carboxamide .

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19x150 mm 5 µm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 30 ml/min; gradient: from 25% B to 55% B in 7 minutes; UV 254 & 220 nm, giving the title compound 1H NMR (300

MHz, DMSO-d ₆ ) δ 14.39 (s, 1H), 8.80 (s, 1H), 7.70-7.65 (m, 2H), 7.41-7.22 (m, 8H ), 7.07 (d, J=1.2 Hz, 1H), 5.40-5.31 (m, 1H), 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][1,2,4]triazolo[4,3-a]azepin-4-yl)-4H1,2,4 -triazole-3-carboxamide (69A) and (R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3a]azepine-4- yl)-4H-1,2,4-triazole-3-carboxamide (69B).

Step 1. Preparation of benzyl-(5,b-dihydro-4H-benzo[1][1,2,4]triazolo[4,3-a]azepin-4-yl) carbamate.

Formylhydrazine (0.54 g, 9 mmol) was added to a stirred solution of (S)-benzyl-(2-thioxo2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-ulcarbamate (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

- 110 044271 high vacuum, diluted with water (50 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.

The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of 5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine-4-amine.

Benzyl (5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)carbamate (0.63 g, 1.9 mmol) in methanol (20 ml) was hydrogenated in the presence of a carbon-supported palladium catalyst (10%, 0.2 g) under a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. Solids were removed by filtration and the filtrate was concentrated under high vacuum to give 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. Preparation of (S)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-amine and (R)-5,6dihydro-4H -benzo[f][1,2,4]triazolo[4,3-a]azepine-4-amine.

Enantiomers of 5,6-dihydro-4H-benzo[1][1,2,4]triazolo[4,3-a]azepin-4-amine (0.36 g, 1.8 mmol) were separated using rep. chiral HPLC under the following conditions: column: Chiralpak IC, 2x25 cm, 5 µm; mobile phase A: MTBE, mobile phase B: EtOH; flow rate: 15 ml/min; gradient: from 60% B to 60% B in 23 min; 220/254 nm; RT 1: 12.04 min; RT 2: 20.81 min, producing title compounds.

(S)-5,6-Dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine-4-amine (first eluting isomer): 110 mg (62%) as solid white substance. LC-MS (method C): m/z=201.1 [M+H] ⁺ , 0.848 min.

(R)-5,6-Dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine-4-amine (second eluting isomer): 110 mg (62%) as solid white substance. LC-MS (method C): m/z=201.1 [M+H] ⁺ , 0.848 min.

Step 4. Preparation of (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)4H- 1,2,4-triazole-3-carboxamide.

The crude product obtained using the amine coupling procedure C was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 20% B to 40% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-dg) 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.

Example 69B. (R)-5-Benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-4H-1,2 ,4triazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 20% B to 40% B in 7 minutes; UV 254 & 220 nm, giving the title compound 1H NMR (300 MHz, DMSO-dg) δ 14.39 (s, 1H), 8.93 (m, 2H), 7.62-7.59 (m, 1H ), 7.56-7.43 (m, 3H), 7.37-7.22 (m, 5H), 5.02-4.92 (m, 1H), 4.14 (s, 2H), 2.84-2.73 (m, 1H), 2.58-2.54 (m, 1H), 2.48-2.41 (m, 2H). LC-MS (method D): m/z=386.2 [M+H] ⁺ , 1.486 min.

- 111 044271

Example 70A. (R)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)isoxazole-3carboxamide.

Step 1. Preparation of (S)-benzyl-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) carbamate

A solution of potassium carbonate (4.8 g, 35 mmol) in water (9 ml) was added to a solution of (S)-3amino-2,3-dihydrobenzo[b][1,4]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. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was collected by filtration, washed with water (20 ml) and dried under high vacuum to give 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. Preparation of (S)-benzyl-4-thioxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate.

Lawson's reagent (2.43 g, 6 mmol) was added to a solution of (S)-benzyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.9 g, 6 mmol) in tetrahydrofuran (50 ml), and the reaction mixture was stirred under nitrogen atmosphere for 16 h at room temperature. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting precipitate was diluted with water (50 ml) and extracted with ethyl acetate (3x100 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. Preparation of (R)-benzyl-4-(2,2-dimethoxyethylamino)-2,3-dihydrobenzo[b][1,4]-oxazepin-3ylcarbamate.

2,2-Dimethoxyethanamine (2.37 g, 22.6 mmol) was added to a solution of (8)-benzyl-4-thioxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate ( 1.85 g, 5.65 mmol) and mercuric 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 temperature. Solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The precipitate was diluted with water (100 ml) and extracted with dichloromethane (3x100 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. LC-MS (method C): m/z=400.2 [M+H] ⁺ , 1.157 min.

Step 4. Preparation of benzyl-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate.

A solution of (R)-benzyl-4-(2,2-dimethoxyethylamino)-2,3-dihydrobenzo[b][1,4]-oxazepin-3-ylcarbamate (2.2 g, 5.5 mmol) in formic acid (15 ml, 96%) was stirred at 100°C for 2 hours. The black precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting precipitate was diluted with water (50 ml), basified with aqueous sodium hydroxide (1N, 30 ml) to pH=6 and extracted with ethyl acetate (3x100 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 give 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. Preparation of (S)-benzyl-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (first eluting isomer) and (R)-benzyl -(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-112 044271 yl)carbamate (second eluting isomer).

Enantiomers of benzyl-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (450 mg,

1.35 mmol) were separated by SLC under the following conditions: column: CHIRALPAK-IC-SFC, 5 cm x 25 cm (5 µm); mobile phase A: CO ₂ 50%, mobile phase B: MeOH: 50%; flow rate: 150 ml/min;

220 nm; RT 1: 5.65 min; RT 2: 6.91 min, producing title compounds:

(S)-Benzyl-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate: (250 mg, 56%) as a white solid. LC-MS (method E): m/z=336.0 [M+H]+, 0.655 min;

(R)-benzyl-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (second eluting isomer): (200 mg, 45%) as solid white substance. LC-MS (method E): m/z=336.0 [M+H] ⁺ , 0.655 min.

Step 6. Preparation of (R)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepine-4-amine.

(R)-Benzyl-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (0.25 g, 0.75 mmol) in methanol (20 ml) was hydrogenated in the presence of a palladium catalyst on a carbon carrier (10%, 0.5 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred for 6 hours at room temperature under a hydrogen atmosphere. Solids were removed by filtration and the filtrate was concentrated under high vacuum to give 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. Preparation of (R)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4yl)isoxazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 20% B to 65% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) 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.

Example 70V. (S)-5-Benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)isoxazole-3carboxamide.

Step 1. Preparation of (S)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepine-4-amine.

(S)-Benzyl-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (0.2 g, 0.6 mmol) in methanol (20 ml) was hydrogenated in the presence of a palladium catalyst on a carbon support (10%, 0.2 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. Solids were removed by filtration and the filtrate was concentrated under high vacuum to give 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. Preparation of (S)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl) isoxazol-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 45% B to 57% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) 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 71A. (S)-5-Benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)isokazol3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 58% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSOL) 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][1,2,4]mriazolo[4,3-a]azepin-4-yl)isoxazole3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 60% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.36 (d, J=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.

Example 72 pyrazole-3-carboxamide.

Stage 1. Preparation of N-methoxy-N-methyl-1-phenylcyclopropanecarboxamide.

N,N-Diisopropylethylamine (47.2 g, 219.6 mmol) was added to a mixture of 1phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol), O,N-dimethylhydroxylamine hydrochloride (6.5 g, 67.8 mmol) , N-(3-dimethylaminopropyl))-N'-ethylcarbodiimide hydrochloride (14.2 g, 73.9 mmol) and 1-hydroxybenzotriazole (10.0 g, 73.9 mmol) in N,N-dimethylformamide (60 ml ). The resulting mixture was stirred overnight at room temperature, diluted with water (300 ml) and extracted with ethyl acetate (3x200 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 give the title compound (11.2 g, 89.6%) as a colorless oil. LC-MS (Method K): m/z=206.0 [M+H] ⁺ , 1.489 min.

Stage 2. Preparation of 1-(1-phenylcyclopropyl)ethanone.

To a solution of methylmagnesium bromide (3 M, 14 ml, 42 mmol) in tetrahydrofuran was added a solution of Nmethoxy-N-methyl-1-phenylcyclopropanecarboxamide (11.2 g, 24.4 mmol) in tetrahydrofuran (50 ml) at 0°C. The resulting mixture was stirred overnight at room temperature, quenched with saturated ammonium chloride (50 ml), extracted with ethyl acetate (3x80 ml). The combined organic layers were washed with brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to give 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. Preparation of ethyl 2,4-dioxo-4-(1-phenylcyclopropyl)butanoate.

To a mixture of 1-(1-phenylcyclopropyl)ethanone (1.92 g, 12 mmol) and diethyl oxolate (2.1 g, 14.4 mmol) in

- 114 044271 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 temperature for 4 hours and concentrated in vacuo. The precipitate was diluted with water (20 ml). The resulting mixture was neutralized to pH=6 with an aqueous solution of hydrochloric acid (1N) and extracted with ethyl acetate (3x20 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 give 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. Preparation of ethyl 5-(1-phenylcyclopropyl)-1H-pyrazole-3-carboxylate.

To a solution of ethyl 2,4-dioxo-4-(1-phenylcyclopropyl)butanoate (800 mg, 3.0 mmol) in ethanol (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 in vacuo. The resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of 5-(1-phenylcyclopropyl)-1H-pyrazole-3-carboxylic acid.

To a solution of ethyl 5-(1-phenylcyclopropyl)-1H-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 overnight at room temperature and concentrated in vacuo. The precipitate was diluted with water (20 ml) and adjusted to pH=5 with aqueous hydrochloric acid (1N) and extracted with ethyl acetate (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 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. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1phenylcyclopropyl)-1H -pyrazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3), ACN (from 40% ACN to 65% B in 7 min); detector, UV 254 & 220 nm, to obtain the title compound. ^1H NMR (300 MHz, DMSO-d ₆ ) 13.16 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 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 )-1H-pyrazole-3-carboxamide.

NH ₂ HCI

NOVT, EDCI, O1EA, DMF

CT scan, during nights

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 50% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-dg) 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), 7.36-7.20 (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][1,4]oxazepin-3-yl) 1(pyridin-2-ylmethyl)-1H-pyrazol-3-carboxamide.

KT, during nights

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 5% B to 57% B in 7 minutes; UV 254 & 220 nm, producing the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) 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, J=4.4 Hz, 1H), 7.87-7.77 (m, 1H), 7.70 (dd, J =8.0, 1.6 Hz, 1H), 7.38-7.31 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 5.47 (s,

- 115 044271

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.

Example 75A and 75B. 5-Benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepine-2 -yl)-4H-1,2,4-triazole-3-carboxamide (75A) and 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo1,1a,2,3, 4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide (75B).

Step 1. Preparation of 5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl )-4H-1,2,4-triazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column: Xbridge Prep C18, 19x150 mm, 5 µm; Mobile phase: phase A: water (10 mmol/l NH ₄ HCO ₃ ); phase B: ACN (20 to 80% in 12 min); Detector, UV 220 & 254 nm to obtain 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. Preparation of 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b ]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide (the first eluting isomer) and 5benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1, 1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)4H-1,2,4-triazole-3-carboxamide (second eluting isomer).

Enantiomers of 5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3b]azepin-2-yl)-4H-1 ,2,4-triazole-3-carboxamide (55 mg, 0.14 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IC, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 19 ml/min; gradient: from 35% B to 35% B in 18.5 minutes; UV 220 & 254 nm; RT 1: 13.00 min; RT 2: 15.67 min, obtaining title compounds:

example 75B (first eluting isomer): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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;

example 75A (second eluting isomer): 1H NMR (400 MHz, DMSO-d ₆ ) 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), 2.322.26 (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 )-1H-pyrazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 32% B to 54% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.37 (dd, J=4.5, 1.5 Hz, 1H), 8.26 (d, J=7.5 Hz, 1H), 8, 15 (d, J=4.5 Hz, 1H), 7.71 (dd, J=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),

- 116 044271

3.36(s, 3H). LC-MS (method D): m/z=396.1 [M+H]+, 1.893 min.

Example 77 )isoxazole-3-carboxamide.

NH ₂ OH HCI, EtOH N- _o NaOH, MeOH, H ₂ O

--------------* 1 Ϊ --------------* heating with reverse O ^CT ' ^during ' ^{the night} by refrigerator, 4 h / \

Stage 1 Stage 2

Step 1. Preparation of ethyl 5-(1-phenylcyclopropyl)isoxazole-3-carboxylate.

To a mixture of ethyl 2,4-dioxo-4-(1-phenylcyclopropyl)butanoate (970 mg, 3.7 mmol) in ethanol (10 ml) was added hydroxylamine hydrochloride (255 mg, 3.7 mmol). The reaction mixture was refluxed and stirred for 4 hours. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give the title compound (260 mg, 27%) as a yellow solid substances. LC-MS (Method K): m/z=258.1 [M] ⁺ , 1.603 min.

Step 2. Preparation of 5-(1-phenylcyclopropyl)isoxazole-3-carboxylic acid.

Sodium hydroxide (93 mg, 2.33 mmol) was added to a solution of ethyl 5-(1-phenylcyclopropyl)isoxazole-3-carboxylate (100 mg, 0.39 mmol) in methanol (3 mL) and water (1 mL). The resulting mixture was stirred at room temperature overnight, concentrated to dryness and diluted with water (10 ml). The reaction mixture was adjusted to pH=5 with aqueous hydrochloric acid (1N, 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 in vacuo to give 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. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ul)-5(1 -phenylcyclopropyl)isoxazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 75% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) 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), 7.437.29 (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.

Example 78. (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl) 1 H-imidazole-2-carboxamide.

Step 1. Preparation of 2-bromo-1-(1-phenylcyclopropyl)ethstone.

To a solution of 1-(1-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 h, 1-bromopyrrolidine-2,5-dione (4.9 g, 27.5 mmol) was added portionwise at 0°C. The reaction mixture was stirred for another 2 hours, quenched with 100 ml water and extracted with dichloromethane (3x80 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using

- 117 044271 column chromatography (ethyl acetate/petroleum ether, 1/20) to obtain 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. Preparation of ethyl 5-(1-phenylcyclopropyl)-1H-imidazole-2-carboxylate.

A solution of 2-bromo-1-(1-phenylcyclopropyl)ethanone (3.4 g, 14.2 mmol), ethyl 2-amino-2-iminoacetate (1.65 g, 14.2 mmol) and triethylamine (4, 3 g, 42.6 mmol) in ethanol (50 ml) was refluxed for 5 hours. After concentration under reduced pressure, the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give 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. Preparation of 5-(1-phenylcyclopropyl)-1H-imidazole-2-carboxylic acid.

To a solution of ethyl 5-(1-phenylcyclopropyl)-1H-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 temperature overnight. This 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 in vacuo to give 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. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1phenylcyclopropyl)-1H -imidazole-2-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH4HCO3), ACN (from 40% ACN to 70% B in 7 min); detector, UV 254 & 220 nm, to obtain the title compound. Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.11-12.79 (m, 1H), 8.328.17 (m, 1H), 7.51 (dd, J=7.6, 1.9 Hz , 1H), 7.37-7.16 (m, 8H), 6.85-6.44 (m, 1H), 4.88-4.74 (m, 1H), 4.66-4.50 (m, 1H), 4.45-4.35 (m, 1H), 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 ]thiazole-2-carboxamide.

Step 1. Preparation of (S)-7-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)benzo[d]thiazol- 2-carboxamide.

Using the procedure described in Example 54, the title compound (370 mg) was obtained as a yellow solid, which was used in the next step without purification. LC-MS (method S): m/z=432.2 [M+H] ⁺ , 1.102 min.

Step 2. Preparation of 7-(2-fluorophenyl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) benzo[d]thiazole-2-carboxamide.

[1,G-Bis(diphenylphosphino)ferrocene]dichloropalladium(P) (29 mg, 0.04 mmol) was added to the mixture of (S)7-bromo-N-(5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzo[d]thiazol-2-carboxamide (170 mg, 0.39 mmol), 2-fluorophenylboronic acid (85 mg, 0.59 mmol) and carbonate potassium (109 mg, 0.79 mmol) in dioxane (2 ml) and water (0.5 ml) under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C. Solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The precipitate was purified using Prep-HPLC under the following conditions: column:

XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 3% B to 38% B in 7 minutes; 254 & 220 nm; Rt: 6.33 min, producing the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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). LC-MS (method T): m/z=448.3 [M+H] ⁺ , 1.884 min.

Example 80A and 80B. 5-Benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepine-2 -yl)-1H-pyrazol-3-carboxamide (80A) and 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3- 118 044271 oxo-1,1a,2,3,4, 8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide (80B).

Stage 1

Stage 2

Step 1. Preparation of 5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl )-1H-pyrazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 50% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. LC-MS (method D): m/z=388.2 [M+H]+, 1.757 min.

Step 2. Preparation of 5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3- b]azepin-2-yl)-1H-pyrazol-3-carboxamide (first eluting isomer) and 5-benzylN-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3 ,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1Hpyrazol-3-carboxamide (second eluting isomer).

5-Benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2yl)-1H-pyrazole racemate -3-carboxamide (60 mg, 0.16 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRAL IC, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 60% B to 60% B in 16.5 minutes; UV 254 & 220 nm; RT 1: 8.27 min; RT 2: 13.00 min, obtaining title compounds:

example 80A (first eluting isomer): 1H NMR (300 MHz, Methanol-d ₄ ) 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), 2.312.23 (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.

example 80B (second eluting isomer): 1H NMR (300 MHz, Methanol-d ₄ ) 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), 2.312.23 (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-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepine-2 -yl)isoxazol-3-carboxamide (81A) and 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido [2,3-b]azepin-2-yl)isoxazole-3-carboxamide (81B).

Stage 1

Stage 2

Step 1. Preparation of 5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl )isoxazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 55% B in 7 minutes; UV 254 & 220 nm, producing the title compound. LC-MS (method D): m/z=389.1 [M+H] ⁺ , 2.036 min.

Step 2. Preparation of 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b ]azepin-2-yl)isoxazol-3-carboxamide (first eluting isomer) and 5-benzyl-N- 119 044271 ((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3 ,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-ul)uzoxazole3-carboxamide (second eluting isomer).

5-Benzyl-N-(cis-4-methyl-3-oxo-1,1 a,2,3,4,8b-hexahydrocyclopropa[d]pyrudo[2,3-b]azepin-2yl)isoxazole-3 racemate -carboxamide (60 mg, 0.15 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IC, 2x25 cm, 5 µm; mobile phase A: hexanes, mobile phase B: EtOH; flow rate: 18 ml/min; gradient: from 50% B to 50% B in 17 minutes; UV 254 & 220 nm; RT 1:12.098 min; RT 2: 14.358 min, obtaining title compounds:

example 81B (first eluting isomer): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.98 (d, J=7.5 Hz, 1H), 8.40 (dd, J=4.5, 1 ,8 Hz, 1H), 7.98 (dd, J=7.5, 1.8 Hz, 1H), 7.40-7.26 (m, 6H), 6.62 (s, 1H), 4 .45 (d, J=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;

example 81A (second eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.98 (d, J=7.2 Hz, 1H), 8.40 (dd, J=4.5, 1, 8 Hz, 1H), 7.98 (dd, J=7.5, 1.8 Hz, 1H), 7.40-7.26 (m, 6H), 6.62 (s, 1H), 4, 45 (d, J=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. 1-Benzyl-4-fluoro-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b ]azepin-2-yl)-1H-nirazol-3-carboxamide (82A) and 1-benzyl-4-fluoro-N-((1aR,2R,8bS)-4methyl-3-oxo-1,1a,2, 3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide (82B).

Step 1. Preparation of 1-benzyl-4-fluoro-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocycloprona[d]pyrido[2,3-b]azepine -2-ul)-1H-pyrazole-3-carboxamide.

The crude product obtained by the Amine C coupling procedure was purified by Prep-HPLC under the following conditions: Column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 65% B in 7 minutes; UV 254 & 220 nm to give 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. Preparation of 1-benzyl-4-fluoro-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrudo[2 ,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide (first eluting isomer) and 1-benzyl-4fluoro-N-((1aS,2S,8bR)-4-methyl-3-oxo- 1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1Hpyrazol-3-carboxamide (second eluting isomer).

Racemate 1-benzyl-4-fluoro-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3b]azepin-2-yl) -1H-pyrazole-3-carboxamide (58 mg, 0.15 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IC, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 18 ml/min; gradient: from 50% B to 50% B in 23 minutes; UV 254 & 220 nm; RT 1: 10.936 min; RT 2: 16.976 min, obtaining title compounds:

example 82B (first eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.39 (dd, J=4.8, 1.8 Hz, 1H), 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). LC-MS (Method v): m/z=406.1 [M+H] ⁺ , 2.852 min;

example 82A (second eluting isomer): 1H NMR (300 MHz, Methanol^ 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+H] ⁺ , 1.932 min.

- 120 044271

Example 83A. 5-Benzyl-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl )-4H-1,2,4-triazole-3-carboxalamide.

Stage 1. Preparation of 2,4-difluoro-6-vinylbenzepamine.

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 nitrogen. The resulting mixture was stirred for 16 hours at 80°C. After cooling to room temperature, the reaction mixture was quenched by adding water (200 ml) and extracted with dichloromethane (3x200 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/17) to give 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. Preparation of N-(2,4-difluoro-6-vinylphenyl)but-3-enamide.

Thionyl chloride (9.3 g, 46.46 mmol) was added dropwise to a solution of but-3-enoic acid (4.0 g, 46.46 mmol) in dichloromethane (20 ml). After stirring for 1 hour at room temperature, the resulting mixture was added to a solution of triethylamine (11.8 g, 116.6 mmol) and 2-ethenyl-4,6-difluoroaniline (6.0 g, 38.67 mmol) in dichloromethane (20 ml). The reaction mixture was stirred for 3 hours at room temperature, quenched by adding water (50 ml) and extracted with dichloromethane (3x100 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/17) to give the title compound (5.7 g, 66%) as a yellow oil. LC-MS (method C): m/z=224.0 [M+H] ⁺ , 1.145 min.

Step 3. Preparation of (Z)-7,9-difluoro-1H-benzo[b]azepin-2(3H)-one.

Tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro(phenylmethylidene)ruthenium (3.4 g, 4.0 mmol) was added to the solution of N-(5-ethenyl-2, 4-difluorophenyl)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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give the title compound (2.8 g, 69%) as a yellow oil. LCMS (method S): m/z=196.0 [M+H] ⁺ , 0.754 min.

Step 4. Preparation of 5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one.

To a solution of potassium hydroxide (40 g, 714 mmol) in water (60 ml) was added dropwise a solution of 1-methyl1-nitrosourea (20.6 g, 199.8 mmol) in ester (150 ml) at 0°C in an atmosphere nitrogen. The resulting mixture was stirred for 1 hour at 0°C and then the organic phase was separated to obtain a diazomethane solution (150 ml). A solution of diazomethane (150 mL) with 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 overnight at room temperature. Solids were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (1.2 g crude) as a yellow oil. LC-MS (method C): m/z=210.0 [M+H] ⁺ , 1.117 min.

- 121 044271

Step 5. Preparation of trans-5,7-difluoro-2-iodo-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin3(4H)-one.

To a mixture of 5,7-difluoro-1,1a,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',N'-tetramethylethylenediamine (2.1 g, 18.0 mmol) followed by 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 in vacuo to give the title compound (1.32 g, crude) as a yellow oil. LC-MS (method C): m/z=336.0 [M+H]+, 1.213 min.

Step 6. Preparation of cis-2-azido-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin3(4H)-one.

Sodium azide (250 mg, 3.84 mmol) was added to a solution of trans-5,7-difluoro-2-iodo-1,1a,2,8bτtetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (860 mg, 2.56 mmol) in N,N-dimethylformamide (40 ml). The resulting mixture was stirred for 16 hours at room temperature, quenched by adding water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (520 mg, crude) as a yellow oil. LC-MS (method C): m/z=251.0 [M+H] ⁺ , 1.176 min.

Step 7. Preparation of cis-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin3(4H)-one.

Triphenylphosphine (629 mg, 2.40 mmol) was added to a solution of cis-2-azido-5,7-difluoro-1,1a,2,8btetrahydrobenzo[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 temperature, 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 in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to give 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. Preparation of (1aR,2R,8bs)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (first eluting isomer ) and (1aS,2S,8bR)-2-amino-5,7-difluoro-1,1α,2,8btetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (second eluting isomer).

The racemate of cis-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (310 mg, 1.38 mmol) was separated using prep. . chiral HPLC under the following conditions: column: Chiralpak IA, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 15 ml/min; gradient: from 50% B to 50% B in 28 minutes; 254/220 nm; RT 1: 10.247 min; RT 2: 20.789 min, obtaining title compounds:

(1aR,2R,8bS)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(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;

(1aS,2S,8bR)-2-amino-5,7-difluoro-1,1a,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.

Step 9. 5-Benzyl-N-((1aS,2S,8R)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin- 2-yl)-4H-1,2,4-triazol-3-carboxamide-N,N-diisopropylethylamine (50 mg, 0.39 mmol) was added to the mixture of (1aS,2S,8R)-2-amino-5, 7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin3(4H)-one (30 mg, 0.13 mmol), 5-benzyl-4H-1,2,4-triazol- 3-carboxylic acid (32 mg, 0.16 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol) and 1-hydroxybenzotriazole (22 mg, 0.16 mmol) in N, N-dimethylformamide (5 ml). The resulting mixture was stirred for 2 hours at room temperature, diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using PrepHPLC under the following conditions: column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (from 30.0% ACN to 60.0% in 7 min); Detector, UV 254 nm, to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 14.30 (br. s, 1H), 9.96 (br. s, 1H), 8.43 (d, J=6.8 Hz, 1H), 7.36-7.19 (m, 7H), 4.61 (d, J=6.8 Hz, 1H), 4.14 (s, 2H), 2.32-2.26 (m, 1H) , 2.07-2.01 (m, 1H), 1.43-1.39 (m, 1H), 1.12-1.07 (m, 1H). LC-MS (method Q): m/z=410.3 [M+H] ⁺ , 1.144 min.

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Example 83B. 5-Benzyl-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azenin-2-yl )-4H-1,2,4-triazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (from 30.0% ACN to 60.0% in 7 min); Detector, UV 254 nm, to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 14.41 (s, 1H), 9.95 (s, 1H), 8.42 (d, J=6.8 Hz, 1H), 7.35- 7.19 (m, 7H), 4.61 (d, J=6.8 Hz, 1H), 4.14 (s, 2H), 2.32-2.26 (m, 1H), 2.07 -2.01 (m, 1H), 1.43-1.39 (m, 1H), 1.12-1.07 (m, 1H). LC-MS (method Q): m/z=410.30 [M+H]+, 1.143 min.

Example 84 2-carboxamide.

[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(P) (34 mg, 0.05 mmol) was added to the mixture of (S)7-bromo-N-(5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzo[d]thiazol-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 nitrogen. The resulting mixture was stirred overnight at 80°C. Solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 3% B to 38% B in 7 minutes; 254 & 220 nm; Rt: 6.33 min, producing the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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), 4.96-4.68 (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][1,4]oxazepin-3-yl)1 ,3,4-thiadiazole-2-carboxamide.

O

Stage 1 Stage 2

Step 1. Preparation of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate.

Ethyl 2-chloro-2-oxoacetate (1.8 g, 13.4 mmol) at 0°C. The resulting solution was stirred for 12 hours at room temperature, diluted with water (20 ml) and extracted with dichloromethane (5x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of ethyl 5-benzyl-1,3,4-thiadiazole-2-carboxylate.

To a mixture of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate (0.65 g, 2.6 mmol) in tetrahydrofuran

- 123 044271 (8 ml) Lawson's reagent (1.89 g, 4.7 mmol) was added. The resulting mixture was stirred for 3 hours at

70°C. After cooling to room temperature, 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%,

3x20 ml) and saline, dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of 5-benzyl-1,3,4-thiadiazole-2-carboxylic acid.

To a mixture of ethyl 5-benzyl-1,3,4-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 temperature and concentrated in vacuo. The precipitate was diluted with water (10 ml), and the pH of the solution was adjusted to 6 using an aqueous solution of hydrochloric acid (1N, 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 in vacuo to give 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. Preparation of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxαzepin-3yl)-1 ,3,4-thiadiazole-2-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 38% B to 70% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.46 (d, J=6.6 Hz, 1H), 8.37 (dd, J=4.8, 1.8 Hz, 1H), 7.71 (dd, J=7.8, 1.5 Hz, 1H), 7.387.26 (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.

Example 86 -carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 38% B to 70% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.95 (d, J=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 1,2,3-triazole-4-carboxamide.

1) DPPA, Et ₃ N, ^toluene 100 °C, 5 h

2) t-BuOH, rt, incl.

NIGHTS

Stage 1

n. HC1 in dioxane

NHBoc _______________,

KT, 3 h

Stage 2

1) MeMdVg.THF, -60 °C, 30 min

2) TsN ₃ , THF, -60 °C to RT, 1 h

NH ₂ HCI

Stage 3 Stage 4

Stage 1. Preparation of tert-butyl-1-phenylcyclopropylcarbamate.

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Triethylamine (18.6 g, 185 mmol) was added to a stirred mixture of 1-phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol) and diphenylphosphorazidate (17.0 g, 61.7 mmol) in toluene (100 ml). The reaction mixture was stirred for 5 hours at 100°C, cooled to room temperature and then 2-methylpropan-2-ol (33.7 mg, 0.216 mmol) was added. The reaction mixture was stirred overnight at room temperature and concentrated under high vacuum. The precipitate was diluted with water (100 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give the title compound (4.00 g, 28%) as a yellow solid. LC-MS (method C): m/z=234.2 [M+H]+, 1.345 min.

Stage 2. Preparation of 1-phenylcyclopropanamine hydrochloride.

Tert-butyl-1-phenylcyclopropylcarbamate (4.0 g, 17.2 mmol) was added to a solution of hydrogen chloride in dioxane (4N, 50 ml, 200 mmol). The reaction mixture was stirred for 3 hours at room temperature and concentrated under high vacuum to give the title compound (2.00 g, 88%) as a white solid. LC-MS (method C): m/z=134.2 [M+H] ⁺ , 0.775 min.

Stage 3. Preparation of (1-azidocyclopropyl)benzene.

To a stirred solution of 1-phenylcyclopropanamine hydrochloride (320 mg, 1.89 mmol) in ester (10 ml) was added a solution of methylmagnesium bromide in ester (3 M, 1.89 ml, 5.67 mmol) at -60°C in argon atmosphere. After stirring for 30 min 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 (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (500 mg, crude) as a yellow solid.

Step 4. Preparation of ethyl 1-(1-phenylcyclopropyl)-1H-1,2,3-triazole-4-carboxylate.

Copper acetate (468 mg, 3.14 mmol) was added to a solution of (1-azidocyclopropyl)benzene in ethyl propiolate (5 ml). The reaction mixture was stirred overnight at room temperature and concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of 1-(1-phenylcyclopropyl)-1H-1,2,3-triazole-4-carboxylic acid.

Lithium hydroxide (18.7 mg, 0.78 mmol) was added to a solution of ethyl 1-(1-phenylcyclopropyl)-1H1,2,3-triazole-4-carboxylate (100 mg, 0.39 mmol) in tetrahydrofuran (3 ml) and water (1 ml). The resulting solution was stirred overnight at room temperature, concentrated in vacuo and diluted with water (5 ml). The pH of this solution was adjusted to 5 using an aqueous solution of hydrochloric acid (1N, 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 in vacuo to give the title compound (30 mg crude) as a white solid. LC-MS (method D): m/z=230.2 [M+H] ⁺ , 0.532 min.

Step 6. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(1phenylcyclopropyl)-1H -1,2,3-triazole-4-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 65% B in 7 minutes; 220 nm; Rt: 6 min, obtaining the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.58 (d, J=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), 1.73-1.64 (m, 2H). LC-MS (method D): m/z=404.1 [M+H] ⁺ , 1.992 min.

Example 88 1H-imidazole-5-carboxamide.

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Step 1. Preparation of (Z)-N'-hydroxy-1-phenylcyclopropanecarboximidamide.

Hydroxylamine hydrochloride (1.4 g, 20.3 mmol) was added to a mixture of 1-phenylcyclopropanecarbonitrile (1.5 g, 10.5 mmol) and sodium carbonate (2.2 g, 20.7 mmol) in ethanol (20 ml) and water (10 ml). The resulting mixture was stirred at 80°C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (3x80 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to give 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. Preparation of ethyl 2-(1-phenylcyclopropyl)-1H-imidazole-5-carboxylate.

A solution of (Z)-N'-hydroxy-1-phenylcyclopropanecarboximidamide (1.2 g, 6.8 mmol) and ethyl propiolate (1.0 g, 10.2 mmol) in ethanol (50 ml) was stirred at 80°C for overnight and concentrated 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 give 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. Preparation of 2-(1-phenylcyclopropyl)-1H-imidazole-5-carboxylic acid.

Lithium hydroxide (288 mg, 7.2 mmol) was added to a solution of 2-(1-phenylcyclopropyl)-1H-imidazole 5-carboxylate (300 mg, 1.2 mmol) in tetrahydrofuran (9 ml) and water (3 ml). The reaction mixture was stirred overnight at room temperature, diluted with water (20 ml), adjusted to pH 5 with aqueous hydrochloric acid (1N, 10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 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. Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(1phenylcyclopropyl)-1H -imidazole-5-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 60% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. ^1H NMR (300 MHz, DMSO-d6) 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), 4.54-4.38 (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-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl )-1,3,4-oxadiazole-2-carboxamide.

- 126 044271 o

Step 1. Preparation of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate.

Ethyl 2-chloro-2-oxoacetate (603 mg, 4.4 mmol) was added to a stirred solution of 2phenylacetohydrazide (660 mg, 4.4 mmol) and triethylamine (1.33 g, 13.2 mmol) in dichloromethane (20 ml). The reaction mixture was stirred at room temperature for 5 hours, quenched by adding water (20 ml) and extracted with dichloromethane (3x25 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of ethyl 5-benzyl-1,3,4-oxadiazole-2-carboxylate.

Tosyl chloride (840 mg, 4.4 mmol) was added to a stirred 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 temperature, quenched by adding water (20 ml) and extracted with dichloromethane (3x25 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of 5-benzyl-1,3,4-oxadiazole-2-carboxylic acid.

Lithium hydroxide (103 mg, 4.3 mmol) was added to a stirred solution of ethyl 5-benzyl-1,3,4oxadiazole-2-carboxylate (500 mg, 2.15 mmol) in tetrahydrofuran (5 ml) and water (2 ml ). The reaction mixture was stirred overnight at room temperature, concentrated in vacuo and diluted with water (20 ml). The pH of the mixture was adjusted to pH=6 using an aqueous solution of hydrochloric acid (1N, 10 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 in vacuo to give 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. Preparation of 5-benzyl-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepine -2-yl)-1,3,4-oxadiazol-2-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 30.0% ACN to 60.0% in 7 min); Detector, UV 254 nm, to obtain the title compound. 1H NMR (400 MHz, CD3OD) δ 7.38-7.29 (m, 5H), 7.12-7.08 (m, 1H), 6.98-6.93 (m, 1H), 4, 82 (d, J=0.8 Hz, 1H), 4.36 (s, 2H), 2.31-2.25 (m, 1H), 2.12-2.07 (m, 1H), 1.671 .63 (m, 1H), 1.23-1.17 (m, 1H). LC-MS (Method V): m/z=411.05 [M+H] ⁺ , 2.915 min.

Example 89B. 5-Benzyl-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl )-1,3,4-oxadiazole-2-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 30.0% ACN to 60.0% in 7 min); Detector, UV 254 nm, to obtain the title compound. 1H 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), 1.671.63 (m, 1H), 1.23-1.17 (m, 1 H). LC-MS (Q method): m/z=411.30 [M+H] ⁺ , 0.965 min.

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Example 90A. 1 -Benzyl-N-(( 1 aR,2R,8bS)-5,7-difluoro-3-oxo-1,1 a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepine-2 -yl)-1H-1,2,3-triazole-4-carboxamide.

CT, 2 hours

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (from 30.0% ACN to 60.0% in 7 min); Detector, UV 254 nm, to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 90V. 1-Benzyl-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl )-1H-1,2,3-triazole-4-carboxamide.

CT, 2 hours

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (from 30.0% ACN to 60.0% in 7 min); Detector, UV 254 nm, to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) 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 1 H-pyrazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column: XBridge Prep Phenyl OBD, 5 µm, 19 x 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 60% B in 7 minutes; UV 254 &220 nm to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) 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 min.

Example 92 1-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin3-yl )-4-fluoro-1H-pyrazole-3-carboxamide.

- 128 044271 he is about

NaH, DMF 0°C to RT, 3 h.

Pd/C, H ₂ , MeOH

KT, 6 hours

Stage 2

Stage 1

Stage 6

Step 1. Preparation of (2S,3R)-2-(tert-butoxycarbonylamino)-3-(2-nitropyrudin-3-uloxy)butanoic acid.

Sodium hydride (60%, 9.2 g, 230 mmol) was added to a stirred solution of (2S,3R)-2-(tert-butoxycarbonylamino)-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 adding 3-fluoro-2-nitropyridine (16.4 g, 115 mmol), the reaction mixture was stirred at room temperature for an additional 2 hours and then quenched by adding hydrochloric acid acid (3N, 20 ml). The pH of the reaction solution was adjusted to 3-4 using hydrogen chloride (3N, 20 ml). The resulting solution was extracted with ethyl acetate (3x150 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 give 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. Preparation of (2S,3R)-3-(2-aminopyridin-3-yloxy)-2-(tert-butoxycarbonylamino)butanoic acid.

(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 a carbon-supported palladium catalyst (10%, 1.0 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred for 6 hours at room temperature. Solids were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (3.12 g, 91%) as a colorless oil. LC-MS (method C): m/z=312.1 [M+H]+, 0.887 min.

Step 3. Preparation of tert-butyl-(2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin3-ylcarbamate.

N,N-Diisopropylethylamine (1.43 g, 11 mmol) was added to a stirred solution of (2S,3R)-3-(2aminopyridin-3-yloxy)-2-(tert-butoxycarbonylamino)butanoic acid (3.0 g, 10 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (4.18 g, 11 mmol) in N,Ndimethylformamide (50 ml). The reaction mixture was stirred for 5 hours at room temperature, quenched by adding water (20 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to give 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. Preparation of tert-butyl-(2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-ylcarbamate.

Iodomethane (388 mg, 2.73 mmol) was added dropwise to the stirred solution of tert-butyl(2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrudo[3,2-b][ 1,4]oxazepin-3-ylcarbamate (800 mg, 2.73 mmol) and cesium 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 temperature, diluted with water (20 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give 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. Preparation of (2R,3S)-3-amino-2,5-dimethyl-2,3-dihydropyrido[3,2] hydrochloride

- 129 044271

b] [1,4]oxazepin-4(5H)-one.

Tert-butyl-(2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate (670 mg, 2.18 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 10 ml, 40 mmol). The reaction mixture was stirred for 5 hours at room temperature and concentrated under reduced pressure to give 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. Preparation of 1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-3- yl)-4-fluoro-1H-pyrazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 60% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (dd, J=4.4, 1.6 Hz, 1H), 8.15 (d, J=4.4 Hz, 1H), 7, 76 (dd, J=8.0, 1.6 Hz, 1H), 7.61 (d, J=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 )-4-fluoro-1 H-pyrazole-3-carboxamide. it

Stage 1 ^OS Stage 2 ^OS Stage 3

Stage 6

The title compound was prepared from (2S,3S)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid using the procedure described in Example 92.

The resulting crude product was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19x150 mm, 5 µm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 55% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) 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), 7.42-7.27 (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] ⁺ , 1.923 min.

Example 94 5-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxαzepin3-yl )-4H-1,2,4-triazole-3-carboxamide.

N,N-Diisopropylethylamine (95 mg, 0.73 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazole-3carboxylic acid (50 mg, 0.24 mmol), hydrochloride (2R,3S)- 3-amino-2,5-dimethyl-2,3dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-oneα (50 mg, 0.24 mmol), N-(3dimethylaminopropyl) hydrochloride) -N'-ethylcarbodiimide (60 mg, 0.32 mmol) and 1-hydroxybenzotriazole (43 mg, 0.32 mmol) in N,N-dimethylformamide (2 ml). The reaction mixture was stirred overnight at room temperature, diluted with water (20 ml) and extracted with ethyl acetate (3x50 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; speed

- 130 044271 flow: 20 ml/min; gradient: from 5% B to 5% B in 4 minutes; UV 254 & 220 nm to obtain the title compound. 'H NMR (400 MHz, DMSO-O 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=6.0 Hz, 3H). LC-MS (method D): m/z=393.1 [M+H]+, 1.725 min.

Example 95 )-4H-1,2,4-triazole-3-carboxamide.

Example 96 5-Benzyl-N-((2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3yl)- 4H-1,2,4-triazole-3-carboxamide.

Stage 1 Stage 2

Step 1. Preparation of (2R,3S)-3-amino-2-methyl-2,3-dihydropyrido[3,2b][1,4]oxazepin-4(5H)-one hydrochloride.

Tert-butyl-(2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate (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 temperature and concentrated under reduced pressure to give 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. Preparation of 5-benzyl-N-((2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3- yl)-4H-1,2,4-triazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 10 µm, 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 in 7 min UV 254 & 220 nm to give title compound. ^1H NMR (300 MHz, DMSO-d6) δ 14.41 (s, 1H), 10.84 (s, 1H), 8.19-8.08 (m, 2H), 7.62 (dd, J =8.1, 1.2 Hz, 1H), 7.37-7.20 (m, 6H), 4.98-4.86 (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][1,4]oxazepin-3yl)- 4H-1,2,4-triazole-3-carboxamide.

K1, during nights

Stage 1 Stage 2

Stage 1. Preparation of (2S,3S)-3-amino-2-methyl-2,3-dihydropyrido[3,2b][1,4]oxazepin-4(5H)-one hydrochloride.

Tert-butyl-(2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]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 temperature and concentrated in vacuo to give the title compound (35 mg, crude) as a white solid. LC-MS (method E): m/z=194.0 [M+H] ⁺ , 0.432 min.

Step 2. Preparation of 5-benzyl-N-((2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3 - yl)-4H-1,2,4-triazole-3-carboxamide.

- 131 044271

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column: X Select CSH prep C18 OBD Prep, 5 µm, 19 mm x 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 15% B to 60% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d6) 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). LC-MS (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'-tetraαhydrospiro[cyclopropane-1,5'pyrido[2,3-b]azepine]-7'- yl)-4H-1,2,4-triαzol-3-carboxamide (98A) and (S)-5-benzyl-N-(8'-oxo-6',7',8',9'tetrahydrospiro[cyclopropαn -1,5'-pyrido[2,3-b]αzepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide (98B).

Step 1. Preparation of 7'-amino-6',7'-dihydrospiro[cyclopropan-1,5'-pyrido[2,3b]azepine]-8'(9'H)-one hydrochloride.

A solution of hydrogen chloride in 1,4-dioxane (4N, 10 ml, 40 mmol) was added to a solution of tert-butyl-(8'-oxo-6',7',8',9'-tetrahydrospiro[cyclopropane-1,5'-pyrido[2,3-b]azepine]-7'-yl)carbamate (100 mg, 0.34 mmol) in 1,4-dioxane (4 ml). The reaction mixture was stirred for 2 hours at room temperature and concentrated under high vacuum to give the title compound (80 mg, crude) as a white solid. LC-MS (method C): m/z=204.1 [M+H] ⁺ , 0.677 min.

Step 2. Preparation of 5-benzyl-X-(8'-oxo-6',7',8',9'-tetrahydrospiro[cyclopropan-1,5'-pyrido[2,3b]azepin]-7'-yl )-4H-1,2,4-triazole-3-carboxamideα.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 65% B in 7 minutes; 254/220 nm to give 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. Preparation of (R)-5-benzyl-N-(8'-OkCO-6',7',8',9'-tetrahydrospiro[cyclopropane-1,5'pyrido[2,3-b]azepine] -7'-yl)-4H-1,2,4-triazole-3-carboxamide (first eluting isomer) and (S)-5benzyl-N-(8'-oxo-6',7',8',9 '-tetrahydrospiro[cyclopropane-1,5'-pyrido[2,3-b]azepin]-7'-yl)-4H-1,2,4triazol-3-carboxamide (second eluting isomer).

Racemate 5-benzyl-N-(8'-oxo-6',7',8',9'-tetrahydrospiro[cyclopropan-1,5'-pyrido[2,3-b]azepin]-7'-yl) 4H-1,2,4-triazole-3-carboxamide (50 mg, 0.128 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak ID-2, 2x25 cm, 5 µm; mobile phase A: hexane/DCM 4.5:1, mobile phase B: EtOH; flow rate: 17 ml/min; gradient: from 50% B to 50% B in 22 min; UV 254 & 220 nm; RT 1: 11.72 min; RT 2: 18.02 min, obtaining title compounds:

example 98A (first eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 14.28 (s, 1H), 10.37 (s, 1H), 8.27 (dd, J=4.8, 1.8 Hz, 1H), 7.69 (dd, J=7.6, 1.8 Hz, 1H), 7.34-7.08 (m, 6H), 4.42-4.33 (m , 1H), 3.30 (s, 3H), 2.82-2.68 (m, 1H), 1.72 (s, 1H), 1.23-1.05 (m, 1H), 0, 88-0.78 (m, 1H), 0.70-0.65 (m, 1H), 0.40-0.25 (m, 1H). LC-MS (method D): m/z=389.2 [M+H] ⁺ , 1.499 min;

example 98B (second eluting isomer): 1H NMR (300 MHz, DMSO-de) δ 10.38 (d, J=2.8 Hz, 1H), 8.37-8.22 (m, 2H), 7, 71-7.67 (m, 1H), 7.44-7.08 (m, 6H), 4.43-4.34 (m, 1H), 4.06 (s, 2H), 2.78- 2.71 (m, 1H), 1.73 (t, J=12.3 Hz, 1H), 1.23-1.05 (m, 2H), 0.86-0.79 (m, 1H) , 0.71-0.64 (m, 1H), 0.27 (s, 1H). LC-MS (method D): m/z=389.2 [M+H] ⁺ , 1.503 min.

Example 99 - 132 044271 phenylcyclopropyl)-1 H-imidazole-2-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: Xbridge Prep C18, 19x150 mm, 5 µm; Mobile phase: phase A: water (10 mmol/l NH4HCO3); phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 55% B in 7 minutes; Detector, UV 220 & 254 nm; Rt: 6.32 min, producing the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) 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-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3-b]azepine -2-yl)picolinamide (100A) and 4-(2-fluorophenoxy)-N((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[ d]pyrido[2,3-b]azepin-2-yl)picolinamide (100B).

F

Step 1. Preparation of 4-(2-fluorophenoxy)-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b] azepin-2-yl)picolinamide.

The crude product obtained using the amine coupling technique C was purified using Rev. TLC (ethyl acetate/petroleum ether, 1/3) to give the title racemic compound. LC-MS (method J): m/z=419.1 [M+H] ⁺ , 1.330 min.

Step 2. Preparation of 4-(2-fluorophenoxy)-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3 -b]azepin-2-yl)picolinamide (first eluting isomer) and 4-(2fluorophenoxy)-N-(( 1 aR,2R,8bS)-4-methyl-3-oxo- 1,1a, 2,3, 4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2yl)picolinamide (second eluting isomer).

Racemate 4-(2-fluorophenoxy)-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydro-cyclopropa[d]pyrido[2,3-b]azepine- 2-yl)picolinamide (25 mg, 0.096 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IA, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 50% B to 50% B in 19 minutes; 220/254 nm; RT 1: 13.609 min; RT 2: 15.738 min, obtaining title compounds:

example 100A (first eluting isomer): 1H NMR (300 MHz, Methanol^ ₄ ) 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;

example 100B (second eluting isomer): 1H NMR (300 MHz, Methanol-d ₄ ) δ 8.58 (d, J=5.6 Hz, 1H), 8.38 (dd, J=4.7, 1, 8 Hz, 1H), 7.95 (dd, J=1.1, 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), 1.241.16 (m, 1H). LC-MS (method T): m/z=419.3 [M+H] ⁺ , 2.774 min.

Example 101A and 101B. (R)-5-Benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)-4H-1, 2,4-triazole-3-carboxamide (101A) and (S)-5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8hexahydropyrazolo[4,3- b]azepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (101B).

- 133 044271

Step 2. Preparation of ethyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)butanoate.

Ethyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)butanoate (405 mg, 1.68 mmol) was hydrogenated in the presence of a carbon-supported palladium catalyst (10%, 41 mg) under a hydrogen atmosphere ( 2-3 atm) in methanol (20 ml). The reaction mixture was stirred for 2 hours at room temperature. The solids were then removed by filtration and the solvents were evaporated in vacuo to give 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. Preparation of 4-(4-amino-1-methyl-1H-pyrazol-5-yl)butanoic acid.

A solution of ethyl 4-(4-amino-1-methyl-1H-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 temperature. The pH value of the solution was adjusted to 6-7 using hydrochloric acid (1N). The resulting solution was concentrated in vacuo to give 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. Preparation of 1-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-one.

N,N-Diisopropylethylamine (465.2 mg, 3.6 mmol) was added to a stirred solution of 4-(4amino-1-methyl-1H-pyrazol-5-yl)butanoic acid (220 mg, 1.2 mmol) and hexafluorophosphate N,N,N',N'tetramethyl-O-(7-azabenzotriazol-1-yl)uronium (548.2 mg, 1.44 mmol) in N,N-dimethylformamide (5 ml). The reaction mixture was stirred for 2 hours at room temperature, diluted with water (10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give the title compound (160 mg, 80.8%) as a yellow solid. LC-MS (method C): m/z=166.2 [M+H] ⁺ , 0.751 min.

Step 5. Preparation of 1,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-one.

Iodmethane (150.5 mg, 1.06 mmol) was added dropwise to a stirred solution of 1-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,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 temperature, quenched with water (10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate, 3/1) to give 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. Preparation of 6-iodo-1,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-one.

N ¹ ,N ¹ ,N ² ,N ² -tetramethylethane-1,2-diamine (271.4 mg, 2.34 mmol) was added to a stirred solution of 1,4-dimethyl-7,8-dihydropyrazolo[4,3- b]azepin-5(1H,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 an additional 1 h at 0°C and quenched with aqueous sodium thiosulfate (5%,

- 134 044271 ml). The reaction mixture was stirred for a further 15 min and extracted with ethyl acetate (3x20 ml).

The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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. Preparation of 6-amino-1,4-dimethyl-7,8-dihydropyrazolo[4,3-b]αzepin-5(1H,4H,6H)-one.

To a solution of 6-iodo-1,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-oneα (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 temperature 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 overnight, diluted with water (10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give 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. Preparation of 5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4H-1, 2,4-triazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: Xbridge Prep C18, 19x150 mm, 5 µm; Mobile phase: phase A: water (10 mmol/l NH4HCO3); phase B: ACN (20% to 80% in 12 min); detector, UV 220 & 254 nm, to obtain the title compound. LC-MS (method C): m/z=380.2 [M+H]+, 1.290 min.

Step 9. Preparation of (R)-5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)- 4H-1,2,4-triazole-3-carboxamide (first eluting isomer) and (S)-5-benzyl-N-(1,4dimethyl-5-oxo-1,4,5,6,7,8- hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triαzol-3-carboxamide (second eluting isomer).

Racemate 5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydronirasolo[4,3-b]azepin-6-yl)-4H1,2,4 -triazole-3-carboxamide (50 mg, 0.13 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IA, 2x25 cm, 5 µm; mobile phase A: Hex, mobile phase B: EtOH; flow rate: 15 ml/min; gradient: from 60% B to 60% B in 21 minutes; 220/254 nm; RT 1: 12.12 min; RT 2: 18.44 min.

Example 101A (first eluting isomer): 1H NMR (400 MHz, Methanol-d ₄ ) 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.

Example 101B (second eluting isomer): 1H NMR (400 MHz, Methanol-d ₄ ) δ 7.51 (s, 1H), 7.35-7.22 (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 and 102B. 5-((R)-2,3-Dihydro-1H-inden-1-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1, 4]oxazepin-3-yl)-4H-1,2,4-triαzol-3-carboxamide and 5-((S)-2,3-dihydro-1H-inden-1-yl)-N-((S )-4oxo-2,3,4,5-tetraαhydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxαmide.

Step 1. Preparation of 5-(2,3-dihydro-1H-inden-1-yl)-X-((8)-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1, 4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 20% B to 36% B in 7 minutes; 254 nm; Rt: 7 min, obtaining the title compound. LC-MS (method D): m/z=391.1 [M+H]+, 1.593 min.

- 135 044271

Step 2. Preparation of 5-((R)-2,3-dihydro-1H-inden-1-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2b ][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide and 5-((S)-2,3-dihydro-1H-inden-1-yl)-N -((S)-4oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide.

Racemate 5-(2,3-dihydro-1H-inden-1-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1, 4]oxazepin-3 yl)-4H-1,2,4-triazole-3-carboxamide (10 mg) was separated using Rev. chiral HPLC under the following conditions: column: CHIRALPAKIA, 2.12x15 cm, 5 µm; mobile phase A: Hex:DCM 4.5:1, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 17.5 minutes; 220/254 nm; RT 1: 10.95 min; RT 2: 15.02 min, producing title compounds.

Example 102A (First eluting isomer): 1H NMR (400 MHz, Methanol- _d4 ) 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, 69-4.61 (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.

Example 102B (Second eluting isomer): 1H NMR (400 MHz, Methanol- _d4 ) 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, 69-4.61 (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-1,2,3,4-tetrahydrosniro[benzo[b]azenin5,1'-cyclopropan]-3-yl)-4H- 1,2,4-triazole-3-carboxamide and (S)-5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4tetrahydrospiro[benzo[b]azepine-5,1 '-cyclopropane]-3-yl)-4H-1,2,4-triazol-3-carboxamide.

Step 1. Preparation of dimethyl 2-(3,5-difluoro-2-nitrophenyl) malonate.

Dimethyl malonate (15 g, 114 mmol) was added dropwise to a stirred mixture of 1,3,5-trifluoro-2nitrobenzene (10 g, 56 mmol) and potassium carbonate (23 g, 168 mmol) in N,N-dimethylformamide (150 ml) . The reaction mixture was stirred overnight at 70°C and quenched by adding water (50 ml). The resulting solution was extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to give the title compound (15 g, 92%) as a yellow oil. LC-MS (method C): m/z=290.0 [M+H] ⁺ , 1.235 min.

Stage 2. Preparation of methyl 2-(3,5-difluoro-2-nitrophenyl) acetate.

- 136 044271

A solution of lithium chloride (6.3 g, 150 mmol) in water (20 ml) was added to a solution of dimethyl 2-(3,5difluoro-2-nitrophenyl) malonate (15 g, 52 mmol) in dimethyl sulfoxide (50 ml). The reaction mixture was stirred overnight at 100°C and quenched by adding water (250 ml). The 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 in vacuo to give the title compound (11 g, crude) as a yellow oil, which was used directly in the next step without further purification.

Step 3. Preparation of methyl 1-(3,5-difluoro-2-nitrophenyl)cyclopropanecarboxylate.

1,2-Dibromoethane (13 g, 70 mmol) was added dropwise to a stirred solution of methyl 2-(3,5difluoro-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 adding water (250 ml). The resulting solution was extracted with ethyl acetate (3x250 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to give the title compound (1.1 g, 9%) as a yellow oil. LC-MS (method C): m/z=258.1 [M+H]+, 1.291 min.

Step 4. Preparation of (1-(3,5-difluoro-2-nitrophenyl)cyclopropyl)methanol.

A solution of diisobutylaluminum hydride in toluene (1 M, 9.4 mL, 9.4 mmol) was added dropwise to a stirred solution of methyl 1-(3,5-difluoro-2-nitrophenyl)cyclopropanecarboxylate (1.1 g, 4.3 mmol) in toluene (30 ml) at -78°C under nitrogen atmosphere. The reaction mixture was stirred at -78°C for 2 hours, quenched by adding water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to give 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. Preparation of 1-(3,5-difluoro-2-nitrophenyl)cyclopropanecarbaldehyde.

Dess-Martin reagent (3.4 g, 8 mmol) was added to a stirred 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 adding water (50 ml) and extracted with dichloromethane (3x50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to give the title compound (0.85 mg, 92%) as a yellow oil.

Step 6. Preparation of (E)-ethyl-3-(1-(3,5-difluoro-2-nitrophenyl)cyclopropyl)acrylate.

Ethyl (triphenylphosphoranylidene) acetate (1.5 g, 4.3 mmol) was added to a stirred solution of 1-(3,5-difluoro-2-nitrophenyl)cyclopropanecarbaldehyde (800 mg, 3.5 mmol) in tetrahydrofuran (50 ml) . The reaction mixture was stirred overnight at 50°C, quenched by adding water (100 ml) and extracted with dichloromethane (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to give 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. Preparation of ethyl 3-(1-(2-amino-3,5-difluorophenyl)cyclopropyl)propanoate.

(E)-ethyl-3-(1-(3,5-difluoro-2-nitrophenyl)cyclopropyl)acrylate (640 mg, 2.2 mmol) in methanol (30 ml) was hydrogenated in the presence of a carbon-supported palladium catalyst (10 %, 65 mg) in a hydrogen atmosphere (2-3 atm). After stirring overnight at room temperature under hydrogen, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo to give 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. Preparation of 3-(1-(2-amino-3,5-difluorophenyl)cyclopropyl)propanoic acid.

Lithium hydroxide (180 mg, 7.5 mmol) was added to a solution of ethyl 3-(1-(2-amino-3,5difluorophenyl)cyclopropyl)propanoate (400 mg, 1.5 mmol) in tetrahydrofuran (30 ml) and water (10 ml). The reaction mixture was stirred at room temperature overnight. After removing the tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH=7 using an aqueous solution of hydrochloric acid (1N, 10 ml). The resulting solution was 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 in vacuo to give 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. Preparation of 7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,1'-cyclopropan]-2(1H)-one.

N,N-diisopropylethylamine (515 mg, 4.0 mmol) was added to a mixture of 3-(1-(2-amino-3,5difluorophenyl)cyclopropyl)propanoic acid (320 mg, 1.3 mmol) and N,N hexafluorophosphate. N',N'

- 137 044271 tetramethyl-O-(7-azabenzotriazol-1-yl)uronium (608 mg, 1.6 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 2 hours and quenched by adding water (50 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to give 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. Preparation of 7,9-difluoro-3-iodo-3,4-dihydrospiro[benzo[b]azepin-5,1'-cyclopropan]2(1H)-one.

N,N,N',N'-tetramethylethylenediamine (418 mg, 3.6 mmol) was added to a solution of 7,9-difluoro-3,4dihydrospiro[benzo[b]azepine-5,1'-cyclopropane]-2(1H )-one (270 mg, 1.2 mmol) in dichloromethane (40 ml) at 0°C followed by the 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) was added to the mixture. After stirring for a further 1 hour at 0°C, the reaction mixture was quenched by adding aqueous sodium thiosulfate (5%, 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 in vacuo to give the title compound (410 mg, crude) as a yellow oil. LC-MS (method C): m/z=350.1 [M+H] ⁺ , 1.262 min.

Step 11. Preparation of 3-azido-7,9-difluoro-3,4-dihydrospiro[benzo[b]azepin-5,1'-cyclopropane] 2(1H)-one.

Sodium azide (117 mg, 1.8 mmol) was added to a solution of 7,9-difluoro-3-iodo-3,4-dihydrospiro[benzo[b]azepine-5,1'-cyclopropane]-2(1H)-one (410 mg, 1.2 mmol) in N,N-dimethylformamide (20 ml). The resulting mixture was stirred overnight at room temperature and quenched by adding water (40 ml). The resulting solution was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (260 mg, crude) as a yellow oil. LC-MS (method E): m/z=265.1 [M+H] ⁺ , 0.875 min.

Step 12. Preparation of 3-amino-7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,1'-cyclopropane]2(1H)-one.

Triphenylphosphine (393 mg, 1.5 mmol) was added to a solution of 3-azido-7,9-difluoro-3,4dihydrospuro[benzo[b]azepine-5,1'-cyclopropane]-2(1H)-one (260 mg , 1.0 mmol) in tetrahydrofuran (10 ml) and water (1 ml). The resulting mixture was stirred overnight at room temperature, diluted with water (20 ml) and extracted with dichloromethane (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 5/1) to give 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. Preparation of 5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1'cyclopropane]-3-yl)-4H -1,2,4-triazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19x150 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 30 ml/min; gradient: from 25% B to 55% B in 7 minutes; UV 254 & 220 nm to give the title compound (30 mg, 26%) as a white solid. LC-MS (method O): m/z=423.9 [M+H] ⁺ , 1.204 min.

Step 14. Preparation of (R)-5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1'-cyclopropane]-3 -yl)-4H-1,2,4-triazole-3-carboxamide (Example 103A) and (S)-5-benzyl-N-(7,9difluoro-2-oxo-1,2,3,4-tetrahydrospiro [benzo[b]azepine-5,1'-cyclopropan]-3-yl)-4H-1,2,4-triazole-3carboxamide (example 103B)

Racemate 5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepin-5,1'-cyclopropan]3-yl)-4H-1, 2,4-triazole-3-carboxamide was separated using Rev. chiral HPLC under the following conditions: column: Chiralpak IA, 2x25 cm, 5 µm; mobile phase A: hexanes, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 55% B to 55% B in 27 minutes; UV 220 & 254 nm; Rt 1: 13.94 min; Rt 2: 21.44 min, producing two title compounds.

Example 103A (first eluting isomer): 1H NMR (400 MHz, Methanol- _d4 ) 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.

Example 103B (second eluting isomer): 1H NMR (400 MHz, Methanol- _d4 ) 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, 1H), 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[4,3-b]azepin6-yl)-4H-1,2, 4-triazole-3-carboxamide and (S)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyr- 138 044271 zolo[4,3-b ]azepin-6-yl)-4H-1,2,4-triazol-3-carboxamide.

CT scan, during nights

Stage 1 Stage 2

BUT

NH ₂ >° N^°

Pd/C, H ₂ , MeOH J.—/ HATU, DIEA, DMF /^ \ TMEDA, TMSI, 1 ₂ , DCM

CT, 5 h / ^N N CT, 3h 0 °C, 2 h o Stage 4 of day 5

Stage 3 stage a

Stage 6 Stage 7

Stage 8

Step 1. Preparation of ethyl 4-(1-methyl-4-nitro-1H-pyrazol-3-yl)butanoate.

A solution of (4-ethoxy-4-oxobutyl)zinc(II) bromide in tetrahydrofuran (0.5 M, 41.5 ml, 20.7 mmol) was added to the stirred mixture of 3-iodo-1-methyl-4-nitro-1H -pyrazole (4.32 g, 17.1 mmol) and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (864 mg, 2.1 mmol) in tetrahydrofuran (50 ml) under nitrogen, followed by by adding dropwise a mixture of palladium diacetate (432 mg, 1.9 mmol) in tetrahydrofuran. The resulting mixture was stirred overnight at room temperature and concentrated under high vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/99) to give the title compound (1.7 g, 41.3%) as a yellow oil. LCMS (method E): m/z=242.1 [M+H]+, 0.852 min.

Step 2. Preparation of 4-(1-methyl-4-nitro-1H-pyrazol-3-yl)butanoic acid.

Lithium hydroxide (339 mg, 14.1 mmol) was added to a mixture of ethyl 4-(1-methyl-4-nitro-1H-pyrazol-3yl)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 temperature. After removing tetrahydrofuran under reduced pressure, the pH of the solution was adjusted to 6-7 using an aqueous solution of hydrochloric acid (1N, 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 and filtered. The filtrate was concentrated under high vacuum to give the title compound (1.2 g, crude) as a yellow solid. LC-MS (method E): m/z=213.9 [M+H] ⁺ , 0.617 min.

Step 3. Preparation of 4-(4-amino-1-methyl-1H-pyrazol-3-yl)butanoic acid.

A solution of 4-(1-methyl-4-nitro-1H-pyrazol-3-yl)butanoic acid (1.2 g, 5.61 mmol) in methanol (20 ml) was hydrogenated in the presence of a carbon-supported palladium catalyst (10% , 120 mg) in a hydrogen atmosphere (2-3 atm). After stirring for 5 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo to give the title compound (1 g, crude) as a yellow solid. LC-MS (method C): m/z=184.1 [M+H] ⁺ , 0.304 min.

Step 4. Preparation of 2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one.

N,N-Diisopropylethylamine (2.2 g, 17.05 mmol) was added to a stirred mixture of 4-(4-amino-1methyl-1H-pyrazol-3-yl)butanoic acid (1.0 g, 5.46 mmol) and N,N,N',N'-tetramethylO-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.5 g, 6.58 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred for 3 hours at room temperature and diluted with water (50 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give 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. Preparation of 6-iodo-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one.

N ¹ ,N ¹ ,N ² ,N ² -tetramethylethane-1,2-diamine (1.01 g, 8.73 mmol) was added to the stirred mixture of 2methyl-7,8-dihydropyrazolo[4,3-b]azepine- 5(2H,4H,6H)-one (0.48 g, 2.91 mmol) in dichloromethane (30 ml) at 0°C followed by the addition of iodotrimethylsilane (1.16 g, 5.82 mmol) dropwise over 20 min. The reaction mixture was stirred for 1 hour at 0°C. Iodine (1.11 g, 4.37 mmol) was added to the mixture. The reaction mixture was stirred for another 1 hour at 0°C and quenched by adding aqueous sodium thiosulfate (5%, 20 ml). The resulting solution was stirred for 15 min 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 in vacuo to give 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. Preparation of 6-azido-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one.

Sodium azide (246 mg, 3.78 mmol) was added to a solution of 6-iodo-2-methyl-7,8-dihydropyrazolo[4,3b]azepin-5(2H,4H,6H)-one (550 mg, 1. 89 mmol) in N,N-dimethylformamide (4 ml). The reaction mixture was stirred overnight at 40°C, 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, filtered and concentrated under reduced pressure to give 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.

Step 7. Preparation of 6-amino-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one.

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 resulting mixture was stirred for 16 hours at room temperature, 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 in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to give 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. Preparation of 5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6yl)-4H-1,2, 4-triazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XSelect CSH Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 5% B to 47% B in 7 minutes; UV 254 & 220 nm; Rt: 6.22 min to give 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. Preparation of (R)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4H- 1,2,4-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-1,2,4-triazole-3-carboxamide (Example 104B).

Racemate 5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4triazole -3-carboxamide (50 mg, 0.13 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: i-PrOH; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 21 minutes; UV 254 & 220 nm; Rt 1: 9.68 min; Rt 2: 14.84 min, obtaining title compounds:

example 104A (first eluting isomer): 1H NMR (400 MHz, DMSO- _d6 ) δ 14.37 (br.s, 1H), 9.86 (s, 1H), 8.39 (br.s, 1H) , 7.40 (s, 1H), 7.34-7.22 (m, 5H), 4.40-4.35 (m, 1H), 4.11 (s, 2H), 3.74 (s , 3H), 2.90-2.81 (m, 2H), 2.26-2.20 (m, 1H), 2.11-1.97 (m, 1H). LC-MS (method X): m/z=366.2 [M+H] ⁺ , 2.165 min;

example 104B (second eluting isomer): 1H NMR (400 MHz, DMSO- _d6 ) δ 14.37 (br.s, 1H), 9.86 (s, 1H), 8.39 (br.s, 1H) , 7.40 (s, 1H), 7.34-7.22 (m, 5H), 4.40-4.35 (m, 1H), 4.11 (s, 2H), 3.74 (s , 3H), 2.89-2.84 (m, 2H), 2.25-2.21 (m, 1H), 2.11-1.97 (m, 1H). LC-MS (method T): m/z=366.3 [M+H] ⁺ , 0.858 min.

Example 105A and 105B. (S)-5-Benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)-4H-1, 2,4-triazole-3-carboxamide and (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8hexahydropyrazolo[4,3-b]azepine -6-yl)-4H-1,2,4-triazol-3-carboxamide.

- 140 044271

Step 1. Preparation of 6-azido-2,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one.

Pometan (664 mg, 4.68 mmol) was added dropwise to a stirred mixture of 6-azido-2-methyl-7,8dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one (480 mg, 2.33 mmol) and cesium carbonate (1.5 g, 4.66 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred for 2 hours at room temperature and quenched by adding water (50 ml). The resulting solution was extracted with ethyl acetate (3x50 ml). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (480 mg, crude) as a brown solid. LC-MS (method I): m/z=221.0 [M+H]+, 0.565 min.

Step 2. Preparation of 6-amino-2,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,bH)-one.

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 temperature, 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 in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to give the title compound (300 mg, 71%) as a yellow oil. LC-MS (method I): m/z=195.0 [M+H] ⁺ , 0.168 min.

Step 3. Preparation of 5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4H-1, 2,4-triazole-3-carboxamide.

The crude product obtained by the amine coupling procedure C was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 15% B to 30% B in 10 minutes; UV 254 & 220 nm; Rt: 7 min to obtain 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. Preparation of (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)- 4H-1,2,4-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-1,2,4-triazole-3-carboxamide (example 105B)

Racemate 5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)4H-1,2, 4-triazole-3-carboxamide (50 mg, 0.13 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAK IC, 2x25 cm, 5 µm; mobile phase A: hexane:DCM=4.5:1, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 50% B to 50% B in 21 minutes; UV 220 & 254 nm; Rt 1: 8.88 min; Rt 2: 16.76 min, obtaining title compounds:

Example 105A (first eluting isomer): 1H NMR (400 MHz, DMSO-d ₆ ) δ 14.35 (Lg.s, 1H), 8.32 (Lg.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;

example 105B (second eluting isomer): 1H NMR (400 MHz, DMSO-d ₆ ) δ 14.29 (Lg.s, 1H), 8.30 (Lg.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 )-4H-1,2,4-triazole-3-carboxamide.

- 141 044271

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XSelect CSH Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.1% formic acid); mobile phase B: ACN; flow rate: 20 ml/min;

gradient: from 30% B to 60% B in 7 minutes; Detector, UV 254 & 220 nm; Rt: 5.47 min, producing the title compound. 1H NMR (400 MHz, DMSO) 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, J=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), 1.521.27 (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[2,3-b]azepine

7-yl)-4H-1,2,4-triazole-3-carboxamide and (S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5Hpyrido [ 2,3-b]azepin-7-yl)-4H-1,2,4-triazol-3-carboxamide.

Stage 1. Preparation of oxime (E)-6,7-dihydroquinolin-8(5H)-one.

Hydroxylamine hydrochloride (1.4 g, 20.3 mmol) was added to a solution of 6,7-dihydroquinolin-8(5H)one (1.5 g, 10.2 mmol) and sodium hydroxide (1.2 g, 30.0 mmol) in ethanol (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 (3x80 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to give 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.

Stage 2. Preparation of O-methylsulfonyloxime (E)-6,7-dihydroquinolin-8(5H)-one.

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 temperature for 2 hours, diluted with water (30 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give 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. Preparation of 6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one.

Potassium acetate (5 g, 51 mmol) was added to a solution of O-methylsulfonyloxime (E)-6,7dihydroquinolin-8(5H)-one (1.7 g, 7 mmol) in ethanol (40 ml) and water (20 ml) . The reaction mixture was stirred overnight at 110°C and concentrated under reduced pressure. The precipitate was diluted with water (30 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

- 142 044271 vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to give 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. Preparation of 9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one.

Iodomethane (1.0 g, 0.70 mmol) was added dropwise to a stirred mixture of 6,7-dihydro-5Hpyrido[2,3-b]azepin-8(9H)-one (1.0 g, 0.60 mmol ) and cesium carbonate (3.0 g, 0.92 mmol) in N,Ndimethylformamide (20 ml). The reaction mixture was stirred at room temperature overnight, quenched with water (50 ml) and extracted with ethyl acetate (3x60 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/30) to give 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.

Step 5. Preparation of 7-iodo-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one.

N ¹ ,N ¹ ,N ² ,N ² -tetramethylethane-1,2-diamine (1.9 g, 16.4 mmol) was added to the stirred mixture of 9methyl-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 min. 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 a further 4 hours at room temperature before quenching with aqueous sodium thiosulfate (5%, 30 ml). The resulting solution was stirred for 15 min and extracted with ethyl acetate (3x100 ml). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/30) to give 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. Preparation of 7-azido-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one.

Sodium azide (650 mg, 10.0 mmol) was added to a solution of 7-iodo-9-methyl-6,7-dihydro-5H-pyrido[2,3b]azepin-8(9H)-one (1.5 g, 4.9 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred for 5 hours at room temperature, diluted with water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give 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. Preparation of 7-amino-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one.

Triphenylphosphine (1.6 g, 6.1 mmol) was added to a solution of 7-azido-9-methyl-6,7-dihydro-5Hpyrido[2,3-b]azepin-8(9H)-one (0.9 g , 4.1 mmol) in tetrahydrofuran (10 ml) and water (10 ml). The reaction mixture was stirred at room temperature overnight, diluted with water (30 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give 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. Preparation 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.

N,N-Diisopropylethylamine (201.2 mg, 1.56 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazole3-carboxylic acid (104.6 mg, 0.52 mmol), 7-amino -9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin8(9H)-one (100 mg, 0.52 mmol), N-(3-dimethylaminopropyl))-N'- hydrochloride ethylcarbodiimide (119.6 mg, 0.62 mmol) and 1-hydroxybenzotriazole (84.2 mg, 0.62 mmol) in N,N-dimethylformamide (4 ml). The reaction mixture was stirred overnight at room temperature, diluted with water (30 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 10% B to 35% B in 11 minutes; UV 254 & 220 nm; Rt: 10 min to obtain the title compound (50 mg, 25%) as a white solid. LC-MS (method D): m/z=377.2 [M+H] ⁺ , 1.551 min.

Step 9. Preparation of (R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7yl)-4H- 1,2,4-triazole-3-carboxamide (example 107A) and (S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9tetrahydro-5H-pyrido[2,3 -b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide (Example 107B).

Racemate 5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4H-1,2,4triazole -3-carboxamide (50 mg, 0.14 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak ID-2, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: MeOH:EtOH=1:1; flow rate: 17 ml/min; gradient: from 60% B to 60% B in 23 min; UV 220 & 254

- 143 044271 nm; Rt 1: 8.53 min; Rt 2: 18.27 min, obtaining title compounds:

example 107A (first eluting isomer): ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 75-2.62(m,

2H), 2.41-2.16 (m, 2H). LC-MS (method D): m/z=377.2 [M+H]+, 1.551 min;

example 107B (second eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 14.35 (br. s, 1H), 8.458.41 (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+H]+, 1.546 min.

Example 108. (S)-2-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)1 N-imidazole-5-carboxamide.

O

1) EUN, 80°C, nights °

EUN, H ₂ O, 80°C, incl. -hL NH ₂ 2) Ph ₂ O, 130°C, 2 hours N-# 'O—\

NIGHTS

Stage 1 Stage 2

Stage 3

Step 1. Preparation of (Z)-N'-hydroxy-2-phenylacetimidamide.

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 ethanol (15 ml) and water (5.0 ml). The reaction mixture was stirred at 80°C overnight, 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 in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 5/95) to give 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. Preparation of ethyl 2-benzyl-1H-imidazole-5-carboxylate.

A reaction mixture of (Z)-N'-hydroxy-2-phenylacetimidamide (1.0 g, 6.67 mmol) and ethyl propiolate (1.96 g, 20 mmol) in ethanol (20 ml) was stirred at 80°C overnight . Diphenyl ether (50 ml) was added to the mixture and stirred at 130°C for 2 hours. The reaction mixture was quenched by adding water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/99) to give the title compound (650 mg, 43%) as a gray solid. LC-MS (method L): m/z=231.1 [M+H]+, 1.197 min.

Step 3. Preparation of (S)-2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl) -1H-imidazole-5-carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 20% B to 45% B in 7 minutes; UV 254 & 220 nm; Rt: 6 min, obtaining the title compound. 1H NMR (400 MHz, DMSO-de) δ 12.41 (s, 1H), 8.36 (dd, J=4.8, 1.6 Hz, 1H), 8.01 (d, J=8, 0 Hz, 1H), 7.71 (dd, J=8.0, 1.6 Hz, 1H), 7.57 (d, J=2.1 Hz, 1H), 7.38-7.17 ( m, 6H), 4.90-4.76 (m, 1H), 4.64 (dd, J=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 min.

Example 109A and 109B. (S)-1-Benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)-4-fluoro- 1H-pyrazole-3-carboxamide and (R)-1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8hexahydropyrazolo[4,3-b]azepine-6 -yl)-4-fluoro-1H-pyrazole-3-carboxamide.

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Step 1. Preparation of 1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azenin6-yl)-4-fluoro- 1 H-pyrazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 20% B to 50% B in 7 minutes; UV 254 & 220 nm; Rt: 6 min to obtain the title compound (80 mg, 55.6%) as a white solid. LC-MS (Q method): m/z=397.4 [M+H]+, 1.115 min.

Step 2. Preparation of (S)-1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)- 4-fluoro-1H-pyrazole-3-carboxamide (Example 109A) and (R)-1-benzyl-N-(2,4-dimethyl-5-oxo2,4,5,6,7,8-hexahydropyrazolo[4 ,3-b]azenin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide (Example 109B).

1-Benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydronirasolo[4,3-b]azepin-6-yl)-4-fluoro1H-pyrazole racemate -3-carboxamide (80 mg, 0.20 mmol) was separated using rep. chiral HPLC under the following conditions: column: Lux 5u Cellulose-3, AXIA Packed, 2.12x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 40% B to 40% B in 15 minutes; UV 254 & 220 nm; Rt 1: 9.89 min; Rt 2: 12.58 min, obtaining title compounds:

example 109A (first eluting isomer): 1H NMR (400 MHz, DMSO-dg) δ 8.13 (d, J=4.4 Hz, 1H), 7.92 (d, J=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;

example 109B (second eluting isomer): 1H NMR (400 MHz, DMSO-dg) 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.

Example 110A and 110B. 5-benzyl-N-((1aR,2R,8bS)-3-oxo-1,1a,2,3,4,8b-hexahydrocycloprona[d]nirido[2,3-b]azepin-2-yl)- 4H-1,2,4-triazole-3-carboxamide and 5-benzyl-N-((1aS,2S,8bR)-3-oxo-1,1a,2,3,4,8bhexahydrocyclopropa[d]pyrido[2 ,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1. Preparation of 5-benzyl-N-(cis-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3b]azepin-2-yl)-4H-1, 2,4-triazole-3-carboxamide.

The crude product obtained using the amine coupling technique C was purified using Rev. TLC (ethyl acetate/petroleum ether, 1/3) gave the title compound (20 mg, 26.7%) as a yellow solid. LC-MS (method I): m/z=375.2 [M+H] ⁺ , 1.007 min.

Step 2. Preparation of 5-benzyl-N-((1aR,2R,8bS)-3-oxo-1,1a,2,3,4,8b-hexahydrocycloprona[d]pyrido[2,3-b]azepine-2 -yl)-4H-1,2,4-triazole-3-carboxamide (example 110A) and 5-benzyl-N-((1aS,2S,8bR)-3- 145 044271 oxo-1,1a,2,3 ,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide (example 110B).

5-Benzyl-N-(cis-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)4H-1,2 racemate, 4-triazole-3-carboxamide (20 mg, 0.053 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 30% B to 30% B in 20 minutes; UV 254 & 220 nm; Rt 1: 12.8 min; Rt 2: 16.08 min, obtaining title compounds:

example 110A (first eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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;

example 110B (second eluting isomer): 1H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 8.23 (dd, J=4.8, 1.8 Hz, 1H), 7.90 (dd, J= 7.5, 1.8 Hz, 1H), 7.39-7.13 (m, 6H), 4.84 (s, 1H), 4.18 (s, 2H), 2.19-2.09 (m, 2H), 1.64-1.55 (m, 1H), 1.17-1.10 (m, 1H). LC-MS (method F): m/z=374.9 [M+H] ⁺ , 0.919 min.

Example 111A and 111B. (R)-1-Benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)-1H- pyrazole-3-carboxamide and (S)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro5H-pyrido[2,3-b]azepine-7 -yl)-1H-pyrazole-3-carboxamide.

EDCI, NOVT, DIEA DMF

CT scan, in progress nights

Step 1 chiral separation

Stage 2

Step 1 Preparation of 1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)-1H-pyrazole -3-carboxamide.

N,N-Diisopropylethylamine (201.2 mg, 1.56 mmol) was added to a mixture of 1-benzyl-4-fluoro-1H-pyrazole3-carboxylic acid (104.6 mg, 0.52 mmol), 7-amino-9 -methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin8(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,N-dimethylformamide (3 ml). The reaction mixture was stirred overnight at room temperature, 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 in vacuo. The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XSelect CSH Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 55% B in 7 minutes; UV 254 & 220 nm; Rt: 5.6 min to obtain the title compound (32 mg, 25.4%) as a white solid. LC-MS (method D): m/z=394.2[M+H]+, 1.571 min.

Step 2. Preparation of (R)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl )-1H-pyrazole-3-carboxamide (example 111A) and (S)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo6,7,8,9-tetrahydro-5H-pyrido[2 ,3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide (example 111B).

Racemate 1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1Hpyrazol-3 -carboxamide (32 mg, 0.081 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 30% B to 30% B in 15 minutes; UV 254 & 220 nm; Rt 1: 11.47 min; Rt 2: 13.24 min, obtaining title compounds:

example 111A (first eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.42-8.40 (m, 1H), 8.108.02 (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;

example 111B (second eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.42-8.40 (m, 1H), 8.108.02 (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[3,2-b][1,4]oxazepine-3 -yl)isoxazole-3-carboxamide.

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The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 5 µm, 19x250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 60% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min, obtaining the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (dd, J=4.7, 1.5 Hz, 1H), 8.27 (d, J=7.0 Hz, 1H), 7 .73 (dd, J=7.9, 1.5 Hz, 1H), 7.39-7.23 (m, 6H), 6.61 (s, 1H), 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.

Example 113 (S)-N-(1-Methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)-5-(1phenylcyclopropyl )-4H-1,2,4-triazole-3-carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 10% B to 40% B in 7 minutes; UV 254 & 220 nm; Rt: 6 min, obtaining the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)-1-Benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)-4-fluoro- 1H-pyrazole-3-carboxamide and (R)-1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8hexahydropyrazolo[4,3-b]azepine-6 -yl)-4-fluoro-1H-pyrazole-3-carboxamide.

Stage 1

Stage 2

Step 1. Preparation of 1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4-fluoro- 1 H-pyrazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep Phenyl OBD 19x150 mm 5 µm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 50% B in 7 minutes; UV 254 & 220 nm; Rt: 6 min to obtain 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. Preparation of (S)-1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3b]azepin-6-yl)- 4-fluoro-1H-pyrazole-3-carboxamide (Example 114A) and (R)-1-benzyl-N-(1,4-dimethyl-5-oxo1,4,5,6,7,8-hexahydropyrazolo[4 ,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide (Example 114B).

1-Benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro1H-pyrazole racemate -3-carboxamide (50 mg, 0.13 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 18 minutes; UV 254 & 220 nm; Rt 1: 12.54 min; Rt 2: 15.41 min, obtaining title compounds:

Example 114A (first eluting isomer): ¹ H NMR (400 MHz, DMSO-66) δ 8.14 (d, J=4.0 Hz, 1H),

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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.

Example 114B (second eluting isomer): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 -3-yl)-1 H-pyrazol-3-carboxamide.

Stage 1

Stage 2

Step 1. Preparation of 4-fluoro-1-(4-fluorobenzyl)-1H-pyrazole-3-carboxylic acid.

Sodium hydride (60%, 152 mg, 3.8 mmol) was added to a solution of methyl 4-fluoro-1H-pyrazole-3carboxylate (200 mg, 1.27 mmol) in N,N-dimethylformamide (10 ml) at 0° C. The resulting mixture was stirred at room temperature for 0.5 h, followed by the addition of 1-(bromomethyl)-4fluorobenzene (264 mg, 1.40 mmol). The reaction mixture was stirred at room temperature for another 1.5 h and quenched by adding water (20 ml). The resulting solution was then stirred at room temperature for 5 hours. The pH of the solution was adjusted to 7 using an aqueous solution of hydrochloric acid (1N, 10 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 in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 60% B in 9 minutes; UV 254 & 220 nm; Rt: 7 min to give the title compound (100 mg, 33.2%). LC-MS (method S): m/z=239.2 [M+H] ⁺ , 1.093 min.

Step 2. Preparation of (S)-4-fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4] Oxazepin-3-yl)-1 H-pyrazol-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19 x150 mm 5 µm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 55% B in 7 minutes; UV 254 & 220 nm; Rt: 6.32 min, producing the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.37-8.35 (m, 1H), 8.27 (d, J=8 Hz, 1H), 8.14 (d, J=4.4 Hz, 1H), 7.717.69 (m, 1H), 7.36-7.32 (m, 3H), 7.25-7.20 (m, 2H), 5.33 (s, 2H), 4 .87-4.81 (m, 1H), 4.70-4.65 (m, 1H), 4.524.48 (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[1,2-a]azepin-4-yl)-5-(2-fluorophenoxy)pyridazine-3carboxamide.

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Step 1. Preparation of 3-chloro-5-(2-fluorophenoxy)pyridazine.

2-Fluorophenol (2 g, 17.8 mmol) was added dropwise to a stirred mixture of 3,5dichloropyridazine (3.17 g, 21.4 mmol) and cesium carbonate (8.7 g, 26.9 mmol) in acetonitrile (40 ml). The reaction mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether) to give the title compound (2.8 g, 70%) as a white solid. LC-MS (method X): m/z=225.1 [M+H]+, 0.919 min.

Step 2. Preparation of ethyl 5-(2-fluorophenoxy)pyridazine-3-carboxylate.

1,1'-Bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride (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 ethanol (125 ml) and N,N-dimethylformamide (25 ml). The reaction mixture was stirred overnight at 90°C under an atmosphere of carbon monoxide (1 MPa). After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give 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. Preparation of 5-(2-fluorophenoxy)pyridazine-3-carboxylic acid.

Lithium hydroxide (48 mg, 2 mmol) was added to a stirred 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 temperature. After removal of tetrahydrofuran under reduced pressure, the residue was diluted with water (20 ml). The pH of the resulting solution was adjusted to 4 using an aqueous solution of hydrochloric acid (2N, 5 ml). The resulting solution was extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 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. Preparation of (S)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-5-(2-fluorophenoxy)pyridazine-3-carboxamide .

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19 x150 mm 5 µm; mobile phase A: water (10 mmol/L NH4HCO3), mobile phase B: ACN, flow rate: 30 ml/min; gradient: from 45% B to 50% B in 5 minutes; UV 254 & 220 nm to obtain the title compound. Ή NMR (400 MHz, Methanol-d ₄ ) δ 9.25 (d, J=2.8 Hz, 1H), 7.51-7.32 (m, 10H), 7.08 (d, J=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.

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)picolinamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 85% B in 7 minutes; UV 254 & 220 nm; Rt: 6.35 min, producing the title compound. 1H NMR (400 MHz, DMSO-66) 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 and 118B. (R)-5-Benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin6-yl)-4H-1,2, 4-triazole-3-carboxamide and (S)-5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepine-6 -yl)-4H-1,2,4-triazole-3-carboxamide.

Stage 1

Step 1. Preparation of 5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6yl)-4H-1,2, 4-triazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified by Prep-HPLC under the following conditions: column: XBridge Prep Phenyl OBD 19x150 mm 5 µm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 5% B to 35% B in 10 minutes; UV 254 & 220 nm; Rt: 9 min to obtain 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-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H1 ,2,4-triazole-3-carboxamide (Example 118A) and (S)-5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8hexahydropyrazolo[4,3- b]azepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (example 118B).

Racemate 5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4triazole -3-carboxamide (50 mg, 0.14 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 12 minutes; 254/220 nm; Rt 1: 8.84 min; Rt 2: 10.81 min, obtaining title compounds:

example 118A (first eluting isomer): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.00 (s, 1H), 8.53 (d, J=5.6 Hz, 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, 1H). LC-MS (method D): m/z=366.1 [M+H] ⁺ , 1.180 min;

example 118B (second eluting isomer): 1H NMR (400 MHz, DMSO-d ₆ ) 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 and 119B. 5-Benzyl-N-((7R,7aR,8aS)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepine-7 -yl)-4H-1,2,4-triazole-3-carboxamide and 5-benzyl-N-((7S,7aS,8aR)5-methyl-6-oxo-5,6,7,7a,8, 8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3carboxamide.

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Stage 1. Preparation of 3-vinylpyrazine-2-amine.

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) in a nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 80°C, quenched by adding water (200 ml) and extracted with dichloromethane (3x200 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to give 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. Preparation of N-(3-vinylpyrazin-2-yl)but-3-enamide.

Thionyl chloride (9.3 g, 46.5 mmol) was added dropwise to a solution of but-3-enoic acid (4.0 g, 46.5 mmol) in dichloromethane (20 ml). After stirring for 1 hour at room temperature, the resulting mixture was added to a solution of triethylamine (11.8 g, 116.6 mmol) and 3-vinylpyrazin-2-amine (4.7 g, 38.7 mmol) in dichloromethane (20 ml). The reaction mixture was stirred for 2 hours at room temperature, quenched by adding water (50 ml) and extracted with dichloromethane (3x50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/1) to give 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. Preparation of (Z)-5H-pyrazino[2,3-b]azepin-6(7H)-one.

Tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro(phenylmethylidene)ruthenium (340 mg, 0.4 mmol) was added to the N-(3-vinylpyrazin-2-yl) solution 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 5/1) to give 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. Preparation of (Z)-5-methyl-5H-pyrazino[2,3-b]azepin-6(7H)-one.

Pometan (180 mg, 1.3 mmol) was added dropwise to a stirred solution of (Z)-5Hpyrazino[2,3-b]azepin-6(7H)-one (210 mg, 1.3 mmol) and cesium carbonate (1 .3 g, 3.9 mmol) in N,Ndimethylformamide (30 ml). The reaction mixture was stirred for 4 hours at room temperature, 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 4/1) to give 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. Preparation of 5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one.

To a solution of potassium hydroxide (4 g, 71.4 mmol) in water (6 ml) was added dropwise a solution of 1-methyl1-nitrosourea (2.1 g, 20 mmol) in ester (30 ml) at 0°C in an atmosphere nitrogen. The resulting mixture was stirred for 1 hour at 0°C and then the organic phase was separated to obtain a diazomethane solution (30 ml). A solution of diazomethane (30 ml) followed by the addition of a mixture of palladium diacetate (25 mg, 0.11 mmol) in tetrahydrofuran (5 ml) dropwise at 0°C. The reaction mixture was stirred overnight at room temperature. Solids were removed by filtration and the filtrate was concentrated in vacuo to give 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. Preparation of trans-7-iodo-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one.

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 added N,N,N',N'-tetramethylethylenediamine (210 mg, 1.8 mmol) followed by 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 in vacuo to give the title compound (132 mg, crude) as a yellow oil. LC-MS (method E): m/z=316.1 [M+H] ⁺ , 0.840 min.

Step 7. Preparation of cis-7-azido-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one.

Sodium azide (39 mg, 0.6 mmol) was added to the 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) in N,N-dimethylformamide (10 ml). The resulting mixture was stirred for 16 hours at room temperature, quenched by adding water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 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. Preparation of cis-7-amino-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3b]azepin-6(5H)-one.

Triphenylphosphine (102 mg, 0.39 mmol) was added to a mixture of cis-7-azido-5-methyl-7,7a,8,8atetrahydrocyclopropa[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 temperature, diluted with water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/19) to give 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. Preparation of 5-benzyl<M-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl) -4H-1,2,4-triazole-3-carboxamide.

N,N-Diisopropylethylamine (93 mg, 0.72 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazole-3carboxylic acid (51 mg, 0.24 mmol), cis-7-amino-5 -methyl-7,7a,8,8a-tetrahydrocyclone[d]pyrazino[2,3-b]azepin-6(5H)-one (40 mg, 0.20 mmol), hydrochloride N-(3dimethylaminopropyl))-No. -ethylcarbodiimide (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in N,N-dimethylformamide (4 ml). The reaction mixture was stirred overnight at room temperature, 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 in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19x150 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 30 ml/min; gradient: from 25% B to 55% B in 7 minutes; UV 254 & 220 nm to give the title compound (20 mg, 26%) as a white solid. LC-MS (method D): m/z=390.2 [M+H] ⁺ , 1.386 min.

Step 10. Preparation 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)-4H-1,2,4-triazole-3-carboxamide (example 119A) and 5-benzylN-((7S,7aS,8aR)-5-methyl-6-oxo-5,6 ,7,7a,8,8a-hexahydrocyclopropa[d]-pyrazino[2,3-b]azepin-7-yl)-4H1,2,4-triazole-3-carboxamide (Example 119B).

5-Benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]-pyrazino[2,3b]azepin-7-yl)-4H-1 racemate ,2,4-triazole-3-carboxamide (20 mg, 0.05 mmol) was separated using rep. chiral HPLC 152 044271 under the following conditions: column: Chiralpak IA, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 55% B to 55% B in 27 minutes;

220/254 nm; Rt 1: 13.94 min; Rt 2: 21.44 min, obtaining title compounds:

example 119A (first eluting isomer): 1H NMR (400 MHz, Methanol-d ₄ ) 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 .57-1.48 (m, 1H), 1.36-1.25 (m, 1H). LC-MS (method D): m/z=390.1 [M+H]+, 1.389 min;

example 119B (second eluting isomer): 1H NMR (400 MHz, Methanol- _d4 ) 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 120V. 5-Benzyl-N-(1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepine-2- yl)-1,3,4-thiadiazole-2-carboxamide and 5-benzyl-N-((1aR,2R,8bS)-4-methyl3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[ d]pyrido[2,3-b]azepin-2-yl)-1,3,4-thiadiazol-2-carboxamide.

o S'

NOVT, EDCI, DIEA, DMF

O S'

Step 1 chiral separation

About S' about s·

Stage 2

Step 1. Preparation of 5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl )-1,3,4-thiadiazole-2-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19 x150 mm 5 µm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 55% B in 7 minutes; UV 254 & 220 nm; Rt: 6.32 min to obtain 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. Preparation of 5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclonepropa[d]pyrido[2,3-b ]azepin-2-yl)-1,3,4-thiadiazol-2-carboxamide (example 120A) and 5-benzyl-N((1aR,2R,8bS)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa-[d]pyrido[2,3-b]azepin-2-yl)-1,3,4thiadiazol-2-carboxamide (Example 120B).

5-Benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3b]azepin-2-ul)-1,3 racemate ,4-thiadiazole-2-carboxamide (20 mg, 0.049 mmol) was separated using rep. chiral separation under the following conditions: column: Lux Cellulose-4, 0.46x5 cm, 3 µm; mobile phase A: hexane; mobile phase B: EtOH; flow rate: 1.0 ml/min; gradient: from 50% B to 50% B in 8 minutes; UV 254 & 220 nm; Rt 1: 4.09 min; Rt 2: 6.43 min, obtaining title compounds:

example 120A (first eluting isomer): 1H NMR (400 MHz, Methanol-d ₄ ) 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), 2.33-2.25 (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;

example 120B (second eluting isomer): 1H NMR (400 MHz, Methanol-d ₄ ) 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 and 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]azenin-7-yl) picolinamide

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Step 1. Preparation of methyl 4-(2,4-difluorophenoxy)picolinate.

Methyl 4-chloropicolinate (1 g, 5.85 mmol), 2,4-difluorophenol (1.14 g, 8.77 mmol), cesium carbonate (5.7 g, 17.5 mmol) were added to a sealed tube. copper powder (0.38 g, 5.94 mmol) and N,Ndimethylformamide (10 ml). The resulting mixture was heated at 100°C using microwave radiation 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 in vacuo to give the title compound (0.5 g, crude) as a white solid. LC-MS (method I): m/z=265.9 [M+H]+, 0.926 min.

Step 2. Preparation of 4-(2,4-difluorophenoxy)picolinic acid.

Lithium hydroxide (260 mg, 10.8 mmol) was added to a stirred 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 temperature. After removing the tetrahydrofuran under reduced pressure, the pH of the aqueous solution was adjusted to 6 using an aqueous solution of hydrochloric acid (1N, 10 ml). The resulting mixture was extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 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. Preparation of 4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)picolinamide .

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 19x150 mm 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 70% B in 7 minutes; 254 & 220 nm; Rt: 5.590 min to obtain the title compound (80 mg, 40.1%) as a white solid. LC-MS (method R): m/z=425.3 [M+H]+, 1.442 min.

Step 4. Preparation of (R)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepine-7 -yl)picolinamide (Example 121A) and (S)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo6,7,8,9-tetrahydro-5H-pyrido[2,3- b]azepin-7-yl)picolinamide (Example 121B).

4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-nirido[2,3-b]azenin-7yl)picolinamide racemate (80 mg , 0.19 mmol) were separated using rep. chiral HPLC under the following conditions: column: Chiralpak ID-2, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 15 ml/min; gradient: from 55% B to 55% B in 23 minutes; UV 220 & 254 nm; Rt 1: 14.83 min; Rt 2: 18.87 min, obtaining title compounds:

example 121A (first eluting isomer): 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J=8.0 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H ), 8.44-8.43 (m, 1H), 7.84-7.81 (m, 1H), 7.65-7.48 (m, 2H), 7.36-7.22 (m , 4H), 4.36-4.29 (m, 1H), 3.36 (s, 3H), 2.81-2.70 (m, 2H), 2.50-2.44 (m, 1H ), 2.35-2.21 (m, 1H). LC-MS (method T): m/z=425.25 [M+H]+, 1.432 min;

example 121B (second eluting isomer): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J=7.6 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H), 8.44-8.43 (m, 1H), 7.84-7.81 (m, 1H), 7.61-7.50 (m, 2H), 7.34-7.24 ( m, 4H), 4.34-4.31 (m, 1H), 3.36 (s, 3H), 2.77-2.73 (m, 2H), 2.51-2.50 (m, 1H), 2.31-2.21 (m, 1H). LC-MS (method X): m/z=425.25 [M+H]+, 1.437 min.

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Example 122 -yl)isoxazole-5-carboxamide.

Stage 1 Stage 2 \ O N^/N-F

Stage 3

Stage 1. Preparation of oxime (E)-2-phenylacetaldehyde.

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 ethanol (40 ml) and water (20 ml). The resulting mixture was stirred at room temperature for 5 hours, diluted with water (50 ml) and extracted with dichloromethane (3x80 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to give 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. Preparation of ethyl 3-benzylisoxazole-5-carboxylate.

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 give 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. Preparation of 3-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-3- yl)isoxazole-5-carboxamide.

The crude product obtained using the procedure described in example 54 was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 19x250 mm 5 μm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 55% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min, obtaining the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) 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][1,4]oxazepin-3-yl)thiazol-2carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 20% B to 40% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min, obtaining the title compound. 1H NMR (300 MHz, DMSO) 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.

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Example 124. 5-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3 -yl)thiazol-2-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 19x150 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 60% B in 7 minutes; UV 254 & 220 nm to give the title compound (18.8 mg, 9%) as a white semi-solid. ^1H NMR (400 MHz, Methanol- _d4 ) 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 and 125B. (R)-5-Benzyl-N-(9'-methyl-8'-oxo-6',7',8',9'-tetrahydrospiro[cyclopropane-1,5'pyrido[2,3-b]azepine ]-7'-yl)-4H-1,2,4-triazol-3-carboxamide (125A) and (S)-5-benzyl-N-(9'-methyl-8'-oxo6',7', 8',9'-tetrahydrospiro[cyclopropane-1,5'-pyrido[2,3-b]azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide (125B).

Step 1. Preparation of dimethyl-2-(2-nitropyridin-3-yl) malonate.

Dimethyl malonate (14 g, 105.6 mmol) was added dropwise to a stirred mixture of 3-fluoro-2nitropyridine (10 g, 70.4 mmol) and potassium carbonate (19.5 g, 140.8 mmol) in N,N-dimethylformamide (25 ml) at room temperature. The reaction mixture was stirred overnight at 70°C, quenched by adding water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give the title compound (18 g, 89.8%) as a brown oil.

LC-MS (method R): m/z=255.1 [M+H]+, 0.762 min.

Step 2. Preparation of methyl 2-(2-nitropyridin-3-yl) acetate.

A solution of lithium chloride (8 g, 189 mmol) in water (10 ml) was added to a mixture of dimethyl 2-(2nitropyridin-3-yl) malonate (16 g, 63 mmol) in dimethyl sulfoxide (50 ml). The reaction mixture was stirred at 100°C overnight, quenched by adding water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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. Preparation of methyl 1-(2-nitropyridin-3-yl)cyclopropanecarboxylate.

1,2-Dibromoethane (17 g, 91.8 mmol) was added dropwise to a stirred mixture of 3-fluoro-2nitropyridine (12 g, 61.2 mmol) and potassium carbonate (25.3 g, 183.6 mmol) in K ,K-dimethylformamide (25 ml) at room temperature. The reaction mixture was stirred overnight at 70°C, quenched by adding water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of (1-(2-nitropyridin-3-yl)cyclopropyl)methanol.

A solution of diisobutylaluminum hydride in toluene (1 M, 45 ml, 45 mmol) was added dropwise to a stirred solution of methyl 1-(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 adding water (2 ml) and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of 1-(2-nitropyridin-3-yl)cyclopropanecarbaldehyde.

Dess-Martin reagent (13 g, 30.9 mmol) was added to a stirred 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 adding water (50 ml) and extracted with dichloromethane (3x50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of (Z)-methyl-2-(tert-butoxycarbonylamino)-3-(1-(2-nitropyridin-3yl)cyclopropyl)acrylate.

1,8-Diazabicyclo[5,4.0]undec-7-ene (4 g, 26 mmol) was added to a stirred 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). The reaction mixture was then stirred overnight at 70°C, quenched by adding water (50 ml) and extracted with dichloromethane (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give 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. Preparation of methyl 3-(1-(2-aminopyraidin-3-yl)cyclopropyl)-2-(tert-butoxycarbonylamino)propanoate.

(Z)-Methyl 2-(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 a palladium catalyst on a carbon carrier (10%, 0.3 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. Solids were removed by filtration and the filtrate was concentrated under high vacuum to give 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. Preparation of 3-(1-(2-aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbonylamino)propanoic acid.

Lithium hydroxide (358 mg, 14.9 mmol) was added to a solution of methyl 3-(1-(2-aminopyridin-3yl)cyclopropyl)-2-(tert-butoxycarbonylamino)propanoate (2.5 g, 7.46 mmol) in tetrahydrofuran (15 ml) and water (5 ml). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The precipitate was diluted with water (20 ml) and adjusted to pH=7 with aqueous hydrochloric acid (1N, 10 ml), and extracted with ethyl acetate (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and

- 157 044271 was concentrated in vacuo to give the title compound (1 g, crude) as a white solid. LC-MS (method R): m/z=322.1 [M+H]+, 0.580 min.

Step 9. Preparation of tert-butyl-(8'-oxo-6',7',8',9'-tetrahydrospiro[cyclopropane-1,5'-pyrido[2,3b]azepine]-7'-yl)carbamate .

N,N-diisopropylethylamine (1.2 g, 9.34 mmol) was added to a mixture of 3-(1-(2-aminopyridin-3yl)cyclopropyl)-2-(tert-butoxycarbonylamino)propanoic acid (1 g, 3.11 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.59 g, 3.73 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred for 2 hours at room temperature, quenched by adding 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of tert-butyl-(9'-methyl-8'-oxo-6',7',8',9'-tetrahydrospiro[cyclopropane-1,5'pyrido[2,3-b]azepine]- 7'-yl)carbamate.

Iodomethane (52 mg, 0.36 mmol) was added dropwise to a stirred solution of tert-butyl(8'-oxo6',7',8',9'-tetrahydrospiro[cyclopropane-1,5'-pyrido[2,3- L]azepin]-7'-yl)carbamate (110 mg, 0.36 mmol) and cesium carbonate (119 mg, 0.36 mmol) in N,N-dimethylformamide (5 ml) at 0°C. The reaction mixture was stirred for 2 hours at room temperature, quenched by adding water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give 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.

Step 11. Preparation of 7'-amino-9'-methyl-6',7'-dihydrospiro[cyclopropan-1,5'pyrid[2,3-b]azepine]-8'(9'H)-one hydrochloride.

A solution of hydrogen chloride in 1,4-dioxane (4 M, 10 ml, 40 mmol) was added to a solution of tert-butyl-(9'-methyl-8'-oxo-6',7',8',9'-tetrahydrospiro[cyclopropane -1,5'-pyrido[2,3-b]azepine]-7-yl)carbamate (110 mg, 0.34 mmol) in 1,4-dioxane (4 ml). The reaction mixture was stirred for 2 hours at room temperature and concentrated under high vacuum to give the title compound (80 mg, crude) as a white solid. LC-MS (method C): m/z=218.1 [M+H] ⁺ , 0.777 min.

Step 12. Preparation of 5-benzyl-M-(9'-methyl-8'-oxo-6',7',8',9'-tetrahydrospiro-[cyclopropane-1,5'pyrido[2,3-b] azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide.

N,N-diisopropylethylamine (107 mg, 0.828 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazole-3carboxylic acid (62 mg, 0.304 mmol), 7-amino-9'-methyl-6 hydrochloride ',7dihydrospiro[cyclopropane-1,5'-pyrido[2,3-b]azepine]-8'(9'H)-one (60 mg, 0.276 mmol), hydrochloride N(3-dimethylaminopropyl))-N' -ethylcarbodiimide (69 mg, 0.359 mmol) and 1-hydroxybenzotriazole (49 mg, 0.359 mmol) in N,N-dimethylformamide (4 ml). The reaction mixture was stirred overnight at room temperature, 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 in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19x150 mm, 5 µm; mobile phase A: water (10 mmol/l NH4HCO ₃ ), mobile phase B: ACN; flow rate: 30 ml/min; gradient: from 25% B to 55% B in 7 minutes; UV 254 & 220 nm to obtain the title compound. LC-MS (method D): m/z=403.1 [M+H] ⁺ , 1.460 min.

Step 13. Preparation of (R)-5-benzyl-N-(9'-methyl-8'-oxo-6',7',8',9'-tetrahydrospiro-[cyclopropane1,5'-pyrido[2,3 -L]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-1,5'-pyrido[2,3-b]azepin]-7'-yl)-4H1,2,4-triazole-3-carboxamide ( second eluting isomer).

Racemate 5-benzyl-N-(9'-methyl-8'-oxo-6',7',8',9'-tetrahydrospiro-[cyclopropane-1,5'-pyrido[2,3b]azepine]-7 '-yl)-4H-1,2,4-triazole-3-carboxamide (60 mg, 0.149 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak ID-2, 2x25 cm, 5 µm; mobile phase A: hexane/DCM (4.5/1), mobile phase B: EtOH; flow rate: 17 ml/min; gradient: from 50% B to 50% B in 22 min; UV 254 & 220 nm; RT 1: 11.72 min; RT 2: 18.02 min, obtaining title compounds:

example 125A (first eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 14.27 (s, 1H), 8.41 (dd, J=4.8, 1.8 Hz, 2H), 7 .75 (dd, J=7.6, 1.8 Hz, 1H), 7.34-7.18 (m, 6H), 4.42-4.33 (m, 1H), 4.09 (s , 2H), 3.31 (s, 3H), 2.73-2.63 (m, 1H), 1.73-1.62 (m, 1H), 1.09-1.05 (m, 1H ), 0.70 (d, J=5.4 Hz, 2H), 0.36 (d, J=10.0 Hz, 1H). LC-MS (method D): m/z=403.1 [M+H] ⁺ , 1.661 min;

example 125B (second eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 14.27 (s, 1H), 8.41 (dd, J=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 044271

Step 1. Preparation of methyl 4-fluoro-5-methylthiazole-2-carboxylate.

1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2.2]octane bis(tetrafluoroborate) (7.0 g, 19.8 mmol) was added to the methyl 4-fluoro-5-methylthiazol-2-carboxylate mixture (1.6 g, 10.2 mmol) in acetonitrile (50 ml) under nitrogen. The reaction mixture was heated to boiling and stirred overnight, diluted with water (50 ml) and extracted with ethyl acetate (3x40 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of methyl 5-(bromomethyl)-4-fluorothiazole-2-carboxylate.

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-methylthiazol-2-carboxylate (600 mg, 3.4 mmol) in carbon tetrachloride (20 ml). The reaction mixture was stirred overnight at 75°C. Solids were removed by filtration. The filtrate was diluted with water (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with saturated sodium bicarbonate (20 ml) and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to give the title compound (600 mg, 68.9%) as a yellow solid. LC-MS (method F): m/z=254 [M+H] ⁺ , 1.490 min.

Step 3. Preparation of methyl 5-benzyl-4-fluorothiazole-2-carboxylate.

Tetrakis(triphenylphosphine)palladium (147 mg, 0.13 mmol) was added to a mixture of methyl 5-(bromomethyl)-4fluorothiazol-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 ethanol (10 ml) under nitrogen. The reaction mixture was stirred at 80°C overnight, quenched by adding water (20 ml) and extracted with ethyl acetate (3x40 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to give the title compound (400 mg, 66.6%) as a yellow solid. LC-MS (method C): m/z=252.2 [M+H] ⁺ , 1.971 min.

Step 4. (S)-5-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3yl )thiazole-2-carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 19 x 150 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), Mobile phase B: ACN; from 40% ACN to 70% B in 7 min; UV 254 & 220 nm, producing the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) 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 1-(4-cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine -3-yl)-4-fluoro-1H-pyrazole-3-carboxamide.

- 159 044271

CT scan, during nights

Stage 2

Step 1. Preparation of 1-(4-cyanobenzyl)-4-fluoro-1H-pyrazole-3-carboxylic acid.

Sodium hydride (60%, 144 mg, 6 mmol) was added to a stirred mixture of ethyl 4-fluoro-1Hpyrazole-3-carboxylate (474 mg, 3 mmol) in N,N-dimethylformamide (20 ml). The resulting mixture was stirred for 2 hours at room temperature, followed by the addition of 4(bromomethyl)benzonitrile (585 mg, 3 mmol). The resulting mixture was stirred for 2 hours at room temperature. After adding water (20 ml), the reaction mixture was stirred overnight at room temperature, adjusted to pH 6 with aqueous hydrochloric acid (1N, 10 ml) and extracted with ethyl acetate (3x50 ml).

The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using PrepHPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: Water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 50% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min to obtain 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. Preparation of 1-(4-cyanobenzyl)-N-((211.38)-2,5-dimethyl-4-oxo-2,3,4,5 tetrahydropyrido[3,2-b] [1,4 ]oxazepin-3 -yl)-4-fluoro-1 H-pyrazole-3-carboxamide.

The crude product obtained using the amine coupling procedure C was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: Water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 48% B in 12 minutes; UV 254 & 220 nm; Rt: 7 min, obtaining the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (dd, J=4.8, 1.6 Hz, 1H), 8.20 (d, J=4.4 Hz, 1H), 7, 88-7.85 (m, 2H), 7.75 (dd, J=8.0, 1.6 Hz, 1H), 7.61 (d, J=6.4 Hz, 1H), 7.44 -7.41 (m, 2H), 7.36 (dd, J=8.0, 4.8 Hz, 1H), 5.50 (s, 2H), 4.994.88 (m, 2H), 3, 39 (s, 3H), 1.31 (d, J=6.4 Hz, 3H). LC-MS (method X): m/z=435.2 [M+H] ⁺ , 1.355 min.

Example 128 -3-yl)-4-fluoro-1 H-pyrazole-3-carboxamide.

Stage 1

Stage 2

Step 1. Preparation of 1-(3-cyanobenzyl)-4-fluoro-1H-pyrazole-3-carboxylic acid.

Sodium hydride (60%, 144 mg, 6 mmol) was added to a stirred mixture of ethyl 4-fluoro-1Hpyrazole-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 temperature, followed by the addition of 4(bromomethyl)benzonitrile (585 mg, 3 mmol). The reaction mixture was stirred for another 2 hours at room temperature. After adding water (20 ml), the resulting mixture was stirred overnight at room temperature. The pH value of the solution was adjusted to 6 using an aqueous solution of hydrochloric acid (1N, 10 ml). The resulting mixture was extracted with ethyl acetate (3x50 ml).

- 160 044271

The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19x150 mm, 5 µm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 20% B to 50% B in 7 minutes; UV 254 & 220 nm; Rt: 6 min to obtain 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. Preparation of 1-(3-cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1, 4]oxazepin-3-yl)-4-fluoro-1H-pyrazole-3-carboxamide.

The crude product obtained using the amine coupling procedure C was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 48% B in 12 minutes; UV 254 & 220 nm; Rt: 7 min, obtaining the title compound. 1H NMR (400 MHz, DMSO-d,) 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, J=8.0, 4.4 Hz, 1H), 5.45 (s, 2H), 4.99-4.88 (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 min.

Example 129A and 129B. (S)-5-Benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5a][1,3]diazepin-6-yl) -4H-1,2,4-triazole-3-carboxamide and (R)-5-Benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8tetrahydro-4H-pyrazolo[1, 5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide.

Step 1. Preparation of methyl 4-(3-methyl-5-nitro-1H-pyrazol-1-yl)butanoate.

Sodium hydride (60%, 2.5 g, 63 mmol) was added to a mixture of 3-methyl-5-nitro-1H-pyrazole (8 g, 63 mmol) in tetrahydrofuran (80 ml) at 0°C. The resulting mixture was stirred for 0.5 h 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 adding water (40 ml) and extracted with ethyl acetate (3x60 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give 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. Preparation of methyl 4-(5-amino-3-methyl-1H-pyrazol-1-yl)butanoate.

A mixture of methyl 4-(3-methyl-5-nitro-1H-pyrazol-1-yl)butanoate (2.2 g, 9.7 mmol) in methanol (50 ml) was hydrogenated in the presence of a carbon-supported palladium catalyst (10 %, 0.2 g) in a hydrogen atmosphere (2-3 atm). After stirring for 2 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo to give 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. Preparation of 2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

The crude product obtained using the procedure described in Example 54 was purified at

- 161 044271 by column chromatography (methanol/dichloromethane, 1/10) to obtain the title compound (1.0 g, 66%) as a yellow solid. LC-MS (method C): m/z=166.1 [M+H]+, 0.755 min.

Step 4. Preparation of 2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

Pometan (0.74 g, 5.4 mmol) was added dropwise to a stirred mixture of 2-methyl-7,8-dihydro4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one ( 0.90 g, 5.4 mmol) and cesium carbonate (5.28 g, 16.2 mmol) in N,N-dimethylformamide (15 ml). The reaction mixture was stirred for 3 hours at room temperature, 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 in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to give 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. Preparation of 6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

N ¹ ,N ¹ ,N ² ,N ² -tetramethylethane-1,2-diamine (1.2 g, 12.0 mmol) was added to the stirred mixture of 2,4dimethyl-7,8-dihydro-4H-pyrazolo[1, 5-a][1,3]diazepin-5(6H)-one (720 mg, 4.0 mmol) in dichloromethane (10 ml) at 0°C followed by iodotrimethylsilane (2.4 g, 12.0 mmol ) drop by drop over 20 minutes. The reaction mixture was stirred for 1 hour at 0°C. After adding iodine (2.0 g, 8.0 mmol), the reaction mixture was stirred for another 1 hour at 0°C. The mixture was then quenched by adding aqueous sodium thiosulfate (5%, 20 ml), stirred for a further 15 min and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane) to give the title compound (500 mg, 41%) as a yellow solid. LC-MS (method C): m/z=306.0 [M+H] ⁺ , 1.033 min.

Step 6. Preparation of 6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

Sodium azide (137 mg, 2.10 mmol) was added to a mixture of 6-iodo-2,4-dimethyl-7,8-dihydro-4Hpyrazolo[1,5-a][1,3]diazepine-5(6H)- she (500 mg, 1.64 mmol) in N,N-dimethylformamide (10 ml). The resulting mixture was stirred for 2 hours at room temperature, quenched by adding 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 in vacuo to give 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. Preparation of 6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

Triphenylphosphine (734 mg, 2.80 mmol) was added to the stirred mixture of 6-azido-2,4-dimethyl7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepine-5(6H)- it is in tetrahydrofuran (10 ml) and water (2 ml). The reaction mixture was stirred overnight at room temperature, 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 in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give the title compound (200 mg, 62%) as a yellow oil. LC-MS (method I): m/z=195.0 [M+H] ⁺ , 0.263 min.

Step 8. Preparation of 5-benzyl-K-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepine-6- yl)-4H-1,2,4-triazole-3-carboxamide.

N,N-Diisopropylethylamine (140 mg, 1.13 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazole-3carboxylic acid (73 mg, 0.36 mmol), 6-amino-2,4 -dimethyl-7,8-dihydro-4H-pyrazolo[1,5a][1,3]diazepin-5(6H)-one (70 mg, 0.36 mmol), Na(3-dimethylaminopropyl)-Naethylcarbodiimide hydrochloride (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (65 mg, 0.39 mmol) in N,Ndimethylformamide (2 ml). The reaction mixture was stirred overnight at room temperature, diluted with water (10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 15% B to 45% B in 7 minutes; UV 254 & 220 nm; Rt: 6 min to obtain 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. Preparation of (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5a][1,3]diazepine- 6-yl)-4H-1,2,4-triazole-3-carboxamide (129A) and (R)-5-benzyl-N-(2,4-dimethyl-5-oxo5,6,7,8-tetrahydro -4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (129B).

Racemate 5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)4H -1,2,4-triazole-3-carboxamide was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IC, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 22 min; UV 254 & 220 nm; Rt 1: 10.04 min; Rt 2: 18.12 min, obtaining title compounds:

example 129A (first eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 14.31 (s, 1H), 8.55 (s,

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1H), 7.40-7.18 (m, 5H), 6.13 (s, 1H), 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,3H). LC-MS (method D): m/z=380.2 [M+H]+, 1.298 min.

example 129B (second eluting isomer): 1H NMR (300 MHz, DMSO-dg) δ 14.30 (s, 1H), 8.46 (s,

1H), 7.38-7.20 (m, 5H), 6.13 (s, 1H), 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.

Example 130 ,4] oxazepin-3-yl)-1 H-pyrazol-3-carboxamide.

CN CN CN

NaBH ₄ , EtOH, THF .4 PBr ₃ , DCM

0°C, 1h HOKT, incl. nights

Stage 1 Stage 2

F

Stage 3

Stage 1. Preparation of 3-fluoro-5-(hydroxymethyl)benzonitrile.

Sodium borohydride (1.0 g, 6.71 mmol) was added to a stirred mixture of 3-fluoro-5formylbenzonitrile (306 mg, 8.05 mmol) in ethanol (10 ml) and tetrahydrofuran (10 ml) at 0°C under nitrogen atmosphere . After stirring at 0°C for 1 hour, the reaction mixture was concentrated in vacuo, 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, filtered and concentrated in vacuo to give the title compound (980 mg, crude) as a yellow solid. LC-MS (method T): m/z=152.3 [M+H] ⁺ , 0.671 min.

Stage 2. Preparation of 3-(bromomethyl)-5-fluorobenzonitrile.

Tribromophosphine (2.9 g, 10.7 mmol) was added to a stirred mixture of 3-fluoro-5(hydroxymethyl)benzonitrile (0.8 g, 5.30 mmol) in dichloromethane (10 ml). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo to give the title compound (0.8 g, crude) as a yellow solid, which was used directly in the next step without further purification.

Step 3. Preparation of (S)-1-(3-cyano-5-fluorobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b ][1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide

Potassium carbonate (55 mg, 0.40 mmol) was added to the stirred mixture of (S)-4-fluoro-N-(5-methyl-4oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-1H-nirazol-3-carboxamide (40 mg, 0.13 mmol) and 3-(bromomethyl)-5-fluorobenzonitrile (34 mg, 0.16 mmol) in N,N- dimethylformamide (2 ml). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3x20 ml).

The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using PrepHPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 30 ml/min; gradient: from 35% B to 65% B in 5 minutes; UV 254 & 220 nm; Rt: 3.75 min, producing the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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), 4.704.64 (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[1,5a][1,3]diazepin-6-yl) -4H-1,2,4-triazole-3-carboxamide and (R)-5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8tetrahydro-4H-pyrazolo [1, 5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide.

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Step 1. Preparation of methyl 4-(4-methyl-5-nitro-1H-pyrazol-1-yl)butanoate.

Diisopropyl azodicarboxylate (3.4 g, 16.9 mmol) was slowly added to a stirred mixture of methyl 4-hydroxybutanoate (2 g, 16.9 mmol), 4-methyl-5-nitro-N-pyrazole (1 g, 7.8 mmol) and triphenylphosphine (4.44 g, 16.9 mmol) in tetrahydrofuran (40 ml) at 0°C under nitrogen. After stirring overnight at room temperature, the reaction mixture was quenched by adding water (100 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give 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. Preparation of methyl 4-(5-amino-4-methyl-1H-pyrazol-1-yl)butanoate.

A solution of methyl 4-(4-methyl-5-nitro-1H-pyrazol-1-yl)butanoate (1.0 g, 4.4 mmol) in methanol (30 ml) was hydrogenated in the presence of a carbon-supported palladium catalyst (10 %, 0.1 g) in a hydrogen atmosphere (2-3 atm). After stirring for 2 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo to give 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. Preparation of 3-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

The crude product obtained using the procedure described in Example 54 was purified by column chromatography (methanol/dichloromethane, 1/10) to give 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. Preparation of 3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

Sweep (511 mg, 3.6 mmol) was added to a stirred mixture of 3-methyl-7,8-dihydro-4Hpyrazolo[1,5-a][1,3]diazepin-5(6H)-one (600 mg, 3 .6 mmol) and cesium carbonate (3.52 g, 10.8 mmol) in N,Ndimethylformamide (15 ml). The reaction mixture was stirred for 3 hours at room temperature, 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, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to give the title compound (480 mg, 78%) as a yellow solid. LC-MS (method C): m/z=180.1 [M+H] ⁺ , 0.876 min.

Step 5. Preparation of 6-iodo-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

N ¹ ,N ¹ ,N ² ,N ² -tetramethylethane-1,2-diamine (0.82 mg, 8.02 mmol) was added to the stirred mixture of 3,4-dimethyl-7,8-dihydro-4H-pyrazolo[ 1,5-a][1,3]diazepin-5(6H)-one (0.48 mg, 2.67 mmol) in dichloromethane (10 ml) at 0°C followed by 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 adding aqueous sodium thiosulfate (5%, 20 ml). The resulting mixture was stirred for a further 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 in vacuo. The residue was purified by column chromatography (dichloromethane) to give 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. Preparation of 6-azido-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

Sodium azide (137 mg, 2.1 mmol) was added to the stirred mixture of 6-iodo-3,4-dimethyl-7,8dihydro-4H-pyrazolo[1,5-a][1,3]diazepine-5(6H) -one (427 mg, 1.39 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred for 2 hours at room temperature, quenched with water (40 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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. Preparation of 6-amino-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

Triphenylphosphine (734 mg, 2.80 mmol) was added to the stirred mixture of 6-azido-3,4-dimethyl7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepine-5(6H)- it (400 mg, 1.80 mmol) in tetrahydrofuran (10 ml) and water (2 ml). After stirring overnight at room temperature, the reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give the title compound (232 mg, 86%) as a yellow oil. LCMS (method C): m/z=194.7 [M+H] ⁺ , 0.378 min.

Step 8. Preparation of 5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepine-6- yl)-4H-1,2,4-triazole-3-carboxamide.

N,N-Diisopropylethylamine (140 mg, 1.13 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazole-3carboxylic acid (73 mg, 0.36 mmol), 6-amino-3,4 -dimethyl-7,8-dihydro-4H-pyrazolo[1,5a][1,3]diazepin-5(6H)-one (70 mg, 0.36 mmol), N-(3-dimethylαmunopronul)-N hydrochloride 'ethylcarbodiimide (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (65 mg, 0.39 mmol) in N,Ndimethylformamide (2 ml). After stirring overnight at room temperature, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3x40 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep 100 A, 10 µm, 19 mm x 250 mm; mobile phase A: water (0.05% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 22% B to 43% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min to obtain the title compound (50 mg, 36%) as a white solid. LC-MS (method T): m/z=380.3 [M+H] ⁺ , 1.041 min.

Step 9. Preparation of (S)-5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5a][1,3]diazepine- 6-yl)-4H-1,2,4-triazole-3-carboxamide (131A) and (R)-5-benzyl-N-(3,4-dimethyl-5-oxo5,6,7,8-tetrahydro -4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (131B).

Racemate 5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)4H -1,2,4-triazole-3-carboxamide (50 mg, 0.13 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IF, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 17 ml/min; gradient: from 40% B to 40% B in 24 minutes; UV 254 & 220 nm; Rt 1: 7.35 min; Rt 2: 8.28 min, obtaining title compounds:

example 131A (first eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 14.31 (s, 1H), 8.34 (d, J=1.1 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 ). LC-MS (method D): m/z=380.2 [M+H] ⁺ , 1.312 min.

example 131B (second eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) 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 1-Benzyl-4-chloro-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4 ]oxazepin-3-yl)-1 H-pyrazole-3-carboxamide.

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Stage 3

Step 1. Preparation of ethyl 4-chloro-1H-pyrazole-3-carboxylate.

1-Chloropyrrolidine-2,5-dione (5.75 g, 42.9 mmol) was added to a stirred mixture of ethyl 1Hpyrazole-3-carboxylate (5.00 g, 35.7 mmol) in N,N-dimethylformamide (40 ml). The reaction mixture was stirred overnight at room temperature and diluted with water (100 ml). Solids were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (6.0 g, crude) as a yellow oil. LC-MS (method S): m/z=175.2 [M+H]+, 0.695 min.

Step 2. Preparation of ethyl 1-benzyl-4-chloro-1H-pyrazole-3-carboxylate.

Potassium carbonate (7.1 g, 51.4 mmol) was added to a stirred mixture of (ethyl 4-chloro-1H-pyrazole-3carboxylate (3.0 g, 17.1 mmol) and (bromomethyl)benzene (3.6 g , 21.1 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred at room temperature overnight, diluted with water (30 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo.The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of 1-benzyl-4-chloro-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b] [1,4] oxazepin-3-yl)-1 H-pyrazol-3-carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 65% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min, obtaining the title compound. 1H NMR (400 MHz, DMSO-b ₆ ) δ 8.36 (dd, J=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-1-(2-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4 ]oxazepin-3-yl)-1 H-pyrazole-3-carboxamide.

Potassium carbonate (34 mg, 0.25 mmol) was added to the mixture of (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1, 4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide (25 mg, 0.08 mmol) and 1(bromomethyl)-2-fluorobenzene (19 mg, 0.10 mmol) in N,N-dimethylformamide ( 2 ml). After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (2 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 30 ml/min; gradient: from 35% B to 65% B in 5 minutes; UV 254 & 220 nm; Rt: 3.75 min, producing the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J=4.8, 1.6 Hz, 1H), 8.24 (d, J=7.6 Hz, 1H), 8.12 (d, J=4.4 Hz, 1H), 7.71 (dd, J=8.0, 1.6 Hz, 1H), 7.46-7.40 (m, 1H), 7.35- 7.21 (m, 4H), 5.43 (s, 2H), 4.88-4.80 (m, 1H), 4.704.64 (m, 1H), 4.53-4.48 (m, 1H), 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[3,2-b][1,4]oxazepine-3 -yl)-1,3,4-oxadiazol-2-carboxamide.

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The crude product obtained using the procedure described in example 54 was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 15% B to 60% B in 15 minutes; UV 254 & 220 nm; Rt: 14.5 min to obtain the title compound (13.3 mg, 17%) as a white solid. 1H NMR (400 MHz, Methanol- _d4 ) δ 8.33-8.31 (m, 1H), 7.71-7.67 (m, 1H), 7.37-7.28 (m, 6H) , 5.07-4.97 (m, 2H), 4.34 (s, 2H), 3.50 (s, 3H), 1.44 (d, J=6.0 Hz, 3H). LC-MS (method J): m/z=394.15 [M+H]+, 2.483 min.

Example 135. (S)-4-Fluoro-1-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4 ]oxazepin-3-yl)-1H-pyrazole-3-carboxamide.

Stage 1 Stage 2

F Stage 3

Step 1. Preparation of 4-fluoro-1H-pyrazole-3-carboxylic acid.

Sodium hydroxide (253 mg, 6.33 mmol) was added to a mixture of ethyl 4-fluoro-1H-pyrazole-3-carboxylate (500 mg, 3.16 mmol) in methanol (10 ml) and water (4 ml). The resulting solution was heated to 40°C and stirred overnight. After removing the methanol under reduced pressure, the resulting solution was adjusted to pH=6 with aqueous hydrochloric acid (1N, 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 in vacuo to give the title compound (400 mg, 97.2%) as a white solid. LC-MS (method T): m/z=131.4 [M+H] ⁺ , 0.567 min.

Step 2. Preparation of (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxαzepin3-yl)-1H -pyrazole-3-carboxamide.

N,N-Diisopropylethylamine (993 mg, 7.70 mmol) was added to a mixture of (S)-3-αmino-5methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepine-4(5H )-one (354 mg, 1.54 mmol), 4-fluoro-1H-pyrazole-3carboxylic 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) in N,Ndimethylformamide (10 ml). After stirring overnight at room temperature, the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using St. TLC (ethyl acetate) to give 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. Preparation of (S)-4-fluoro-1-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido-[3,2b][1,4 ]oxazepin-3-yl)-1H-pyrazole-3-carboxamide.

Potassium carbonate (68 mg, 0.49 mmol) was added to the mixture of (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1, 4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide (50 mg, 0.16 mmol) and 1(bromomethyl)-3-fluorobenzene (38 mg, 0.20 mmol) in N,N-dimethylformamide ( 5 ml). After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 78% B in 7 minutes; UV 254 & 220 nm; Rt: 6.5 min, obtaining the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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),

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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.

Example 136. 1-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3 -yl)-1H-1,2,4-triazol-3-carboxamide.

Stage 3

Step 1. Preparation of methyl 1-benzyl-1H-1,2,4-triazole-3-carboxylate.

Sodium hydride (60%, 192 mg, 8 mmol) was added to a stirred 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 temperature for 2 hours, followed by the addition of (bromomethyl)benzene (680 mg, 4 mmol) under a nitrogen atmosphere. After stirring for a further 2 hours, the reaction mixture was quenched by adding 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to give 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. Preparation of 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid.

Lithium hydroxide (48 mg, 2 mmol) was added to a stirred mixture of methyl 1-benzyl-1H-1,2,4triazole-3-carboxylate (108 mg, 0.5 mmol) in tetrahydrofuran (3 ml) and water (1 ml ). After stirring at 0°C for 2 hours, the reaction mixture was adjusted to pH 6 with aqueous hydrochloric acid (1N, 10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (80 mg, 79%) as a white solid. LC-MS (method E): m/z=203.9 [M+H] ⁺ , 0.560 min.

Step 3. Preparation of 1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

The crude product obtained by the amine coupling procedure C was purified by Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 75% B in 7 minutes; UV 254 & 220 nm; Rt: 6.3 min to obtain the title compound (31.5 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO-66) δ 8.86 (s, 1H), 8.36 (dd, J=4.4, 1.2 Hz, 1H), 8.01 (d, J=6, 4 Hz, 1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.41-7.31 (m, 6H), 5.50 (s, 2H), 5.004, 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 -b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide.

RBr ₃ , DHM HO^ /C * Br^ - - p KT, in current. nights Stage 1 o N' 1 ___________o n ^{nh F} K ₂ CO ₃ , DMF, rt, 3 h Stage 2 a

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Step 1. Preparation of 3-(bromomethyl)-5-fluoropyridine.

Tribromophosphine (853 mg, 3.15 mmol) was added to a solution of (5-fluoropyridin-3-yl)methanol (200 mg,

1.57 mmol) in dichloromethane (2 ml). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo to give the title compound (150 mg, crude). LC-MS (method S): m/z=190.1 [M+H]+, 0.787 min.

Step 2. Preparation of (S)-4-fluoro-1-((5-fluoropyridin-3-yl)methyl)-N-(5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2- b][1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide.

Potassium carbonate (181 mg, 1.31 mmol) was added to the mixture of (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1, 4]oxazepin-3-yl)-1H-pyrazol-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 temperature for 3 hours, diluted with water (2 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, JOA, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ); mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 15% B to 35% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min, obtaining the title compound. ¹ H NMR (400 MHz, DMSO-b ₆ ) 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-Dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)- 5(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ); mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 60% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min, obtaining the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) 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), 7.44-7.29 (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 5(2-fluorophenoxy)pyridazine-3-carboxamide.

O N=N

The crude product obtained using the procedure described in example 54 was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 mm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ); mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 50% B in 7 minutes; UV 254 & 220 nm; Rt: 6.5 min, obtaining the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) 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 (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 )-1H-imidazole-4-carboxamide.

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\ ABOUT

Step 1. Preparation of ethyl 1-benzyl-1H-imidazole-4-carboxylate.

Sodium hydride (60%, 0.51 g, 21.3 mmol) was added to a stirred solution of ethyl 1H-imidazole 4-carboxylate (2.0 g, 14.3 mmol) in N,N-dimethylformamide (15 ml). The resulting mixture was stirred for 30 min at 0°C followed by the addition of (bromomethyl)benzene (2.93 g, 17.13 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture was quenched by adding water (30 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.

The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to give 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. Preparation of 1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-3 - yl)-1 H-imidazole-4-carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ); mobile phase B: ACN; flow rate: 20 ml/min;

gradient: from 30% B to 55% B in 7 minutes; detector: UV 254 & 220 nm, producing the title compound. Ή NMR (400 MHz, DMSO-Y6) 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),

7.37-7.27 (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.

Example 141A and 141B. (S)-5-Benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4H1,2,4-triazole -3-carboxamide and (R)-5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)4H-1 ,2,4-triazole-3-carboxamide.

To ₂ CO ₃ , MeCN heating with reverse

Stage 1 refrigerator, 2 hours

Stage 2

Ph

ABOUT

Stage 3

Cui, K ₂ CO ₃ , DMF

100°C, during nights

NH ₄ OAc, NaBH ₃ CN

MeOH, CT, in progress. nights

NH ₂

Stage 4

EDCI, HOBT, EEA.DMFA

CT scan, during nights Stage 6

Stage 5

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Step 1. Preparation of 2-chloro-1-(1-trityl-1H-imidazol-2-yl)ethanone.

A solution of n-butyllithium in hexane (2.5 M, 13.2 mL, 33.0 mmol) was added dropwise to a stirred mixture of 1-trityl-1H-imidazole (9.3 g, 30.0 mmol) in tetrahydrofuran (190 ml) at -78°C in a nitrogen atmosphere. After addition was complete, the reaction mixture was slowly warmed to -10°C and stirred for 1 hour. The mixture was then cooled again to -78°C and a solution of tert-butyl 2-chloroacetate (5.4 g, 36.0 mol) was added ) in tetrahydrofuran (10 ml) in one serving. The resulting mixture was warmed to room temperature with stirring for 2-3 hours, quenched with ice water (100 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give the title compound (900 mg, 7.8%) as a yellow solid.

Step 2. Preparation of 2-(2-bromopyridin-3-yloxy)-1-(1-trityl-1H-imidazol-2-yl)ethanone.

2-Chloro-1-(1-trityl-1H-imidazol-2-yl)ethanone (772.0 mg, 2.0 mmol) was added to the stirred mixture of 2-bromopyridin-3-ol (346.0 mg, 2.0 mmol) 0 mmol) and potassium carbonate (414.0 mg, 3.0 mmol) in acetonitrile (10 ml) under nitrogen atmosphere. The resulting mixture was heated to boiling and stirred for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give the title compound (700 mg, 66.9%) as a yellow solid. LC-MS (method C): m/z=524.1 [M+H]+, 1.490 min.

Step 3. Preparation of 2-(2-bromopyridin-3-yloxy)-1-(1H-imidazol-2-yl)ethanone.

Mixture of 2-(2-bromopyridin-3-yloxy)-1-(1-trityl-1H-imidazol-2-yl)ethanone (700 mg, 1.34 mmol) in methanol/acetic acid (5 ml/1 ml) refluxed and stirred overnight. After cooling to room temperature, the resulting mixture was concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to give 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. Preparation of imidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7(6H)-one.

Copper iodide (19 mg, 0.1 mmol) was added to a mixture of 2-(2-bromopyridin-3-yloxy)-1-(1H-imidazol-2yl)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 nitrogen. The resulting mixture was stirred overnight at 100°C. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous ammonium chloride (20 ml) and extracted with dichloromethane/methanol (10/1) (3x20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/40) to give 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. Preparation of 6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-amine.

Sodium cyanoborohydride (11.0 mg, 0.17 mmol) was added to the stirred mixture of imidazo[1,2d]pyrido[3,2-b][1,4]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 overnight at room temperature. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/15) to give 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. Preparation of 5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4H1,2,4-triazole -3-carboxamide.

The crude product obtained using the amine coupling technique C was purified using Rev. TLC (ethyl acetate/petroleum ether, 3/1) gave 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. Preparation of (S)-5-benzyl-N-(6,7-dihydroumidazo[1,2-d]nupydo[3,2-b][1,4]oxazepin-7-yl)-4H1,2 ,4-triazole-3-carboxamide (141A) and (R)-5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxase

- 171 044271 pin-7-yl)-4H-1,2,4-triazole-3-carboxamide (141B).

Racemate 5-benzyl-N-(6,7-dihydroimidazo[1,2-d]nupugo[3,2-b][1,4]oxazepin-7-yl)-4H-1,2,4-triazol- 3carboxamide (16 mg, 0.041 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IC, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 50% B to 50% B in 30 minutes; UV254 & 220 nm; Rt 1: 16.881; Rt 2: 24.391, obtaining title compounds:

example 141A (first eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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;

example 141B (second eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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 -carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 50% B in 7 minutes; UV 254 & 220 nm; Rt: 5.6 min, producing the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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.

Example 143. N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)- 4fluoro-1 -(4-fluorobenzyl)-1 H-pyrazole-3-carboxamide.

The crude product obtained using the procedure described in example 54 was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP 18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 65% B in 7 minutes; UV 254 & 220 nm; Rt: 5 min to obtain the title compound (26.2 mg, 28%) as a white solid. 1H NMR (300 MHz, DMSO-d 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 -3 -yl)-1 H-pyrazol-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP 18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 50% B in 7 minutes; UV 254 & 220 nm; Rt: 5.5 min to obtain the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) 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.

Example 145A and 145B. (S)-N-(9-Methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1phenylcyclopropyl)-1, 3,4-oxadiazole-2-carboxamide and (R)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepin-7-yl)- 5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-carboxamide.

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Step 1. Preparation of N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)- 1,3,4-oxadiazole-2-carboxamide.

The crude product obtained using the procedure described in example 54 was purified using Prep-HPLC: Column: XBridge Shield RP18 OBD, 19x150 mm, 5 µm; Mobile phase: phase A: water (10 mmol/l NH ₄ HCO ₃ ); phase B: ACN (from 35.0% ACN to 41.0% in 7 min); Detector, UV220 & 254 nm; Rt: 5.88 min to give 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. Preparation of (S)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-nirido[2,3-b]azepin-7-yl)-5-(1phenylcyclopropyl) )-1,3,4-oxadiazole-2-carboxamide (first eluting isomer) and (R)-N-(9-methyl-8oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3- b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2carboxamide (second eluting isomer).

Racemate N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3 ,4-oxadiazole-2-carboxamide (45 mg, 0.11 mmol) was separated using rep. chiral HPLC under the following conditions: column: Chiralpak IA, 5 µm, 2.12x15 cm; mobile phase A: hexane, mobile phase B: IPA; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 13.5 minutes; UV 220 & 254 nm; Rt 1: 8.78; Rt 2: 11.03, obtaining title compounds:

example 145A (first eluting isomer): 1H NMR (400 MHz, Methanol-d ₄ ) 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;

example 145B (second eluting isomer): 1H NMR (400 MHz, MethanolA) 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][1,4]oxazepin-3-yl)1 ,3,4-oxadiazole-2-carboxamide.

The crude product obtained using the procedure described in example 54 was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 mm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 65% B in 7 minutes; UV 254 & 220 nm; Rt: 5 min, obtaining the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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]+, 1.531 min.

Example 147. 5-Benzyl-N-((2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

- 173 044271

Stage 1 Stage 2

Stage 3 Stage 4

Stage 5

Step 1. Preparation of tert-butyl-(2R,3S)-8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-ylcarbamate .

Bromine (1.63 g, 10.2 mmol) was added to the stirred mixture of tert-butyl-(2R,3S)-2-methyl-4-oxo2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-ylcarbamate (1.0 g, 3.4 mmol) in N,Ndimethylformamide (30 ml). The reaction mixture was stirred at room temperature for 4 hours and quenched by adding 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 in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give 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. Preparation of tert-butyl-(2R,3S)-8-bromo-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-3 -ylcarbamate.

Sweep (306 mg, 2.2 mmol) was added to the stirred mixture of tert-butyl-(2R,3S)-8-bromo-2methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepin-3-ylcarbamate (800 mg, 2.2 mmol) and cesium carbonate (703 mg, 2.2 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred for 2 hours at room temperature, 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, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to give 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. Preparation of tert-butyl-(2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1,4]oxazepine -3-ylcarbamate.

A solution of isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 0.52 ml, 1.04 mmol) was added to the stirred mixture of tert-butyl-(2R,3S)-8-bromo-2,5-dimethyl-4-oxo-2 ,3,4,5-tetrahydropyrido[3,2b][1,4]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 a further 2 hours at room temperature, diluted with water (15 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give the title compound (55 mg, 28%) as a white solid. LC-MS (method C): m/z=330.1 [M+H-56] ⁺ , 1.208 min.

Step 4. Preparation of (2R,3S)-3-amino-2,5-dimethyl-8-(methylsulfonyl)-2,3dihydropyrido-[3,2-b][1,4]oxazepine-4(5H)- hydrochloride she.

To a stirred mixture of tert-butyl-(2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1,4]oxazepine- 3-ylcarbamate (55 mg, 0.15 mmol) in 1,4-dioxane (5 ml), a solution of hydrogen chloride in 1,4-dioxane (4 M, 2 ml, 8 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature and concentrated under high vacuum to give the title compound (46 mg, crude) as a white solid, which was used directly in the next step without further purification. LC-MS (method C): m/z=286.1 [M+H]+, 0.783 min.

Step 5. Preparation of 5-benzyl-N-((2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5tetrahydropyrido[3,2-b] [1, 4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

The crude product obtained using the amine coupling procedure C was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 60% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min, obtaining the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H ), 8.01 (br s, 1H), 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[2,3-b]azepin-7yl)-1,3,4- oxadiazole-2-carboxamide and (R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepin-7-yl)- 1,3,4-oxadiazole-2-carboxamide.

Step 1 chiral separation

Stage 2

Step 1. Preparation 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.

The crude product obtained using the procedure described in example 54 was purified using Prep-HPLC under the following conditions: column: XSelect CSH Prep C18 OBD, 5 mm, 19x150 mm; mobile phase A: water (0.1% formic acid); mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 52% B in 4 minutes; UV 254 & 220 nm; Rt: 4 min to obtain 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. Preparation of (S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7yl)-1, 3,4-oxadiazole-2-carboxamide (first eluting isomer) and (R)-5-benzyl-N-(9-methyl-8-oxo6,7,8,9-tetrahydro-5H-pyrido[2,3- b]azepin-7-yl)-1,3,4-oxadiazol-2-carboxamide (second eluting isomer).

Racemate 5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1,3,4oxadiazol-2 -carboxamide (20 mg) was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAKIA, 2.12x15 cm, 5 µm; mobile phase A: hexane; mobile phase B: IPA; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 12 minutes; UV 254 & 220 nm; Rt 1: 7.106; Rt 2: 9.363 min, obtaining title compounds:

example 148A (first eluting isomer): 1H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 8.44 (dd, J=5.1, 1.8 Hz, 1H), 7.81 (dd, J= 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;

example 148B (second eluting isomer): 1H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 8.41 (dd, J=4.8, 1.8 Hz, 1H), 7.78 (dd, J= 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 -yl)pyridazin-3-carboxamide.

NH ₂ HCI

ΑΙΜθ3, toluene, 0°C to RT, during. nights

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 mm, 19 mm x 250 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate:

- 175 044271 ml/min; gradient: from 40% B to 60% B in 7 minutes; UV 254 & 220 nm; Rt: 6.5 min, obtaining the title compound. 1H NMR (300 MHz, DMSO-d ₆ ) 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, J=3.6 Hz, 1H), 4.91-4.74 ( m, 2H), 4.56-4.50 (m, 1H), 3.32 (s,

3H). LC-MS (Method V): m/z=410.1 [M+H]+, 2.765 min.

Example 150 5-Benzyl-N-((2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4 ]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

\ o \ o < ^N <S/ ^N ~\ Zn(CN) ₂ , P0(PPb ₃ ) ₄ , DMF D 4 n HCI in dioxane

Η I )—NH --------------------Η I )—NH -------------- ^Vos MV reactor, 140 ° C Zh ^Vos CT, 2 h

Stage 1 Stage 2

Stage 3

Step 1. Preparation of tert-butyl-(2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-ylcarbamate.

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 -2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-ylcarbamate (200 mg, 0.52 mmol) in N,N-dimethylformamide (2 ml) under nitrogen atmosphere. The reaction mixture was heated at 140°C under microwave radiation and stirred for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of (2R,3S)-3-amino-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-8-carbonitrile hydrochloride.

To a solution of tert-butyl-(2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-3 -ylcarbamate (68 mg, 0.21 mmol) in 1,4-dioxane (5 ml), a solution of hydrogen chloride in 1,4-dioxane (4 M, 2 ml, 8 mmol) was added. The resulting mixture was stirred for 2 hours at room temperature and concentrated under high vacuum to give 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. Preparation of 5-benzyl-1H-((2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1, 4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XSelect CSH Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 65% B in 7 minutes; UV 254 & 220 nm; Rt: 6 min, obtaining the title compound. 1H NMR (400 MHz, DMSO-d6) 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 )thiazole-2-carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 55% B in 7 minutes; 254 nm; Rt: 6.32 min, producing the title compound. 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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)-1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7 -yl)-1H-pyrazol-3-carboxamide and (S)-1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo6,7,8,9-tetrahydro-5H-pyrido [2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide.

- 176 044271

Step 1. Preparation of 1-(3-cyanobenzyl)-4-fluoro^-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7- yl)-1H-pyrazole-3-carboxamide.

The crude product obtained using the amine coupling procedure C was purified using Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19x250 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 20% B to 50% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min to obtain 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. Preparation of (R)-1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepine -7-yl)-1H-pyrazol-3-carboxamide (first eluting isomer) and (S)-1-(3cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8, 9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazol-3carboxamide (second eluting isomer).

Racemate 1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7yl)-1H -pyrazole-3-carboxamide (65 mg, 0.16 mmol) was separated using Rev. chiral HPLC under the following conditions: column: Chiralpak ID-2, 5 µm, 2x25 cm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 60% B to 60 V% in 20 minutes; UV 254 & 220 nm; Rt 1: 12.92 min; Rt 2: 16.60 min, obtaining title compounds:

example 152A (first eluting isomer): 1H NMR (400 MHz, DMSO-d ₆ ) δ 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, 30-7.26 (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). LC-MS (method F): m/z=419.0 [M+H] ⁺ , 1.070 min;

example 152B (second eluting isomer): 1H NMR (400 MHz, DMSO-d ₆ ) δ 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, 30-7.26 (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). LC-MS (method F): m/z=419.1 [M+H] ⁺ , 1.071 min.

Example 153 (S)-1-(2-Cyanobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine -3-yl)-1H-pyrazole-3-carboxamide.

2-(Bromomethyl)benzonitrile (39 mg, 0.20 mmol) was added to a stirred mixture of (S)-4-fluoro-N(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2 -b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide (50 mg, 0.16 mmol) and potassium carbonate (68 mg, 0.49 mmol) in N,N-dimethylformamide ( 4 ml). The resulting mixture was stirred at room temperature for 3 hours, diluted with water (5 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 55% B in 7 minutes; 254 nm; Rt: 6.32 min, producing the title compound. 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.35 (dd, J=4.8, 1.6 Hz, 1H), 7.88 (d, J=4.5 Hz, 1H), 7.83 (dd, J=7.7, 1.3 Hz, 1H), 7.73-7.66 (m, 2H), 7.56 (td, J=7.6, 1.1 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.32 (dd, J=8.0, 4.8 Hz, 1H), 5.59 (s, 2H), 5, 01 (dd, J=11.5, 7.2 Hz, 1H), 4.68 (dd, J=9.8, 7.2 Hz, 1H), 4.50 (dd, J=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)-1-Benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)4-fluoro-1H-pyrazole -3-carboxamide and (S)-1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine- 177 044271

7-yl)-4-fluoro-1 H-pyrazole-3-carboxamide.

Stage 2

Step 1. Preparation of 1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4fluoro-1H-pyrazol- 3-carboxamide.

The crude product obtained using the amine coupling technique C was purified using Rev. TLC (ethyl acetate/petroleum ether, 3/1) gave 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. Preparation of (S)-1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)4-fluoro- 1H-pyrazole-3-carboxamide (first eluting isomer) and (R)-1-benzyl-N-(6,7dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-7 -yl)-4-fluoro-1 H-pyrazole-3-carboxamide (second eluting isomer)

1-Benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4-fluoro-1Hpyrazole-3-carboxamide racemate ( 16 mg, 0.039 mmol) were separated using Rev. chiral HPLC under the following conditions: column: CHIRALPAK IC, 5 µm, 2x25 cm; mobile phase A: hexane: DCM=5:1, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 50% B to 50% B in 26 minutes; UV 254 & 220 nm; Rt 1: 3.96 min; Rt 2: 6.18 min, obtaining title compounds:

example 154A (first eluting isomer): 1H NMR (300 MHz, Methanol-d ₄ ) 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] ⁺ , 1.063 min;

example 154B (second eluting isomer): 1H NMR (300 MHz, Methanol-d ₄ ) 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 )-1 H-pyrazole-3-carboxamide.

Stage 2

Step 1. Preparation of 1-benzyl-1H-pyrazole-3-carboxylic acid.

Sodium hydride (96 mg, 4 mmol) was added to a stirred mixture of ethyl 1H-pyrazole-3carboxylate (280 mg, 2 mmol) in N,N-dimethylformamide (20 ml). The resulting mixture was stirred at room temperature 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 temperature, adjusted to pH 6 with hydrochloric acid (2N, 20 ml), and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 55% B in 7 minutes; UV 254 & 220 nm; Rt: 4.9 min to obtain the title compound (220 mg, 54.4%) as a white solid. LC-MS (method E): m/z=202.9

[M+H]+, 0.855 min.

Step 2. Preparation of 1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-nirido[3,2b][1,4]oxazepine- 3 -yl)-1 H-pyrazol-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 75% B in 7 minutes; UV 254 & 220 nm; Rt: 3.3 min to obtain the title compound. 1H NMR (400 MHz, DMSO-06) 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-1-(4-fluorobenzyl)-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8bhexahydrocyclopropa[d]pyrido[2,3 -b]azepin-2-yl)-1H-pyrazol-3-carboxamide and 4-fluoro-1-(4-fluorobenzyl)-N((1aS,2S,8bR)-4-methyl-3-oxo-1, 1a,2,3,4,8b-hexahydrocycloprona[d]nirido[2,3-b]azepin-2-yl)-1H-pyrazol-3carboxamide.

Stage 1

The crude product obtained using the amine coupling technique C was purified using Rev. TLC (methanol/dichloromethane, 1/20) gave the title compound as a white solid.

The racemate was separated using Rev. chiral HPLC under the following conditions: column: Chiralpak IC, 2x25 cm, 5 µm; mobile phase A: Hexane, mobile phase B: EtOH; flow rate: 19 ml/min; gradient: from 35% B to 35% B in 18.5 minutes; UV 220 & 254 nm; Rt 1: 13.00; Rt 2: 15.67, obtaining title compounds:

example 156A (first eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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), 7.147.07 (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] ⁺ , 1.658 min;

example 156B (second eluting isomer): ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) 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), 7.127.08 (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-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocycloprona[d]pyrido[2,3-b]azenine-2 -yl)-1,3,4-oxadiazol-2-carboxamide and 5-benzyl-N-((1aS,2S,8bR)-4-methyl3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d]pyrido[2,3-b]azepin-2-yl)-1,3,4-oxadiazol-2-carboxamide.

The crude product obtained using the procedure described in Example 54 was purified using column chromatography (ethyl acetate/petroleum ether, 1/1) to obtain the title compound as a white solid.

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The racemate was separated using Rev. chiral HPLC under the following conditions: column: CHIRALPAK AS-H, 2.0 cm I.D x 25 cm, 5 µm; mobile phase A: Hexane, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 50% B to 50% B in 16 minutes; UV 220 & 254 nm; Rt 1: 8.212; Rt 2: 10.554, obtaining title connections:

example 157A (first eluting isomer): 1H NMR (300 MHz, DMSO-dg) 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), 7.37-7.27 (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;

example 157B (second eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.47 (d, J=6.0 Hz, 1H), 8.39 (dd, J=6.6, 1, 8 Hz, 1H), 7.97 (dd, J=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.

Example 158 )-1 H-pyrazole-3-carboxamide.

^{HCI H} 2 ^N ^^ /4Z ^CN NaOH, EtOH, H ₂ O ° 1) NaNO ₂ , CHCI ₃ /H ₂ O, KT, 12 h q^n^ ^NH KT, 4 h

2) 60 °C, bh ’

Stage 1 Stage 2

Stage 3 Stage 4

Step 1. Preparation of ethyl 5-cyano-1H-pyrazole-3-carboxylate.

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 temperature, then heated to 60°C and stirred for another 6 hours. After cooling to room temperature, the resulting mixture was filtered. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/9) to give the title compound (2.90 g, 35%) as a yellow solid. LC-MS (method C): m/z=166.1[M+H]+, 1.032 min.

Step 2. Preparation of 5-cyano-1H-pyrazole-3-carboxylic acid.

A solution of sodium hydroxide in water (2 M, 30 ml, 60 mmol) was added to a mixture of ethyl 5-cyano-1Hpyrazole-3-carboxylate (1.5 g, 9.09 mmol) in ethanol (25 ml). The reaction mixture was stirred for 4 hours at room temperature. After removing ethanol under reduced pressure, the pH of the solution was adjusted to 3-4 using an aqueous solution of hydrochloric acid (1 M, 100 ml, 100 mmol). 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 high vacuum to give the title compound (400 mg, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-dg) δ 14.89 (s, 1H), 7.43 (s, 1H), 3.15 (s, 1H).

Step 3. Preparation of (S)-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl) -1H-pyrazole-3-carboxamide.

The crude product obtained by the amine coupling procedure C was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to give 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. Preparation of ((S)-1-benzyl-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-3 -yl)-1 H-pyrazol-3-carboxamide.

Cesium carbonate (80 mg, 0.25 mmol) was added to a mixture of (S)-5-cyano-N-(5-methyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1, 4]oxazepin-3-yl)-1H-pyrazol-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 h at room temperature, diluted with water (50 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: Water (0.1% formic acid); mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 20% B to 45% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min, giving the title compound: 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (d, J=7.9 Hz, 1H), 8.35 (dd, J=4.7, 1.6 Hz, 1H), 7.69 (dd, J=8.0, 1.6 Hz, 1H), 7.58 (s, 1H), 7.44-7.29 (m, 4H), 7.28-7.22 (m, 2H), 5.65 (s, 2H), 4.90-4.84 (m, 1H), 4.73-4.67 (m, 1H), 4, 54-4.50 (m, 1H), 3.35 (s, 3H). LC-MS (method T): m/z=403.2 [M+H]+, 1.412 min.

Example 159 ]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide.

The crude product obtained using the procedure described in example 158, step 4, was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 μm, 19x150 mm; mobile phase A: Water (10 mmol/l NH4HCO3); phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 60% B in 12 minutes; UV 254 & 220 nm; Rt: 6.5 min, giving the title compound: ¹ H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=7.9 Hz, 1H), 8.36 (dd, J=4, 8, 1.6 Hz, 1H), 7.70 (dd, J=7.9, 1.6 Hz, 1H), 7.59 (s, 1H), 7.36-7.29 (m, 3H ), 7.27-7.20 (m, 2H), 5.64 (s, 2H), 4.90-4.84 (m, 1H), 4.72-4.67 (m, 1H), 4.54-4.50 (m, 1H), 3.36 (s, 3H). LC-MS (method T): m/z=421.1 [M+H]+, 1.433 min.

Example 160A and 160B. (S)-5-Benzyl-N-(5'-methyl-4'-oxo-4',5'-dihydro-3Ή-spiro[cyclopropane-1,2'pyrido[3,2-b][1, 4]oxazepin]-3'-yl)-1,3,4-oxadiazol-2-carboxamide and (R)-5-benzyl-N-(5'-methyl-4'-oxo-4',5'dihydro -3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]-3'-yl)-1,3,4-oxadiazol-2-carboxamide.

Step 10 chiral separation

Stage 1. Preparation of ethyl 2-cyclopropylidene acetate.

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 overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/petroleum ether, 1/1) to give the title compound (2.1 g, 14%) as a colorless oil. LC-MS (method S): m/z=127.2 [M+H]+, 0.886 min.

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Step 2. Preparation of ethyl 2-(1-((2-nitropyridin-3-yl)oxy)cyclopropyl)acetate.

2-Nitropyridin-3-ol (3.36 g, 24.00 mmol) was added to a mixture of ethyl 2-cyclopropylidene acetate (1.00 g, 7.93 mmol) and 4A molecular sieves (2.80 g) in dimethyl acetamide (40 ml). The reaction mixture was stirred at 130°C overnight under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with diethyl ether (150 ml) and washed with aqueous sodium hydroxide (0.2 M, 3x200 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/petroleum ether, 2/1) to give the title compound (450 mg, 21%) as a yellow oil. LC-MS (method S): m/z=267.2 [M+H]+, 0.935 min.

Step 3. Preparation of ethyl 2-(1-((2-aminopyridin-3-yl)oxy)cyclopropyl)acetate.

A mixture of ethyl 2-(1-((2-nitropyridin-3-yl)oxy)cyclopropyl)acetate (800 mg, 3.00 mmol) in methanol (30 ml) was hydrogenated in the presence of a carbon-supported palladium catalyst (10%, 80 mg) in a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred for 2 hours at room temperature. The mixture was filtered through Celite and the filtrate was concentrated under high vacuum to give 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. Preparation of 3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]-4'(5'H)-one.

A solution of trimethylaluminum in toluene (2 M, 5.3 mL, 10.55 mmol) was added dropwise to a stirred 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 temperature, quenched by adding water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give 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. Preparation of 5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepin]-4'(5'H)-one.

Iodomethane (178 mg, 1.26 mmol) was added dropwise to the stirred mixture of 3'Hspiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]-4'(5'H) -one (200 mg, 1.05 mmol) and cesium 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 (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/17) to give the title compound (150 mg, 69%) as a white solid. LC-MS (method S): m/z=205.1 [M+H] ⁺ , 0.767 min.

Step 6. Preparation of 3'-iodo-5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]4'(5'H)- she.

Ν,Ν,Ν',N'-tetramethylethylenediamine (0.49 g, 4.25 mmol) was added to the mixture of 5'-methyl-3'Hspiro[cyclopropane-1,2'-pyrido[3,2-b][ 1,4]oxazepine]-4'(5'H)-one (0.18 g, 0.85 mmol) in dichloromethane (40 ml) at 0°C followed by iodotrimethylsilane (1.70 g, 8.50 mmol) drop by drop 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 a further 1 hour at 0°C, quenched with aqueous sodium thiosulfate (5%, 20 ml) and extracted with dichloromethane (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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. Preparation of 3'-azido-5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]4'(5'H)- she.

Sodium azide (109 mg, 1.68 mmol) was added to the mixture of 3-iodo-5-methyl-3H-spiro[cyclopropane-1,2'pyrido[3,2-b][1,4]oxazepine]-4'(5'H)-one (280 mg, 0.84 mmol) in N,N-dimethylformamide (5 ml). The resulting mixture was stirred for 2 hours at room temperature, quenched by adding 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 in vacuo. The precipitate was purified using St. TLC (ethyl acetate/petroleum ether, 1/2) gave 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. Preparation of 3'-amino-5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]4'(5'H)- she.

A mixture of 3'-Azido-5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]-4'(5'H)-one ( 70 mg, 0.28 mmol) in methanol (10 ml) was hydrogenated in the presence of a carbon-supported palladium catalyst (10%, 10 mg) under a hydrogen atmosphere (2-3 atm). After stirring for 30 minutes at room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the title compound (50 mg, 78%) as a white solid. LC-MS

- 182 044271 (method S): m/z=220.2 [M+H]+, 0.690 min.

Step 9. Preparation of 5-benzyl-X-(5'-methyl-4'-oxo-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'pyrido [3,2-b][ 1,4]oxazepine]-3'-yl)-1,3,4-oxadiazol-2-carboxamide.

The crude product obtained using the procedure described in example 54 was purified using Rev. TLC (ethyl acetate/petroleum ether, 1/1) gave the title compound (42 mg, 45%) as a white solid. LC-MS (method S): m/z=406.0 [M+H] ⁺ , 1.024 min.

Step 10. Preparation of (S)-5-benzyl-N-(5'-methyl-4'-oxo-4',5'-dihydro-3Ή-spiro[cyclopropane-1,2'pyrido[3,2-b ][1,4]oxazepin]-3'-yl)-1,3,4-oxadiazol-2-carboxamide and (R)-5-benzyl-N-(5'-methyl-4'-oxo-4' ,5'dihydro-3Ή-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepin]-3'-yl)-1,3,4-oxadiazol-2-carboxamide.

Racemate 5-benzyl-N-(5'-methyl-4'-oxo-4',5'-dihydro-3Ή-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4] Oxazepin]-3'-yl)-1,3,4-oxadiazol-2-carboxamide (42 mg, 0.10 mmol) was separated using Rev. chiral HPLC under the following conditions: column: CHIRALPAK IA, 2.12x15 cm, 5 µm; mobile phase A: Hexane, mobile phase B: IPA; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 14 minutes; UV 254 & 220 nm; Rt 1: 12.359; Rt 2: 20.087, obtaining title compounds:

Example 160A (first eluting isomer): ¹ H NMR (300 MHz, DMSO-d ₆ ) 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.

Example 160B (second eluting isomer): 1H NMR (300 MHz, DMSO-d ₆ ) 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 )-4H-1,2,4-triazole-3-carboxamide.

Stage 6

Stage 1. Preparation of methyl 2-(3-cyanophenyl) acetate.

Sulfuric 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 temperature for 3 hours and concentrated in vacuo. The precipitate was diluted with water (40 ml) and extracted with ethyl acetate (3x60 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (3.30 g, 87%) as a colorless oil. LC-MS (method S): m/z=176.2 [M+H] ⁺ , 0.504 min.

Step 2. Preparation of 2-(3-cyanophenyl)acetohydrazide.

Hydrazine hydrate (80%, 3.3 mL, 85.0 mmol) was added to a mixture of methyl 2-(3-cyanophenyl) acetate in methanol (50 mL). The reaction mixture was stirred at 65°C overnight and then concentrated under reduced pressure. The precipitate was diluted with water (40 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give 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. Preparation of ethyl 2-(2-(2-(3-cyanophenyl)acetyl)hydrazinyl)-2-iminoacetate.

Ethyl 2-ethoxy-2-iminoacetate (1.82 g, 12.6 mmol) was added to a stirred mixture of 2-(3cyanophenyl)acetohydrazide (2.0 g, 11.5 mmol) in ethanol (20 ml) and diethyl ether (60 ml). The reaction mixture was stirred at room temperature overnight. The white solid was collected by filtration and washed with diethyl ether to give 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. Preparation of ethyl 5-(3-cyanobenzyl)-4H-1,2,4-triazole-3-carboxylate.

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4A molecular sieves (50 mg) were 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 overnight in a sealed tube and concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to give 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. Preparation of 5-(3-cyanobenzyl)-4H-1,2,4-triazole-3-carboxylic acid.

A solution of lithium hydroxide (94 mg, 4.0 mmol) in water (5 ml) was added to a solution of ethyl 5-(3cyanobenzyl)-4H-1,2,4-triazole-3-carboxylate (500 mg, 2.0 mmol ) in tetrahydrofuran (15 ml). The resulting mixture was stirred at room temperature overnight. After removing the tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH=7 with aqueous hydrochloric acid (1N, 10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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. Preparation of (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2

b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide.

The crude product obtained by the amine coupling procedure C was purified by Prep-HPLC under the following conditions: column: XBridge C18 OBD Prep, 100 A, 5 µm, 19 mm x 250 mm; mobile phase A: Water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 ml/min;

gradient: from 20% B to 45% B in 7 minutes; UV 254 & 220 nm; Rt: 7 min, giving the title compound: 1H NMR (400 MHz, DMSO-Y6) 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,

3H), 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 (m, 1H), 4.22 (s, 2H), 3.36 (s, 3H). LC-MS (method T): m/z=404.2 [M+H] ⁺ , 1.095 min.

Example 162 ]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

Stage 7

Stage 1. Preparation of methyl 2-(3-bromo-5-fluorophenyl) acetate.

Thionyl chloride (4.26 g, 35.8 mmol) was added dropwise to a stirred mixture of methyl 2-(3-bromo5-fluorophenyl)acetic acid (2.6 g, 11.93 mmol) in methanol (30 ml), with followed by the addition of N,N-dimethylformamide (two drops). The reaction mixture was stirred for 2 hours at room temperature and concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to give 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. Preparation of methyl 2-(3-cyano-5-fluorophenyl) acetate.

Tetrakis(triphenylphosphanyl)palladium (1.2 g, 1.05 mmol) was added to a mixture of methyl 2-(3-bromo-5fluorophenyl) acetate (2.6 g, 10.5 mmol) and dicyanozinc (1.64 g, 14.17 mmol) in N,N-dimethylformamide (30 ml) under nitrogen. The reaction mixture was heated at 140°C using microwave radiation and stirred for 3 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give the title compound (1.12 g, 54%) as a yellow solid. LC-MS (method C): m/z=194 [M+H]+, 0.914 min.

Step 3. Preparation of 2-(3-cyano-5-fluorophenyl)acetohydrazide.

Hydrazine hydrate (1.45 g, 29 mmol) was added to a mixture of methyl 2-(3-cyano-5-fluorophenyl) acetate (1.12 g, 5.80 mmol) in methanol (20 ml). The resulting mixture was refluxed, stirred for 3 hours and concentrated under high vacuum. The precipitate was diluted with water (30 ml) and extracted with ethyl acetate (3x20 ml).

The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/1) to give 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. Preparation of ethyl 2-(2-(2-(3-cyano-5-fluorophenyl)acetyl)hydrazinyl)-2-iminoacetate.

Ethyl 2-ethoxy-2-iminoacetate (692 mg, 4.77 mmol) was added to a stirred mixture of 2-(3-cyano5-fluorophenyl)acetohydrazide (910 mg, 4.77 mmol) in ethanol (5 ml) and diethyl ether (15 ml). The reaction mixture was stirred for 4 hours at room temperature. The solid was collected by filtration and dried under high vacuum to give 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. Preparation of ethyl 5-(3-cyano-5-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylate.

A mixture of ethyl 2-(2-(2-(3-cyano-5-fluorophenyl)acetyl)hydrazinyl)-2-iminoacetate (1 g, 3.42 mmol) and 4A molecular sieves in xylenes (20 ml) was stirred in for 4 hours at 160°C. After cooling to room temperature, the reaction mixture was concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to give 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. Preparation of 5-(3-cyano-5-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylic acid.

Lithium hydroxide (79.2 mg, 3.3 mmol) was added to a stirred mixture of ethyl 5-(3-cyano-5fluorobenzyl)-4H-1,2,4-triazole-3-carboxylate (140 mg, 0.78 mmol ) in tetrahydrofuran (10 ml) and water (3 ml). The reaction mixture was stirred overnight at room temperature. After removing the 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 (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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. Preparation 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-1,2,4-triazol-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: Xbridge Prep C18, 19x150 mm, 5 µm; Mobile phase: phase A: water (10 mmol/l NH4HCO3); phase B: MeCN (20 to 80% in 12 min); Detector, UV 220 & 254 nm, producing title compound: 1H NMR (300 MHz, DMSO- _d6 ) δ 14.37 (s, 1H), 8.56 (s, 1H), 8.37 (dd, J =4.8, 1.5 Hz, 1H), 7.77-7.67 (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][1,4]oxazepin-3yl)-4H- 1,2,4-triazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: SunFire Prep C18 OBD 19x150 mm 5 µm 10 nm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 75% B in 7 minutes; UV 254 & 220 nm; Rt: 6.34 min: 1H NMR (400 MHz, DMSO-d ₆ ) 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.

Example 164. (S)-5-(3-Cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)thiazol-2 -carboxamide.

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Step 1. Preparation of ethyl 5-(bromomethyl)thiazole-2carboxylate.

Benzoyl peroxide (6 mg, 0.02 mmol) was added to a mixture of ethyl 5-methylthiazole-2-carboxylate (420 mg, 2.45 mmol) and N-bromosuccinimide (459 mg, 2.58 mmol) in carbon tetrachloride (6 ml ). The resulting mixture was stirred overnight at 75°C under nitrogen, quenched by adding water (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to give 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. Preparation of 5-(3-cyanobenzyl)thiazole-2carboxylic acid.

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. The resulting mixture was stirred for 2 hours at 90°C. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The precipitate was diluted with water (30 ml), the resulting solution was adjusted to pH 3 with aqueous hydrochloric acid (1 M, 50 ml, 50 mmol) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give the title compound (100 mg, 34.1%) as a yellow oil. LC-MS (method C): m/z=245.2 [M+H] ⁺ , 1.208 min.

Step 3. Preparation of (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) thiazole-2-carboxamide.

The crude product obtained from the amine coupling procedure B was purified by Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 65% B in 7 minutes; UV 254 & 220 nm; Rt: 6.5 min, giving the title compound: ¹ H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J=8.0 Hz, 1H), 7.93-7.90 (m, 1H), 7.84-7.80 (m, 1H), 7.78-7.71 (m, 1H), 7.70-7.63 (m, 1H), 7.62-7.44 ( m, 2H), 7.40-7.20 (m, 3H), 4.88-4.75 (m, 1H), 4.73-4.60 (m, 1H), 4.48-4, 37 (m, 1H), 4.34 (s, 2H), 3.30 (s, 3H). LC-MS (Method V): m/z=419.2 [M+H] ⁺ , 3.361 min.

Example 165. (S)-1-Benzyl-5-fluoro-N-(5-methyl-4-okCO-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin3-yl )-1H-pyrazole-3-carboxamide.

Stage 3

Stage 1. Preparation of 5-fluoro-1H-pyrazole-3-carboxylic acid.

A solution of sodium hydroxide (2 M, 0.63 mL, 1.26 mmol) was added to a stirred mixture of ethyl 5fluoro-1H-pyrazole-3-carboxylate (100 mg, 0.63 mmol) in methanol (5 mL). The reaction mixture was stirred at room temperature overnight. After removing the methanol under reduced pressure, the resulting solution was adjusted to pH=5 with aqueous hydrochloric acid (1N, 2 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated

- 186 044271 under vacuum to obtain the title compound (80 mg, 97%) as a white solid. 1H

NMR (300 MHz, DMSO-d ₆ ) δ 13.67 (s, 1H), δ 13.49 (s, 1H), δ 6.47 (dd, J=6.3, 2.2 Hz, 1H) .

Step 2. Preparation of (S)-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydronirido[3,2-b][1,4] oxazepin3 -yl)-1 N-pyrazole-3-carboxamide.

The crude product obtained by the amine coupling procedure C was purified by column chromatography (methanol/dichloromethane, 1/10) to give 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. Preparation of (S)-1-benzyl-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydronirudo[3,2-b][1,4]oxazepine- 3 -yl)-1 H-pyrazol-3-carboxamide.

The crude product obtained using the procedure described in Example 158, step 4, was purified using Prep-HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 μm, 19x150 mm; Mobile phase: phase A: Water (0.05% TFA), phase B: MeCN; flow rate: 20 ml/min; gradient: from 25% B to 55% B in 7 minutes; Detector, UV 254 & 220 nm, producing title compound: 1H NMR (300 MHz, CD ₃ OD-d ₄ ) 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 ]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide.

The crude product obtained using the procedure described in Example 158, step 4, was purified using Prep-HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 μm, 19x150 mm; mobile phase A: Water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 5% B to 55% B in 7 minutes; Detector, UV 254 & 220 nm, producing title compound: 1H NMR (300 MHz, CD ₃ OD-d ₄ ) 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 ]oxazepin-3-yl)-1 H-pyrazole-3-carboxamide.

The crude product obtained using the procedure described in example 158, step 4, was purified using Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 μm, 19x150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ); mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 25% B to 55% B in 7 minutes; UV 254 & 220 nm; Rt: 6.32 min, giving the title compound: 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (d, J=7.9 Hz, 1H), 8.36 (dd, J=4, 7, 1.6 Hz, 1H), 7.877.82 (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 -b][1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide.

5-(Bromomethyl)nicotinonitrile (35 mg, 0.18 mmol) was added to the stirred mixture of (S)-4-fluoro-N(5-methyl-4-oxo-2,3,4,5-tetrahydronirudo[3,2 -b][1,4]oxazenun-3-ul)-1H-pyrazole-3-carboxamide (45 mg, 0.15 mmol) and potassium carbonate (62 mg, 0.45 mmol) in N,N-dimethylformamide ( 4 ml). The resulting mixture was stirred at room temperature for 3 hours, diluted with water (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product obtained using the procedure described in Example 158, Step 4 was purified using

- 187 044271

Pre-HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19x150 mm; mobile phase A: Water (10 mmol/l NH4HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35% B to 50% B in 7 minutes; UV 254 & 220 nm; Rt: 6.5 min, giving the title compound: 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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, J=2.0 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 7.68 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (dd, J=8.0, 4.8 Hz, 1H), 5.48 (s, 2H), 5.02 (dd, J=11.5, 7.2 Hz, 1H), 4.69 (dd, J=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.

Example 169 (S)-5-Benzyl-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)- 4H-1,2,4-triazole-3-carboxamide.

Stage 1 Stage 2

Stage 3

Step 1. Preparation of (B)-tert-butyl-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)carbamate.

Trideuterated iodomethane (233.5 mg, 1.61 mmol) was added to the stirred mixture of (S)-tertbugyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin- 3-ylcarbamate (450 mg, 1.61 mmol) and cesium 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 (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 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. Preparation of (S)-3-amino-5-trideuteriomethyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride.

(S)-tert-butyl-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (200 mg, 0 .68 mmol) was added to a solution of the hydrochloride in 1,4-dioxane (4 M, 5 ml, 20 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo to give 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. Preparation of (S)-5-benzyl-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-4H -1,2,4-triazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: Water (10 mmol/l NH4CO3), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 25% B to 50% B in 7 minutes; Detector, UV 254 & 220 nm, producing title compound: ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.33 (dd, J=4.8, 1.6 Hz, 1H), 7, 66 (dd, J=8.0, 1.6 Hz, 1H), 7.38-7.22 (m, 6H), 5.02 (dd, J=11.6, 7.2 Hz, 1H) , 4.67 (dd, J=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. 1-(3-Cyanobenzyl)-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepine -2-yl)-4-fluoro-1 H-pyrazole-3-carboxamide and 1 -(3-cyanobenzyl)-N((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a ,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4-fluoro-1Hpyrazole-3-carboxamide.

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The crude product obtained using the amine coupling technique C was purified using Rev. TLC (ethyl acetate/petroleum ether, 3/1) gave the title compound as a white solid.

The racemate was separated using Rev. chiral HPLC under the following conditions: column:

(R,R)WHELK-O1 5/100 Kromasil, 2.11 cm x 25 cm (5 µm); mobile phase A: Hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 60% B to 60% B in 22 minutes; UV 254 & 220 nm; Rt 1: 14.06; Rt 2: 18.79, obtaining title compounds:

example 170A (first eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d 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;

example 170B (second eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 7.88 (d, J=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.

Example 171 )-1H-1,2,4-triazole-3-carboxamide.

Step 1. Preparation of methyl 1-(3-cyanobenzyl)-1H-1,2,4-triazole-3-carboxylate.

Sodium hydride (60%, 0.38 g, 9.5 mmol) was added to a stirred mixture of methyl 1H-1,2,4triazole-3-carboxylate (1.0 g, 7.87 mmol) in X,X-dimethylformamide (20 ml). The resulting mixture was stirred for 1 hour at room temperature, 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 temperature, diluted with water (30 ml) and extracted with dichloromethane (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give 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. Preparation of 1-(3-cyanobenzyl)-1H-1,2,4-triazole-3-carboxylic acid.

A solution of lithium hydroxide (360 mg, 15.0 mmol) in water (10 ml) was added to a stirred mixture of 1-(3-cyanobenzyl)-1H-1,2,4-triazole-3-carboxylate (600 mg, 2.48 mmol) in tetrahydrofuran (20 ml). The reaction mixture was stirred at room temperature for 2 hours. After removing the tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH=7 with aqueous hydrochloric acid (1N, 10 ml), and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (250 mg, 17.7%) in

- 189 044271 in the form of a white solid substance. LC-MS (method X): m/z=229.1 [M+H]+, 1.227 min.

Step 3. Preparation of (S)-1-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-3 - yl)-1 H-1,2,4-triazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD 19x150 mm 5 µm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 20% B to 45% B in 7 minutes; 254 nm; Rt: 6 min, giving the title compound: 1H NMR (400 MHz, CD3OD-d4) δ 8.64 (s, 1H), 8.33 (dd, J=4.8, 1.6 Hz, 1H), 7.77-7.64 (m, 4H), 7.57 (t, J=7.7 Hz, 1H), 7.30 (dd, J=8.0, 4.8 Hz, 1H), 5 .55 (s, 2H), 5.03 (dd, J=11.7, 7.3 Hz, 1H), 4.69 (dd, J=9.9, 7.1 Hz, 1H), 4, 52 (dd, J=11.2, 9.6 Hz, 1H), 3.47 (s, 3H). LC-MS (method D): m/z=404.2 [M+H] ⁺ , 1.371 min.

Example 172 -3 -yl)-1 H-1,2,4-triazol-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19x150 mm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 25% B to 75% B in 7 minutes; 254 nm; Rt: 6.25 min, giving the title compound: 1H NMR (300 MHz, CD3OD-d4) δ 8.66 (s, 1H), 8.33 (dd, J=4.8, 1.6 Hz, 1H ), 7.78-7.65 (m, 4H), 7.57 (t, J=7.8 Hz, 1H), 7.32 (dd, J=8.0, 4.8 Hz, 1H) , 5.56 (s, 2H), 5.07-5.01 (m, 2H), 3.49 (s, 3H), 1.38 (d, J=5.9 Hz, 3H). LC-MS (method D): m/z=418.2 [M+H] ⁺ , 1.477 min.

Example 173 )-1,3,4-oxadiazole-2-carboxamide.

The crude product obtained using the procedure described in example 54 was purified using Prep-HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 μm, 19x150 mm; Mobile phase: phase A: Water (10 mmol/l NH4HCO3), phase B: MeCN; flow rate: 20 ml/min; gradient: from 25% B to 50% B in 7 minutes; Detector, UV 254 nm, producing the title compound: 1H NMR (300 MHz, DMSO-d6) δ 9.49 (d, J=7.6 Hz, 1H), 8.36 (dd, J=4.7, 1.6 Hz, 1H), 7.70 (dd, J=8.0, 1.6 Hz, 1H), 7.507.28 (m, 6H), 4.87-4.62 (m, 2H), 4.50 (dd, J=9.3, 7.1 Hz, 1H), 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.

Example 174 -yl)-1,3,4-oxadiazol-2-carboxamide.

Stage 1 Stage 2

Stage 3

Step 1. Preparation of tert-butyl-((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine- 3-yl)carbamate.

Trideuterated iodomethane (124 mg, 0.85 mmol) was added to the stirred mixture of tert-butyl-(2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1, 4]oxazepin-3-ylcarbamate (250 mg, 0.85 mmol) and cesium carbonate (278 mg, 0.85 mmol) in X,X-dimethylformamide (30 ml). Reactionary

- 190 044271 the mixture was stirred at room temperature for 5 hours, diluted with water (20 ml) and extracted with ethyl acetate (3x100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to give 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. Preparation of (2R,3S)-3-amino-2-methyl-5-trideuterated methyl-2,3dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride.

Tert-butyl((2R,3S)-2-methyl-5-mrideuteriomethyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1,4]oxazepin3-yl)carbamate (100 mg, 0.32 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4N, 6.0 ml, 24 mmol). The reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo to give 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. Preparation of 5-benzyl-N-((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4] Oxazepin-3-yl)-1,3,4-oxadiazol-2-carboxamide.

The crude product obtained using the procedure described in example 54 was purified using Prep-HPLC under the following conditions: column: XBridge Prep OBD C18 19x250 mm, 5 μm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 25% B to 75% B in 7 minutes; UV 254 & 220 nm; Rt: 6.85 min, giving the title compound: ¹ H NMR (400 MHz, DMSO-d 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 -yl)-1 H-pyrazole-3-carboxamide.

The crude product obtained by the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19x150 mm; Mobile phase: phase A: Water (10 mmol/l NH4HCO3), phase B: MeCN; flow rate: 20 ml/min; gradient: from 25% B to 65% B in 7 minutes; Detector, UV 254 nm, producing the title compound: 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.32 (dd, J=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 2-yl)-4H-1,2,4-triazol-3-carboxamide.

The crude product obtained by the Amine C coupling procedure was purified using Prep-HPLC under the following conditions: Column: Column: XBridge Prep OBD C18 30x150mm 5 µm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: MeCN; flow rate: 60 ml/min; gradient: from 25% B to 55% B in 7 minutes; 254 nm; Rt: 6.32 min, giving the title compound: 1H NMR (400 MHz, DMSO-d6) 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, 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). LC-MS (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,8,8a-hexahydrocycloprona[d]pyrazino[2,3-b]azepine-7 -yl)-1,3,4-oxadiazol-2-carboxamide and 5-benzyl-N-((7R,7aR,8aS)-5-methyl-6oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d]pyrazino[2,3-b]azenin-7-yl)-1,3,4-oxadiazole-2-carboxamide.

- 191 044271

Stage 2

The crude product obtained using the procedure described in example 54 was purified using Rev. TLC (ethyl acetate/petroleum ether, 3/1) gave the title compound as a white solid.

Racemate 5-benzyl-N-(cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazuno[2,3-b]azepin7-yl)-1,3 ,4-oxadiazole-2-carboxamide (40 mg, 0.10 mmol) was separated using rep. chiral

HPLC under the following conditions: column: CHIRAL ART Cellulose-SB S-5 µm, 250x20 mm, 5 µm; mobile phase A: Hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 50% B to

50% B in 26 min; 220/254 nm; Rt 1: 19.32; Rt 2: 23.55 to obtain title compounds:

example 177A (first eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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) , 1.55-1.48 (m, 1H), 1.35-1.30 (m, 1H). LCMS (method D): m/z=391.1 [M+H]+, 1.231 min;

example 177B (second eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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), 1.54-1.46 (m, 1H), 1.34-1.28 (m, 1H). LC-MS (method D): m/z=391.1 [M+H]+, 1.225 min.

Example 178A and 178B. (S)-4-Fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5Hnyrazino[2,3-b]azepin-7-yl )-1H-pyrazole-3-carboxamide and (R)-4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6oxo-6,7,8,9-tetrahydro-5H-pyrazino[2 ,3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide.

N NHo n^.NH ₂ ~ .. Η /P < Ж ² О А 4^ 9 А1Ме ₃ in toluene

Pd(PPh ₃ ) ₄ , THF, 70°C, during. ~*Id)

N Br ^{v 074} _nights ^1X1 CT, during. nights J

Stage 1 Stage 2

Step 1. Preparation of ethyl 4-(3-aminopyrazin-2-yl)butanoate.

A solution of (4-ethoxy-4-oxobutyl)zinc(P) 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 tetrahydrofuran (60 ml) under a nitrogen atmosphere. The resulting mixture was stirred overnight at 70°C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give the title compound (0.45 g, 37.0%) as a light yellow

- 192 044271 oil. LC-MS (method S): m/z=210.2 [M+H]+, 0.592 min.

Step 2. Preparation of 8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one.

A solution of trimethylaluminum in toluene (2 M, 6.0 ml, 12.0 mmol) was added to a stirred mixture of ethyl 4-(3-aminopyrazin-2-yl)butanoate (450 mg, 2.2 mmol) in toluene (20 ml ). After stirring overnight at room temperature, the reaction mixture was quenched by adding 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 under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give the title compound (0.32 g, 91.0%) as a light yellow solid. LCMS (method S): m/z=164.2 [M+H] ⁺ , 0.473 min.

Step 3. Preparation of 5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one.

Pometan (313 mg, 2.2 mmol) was added dropwise to a stirred mixture of 8,9-dihydro-5Hpyrazino[2,3-b]azepin-6(7H)-one (320 mg, 2.0 mmol) and cesium carbonate (717 mg, 2.2 mmol) in N,Ndimethylformamide (15 ml). After stirring overnight at room temperature, the reaction mixture was 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 reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to give the title compound (300 mg, 87.0%) as a light yellow solid. LC-MS (method S): m/z=178.1 [M+H] ⁺ , 0.570 min.

Step 4. Preparation of 7-iodo-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one.

To a mixture of 5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one (300 mg, 1.70 mmol) and N,N,N',N'tetramethylethylenediamine (1.97 g, 17.0 mmol) in dichloromethane (80 ml) at 0°C, iodotrimethylsilane (2.38 g, 17.0 mmol) was added dropwise over 30 min. 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 temperature, the reaction mixture was quenched by adding aqueous sodium thiosulfate (5%, 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 reduced pressure to give the title compound (450 mg, crude, 87.7%) as a yellow oil. LC-MS (method S): m/z=304.1 [M+H] ⁺ , 0.610 min.

Step 5. Preparation of 7-azido-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one.

Sodium azide (290 mg, 4.47 mmol) was added to a stirred mixture of 7-iodo-5-methyl-8,9-dihydro-5Hpyrazino[2,3-b]azepin-6(7H)-one (450 mg, 1 .49 mmol) in N,N-dimethylformamide (50 ml). After stirring at room temperature for 3 hours, the reaction mixture was quenched by adding 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 in vacuo to give the title compound (260 mg, crude) as a yellow oil. LC-MS (method S): m/z=219.1 [M+H] ⁺ , 0.600 min.

Step 6. Preparation of 7-amino-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one.

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 palladium catalyst on a carbon carrier (10%, 26 mg) in a hydrogen atmosphere (2-3 atm). After stirring for 5 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and dried under high vacuum to give the title compound (200 mg, 88%) as a colorless oil. LC-MS (method S): m/z=193.1 [M+H] ⁺ , 0.356 min.

Step 7. Preparation of 4-fluoro-1-(2-fluorobenzyl)<I-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5Hpyrazino[2,3-b]azepin-7-yl )-1H-pyrazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield C18 OBD, 5 µm, 19x150 mm; mobile phase A: Water (10 mmol/l ΝΗ ₄ №0 ₃ ), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 35% B to 50% B in 8 minutes; UV 254 & 220 nm; Rt: 6.82 min to give 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. Preparation of (S)-4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5Hpyrazino[2,3-b]azepine -7-yl)-1H-pyrazol-3-carboxamide and U)-4-fluoro-1-(2-fluorobenzyl)-I-(5-methyl-6oxo-6,7,8,9-tetrahydro-5H- pyrazino[2,3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide.

Racemate 4-fluoro-1-(2-fluorobenzyl)-I-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin7-yl)-1H -pyrazole-3-carboxamide (30.0 mg, 0.07 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAK IF, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 50% B to 50% B in 30 minutes; UV 254 & 220 nm; Rt 1: 17.00 min; Rt 2: 24.16 min, obtaining title compounds:

example 178A (first eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.48 (d, J=2.8 Hz, 1H),

- 193 044271

8.39 (d, J=2.8 Hz, 1H), 7.77 (d, J=4.4 Hz, 1H), 7.45-7.38 (m, 1H), 7.34-7 .29 (m, 1H), 7.24-7.15 (m, 2H), 5.41 (s,

2H), 4.58-4.52 (m, 1H), 3.50 (s, 3H), 3.18-3.08 (m, 1H), 3.04-2.98 (m, 1H) , 2.80-2.69 (m, 1H), 2.41-2.31 (m,

1h). LC-MS (method t): m/z=413.1 [M+H]+, 1.198 min;

example 178B (second eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.47 (d, J=2.8 Hz, 1H), 8.38 (d, J=2.8 Hz , 1H), 7.78 (d, J=4.4 Hz, 1H), 7.45-7.38 (m, 1H), 7.34-7.29 (m, 1H), 7.25- 7.15 (m, 2H), 5.41 (s, 2H), 4.58-4.52 (m, 1H), 3.50 (s, 3H), 3.19-3.08 (m, 1H), 3.05-2.98 (m, 1H), 2.81-2.69 (m, 1H), 2.41-2.32 (m, 1h). LC-MS (method X): m/z=413.1 [M+H]+, 2.354 min.

Example 179A and 179B. 4-Fluoro-1-(2-fluorobenzyl)-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8ahexahydrocyclonepropα[d]pyrazino[2,3 -b]αzenin-7-yl)-1H-pyrazol-3-carboxamide and 4-fluoro-1-(2-fluorobenzyl)N-((7R,7aR,8aS)-5-methyl-6-oxo-5, 6,7,7a,8,8a-exahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1Hpyrazole-3-carboxamide.

The crude product obtained using the amine coupling technique C was purified using Rev. TLC (ethyl acetate/petroleum ether, 3/1) gave the title compound as a white solid.

The racemate was separated using Rev. chiral HPLC under the following conditions: column: CHIRALPAK IF, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 50% B to 50% B in 38 minutes; UV 254 & 220 nm; Rt 1: 22.995; Rt 2: 30.882, obtaining title connections:

example 179A (first eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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;

example 179B (second eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d 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.

Example 180A and 180B. (S)-N-(5-Methyl-6-oxo-6,7,8,9-tetraαhydro-5H-πyrazino[2,3-b]azepin-7-yl)-5(1-phenylcyclopropyl)-1 ,3,4-oxadiazol-2-carboxamide and (R)-N-(5-methyl-6-oxo-6,7,8,9-tetraαhydro-5Hpyrazino[2,3-b]azepin-7-yl) -5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide.

The crude product obtained using the amine coupling technique C was purified using Rev. TLC (ethyl acetate/petroleum ether, 1/1) to give the title compound.

Racemate N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3 ,4-oxadiazole-2-carboxamide (30 mg, 0.08 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAK IE, 2x25 cm, 5 µm; mobile phase A: hexane,

- 194 044271 mobile phase B: MeOH; flow rate: 20 ml/min; gradient: from 100% B to 100% B in 16 minutes; UV

254 & 220 nm; Rt 1: 10.459 min; Rt 2: 12.463 min, obtaining title compounds:

example 180A (first eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.49 (d, J=2.4 Hz, 1H), 8.40 (d, J=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), 1.59-1.55 (m, 2H). LC-MS (method D): m/z=405.0 [M+H]+, 1.260 min;

example 180B (second eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.49 (d, J=2.4 Hz, 1H), 8.40 (d, J=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), 1.60-1.55 (m, 2H). LC-MS (method D): m/z=405.0 [M+H] ⁺ , 1.261 min.

Example 181A and 181B. 5-(3-Cyanobenzyl)-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepine -2-yl)-4H-1,2,4-triazole-3-carboxamide and 5-(3-cyanobenzyl)-N((1aS,2S,8bR)-5,7-difluoro-3-oxo-1, 1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4triazol-3-carboxamide.

Stage 1

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield C18 OBD, 5 µm, 19x150 mm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 30% B to 53% B in 8 minutes; 254 & 220 nm Rt: 7.43 min, giving the title compound as a white solid.

The racemate was separated using Rev. chiral HPLC under the following conditions: column: CHIRALPAK IE, 2x25 cm, 5 µm; mobile phase A: hexane:DCM=5:1, mobile phase B: EtOH; flow rate: 16 ml/min; gradient: from 50% B to 50% B in 23 minutes; 254 & 220 nm; Rt 1: 9.885; Rt 2: 16.633, obtaining title connections:

example 181A (first eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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+H] ⁺ , 1,200 min;

example 181B (second eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 7.70 (s, 1H), 7.66-7.62 (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) , 2.32-2.23 (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.

Example 182A and 182B. (R)-4-Fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin7-yl)-1-((2- methylpyridin-3-yl)methyl)-1H-pyrazol-3-carboxamide and (S)-4-fluoro-N-(5-methyl-6-oxo6,7,8,9-tetrahydro-5H-pyrazino[2, 3-b]αzepin-7-yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazol-3carboxamide.

Stage 1 Stage 2

Stage 3

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Step 1. Preparation of ethyl 4-fluoro-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxylate.

3-(Bromomethyl)-2-methylpyridine (283 mg, 1.52 mmol) was added to a stirred mixture of ethyl 4fluoro-1H-pyrazole-3-carboxylate (200 mg, 1.27 mmol) and cesium carbonate (1.24 g , 3.80 mmol) in N,Ndimethylformamide (20 ml). The reaction mixture was stirred at room temperature for 3 hours, quenched by adding water (100 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give 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. Preparation of 4-fluoro-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxylic acid.

Lithium hydroxide (82 mg, 3.42 mmol) was added to a mixture of ethyl 4-fluoro-1-((2-methyl pyridin-3yl)methyl)-1H-pyrazole-3-carboxylate (300 mg, 1.14 mmol) in tetrahydrofuran (12 ml) and water (4 ml). The reaction mixture was stirred at room temperature overnight. After removing the tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH=6 with aqueous hydrochloric acid (1N, 10 ml), and extracted with ethyl acetate (3x60 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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. Preparation of 4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)1-((2 -methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxamide.

The crude product obtained using the amine C coupling procedure was purified using Prep-HPLC under the following conditions: column: XBridge Shield C18 OBD, 5 µm, 19x150 mm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 20% B to 33% B in 8 minutes; UV 254 & 220 nm; Rt: 7.28 min, producing the title compound. LC-MS (Method Y): m/z=410.2 [M+H] ⁺ , 0.841 min.

Step 4. Preparation of (R)-4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)1 -((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxamide and (S)-4-fluoro-N-(5-methyl-6-oxo-6,7,8,9tetrahydro-5H -pyrazino[2,3-b]azepin-7-yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazol-3-carboxamide.

Racemate 4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1-((2methylpyridin-3 -yl)methyl)-1H-pyrazole-3-carboxamide (40 mg, 0.10 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 µm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 50 V% to 50 V% in 13 min; UV 254 & 220 nm; Rt 1: 9.428 min; Rt 2: 11.106 min, obtaining title compounds:

example 182A (first eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d 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;

example 182B (second eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.49 (d, J=2.8 Hz, 1H), 8.42-8.39 (m, 2H) , 7.80 (d, J=4.4 Hz, 1H), 7.52-7.48 (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.

Example 183A and 183B. 1-Benzyl-4-fluoro-N-((1aR,2R,8bS)-4-trideuteriomethyl-7-(methylsulfonyl)-3oxo-1,1 a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[ d]azepin-2-yl)-1H-pyrazol-3-carboxamide and 1-benzyl4-Φτορ-Ν-((1aS,2S,8bR)-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1, 1 a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamide.

- 196 044271

Step 1. Preparation of 7-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one.

A solution of bromine (8 ml, 155 mmol) in acetic acid (100 ml) was added dropwise to a solution of 4,5dihydro-1H-benzo[b]αzenin-2(3H)-one (10 g, 62 mmol) and sulfuric acid ( 5 ml) in acetic acid (100 ml) at 0°C. After stirring overnight at room temperature, the reaction mixture was poured into ice water (200 ml), neutralized with ammonium hydroxide (28%, 100 ml) and extracted with ethyl acetate (3x80 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 99/1) to give 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. Preparation of 7-bromo-1-trideuteriomethyl-4, 5-dihydro-1H-benzo[b]azepin-2(3H)-one.

Trideuterated iodomethane (5.9 g, 41 mmol) was added dropwise to a stirred mixture of 7bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (9 g, 38 mmol) and cesium carbonate ( 13.4 g, 41 mmol) in N,N-dimethylformamide (30 ml). The reaction mixture was stirred for 2 hours at room temperature, diluted with water (60 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to give 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. Preparation of 1-trideuteriomethyl-7-(methylsulfonyl)-4,5-dihydro-1H-benzo[L]azepin2(3I)-one.

Copper iodide (304 mg, 1.6 mmol) was added to a mixture of 7-bromo-1-trideuteriomethyl-4,5-dihydro-1Hbenzo[L]azepin-2(3I)-one (4.1 g, 16 mmol), L-proline (368 mg, 3.2 mmol), sodium hydroxide (64 mg, 1.6 mmol) and sodium methanesulfinate (8.16 g, 80 mmol) in dimethyl sulfoxide (20 ml) under nitrogen. The reaction mixture was stirred overnight at 120°C. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous ammonium chloride (40 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to give 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. Preparation of 3-iodo-1-trideuteriomethyl-7-(methylsulfonyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one.

N ¹ ,N ¹ ,N ² ,N ² -tetramethylethane-1,2-diamine (3.8 g, 33 mmol) was added to a stirred mixture of 1trideuteriomethyl-7-(methylsulfonyl)-4,5-dihydro-1H-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

- 197 044271 lyam for 30 min. 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 adding aqueous sodium thiosulfate (5%, 60 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane) to give 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. Preparation of 1-trideuterated methyl-7-(methylsulfonyl)-1H-benzo[b]azepin-2(3H)-one.

1,8-Diazabicyclo[5.4.0]undec-7-ene (3.8 g, 25.2 mmol) was added to the stirred mixture of 3-iodo-1trideuterated methyl-7-(methylsulfonyl)-4,5-dihydro-1H -benzo[b]azepin-2(3H)-one (3.2 g, 8.4 mmol) in N,N-dimethylformamide (10 ml) at room temperature. The reaction mixture was stirred overnight at 80°C, quenched by adding water (30 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane) to give 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. Preparation of 4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclonropa[d]azepin-3(4H)-one.

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 ester (100 ml) at 0°C. The resulting mixture was stirred for 1 hour at 0°C and then the organic phase was separated to obtain a solution of diazomethane in ester (100 ml). A solution of diazomethane (100 ml) was added dropwise to a mixture of 1-trideuteriomethyl-7(methylsulfonyl)-1H-benzo[b]azepin-2(3H)-one (1.8 g, 7 mmol) in tetrahydrofuran (30 ml), followed by adding 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 temperature. Solids were removed by filtration and the filtrate was concentrated in vacuo to give 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. Preparation of trans-2-iodo-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one.

N ¹ ,N ¹ ,N ² ,N ² -tetramethylethane-1,2-diamine (1.95 g, 16.8 mmol) was added to the stirred mixture of 4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2, 8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (1.5 g, 5.6 mmol) in dichloromethane (30 ml) at 0°C, followed by iodotrimethylsilane (3.4 g, 16.8 mmol) drop by drop 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 adding 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, filtered and concentrated in vacuo to give the title compound (1.6 g, crude) as a yellow oil. LC-MS (method S): m/z=394.9 [M+H] ⁺ , 0.892 min.

Step 8. Preparation of cis-2-azido-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8btetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one.

Sodium azide (390 mg, 6 mmol) was added to a stirred mixture of trans-2-iodo-4-trideuteriomethyl7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)- she (1.6 g, 4 mmol) in N,Ndimethylformamide (10 ml). The reaction mixture was stirred overnight at room temperature, quenched with water (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 in vacuo to give 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. Preparation of cis-2-amino-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one.

Solution of cis-2-azido-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclonropa[d]azepin-3(4H)-one (800 mg, 2.59 mmol) in methanol (30 ml) was hydrogenated in the presence of a palladium catalyst on a carbon carrier (10%, 100 mg) in a hydrogen atmosphere (2-3 atm). After stirring for 2 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (dichloromethane) to give 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. Preparation of 1-benzyl-4-fluoro-M-(cis-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepine -2-yl)-1H-pyrazole-3-carboxamide.

The crude product obtained using the amine coupling procedure C was purified using Prep-HPLC under the following conditions: column: Xbridge Prep C18, 5 µm, 19x150 mm; movable

- 198 044271 phase A: Water (0.1% NH4HCO ₃ ), mobile phase B: MeCN flow rate: 20 ml/min; gradient: from 32%

B up to 55% B in 8 minutes; 254 & 220 nm; Rt: 7.38 min, producing the title compound. LC-MS (method

E): m/z=486.1 [M+H]+, 1.037 min.

Step 11. Preparation of 1-benzyl-4-fluoro-N-((1aR,2R,8bS)-4-trideuteriomethyl-7-(methylsulfonyl)3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[ b]cyclopropa[d]azepin-2-yl)-1 H-pyrazol-3-carboxamide and 1benzyl-4-fluoro-N-((1aS,2S,8bR)-4-trideuteriomethyl-7-(methylsulfonyl)-3 -oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamide.

Racemate 1-benzyl-4-fluoro-N-(cis-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepine- 2-yl)-1H-pyrazole-3-carboxamide was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAKIA, 2.12x15 cm, 5 µm; mobile phase A: Hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 22 min; 254 & 220 nm; Rt 1: 10.61; Rt 2: 16.166, obtaining title compounds:

example 183A (first eluting isomer): ¹ H NMR (400 MHz, CD ₃ OD-d 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), 1.26-1.17 (m, 1H). LC-MS (Method V): m/z=486.1 [M+H] ⁺ , 3.132 min;

example 183B (second eluting isomer): 1H NMR (400 MHz, CD ₃ OD-d 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), 1.28-1.17 (m, 1H). LC-MS (method D): m/z=486.1 [M+H] ⁺ , 1.390 min.

Example 184 [3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide.

Cesium carbonate (453 mg, 1.39 mmol) was added to the stirred mixture of (S)-4-fluoro-N-(5-methyl-4oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide (100 mg, 0.33 mmol) and 4-(bromomethyl)-1-methyl-1H-pyrazole hydrochloride (208 mg, 0.82 mmol) in N,N-dimethylformamide (7 ml). After stirring for 3 hours at room temperature, the reaction mixture was quenched by adding water (50 ml) and extracted with dichloromethane (3x50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The precipitate was purified using Prep-HPLC under the following conditions: Column; Xbridge Prep C18, 5 µm, 19x150 mm; mobile phase A; Water (0.1 mmol/l NH ₄ HCO ₃ ), mobile phase B; MeCN; flow rate: 20 ml/min; gradient: from 15% B to 36% B in 10 minutes; UV 254 & 220 nm, giving title compound: 1H NMR (300 MHz, DMSO-d6) 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.

Example 188 carboxamide

Stage 1

The crude product was purified using St. TLC (ethyl acetate/hexane, 3/1) to give the racemate. LC-MS (method E): m/z=378.2 [M+H] ⁺ , 0.998 min. The racemate of 5-benzyl-N-(5-methyl-6-oxo-6,7,8,9tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)isoxazol-3-carboxamide was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAK IA, 2x25 cm, 5 µm; mobile phase A: Hexane: DCM=5:1, mobile phase B: EtOH; flow rate: 15 ml/min; gradient: from 50% B to 50% B in 20 minutes; UV 254 & 220 nm; Rt 1: 11.1; Rt 2: 15.01, obtaining the title compound as the first

- 199 044271 eluting isomer: 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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), 2.43-2.34 (m, 1H). LC-MS (method D): m/z=378.0 [M+H]+, 1.645 min.

Example 190 3,4-oxadiazole-2-carboxamide.

Stage 1

The precipitate was purified using St. TLC (ethyl acetate/hexane, 3/1) to give the racemate. LC-MS (method C): m/z=378.1 [M+H] ⁺ , 1.141 min. Racemate 5-benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5Hpyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazol-2 -carboxamide was separated using Rev. chiral HPLC under the following conditions: column: CHIRALPAK IA, 2x25 cm, 5 µm; mobile phase A: Hexane: DCM=5:1, mobile phase B: EtOH; flow rate: 15 ml/min; gradient: from 50% B to 50% B in 20 minutes; UV 254 & 220 nm; Rt 1: 11.1; Rt 2: 15.01, giving the title compound as the first eluting isomer: 1H NMR (400 MHz, CD3OD-d4) δ 8.46 (d, J=2.8 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.37-7.26 (m, 5H), 4.53 (dd, J=12.0, 7.6 Hz, 1H), 4.32 (s, 2H ), 3.48 (s, 3H), 3.18-3.06 (m, 1H), 3.03-2.97 (m, 1H), 2.73-2.62 (m, 1H), 2.49-2.39 (m, 1H). 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[3,2-b][1,4]oxazepin3-yl )oxazole-2-carboxamide.

The resulting crude product was purified by Prep-HPLC under the following conditions:

column: Xbridge Prep C18, 5 µm, 19x150 mm; mobile phase A: water (0.1% NH4HCO3), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 35% B to 66% B in 8 minutes; UV 254 & 220 nm; Rt: 6.98 min, producing the title compound. 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.34 (dd, J=4.8, 1.6 Hz, 1H), 7.69 (dd, J=8.0, 1.6 Hz , 1H), 7.38-7.22 (m, 6H), 7.04 (s, 1H), 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)-1,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin3-yl )-1,3,4-oxadiazole-2-carboxamide.

Stage 3

The crude product was purified using St. TLC (ethyl acetate/petroleum ether, 3/1) to give the title compound: 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.22-8.19 (m, 1H), 7.94-7.90 (m, 1H), 7.43-7.39 (m, 1H), 7.35-7.26 (m, 5H), 5.14-5.07 (m, 2H), 4.31 (s , 2H), 3.44 (s, 3H), 1.45 (d, J=6.0 Hz, 3H). LCMS (Method T): m/z=394.1 [M+H] ⁺ , 1.202 min.

Example 194 azepin-7-yl)oxazol-2-carboxamide.

- 200 044271

Stage 1

The crude product was purified using St. TLC (ethyl acetate/petroleum ether, 3/1) to give the racemate. LC-MS (method E): m/z=390.2 [M+H]+, 1.018 min. 5-Benzyl-N-cis-5-methyl-6oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-oxazol-2-racemate carboxamideα (50 mg, 0.13 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 µm; mobile phase A: MTBE, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 30 V to 30 V in 15 minutes; UV 254 & 220 nm; Rt 1: 7.635; Rt 2: 9.685 to give the title compound as the first eluting isomer: 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.45-8.40 (m, 2H), 7.39-7.23 (m , 5H), 7.04 (s, 1H), 4.77 (s, 1H), 4.14 (s, 2H), 3.42 (s, 3H), 2.67-2.59 (m, 1H), 2.28-2.20 (m, 1H), 1.57-1.50 (m, 1H), 1.37-1.28 (m, 1H). LC-MS (method D): m/z=390.1 [M+H] ⁺ , 1.361 min.

Example 195. 1-Benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b] azepin-7-yl)-1H-1,2,3-triazol-4-carboxamide.

Stage 1

The crude product was purified using St. TLC (ethyl acetate/hexane, 3/1) to give the racemate. LC-MS (method E): m/z=390.2 [M+H] ⁺ , 0.932 min. Racemate 3-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8αhexahydro-cyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1H- 1,2,3-triazole-2-carboxamide (50 mg, 0.129 mmol) was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAKIA, 2.12x15 cm, 5 µm; mobile phase A: Hexane, mobile phase B: IPA; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 20 minutes; UV 254 & 220 nm; Rt 1: 11.273; Rt 2: 15.609, giving the title compound as the first eluting isomer: 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.42-8.38 (m, 3H), 7.41-7.32 ( 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,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b] azepin-7-yl)isoxazol-3-carboxamide.

Stage 1

The crude product was purified using St. TLC (ethyl acetate/hexane, 3/1) to give the racemate. LC-MS (method E): m/z=390.2 [M+H] ⁺ , 1.072 min. Racemate 5-benzyl-N-cis-5-methyl-6-oxo5,6,7,7a,8,8a-hexahydro-cyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-isoxazol- 2-carboxamide was separated

- 201 044271 with the help of Rev. chiral HPLC under the following conditions: column: CHIRALPAK IA, 2x25 cm, 5 µm; mobile phase A: hexane:DCM = 5:1, mobile phase B: EtOH; flow rate: 15 ml/min; gradient: from 50% B to 50% B in 24 minutes; UV 254 & 220 nm; Rt 1: 15.4; Rt 2: 19.4, giving the title compound as the first eluting isomer: 1H NMR (400 MHz, CD3OD-d 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.

Example 198. 5-Benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b] azepin-7-yl)-1,3,4-thiadiazol-2-carboxamide.

chiral separation

Stage 2

The crude product was purified using St. TLC (ethyl acetate/hexane, 3/1) to give the racemate. LC-MS (method E): m/z=407.1 [M+H] ⁺ , 1.017 min.

Racemate 5-benzyl-N-(cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3b]azepin-7-yl)-1,3 ,4-thiadiazole-2-carboxamide was separated using Rev. chiral HPLC under the following conditions: column: Chiralpak ID-2, 2x25 cm, 5 µm; mobile phase A: MTBE, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 30% B to 30% B in 26 minutes; UV 254 & 220 nm; Rt 1: 19.418; Rt 2: 22.874, giving the title compound as the first eluting isomer: 1H NMR (400 MHz, CD3OD-d ₄ ) δ 8.41-8.37 (m, 2H), 7.38-7.26 (m, 5H), 4.77 (s, 1H), 4.51 (s, 2H), 3.48 (s, 3H), 2.652.58 (m, 1H), 2.28-2.22 (m, 1H ), 1.56-1.50 (m, 1H), 1.34-1.27 (m, 1H). LC-MS (method D): m/z=407.1 [M+H] ⁺ , 1.680 min.

Example 200. (S)-5-Benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl) 1,3,4-oxadiazole-2-carboxamide.

Stage 1

The crude product was purified using St. TLC (ethyl acetate/petroleum ether, 3/1) to give the racemate. LC-MS (method D): m/z=398.10 [M+H] ⁺ , 1.284 min. 5-Benzyl-N-(2,4dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azenin-6-yl)-1,3,4-oxadiazole racemate -2-carboxamide was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAK IA, 2.12x15 cm, 5 µm; mobile phase A: Hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 13 minutes; UV 220 & 254 nm; Rt 1: 7.88; Rt 2: 10.109, giving the title compound as the first eluting isomer: 1H NMR (400 MHz, CD ₃ OD-d ₄ ) 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] ⁺ , 1.283 min.

Example 201. (S)-1-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)1H -1,2,3-triazole-4-carboxamide.

The crude product was purified by column chromatography (ethyl acetate/petroleum

- 202 044271 ether, 2/1) to obtain the title compound: 1H NMR (400 MHz, CD3OD-d ₄ ) 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 min.

Example 203. 1 -Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3yl )- 1H-1,2,3-triazole-4-carboxamide.

The crude product was purified by Prep-HPLC under the following column conditions:

Xbridge Prep C18, 5 µm, 19x150 mm; mobile phase A: Water (0.1% NH4HCO3), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 25% B to 66% B in 8 minutes; UV 254 & 220 nm; Rt: 6.68 min, producing the title compound. ¹ H NMR (300 MHz, CD ₃ OD-d ₄ ) 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). LC-MS (method Q): m/z=393.2 [M+H] ⁺ , 1.354 min.

Example 204. 2-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3yl )-2H-1,2,3-triazole-4-carboxamide.

The crude product was purified by Prep-HPLC under the following column conditions:

Xbridge Prep C18, 5 µm, 19x150 mm; mobile phase A: Water (0.1% NH4HCO3), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 35% B to 72% B in 8 minutes; UV 254 & 220 nm; Rt: 5.95 min, producing the title compound. 1H NMR (300 MHz, CD ₃ OD-d ₄ ) 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. 1 - Benzyl-N-((3S,4R)-1-trideuteriomethyl-4-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3b][1,4]oxazepine-3 -yl)-4-fluoro-1H-pyrazole-3-carboxamide.

SOCI ₂ (1EQ.), DMF

MeOH, CT, 5 h

Stage 3

Stage 4

A1Me ₃ in toluene

60°C during nights

Cs ₂ CO ₃ , CD ₃ DMF

0°C before RT, during nights

Stage 5

- 203 044271

EDCI, HOBT, DIEA, dmfa

KT, during nights Stage 7

D ₃ C

The crude product was purified by Prep-HPLC under the following conditions: column: Kinetex 5 µm EVO C18 OBD, 21.2x150 mm, 5 µm; mobile phase A: Water (0.1% formic acid), mobile phase B: MeCN; flow rate: 25 ml/min; gradient: from 30% B to 60% B in 8 minutes; UV 254 & 220 nm; Rt: 7.52 min, giving the title compound: 1H NMR (400 MHz, CD ₃ OD-d 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 d]azepine-2-ul)-4-fluoro-1H-pyrazole-3-carboxamide.

TMEDA, TMSI, I,

Zn CN ) ₂ , Pd(PPh ₃ Π

DMF, MB, 140 C, 3 h

2) Pd(OAc) ₂ , tHF, oh, 1 h

DM.FA, CT, incl. nights

EDCI, HOBT,

The crude product was purified using St. TLC (ethyl acetate/hexane, 3/1) to give the racemate. LC-MS (method C): m/z=433.1 [M+H]+, 1.078 min. Racemate 1-benzyl-A(cis-7-cyano-4trideuteriomethyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-ul)-4-fluoro- 1H-pyrazole3-carboxamide was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAKIA, 2.12x15 cm, 5 µm; mobile phase A: Hexane, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 50% B to 50% B in 18 minutes; UV 254 & 220 nm; Rt 1: 8.283; Rt 2: 14.011, giving the title compound as the second eluting isomer: 1H NMR (400 MHz, DMSO-dg) 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),

- 204 044271

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 1(oxazol-4-ylmethyl)-1H-pyrazol-3-carboxamide.

The crude product was purified by Prep-HPLC under the following conditions: column: Xbridge Prep C18; 19x150 mm; 5 µm; mobile phase A: Water (0.1% NH ₄ HCO ₃ ), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 21% B to 25% B in 10 minutes; UV 254 & 220 nm, giving the title compound: 1H NMR (300 MHz, DMSO-d ₆ ) 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 Hz, 1H), 8.04 (d, J=4 .5 Hz, 1H), 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.

Example 213 -ylmethyl)thiazol-2-car boxamide.

The title compound was prepared according to the methods described herein using suitable starting material. The crude product was purified using St. TLC (ethyl acetate/petroleum ether, 3/1) to give the title compound: 1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.51-8.48 (m, 1H), 8.33 (dd, J =4.8, 1.6 Hz, 1H), 7.84-7.77 (m, 2H), 7.66 (dd, J=8.0, 1.6 Hz, 1H), 7.44- 7.38 (m, 1H), 7.34-7.27 (m, 2H), 4.97 (dd, J=11.5, 7.2 Hz, 1H), 4.67 (dd, J= 9.9, 7.2 Hz, 1H), 4.52 (dd, J=11.5, 9.9 Hz, 1H), 4.40 (s, 2H), 3.47 (s, 3H). LC-MS (method D): m/z=396.0 [M+H] ⁺ , 1.786 min.

Example 214 1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide.

The crude product was purified by Prep-HPLC under the following conditions: column: Gemini-NX/5u, C18 150x21.2 mm; mobile phase A: Water (10 mmol/L NH4HCO3), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 45% B to 50% B in 8 minutes; UV 254 & 220 nm; Rt: 7.33, giving the title compound: 1H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 8.45 (d, J=3.0 Hz, 1H), 7.84 (d, J=4 .5 Hz, 1H), 7.65-7.58 (m, 1H), 7.44-7.20 (m, 5H), 5.43 (s, 2H), 4.97 (dd, J= 11.4, 7.5 Hz, 1H), 4.56 (dd, J=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-tetraαhydropyrido[3,2-b][1,4]oxazepin-3-yl) ,2,4-oxadiazole-3-carboxamide.

- 205 044271

CT scan, during nights

The precipitate was purified using Prep-HPLC under the following conditions: column: Xbridge Prep C18, 5 µm, 19x150 mm; mobile phase A: Water (0.1% NH4HCO ₃ ), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 30% B to 60% B in 8 minutes; UV 254 & 220 nm; Rt: 6.65 min, giving the title compound: ¹ H NMR (300 MHz, CD ₃ OD-d4) 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 1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide.

Stage 1

Stage 2 Stage 3

The precipitate was purified using Prep-HPLC under the following conditions: column: Gemini-NX/5u, C18

150x21.2 mm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 40% B to 55% B in 8 minutes; UV 254 & 220 nm; Rt: 6.73 min, giving the title compound: ¹ H NMR (300 MHz, CD ₃ OD-d ₄ ) 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, J=11.4, 7.5 Hz, 1H), 4.54 (dd, J=9.9, 7.5 Hz, 1H), 4.34 (dd, J=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-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3yl )-1,3,4-thiadiazole-2-carboxamide.

The crude product obtained using the amine coupling procedure C was purified using Prep-HPLC under the following conditions: column: Gemini-NX/5u, C18 150x21.2 mm; mobile phase A: Water (10 mmol/L NH4HCO3), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 55% B to 80% B in 6 minutes; UV 254 & 220 nm; Rt: 4.60 min, obtaining the title compound. 1H NMR (300

MHz, CD ₃ OD-d4) 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, J=6.0 Hz, 3H). LC-MS (method D): m/z=410.0 [M+H] ⁺ , 1.725 min.

Example 218 ,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide.

- 206 044271

The crude product was purified using St. TLC (ethyl acetate/hexane, 3/1) to give the racemate. LC-MS (method D): m/z=414.1 [M+H]+, 1.222 min. Racemate 3-benzyl-N-(cis-7-cyano-4-methyl-3oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl) -4H-1,2,4-triazole-3-carboxamide was separated using rep. chiral HPLC under the following conditions: column: CHIRAL ART Cellu lose-SB, 2x25 cm, 5 µm; mobile phase A: MTBE, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 20% B to 20% B in 16 minutes; UV 254 & 220 nm; Rt 1: 7.89; Rt 2: 8.598, giving the title compound as the second eluting isomer: Ή NMR (400 MHz, CD ₃ OD-d ₄ ) 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) , 2.40-2.33 (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 thiazol-2-carboxamide.

The crude product obtained using the amine coupling technique C was purified using Rev. TLC (ethyl acetate/petroleum ether, 3/1) to give the racemate. LC-MS (method S): m/z=418.1 [M+H] ⁺ , 1.025 min. Racemate 5-(3-cyanobenzyl)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H

- 207 044271 pyrido[2,3-b]azepin-7-yl)thiazol-2-carboxamide was separated using Rev. chiral HPLC under the following conditions: column: (R,R)Whelk-O1, 21.1x250 mm, 5 µm; mobile phase a: hexane:dichloromethane = 4.5:1, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 70% B to 70% B in 23 min; UV 254 & 220 nm; Rt 1: 12.88; Rt 2: 18.81 to give the title compound as the first eluting isomer: ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) 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), 4.524.46 (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-1-((6-methoxypyridin-2-yl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-1 H-pyrazole-3-carboxamide.

Stage 1 Stage 2

The crude product was purified by Prep-HPLC under the following conditions: column: Gemini-NX/5u, C18 150x21.2 mm; mobile phase A: Water (10 mmol/L NH4HCO3), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 40% B to 50% B in 8 minutes; UV 254 & 220 nm; Rt: 8.07 min, producing the title compound. 1H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 7.85 (d, J=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.

Example 221 ]oxazepin-3-ul)-1,3,4-oxαdiazole-2-carboxamide.

Stage 1 Stage 2

Stage 3

The crude product was purified by Prep-HPLC under the following conditions: column: Gemini-NX/5u, C18 150x21.2 mm; mobile phase A: Water (10 mmol/L NH4HCO3), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 47% B to 60% B in 10 minutes; UV 254 & 220 nm; Rt: 8.82 min, producing the title compound. 1H NMR (300 MHz, CD ₃ OD-d 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, J=8.1, 4.8 Hz, 1H), 5.08-4.93 (m, 2H), 3.50 (s, 3H ), 1.44 (d, J=6.3 Hz, 3H). LC-MS (method O): m/z=430.1 [M+H] ⁺ , 1.679 min.

Example 222 5-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3yl )-1,2,4-oxadiazole-3-carboxamide.

The crude product was purified by Prep-HPLC under the following column conditions:

Xbridge Prep C18, 5 µm, 19x150 mm; mobile phase A: Water (0.1% NH4HCO3), mobile phase B:

- 208 044271

MeCN; flow rate: 20 ml/min; gradient: from 40% B to 70% B in 8 minutes; UV 254 & 220 nm; Rt: 5.87 min, producing the title compound. 1H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 8.35-8.31 (m, 1H), 7.71-7.66 (m, 1H), 7.41-7.27 (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.

Example 223 3-b]azepin-7-yl)-1,3,4-oxadiazol-2-carboxamide.

The crude product was purified using St. TLC (ethyl acetate/petroleum ether, 3/1) to give the racemate. LC-MS (method D): m/z=409.05 [M+H] ⁺ , 1.255 min. Racemate 5-(4-fluorobenzyl)-N-cis5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)- 1,3,4-oxadiazole-2carboxamide was separated using rep. chiral HPLC under the following conditions: column: CHIRALPAK IE, 2x25 cm, 5 µm; mobile phase A: MTBE, mobile phase B: EtOH; flow rate: 20 ml/min; gradient: from 30% B to 30% B in 16 minutes; UV 254 & 220 nm; Rt 1: 10.514; Rt 2: 13.482, giving the title compound as the first eluting isomer: 1H NMR (400 MHz, CDCl ₃ -d) δ 8.498.32 (m, 3H), 7.39-7.28 (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 V): m/z=409.05 [M+H] ⁺ , 2.450 min.

Example 224 2-ylmethyl)-1 H-pyrazol-3-carboxamide.

The crude product was purified using St. HPLC under the following conditions: column: Xbridge Prep C18, 5 µm, 19x150 mm; mobile phase A: water (0.1% NH4HCO3), mobile phase B: MeCN; flow rate: 20 ml/min; gradient: from 16% B to 43% B in 8 minutes; UV 254 & 220 nm; Rt: 7.47 min, producing the title compound. 1H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 8.81-8.77 (m, 2H), 7.91-7.87 (m, 1H), 7.48-7.41 (m, 2H), 7.38-7.21 (m, 3H), 5.58 (s, 2H), 5.03-4.95 (m, 1H), 4.62-4.56 (m, 1H) , 4.43-4.34 (m, 1H), 3.42 (s, 3H). LC-MS (method D): m/z=397.0 [M+H] ⁺ , 2.334 min.

Example 225 -2-carboxamide.

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1H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 7.47-7.18 (m, 9H), 4.47 (dd, J=11.7, 7.9 Hz, 1H), 4.31 (s, 2H), 3.40 (s, 3H), 2.93-2.82 (m, 1H), 2.73 (dd, J=13.6, 6.8 Hz, 1H), 2, 52-2.43 (m, 1H), 2.33-2.21 (m, 1H). LC-MS (method D): m/z=377.0 [M+H]+, 1.732 min.

Other compounds from the table. 1 were, or can be, prepared according to the Examples above and/or the general procedures described herein using suitable starting materials.

Biological analyses.

Compounds were tested for binding and cellular kinase activity according to the following protocols. The proGST-hRIPK1 (8-327) enzyme was generated by Proteros GmbH using a baculovirus expression system.

The cell necroptosis assay (IC ₅₀ per cell in Tables 5-7) evaluates the ability of compounds to reverse necrosis caused by human TNF-α. Tenfold concentrations of test compounds were assessed in duplicate in two different sampling runs. FADD-deficient Jurkat cells were purchased from ATCC (ATCC-CRL-2572) and cultured in suspension in RPMI medium supplemented with 10% heat-inactivated PBS and 1% Pen-Strep. On the day of the experiment, cells were diluted to a density of 0.12x105 cells/ml (5000 cells/well) with culture medium and added (40 µl) to a 384-well plate containing 0.2 µl/well of test compounds and control compounds (CRC) (200x ). Then the plates with cells were incubated at 37°C -5% CO ₂ . After 30 min, necroptotic cell death was induced with human TNFα (10 ng/ml), and cell survival was assessed after 48 h by measuring cell ATP levels using the CellTiter-Glo® kit (Promega). Luminescence was read using a Victor V multichannel plate reader (Perkin Elmer). Data were expressed as % maximum cell survival compared to values for control cells not treated with TNF, representing 100% cell survival. CRC was analyzed using Dotmatics and IC ₅₀ values were calculated by non-linear regression using a 4-parameter logistic equation.

Fluorescence 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 low volume black polystyrene 384-well plate at room temperature (RT) in a final volume of 10.1 μl/well using 10 nM GST-hRIPK1 enzyme (8-327) and 5 nM fluorescently labeled ligand (14-(2-{[3 ({2- {[4-(cyanomethyl)phenyl]amino}-6-[(5-cyclopropyl-1 H-pyrazol-3-yl)amino]-4-pyrimidinyl}amino) propyl]amino}-2-oxoethyl )-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[1,2-a]indol-5-ia-2-sulfonate.

Test compounds were serially diluted in DMSO at 100-fold final concentrations in this assay (1% DMSO final). Each well of a 384-well plate was dispensed with 0.1 μl of compound solution (or DMSO for control samples), followed by the addition of 5 μl of GST-hRIPK1 (8-327) at twofold final concentrations in assay buffer (50 mM HEPES pH 7.5, 10 mM NaCl, 50 mM MgCl2, 0.02% CHAPS, 0.5 mM DTT and 0.01% Pluronic F127). For negative controls, only assay buffer was added instead of adding enzyme.

After adding 5 μl of fluorescently labeled ligand at twofold final concentrations in assay buffer, the plate was incubated at RT for 30 min. Finally, binding was measured as FP value using an Envision plate reader (PerkinElmer) using a filter for λ = 531 nm FP excitation and λ = 595 nm FP emission (S&P-pol).

The proGST-hRIPK1 (8-327) enzyme was generated by Proteros GmbH using a baculovirus expression system.

Test compounds were diluted in DMSO, and 0.1 μl of the solution was dispensed into each well of a 384-well white solid microplate. The analytical buffer was 50 mM HEPES pH 7.5, 50 mM NaCl, 30 mM MgCl ₂ . The buffer was supplemented with 0.02% CHAPS, 0.01% Pluronic F127, 0.1 mg/ml BSA, and 1 mM DTT. MnCl ₂ , 5 mM, was added to the analytical buffer on the day of the experiment. The enzyme reaction mixture included 1.5 μg/ml GST-hRIPK1 (8-327) and 50 μM ATP for receptor-interacting protein kinase 1 and 15 μM ATP. 5 μl of enzyme and 5 μl of ATP were added to the plate at 2 times the final assay concentration and incubated at room temperature for 3 h. After this reaction, 10 μl of ADP-Glo reagent (Promega) was added to each well and incubated for 40 min at room temperature. temperature. This stopped the kinase reaction and used up all remaining ATP. 20 μl of ADP-Glo detection reagent was then added to each well and incubated at room temperature for at least 15 min. The detection reagent converts ADP to ATP and provides luciferase and luciferin for ATP detection. Luminescence is then measured using an Envision plate reader (PerkinElmer). Inhibition of test compounds was expressed as percentage inhibition of internal controls for the assay. For concentration curves, normalized data are suitable, and 1C ₅₀ is determined using the XL-fit (IDBS) utility for Excel. _IC5o values were averaged to determine the mean value for at least two independent experiments.

Inhibition of test compounds was expressed as percent inhibition of internal controls for the assay. For concentration curves, normalized data are suitable, and 1C ₅₀ is determined using the XL-fit (IDBS) utility for Excel. _1C50 values were averaged to determine the average value for at least two independent experiments.

Cellular activity of receptor-interacting protein kinase 1 and binding of exemplary compounds were determined according to the general procedure described above. The results are summarized in table. 5. In the table below, the activity is displayed as follows: +++ = 0.0001 µM < 1C ₅₀ < 1 µM; ++ = 1 µM < 1С ₅₀ <10 µM; + = 10 µM < 1С ₅₀ ; +*** = 3 µM < 1С ₅₀ .

Compound FP 1C ₅₀ (µM) IC50 ADP (µM) IC50 cells (µM) 1A +++ +++ 1B +++ 2 +++ +++ +++ 2A +++ +++ 2B +++ +++ 7A +++ +++ 7V + ++ 8 +++ +++ 9 +++ +++ 10 +++ +++ eleven +++ +++ PA +++ +++ 11V ++ +++ 12 +++ +++ 12A +++ +++ 12V +++ +++ 13 +++ 14 +++ 15 + 16 + 17 + 18 + 19 ++ 20 ++ 21 + 22 + 23 + 24 + 25 + 26 +

Table 5

Compound FP 1C ₅₀ (µM) IC50 ADP (µM) IC50 cells (µM) 3 +++ +++ 4 +++ +++ 5 +++ +++ 6 +++ +++ 7 +++ +++ 27 + thirty +++ +++ 32 +++ +++ 33 + 35 +++ +++ 38A +++ +++ 38V +*** 41 +++ +++ 42 +++ +++ 43 ++ 44 +++ +++ 45 +++ +++ 46A +++ +++ 46V +*** 49 ++ 50A +++ 50V ++ 51 +++ +++ 52 +++ +++ 54A +++ +++ 54V +++ +++ 55 +++ +++ 56 +++ +++ 57 +++ +++ 58 +++ +++

-211 044271

59 +++ +++ 60 60A +++ +++ 60V +*** 61 +++ +++ 62 +++ +++ 63 +++ +++ 64 +++ +++ 65 + 66 +++ +++ 67A +++ 67V +*** 68A +++ +++ 68V +*** 69A +++ +++ 69V +*** 70A +++ +++ 70V +*** 71A +++ +++ 71B +*** 72 +++ +++ 73 +++ +++ 74 +++ +++ 75A +++ +++ 75V +***

76 +++ +++ 77 +++ +++ 78 +++ +++ 79 +++ +++ 80A +++ +++ 80V +*** 81A +++ +++ 81B +*** 82A +++ +++ 82V +*** 83A +++ +++ 83B ++ 84 +++ +++ 85 +++ +++ 86 +++ +++ 87 +++ 88 +*** ++ 89A ++ 89V +++ +++ 90A ++ 90V +++ +++ 91 +++ 92 +++ +++ 93 +++ 94 +++ +++

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95 +*** 96 +++ +++ 98A +*** 98V +++ 99 ++ +++ 100A +++ +++ 100B +++ 101A +*** 101B +++ +++ 102A ++ 102B +++ 103A +*** 103B +++ +++ 104A +*** 104B +++ 105A +++ +++ 105B +*** 106 +++ 107A +*** 107B +++ +++ 108 +++ 109A +++ +++ 109B +*** 110A +*** HOB +++ +++

I.H.A. ++ 111B +++ +++ 112 +++ +++ 113 +++ 114A +++ +++ 114B +*** 115 +++ +++ 116 +++ +++ 117 +++ +++ 118A +*** 118B ++ 119A +*** 119B +++ +++ 120 A +++ +++ 120B +*** 121A +*** 121B +++ 122 +++ +++ 123 +++ +++ 124 +++ +++ 125A +*** 125B +++ +++ 126 +++ +++ 127 +++ 128 +++ +++

- 213 044271

129A +++ 129V +*** 130 +++ +++ 131A +++ 131V +*** 132 +++ +++ 133 +++ +++ 134 +++ +++ 135 +++ +++ 136 +++ +++ 137 +++ +++ 138 +++ +++ 139 +++ +++ 140 +++ +++ 141A +*** 141V +++ 142 +++ +++ 143 +++ +++ 144 +++ +++ 145A +++ +++ 145V +*** 146 +++ +++ 147 +++ +++ 148A +++ +++ 148V ++

149 +++ +++ 150 +++ +++ 151 +++ +++ 152A +*** 152V +++ +++ 153 +++ +++ 154A +*** 154V +++ +++ 155 +++ 156A +*** 156V +++ +++ 157A +*** 157V +++ +++ 158 +++ +++ 159 +++ 160A +++ +++ 160V +*** 161 +++ +++ 162 +++ +++ 163 +++ +++ 164 +++ +++ 165 +++ +++ 166 +++ +++ 167 +++ +++ 168 +++ +++

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169 +++ +++ 170A +++ +++ 170V +*** 171 +++ +++ 172 +++ +++ 173 +++ +++ 174 +++ +++ 175 +++ +++ 176 +++ 177A +++ +++ 177V +*** 178A +++ +++ 178V +*** 179A +++ +++ 179V +*** 180A +++ +++ 180V +*** 181A +*** 181V +++ +++ 182A +*** 182V +++ +++ 183A +*** 183V +++ +++ 184 +++ 188 +++ +++ 222 +++ +++ 223 +++ +++ 224 +++ +++

190 +++ 192 +++ +++ 193 +++ +++ 194 +++ 195 +++ +++ 197 +++ +++ 198 +++ +++ 200 +++ +++ 201 +++ +++ 203 +++ +++ 204 +++ 205 +++ +++ 206 +++ +++ 207 +*** 208 +++ 209 +++ +++ 213 +++ 214 +++ +++ 215 +++ +++ 216 +++ +++ 217 +++ +++ 218 +++ +++ 219 +++ +++ 220 +++ +++ 221 +++ +++ 225 +++ +++ 226 +++ 227 +++

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Table 6

Compound Cell IC50 (µM) Avg. C1 _hep in human hepatocytes (ml/min/kg) ER MDR1 Unbound CL in rat (ml/min/kg) Unbound CL in dog (ml/min/kg) Unbound CL in macaque (ml/min/kg) 119V 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 32 172 0.001 5.3 65 183V 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 eleven 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

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Table 7

Comparisons

Structure 1C ₅₀ cells (µM) Avg. C1 _hep in human hepatocytes (ml/min/k g) ER MDR1 Unbound CL in rat (ml/min/kg) Unbound CL in dogs (ml/min/kg) Unbound CL in macaque (ml/min/kg) A OS xx st p I o νΑχΑΖ n 0.0005 6.8 6.4 77 240 117 IN 3 X ζ 'O 0.0003 14 1.0 WITH I O S.A. cuz G o 0.001 19 0.9

Comparable compounds in table. 7 was prepared as described in examples 12, 146 and 77, respectively, of international application publication WO 2014/125444.

The in vivo efficacy of the compounds can be determined in mice using the TNF systemic inflammatory response syndrome model 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, exposure to TNF/zVAD (tumor necrosis factor/Z-Vαl-Alα-DL-Asp-fluoromethylketone, caspase inhibitor) results in a drop in temperature 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 the test compound 15 minutes before TNF/zVAD administration and measuring the inflammatory response. The dose required to inhibit the inflammatory response is a measure of the effectiveness of the compounds at that dose. Using this model, compound 42 was preadministered orally at a dose of 5 mg/kg 15 min before intravenous administration of TNF/zVAD, and the temperature drop in mice was measured using an implanted temperature chip. Treatment of mice with 5 mg/kg Compound 42 resulted in a 96% inhibition of temperature decline compared to control animals treated with TNF/zVAD alone. For comparison, in the publication of international application WO 2014/125444 in table. 2 reveals that for Example 12, corresponding to Example A from table. 7 above, a dose of 30 mg/kg was required to achieve 93% inhibition. Dosage reduction has a number of important potential benefits, including the need for less frequent patient administration, increased patient compliance, and an improved safety profile such as reduced toxicity while achieving similar efficacy.

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-bearing carbon atom adjacent to the azepinone moiety ( i.e. X ⁹ in the formulas described herein) interacts with the lipophilic pocket of receptor-interacting protein kinase 1.

Specific compounds have been found to have significantly improved metabolic stability when X ⁹ in the formulas described herein is an N atom compared to when it is a carbon atom. For example, Compound 42, compared to comparative Example A, when tested according to the assay described below, was found to have an average human hepatocyte clearance of 0.8 ml/min/kg compared to 6.8 ml /min/kg for Comparative Example A. As described in the metabolic stability section below, a Cl hep value of 6.8 ml/min/kg corresponds to clearance of approximately 32% of hepatic blood flow, while for Compound 42 a Cl hep value of 0.8 ml/min/kg corresponds to a clearance of less than 4% of the blood flow through the liver, which demonstrates a significant improvement in the stability of compounds when X ⁹ is an N atom. Based on the data above, it will be obvious to those skilled in the art that compounds with lower Cl values hep will provide the ability to use lower clinical dosages in humans, less frequent patient administration, increased patient compliance, and an improved safety profile, such as reduced toxicity.

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MDCKII-MDR1 permeability.

The blood-brain barrier (BBB) separates circulating blood from the extracellular fluid of the central nervous system (CNS). Passive membrane permeability (Papp) and P-glycoprotein (P-glycoprotein) substrate efflux potential were determined using the MDCKII-MDR1 cell line as an in vitro model of effective junctional permeability across the BBB. Bilateral analysis (apical-basolateral (A^B) and basolateral-apical (B^A)), in the absence and presence of GF120918 (a P-gp inhibitor), was performed using pre-plated MDCKII-MDR1 cells (Corning HTS Transwell-96 ), purchased from SOLVO Biotechnology. The assay was performed at 3 μM for 90 min (minutes) in triplicate using HBSS + 12.5 mM HEPES pH 7.4 transport buffer. After incubation of the donor and recipient samples, the wells were emptied and measured by LC-MS/MS. Samples were extracted by protein precipitation using acetonitrile containing a suitable internal standard (IS) of known mass and molecular weight. The sediment was centrifuged for 10 minutes. at 3000 rpm (rpm). The supernatant was then collected, diluted if necessary, and injected into the LC-MS/MS system. Specific parent/daughter ion pairs for the test sample and BCs were used to selectively measure the test samples. Papp values (effective permeability, measured in nm/s [nanometer/second]) were calculated according to the following equation:

_n (dQ} ( 1 VO

Rarr (nm/s) H “OI™ gY /dt ) (.CO) /A)

Where dQ/dt represents the percentage of permeability, C ₀ represents the initial concentration in the donor solution (expressed as coefficient BC), A and B represent the filter surface areas (surface area of the cell monolayer).

Monolayer efflux ratios (ER) were obtained using the following equation:

\ B - ARarr (nm/s) Coefficient, outflow = ———-----/A - VRarrrnm/s)

Compounds with an MDCKII-MDR1 efflux ratio less than or equal to 2.5 are most likely to demonstrate the ability to cross the blood-brain barrier.

Metabolic stability (hepatocytes).

The metabolic stability of the compounds was measured in cryopreserved human hepatocytes (BioreclamationIVT, New York, USA) in duplicate. Test samples (or control samples) were added to a 24-well incubation plate (Becton Dickinson Labware, USA) containing 0.5x106 hepatocytes/ml in suspension. The plate was kept at 37°C and mixed by constant circular shaking (rotation speed 350 rpm). At each time point (0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150 and 180 min), the Tecan Evo robot aspirated 50 μl of incubation mixture and 100 μl of acetonitrile containing internal standard for quenching reactions. The quenched mixtures were dispensed into a 96-well plate along with 120 μL of aqueous solution to equilibrate the solvent contents to 37%. Samples were centrifuged (300 rpm for 10 min) and the plate was sealed before injection into the LC-MS/MS system.

The appropriate parent/daughter ions for the test sample and BC were monitored using an LC-MS/MS system. Intrinsic clearance (Cl _intrinsic ; expressed in μl/min/million cells) was determined based on the first-order elimination constant (k, min ^-1 ) of the decay of the test sample and the incubation volume. These values were adjusted to natural organ clearance (CL _eat .) using human-specific correction factors (139x106 hepatocytes/g liver and 25.7 g liver/kg body weight). Natural organ clearance was then converted to hepatic clearance (Cl _hep ) using a well-mixed model as shown below, where Q _h represents blood flow through the human liver.

Qh* _CLecT

Г J —___________ ^r ' (Q, + CL _e „)

Hepatic clearance is expressed in ml/min/kg. Hepatic clearance refers to the blood flow through the liver that is completely cleared of the compound. A human _hep Cl value of 20.9 ml/min/kg correlates with almost complete hepatic clearance of the compound or 100% hepatic blood flow. Accordingly, a human _hepatic Cl value of 6 ml/min/kg corresponds to clearance of approximately 29% of hepatic blood flow. A human _hepatic Cl value of 2 ml/min/kg corresponds to clearance of approximately 10% of hepatic blood flow. A human _hepatic Cl value of 1 mL/min/kg or less corresponds to a clearance of approximately 5% of hepatic blood flow or less. A human _hep Cl value of 0 ml/min/kg correlates with undetectable clearance of the compound by the liver.

Specific embodiments provide compounds having a Cl _hep of less than 5, 4, 3, 2, or 1 ml/min/kg when tested according to the liver enzyme resistance assay described above. IN

- 218 044271 specific embodiments, such compounds do not readily penetrate the blood-brain barrier. In specific embodiments, such connections have a churn ratio

MDCKII-MDR1 more than 2.5.

Specific embodiments provide compounds having a Cl hep of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mL/min/kg when tested according to the liver enzyme resistance assay described above. In certain embodiments, such compounds penetrate the blood-brain barrier. In specific embodiments, such compounds have an MDCKII-MDR1 efflux ratio of 2.5 or less.

Protein binding.

Plasma protein binding was determined using a Rapid Equilibrium Dialysis Device (Thermo Scientific RED Device) or a 96-well dialysis device (HTDialysis LLC). Test/control compounds were added to plasma to provide a final concentration of 0.5 μM (plasma). When necessary, plasma samples were preincubated (2 h at 37°C) with diisopropyl fluorophosphate (DFP) at a final concentration of 100 μM to prevent degradation of compounds due to amide hydrolysis. Appropriate volumes of spiked samples, as well as phosphate buffer without additives, were introduced into one of the devices and incubated at 37°C for 5 h with stirring at 500 rpm. After incubation, an equal aliquot of the dialyzed matrix (plasma or buffer) was added in an equal volume to the opposite control matrix such that the volume of buffer and plasma was equal. Mixed matrix samples were extracted by protein precipitation using acetonitrile containing suitable BC. The samples were then centrifuged for 10 min at 2800 rpm. The supernatant was collected, diluted and then injected into the HPLC-MS/MS or UHPLC-MS/MS system. Samples were analyzed by observing suitable parent/daughter ion transitions for test and control compounds. Peak area ratios were used to measure the concentrations of test compounds. The unbound fraction (Afu) was determined as the peak area ratio in buffer divided by the peak area ratio in plasma.

In vivo pharmacokinetic (PK) studies.

The PK properties of the test compounds were determined in male Sprague-Dawley Crl:CD(SD) rats, male beagle dogs and male cynomolgus macaques. Studies were conducted to the highest standards of animal welfare in accordance with national legislation and with the approval of internal animal care and use committees.

The compounds were administered by IV bolus to animals after an overnight fast. Compounds for IV administration were formulated as solutions of either 1% DMSO:20% PEG400:79% saline or 5-50% NMP in D5W (5% dextrose in water). The formulations were administered in a dose range from 0.5 to 2 ml/kg. The IV dose ranged from 0.5 to 1 mg/kg.

After dosing, 8-9 serial blood samples were collected over 24 hours. Samples were mixed with anticoagulant and placed on wet ice before processing. Plasma was collected after centrifugation and extracted by protein precipitation using acetonitrile containing BC. The treated supernatant was analyzed by UHPLC or LC-MS/MS using specific parent/daughter ion pairs for the test sample and VS. Plasma concentrations were determined using a calibration curve generated using known analyte concentrations. Pharmacokinetic parameters using measured concentrations were calculated using Phoenix WinNonlin. Unbound plasma clearance was calculated as the ratio of total body clearance divided by the unbound plasma fraction.

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains.

The inventions that have been described herein by way of illustration may be suitably practiced in the absence of any element or elements, limitation or restrictions not specifically described herein. Thus, for example, the terms containing, including, comprising, etc. should be interpreted broadly and without limitation. In addition, the terms and expressions used herein have been used as terms of description and not limitation, and in the use of such terms and expressions there is no intention to exclude any equivalents of the features shown and described, or portions thereof, but it is understood that possible various modifications within the scope of the present claimed invention.

All publications, patent applications, patents and other literature references mentioned in the present invention are expressly incorporated by reference in their entirety to the same extent as if each were separately incorporated by reference. In the event of a conflict, this description, including definitions, will govern.

It should be understood that although the present invention has been described in conjunction with

- 219 044271 by the above embodiments, it is intended that the foregoing description and examples merely illustrate and do not limit the scope of the present invention.

Other aspects, advantages and modifications within the scope of the present invention will be apparent to those skilled in the art to which the present invention relates.

Claims (5)

CLAIM 1. Compound of formula II R ⁴ II or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, where q is 0, 1 or 2; X ⁶ , X ⁷ , X ⁸ and X ⁹ are each N or CH; R ¹ represents H or C ₁ -C ₆ -alkyl, optionally substituted with halogen, hydroxy or cyano; Y ² represents -O- or -C(R ⁶ ) ₂ -; each R ⁶ independently represents H, halogen or C1-C6 alkyl, or two R ⁶ together with the carbon atom to which they are attached form a C1-C ₅ alken-1-yl or cycloalkyl ring; R ³ and R ⁴ independently represent H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁴ together with the carbon atoms to which they are attached form a cycloalkyl ring, or R ³ and R ⁶ together with the carbon atoms , to which they are attached form a cycloalkyl ring; A represents a cycloalkyl ring, a heterocyclyl ring or a heteroaryl ring, optionally substituted with halogen, C ₁ -C ₆ alkyl or cyano; L is absent or represents -O-, -S(O) ₂ - or -C(R ⁸ ) ₂ -; each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring; R ⁹ represents cycloalkyl, aryl, optionally substituted with halogen or cyano, or heteroaryl, optionally substituted with halogen, C ₁ -C ₆ -alkyl, cyano or C ₁ -C ₆ -alkoxy; each R ¹⁰ independently represents cyano, halogen or C ₁ -C ₆ -alkyl; provided that at least one of the following occurs: (1) at least one of R ³ and R ⁴ is halogen or C ₁ -C ₆ alkyl, or R ³ and R ⁴ together with the carbon atoms to which they are attached form a cycloalkyl ring, or R ³ and R ^6, together with the carbon atoms to which they are attached, form a cycloalkyl ring; (2) L is absent or is -C(R ⁸ )2-, and each R ⁸ is C1-C ₆ -alkyl or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring; (3) Y ² is -C(R ⁶ )2-, and one R ⁶ is H, halogen or C1-C ₆ alkyl, and the other R ⁶ is halogen or C1-C6 alkyl; or two R ⁶ together with the carbon atom to which they are attached form a C1-C ₅ -alken-1-yl or cycloalkyl ring; (4) Y ² represents -O-, and A represents a heteroaryl ring substituted with halogen or cyano, or A represents a thiazolyl or a 3- or 4-membered ring; one of X ⁷ and X ⁹ represents a nitrogen atom, and A is not an isoxazole; (5) R ¹ represents C ₂ -C ₆ -alkyl; or (6) when X ⁹ and X ⁶ are both CH, forming an optionally substituted phenyl ring- That is, as in fragment ⁴ ' at least one substituent is at position 1 or 4 and is (a) not fluorine, chlorine or methyl at position 1 and/or (b) not fluorine or methyl at position 4; and with the further condition that said compound is not 5-(difluoro(phenyl)methyl)-N-(4oxo-2,3,4,5-tetraαhydrobenzo[b][1,4]oxazepin-3-yl)isoxazol- 3-carboxamide; 5-(difluoro(phenyl)methyl)N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3-carboxamide; 2-(4bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide or 2-benzyl- N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazenin-3-yl)thiazol-4-carboxamide; wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 carbon atoms in the ring, having a single ring or multiple rings, where the cycloalkyl may be fused, bridged or spiro; each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo( C=O) or N-oxide (N-O-) moieties, and/or a single ring, or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2. A compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, where the compound is a compound of formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) : or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof. 3. A compound according to claim 2, wherein the compound is a compound of formula IIe: or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof. 4. Compound of formula V: or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0, 1 or 2; X ⁶ and X ⁹ are independently N or CR ¹⁴ ; R ¹ represents H or C ₁ -C ₆ -alkyl; Y ² represents -O- or -C(R ⁶ ) ₂ -; each R ⁶ independently represents H, halogen or C ₁ -C ₆ -alkyl; R ³ represents H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl ring; L represents -C(R ⁸ ) ₂ -; each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring; R ⁹ is aryl, optionally substituted with halogen or cyano, or heteroaryl, optionally substituted with halogen, C ₁ -C ₆ -alkyl, cyano or C ₁ -C ₆ -alkoxy; each R ¹⁰ independently represents cyano, halogen or C ₁ -C ₆ -alkyl; and each R ¹⁴ independently represents hydrogen, cyano, halogen, C ₁ -C ₃ alkyl, optionally substituted with halogen, or C ₁ -C ₃ alkoxy, optionally substituted with halogen; provided that when both of X ⁶ and X ⁹ are CR ¹⁴ , one or more of (i), (ii), (iii), (iv) and (v) are true: (i) R ³ and R ⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, (ii) L is -C(R ⁸ ) ₂ -, and each R ⁸ is combined with the carbon atom to which they are attached, with formation of cyclopropyl, (iii) R ⁹ is substituted with at least one cyano, (iv) X ⁹ is not C-H, CF, C-Cl or C-CH3 and/or (v) X ⁶ is not C-H, CF or C-CH3; and further wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 ring carbon atoms, having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged or spiro; each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo (C=O) or N-oxide (N-O-) moieties and/or single ring or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5. The connection according to any of the previous paragraphs, in which, when the fragment is q is 0 or R ¹⁰ is halogen or C ₁ -C ₆ -alkyl, and L is absent, then ring A is a 3-, 4- or 5-membered monocyclic ring. 6. A compound according to claim 4, wherein the compound of formula V is represented by formula Va: or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0, 1 or 2; X ⁶ represents N or CR ¹⁴ ; R ¹ represents H or C ₁ -C ₆ -alkyl; Y ² represents -O- or -C(R ⁶ )2-; each R ⁶ independently represents H, halogen or C ₁ -C ₆ -alkyl; R ³ represents H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl ring; L represents -C(R ⁸ ) ₂ -; each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring; R ⁹ is aryl, optionally substituted with halogen or cyano, or heteroaryl, optionally substituted with halogen, C ₁ -C ₆ -alkyl, cyano or C ₁ -C ₆ -alkoxy; each R ¹⁰ independently represents cyano, halogen or C ₁ -C ₆ -alkyl; And R ¹⁴ represents hydrogen, cyano, halogen, C ₁ -C ₃ -alkyl, optionally substituted with halogen, or C ₁ -C ₃ -alkoxy, optionally substituted with halogen; and further wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 ring carbon atoms, having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged or spiro; each heterocyclyl independently represents a saturated or unsaturated cyclic alkyl group containing from 2 to 20 carbon atoms in the ring with one or more heteroatoms in the ring independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo ( C=O) or N-oxide (N-O-) moieties, and/or a single ring, or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7. Compound of formula VI or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0, 1 or 2; X ⁶ represents N or CR ¹⁴ ; R ¹ represents H or C ₁ -C ₆ -alkyl; Y ² represents -O- or -C(R ⁶ ) ₂ -; each R ⁶ independently represents H, halogen or C ₁ -C ₆ -alkyl; R ³ represents H, halogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl ring; L represents -C(R ⁸ ) ₂ -; each R ⁸ independently represents H or halogen, or two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring; R ⁹ is aryl, optionally substituted with halogen or cyano; each R ¹⁰ independently represents halogen or C ₁ -C ₆ -alkyl; And R ¹⁴ represents hydrogen, cyano, halogen, C ₁ -C ₃ -alkyl, optionally substituted with halogen, or C ₁ -C ₃ -alkoxy, optionally substituted with halogen; and further wherein each cycloalkyl independently represents a saturated or partially unsaturated cyclic alkyl group containing from 3 to 20 ring carbon atoms, having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged or spiro; each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group containing from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain one or more oxo(OO) or N -oxide (N-O-) moieties, and/or a single ring, or multiple rings, where multiple rings may be fused, bridged or spiro; and each heteroaryl independently represents an aromatic group having from 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8. The compound according to claim 6 or 7, in which R ⁶ represents CR ¹⁴ . 9. The compound according to claim 6 or 7, in which R ⁶ represents N. 10. A compound according to claim 6 or 7, wherein R ¹⁴ represents hydrogen. 11. A compound according to any of the previous paragraphs, in which R ¹ represents C ₁ -C ₆ -alkyl. 12. The compound according to any of the previous paragraphs, wherein R ¹ represents methyl. 13. A compound according to any of the preceding claims, wherein R ³ is hydrogen. 14. A compound according to any one of claims 1 to 13, wherein R ³ and R ⁶ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl. 15. A compound according to any one of claims 1 to 3, in which R ³ and R ⁶ together with the carbon atoms to which they are attached form cyclopropyl. 16. A compound according to any of the previous claims, wherein L is absent or is -S(O)2- or -C(R ⁸ )2-. 17. A compound according to any of the preceding claims, wherein the two R ⁸ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring. 18. The compound of claim 17, wherein L is -C(R ⁸ ) ₂ - and the two R ⁸ are taken together with the carbon atom to which they are attached to form cyclopropyl. 19. A compound according to any of the preceding claims, wherein R ⁹ is optionally substituted pyridyl, phenyl or 2,3-dihydro-1H-indenyl. 20. A connection that is: - 223 044271 - 224 044271 12A \ 0 X ^x AJ L 121A \ ,o .ΝΆΌ ShnL 0 \=\ /=\ °4r ^F F 12V CO street χ, Г 0 nAAU 121B \ .O CO Ln O ^=( /=\ °Xr ^F F 13 122 °0χνΟ 14 OS ^ ^N w'° MD _rp 123 OCA! n 15 BEHIND 124 ^Chi”1P 16 i oA 125A \ .o Il Ύ )NH _N Xaxo 17 Cjl. ΟζΧ^ ^Ν 125B \ .0 / ⁿ ^z ^N A Ο >χ N' _N l and G π FS ο Ν-^^ΧχΑ Η 18 ' 0 H _N ^ oC^° 126 Cc^a ⁿ x ^f η o sA>v 19 OS^YACHA Hi θ' 127 AGahg 20 \ ου ^ν λ g 1 / \ ^H / ⁿ 'n and Г J o n^AxJ h 128 0¼ 130 24 Οζ^οχ ° Ύ3Ν 25 0/ ^N o O N^XH 26 Ό 0 132 133 F 134 fOi+W 135 Au F - 225 044271 - 226 044271 4 6V \ 0 .. NA ί Ύ )NH N. _n /k - lumz 152Β CN 153 ''Μι NC 49 GH 'Vnh Ayo o ^{z 4} o 50 oA ⁰ \ / ⁼ \ 155 ^α »ίΗΑ 50A θΑ-<ι O\/^\ 156Α Γο- 50V PG^MN o g /^\ ~AJ 156Β A~ 51 Ay /-, 157Α \ .ο ί /I / \ ^Η / ^Ν 'Ν 157Β ^НЪО 158 ^α ^ΚίΌ 54А ^nPL h A yr Diastereomer 1 159 ^α “^Ηΐχτ 54V ° aur Diastereomer 2 160Α ^α Χ·Αθ 55\ _Ν 0 θΟρρΊΟ F 160Β ^α ^Αθ 56 9^“н1п CN Ο [j^V 161 %^ ^Ν Αρη ^Χ Ν 57 Η ,ο ^a JAoE 162 \ .Ο F LA γΆ ^ν 'ν A )τ \ Λ Γ η η A ^Χ Ν 58 ΓΎ ^Ν ^νη AA 163 QJ~TA a ο ν·^Χα4Α< η A ^Χ Ν 59\.ο <γ ^Ν Λ. L ί DTA 41 164 ΓΎ Vnh ^ΛΗλΧί 60 \ .ο α ^ν V l I gaa Ά/ %Χί J 165 I J 60A \ 0 °Αχο 166 ° / V ^N JJ - 227 044271 60V \ 0 Sd )F ^M nn 167 HchSh w 61 \ 0 AadAo ⁰ w = 168 Aa A 62 But O 169 D and o nAAJ n 63 gUZH, 0^0^ УУ1 /A) about health and safety 170A DAo, 64 Ato F 170V Hell A 171 F! θ'N' ^N AAL 66 \ .0 Os Uzh ^m ~ « f UCH A G no o oALD 172 \ .0 JA I A UCH ^N / A ^ChlDD! 67A \ O ZhzhAA O GUU Dx UCH A 1 » 0 N^A-J n 173 D OS U Zh!H w UC a 1 and o oA>D 67B \ 0 ^Kiz 174 D A ^D □ZH η ⁴ o o-ZhZh%D 175 CHUD 176 ί Η η Αζ χ 1 А У\ ⁿ An UCH A G /) o nAA> n 177А \ .о ^аА'Ч' ί A A ⁿ An zh n^vv Y \ 1 f and V o dAD ¹ 177V sAtd w 178A F 178V Audit F 179A F 179V ¢++.: F - 228 044271 72 \ 0 QC ^N 'NH θ AfA 18 0Α with χΧ ^ν α- ^ν ' ^ν ο У \ JI f Π 73 ¹ .0 СХ X ⁿ a ⁿ 'nh o A/v 180Β s χΧ ^,ν χ/ ^ν 'ν 74\0 18 ΙΑ F Η Ό Ar ^N A ΛΑ / ^Ν χχ ° Α-ΑΛ ^Χ Ν 7 5A \ o ( Ύ / ^Ν \ ^Η Λν X/ .%W 181Β f Η _y o Ατ ^ν λ1 ΛΑ Χ ^ν Α/ ^ν 'ν ,^χ Α< A 1 il ο nAaA n x> ^X N 75V \ 0 ( Ύ > ·ΝΗ μ ^ΑΑ Λ ί /) η 182Α CX-A n o N' ^N ^^N 76 \ 0 ¢:-:.4 182Β CiXA n Ο Ν' ^Ν Αγ N 77 ' Ζ ^Ο Λ α ^ν %α η o ^χΑΑ 18 FOR D A Aw 78 \ 0 1 U-NH UCH ⁷ X XX ⁰ YHrA 183Β D Ako 79 \ 0 θΓ ρ-ΝΗ Νγχ 184 Na, 8 0A 1 0 °7hw 80V ' / ⁰ Ν Μ'-/' ΙΑ ) ^ν α ^ν 'νη o^Aa^Qj) 81A 1 0 Akw 81В 1 0 Ν^/Ν-Α ί Ύ )ΝΗ Ν. _ο 188 ζχΧ^ο A- 82A AND-: 82V 'Αί·': 190 CC^T?x a o o^AA^A 8 FOR ί ^Η ο χ4/ ^Ν ·^ f 0 >ΝΗ Ν- _ν All V 0 nXAU 83В ί Η ο f jf )ΝΗ Ν. _ν AA Λ f π - 0 χχχ 192 \ ,o rVX 1 r ^NH N^ ^www 193 AHadp ⁴ o o^AA^A - 229 044271 85 \ 0 η o sA>V' 194 \ .О < ^ν <ζ ^ν Ό [| Ύ Χνη ^ ^Ν<ί χ/ X ⁴ ? X XX Ν ο oA%V 86 \ 0 ^η ^ν 1Η o 195 \ .о ( J Л\ ⁿ An ^N N 87 \ 0 OS Htzh o ₀ Hn%) 88 \ 0 197 \ .o < ^ν <ζ ^ν Ό ( X / \ ^H Ao ZH ^N '/VA XW N o 8 9A Gno jl n-zh ΧΊ /\ ⁿ λν rZhZhD h g > o oZhLA 198 \ .o ί X Χ\ ^Η Αν zh Αχ u 1 h y o 8 9В 00 У ^ΖΙ ь 90A ί n about in-zh ίΎ / ^Ν \ ^Η An γ\ 90V Kh° ΧΎ >ΝΗ Ν _ΐΝ ^f A/ o^AnUO 201 ^Οκϊχί 91 Η 0 OS HtZh ⁿ 43 o 92 « b lx 203 93 "Ίί.:~ 204 '-YH 94 Αθΐη n 205 ^D D ΟΑ-Χϊ 95 C(Hjo η ^g o nAAJ n 206 ^D D Ha 96 n ,o AO+up ⁴ o nA^V n 207 ^D D z Okzhtzh? h 208 \ .o ί X / ^NH LC ^N Y o^n^Q 98А Η 0 ζ ^Ν γ ^Ν 0 00\ /Ч z\ ЖО Л 1 /) Ж о ыААж n 209 qXto Ж ⁰ Pn- ⁿ vV 98В n ζ ^Ν γ ^Ν Ο ОН) +'N Ж Ж l 1 ί 99\.0 1 r ^NH w ⁰ - 230 044271 or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. 21. A connection that is: - 231 044271 - 232 044271 - 233 044271 - 234 044271 - 235 044271 - 236 044271 - 237 044271 or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. 22. The connection according to claim 21, where the connection is: or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. 23. The connection according to claim 22, where the connection is: or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition containing a compound according to any of the previous paragraphs and an excipient. 25. A method of treating a disease or disorder mediated by receptor-interacting protein kinase 1, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 23 or a pharmaceutical composition of claim 24 to a subject in need thereof. 26. The method of claim 25, wherein the disease or disorder is an inflammatory disease or disorder, necrotizing cell disease, neurodegenerative disease, central nervous system disease, ocular disease, malignancy, immune-mediated disease, allergic disease, autoimmune disease, inflammatory bowel disease , Crohn's disease, ulcerative colitis, retinal detachment, retinal pigmentary degeneration, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic arthritis with systemic onset, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune diseases of the liver and biliary tract, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune idiopathic thrombocytopenic purpura (ITP), transplant rejection, ischemic and reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, acute cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, diabetes I - 238 044271 type, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, fever associated with interleukin-1-converting enzyme, chronic obstructive pulmonary disease, periodic syndrome associated with tumor necrosis factor, periodontitis, trauma, ischemia, stroke, myocardial infarction, infection, lysosomal storage disease, Gaucher disease, Krabbe disease, Niemann-Pick disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), HIV-related dementia, degenerative retinal disease, glaucoma, age-related macular degeneration, psoriasis, psoriatic arthritis, damage brain, spinal cord injury, dementia, Huntington's disease, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr's disease, Menkes' disease, Wilson's disease, cerebral ischemia, Friedreich's ataxia, rheumatoid arthritis, Lewy body disease or prion disorder.