EA045696B1 - RIP1 INHIBITORY COMPOUNDS AND METHODS OF THEIR PREPARATION AND APPLICATION - Google Patents

Description

Field of invention

The present disclosure relates to compounds and methods for making and using the compounds, for example, for inhibiting receptor interacting protein 1 (RIP1) kinase and for treating diseases and/or conditions associated with RIP1.

State of the art

Receptor interacting protein 1 kinase (referred to herein as RIP1) belongs to the tyrosine kinase-like family and is a serine/threonine protein kinase involved in innate immune signaling. RIP1 plays a central role in the regulation of cell signaling, and its role in programmed cell death has been associated with various inflammatory diseases, such as inflammatory bowel disease, psoriasis, and other diseases and/or conditions associated with inflammation and/or necroptosis of cells.

The essence of the invention

The disclosed compounds of the present invention may have formula I

Formula I, or represent a pharmaceutically acceptable salt, N-oxide, solvate, tautomer or stereoisomer thereof. With respect to Formula 1, ring B is a 5-membered or 6-membered heteroaryl, wherein the heteroaryl has at least one ring atom and the remaining ring atoms are carbon; L represents a heteroatom or R ^a , with the proviso that R ^a does not represent H or D; Z represents a C1-10 aliphatic group, including a cycloaliphatic group, or aryl; each R ¹ independently represents a halogen, -C=CH or a -linker-R ⁶ group, where the linker is a bond or R ^a , provided that R ^a is not H or D, and R ⁶ is a heterocyclyl, R ^b , -C(R ^f )3 or -C(R ^f )=C(R ^f )2; R ² represents R ^a ; R ³ represents R ^a ; each R ⁴ is independently R ^e ; R ^a represents, independently for each occurrence, H or D, for embodiments except where L represents R ^a , a C1-10 aliphatic group, a C1-10 haloaliphatic group, a C1-10 heteroaliphatic group, a C5-10 αryl group, a C3-6 cycloaliphatic group, or a C3-6 heterocycloaliphatic group; R ^b independently for each case represents -OH, -SH, -OR ^c , -SR ^c , -NR ^d R ^d , -Si(R ^a )3, -C(O)OH, -C(O)OR ^c , -C(O)NR ^d R ^d , -OC(O)NR ^d R ^d , -OC(O)C1-10alkyl substituted with one or two NR ^d R ^d , carboxyl or a combination thereof, and optionally further substituted an aromatic fragment, -SH, -O-acyl or -C(O)NH2; R ^c is independently in each instance C1-10alkyl, optionally substituted with 1, 2 or 3 ^Re , C2-10alkenyl, optionally substituted with 1, 2 or 3 ^Re , C2-10alkynyl, optionally substituted with 1, 2 or 3 ^Re , C3-6cycloalkyl, optionally substituted with 1, 2 or 3 R ^e , or C5-10 aromatic group, optionally substituted with 1, 2 or 3 R ^e ; R ^d is independently for each case H; C1-6 alkyl, optionally substituted with 1, 2 or 3 R ^e or C3-9 heterocyclyl; C3-6cycloalkyl, which may be substituted with 1, 2 or 3 R ^e ; a C3-6 heterocyclic group, optionally substituted with 1, 2 or 3 R ^e ; C5-10aryl, optionally substituted with 1, 2 or 3 R ^B ; C5-10heteroaryl, optionally with 1, 2 or 3 R ^e ; or two R ^d groups together with the associated nitrogen atom form a ^^heterocyclic group, optionally substituted by one or more ^Re , or a C5-10 heteroaryl, optionally one or more ^Re ; R ^e is independently in each case halogen, C1-6alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C1-6 haloalkyl, _C3-6 cycloalkyl, _C5-10 heteroaryl or -OR ^a ; and R ^f is independently in each case an alkyl phosphate, R ^a , R ^b or R ^e , or two R ^f groups together with a carbon atom bonded thereto form a C2-6alkenyl group, a C3-6cycloalkyl group, optionally substituted by one or more R ^e or C3-10 heterocycle, optionally one or more R ^e or acyl; m is equal to 1, 2, 3 or 4; and n is 0, 1 or 2.

For some embodiments, the compound is not: I-56-(S)-i-(7-(3hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4phenoxypicolinamide; I-64-(S)-N-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-68-(S)-N-(7-(3-hydroxy-3-(methyld3)but-1-in-1-yl-4,4,4-d3)-5-methyl-4-oxo- 2,3,4,5-tetraαhydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-72-(S)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4 ]oxazepin-3-yl)-4-phenoxypicolinamide; or I-7 7-(S)-1 -benzyl-N-(7-(3 -hydroxy-3 -methylbut-1 - 1 045696 in-1 -yl)-5 -methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide. In certain other embodiments, the compound is not I-1 to I-97 or I-187 to I-189.

In certain embodiments, Ring B is pyrazolyl or pyridinyl. For example, when ring B is pyrazolyl or pyridinyl, L may be a heteroatom or a C _1-10 aliphatic group; Z may represent a C _1-10 aliphatic group or aryl; each R ¹ may represent a heterocyclyl or a C1-10 aliphatic group; R ² may represent an H or a C1-10 aliphatic group; R ³ may be H or C1-10 aliphatic; each R ⁴ independently can represent a halogen or a C1-10 aliphatic group; m may be 1, 2, 3, or 4 and n may be 0, 1, or 2. One of ordinary skill in the art will appreciate that compounds of all stereoisomers are included in Formula 1, including, but not limited to, compounds having the formula

With respect to specific illustrative embodiments of the disclosed pyridine and pyrazole compounds, such compounds may have the formula set forth below, including any and all stereoisomers thereof

With respect to each of the preceding general formulas, specific compounds have R ² and/or R ³ as H or C1-6 alkyl, such as methyl; each R ⁴ independently represents halogen or C1-6 alkyl such as chlorine, fluorine or methyl; n is 0, 1 or 2; L represents a heteroatom such as oxygen, or C _1-10 alkyl or C _1-6 alkyl such as -CH ₂ -; and Z is aryl or C _3-6 cycloalkyl.

For specific compounds, Z is

wherein each R ⁵ is independently R ^e and p is 0, 1, 2, 3, 4 or 5. For example, each R ⁵ can independently be halogen or C _1-6 alkyl such as fluorine or methyl. Z may also be C _1-6 alkyl such as methyl; or cycloalkyl such as cyclobutyl or cyclopentyl. For certain embodiments, the -LZ moiety is phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 2-fluorophenoxy, 2,4-difluorophenoxy, 2,6-difluorophenoxy, 4-fluorobenzyl, 2,6-dimethylphenoxy, cyclobutyloxy, cyclopentyloxy, methoxy, 4 -methylphenoxy or benzyl.

For specific compounds, each R ¹ is independently heterocyclyl, unsubstituted aliphatic C1-10, or aliphatic C1-10 substituted with one or two substituents selected from -OH, halogen, carboxyl, carboxylic acid ester, heterocyclyl, amino, alkoxy, phosphate, cycloalkyl, alkenyl, -OC(O)NH(C1-4alkyl)-amino, -OC(O)R ⁸ ; or -OC(O)(CHR ⁹ )2CO ₂ H. The -OC(O)-R ⁸ substituent can be derived from an amino acid, especially a naturally occurring amino acid, where the -OC(O)- moiety -OC(O)-R ⁸ corresponds to acid moiety of an amino acid and R ⁸ contains -N(R ¹⁰ )2 or a nitrogen-containing non-aromatic heterocyclyl, where R ¹⁰ represents H or a carboxylic acid ester. R ¹ can also be a C1-10 alkyne or a substituted alkyne, such as an alkyne substituted with hydroxyl, oxetanyl, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or phosphate. R ¹ may also be an 8-12 membered spiroheterocyclyl.

Examples of the disclosed compounds include compounds I-98 to I-211 and II-1 to II-61, including picolinamide compounds I-98 to I-174, I-177 and I-190 to I-211; and pyrazole compounds I-175 and I-178 to I-184.

The disclosed embodiments also include pharmaceutical compositions containing the disclosed compounds. Such compositions may additionally contain an excipient,

- 2 045696 additional therapeutic agent or combinations thereof.

The method may include administering to a subject the disclosed compound or compounds, or a composition containing the disclosed compounds or compounds, for example, to treat a disease. In some embodiments, the subject may have or be suspected of having or developing a disease, such as a disease involving receptor-interacting protein 1 (RIP1) kinase. Examples of diseases that can be treated in accordance with this embodiment of the method include diseases or disorders associated with inflammation, necroptosis, or both. In some embodiments, the diseases to be treated with the compounds of the present invention are inflammatory or immunoregulatory disorders, including autoimmune and proliferative disorders. Illustrative examples of diseases are disclosed herein.

The above and other objects and features of the present disclosure will become more apparent from the following detailed description.

Detailed description of the invention

I. Review of terms

The following explanations of terms and methods are provided to better describe the present disclosure and to guide those skilled in the art in the practice of the present disclosure. Singular forms include plural equivalents unless the context clearly indicates otherwise. The term or refers to one element of specified alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, the term contains means includes. Thus, containing A or B means including A, B, or A and B without excluding additional elements.

Unless otherwise indicated, all numbers expressing amounts of components, molecular weights, percentages, temperatures, times, etc., used in the specification or claims are to be understood as modified by the term about. Accordingly, unless explicitly or implicitly stated otherwise, numerical parameters stated are approximate values that may depend on desired properties sought and/or detection limits under standard test conditions/methods. While the embodiments differ directly and clearly from the prior art discussed, embodiment numbers are not approximate unless the word about is explicitly stated.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure applies. Although methods and materials similar or equivalent to those described herein may be used in the practice or investigation of the present invention, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

When chemical structures are depicted or described, unless explicitly stated otherwise, all carbon atoms are assumed to include hydrogen, so that each carbon has a valency of four. For example, the structure on the left side of the diagram below assumes nine hydrogen atoms. Nine hydrogen atoms are shown in the right structure.

Sometimes a particular atom in a structure is described in a text formula as having a hydrogen or hydrogen atoms, such as -CH2CH2-. One skilled in the art will appreciate that the above description techniques are common in the field of chemistry to provide brevity and simplicity in the description of organic structures.

If the R group is depicted as floating in a ring system, such as with R ¹ in the group:

then, unless otherwise specified, the substituent R (eg, R ¹ above) can be located on any atom of the fused bicyclic ring system, with the exception of the atom bearing a bond with ~'~, as long as a stable structure is formed.

When the R group is depicted as existing in a ring system containing saturated carbon atoms, as in the formula

where in this example y can be more than one, assuming that each replaces the currently depicted, implied, or explicitly defined hydrogen in the ring; then, unless otherwise noted, two R's can be on the same carbon. A simple example is when

R represents a methyl group. The structure depicted may exist as a geminal dimethyl on the carbon of the depicted ring (ring carbon). In another example, two R's on the same carbon, including the same carbon, can be included in a ring, thereby creating a spirocyclic ring structure (spirocyclyl group).

As used herein, the term substituted refers to all subsequent modifiers in the term, for example, in the term substituted arylC^alkyl, substitution may occur at the C _1-8 alkyl moiety, the aryl moiety, or both of the arylC1 moieties. ₈ alkyl group.

Substituted, when used to modify a specified group or moiety, means that at least one and possibly two or more hydrogen atoms of the specified group or moiety are independently replaced by the same or different substituent groups, as defined below. In a particular embodiment, a group, moiety, or substituent may be substituted or unsubstituted unless specifically stated as unsubstituted or substituted. Accordingly, any of the groups specified herein may be unsubstituted or substituted unless the context indicates otherwise or the particular structural formula precludes substitution. In particular embodiments, the substituent may or may not be explicitly designated as substituted, but is still intended to not necessarily be substituted. For example, an aliphatic or cyclic moiety may be unsubstituted or substituted, but an unsubstituted aliphatic or unsubstituted cyclic moiety is not substituted.

Substituents or groups of substituents for replacing one or more hydrogen atoms on saturated carbon atoms in the specified group or fragment may be, unless otherwise indicated, -R ⁶⁰ , halogen, =O, -OR ⁷⁰ , -SR ⁷⁰ , -N(R ⁸⁰ )2, haloalkyl, perhaloalkyl, -CN, -NO2, =N ₂ , -N ₃ , -SO2R ⁷⁰ , -SO;M'„ -SO3R ⁷⁰ , -OSO2R ⁷⁰ , -OSO;M'„ -OSO3R ⁷⁰ , -P(O)(O')2(M ⁺ )2, -P(O)(O')2M2 ⁺ ,

-P(O)(OR ⁷⁰ )OM ⁺ , -P(O)(OR ⁷⁰ )2, -C(O)R ⁷⁰ , -C(S)R ⁷⁰ , -C(NR ⁷⁰ )R ⁷⁰ , -CO2 M', -CO2R ⁷⁰ , -C(S)OR ⁷⁰ , -C(O)N(R ⁸⁰ )2, -C(NR ⁷⁰ )(R ⁸⁰ )2, -OC(O)R ⁷⁰ , -OC( S)R ⁷⁰ , -OCO2 M', -OCO2R ⁷⁰ , -OC(S)OR ⁷⁰ , -NR ⁷⁰ C(O)R ⁷⁰ , -NR ⁷⁰ C(S)R ⁷⁰ , -NR^-M, -NR ⁷⁰ CO2R ⁷⁰ , -NR ⁷⁰ C(S)OR ⁷⁰ , -NR ⁷⁰ C(O)N(R ⁸⁰ )2, -NR ⁷⁰ C(NR ⁷⁰ )R ⁷⁰ and -NR ⁷⁰ C(NR ⁷⁰ )N(R ⁸⁰ )2, where R ⁶⁰ represents a _C1-10 aliphatic, heteroaliphatic or cycloaliphatic group, typically a C ₁ - ₆ aliphatic group, more typically a C 1 - ₆ alkyl, where R ⁶⁰ may optionally be substituted; each R ⁷⁰ is independently for each case hydrogen or R ⁶⁰ ; each R ⁸⁰ is independently in each case an R ⁷⁰ or, alternatively, two R ⁸⁰ groups together with the nitrogen atom to which they are bonded form a 3-7 membered heterocycloaliphatic group which optionally contains 1-4 identical or different additional heteroatoms, selected from O, N and S, of which N optionally has an R ⁷⁰ substitution, such as an H or C1-C3 alkyl substitution; and each M ⁺ is a counterion with a net unit positive charge. Each M ⁺ independently for each case represents, for example, an alkali metal ion such as K ⁺ , Na ⁺ , Li ⁺ ; ammonium ion such as +N(R ⁶⁰ )4; a protonated amino acid ion such as a lysine ion or an arginine ion; or an alkaline earth metal ion such as [Ca ²⁺ ]0.5, [Mg ²⁺ ] _0.5 or [Ba ²⁺ ]0.5 (the subscript 0.5 means, for example, that one of the counterions for such divalent The alkaline earth metal ions may be the ionized form of the compound of this invention, and another typical counterion such as chloride, or two ionized compounds may serve as counterions for such divalent alkaline earth metal ions, or a doubly ionized compound may serve as the counterion for such divalent alkaline earth metal ions ). As specific examples, -N(R ⁸⁰ )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, N-morpholinyl and the like. similar. Any two hydrogen atoms on one carbon can also be replaced, for example, by =O, =NR ⁷⁰ , =N-OR ⁷⁰ , =N2 or =S.

Substituent groups for replacing hydrogen atoms on unsaturated carbon atoms in groups containing unsaturated carbon atoms are, unless otherwise noted, -R⁶⁰, halogen, -O M⁺, -OR⁷⁰,-SR⁷⁰, -S M', -N(R⁸⁰)2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R⁷⁰, -SO3^-M⁺, -SO3R⁷⁰,-OSO2R⁷⁰,-OSO3^-M⁺,-OSO3R⁷⁰, -PO3^-2(M⁺)2, -PO3^-2M²⁺, -P(O)(OR⁷⁰)O'M⁺, -P(O)(OR⁷⁰)2, -C(O)R⁷⁰, -C(S)R⁷⁰, -C(NR⁷⁰)R⁷⁰, -CO2M⁺, -^R⁷⁰, -C(S)OR⁷⁰, -C(O)NR⁸⁰R⁸⁰, -C(NR⁷⁰)N(R⁸⁰)2, -OC(O)R⁷⁰,-OC(S)R⁷⁰, -OCO2M⁺,-OCO2R⁷⁰,-OC(S)OR⁷⁰, -NR⁷⁰C(O)R⁷⁰, -NR⁷⁰C(S)R⁷⁰, -NR^O^', -NR⁷⁰CO2R⁷⁰, -NR⁷⁰C(S)OR⁷⁰, -NR⁷⁰C(O)N(R⁸⁰)2, -NR⁷⁰C(NR⁷⁰)R⁷⁰ and -NR⁷⁰C(NR⁷⁰)N(R⁸⁰)2, where R⁶⁰, R⁷⁰, R⁸⁰ them⁺ previously defined. In an independent embodiment of the invention, the substituents are not -O M^', -OR⁷⁰, -SR⁷⁰ or -S^-M^'.

Substituent groups for replacing a hydrogen atom on nitrogen atoms in groups containing such nitrogen atoms are, unless otherwise indicated, -R ⁶⁰ , -O ^- M ^' , -OR ⁷⁰ , -SR ⁷⁰ , -S ^- M ^' , - N(R ⁸⁰ )2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R ⁷⁰ , -SO3 ^- M ⁺ , -SO3R ⁷⁰ , -OS(O)2R ⁷⁰ , -OSO3 ^- M ⁺ , -OSO3R ⁷⁰ , -PO32 ^- (M ⁺ )2, -PO3 ^2- M ²⁺ , -P(O)(OR ⁷⁰ )O'M ⁺ , -P(O)(OR ⁷⁰ )(OR ⁷⁰ ), - C(O)R ⁷⁰ , -C(S)R ⁷⁰ , -C(NR ⁷⁰ )R ⁷⁰ , -^R ⁷⁰ , -C(S)OR ⁷⁰ , -C(O)NR ⁸⁰ R ⁸⁰ , -C( NR ⁷⁰ )NR ⁸⁰ R ⁸⁰ , -OC(O)R ⁷⁰ , -OC(S)R ⁷⁰ , -O^R ⁷⁰ , -OC(S)OR ⁷⁰ , -NR ⁷⁰ C(O)R ⁷⁰ , -NR ⁷⁰ C(S)R ⁷⁰ , -NR ⁷⁰ CO2R ⁷⁰ , -NR ⁷⁰ C(S)OR ⁷⁰ , -NR ⁷⁰ C(O)N(R ⁸⁰ )2, -NR ⁷⁰ C(NR ⁷⁰ )R ⁷⁰ and - NR ⁷⁰ C(NR ⁷⁰ )N(R ⁸⁰ ) ₂ where R ⁶⁰ , R ⁷⁰ , R ⁸⁰ and M ^' are as previously defined.

- 4 045696

In one embodiment, the substituted group has at least one substituent, up to the number of substituents possible for a particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

Additionally, in embodiments where a group or moiety is substituted with a substituted substituent, the nesting of such substituted substituents is limited to three, thereby preventing the formation of polymers. Thus, in a group or moiety containing a first group that is a substituent of a second group that is itself a substituent of a third group attached to the parent structure, the first (outermost) group can be substituted only with unsubstituted substituents. For example, in a group containing -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with substituents that are not themselves substituted.

Any group or moiety defined herein may be related to any other part of the disclosed structure, such as the parent or core structure, as will be appreciated by one skilled in the art, for example, by consideration of valence rules, comparison with exemplary views, and/or taking into account functionality, unless the group or fragment's relationship to another part of the structure is expressly indicated or implied by the context.

Acyl refers to the group -C(O)R, where R represents H, an aliphatic, heteroaliphatic or aromatic group (including both aryl and heteroaryl).

Illustrative examples of acyl groups include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C ₁ -C ₆ -alkyl, -C(O)C ₁ -C ₆ -haloalkyl , -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl or -C(O)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

Aliphatic refers to a group or moiety primarily based on hydrocarbons. The aliphatic group or moiety may be acyclic, including alkyl, alkenyl, or alkynyl groups (as well as alkylene, alkenylene, or alkynylene groups), cyclic variants thereof, such as cycloaliphatic groups or moieties, including cycloalkyl, cycloalkenyl, or cycloalkynyl, and further including straight line arrangements. and branched chain, as well as all stereoisomers and positional isomers. Unless specifically stated otherwise, an aliphatic group contains from one to twenty-five carbon atoms (C ₁ _ ₂₅ ); for example, from one to fifteen (C _1-15 ), from one to ten (Cm ₀ ), from one to six (C _1-6 ) or from one to four carbon atoms (Cm) for an acyclic aliphatic group or moiety, or three to _fifteen ( _C3-15 ), three to ten ( _{C3_10} ), three to _{six (C3-6 )} or three to _four ( _{C3_4} ) carbon atoms for a cycloaliphatic group or moiety . An aliphatic group may be substituted or unsubstituted unless specifically stated as an unsubstituted aliphatic group or a substituted aliphatic group. The aliphatic group may be replaced by one or more substituents (up to two substituents for each methylene carbon in the aliphatic chain, or up to one substituent for each carbon of the C=C- double bond in the aliphatic chain, or up to one substituent for the carbon atom of the terminal methine group).

A lower aliphatic group refers to an aliphatic group containing one to ten carbon atoms (Cm ₀ ), such as one to six (C _1-6 ) or one to four (Cm) carbon atoms; or from three to ten (C ₃ . ₁₀ ), for example, from three to six (C ₃ - ₆ ) carbon atoms for the lower cycloaliphatic group.

Alkoxy refers to the group -OR, where R represents a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group. In some examples, R is C ₁ . ₆ alkyl group or C ₃ . ₆ cycloalkyl group. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are illustrative examples of alkoxy groups. In substituted alkoxy, R is substituted alkyl or substituted cycloalkyl, examples of which in currently disclosed compounds include haloalkoxy groups such as -OCF2H.

Alkoxyalkyl refers to the group -alkyl-OR, where R represents a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group; -CH ₂ CH ₂ -O-CH ₂ CH ₃ is an exemplary alkoxyalkyl group.

Alkyl refers to a saturated aliphatic hydrocarbyl group having from 1 to at least 25 (C ₁ - ₂₅ ) carbon atoms, more typically from 1 to 10 (Cm ₀ ) carbon atoms, for example from 1 to 6 (Cm) carbon atoms. The alkyl group may be substituted or unsubstituted. The term includes, by way of example, linear and branched hydrocarbon groups such as methyl (CH ₃ ), ethyl (-CH ₂ CH ₃ ), n-propyl (-CH ₂ CH ₂ CH ₃ ), isopropyl (-CH (CH ₃ ) ₂ ), n-butyl (-CH ₂ CH ₂ CH ₂ Ch ₃ ), isobutyl (-CH ₂ CH ₂ (CH ₃ ) ₂ ), sec-butyl (-CH(CH ₃ )(CH ₂ Ch ₃ ), tert-butyl (-C(CH ₃ ) ₃ ), npentyl (-CH2CH2CH2CH2CH3) and neopentyl (-CH2C(CH3)3).

Amino refers to a -NH ₂ , -NHR or -NRR group, where each R is independently selected from H, an aliphatic, a heteroaliphatic, an aromatic group including both aryl and heteroaryl, or a heterocycloaliphatic group, or two R groups together with a nitrogen atom, attached to them form a heterocyclic ring. Examples of such heterocyclic rings include rings in which two R groups, together with the nitrogen atom to which they are attached, _form a -(CH ₂ ) _{2_5} - ring, optionally interrupted by one or two heteroatom groups such as -O- or -N (R ^g ), such as in

- 5 045696 groups, \/ and ^N \— ^/NR , where R ^g represents R ⁷⁰ , -C(O)R ⁷⁰ , -C(O)OR ⁶⁰ or -C(O)N(R ⁸⁰ ) ₂ .

Amide refers to the group -N(R)acyl, where R represents hydrogen, a heteroaliphatic or aliphatic group such as alkyl, in particular C _1-6 alkyl.

Aromatic refers to a cyclic conjugated group or group consisting, unless otherwise noted, of 5-15 ring atoms, having a single ring (such as phenyl, pyridinyl or pyrazolyl) or multiple fused rings in which at least one ring is aromatic (eg naphthyl, indolyl or pyrazolopyridinyl), that is, at least one ring and optionally more than one fused ring, have a continuous delocalized π electron system. Typically, the number of π electrons out of plane follows Hückel's rule (4n+2). The point of attachment to the parent structure is usually through the aromatic part of the fused ring system.

For example, o. However, in certain examples, the context or express disclosure may indicate that the point of attachment passes through the non-aromatic portion of the fused ring system. For example,

. An aromatic group or moiety may contain only ring carbon atoms, such as an aryl group or moiety, or it may contain one or more ring carbon atoms and one or more ring heteroatoms containing a lone pair of electrons (e.g., S, O, N, P or Si), for example, in a heteroaryl group or fragment. Unless otherwise specified, an aromatic group may be substituted or unsubstituted.

Aryl refers to an aromatic carbocyclic group containing, unless otherwise indicated, from 6 to 15 carbon atoms, having a single ring (for example, phenyl) or multiple fused rings in which at least one ring is aromatic (for example, 1,2, 3,4tetrahydroquinoline, benzodioxole, etc.). If any part of the aromatic ring contains a heteroatom, the group is heteroaryl rather than aryl. Aryl groups can be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise specified, the aryl group may be substituted or unsubstituted.

Araliphatic refers to an aryl group attached to the parent component through an aliphatic moiety. Araliphatic groups include aralkyl or arylalkyl groups such as benzyl and phenylethyl.

Carboxyl is related to -CO2H.

Carboxamide belongs to -C(O)amino.

Carboxyl ether or carboxyether refers to the group -C(O)OR, where R represents an aliphatic, heteroaliphatic or aromatic group (including both aryl and heteroaryl).

Carboxylate refers to -C(O)O or its salt.

Cyano belongs to the -CN group.

Cycloaliphatic refers to a cyclic aliphatic group having one ring (eg cyclohexyl) or multiple rings, for example, in a fused, bridged or spirocyclic system, the ring or at least one of the rings in the system is aliphatic. Typically, the point of attachment to the parent structure is through the aliphatic portion of the multiple ring system. Cycloaliphatics include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl and cycloalkynyl. A cycloaliphatic group can contain from three to twenty-five carbon atoms; for example, three to fifteen, three to ten, or three to six carbon atoms. Unless otherwise specified, the cycloaliphatic group may be substituted or unsubstituted. Examples of cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

Halogen, halide refers to fluorine, chlorine, bromine or iodine.

Haloalkyl refers to an alkyl moiety substituted with one or more halogen atoms. Examples of haloalkyl moieties include -CH2F, -CHF2 and -CF ₃ .

'Teteroaliphatic refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, that is, at least one carbon atom from an aliphatic compound or group containing at least two carbon atoms is replaced by an atom having at least one lone pair of electrons, usually nitrogen, oxygen, phosphorus, silicon or sulfur. Heteroaliphatic compounds or groups may be substituted or unsubstituted, branched or unbranched, chiral or achiral and/or acyclic or cyclic, such as a heterocycloaliphatic group.

Heteroaryl refers to an aromatic group or moiety having, unless otherwise indicated, from 5 to 15 ring atoms containing at least one carbon atom and at least one heteroatom, such as N, S, O, P or Si. A heteroaryl group or moiety may contain one

- 6 045696 ring (for example, pyridinyl, pyrimidinyl or pyrazolyl) or several fused rings (for example, indolyl, benzopyrazolyl or pyrazolopyridinyl). Heteroaryl groups or moieties may be, for example, monocyclic, bicyclic, tricyclic or tetracyclic.

Unless otherwise indicated, the heteroaryl group or moiety may be substituted or unsubstituted.

Heterocyclyl, heterocyclo and heterocycle refer to both aromatic and non-aromatic ring systems and, more specifically, refer to a stable ring moiety of three to fifteen members containing at least one carbon atom and typically multiple carbon atoms, and at least one, for example one to five heteroatoms. The heteroatom(s) may be nitrogen, phosphorus, oxygen, silicon or sulfur atom(s). The heterocyclyl moiety may be monocyclic or may contain multiple rings, for example in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such a multi-ring ring fragment may include fused or bridged ring systems, as well as spirocyclic systems; and any nitrogen, phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl moiety may optionally be oxidized to various oxidation states. For convenience, nitrogen atoms, particularly but not exclusively those defined as ring-shaped aromatic nitrogens, are meant to include their corresponding N-oxide form, although this is not explicitly defined as such in the specific example. Thus, for a compound having, for example, a pyridinyl ring, the corresponding pyridinyl-N-oxide is included as another compound of the present invention unless expressly excluded or excluded by context. In addition, the ring nitrogen atoms may optionally be quaternized. The heterocycle includes heteroaryl moieties as well as heteroalicyclyl or heterocycloaliphatic moieties, which are heterocyclyl rings that are partially or fully saturated. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, quinolinyl, chi noxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolinyl, im idazolinyl dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl . tahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl , thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothielyyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl and oxadiazolyl.

Hydroxyl belongs to the -OH group.

Nitro belongs to the -NO2 group.

Phosphate belongs to the group -OP(O)(OR') ₂ where each -OR' independently represents -OH; O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; -O-aralkyl; or -OR' is -O ^- M ⁺ , where M ⁺ is a counterion with a single positive charge. Each M ⁺ may be an alkali metal ion such as K ⁺ , Na ⁺ , Li ⁺ ; an ammonium ion such as +N(R) ₄ where R is H, an aliphatic, heteroaliphatic or aromatic group (including both aryl and heteroaryl); or an alkaline earth metal ion such as [Ca ²⁺ ]0.5, [ _Mg ²⁺ ] _0.5 or [Ba ²⁺ ] _0.5 . Phosphonooxyalkyl refers to the alkyl phosphate group, such as -CH ₂ OP(O)(OH) ₂ , or its salts, such as -CH ₂ OP(O)(O ^- Na ⁺ ) ₂ , and ((( dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ether of a phosphonooxyalkyl group, such as, for example, -CH ₂ OP(O)(O-tert-butyl) ₂ .

Phosphonate belongs to the group -P(O)(OR') ₂ where each -OR' independently represents -OH; O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic group, including both -Oaryl and -O-heteroaryl; or -O-aralkyl; or -OR' represents -O ^- M ⁺ , and M ⁺ represents a counterion with a single positive charge. Each M ⁺ is a positively charged counterion and may be, for example, an alkali metal ion such as K ⁺ , Na ⁺ , Li ⁺ ; an ammonium ion such as +N(R) ₄ where R is H, an aliphatic, heteroaliphatic or aromatic group (including both aryl and heteroaryl); or an alkaline earth metal ion such as [Ca ²⁺ ]0.5, [ _Mg ²⁺ ] _0.5 or [Ba ²⁺ ] _0.5 . Phosphonoalkyl refers to the -alkylphosphonate group, such as -CH ₂ P(O)(OH) ₂ , or -CH ₂ P(O)(O ^- Na ⁺ ) ₂ , and ((dialkoxyphosphoryl)alkyl) refers to dialkyl an ester of a phosphonoalkyl group, such as, for example, -CH ₂ P(O)(O-tert-butyl) ₂ .

Patient or subject in general can refer to any living creature, but more commonly refers to mammals and other animals, particularly humans. Thus, the disclosed methods are applicable in both human and veterinary medicine.

A pharmaceutically acceptable excipient refers to a substance other than the active ingredient that is included in a composition containing the active ingredient. The excipient used herein may be included in the particles of the pharmaceutical composition or may be physically mixed with the particles of the pharmaceutical composition. The excipient can be used, for example, to dilute the active agent and/or to change the properties of the pharmaceutical composition. Excipients may include, but are not limited to, release agents, binders, coatings, enteric coatings, disintegrating agents, flavoring agents, sweeteners, coloring agents, lubricants, lubricants, sorbents, preservatives, carriers or excipients.

Excipients may be starches and modified starches, cellulose and cellulose derivatives, saccharides and their derivatives such as disaccharides, polysaccharides and sugar alcohols, protein, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Examples of excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starches, hydroxypropylcellulose, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silicon dioxide, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite or lanolin.

An adjuvant is a component that modifies the action of other agents, usually the active ingredient. Adjuvants are often pharmacological and/or immunological agents. An adjuvant can modify the action of the active ingredient by enhancing the immune response. An adjuvant may also act as a stabilizing agent for the drug. Examples of adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants such as Freund's complete adjuvant or Freund's incomplete adjuvant.

A pharmaceutically acceptable carrier refers to an excipient that is a carrier or carrier medium, such as a suspension additive, a solubilizing additive, or an aerosol additive. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, Pennsylvania, ^21st edition (2005), incorporated herein by reference, describes illustrative examples compositions and formulations suitable for the pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

In general, the nature of the carrier will depend on the particular route of administration used. For example, formulations for parenteral administration typically contain injectable liquids that include pharmaceutically and physiologically acceptable liquids such as water, saline, balanced salt solutions, aqueous dextrose, glycerin, and the like. as a carrier. In some examples, the pharmaceutically acceptable carrier may be sterile so as to be suitable for administration to a subject (eg, by parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the administered pharmaceutical compositions may contain minor amounts of non-toxic excipients such as wetting or emulsifying agents, preservatives and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

Pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of a compound that are derived from various organic and inorganic counterions known to those skilled in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. Pharmaceutically acceptable acid addition salts are a subset of pharmaceutically acceptable salts that retain the biological effectiveness of the free bases when formed by acidic partners. In particular, the disclosed compounds form salts with various pharmaceutically acceptable acids, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid and the like. Pharmaceutically acceptable base addition salts are a subset of pharmaceutically acceptable salts derived from inorganic bases, such as salts on

- 8 045696 trium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Examples of salts are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine , tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Examples of organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. (See, for example, S. M. Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 1977; 66:1-19, which is incorporated herein by reference.) In certain disclosed embodiments, the compounds may be formate , trifluoroacetate, hydrochloride or sodium salt.

An effective amount, with respect to a compound or pharmaceutical composition, refers to an amount of the compound or pharmaceutical composition sufficient to achieve a particular desired result, such as inhibition of a protein or enzyme. In specific embodiments, the effective amount is an amount sufficient to inhibit RIP1; to induce a desired biological or medical response in a tissue, system, subject or patient; to treat a specific disorder or disease; to improve or eliminate one or more of its symptoms; and/or to prevent the occurrence of a disease or disorder. The amount of the compound that constitutes an effective amount may vary depending on the compound, the desired result, the condition of the disease and its severity, the size, age and sex of the patient to be treated, and the like. will be clear to one skilled in the art.

Prodrug refers to compounds that are converted in vivo to produce a biologically active compound or a compound that is more biologically active than the parent compound. In vivo conversion can occur, for example, by hydrolysis or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds herein include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, in particular alkyl esters (eg, C ₁ . ₆ alkyl esters). Other prodrug moieties include phosphoric acid esters such as -CH2-OP(O)(OR') ₂ or a salt thereof, where R' is H or C ₁ . ₆ alkyl. Suitable esters also include cycloalkyl ethers and arylalkyl esters such as, but not limited to, benzyl. Examples of pharmaceutically acceptable amides of the compounds of the present invention include, but are not limited to, primary amides, as well as secondary and tertiary alkylamides (eg, those containing from about one to about six carbon atoms). The amides and esters of the disclosed illustrative embodiments of the compounds of the present disclosure can be prepared in accordance with conventional methods. A detailed discussion of prodrugs is presented in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, volume 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

Solvate refers to a complex formed by the combination of solvent molecules with solute molecules or ions. The solvent may be an organic solvent, an inorganic solvent, or a mixture thereof. Examples of solvents include, but are not limited to, alcohols such as methanol, ethanol, propanol; amides such as N,N-diαliphatic amides such as N,N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides such as dimethyl sulfoxide; water; and their combinations. The compounds described herein may exist in either unsolvated or solvated forms when combined with solvents, whether pharmaceutically acceptable or not, such as water, ethanol, and the like. Solvated forms of the compounds disclosed herein are within the scope of the embodiments disclosed herein.

Sulfonamide refers to the group or moiety -SO2 amino or -N(R)sulfonyl, where R is H, an aliphatic, heteroaliphatic or aromatic group (including both aryl and heteroaryl).

Sulfanyl refers to the group or -SH, -S-aliphatic, -S-heteroaliphatic, -Saromatic (including both -S-aryl and -S-heteroaryl) group.

Sulfinyl refers to a -S(O)H, -S(O)aliphatic, -S(O)heteroαliphatic, or -S(O)aromatic group or moiety (including both -S(O)aryl and -S(O) heteroaryl) group.

Sulfonyl belongs to the group: -SO2H, -SO ₂ aliphatic, -SO ₂ heteroaliphatic, -SO ₂ aromatic (including both -SO ₂ aryl and -SO ₂ heteroaryl) group.

- 9 045696

Treating or treatment as used herein refers to the treatment of a disease or condition of interest in a patient or subject, particularly a person suffering from the disease or condition of interest, and includes by way of example, but without limitation:

(i) preventing the occurrence of a disease or condition in a patient or subject, particularly when such patient or subject is susceptible to the condition but has not yet been diagnosed as having it;

(ii) inhibiting a disease or condition, such as stopping or slowing its progression;

(iii) alleviating a disease or condition, such as by causing symptom relief or regression of the disease or condition or a symptom thereof; or (iv) stabilization of the disease or condition.

As used herein, the terms disease and condition may be used interchangeably or may be distinguished in that a particular disease or condition may have no known causative agent (so the etiology has not yet been determined) and therefore cannot be defined as a disease, but only as an undesirable condition or syndrome, where clinicians identify a more or less specific set of symptoms.

The above definitions and the following general formulas are not intended to include invalid substitution patterns (eg, methyl substituted with 5 fluorine groups). Such invalid substitution patterns are readily recognized by one of ordinary skill in the art.

One of ordinary skill in the art will appreciate that compounds may exhibit tautomerism, conformational isomerism, geometric isomerism, and/or optical isomerism. For example, some of the disclosed compounds may include one or more chiral centers and/or double bonds and, as a result, may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, some of the disclosed compounds may exist in multiple tautomeric forms, including the enol form, the keto form, and mixtures thereof. Since the various compound names, formulas, and drawings of compounds in the specification and claims may represent only one of the possible tautomeric, conformational isomeric, optical isomeric, or geometric isomeric forms, one skilled in the art will recognize that the disclosed compounds include any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the compounds described herein, as well as mixtures of these different isomeric forms. Mixtures of different isomeric forms, including mixtures of enantiomers and/or stereoisomers, can be separated to obtain each individual enantiomer and/or stereoisomer using methods known to those skilled in the art, especially in view of the present invention. In cases of limited rotation, for example around an amide bond or between two directly attached rings, such as pyridinyl rings, biphenyl groups, etc., atropisomers are also possible and are also specifically included in the compounds of this invention.

In any embodiments, any or all of the hydrogen atoms present in a compound, or in a particular group or fragment of a compound, may be replaced by deuterium or tritium. Thus, alkyl includes deuterated alkyls in which from one to the maximum number of hydrogen atoms present may be replaced by deuterium. For example, ethyl refers to both C2H ₅ or C2H ₅ where 1 to 5 hydrogen atoms are replaced by deuterium, such as in C2DxH _5-x .

II. RIPl-active compounds and pharmaceutical compositions containing RIPl-active compounds

A. Connections

Disclosed herein are compounds and pharmaceutical compositions containing such compounds that are useful for inhibiting RIP1 and/or treating diseases and/or conditions associated with RIP1. In some embodiments, the compounds are selective kinase inhibitors. For example, typical compounds are capable of selectively inhibiting RIP1 over RIP2, RIP3, or both RIP2 and RIP3.

In some embodiments, a compound of the present invention has a structure according to Formula I

Formula I or a pharmaceutically acceptable salt thereof. One skilled in the art will appreciate that compounds of formula I also include stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes and/or prodrugs thereof unless otherwise indicated. Regarding formula I, ring B is a goethe

- 10 045696 roaryl, such as 5-membered or 6-membered heteroaryl. In some embodiments, ring B is a 5-membered or 6-membered heteroaryl, wherein the heteroaryl has at least one ring nitrogen atom and optionally one, two, or three ring nitrogen atoms, and the remaining ring atoms are carbon . In some embodiments, ring B does not include three ring nitrogen atoms and ring B is not a triazole, triazine, or heteroaryl containing an oxygen or sulfur atom on the ring, such as an oxazole, thiazole, or isoxazole. In some embodiments, ring B is pyrazolyl, and in other specific embodiments, ring B is pyridinyl.

Each R ¹ may independently represent a halogen, -C=CH, or a -linker-R ⁶ group, where the linker is a bond or R ^a , provided that R ^a is not H or D, and R ⁶ is a heterocyclyl, R ^b , -C(R ^f ) ₃ or -C(R ^f )=C(R ^f )2.

R2 represents R ^a .

R ³ represents R ^a .

If present, each R ⁴ is independently R ^e .

L represents a heteroatom or R ^a , provided that R ^a does not represent H or D.

Z, if present, is aryl or a cycloaliphatic group, including cycloalkyl, such as C _3-6 cycloalkyl;

m is 1, 2, 3 or 4 and n is 0, 1 or 2.

In each case, R ^a is independently H or D, for embodiments except where L is R ^a , a C _1-10 aliphatic group, a C _1-10 halogen aliphatic group, a C _1-10 heteroaliphatic group, a C _5-10 aryl, C _3-6 cycloaliphatic group or C _3-6 heterocycloaliphatic group;

R ^b independently for each case represents -OH, -SH, -OR ^c , -SR ^c , -NR ^d R ^d , -Si(R ^a )3, -C(O)OH, -C(O)OR ^c , -C(O)NR ^d R ^d , -OC(O)NR ^d R ^d , -OC(O)C1-10αalkyl substituted with one or two NR ^d R ^d , carboxyl or a combination thereof, and optionally further substituted with an aromatic moiety , -SH, -O-acyl or -C(O)NH ₂ .

R ^c is independently in each case C1-10alkyl, which may be substituted by 1, 2 or 3 R ^e ; C2-10 alkenyl, which may be substituted with 1, 2 or 3 R ^e ; C2-10alkynyl, which may be substituted with 1, 2 or 3 R ^e ; C3-6cycloalkyl, which may be substituted with 1, 2 or 3 R ^e ; or a C _5-10 aromatic group, which may be substituted with 1, 2 or 3 R ^e .

^Rd is independently for each case H; C _1-6 alkyl, which may be substituted with 1, 2 or 3 R ^e or C 3-9 heterocyclyl; C3-6cycloalkyl, which may be substituted with 1, 2 or 3 R ^e ; C3-6 heterocycle which may be substituted with 1, 2 or 3 R ^e ; C _5-10 aryl, which may be substituted with 1, 2 or 3 R, C _5- logheteroaryl, which may be substituted with 1, 2 or 3 R ^e ; or two R ^d groups together with the associated nitrogen atom form a C3-9 heterocycle, which may be substituted by one or more R ^e ; or C5-10heteroaryl, which may be substituted with one or more R ^e .

R ^e is independently in each case halogen, C _1-6 alkyl, C _2-10 alkenyl, C _2- loalkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _5-10 heteroaryl or -OR ^a .

And R ^f is independently in each case an alkyl phosphate, R ^a , R ^b or R ^e , or two R ^f groups together with the carbon atom bonded to it form a C2-6alkenyl group, a C3-6cycloalkyl group, which may be substituted with one or more ^Re , or a C3-10 heterocyclic group which may be substituted with one or more ^Re or acyl.

In some embodiments of Formula I, the compound is not any of I-1 to I-97 or I-187 to I-189. In other embodiments, the connection is not:

1-56: (5)-4-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-64: (S)-N-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-68: (S)-N-(l-(3 -hydroxy-3 -(methylh/3)but-1 -in-1 -yl-4,4,4-<73 )-5 -methyl-4 -oxo2,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-72: (S)-7V-(8-((3 -hydroxyoxetan-3 -yl)ethynyl)-5 -methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4] oxazepin-3-yl)-4-phenoxypicolinamide; or

1-77: (5)-1-benzyl-7U-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [/>] [1,4]oxazepin-3-yl)-1R-pyrazol-3-carboxamide.

In an independent embodiment, the connection is none of the following:

- 11 045696 (8)-M-(7-(4-(chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-1 -(4-fluorobenzyl)-1H-1,2,4triazol-3-carboxamide;

(8)-1-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2yl)-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3carboxamide;

(8)-5-benzyl-X-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)isoxazole-3-carboxamide;

(8)-1-(4-fluorobenzyl)-X-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]nonan-7yl)-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3carboxamide;

(8)-5-benzyl-X-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

X-((8)-7-((18.48)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

X-((8)-7-((18.48)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1 -(4-fluorobenzyl)-1H-1,2,4triazol-3-carboxamide;

(8)-1-(4-fluorobenzyl)-M-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-M-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin- 3-yl)isoxazole-3-carboxamide;

(8)-5-(4-fluorobenzyl)-M-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-(4-fluorobenzyl)-X-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2yl)-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3carboxamide;

(8)-5-benzyl-M-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin- 3-yl)-1H-1,2,4-triazol-3-carboxamide;

X-((38)-7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

(8)-M-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4] oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

(5)-5-benzyl-A-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)2,3,4,5-tetrahydrobenzo[th] [1,4]oxazepin-3-yl)-\H-1,2,4-triazol-3-carboxamide;

(8)-M-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4] oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazol-3carboxamide;

(8)-5-benzyl-M-(7-((3-chloropropyl)amino)-5-methyl-4-oxo-2,3,4,5

- 12 045696 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-^(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-(4-fluorobenzyl)^-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8yl)-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3carboxamide;

(8)-T4-(7-(azetidin-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl -1H-1,2,4-triazole-3carboxamide;

(8)-5-benzyl-M-(5-methyl-4-oxo-7-(2-oxa-8-azaspiro[4.5]decan-8-yl)2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-^(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-^(7-(2-benzyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)-5methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

(8)-5-benzyl-^(7-(2-benzyl-1-oxo-2,9-diazaspiro[5.5]undecan-9-yl)-5methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

(8)-5-benzyl-M-(5-methyl-4-oxo-7-(3-oxa-9-azaspiro[5.5]undecan-9-yl)2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(S)-5-benzyl-M-(7-(3,3-difluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine- 3-yl)-1H-1,2,4-triazole-3-carboxamide; and (8)-5-benzyl-M-(7-(3-fluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-1H-1,2,4-triazole-3-carboxamide.

In some embodiments of Formula I, ring B is pyridinyl or pyrazolyl; L represents a heteroatom such as oxygen, or C ₁ . ₁₀ aliphatic group such as C ₁ . ₅ an aliphatic group including -CH2 or substituted _C1 . ₅ aliphatic group such as C ₁ . ₅ aliphatic group substituted with cycloaliphatic groups, for example C^cycloaliphatic groups, for example cyclopropyl; Z is aryl, and in some illustrative embodiments it is phenyl or substituted phenyl, or C1. ₁₀ an aliphatic group, including a cycloaliphatic group such as cycloalkyl, in which certain illustrative embodiments are C ₃ . ₆ cycloalkyl; each R ¹ represents a heterocyclyl or a C1.10 aliphatic group; R ² represents an H or C1.10 aliphatic group; R ³ represents H or a C1-10αluphatic group; each R ⁴ is independently halogen or C1. ₁₀ aliphatic group; m is 1, 2, 3 or 4 and n is 0, 1 or 2.

In some embodiments, each R ¹ is independently heterocyclyl, an unsubstituted C1.10 aliphatic group, or a C1.10 aliphatic group substituted with one or two substituents selected from -OH, halogen, carboxyl, carboxylic acid ester, heterocyclyl, amino, alkoxy, phosphate , cycloalkyl, alkenyl, -OC(O)NH(C1.4alkyl)-amino, -OC(O)R ⁸ or -OC(O)(CHR ⁹ )2CO ₂ H. The -OC(O)-R ⁸ fragment can be derived from an amino acid, where the -OC(O)- fragment -OC(O)-R ⁸ corresponds to the acidic fragment of the amino acid, and R ⁸ contains -N(R ¹⁰ ) ₂ or a nitrogen-containing non-aromatic heterocyclyl, where R ¹⁰ represents H or a complex carboxylic acid ester. And each R ⁹ independently represents H or -O-acyl.

With respect to the -OC(O)-R ⁸ moiety, the nitrogen-containing non-aromatic heterocyclyl may be a 5- or 6-membered unsaturated nitrogen-containing heterocyclyl, such as pyrrolidinyl. The amino acid may be any amino acid, such as a naturally occurring amino acid, and may be an amino acid selected from glycine, valine, alanine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine, glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine or proline. One skilled in the art will appreciate that when an amino acid contains one or more chiral centers, all enantiomers, diastereomers, and/or mixtures thereof are considered. For example, the amino acid may be an L-amino acid, a D-amino acid, or a mixture thereof. In some embodiments, the amino acid is an L-amino acid. And in certain embodiments

- 13 045696 o

- OC(O)-R ⁸ is -OC(O)CH(NH ₂ )R ¹¹ , ^ΗΝ Λ or -OC(O)-(CH2)1-2C(NH2)CO2H, where R ¹¹ is a side chain amino acids, and/or may be H, -CH ₃ , isopropyl, χχ xx*

- CH2CH(CH3)2, -CH(CH3)Et, -CH2CH2SCH3, > ^Н > , -CH2OH, -CH(OH)CH3,

- CH ₂ C(O)NH ₂ , -CH ₂ CH ₂ C(O)NH ₂ , -CH ₂ SH, -CH ₂ CH ₂ CH ₂ NHC(O)(NH)NH ₂ , nA -ch ₂ ch ₂ ch ₂ ch ₂ nh ₂ ,

-CH ₂ CO ₂ H or -CH ₂ CH ₂ CO ₂ H.

As for R ¹ , at least one R ¹ may be an 8-12 membered spiroheterocyclyl or a C _1-10 alkyne. The _1-10 alkyne may contain substituents, for example one or two substituents. One specific illustrative example of a substituent may be -OH. In some embodiments, one substituent is oxetanyl, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or phosphate, and/or in some embodiments, one substituent is -OC(O)-R ⁸ .

In some embodiments, m is 1, 2, or 3, and may be 1 or 2, and in some embodiments, m is 1.

R ² may be H or C _1-6 alkyl, for example methyl.

R ³ may be H or C _1-6 alkyl, and in some embodiments, R ³ is H.

Each R ⁴ can independently represent a halogen such as F, Br, Cl or I, or a C _1-10 aliphatic group, such as a C _1-6 alkyl. In some embodiments, each R ⁴ is independently chlorine, fluorine, or methyl.

In some embodiments, n is 0, and in other specific embodiments, n is 1.

Also with respect to formula I, L may be a heteroatom or R ^a , provided that R ^a is not H or D. L may be oxygen or C _1-10 alkyl, for example C _1-6 alkyl, in particular methylene (-CH ₂ -). Z represents a C _1-10 aliphatic group or aryl. In some embodiments, Z is C _3-6 cycloalkyl, such as cyclobutyl or cyclopentyl, or C _1-6 alkyl, such as methyl. In some embodiments, the -LZ moiety is phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 2-fluorophenoxy, 2,4-difluorophenoxy, 2,6difluorophenoxy, 4-fluorobenzyl, 2,6-dimethylphenoxy, cyclobutyloxy, cyclopentyloxy, methoxy, 4methylphenoxy or benzyl.

In some embodiments of Formula I, the compound may have a structure according to Formulas I-1 or I-2:

Formula 1-1

Formula 1-2.

In some embodiments, the compound may have a structure according to one or more of the following formulas:

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With respect to Formulas I-1 through I-20, ring B, L, Z, R ¹ , R ² , R ³ , R ⁴ , m and n, if present, are as defined herein for Formula I .

In any of the above embodiments relating to Formula I and/or Formulas I-1 to I-20, R ¹ may be selected from any of the following:

- 15 045696

- 16 045696

And, in some embodiments of Formula I and/or Formulas I-1 through I-32, R ¹ may be selected from any of the following:

- 17 045696

In other embodiments of Formula I

Formula I ring B is a 5-membered or 6-membered heteroaryl;

L represents a heteroatom or R ^a with the proviso that R ^a does not represent H or D;

Z represents a C _1-10 aliphatic group (such as C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl

- 18 045696 or C ₃ . ₆ cycloalkyl); or ^p

R ¹ represents a halogen (-F, -Cl, -Br, -1)-C^CH, or the linker - R ⁶ represents a group where the linker is R ^a , provided that R ^a is not H or D, and R ⁶ is R ^b , -C(R ^f ) ₃ or -C(R ^f )=C(R ^f b;

R ² and R ³ are independently R ^a ;

R ⁴ and R ⁵ are independently R ^e ;

R ^a is independently in each case H or D (except for embodiments where L is R ^a ), C ₁ . ₁₀ aliphatic group (for example, C ₁ . ₁₀ alkyl, C ₂ . ₁₀ alkenyl, C ₂ . ₁₀ alkynyl or C ₃ . ₆ cycloalkyl), C ₁ . ₁₀ halogen aliphatic group, C ₅ . ₁₀ aryl, C ₃ . ₆ cycloaliphatic group or C ₃ . ₆ heterocycloaliphatic group;

R ^b independently for each case represents -OH, -SH, -OR ^c , -SR ^c , -NR ^d R ^d , -Si(R ^a ) ₃ , -C(O)OH, -C(O)OR ^c or -C(O)NR ^d R ^d ;

R ^c is independently in each case a C1.10 alkyl (which may be substituted with 1, 2 or 3 R ^e ), C2. ₁₀ alkenyl (which may be substituted with 1, 2 or 3 R ^e ), C2.10 alkynyl (which may be substituted with 1, 2 or 3 R ^e ), C3. ₆ cycloalkyl (which may be substituted with 1, 2 or 3 R ^e ) or ^-^ aromatic group (which may be substituted with 1,2 or 3 R ^e );

^Rd is independently for each case H; C1.6alkyl (which may be substituted with 1, 2 or 3 R ^e ); C3. ₆ cycloalkyl (which may be substituted with 1, 2 or 3 R ^e ); a C3.6 heterocyclic group (which may be substituted with 1, 2 or 3 R ^e ); C5. ₁ oaryl (which may be substituted with 1, 2 or 3 R ^b ); C5.1oheteroaryl (which may be substituted with 1, 2 or 3 R ^e ); or two R ^d groups together with the nitrogen atom attached to them form C3. ₉ heterocyclic group (which may be substituted by one or more ^Re ) or heteroaryl C _5-10 (which may be substituted by one or more ^Re );

R ^e is independently in each case a halogen, C ₁ . ₆ alkyl, C ₂ . ₁ oalkenyl, C ₂ . ₁ oalkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, C ₅ . ₁ oheteroaryl or -OR ^a ;

R ^f is independently in each case R ^a , R ^b or R ^e or the two R ^f groups together with the carbon atom bonded thereto form C ₃ . _{a 6} cycloalkyl group (which may be substituted by one or more ^Re ), or a ^-^ heterocyclic group (which may be substituted by one or more ^Re );

m is from 1 to 4, for example 1, 2, 3 or 4, in certain embodiments equal to 1 or 2;

n is 0, 1 or 2; and p is 0, 1, 2, 3, 4 or 5.

In some embodiments, a compound of the present invention may have a structure satisfying Formula IA

Formula IA, or a pharmaceutically acceptable salt thereof. One skilled in the art will appreciate that the general formulas disclosed include all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and/or prodrugs of compounds otherwise having the structural features required by such formulas.

With reference to formula IA, ring B is a 5-membered or 6-membered heteroaryl;

L represents a heteroatom or R ^a , with the proviso that R ^a does not represent H or D;

R ¹ is halogen, -C^CH, or linker-R ⁶ is a group wherein the linker is R ^a , provided that R ^a is not H or D, and R ⁶ is R ^b , -C(R ^f )3 or -C(R ^f )=C(R ^f )2;

R ² and R ³ are independently R ^a ;

R ⁴ and R ⁵ are independently R ^e ;

R ^a is independently in each case H or D (except for embodiments where L is R ^a ), C ₁ . ₁₀ aliphatic group (for example, C ₁ . ₁₀ alkyl, C ₂ . ₁₀ alkenyl, C ₂ . ₁₀ alkynyl or C ₃ . ₆ cycloaliphatic group, for example C ₃ . ₆ cycloalkyl), C ₁ . ₁₀ halogen aliphatic group, C ₁ . ₁₀ heteroaliphatic group, C ₅ . ₁₀ aryl, or C ₃ . ₆ heterocycloaliphatic group, for example C ₃ . ₆ heterocycloalkyl;

R ^b independently for each case represents -OH, -SH, -OR ^c , -SR ^c , -NR ^d R ^d , -Si(R ^a ) ₃ , -C(O)OH, -C(O)OR ^c or -C(O)NR ^d R ^d ;

R ^c is independently in each case a C1.10 alkyl (which may be substituted with 1, 2 or 3 R ^e ), C2. ₁₀ alkenyl (which may be substituted with 1, 2 or 3 R ^e ), C2.10 alkynyl (which may be substituted with 1, 2 or 3 R ^e ), C3. ₆ cycloalkyl (which may be substituted with 1, 2 or 3 R ^e ) or C ₅ . ₁₀ aromatic group (which may be substituted with 1, 2 or 3 R ^e );

- 19 045696

R ^d is independently for each case H; C1-6alkyl (which may be substituted with 1, 2 or 3 R ^e ); C3-6cycloalkyl (which may be substituted with 1, 2 or 3 R ^e ); a C3-6 heterocyclic group (which may be substituted with 1, 2 or 3 R ^e ); C5-10aryl (which may be substituted with 1, 2 or 3 R ^b ); C5-10heteroaryl (which may be substituted with 1, 2 or 3 R ^e ); or two R ^d groups together with the associated nitrogen atom form a ^^heterocyclic group (which may be substituted by one or more ^Re ) or a C5-10 heteroaryl (which may be substituted by one or more ^Re );

R ^e is independently in each case halogen, C _1-6 αalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _5-10 heteroaryl or -OR ^a ;

R ^f is independently in each instance R ^a , R ^b , or R ^e , or the two R ^f groups together with the carbon atom attached thereto form a C3-6 cycloalkyl group (and in some embodiments, the C3-6 cycloalkyl group is substituted with one or more ^Re ), or a C3-10 heterocycle (and in some embodiments, the C3-10 heterocycle is substituted with one or more ^Re );

m is from 1 to 4, for example 1, 2, 3 or 4, in certain embodiments equal to 1 or 2;

n is 0, 1 or 2 and p is 0, 1, 2, 3, 4 or 5.

In specific embodiments of Formulas I or IA, the 5-membered heteroaryl group may fi,.

have a structure satisfying the formula wherein at least one W is nitrogen and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen or NH. In some embodiments, the 5-membered heteroaryl group is a diazole, triazole, oxadiazole, or oxazole. Examples of triazoles include any of the following:

Illustrative examples of diazoles are selected from any of the following:

OR .

Illustrative examples of oxazoles are selected from any of the following:

Illustrative examples of oxadiazoles are selected from any of the following:

In specific embodiments of Formulas I or IA, L is oxygen or R ^a where R ^a is C ₁ -C ₄ alkyl such as -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-. In some embodiments, L is -CH2- or oxygen.

The linker group of R ¹ groups, where R ¹ is a linker-R ⁶ , is a C1, C2, C3 or C4 aliphatic group, such as a C2 alkyl group, alkenyl group or alkynyl group, or a C1, C2, C3 or C4 haloaliphatic group , such as a C2 haloalkyl group or haloalkenyl group. In some embodiments, the linker group R ¹ is R ^a where R ^a is a C1-C4 alkyl such as -CH2-, -CH2CH2-, _{-CH2CH2CH2- or} -CH2CH2CH2CH2-; or the linker group is a C ₂ -C ₄ alkenyl such as -CH=CH-, -CH=CHCH ₂ -, -CH ₂ CH=CH- or -CH ₂ CH=CHCH ₂ -; or the linker group is a C2-C4 alkynyl such as -C=C-, -C=CCH ₂ -, -CH ₂ C=C- or -CHC=C-CH ₂ -. In some embodiments, the linker group is a C2-C4 haloalkenyl such as -CF=CH-, -CCl=CH-, -CH=CCl-, -CH=CF-, -CCl=CCl-, -CF=CF -or -CCl=CF-, -CF=CCl-. In some embodiments, the linker group is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, -CCl=CH-, -CH=CCl-, or -C=C-.

R ⁶ , the group R ¹ is C(R ^f ) 3 in some embodiments, where one R ^f is R ^e , where R ^e is -OR ^a (eg, hydroxyl or OMe) and each other R ^f is independently R ^a where R ^a represents a C1-4 aliphatic group, and preferably each of R ^f represents R ^a , where R ^a is independently in each case a C1-4 alkyl. In specific embodiments, each other R ^f is R ^a where R ^a is methyl or CD3. In some further embodiments, R ⁶ is -C(R ^f ) 3 , wherein each R ^f is R ^a , wherein R ^a is methyl or H, or where each R ^f

- 20 045696 is R ^a where R ^a is methyl, or R ^b where R ^b is -C(O)OR ^c . In some additional embodiments, one R ^f is R ^e which is -OR ^a (eg, hydroxyl or OMe) and two other R ^f groups are joined together to form an alicyclic (eg, cyclopropane, cyclobutane, cyclopentane, or cyclohexane) or heterocyclic group (for example, epoxide, oxetane, tetrahydrofuran, tetrahydropyran or hexahydrofuro[3,2-b]furan) with the carbon atom to which they are bonded. In some such embodiments, the alicyclic and/or heterocyclic group may be substituted, and in some particular embodiments, it is substituted by one or more hydroxyl groups or benzylcarbonyl groups.

Some variant compounds have a linker group that is a C _2-4 group, which may contain an alkyne. In specific embodiments, R ¹ is a -linker-R ⁶ group and the linker is R ^a where R ^a is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, or - C^C- or -CH2C C-, and R ⁶ is R ^b , where R ^b is -C(O)OEt or is -C(O)NR ^d R ^d or -NR ^d R ^d , where each ^Rd is independently in each case hydrogen, _{C5_10} heteroaryl, _{C3_6} cycloalkyl, or both ^Rd groups combine together to form a heterocyclic group with _the nitrogen atom to which they are bonded, which may further contain one or more additional heteroatoms in addition to the atom nitrogen to which R ^d groups are bonded. In some embodiments, one ^Rd is hydrogen and _the other ^Rd is _{C5_10} heteroaryl, which may be substituted by one or more ^Res , such as one of the following:

R ⁶ may also be R ^b , where R ^b is a heterocyclyl such as pyridinyl, which may be substituted or unsubstituted. In still further embodiments, ^R6 may be ^Rb , wherein ^Rb is -OH or ^-ORc (wherein ^Rc is C1_6alkyl, and in some embodiments, C1_6alkyl is substituted with C5_10heteroaryl, such as pyridinyl; or wherein ^Rc is a _C5-10 heteroaryl such as quinolinyl), or R ^b may be -NR ^d R ^d , where R ^d is independently in each case H, a C5-10 heteroaryl (and in some embodiments, the C5-10 heteroaryl group is substituted one or more R ^e groups or two R ^d groups together with a nitrogen bonded thereto to form a _C3-9 heterocycle (and in some embodiments _, the C _3-9 heterocycle is substituted with one or more R ^e groups) or C5 heteroaryl -10 (and in some embodiments, the C5_10 heteroaryl is substituted with one or more R ^e groups). In embodiments with R ^e substitution, R ^e is independently for each occurrence _{C5_10} heteroaryl or -OR ^a where R ^a is C _{1_10} alkyl _.

Some compounds contain a linker which is a C ₁ group and an R ⁶ group which is R ^b where R ^b is -NR ^d R ^d where one R ^d is H and the other R ^d is pyridinyl, or where both R ^d groups together with the nitrogen bound to it form a C5-10 heteroaryl; or R ^b is OR ^c where R ^c is C1_ ₄ alkyl substituted with a pyridinyl group. In some embodiments, R ^b is

In some embodiments, R ¹ may be selected from any of the following:

- 21 045696

In some embodiments, R ² and R ³ are each independently R ^a , wherein R ^a is independently in each case hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In specific embodiments, R ² and R ³ are each independently R ^a , which independently in each case is hydrogen, methyl or ethyl. In illustrative embodiments, R ² is methyl and R ³ is hydrogen.

In some embodiments, each R ⁴ independently and/or each R ⁵ independently represents R ^e , where R ^e is alkyl, alkenyl, alkynyl, chlorine, bromine, iodo, or fluorine. In specific embodiments, each R ⁴ and/or each R ⁵ independently represents R ^e , where R ^e represents a lower aliphatic group (eg, methyl), fluorine, or chlorine.

In some embodiments, m is equal to 1; n is 0 or 1; and p is 0, 1, or 2. In particular embodiments, m is 1, n is 0, and p is 0, 1, or 2.

Compounds of formulas I or IA may also have a structure satisfying any one or more of formulas II and IIA-IIF.

- 22 045696

and/or IA. In certain embodiments, 0, 1, or 2 R ⁵ groups are present. R ⁵ may be R ^e , especially when R ^e is fluorine or chlorine. In other specific embodiments, R ⁵ is absent. With regard to formulas IIA-IIE, each W independently represents nitrogen or oxygen, and in particular nitrogen.

Certain disclosed embodiments have formula IIF.

Formula IIF

With respect to Formula IIF, R ¹ , R ² and R ³ have the meanings stated above. R ¹⁰ represents alkyl, cyclic alkyl or aryl. In particular, R ¹⁰ represents lower alkyl such as C _1-10 alkyl, more particularly C _1-5 alkyl, including methyl, ethyl, propyl, butyl and pentyl. The cyclic alkyl groups are typically selected from cyclobutyl, cyclopentyl or cyclohexyl, particularly cyclobutyl or cyclopentyl. In some embodiments, the compounds of the present invention have formula IIG.

Formula IIG

For many disclosed embodiments, R ¹⁰ is phenyl. Accordingly, certain disclosed embodiments of the present invention have formula IIH.

PN formula

With respect to Formulas IIG and IIH, R ¹ and R ⁵ each have the meanings given above for Formulas I and/or IA. R ⁵ may be R ^e . In certain embodiments, 0, 1, or 2 R ⁵ groups are present. In some embodiments, R ⁵ is absent or is a halogen, such as fluorine or chlorine, particularly fluorine, or a C _1-6 alkyl, such as methyl.

- 23 045696

In some embodiments, compounds of Formulas I or IA may also have a structure satisfying any one or more of Formulas III-VI

With respect to Formulas III-VI, each R ⁵ independently can be as defined above, and in some specific embodiments, is a lower aliphatic group (eg, methyl) or a halogen such as chlorine or fluorine. In addition, ring B is as defined above, and in some embodiments may be selected from

R ⁶ as depicted in Formulas III-VI is as defined above, and in some embodiments is selected from one of the following:

- 24 045696

Certain disclosed illustrative examples of compounds within one or more of formulas I, I-1 to I-35, IA, II, IIA-IIJ, and III-VI include

- 25 045696

- 26 045696

1-36,

- 27 045696

- 28 045696

- 29 045696

- 30 045696

- 31 045696

- 32 045696

- 33 045696

- 34 045696

- 35 045696

- 36 045696

- 37 045696

1-183;

- 38 045696

- 39 045696

- 40 045696

- 41 045696

- 42 045696

Π-39.

Examples of compounds within one or more of formulas I, I-1-I-32, IA, II, PA-PN and III-VI include:

- 43 045696

I-1: Ethyl-(5)-3-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-7-yl)propanoate;

1-2: (S)-N-(l-(3 -((7H-indazol-5-yl)amino)-3-oxopropyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-5-benzyl-177-1,2,4-triazole3-carboxamide;

1-3: (S)-N-(7-(3 -(( /R-ind azol-6-yl)am and no)-3-oxopropyl)-5-methyl-4-oxo2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-177-1,2,4-triazole-3 carboxamide;

1-4: (S)-5-benzyl-L-(7-(3 -((6,7-dimethoxyquinazolin-4-yl)amino)-3 oxopropyl)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)1H-1,2,4-triazol-3-carboxamide;

1-5: Ethyl-(3)-3-(3-(1 -(2-fluorobenzyl)-1R-1,2,4-triazol-3-carboxamido)5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[Z>][1,4]oxazepin-7-yl)propanoate;

1-6 (S)-3-(3-(1 -(2-fluorobenzyl)-\H-1,2,4-triazol-3-carboxamide o)-5methyl-4-oxo-2,3, 4, 5-tetrahydrobenzo[/>][1,4]oxazepin-7-yl)propanoic acid;

1-7: (S)-N-(7-(3 -((177-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[ />][ 1,4]oxazepin-3-yl)-1 -(2-fluorobenzyl)-177-1,2,4triazol-3-carboxamide;

1-8: Ethyl-(5)-3-(3-(1 -(2,6-dichlorobenzyl)-1R-1,2,4-triazol-3-44 045696 carboxamido)-5-methyl-4-oxo -2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7yl)propanoate;

1-9: (5)-3 -(3 -(5-benzyl-III-1,2,4-triazol-3-carboxamide o)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[ />][1,4]oxazepin-7-yl)propanoic acid;

1-10: (5)-5 -benz yl-A-(5 -methyl-4-oxo-7-(3 -oxo-3 -(pyrrolidin-1 yl)propyl)-2,3,4,5 - tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-\H-1,2,4-triazol-3 carboxamide;

1-11: (5)-5-benzyl-7U-(5-methyl-7-(3-morpholino-3-oxopropyl)-4-oxo2,3,4,5-tetrahydrobenzo[/>] [ 1,4 ]oxazepin-3 -yl)- 1H-1,2,4-triazol-3 carboxamide;

1-12: (S)-5-benzyl-A-(5-methyl-4-oxo-7-(3-oxo-3-(quinolin-7ylamino)propyl)-2,3,4,5-tetrahydrobenzo [/>] [1,4]oxazepin-3-yl)-1H-1,2,4triazol-3-carboxamide;

1-13: (8)-5-benzyl-A-(7-(3 -(cyclopropylamino)-3-oxopropyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[/>] [ 1,4]oxazepin-3 -yl)-\H-1,2,4-triazol-3 carboxamide;

1-14: {S)-5-benzyl-A-(7-(3-hydroxypropyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[0] [1,4]oxazepine-3 -yl)-\H-1,2,4-triazol-3-carboxamide;

1-15: (5)-5-benzyl-A-(7-(4-hydroxybutyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepine- 3 -yl)-1H-1,2,4-triazol-3-carboxamide;

1-16: (5)-5-benzyl-A-(5-methyl-4-oxo-7-(4-(pyride in-2-ylmethoxy)butyl)2,3,4,5-tetrahydrobenzo[/ >][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-17: (S)-5-benzyl-A-(5-methyl-4-oxo-7-(4-(pyride in-2-ylamino)butyl)2,3,4,5-tetrahydrobenzo[/ >][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-18: (5)-1 -(2,6-dichlorobenzyl)-75-(5 -methyl-4-oxo-7-(3 -oxo-3 (pyrrolidin-1 -yl)propyl)-2,3 ,4,5-tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-1H1,2,4-triazole-3-carboxamide;

1-19: (S)-N-(l-(3 -(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[/>] [1,4]oxazepine -3 -yl)-1 -(2,6-dichlorobenzyl)-\H-1,2,4triazol-3-carboxamide;

1-20: {S)-5 -benzyl-A-(5 -methyl-4-oxo-7-((4-(pyridin-4-yl)piperazin-1 yl)methyl)-2,3,4, 5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-\H-1,2,4-triazol-3 carboxamide;

- 45 045696

1-21: (5)-1 -(2,6-d their lorbenzyl)-A ^f -(5 - methyl-4-oxo-7-((4-(p yrid and n-4yl)piperazin- 1-yl)methyl) 2D4,5-tetrahydrobenzo[d][1,4]oxazepin-3-yl)-1R1,2,4-triazole-3-carboxamide;

1-22: (S,E)-5 -benzyl-A-(5 -methyl-4-oxo-7-(3 -oxo-3 -(pyrrolidin-1 yl)prop-1 -ey-1 -yl ))-2,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1R-1,2,4triazol-3-carboxamide;

1-23: (S,E)-5-benzyl-A-(7-(3 -(cyclopropylamino)-3-oxoprop-1-ey-1-yl)5-methyl-4-oxo-2,3 , 4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4triazol-3-carboxamide;

1-24: (5)-5-benzyl-R-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin7(877)-yl)methyl)- 5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3yl)-1R-1,2,4-triazole-3-carboxamide;

1-25: (5)-1-benzyl-R-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin7(8R)-yl)methyl)- 5 -methyl-4-oxo-2,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3 yl)-1H-1,2,4-triazole-3-carboxamide;

1-26: (5)-1-benzyl-A-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[/>] [ 1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-27: (S)-N-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine- 3 -yl)-5-(2,4-difluorobenzyl)-1H-1,2,4triazol-3-carboxamide;

1-28: (5)-5-benzyl-R-(7-(3-hydroxy-3-methylbutyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[/>] [1,4 ] oxazepin-3 -yl)- 1H-1,2,4-triazol-3 carboxamide;

1-29: (S)-1-benzyl-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo [/>] [1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-30: (S)-5-benzyl-A'-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5 -tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-31: (8)-M-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>][1,4]oxazepine-3 -yl)-5-benzyl-1H-1,2,4-triazol-3 carboxamide;

1-32: (8)-M-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>][1,4]oxazepine-3 -yl)-1-benzyl-1H-1,2,4-triazol-3 - 46 045696 carboxamide;

1-33: (S)-1-benzyl-M-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1 yl)propyl)-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3carboxamide;

1-34: (8)-5-(2,4-difluorobenzyl)-M-(5-methyl-4-oxo-7-(3-oxo-3(pyrrolidin-1 -yl)propyl)-2,3 ,4,5-tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-1H1,2,4-triazole-3-carboxamide;

1-35: (8)-5-benzyl-U-(7-(5-hydroxypent-1-in-1-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-3 6: (S)-5 -benzyl-3 -((7-(3 -hydroxy-3 -methylbut-1 -in-1 -yl)-5-methyl-4oxo-2,3,4,5 -tetrahydrobenzo[/>][1,4]oxazepin-3-yl)carbamoyl)-1,2,4-triazol-1ide;

1-3 7: (5)-1-benzyl-#-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-in-1 yl)-2,3, 4,5-tetrahydrobenzo[th][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3 carboxamide;

1-3 8: (S)-5-benzyl-A-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-in-1 yl)-2,3 ,4,5-tetrahydrobenzo[L][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3 carboxamide;

1-39: (5)-1-benzyl-U-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5 -a]pyrazin-7(8R-yl)methyl)-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepin-3 -yl)- 1H-1,2,4-triazol-3 - carboxamide;

1-40: (5)-5-benzyl-U-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5 -a]pyrazin-7(8R)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 - carboxamide;

1-41: (5)-5-benzyl-A-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-in-1 yl)-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-III-1,2,4-triazole-3carboxamide;

1-42: (5)-1-benzyl-#-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1 -in-1 yl)-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-43: (S)-5 -(2,4-difluorobenzyl)-U-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4-triazole3-carboxamide;

1-44: (5)-1-benzyl-#-(5-methyl-4-oxo-7-(4-(quinolin-5 -yloxy)but-1 -in-1 - 47 045696 yl)-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 N-1,2,4-triazole-3 carboxamide;

1-45: (5)-5-benzyl-R-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-in-1 yl)-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4-triazol-3 carboxamide;

1-46: (5)-1-benzyl-A-(5 -methyl-4-oxo-7-((3 -(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4, 3-a]pyrazin-7(8R-yl)methyl)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 - carboxamide;

1-47: (5)-5-benzyl-R-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3 -a]pyrazin-7(8R)-yl)methyl)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine-31,2,4-triazol-3-carboxamide;

1-48: (S)-1-benzyl-R-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3carboxamide;

1-49: (5)-5-benzyl-R-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-III-1,2,4-triazole-3carboxamide;

1-50: (5)-1-benzyl-A-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b] [1,4] oxazepin-3 yl)-1R-1,2,4-triazol-3-carboxamide;

1-51: (5)-5-benzyl-R-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1R-1,2,4-triazol-3carboxamide;

1-52: (5)-1-benzyl-A-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1,4] oxazepin-3-yl)-1R-1,2,4-triazol-3 carboxamide;

1-53: (5)-5-benzyl-A-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1,4] oxazepin-3 yl)-1R-1,2,4-triazole-3carboxamide;

1-54: (5)-1-benzyl-A-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1R-1,2,4triazol-3-carboxamide;

1-55: (5)-5-benzyl-A-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1R-1,2,4triazol-3-carboxamide;

1-56: (5)-i -(7-(3 -hydroxy-3 -methylbut-1 -in-1 -yl)-5 -methyl-4-oxo-2,3,4,5- 48 045696 tetrahydrobenzo [b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-57: (S)-5-benzyl-A-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-58: (5)-1-benzyl-#-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-59: (S)-5-benzyl-A-(5-methyl-7-(3-methylbut-3-ey-1-in-1-yl)-4-oxo2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-60: (S)-5-benzyl-A-(7-isopentyl-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-1,2,4-triazole-3-carboxamide;

1-61: (S)-5-benzyl-A-(7-(3-methoxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-62: (5)-1-benzyl-#-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-63: (S)-5-benzyl-#-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-64: (L')-A-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-65: (S)-5-(2,6-dichlorobenzyl)-#-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole3-carboxamide;

1-66: (5)-5-benzyl-A-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5 -a]pyrazin-7(8R)-yl)methyl)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide ;

1-67: (5)-1-benzyl-A-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5 -a]pyrazin-7(8R)-yl)methyl)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide ;

1-68: (5)-U-(7-(3 -hydroxy-3-(methylh/3)but-1 -in-1 -yl-4,4,4-J 3)-5-methyl4-oxo -2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-69: (S)-5-benzyl-TV -(7-(3-hydroxy-3-(methyl-g/3)-but-1-in-1-yl-4,4,4- 49 045696 <73)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-\H-1,2,4triazol-3-carboxamide;

1-70: (R)-5-benzyl-L-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5- tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-\H-1,2,4-triazol-3 carboxamide;

1-71: (5)-5-benzyl-L-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5- tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1,3,4-oxadiazol-2carboxamide;

1-72: (6)-7V-(8-((3 -hydroxyoxetan-3 -yl)ethynyl)-5 -methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4] oxazepin-3-yl)-4-phenoxypicolinamide;

1-73: (6)-5-benzyl-R-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[/>] [ 1,4]oxazepin-3 -yl)-\H-1,2,4-triazol-3 carboxamide;

1-74: (3S,3aR,6R,6aS)-6 -(((6)-3-(5-benzyl-1R-1,2,4-triazol-3carboxamido)-5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[th][1,4]oxazepin-7yl)ethynyl)-6-hydroxyhexahydrofuro[3,2- />]furan-3-ylbenzoate;

1-75: 5-benzyl-R-((5)-7-(((3^3a5,65,6a7^d ihydroxyhexahydrofuro[[3,2-b]furan-3-yl)ethynyl)-5-methyl -4-oxo-2,3,4,5tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-76: methyl-(6)-4-(3-(5-benzyl-III-1,2,4-triazole-3-carboxamido)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo [d][1,4]oxazepin-7-yl)-2,2-dimethylbut-3inoate;

1-77: (6)-1-benzyl-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo [/>] [1,4]oxazepin-3-yl)-1R-pyrazol-3 carboxamide;

1-78: (S)-5 -(3-fluorobenzyl)-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4-triazole3-carboxamide;

1-79: (S)-5 -(4-fluorobenzyl)-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4-triazole3-carboxamide;

1-80: (S)-5 -(2-fluorobenzyl)-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4-triazole3-carboxamide;

1-81: (6)-5-benzyl-R -(7-ethynyl-5-methyl-4-oxo-2,3,4,5- 50 045696 tetrahydrobenzo[/>] [1,4]oxazepine-3 -yl)-(H-1,2,4-triazol-3-carboxamide;

1-82: (S)-N-(7-(3 -hydroxy-3 -methylbut-1 -in-1 -yl)-5 -methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-1 -(2-methylbenzyl)-1 Η-1,2,4-triazol-3 carboxamide;

1-83: (S)-1 -([ 1,1 '-biphenyl]-4-ylmethyl)-7U-(7-(3-hydroxy-3-methylbut-1 -in1-yl)-5-methyl- 4-oxo-2,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4triazol-3-carboxamide;

1-84: (5)-1 -(2,6-dimethylbenzyl)-7U-(7-(3-hydroxy-3-methylbut-1-in-1-yl)5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4triazol-3-carboxamide;

1-85: (S)-N-(7-(3 -hydroxy-3 -methylbut-1 -in-1 -yl)-5 -methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-1-isobutyl-1 N-1,2,4-triazol-3 carboxamide;

1-86: (5)-5-benzyl-TV-ethyl-LC7-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4,5- tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-(H-1,2,4-triazole3-carboxamide;

1-87: (5)-5 -benzyl-7U-(7-(3 -hydroxy-3 -methylbut-1 -in-1 -yl)-5 -methyl-4oxo-2,3,4,5-tetrahydrobenzo [/»] [1,4]oxazepin-3-yl)isoxazol-3-carboxamide;

1-88: (5)-5-benzyl-7U-(5-methyl-4-oxo-7-((1,2,3,4-tetrahydroisoquinolin-7yl)ethynyl)-2,3,4,5- tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1R-1,2,4-triazole-3carboxamide;

1-89: (S)-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[/>] [ 1,4]oxazepin-3-yl)-5-(2-fluorobenzyl)-\H-1,2,4-triazol-3 carboxamide;

1-90: (5)-1 -(2,6-dimethylbenzyl)-7U-(7-(3,3-dimethylbut-1 -in-1 -yl)-5methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-\H-1,2,4-triazole3-carboxamide;

1-91: (S)-5-benzyl-LC5-ethyl-7-(3-hydroxy-3-methylbut-1-in-1-yl)-4-oxo2,3,4,5-tetrahydrobenzo[/> ][1,4]oxazepin-3-yl)-1 Η-1,2,4-triazol-3 carboxamide;

1-92: (S)-N-(5 -ethyl-7-(3 -hydroxy-3 -methylbut-1 -in-1 -yl)-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-5-(3-fluorobenzyl)-1H-1,2,4-triazol-3 carboxamide;

1-93: (8)-5-benzyl-#-(7-(3-methylbut-3-ey-1-in-1-yl)-4-oxo-2,3,4,5 tetrahydrobenzo[/> ] [1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

- 51 045696

1-94: (S,Z)-5-benzyl^-(7-(2-chloro-3-hydroxy-3-methylbut-1-ey-1-yl)-5methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole3-carboxamide;

1-95: (S)-5 -benzyl-A-(5 -methyl-4-oxo-7-(3 -(pyrrolidin-1 -yl)prop-1 -in-1 yl)-2,3, 4,5-tetrahydrobenzo[L][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-96: (S)-5-benzyl-A-(5-methyl-7-(3-morpholinoprop-1-in-1-yl)-4-oxo2,3,4,5-tetrahydrobenzo[/> ] [1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-97: (S)-5-benzyl-A-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5 idrobenzo[/>] [1,4] oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-98: (S)-N-(7-((l-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl )-4-phenoxypicolinamide;

1-99: (S)-N-(5-methyl-7-(3-methylbut-3-eu-1-in-1-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-100: (8)-4-(4-fluorophenoxy)-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5 methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

1-101: (S)-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1, 4]oxazepin-3-yl)-4-(4-fluorophenoxy)picolinamide;

1-102: (S)-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1, 4]oxazepin-3-yl)-4-(2-fluorophenoxy)picolinamide;

1-103: (8)-4-(2-fluorophenoxy)-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5 methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

1-104: (8)-4-(2,4-difluorophenoxy)-M-(7-(3,3-dimethylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

1-105: (8)-4-(2,4-difluorophenoxy)-M-(7-(3-hydroxy-3-methylbut-1-in-1 yl)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)picolinamide;

1-106: (S)-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1, 4]oxazepin-3-yl)-4-(3-fluorophenoxy)picolinamide;

1-107: (8)-4-(3-fluorophenoxy)^-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

1-108: (8)-M-(7-isopentyl-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-109: (8)-M-(7-(4-hydroxy-3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo- 52 045696

2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

I-110: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b] [1,4] oxazepin-3-yl)-4-phenoxypicolinamide;

1-111: (8)-4-(4-fluorophenoxy)^-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)picolinamide;

1-112: (8)-4-(2-fluorophenoxy)^-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)picolinamide;

1-113: (R)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-114: (8)-4-(2,4-difluorophenoxy)-M-(7-((3-hydroxyoxetan-3-yl)ethynyl)5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

1-115: (8)-4-(3-fluorophenoxy)-M-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)picolinamide;

1-116: (S)-N-(5-methyl-4-oxo-7-(3 -(pyrrolidin-1 -yl)prop-1 -yn-1 -yl)2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-117: (8)-M-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4] Oxazepin-3-yl)-4-phenoxypicolinamide:

1-118: (8)-4-(2,6-difluorophenoxy)-T4-(7-(3-hydroxy-3-methylbut-1-in-1 yl)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)picolinamide;

1-119: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-6-methyl-4phenoxypicolinamide;

1-120: (S)-N-(7-(( 1 -hydroxycyclobutyl)ethynyl)-5 -methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl )-4-phenoxypicolinamide;

1-121: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-122: (8)-4-(3-fluorophenoxy)-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5 methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

1-123: (8)-M-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl4-oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-124: (8)-4-(2,6-dimethylphenoxy)-M-(7-(3-hydroxy-3-methylbut-1-in-1 yl)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)picolinamide;

1-125: (8)-4-(4-fluorophenoxy)-M-(7-(3-hydroxy-3-methylbut-1 -in-1 -yl)-5-53 045696 methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

1-126: (8)-4-(4-fluorophenoxy)-M-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)picolinamide;

1-127: (S)-N-(5-methyl-7-((3-methyloxetan-3-yl)ethynyl)-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenoxypicolinamide;

1-128: (S)-N-(7-((3-methoxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenoxypicolinamide;

1-129: (8)-M-(7-((3-fluoroxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenoxypicolinamide;

1-130: (S)-3 -((5-methyl-4-oxo-3 -(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl )oxetan-3-yl(3morpholinopropyl)carbamate;

1-131: (8)-M-(7-((4-hydroxy-1-(4-phenoxypicolinoyl)piperidin-4yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-4phenoxypicolinamide;

1-132: (8)-M-(7-((4-hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenoxypicolinamide;

1-133: (8)-4-(4-fluorophenoxy)-M-(7-((4-hydroxypiperidin-4-yl)ethynyl)5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)picolinamide;

1-134: (S)-N-(7-(( 1 -acetyl-4-hydroxypiperidin-4-yl)ethynyl)-5 -methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [ 1 ,4]oxazepin-3-yl)-4-(4fluorophenoxy)picolinamide;

1-135: (8)-4-(4-fluorophenoxy)-M-(7-((4-hydroxy-1-methylpiperidin-4yl)ethynyl)-5-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3yl)picolinamide;

1-136: (S)-N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenoxypicolinamide;

1-137: (S)-N-(7-((3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-138: (8)-4-(4-fluorophenoxy)^-(5-methyl-7-(5-(methylamino)-3 methylenepent-1-in-1-yl)-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 yl)picolinamide;

1-139: (S)-N-(7-(3-amino-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-140: (S)-N-(7-(3,3-dimethyl-4-morpholinobut-1-in-1-yl)-5-methyl-4-oxo- 54 045696

2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-141: tert-butyl-((8)-1-((2,2-dimethyl-4-((8)-5-methyl-4-oxo-3-(4phenoxypicolinamido)-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3 in-1-yl)oxy)-1-oxopropan-2-yl)-12-azancarboxylate;

1-142: 2,2-dimethyl-4-(( S)-5 -methyl-4-oxo-3 -(4-phenoxypicolinamido)2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -7-yl)but-3-yn-1-yl-E-alaninate;

1-143: (8)-M-(7-((3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenoxypicolinamide;

1-144: (8)-4-((2,2-dimethyl-4-(5-methyl-4-oxo-3 -(4phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b] [1, 4]oxazepin-7-yl)but-3 in-1 -yl)oxy)-4-oxobutanoic acid;

1-145: (2R,3R)-2,3-diacetoxy-4-((2,2-dimethyl-4-((8)-5-methyl-4-oxo-3(4-phenoxypicolinamido)-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3yn-1-yl)oxy)-4-oxobutanoic acid;

1-146: (S)-N-(7-((3-fluoro-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-147: (R)-4-((3 -((5 -methyl-3 -(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl )oxetan-3-yl)oxy)-4oxobutanoic acid;

1-148: (8)-4-(4-fluorophenoxy)-M-(7-(4-hydroxy-3,3-dimethylbut-1-in-1 yl)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)picolinamide;

1-149: (8)-M-(7-((3-oxa-9-azaspiro[5.5]undecan-9-yl)methyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide a;

1-150: (8)-M-(7-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide a;

1-151: (S)-N-(7-((3-hydroxy-1 -(2,2,2-trifluoroacetyl)azetidin-3 yl)ethynyl)-5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4phenoxypicolinamide;

1-152: (8)-4-cyclobutoxy-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)picolinamide;

1-153: (8)-4-cyclobutoxy-M-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]oxazepin-3-yl)picolinamide;

1-154: (S)-N-(7-((3-methoxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenoxypicolinamide;

- 55 045696

1-155: (S)-N-(7-((3-methoxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-156: (S)-4-(cyclopentyloxy)-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)5-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

1-157: (8)-4-(cyclopentyloxy)-M-(7-((3-hydroxyoxetan-3-yl)ethynyl)5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)picolinamide;

1-158: (8)-M-(5-methyl-7-(3-methyl-3-(4-methylpiperazin-1 -yl)but-1 -in-1 yl)-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4phenoxypicolinamide:

1-159: methyl-(8)-3 -(5 -methyl-4-oxo-3 -(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-7-yl) propiolate;

1-160: 3 -(((S)-5 -methyl-4-oxo-3 -(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl )oxetan-3-yl-b-valinate;

1-161: (8)-3-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-7-yl)propiolic acid ;

1-162: (S)-N-(7-((3 -hydroxyoxetan-3 -yl)ethynyl)-5 -methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b] [1,4] oxazepin-3-yl)-4-methoxypicolinamide;

1-163: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-methoxypicolinamide;

1-164: 3 -(((S)-5 -methyl-4-oxo-3 -(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl )oxetan-3-yl L-valinate salt of benzenesulfonic acid;

1-165: (8)-4-((3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine-7 -yl)ethynyl)oxetan-3 -yl)oxy)-4oxobutanoic acid tris salt;

1-166: (S)-N-(7-((3-fluoro-1-isopropylazetidin-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-167: (S)-N-(7-(3-amino-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide hydrochloride;

1-168: (S)-N-(7-((3-fluoro-1 -(2,2,2-trifluoroethyl)azetidin-3-yl)ethynyl)-5methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4phenoxypicolinamide;

1-169: (S)-N-(7-(( 1 -(cyclopropylmethyl)-3-fluoroazetidin-3-yl)ethynyl)-5 methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-4phenoxypicolinamide;

- 56 045696

1-170: (8)-4-((4-(3 -(4-(4-fluorophenoxy)picolinamido)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl)oxy)4-oxobutanoic acid;

1-171: 4-((S)-3 -(4-(4-fluorophenoxy)picolinamido)-5 -methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepine- 7-yl)-2,2-dimethylbut-3-yn-1-yl-L-alaninate;

1-172: 4-((S)-3-(4-(4-fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepine-7 -yl)-2,2-dimethylbut-3-yn-1-yl-L-valinate;

1-173: (8)-2,2-dimethyl-4-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -7-yl)but-3-yn-1-yl dihydrogen phosphate;

1-174: (8)-4-(3-(4-(4-fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine-7 -yl)-2,2-dimethylbut-3-yne-1 yl dihydrogen phosphate.

1-175: (8)-4-(4-fluorobenzyl)-H-(7-((4-hydroxytetrahydro-2H-pyran-4yl)ethynyl)-5-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1Hpyrazol-1-carboxamide;

1-177: (8)-M-(5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenoxypicolinamide

1-178: (8)-4-(4-fluorobenzyl)-I-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1 methyl-2-oxo-2,3,4,5-tetrahydro -1H-benzo[b]azepin-3-yl)-1H-pyrazol-1carboxamide;

1-179: (S)-l-benzyl-4-fluoro-M-(5-methyl-7-((6-methylpyridin-2-yl)ethynyl)4-oκco-2,3,4,5-tetrahydrobenzo [b] [1,4]oxazepin-3-yl)-1 H-pyrazol-3 carboxamide;

1-180: (8)-4-(4-fluorobenzyl)-M-(5-methyl-7-((3-methyloxetan-3-yl)ethynyl)4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-pyrazol-1 carboxamide;

1-181: (8)-1-benzyl-4-fluoro-M-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2yl)-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide;

1-182: (8)-1-benzyl-4-fluoro-H-(5-methyl-4-oxo-7-(7-oxa-2azaspiro[3.5]nonan-2-yl)-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1Hpyrazol-3-carboxamide;

1-183: (8)-4-(4-fluorobenzyl)-M-(5-methyl-7-((6-methylpyridin-2yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1H-pyrazol1-carboxamide;

1-184: (8)-4-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(7-oxa-2-57 045696 azaspiro[3.5]nonan-2-yl)-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1Hpyrazol-1-carboxamide;

1-187: (8)-5-benzyl-M-(7-(3-chloro-3-methylbut-1-in-1-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3carboxamide;

1-188: (8)-5-benzyl-H-(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-in1-yl)-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3carboxamide;

1-189: (8)-5-benzyl-H-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3carboxamide;

1-190: (S)-N-(7-((3 -hydroxyoxetan-3 -yl)ethynyl)-5 -methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-(phenoxy-d5)picolinamide;

1-191: (S)-N-(7-((1-acetyl-3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-194: 3-(((5)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[th][1,4]oxazepin-7-yl)ethynyl )oxetan-3-yl-£-alaninate salt of trifluoroacetic acid;

1-195: (S)-N-(7-((3-hydroxy-1-isopropylazetidin-3-yl)ethynyl)-5-methyl4-oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide:

1-196: (S)-N-(7-(( 1 -(cyclopropylmethyl)-3-hydroxyazetidin-3 yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-4phenoxypicolinamide;

1-197: (S)-N-(7-((1-acetyl-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-198: (S)-N-(7-(( 1 -(ethylcarbamoyl)-3-hydroxyazetidin-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4phenoxypicolinamide;

1-199: (S)-3 -((5-methyl-4-oxo-3 -(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl )oxetan-3-ylethylcarbamate;

1-200: (S)-N-(7-((3-hydroxy-1-neopentyl azetidin-3-yl)ethynyl)-5-methyl4-oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide:

1-203: (S)-N-(5-methyl-7-(( 1 -methyl-1 H-imide azol-4-yl)ethynyl)-4-oxo2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-204: (S)-N-(7-(3 -(butylamino)-3 -methylbut-1 -in-1 -yl)-5 -methyl-4-oxo- 58 045696

2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-205: (S)-N-(7-(3-((4-fluorobenzyl)amino)-3-methylbut-1-in-1-yl)-5-methyl4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-206: (S)-N-(5-methyl-7-(3-methyl-3-morpholinobut-1-in-1-yl)-4-oxo2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-207: (8)-M-(7-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4yl)ethynyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4phenoxypicolinamide;

1-208: (8)-M-(7-((3-hydroxy-1-oxidothietane-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-209: (S)-N-(7-((3-hydroxy-1,1-dioxidothietane-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-210: (S)-N-(5-methyl-7-(3 -methyl-3 -(pyrrolidin-1 -yl)but-1 -in-1 -yl)-4oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-211: (S)-N-(7-(3 -(1,1-dioxidothiomorpholino)-3-methylbut-1-in-1-yl)-5 methyl-4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4phenoxypicolinamide;

1-212: (8)-4-benzyl-M-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b ] [ 1,4]oxazepin-3 -yl)-1 H-pyrazol-1 -carboxamide;

1-213: (8)-4-benzyl-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1 H-pyrazol-1 carboxamide;

1-214: (8)-4-benzyl-M-(5-methyl-4-oxo-7-(pyridin-3-ylethynyl)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin- 3 -yl)-1 H-pyrazol-1-carboxamide;

1-215: (8)-4-benzyl-M-(5-methyl-4-oxo-7-(pyridin-2-ylethynyl)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine- 3 -yl)-1 H-pyrazol-1-carboxamide;

1-216: (8)-4-benzyl-I-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4] oxazepin-3 -yl)-1 H-pyrazol-1 carboxamide;

1-217: (8)-4-benzyl-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2yl)-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1 H-pyrazol-1-carboxamide;

1-218: (8)-4-(4-fluorobenzyl)-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-pyrazol-1 carboxamide;

1-219: (8)-4-benzyl-M-(7-(( 1 -hydroxycyclobutyl)ethynyl)-5-methyl-4-59 045696 oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4] oxazepin-3 -yl)-1 H-pyrazol-1 carboxamide;

1-220: (8)-4-benzyl-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-5-methyl-1 H-pyrazol-1 carboxamide;

1-221: (8)-4-(4-fluorobenzyl)-M-(7-((1-hydroxycyclobutyl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-1 H-pyrazol-1 carboxamide;

1-222: (8)-4-(4-fluorobenzyl)-M-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1 H-pyrazol-1 carboxamide;

1-223: (8)-3-(4-fluorobenzyl)-M-(7-((1-hydroxycyclobutyl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-1 H-pyrazol-1 carboxamide;

1-224: (8)-4-(4-fluorobenzyl)-H-(7-((2-hydroxyspiro[3.3]heptan-2yl)ethynyl)-5-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1Hpyrazol-1-carboxamide;

1-225: (8)-4-(4-fluorobenzyl)-H-(7-((6-hydroxy-2-oxaspiro[3.3]heptan-6yl)ethynyl)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1Hpyrazol-1-carboxamide;

1-226: (S)-N-(7-(3-amino-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-(4-fluorobenzyl)-1H-pyrazol-1 carboxamide;

1-227: (8)-4-(4-fluorobenzyl)-M-(5-methyl-7-(3-methyl-3-(4-methylpiperazin1 -yl)but-1-in-1 -yl)) -4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1Hpyrazol-1-carboxamide;

1-228: (5)-4-benzyl-#-(7-bromo-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-\ H-pyrazole-1-carboxamide;

1-229: (5)-R-(7-bromo-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-4-(4 -fluorobenzyl)-1R-pyrazole1 carboxamide;

1-230: (5)-4-benzyl-R-(7-bromo-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>][1,4]oxazepin-3-yl)- 5-methyl-1R-pyrazole-1-carboxamide;

1-231: (5)-R-(7-bromo-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-3-(4 -fluorobenzyl)- 1R-pyrazolepyrazole- 60 045696

1-carboxamide;

1-232: (5)-#-(7-bromo-5 -methyl-4-oxo-2,3,4,5 tetrahydrobenzo[/>] [1,4]oxazepin-3 -yl)-5-( 4-fluorobenzyl)-I //-pyrazole-1 carboxamide;

1-233: (S)-5-benzyl-M-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-1 Η-1,2,4-triazol-3 carboxamide;

1-234: (S)-5-benzyl-M-(7-((3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole3-carboxamide;

1-235: (8)-X-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4oxadiazol-2-carboxamide;

1-236: (8)-5-benzyl-X-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2yl)-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1,3,4-oxadiazol-2carboxamide;

1-237: (5)-#-(7-bromo-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-4-( 2,4-difluorobenzyl)-177-pyrazole-1 carboxamide;

1-23 8 : (3) ^- 4-(2,4-difluorobenzyl)-A-(7-(3-hydroxy-3-methylbut-1 -in-1 -yl)5 -methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1R-pyrazol-1 carboxamide;

1-239: (5)-4-(2,4-difluorobenzyl)-R-(7-(4-hydroxy-3,3-dimethylbut-1-in-1 yl)-5-methyl-4-oxo 2 ,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1R-pyrazol1-carboxamide;

1-240: Tert-butyl-(5)-(4-(3-(4-(2,4-difluorobenzyl)-1R-pyrazol-1carboxamide o)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[/>][1,4]oxazepin-7-yl)2,2-d immethylbut-3-in-1-yl)carbamate;

1-241: (S)-N-(7-(4-aMHHO-3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b ] [ 1,4]oxazepin-3 -yl)-4-(2,4-difluorobenzyl)-1Hpyrazole-1-carboxamide hydrochloride;

P-16: (8)-X-(5-methyl-4-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl) -4-phenoxypicolinamide;

II-17: (8)-4-(4-cyanophenoxy)-M-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

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II-18: (8)-4-(4-cyanophenoxy)-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

II-19: (8)-4-(4-cyanophenoxy)-M-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)picolinamide;

P-20: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenylpicolinamide;

P-21: (8)-4-(3-cyanophenoxy)-M-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

P-22: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-(4-methoxyphenyl)picolinamide;

P-23: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-(3-methoxyphenyl)picolinamide;

P-24: (8)-M-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepine-3 - yl)-4-phenoxypicolinamide;

P-25: (8)-M-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1, 4]oxazepin-3-yl)-4-phenoxypicolinamide;

P-26: (8)-M-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

P-27: (8)-M-(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-4oxo-2,3,4,5-tetrahydrobenzo[b ] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

P-28: (8)-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

P-31: (8)-M-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

P-32: (S)-N-(7-(3-methoxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

P-33: (S)-N-(7-((6-cyanopyridin-2-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenoxypicolinamide;

P-35: (S)-N-(7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4] oxazepin-3-yl)-4-phenoxypicolinamide;

P-36: (S)-N-(7-(3-(dimethylamino)prop-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide; or

P-39: N-((38)-5-methyl-4-oxo-7-(pyrrolidin-2-ylethynyl)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl) -4-phenoxypicolinamide.

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In some embodiments, one or more compounds may be included in a pharmaceutical composition or drug, and in some embodiments, the compound or compounds may be in the form of the parent compound or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotopic analogue or prodrug. The pharmaceutical composition typically includes at least one additional component other than the disclosed compound or compounds, such as a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent (described in the next section), or any combination thereof.

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Pharmaceutically acceptable excipients may be included in pharmaceutical compositions for various purposes, for example, to dilute the pharmaceutical composition for delivery to a subject, to facilitate processing of the formulation, to impart favorable material properties to the formulation, to facilitate dispersion from the delivery device, to stabilize the formulation (e.g., antioxidants or buffers) to impart a pleasant or pleasant taste or consistency to a composition, or the like. The pharmaceutically acceptable excipient(s) may include pharmaceutically acceptable carrier(s). Examples of excipients include, but are not limited to: mono-, di- and polysaccharides, sugar alcohols and other polyols such as lactose, glucose, raffinose, melesitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch or combinations thereof; surfactants such as sorbitol, diphosphatidylcholine and lecithin; bulk-forming substances; buffers such as phosphate and citrate buffers; anti-blocking agents such as magnesium stearate; binders such as saccharides (including disaccharides such as sucrose and lactose), polysaccharides (such as starches, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropylcellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coatings (such as cellulose ethers, including hydroxypropyl methylcellulose, shellac, corn protein zein, and gelatin); anti-blocking agents (such as enteric coatings); disintegrants (such as crospovidone, crosslinked sodium carboxymethylcellulose, and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate and magnesium stearate); flavors and sweeteners (such as mint, cherry, anise, peach, apricot or licorice, raspberry and vanilla); lubricants (such as minerals , for example talc or silicon dioxide, fats, for example vegetable stearin, magnesium stearate or stearic acid); preservatives (eg, antioxidants represented by vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium, amino acids represented by cysteine and methionine, citric acid and sodium citrate, parabens, such as methylparaben and propylparaben); dyes; compression products; emulsifiers; encapsulating agents; gums; granulators; and their combinations.

B. Combinations of therapeutic agents

The compounds described herein may be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to, or in combination with, other established therapies. The compound or compounds or a composition containing the compound (or compounds) may be administered once or repeatedly. In some embodiments, the compounds of the present invention may be used in combination with other therapeutic agents suitable for treating the disorder or condition. These other therapeutic agents may be administered simultaneously, sequentially, in any order, by the same route of administration or by a different route as the compounds disclosed herein. For sequential administration, the compound(s) and therapeutic agent(s) can be administered such that the period of action of at least one compound and therapeutic agent overlaps with the period of action of at least one other compound and/or therapeutic agent. In an illustrative embodiment of a combination containing four components, the effective time period of the first component administered may overlap with the effective time periods of the second, third, and fourth components, but the effective time periods of the second, third, and fourth components may or may not independently overlap with each other. friend. In another illustrative embodiment of a combination containing four components, the period of action of the first administered component overlaps with the period of action of the second component, but not the period of action of the third or fourth; the effective time period of the second component overlaps with the period of action of the first and third components; and the effective time period of the fourth component overlaps only with the period of action of the third component. In some embodiments, the effective time periods of all compounds and/or therapeutic agents overlap with each other.

In some embodiments, the compounds are administered with another therapeutic agent, such as an analgesic, antibiotic, anticoagulant, antibody, anti-inflammatory agent, immunosuppressant, guanylate cyclase-C agonist, intestinal secretagogue, antiviral agent, anticancer agent, antifungal agent, or a combination thereof. The anti-inflammatory agent may be a steroidal or non-steroidal anti-inflammatory agent. In some embodiments, the nonsteroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam , salsalata, sulindaka , tolmetin or combinations thereof. In some embodiments, the immunosuppressant is a mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an antilymphocyte globulin, an antithymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

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In some embodiments, the present compounds can be used with anticancer or cytotoxic agents. Various classes of anticancer and antineoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, BCL2 inhibitors, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents, such as DNMT inhibitors such as azacitidine and decitabine. Examples of alkylating agents include, but are not limited to, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethylene imines, methylmelamines, alkyl sulfonates (eg, busulfan) and carmustine. Typical antimetabolites include, by way of example, but are not limited to, the folic acid analogue methotrexate; pyrimidine analogue of fluorouracil, cytosine arbinoside; purine analogs of mercaptopurine, thioguanine and azathioprine. Typical vinca alkyloids include, for example, but are not limited to, vinblastine, vincristine, paclitaxel and colchicine. Examples of antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. An illustrative example of an enzyme effective as an antitumor agent includes La asparaginase. Examples of coordination compounds include, by way of example, but are not limited to, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, by way of example and not limitation, the adrenocorticosteroids prednisolone and dexamethasone; aromatase inhibitors aminoglutethimide, formestane and anastrozole; progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogenic compound tamoxifen.

These and other suitable anticancer compounds are described in Merck Index, 13th ed. (O'Neil MJ et al., ed.) Merck Publishing Group (2001) and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th edition, Brunton LL ed., chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

Ipilimumab, which is marketed as YERVOY® from Bristol-Myers Squibb, is one CTLA 4 antibody that can be used in combination with the inhibitors described herein.

Other chemotherapy agents for combination include immuno-oncology agents such as checkpoint inhibitors, such as PD-1 inhibitors such as nivolumab and lambrolizumab, and PD-L1 inhibitors such as pembrolizumab, MEDI-4736 and MPDL3280A/RG7446. Additional checkpoint inhibitors for combination with the compounds disclosed herein include anti-LAG-3 agents such as BMS-986016 (MDX-1408).

Additional chemotherapeutic agents for combination with inhibitors disclosed herein include anti-SLAMF7 agents, such as the humanized monoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such as the anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137 agents. such as the fully human monoclonal antibody urelumab (BMS-663513).

The compounds disclosed herein may also be useful in CAR-T therapies. Examples of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

Additional antiproliferative compounds useful in combination with the compounds of the present invention include, by way of example, and not limitation, antibodies directed against growth factor receptors (eg, against Her2); and cytokines such as interferon-α and interferon-γ, interleukin-2 and GM-CSF.

Additional chemotherapeutic agents useful in combination with the compounds of the present invention include proteasome inhibitors such as bortezomib, carfilzomib, marizomib, and the like.

Examples of kinase inhibitors that may be used in combination with the compounds described herein, particularly in the treatment of cancer, include: Btk inhibitors, such as ibrutinib; CDK inhibitors such as palbociclib; EGFR inhibitors such as afatinib, erlotinib, gefitinib, lapatinib, osimertinib and vandetinib; Mek inhibitors such as trametinib; Raf inhibitors such as dabrafenib, sorafenib and vemurafenib; VEGFR inhibitors such as axitinib, lenvatinib, nintedanib, pazopanib; BCR-Abl inhibitors such as bosutinib, dasatinib, imatinib and nilotinib; FLT-3 inhibitors such as gilteritinib and quizartinib, PI3-kinase inhibitors such as idelalisib, Syk inhibitors such as fostamatinib; and JAK inhibitors such as ruxolitinib and fedratinib.

In other embodiments, the second therapeutic agent may be selected from any of the following:

analgesics - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

aminoglycoside antibiotics (eg, amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin and paromycin), carbapenems (eg, ertapenem, doripenem, imipenem, cilastatin and

- 91 045696 meropenem), cephalosporins (for example, cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazide im, ceftibuten, ceftizoxime, ceftriaxone, cefepime and cefobiprole), glycopeptides (eg, teicoplanin, vancomycin and telavancin), lincosamides (eg, clindamycin and incomisin), lipopeptides (eg, daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin and spectinomycin), monobactams (eg, aztreonam), nitrofurans (eg, furazolidone and nitrofurantoin), penicillins (eg, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, pi peracillin, temocillin and ticarcillin), penicillin combinations (eg, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, and ticarcillin/clavulanate), polypeptides (eg, bacitracin, colistin, and polymyxin B), quinolones (eg, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin and temafloxacin), sulfonamides (eg, mafenide, sulfonamido-chrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole , sulfonamide, sulfasalazine, sulfisoxazole, trimethoprim and trimethoprim-sulfamethoxaxole ), tetracyclines (eg, demeclocycline, doxycycline, minocycline, oxytetracycline and tetracycline), antimycobacterial compounds (eg, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine and streptomycin), and others such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimicin, quinuprisin/dalfopristin, rifaximin, thiamphenicol, tigecycline and timidazole;

antibodies - antibodies against TNF-α, for example, infliximab (Remicade™), adalimumab, golimumab, certolizumab; anti-B cell antibodies, such as rituximab;

antibodies against IL-6, for example, tocilizumab; antibodies against IL-1, such as anakinra; anti-PD-1 and/or anti-PD-L1 antibodies, for example nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fleticumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab;

anticoagulants - warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin;

anti-inflammatory drugs - steroids, for example, budesonide, non-steroidal anti-inflammatory drugs, for example, aminosalicylates (for example, sulfasalazine, mesalamine, olsalazine and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen , flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

immunosuppressants - mercaptopurine, corticosteroids such as dexamethasone, hydrocortisone, prednisolone, methylprednisolone and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus and tacrolimus, inosine monophosphate dehydrogenase inhibitors (IMPDH) such as mycophenolate, mycophenolate mofetil and azathioprine and agents designed to suppress cellular immunity while maintaining the recipient's humoral immunological response, including various antibodies (eg, antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3)) and radiation. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the Azasan brand; Mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the brand name Purinethol; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from WyethAyerst under the brand name Rapamune; tacrolimus is currently available from Fujisawa under the brand name Prograf; cyclosporine is currently available from Novartis under the brand name Sandimmune and Abbott under the brand name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the brand name Cellcept and Novartis under the brand name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the brand name Imuran; and antibodies are currently available from Ortho Biotech under the brand name Orthoclone, Novartis under the brand name Simulect (basiliximab), and Roche under the brand name Zenapax (daclizumab); And

Guanylate cyclase-C receptor agonists or intestinal secretagogues, such as linaclotide, sold under the name Linzess.

These various agents may be used in accordance with their standard or customary dosages as specified in the prescribing information accompanying commercially available drug forms (see also prescribing information in The Physician's Desk Reference 2006

- 92 045696

g.), the description of which is incorporated herein by reference.

III. Methods for obtaining compounds

In the disclosed embodiments, the present compounds can be prepared by any suitable method that will be understood by one skilled in the art. One illustrative suitable method is presented below with reference to the specific compounds in the examples and may include the following first reaction step in accordance with Scheme 1.

Scheme 1

GT VNI1PG

If х Metal-lined XTf T

Ή (G ⁰ reaction croos-coupling L · y NHPG ¹⁰⁰ --------------------------► (and ⁶ Linker ^2 O . 104

R ⁶ -Linker

102

With respect to Scheme 1, the protected amine precursor 100 can be coupled to an R ¹ group 102 that contains an R ⁶ linker group as depicted in Scheme 1, using a metal-mediated cross-coupling reaction to provide a cross-coupling reaction product 104. In some embodiments, the metal-mediated cross-coupling reaction can be carried out using a transition metal catalyst, such as a palladium catalyst. Examples of palladium catalysts include, but are not limited to, Pd(0) catalysts (eg, Pd ₂ (dba) ₃ , Pd(dba) ₂ , Pd(PPh ₃ ) ₄ , etc.) or Pd(II) catalysts ( for example, XPhos Pd generation 2 or generation 3, PdCl ₂ , Pd(OAc) ₂ , etc.). In some embodiments, a palladium catalyst can be used in combination with another cocatalyst, such as CuI, to accelerate a cross-coupling reaction, such as the Sonogoshira reaction. Metal-mediated cross-coupling may also involve the use of a base, such as an amine base (eg, Et ₃ N) or an inorganic base (eg, Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , etc.) and a solvent (eg dimethylformamide). With respect to Scheme 1, X is a suitable metal-mediated cross-coupling group, such as a halogen or triflate group, and PG is an amine protecting group, which may be selected from, but is not limited to, a 9fluorenylmethoxycarbonyl (Fmoc) group, tert- butyloxycarbonyl (Boc) group, trityl (Tr) group, allyloxycarbonyl (Alloc) group, benzyloxycarbonyl (Cbz) group and the like.

Representative examples of the process steps depicted in Scheme 1 are presented below in Schemes 2A-2F. A method similar to that illustrated in Scheme 2A can be used to prepare compounds I-14 to I-17 and I-35 by replacing the propargyl alcohol in Scheme 2A with the appropriate alkyne group, which gives each of compounds I-14 to I-17 and I-35; further modifications that can be used to obtain the final structure of compounds I-14 to I-17 are discussed below.

Scheme 2A

Scheme 2B

Scheme 2C

2D diagram

- 93 045696

Scheme 2E

20D 212

Scheme 2F

2ΰώ 214

Once the cross-coupling reaction product 104 is obtained, it can be subjected to an optional linker group reduction step in which linker groups containing one or more unsaturation sites can be reduced to saturated linker groups and/or linker groups having less unsaturation. If a reducing linker group is used, it may be followed by a deprotection step and then an amide formation step, as depicted in Scheme 3. Alternatively, if a reducing linker group step is not used, the cross-coupling reaction product 104 may be deprotected, and it is converted into amide compound 302.

Scheme 3

With reference to Scheme 3, an optional linker reduction step can be performed. For example, if the linker contains a site of unsaturation (e.g., a double or triple bond), the site of unsaturation can be reduced to become fully saturated (e.g., reducing the double bond and/or triple bond to a single bonds) or to have several degrees of unsaturation (for example, reducing a triple bond to a double bond). Suitable reagents for carrying out such an optional linker reduction step are known to those skilled in the art in view of the present invention; however, one typical set of conditions involves exposing product 104 to an H ₂ cross-coupling reaction in the presence of Pd on carbon. Because these steps are optional, they do not need to be performed in all embodiments. Instead, in some embodiments, cross-coupling reaction product 104 may be deprotected to produce an amine, which is then converted to amide compound 302 by reacting the amine with a suitable condensation partner 300, as depicted in Scheme 3.

Representative examples of the process steps depicted in Scheme 3 are presented below in Schemes 4A-4M. A method similar to that described in Scheme 4A can be used to prepare compounds I-14 to I-17. Compounds I-16 and I-17 can be further functionalized as described below.

Scheme 4A

- 94 045696

Scheme 4B

HCI, but

Scheme 4E

EY iPr ₃ NEt, HATU

DMF. eouh. temp_ 4 ί

Scheme 4C

4D diagram

Scheme 4F

EY

209

Ι₽γ ₇ νΕ|. Η,ΑΤ

DMF. εομη. thein., 4 iPr^MEf. HATU DMF. 5-C iPr^MEt. HATU DMF. PC.

- 95 045696

EY

208

2} BUT. GHjGli4G scheme

1)H,FWC. EtOAc

N^NVas eoin. warm, 14 h

lPr ₂ NE1. HATU DMF. CPC.

Scheme 4H n _; M

Ts.Y |Rg _g

DMF. eoin. T

Scheme 4J

4K circuit

Scheme 4I

DMF. EOIN.

DMF.

IPrjNEl. go

DMF. horses. thein.. 4 h

14!

- 96 045696

Scheme 4L

Scheme 4M

In some embodiments, the method may further include making one or more additional modifications to amide compound 302 to produce amide compound 500, such as modifying an ^R6 group to form another ^R6 group, as depicted in Scheme 5.

Scheme 5

With regard to scheme 5, one or more modifications of the R ⁶ group can be carried out. For example, if R ⁶ is an ester group, it can be converted to a carboxylic acid or a primary alcohol. Suitable reagents for carrying out such an optional modification step are known to those skilled in the art in view of the present invention; however, one typical set of conditions involves exposing the R ⁶ ester group to LiOH to produce the corresponding acid, as depicted in Schemes 6A-6E below. The resulting acid can even be further modified to provide an amide-containing product using suitable amide condensation conditions (such as those described above) in combination with an amine condensation partner, as depicted in Schemes 6A-6E. Similar methods can be used to prepare compounds I-10, I11, I-13, I-18, I-19, I-26, I-27, I-33, I-34 and I-22 and I-23 (where the double bond of the linker group is not reduced before binding). In still further embodiments, compounds I-16 and I-17 can be prepared by converting the terminal alcohol produced by the methods described above into a functionalized alcohol, for example for compound I-16, or to an amine, for example for compound I-17.

Scheme 6A

- 97 045696

Circuit 6B

Scheme 6C

6D scheme

1N-nndaash1-5-aynn. DMF

ELNii-Pri;. HATU.dt O ‘3 to room. rascu.

Scheme 6E

A number of illustrative compounds disclosed are alkynyl-substituted analogues. These compounds can be prepared using a metal-mediated coupling strategy as discussed above with reference to Scheme 1. Scheme 7 illustrates a more detailed general method for preparing alkynyl-substituted analogues in accordance with the present invention, including but not limited to Examples 21 and 22.

Scheme 7

For Scheme 7, nitrogen was bubbled through a stirred solution of aryl halide (1 eq.), compound 700, CuI (0.1-0.2 eq.) and Pd(PPh3) ₄ (0.05-0.1 eq.) in dry DMF (3-4 ml/mmol) for 3 minutes in a vessel. NEt ₃ (10 eq.) was then quickly added to the dark reaction solution, followed by the corresponding

- 98 045696 existing alkyne (1.5-3 eq.), compound 702. Nitrogen was bubbled through the reaction mixture for 2 minutes and the vessel was capped. The reaction mixture is stirred at an effective reaction temperature, such as 70-90°C, for an effective reaction period, for example 3-6 hours. Alternatively, the reaction mixture can be heated in a microwave reactor (30-45 minutes) until aryl halide 700 is consumed. The dark reaction solution is treated by one of the following methods: a) ice-water/organic solvent dilution treatment; b) concentrated to dryness followed by dilution with ice water/organic solvent; or c) the crude residue was diluted with ice water, sonicated and the suspension allowed to warm to room temperature. The resulting gray/dark solid was collected by filtration, suction dried, dissolved in THF (20 ml), filtered through a pad of celite®/silica gel and the layer washed with THF. The crude material was then purified by reverse phase column chromatography or normal phase flash column chromatography on silica gel to give the corresponding alkynyl-substituted analogs (yield: 25-69%), compounds 704.

IV. Methods of using compounds A.

Diseases/disorders

The disclosed compounds, as well as combinations and/or pharmaceutical compositions thereof, can be used to inhibit RIP1 kinase by contacting the kinase in vivo or ex vivo with a compound or compounds of the present invention, or a composition containing a compound or compounds of the present invention. The disclosed compound or compounds, or compositions containing the disclosed compound or compounds, may also be used to alleviate, treat, or prevent various diseases and/or disorders. In specific embodiments, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof may be useful for treating conditions for which inhibition of RIP1 or a pathway involving RIP1 is therapeutically useful. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In some embodiments, the disclosed compounds are useful for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, nervous disorders, neurodegenerative diseases, allergic diseases, respiratory diseases, kidney diseases, cancer, ischemic conditions, red blood cell deficiencies, lung and brain damage (eg induced by ischemia-reperfusion or cisplatin and/or cerebrovascular accident), as well as bacterial and viral infections.

In some embodiments, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof may be used for the treatment or prevention of allergic diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmyopathy or asthma.

The disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof may also be useful for the treatment of immune system dysregulation associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunoregulatory disorders that can be treated with the compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, organ or tissue transplantation, graft-versus-host disease caused by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, thyroiditis Hashimoto's, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes mellitus, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases, including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis junctivitis, uveitis, associated with Behçet's disease, keratitis, herpetic keratitis, conical cornea, epithelial corneal dystrophy, corneal leukoma, pemphigus, Moray's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, congenital asthma, bronchial asthma, dust asthma, chronic or old asthma, late asthma and airway hyperresponsiveness, bronchitis, stomach ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic intestinal disease, ischemia-reperfusion injury, inflammatory intestinal diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome,

- 99 045696 diabetic nephropathy, multiple myositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis uritis, radiculopathy, hyperthyroidism, Graves' disease, true erythrocyte aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolyses tic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, pulmonary fibroids, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, atherosclerosis, atherosclerosis, syndrome aortitis, polyarteritis nodosa , myocardosis or myocardial infarction, scleroderma (including systemic scleroderma), antiphospholipid syndrome, Wegener's granuloma, Sjögren's disease, obesity, eosinophilic fasciitis, gingival, periodontal, alveolar, osteodental, glomerulonephritis, male pattern alopecia or senile alopecia , preventing hair removal or providing hair germination and/or stimulating hair formation and growth, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, ischemic-reperfusion injury of organs that occurs during conservation, transplantation or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis, drug- or radiation-induced, ischemic acute renal failure, chronic renal failure, pulmonary oxygen or drug-induced toxicosis, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, alkaline corneal burn, dermatitis multiforme, erythema, linear IgA ballous dermatitis and cementitious dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and hypobaropathy, disease caused by the release of histamine or leukotriene - C4, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, toxin-induced necrosis, viral hepatitis, shock or anoxia, B-viral hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic liver disease, including alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), autoimmune hepatobiliary diseases, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, late-onset liver failure, acute-chronic liver failure, chronic kidney disease, injury/ kidney injury (caused, for example, by nephritis, kidney transplantation, surgery, nephrotoxic drugs, acute renal failure), increased chemotherapy effect, cytomegalovirus infection, cytomegalovirus infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma or chronic bacterial infection.

In certain embodiments, the compounds of the present invention are useful for the treatment of nerve pain, including neuropathic pain and pain caused by inflammation.

In some embodiments, the compounds are useful for the treatment of interleukin-1 converting enzyme-associated fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases (eg, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartyl glucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, free sialic acid storage disease in early life, hexosaminidase A deficiency in early life, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, storage disease sialic acid, Tay-Sachs disease and Wolman disease).

In some embodiments, the disclosed compound, combinations of disclosed compounds, or pharmaceutical compositions thereof are useful for the treatment and/or prevention of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, etc. in particular, pustular psoriasis, diabetes mellitus type I, diabetes mellitus type II, inflammatory bowel diseases (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, Still's disease with onset in adulthood, gout, gout exacerbation, pseudogout, sappho-syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Huntington's disease or Parkinson's disease.

The use of the present compounds in combination with other therapies is particularly useful in the treatment of hyperproliferative diseases. The compounds of the present invention can be used to treat diseases such as cancer, leukemia and lymphoma, in combination with standard treatment

- 100 045696 niya. For example, myelodysplastic syndrome (MDS) can be treated with a compound described herein, along with standard treatment. Therapeutics for use in combination with the compounds of this invention include hypomethylating agents such as azacitidine and decitabine, and other chemotherapeutic agents such as cytarabine, daunorubicin and idarubicin. Immunomodulatory therapies, such as lenalidomide and CAR-T therapy, can also be used in combination with the compounds of this invention for the treatment of MDS.

Proliferative diseases that can be treated with the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof, including benign or malignant tumors, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric, ovarian, colon colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially carcinoma colon or colorectal adenoma, neck and head tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, such as Hodgkin's lymphoma and non-Hodgkin's lymphoma , breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-induced disorders, hematopoietic neoplasms such as the lymphomas mentioned above, MyD88 disorder (eg, ABC diffuse large B-cell lymphoma (DLBCL) ) and Waldenström's macroglobulinemia), Hodgkin's lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia) sluggish or indolent multiple myeloma or hematological malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphoma quotation lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström's macroglobulinemia (MB), marginal zone lymphoma with spleens, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds disclosed herein are useful for the treatment of drug-resistant cancers, such as JAK inhibitor-resistant CLL, ibrutinib-resistant cancers, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL, and ibrutinib-resistant CLL. Waldenström's macroglobulinemia to ibrutinib.

Examples of allergic diseases that can be treated using the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, atopic IgE-mediated asthma, non-atopic asthma, bronchial asthma, nonallergic asthma, essential asthma, true asthma, internal asthma caused by pathophysiological disorders, essential asthma of unknown or non-evident cause, emphysematous asthma, exercise-induced asthma, emotional asthma, external asthma caused by environmental factors, cold air-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoan or viral infection, early stage asthma, wheezing syndrome in infants, bronchiolitis, cough variant asthma or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, purulent or non-purulent sinusitis, acute or chronic sinusitis, as well as ethmoid, frontal, maxillary or sphenoid sinusitis.

As another example, rheumatoid arthritis (RA) typically results in swelling, pain, loss of motion, and tenderness in affected joints throughout the body. RA is characterized by a chronically inflamed synovium densely filled with lymphocytes. The synovium, which is usually one cell layer thick, becomes intensely cellular and takes on a form similar to lymphoid tissue, including dendritic cells, T, B, and NK cells, macrophages, and aggregates of plasma cells. This process, as well as a variety of immunopathological mechanisms, including the formation of antigen-immunoglobulin complexes, ultimately leads to disruption of joint integrity, resulting in deformity, irreversible loss of function, and/or erosion of bone in or near the joint. The claimed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof may be used to treat, alleviate, or prevent any one, more, or all of these symptoms of RA. Thus, in the context of RA, compounds are considered to provide a therapeutic effect when a reduction or improvement in any of the symptoms commonly associated with RA is achieved, regardless of whether the treatment results in concomitant treatment of the underlying RA and/or a reduction in the amount of circulating rheumatoid factor (RF). ).

The American College of Rheumatology (ACR) has developed criteria to determine improvement and

- 101 045696 clinical remission in RA. If a parameter such as ACR20 (ACR criterion for 20% clinical improvement) requires a 20% improvement in the number of tender and swollen joints, as well as a 20% improvement in 3 of the following 5 parameters: patient global rating, physician global rating, patient pain rating, degree disability and the level of acute phase reagent. These criteria were expanded to improve ACR50 and ACR70 by 50 and 70%, respectively. Other criteria include Paulou criteria and radiographic progression (eg, Sharpe score).

In some embodiments, a therapeutic effect in patients suffering from rheumatoid arthritis is achieved when the patient exhibits ACR20. In certain embodiments, improvements in ACR over ACRC50 or even ACR70 can be achieved.

In one embodiment, the currently disclosed compounds can be used to slow the onset of the effects of aging. For example, the compounds of the present invention reduce severe chronic inflammation associated with old age (inflammation). A variety of symptoms and conditions are associated with inflammation, for example, conditions that can be treated with the compounds of the present invention include neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, hematopoietic neoplasms and myeloproliferative disorders. Additional conditions that may be treated or improved by the compounds of the present invention include those described by Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014; 69 Suppl 1:S4-S9.

In another aspect, the compounds of this invention can be used to reduce the effects of aging on the reproductive system. For example, necroptosis induced by RIP1 signaling has been implicated in reproductive organ aging by Li et al. eLife 2017;6:e27692 and Chaudhary et al. Journal of Biomedical Science (2019) 26:11 therefore, the compounds of this invention can be used to treat symptoms associated with aging, such as decreased testosterone levels, decreased fertility and prostatic hyperplasia.

Additional diseases or disorders that may be treated and/or prevented by the compounds and compositions of the present invention include: amyotrophic lateral sclerosis (ALS), autoimmune syndrome, rheumatoid arthritis, type I diabetes, inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, internal asthma, external asthma, dust asthma, chronic or inveterate asthma, advanced asthma and airway hyperresponsiveness, allergic rhinitis, spondyloarthritis, ankylosing spondylitis, autoimmune hepatitis, autoimmune diseases of the hepatobiliary system, cerebrovascular accident, allergic diseases, chronic obstructive pulmonary disease, pulmonary emphysema, Friedreich's ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (polyQ ) diseases, Fahr's disease, Menke's disease, Wilson's disease, prion disorder, destructive bone diseases such as bone resorption disease, multiple myeloma-related bone disease; benign tumor, proliferative diseases, inflammatory and hyperproliferative skin diseases, epidermal hyperproliferation, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, erythemal dermatitis multiforme, linear IgA bullous dermatitis, cementitious dermatitis, gingivitis, periodontitis, damage to the gums, alveolar bone, bone substance sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, obesity, eosinophilic fasciitis, acne, alopecia areata, alopecia male type, senile alopecia, keratoconjunctivitis, spring conjunctivitis of alkaline burn, ankylide disease, uveit, associated with the disease of Bekhceta, keratitis, herpetic keratitis, conical cornea, epithelial dystrophy of the cornea, leico corneum, eye pussy, ulcer of muran Nagi -Harads, hematologic disorders, hematologic malignancies, lymphomas, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, ABC diffuse large B-cell lymphoma (DLBCL), Waldenström's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or indolent multiple myeloma, leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyte ny leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1 disorders, MyD88 disorders, drug-related resistant malignancies, such as JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies, such as ibrutinib-resistant

- 102 045696 hematological malignancies, ibrutinib-resistant CLL and ibrutinib-resistant Waldenström macroglobulinemia, acute myelogenous leukemia, chronic myelogenous leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovascularization, hemangiomas such as infantile hemangiomas; sepsis, septic shock, shigellosis; migraine, bronchitis, gastric ulcer, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 conversion-related fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, deficiency syndrome NEMO, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage disease, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, early-life free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, Wolman disease, Huntington disease, Parkinson disease, neurodegenerative diseases, Huntington disease, Parkinson disease, metastatic melanoma, HIV-associated neurodegeneration infection and CMV retinitis, such as associated neurocognitive disorders or dementia, fibrotic conditions such as non-alcoholic steatohepatitis, and cardiac conditions such as ischemia reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythematosis, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, syndrome Reiter's, rubella arthritis, acute synovitis, pancreatic β-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis, psoriatic arthritis and other arthritic conditions, cerebral malaria, chronic inflammatory pulmonary disease, silicosis, pulmonary sarcoidosis, pulmonary fibroma, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgias due to infection, keloid formation, formation scar tissue, fever, flu, chronic myelogenous leukemia; angiogenic disorders, including solid tumors; viral diseases, including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), AIDS, ARC or malignancy, herpes; stroke, myocardial infarction, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardial ischemia, ischemia during stroke infarction, organ hypoxia, vascular hyperplasia, reperfusion damage to the heart and kidneys, ischemic-reperfusion damage to organs that occurs during preservation, transplantation or ischemic disease, cardiac hypertrophy , thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, prostaglandin endoperoxidase-2 syndase-related conditions, pemphigus vulgaris, autoimmune/multiple myositis, dermatomyositis, leukoderma vulgaris, photoallergic sensitivity, ischemia, reperfusion injury, cardiac ischemia, reperfusion injury damage due to myocardial infarction, multiple system atrophy, Parkinson plus syndromes, frontotemporal dementia, intracranial hemorrhage, cerebral hemorrhage, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathies, progressive supranuclear palsy , corticobasal degeneration, demyelinating diseases, systemic juvenile idiopathic arthritis (JIA) or Still's disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), kidney transplantation, surgery, acute renal deficiency (AKI), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), COVID-19 ARDS, post-infectious inflammatory autoimmune diseases, rheumatism, post-infectious glomerulonephritis, systemic scleroderma, disorder cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO deficiency syndrome (Fkappa-B essential modulator gene deficiency syndrome (also known as IKK gamma or IKKG)), solid organ malignancies, lysosomal storage diseases glaucoma, degenerative retinal disease , retinal ischemia/reperfusion injury, renal ischemia reperfusion injury, cataract, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, lethal anthrax toxin-induced septic shock, LPS-induced cell death, infectious encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent

- 103 045696 diabetes mellitus, scleroderma, systemic scleroderma, macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, Northern dystrophy Carolinas, infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, toxic retinitis and light-induced toxicity, macular edema, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, optic nerve damage, optic neuritis, optic neuropathy, central retinal artery occlusion, ischemic optic neuropathy (eg, anterior ischemic neuropathy with or without arteritis and posterior ischemic optic neuropathy), compression optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (eg, Leber's optic neuropathy) , nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, dominant optic neuropathy, Beer syndrome, Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paresis, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury , anoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia and hypoxic hypoxia, peritoneal dialysate-induced injury (PDF) and PD-related side effects, glomerular diseases, tubulointerstitial diseases, interstitial nephritis, obstruction , polycystic kidney disease), focal glomerulosclerosis, immune complex nephropathy, diabetic nephropathy, Goodpasture's syndrome, hepatocellular cancer, pancreatic cancer, urological cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostate hyperplasia, kidney cancer, kidney cancer, liver cancer, adrenal cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, stomach cancer, endometrial cancer, esophageal cancer, stomach cancer, head and neck cancer, neuroendocrine cancer cancer , CNS cancer, brain tumors (eg, brain carcinoma, 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 neoplasms, epithelial neoplasia, gastric carcinoma, ovarian carcinoma, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer , bone cancer, thyroid cancer, sarcoma, glioblastomas, neuroblastomas, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid cancer, large cell cancer, non-small cell lung cancer, lymphomas, colon cancer, colorectal adenoma, hemangiopericytomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral carcinoma, vulvar cancer, adrenal cancer, ACTH-producing tumors and leukemia, respiratory infectious viruses such as influenza virus, rhinovirus, corona virus, parainfluenza virus, RS virus, adenovirus , reovirus, etc.), herpes zoster, diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infectious diseases such as Bacillus cereus, Vibrio parahaemolyticus, enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRS A, Salmonella, Botulinus, Candida, Paget's disease, achondroplasia, osteochondrosis, hyperparathyroidism, osteogenesis imperfecta, partial liver resection, acute liver necrosis, toxin-induced necrosis, viral hepatitis-induced necrosis, shock-induced necrosis, anoxia-induced necrosis, B-viral hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, late-onset liver failure, acute chronic liver failure, chronic diseases kidney damage/trauma, kidney damage/trauma caused by nephritis, kidney damage/trauma caused by kidney transplantation, kidney damage/trauma caused by surgery, kidney damage/trauma caused by nephrotoxic drugs, enhanced chemotherapy effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, hypobaropathy, diseases caused by the release of histamine or leukotriene-C4, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, pulmonary oxygen or drug-induced toxicosis, congenital hypophosphatasia, fibromatous lesions, fibrous dysplasia, bone metabolism, osteolytic bone disease, treatment of post-traumatic bone surgery, treatment after joint replacement , treatment after plastic surgery on bones, treatment after dental surgery, bone chemotherapy treatment or radiation treatment

- 104 045696 bone therapy, bone cancer, fragile plaque, disorder, occlusive disorder, stenosis, coronary artery disease, peripheral artery disease, arterial occlusion, neurosm formation, post-traumatic aneurysm formation, restenosis, postoperative graft occlusion, Guillain-Barré syndrome, Meniere's disease , polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoito's thyroiditis, myasthenia gravis, diseases

Cold and warm agglutinins, Evan's syndrome, hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, aerythroplasia and combinations thereof.

In specific embodiments, at least one compound, or a composition containing at least one compound, according to the present invention is administered to a subject having or potentially developing atopic dermatitis. In another specific embodiment, at least one compound, or a composition containing at least one compound, according to the present invention is administered to a subject having or potentially developing rheumatoid arthritis. In another specific embodiment, at least one compound, or a composition containing at least one compound, according to the present invention is administered to a subject having or potentially developing ankylosing spondylitis. In another specific embodiment, at least one compound, or a composition containing at least one compound, according to the present invention is administered to a subject having or potentially developing myelodysplastic syndrome.

B. Formulations and Introduction

Pharmaceutical compositions containing one or more active compounds of the present invention can be produced by any suitable method, such as mixing, dissolving, granulating, drageeing, trituration, emulsification, encapsulation, entrapment or lyophilization. Pharmaceutical compositions can be formulated using one or more physiologically acceptable excipients (eg, diluents, carriers or excipients), one or more adjuvants, or combinations thereof to produce pharmaceutically usable formulations.

The active compound(s) may be included in pharmaceutical compositions per se or in the form of a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotopic analog or prodrug thereof. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts with less solubility than the corresponding free acids and bases can also be formed.

The pharmaceutical compositions of the present invention may be in a form suitable for virtually any route of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injectable, such as intravenous or intraperitoneal, transdermal, rectal, vaginal, etc. or a form suitable for administration by inhalation or insufflation.

For topical administration, the active compound(s), pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotopic analog or prodrug may be formulated as solutions, gels, ointments, creams, suspensions, etc. . known in the art.

Formulations for systemic administration include those intended for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those intended for transdermal, transmucosal oral or pulmonary administration.

Suitable injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in an aqueous or oily medium. The pharmaceutical compositions may also contain formulation agents such as a suspending, stabilizing and/or dispersing agent. Injectable compositions may be presented in unit dosage form, for example, ampoules or multi-dose containers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, etc., prior to use. To this end, the active compound(s) can be dried by any method known in the art, such as lyophilization, and reconstituted before use.

For transmucosal administration, the drug uses penetrants that match the barrier that needs to be penetrated. Such penetrants are known in the art.

For oral administration, the pharmaceutical compositions may be in the form of, for example, mouth

- 105 045696 lok, tablets or capsules, prepared by conventional methods, with pharmaceutically acceptable excipients such as: binding agents (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (eg lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or silicon dioxide); leavening agents (for example, potato starch or sodium starch glycolate); and/or wetting agents (eg sodium lauryl sulfate). Tablets can be coated by methods well known in the art, such as sugars, films or enteric coatings.

Liquid preparations for oral administration may be in the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable carrier before use. Such liquid preparations can be prepared by conventional methods with pharmaceutically acceptable excipients such as: suspending agents (eg sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (for example, lecithin or acacia); non-aqueous vehicles (eg, almond oil, oily esters, ethyl alcohol, cremophore™ or fractionated vegetable oils); and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavorings, colors and sweeteners as needed.

It is well known that oral preparations can be formulated to provide controlled release of the active compound.

For buccal administration, the pharmaceutical compositions may be in the form of tablets or lozenges formulated in conventional manner.

For the rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas), suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation or insufflation, the active compound(s), pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug can be conveniently delivered as an aerosol spray from a pressurized can or spray using a suitable propellant, for example) dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be defined by providing a valve for delivering the metered amount. Capsules and cartridges for use in an inhaler or insufflator (eg, capsules and cartridges consisting of gelatin) can be formulated using a powder mixture of the compound and a suitable powder base such as lactose or starch.

A specific example of an aqueous suspension formulation suitable for nasal administration using commercially available nasal spray devices includes the following ingredients: active compound (0.5-20 mg/ml); benzalkonium chloride (0.1-0.2 mg/ml); polysorbate 80 (TWEEN®; 0.5-5 mg/ml); sodium carboxymethylcellulose or microcrystalline cellulose (1-15 mg/ml); phenylethanol (1.4 mg/ml); and dextrose (20-50 mg/ml). The pH of the final suspension can be adjusted to range from about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable for administering compounds by inhalation contains 20 mg/ml of the disclosed compound(s), 1% (v/v) polysorbate 80 (TWEEN® 80), 50 mM citrate and/or 0.9% sodium chloride.

For ocular administration, the active compound(s) may be formulated as a solution, emulsion, suspension, etc., suitable for ocular administration. A variety of carriers suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in US patent No. 6261547; 6197934; 6056950; 5800807; 5776445; 5698219; 5521222; 5403841; 5077033; 4882150; and 4738851, which are incorporated herein by reference.

For sustained delivery, the active compound(s) may be formulated as a depot formulation for administration by implantation or intramuscular injection. The active ingredient may be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, eg, as a sparingly soluble salt. Alternatively, transdermal delivery systems can be used, formulated as an adhesive disc or patch that slowly releases the active compound(s) for transdermal absorption. To this end, permeation enhancers can be used to facilitate transdermal penetration of the active compound(s). Suitable transdermal patches are described, for example, in US patent No. 5407713; 5352456; 5332213; 5336168; 5290561; 5254346; 5164189; 5163899; 5088977; 5087240; 5008110; and 4921475, which are incorporated herein by reference.

Alternatively, other pharmaceutical delivery systems may be used.

- 106 045696

Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver the active compound(s). Some organic solvents, such as dimethyl sulfoxide (DMSO), can also be used, although usually at the expense of greater toxicity.

Pharmaceutical compositions may, if desired, be presented in a package or dispenser, which may contain one or more unit dosage forms containing the active compound(s). The packaging may, for example, comprise metal or plastic foil, such as a blister pack. The package or dosing device may be accompanied by instructions for administration.

There are several approaches to transport molecules across the blood-brain barrier. These include, but are not limited to, physical methods, lipid-based methods, and receptor and channel based methods. Physical methods of transporting a compound across the blood-brain barrier include, but are not limited to, completely bypassing the blood-brain barrier and/or creating holes in the blood-brain barrier. Bypass methods include, but are not limited to, direct injection (eg, Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial infusion/convection enhanced delivery (Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91:2076-2080, 1994) and implantation of a delivery device into the brain (see, for example, Gill et al., Nature Med. 9:589595, 2003. Holes in the blood-brain barrier include, but are not limited to, ultrasound, osmotic pressure (for example, by administering hypertonic mannitol and permeabilization, for example, with bradykinin or permeabilizer A-7 (see, for example, US Pat. Nos. 5112596, 5268164, 5506206 and 5686416). The compounds can also be encapsulated in liposomes that are associated with fragments binding antibodies that bind to vascular endothelial receptors of the blood-brain barrier.

In some embodiments, the compounds may be administered continuously by infusion into CNS fluid reservoirs or by bolus injection. The compounds can be administered via an indwelling catheter and continuous delivery means such as a pump, or via sustained release drug implantation. For example, compounds can be administered through permanently implanted cannulas or chronically administered using osmotic minipumps. Subcutaneous pumps can deliver compounds to the ventricles of the brain.

C. Dosages

The claimed compound, pharmaceutical compositions or combinations of disclosed compounds will generally be used in an amount effective to achieve the intended result, for example, in an amount effective to inhibit RIP1 kinase and/or to treat, prevent or alleviate a particular condition. The claimed compound(s) or pharmaceutical compositions thereof may be administered therapeutically to achieve a therapeutic effect or prophylactically to achieve a prophylactic effect. Therapeutic effect means the elimination or improvement of the underlying disease being treated and/or the elimination or improvement of one or more symptoms associated with the underlying disease, such that the patient reports an improvement in health or condition, although the patient may still be suffering from the underlying disease. disorder. For example, administration of a compound to a patient suffering from an allergy provides a therapeutic benefit not only when the underlying allergic reaction is eliminated or reduced, but also when the patient reports a decrease in the severity or duration of allergy-related symptoms following exposure to the allergen. As another example, a therapeutic effect in the context of asthma includes improving breathing after the onset of an asthmatic attack or reducing the frequency or severity of asthmatic episodes. The therapeutic effect also includes stopping or slowing the progression of the disease, regardless of whether improvement is achieved.

As is known to those skilled in the art, the preferred dosage of the disclosed compounds may depend on various factors, including the age, weight, general health and severity of the patient or subject being treated. The dosage may also be tailored to the gender of the individual and/or the lung capacity of the individual when administered by inhalation. Dosage may also be adjusted for individuals suffering from more than one condition or for individuals with additional conditions that affect lung capacity and ability to breathe normally, such as emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and from respiratory infections. The dosage and frequency of administration of the disclosed compound(s), or pharmaceutical compositions thereof, will also depend on whether the disclosed compound(s) are formulated for the treatment of acute episodes of a condition or for the prophylactic treatment of a disorder. One skilled in the art will be able to determine the optimal dosage for a particular individual.

For prophylactic administration, a disclosed compound, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered to a patient or subject at risk of developing one of the previously described conditions. For example, if it is unknown whether a patient or subject is allergic to a particular drug, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof may be administered prior to administration of the drug to avoid or reduce an allergic reaction to the drug. Alternatively, prophylactic administration

- 107 045696 can be used to prevent or alleviate the onset of symptoms in a patient who has been diagnosed with an underlying disease. For example, the disclosed compound(s) or pharmaceutical composition thereof may be administered to an allergy sufferer prior to expected exposure to the allergen. The described compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof can also be administered prophylactically to healthy individuals who have been repeatedly exposed to agents known for one of the above-described diseases to prevent the onset of the disorder. For example, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a healthy individual who is repeatedly exposed to an allergen known to cause allergy, such as latex, for the purpose of preventing the individual from developing an allergy. Alternatively, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a patient suffering from asthma prior to engaging in activities that trigger asthma attacks to reduce the severity of an asthmatic episode or avoid it altogether.

Effective doses can be initially estimated from in vitro assays. For example, an initial dose for use in subjects may be formulated to achieve a circulating blood or serum concentration of the active compound equal to or greater than the _IC50 or _EC50 of the particular compound as measured in an in vitro assay. Doses may be calculated to achieve such concentrations in circulating blood or serum, taking into account the bioavailability of the particular compound. Fingl & Woodbury, General Principles, In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, chapter 1, pages 1-46, Pergamon Press, and references cited therein provide additional guidance regarding effective dosages.

In some embodiments, the disclosed compounds have an EC ₅₀ of greater than 0 to 20 μM, e.g., greater than 0 to 10 μM, greater than 0 to 5 μM, greater than 0 to 1 μM, greater than 0 to 0. 5 µM, from more than 0 to 0.1 µM or from more than 0 to 0.05 µM.

Initial doses can also be estimated from in vivo data, for example, in animal models. Animal models suitable for testing the effectiveness of compounds for the treatment or prevention of various diseases described above are well known in the art. Suitable animal models of hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50(21 Suppl):6-9, discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol. 107(6): 1025-1033. Suitable animal models of allergic rhinitis are described by Szelenyi et al., (2000), Arzneimittelforschung 50(11): 1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy 24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1): 1-7. Those skilled in the art can adapt such information to determine doses suitable for administration to humans.

In some embodiments, assays suitable for determining RIP1 activity can be used. Such assays can be used to evaluate the effectiveness of embodiments of a compound disclosed herein and/or they can be used to determine amounts/doses of embodiments of a compound that can provide the desired effectiveness. In some embodiments, the assay may be an ADP-Glo™ assay, which assesses the ability of a compound to inhibit RIP1. In other embodiments, whole cell assays can be performed using mouse and/or human cells, such as U937 and/or L929 cell necroptosis assays, to determine safe and effective doses of compounds that can be used in human in vivo studies. Using these whole cell assays, the activity of a compound against human and/or murine RIP1 can be assessed in an in vitro context, which then allows one of skill in the art to determine safe and effective doses for in vivo use. Another assay that can be used to evaluate the activity of the compounds described herein for the treatment of a disease or condition associated with RIP1 is an acute hypothermia mouse model that evaluates the ability of the compound to inhibit TNF-alpha-induced hypothermia. Each of these assays and the various results from using these assays are described in detail in the Examples section of this specification.

Dose amounts of the disclosed compounds typically range from greater than 0 mg/kg/day, for example, 0.0001 mg/kg/day, or 0.001 mg/kg/day, or 0.01 mg/kg/day, at least up to about 100 mg/kg/day. More typically, the dose (or effective amount) may range from about 0.0025 mg/kg to about 1 mg/kg, administered at least once daily, for example, from 0.01 mg/kg to about 0.5 mg /kg or from about 0.05 mg/kg. kg to about 0.15 mg/kg. The total daily dose is typically from about 0.1 mg/kg to about 5 mg/kg or up to about 20 mg/kg per day, such as from 0.5 mg/kg to about 10 mg/kg per day or from about 0. 7 mg/kg per day to about 2.5 mg/kg/day. Dosage levels may be higher or lower depending on, among other factors, the activity of the disclosed compound, its bioavailability, route of administration and various factors discussed above.

The dosage amount and dosing interval may be adjusted for individuals to provide plasma levels of the disclosed compound sufficient to maintain a therapeutic or prophylactic effect. For example, the compounds can be administered once a day, several times a day, once a week, several times a week (eg, every other day), once a month,

- 108 045696 several times a month or once a year, depending, among other things, on the route of administration, the specific indication for treatment and the opinion of the attending physician. Those skilled in the art will be able to optimize effective local dosages without unnecessary experimentation.

Pharmaceutical compositions comprising one or more disclosed compounds typically contain from greater than 0 to 99% of the disclosed compound or compounds and/or other therapeutic agent as a percentage of the total weight. Typically, pharmaceutical compositions comprising one or more disclosed compounds contain from about 1 to about 20% by weight of the disclosed compound and another therapeutic agent and from about 80 to about 99% by weight of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition may further comprise an adjuvant.

Preferably, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof will provide a therapeutic or prophylactic effect without causing significant toxicity. The toxicity of the disclosed compound can be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effect is the therapeutic index. Preference is given to the disclosed compounds which exhibit high therapeutic indices.

V. Examples

Example 1.

The compounds of the present invention can be prepared using a suitable starting compound, such as compound 200 or compound 206, illustrated in the diagrams above. A typical method for preparing compound 200 is illustrated in Scheme 8A, and a typical method for preparing compound 206 is illustrated in Scheme 8B.

Scheme 8A

Circuit 8B

t X) DMF. Eoin. n Ό temp.. 14 h

Spectral characteristic for 3-(S)-N-tritylamino-7-bromo-5-methyl-4-oxobenzooxazapine (200): ¹ H NMR (400 MHz, CDCl3) δ 7.41-7.38 (6H, m, 6H QQ^h), 7.25-7.15 (10H, m, oxobenzoxazapine H-8, 9H C(C ₆ H ₅ ) ₃ ), 7.00 (1H, d, J=2.5 Hz, oxobenzoxazapine Н-6), 6.91 (1H, d, J=8.5 Hz, oxobenzoxazapine Н-9), 4.50 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine Н-2 ), 4.37 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.53 (1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine H- 3), 3.30 (1H, b.s., NH), 2.87 (3H, s. NCH3).

Characterization data and specific methods for preparing representative compounds disclosed herein are provided below.

Example 2.

Synthesis of (S)-7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepine -4(5H)-one: Mixture of bromoxazapine (0.210 g, 0.410 mmol, 1.0 eq.), potassium carbonate (0.566 g, 4.101 mmol, 10.0 eq.) and copper(I) iodide (0.008 g, 0.041 mmol, 0.1 eq.) in dimethylformamide (3.0 ml) was degassed by bubbling argon for 5 min. 2-Methyl-2-hydroxybut-3-yne (0.052 g, 0.060 mL, 0.615 mmol, 1.5 eq.) and tetrakis(triphenylphosphine)palladium (0.024 g, 0.021 mmol,

- 109 045696

0.05 eq.), and the reaction mixture was sealed before heating in a microwave reactor to

120°C for 1 hour. The reaction mixture was partitioned between EtOAc (80 ml) and water (80 ml). The organic layers were washed with brine (80 ml), water (80 ml) and brine (80 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. HPLC (10^80% EtOAc-hexane) gave the starting material (0.091 g) and the title compound (0.079 g) as a colorless oil;

'H NMR (400 MHz, CDCI3) δ 7.40-7.38 (6H, m, 6H C(C ₆ H ₅ ) ₃ ), 7.24-7.7.14 (9H, m, 9H C( C6H ₅ ) ₃ ), 7.13 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine H-8), 6.96 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9 ), 6.95 (1H, d, J=2.5 Hz, oxobenzoxazapine H-6), 4.48 (1H, dd, J=10.0, 7.5 Hz), 1H oxobenzoxazapine H-2), 4.37 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.55 (1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine H-3) , 2.78 (3H, s, NCH ₃ ), 1.62 (6H, s, C(CH ₃ ) ₂ ); mz: 555 [M+K]+, 243 [C(C ₆ H ₅ ) ₃ ] ⁺ .

Deprotection of the trityl group:

To a solution of trityl protected amine (0.079 g, 0.153 g, 1.0 eq.) in dioxane (2.0 mL) was added a solution of hydrogen chloride (0.15 mL of 4M dioxane, 0.614 mmol, 4.0 eq.). The reaction mixture was stirred at room temperature for 6 hours, then concentrated to dryness to give a white solid, which was used without purification; m/z: 275 [M+H]+.

Synthesis of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide: To a solution of aminooxobenzoxazapine hydrochloride (0.076 mmol, 1.0 eq.) and benzyltriazolecarboxylic acid (0.017 g, 0.084 mmol, 1.1 eq.) in dimethylformamide (1.0 mL) was added diisopropylamine (0.025 g, 0.033 mL, 0.190 mmol, 2.5 eq.) followed by the addition of HATU (0.032 g, 0.084 mmol, 1.1 eq. ). The reaction mixture was stirred at room temperature for 4 hours and partitioned between EtOAc-CH ₂ Cl ₂ (5:1, 60 ml) and NaHCO ₃ (60 ml). The organic layers were washed with brine (50 ml), water (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. HPLC (0^10% MeOH-CH ₂ Cl ₂ ) gave the title compound as a white solid;

1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (1H, d, J=7.5 Hz, NH), 7.30-7.22 (7H, m, 7 x ArH), 7.11 (1H , d, J=9.0 Hz, oxobenzoxazapine N-9), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.68 (1H, dd, J =10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.14 (2H, s ,СН ₂ СН ₅ ), 3.40 (3H, s, NCH ₃ ), 1.63 (6H, s, C(CH ₃ ) ₂ OH); m/z: 442 [M+HH ₂ O]+. To obtain compounds I-14, I-17 and I-35, steps similar to those described above for example 2 can be used.

Example 3.

Synthesis of ethyl-(8,E)-3-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin- 7-yl)acrylate: To a suspension of tert-butyl-(8)-(7-bromo-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl) carbamate (0.500 g, 1.35 mmol, 1.0 eq.) in dimethylformamide (8 ml) was degassed by bubbling argon for five minutes. Ethyl acrylate (0.270 g, 0.29 mL, 2.70 mmol, 2.0 eq) and triethylamine (0.272 g, 0.37 mL, 2.0 eq) were added followed by tetrakis(triphenylphosphine) (0.156 g, 0.14 mmol, 0.1 eq.). The reaction mixture was sealed and heated in a microwave reactor to 100°C for 1 hour and 120°C for 1 hour. The reaction mixture was partitioned between EtOAc (100 ml) and water (100 ml). The organic layers were washed with brine (70 ml), water (100 ml) and brine (70 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Column chromatography (10^40% EtOAc-hexane) gave the title compound (0.250 g, %) as a yellow foam; 1H NMR (400 MHz, CDCl ₃ ) δ 7.62 (1H, d, J=16.0 Hz, ArCH=CHCO), 7.35 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazepine N-8), 7.33 (1H, d, J=2.0 Hz, oxobenzoxazepine N-6), 7.14 (1H, d, J=8.0 Hz, oxobenzoxazepine N-9), 6.37 (1H, d, J=16.0 Hz, ArCH=CHCO), 5.49 (1H, d, J=7.0 Hz, NH), 4.65 (1H, dt, J=11.0, 7 ,0 Hz, oxobenzoxazepine H-3), 4.57 (1H, dd, J=9.5, 7.0 Hz, 1H oxobenzoxazepine H-2), 4.27 (2H, k, J=7.0 Hz ,OSH ₂ CH ₃ ), 4.19 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazepine H-2), 3.41 (3H, s, NCH3), 1.39 (9H, s, C(CH ₃ ) ₃ ), 1.34 (3H, t, J=7.0 Hz, OCH ₂ CH ₃ ); mz: 291 [M+H-CO2C4H8]+.

Synthesis of ethyl-(8)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)pro-110 045696 panoate : A solution of α,β-unsaturated ester (0.25 g, 0.64 mmol, 1.0 eq.) in ethyl acetate (20 ml) was added palladium on carbon (0.23 g). The reaction mixture was purged with hydrogen and stirred under hydrogen for 14 hours. The reaction mixture was purged with nitrogen and filtered through celite®, eluting with ethyl acetate (2x20 ml). The filtrate was concentrated under reduced pressure; 1H NMR (400 MHz, CDCl ₃ ) δ 7.04-6.82 (3H, m, oxobenzoxazepine H-6, H-8, H-9), 5.50 (1H, d, J=7.5 Hz , NH), 4.61 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.52 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazepine H-2), 4.14-4.07 (1H, m, 1H oxobenzoxazepine H-2), 4.12 (2H, k, J=7.0 Hz, OCH2CH3), 3.36 (3H, s, NCH3), 2.91 (2H, t, J=7.5 Hz, 2H ArCHSCHSO), 2.59 (2H, t, J=7.5 Hz, 2H ArCH ₂ CH ₂ CO), 1.37 (9H , s, C(CH3)z), 1.23 (3H, t, J=7.0 Hz, OCH ₂ CH ₃ ); m/z: 337 [M+HC ₄ H ₈ ]+, 293 [M+H-CO ₂ -C ₄ H ₈ ] ⁺ . The crude material was dissolved in dichloromethane (10 ml). Hydrogen chloride (0.80 ml of 4M solution in dioxane, 3.21 mmol, 5.0 eq.). The reaction mixture was stirred at room temperature for 14 hours before adding more hydrogen chloride solution (0.8 mL, 5.0 eq.). After stirring for an additional 2 hours, the reaction mixture was concentrated under reduced pressure and dried in vacuo to give a brown solid. The crude material was used without further purification; m/z: 293 [M+H] ⁺ .

F

Synthesis of ethyl-(S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4, 5tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate:

Fluorobenzyltriazole (0.116 g, 0.525 mmol, 1.1 eq.) was added to a solution of ethyl-(S)-3-(3-(1-(2fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)- 5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate (0.140 g, 0.477 mmol, 1.0 eq.) and diisopropylethylamine (0.154 g , 0.21 mmol, 2.5 eq.) in dimethylformamide (5.0 eq.). HATU (0.199 g, 0.525 mmol, 1.1 eq) was added and the reaction mixture was stirred at 0°C for 1 hour and at room temperature for 1 hour. The reaction mixture was partitioned between EtOAc (120 ml) and NaHCO ₃ -water (1:1, 120 ml). The organic layers were washed with brine (100 ml), water (100 ml) and brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (40^80% EtOAc-hexane) gave the title compound (0.138 mg) as a white solid; 1H NMR (400 MHz, CDCl ₃ ) δ 8.11 (1H, s, triazole H-5), 8.05 (1H, d, 7.0 Hz, NH), 7.38-7.30 (2H, m, 2H C ₆ H ₄ F), 7.26-7.07 (6H, m, 2H C ₆ H ₄ F, oxobenzoxazapine H-6, H-7, H-8, H-9), 5.42 (2H, s, CH ₂ SwH ₄ P), 5.08 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.75 (1H, dd, J=9.5 , 7.5 Hz, 1H oxobenzoxazapine H-2), 4.24 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH3); ¹³ C NMR (100 MHz, CDCl3) δ 168.9, 160.6 (d, J 248.5 Hz), 158.3, 156.7, 150.1, 144.1 (d, J=2.0 Hz), 136.0, 131.1 (d, J=8.5 Hz), 130.9 (d, J=2.5 Hz), 127.6, 125.7, 124.9 (d, J Hz), 123.3, 123.1, 121.2 (d, J 14.0 Hz), 115.8 (d, J 21.5 Hz), 77.3, 49.2, 47.9 (d , J=4.0 Hz), 35.5; ¹⁹ F NMR (380 MHz, CDCl3) δ -118.1; m/z: 518 [M+Na] ⁺ , 496 [M+H] ⁺ (found [M+H] ⁺ , 496.1991, C ₂₅ H ₂₆ FN ₅ O ₅ requires [M+H] ⁺ 496.1973 ).

You can use steps similar to those described above for example 3 and below for examples 4 and 5 to obtain compounds I-10, I-11, I-13, I-18, I-19, I-26, I-27, I -33, I-34 and I-22 and I-23 (where the double bond of the linker group is not reduced before binding).

Example 4.

F F

Synthesis of (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-7-yl)propanoic acid: to a solution of ethyl ester (0.103 g, 0.208 mmol, 1.0 eq.) in tetrahydrofuran (3 ml) was added an aqueous solution of lithium hydroxide (0.017 g), g , 0.416 mmol, 2.0 eq. in 1 ml of water). The reaction mixture was stirred at room temperature for 3 hours before partitioning between EtOAc (80 ml) and NH ₄ Cl (80 ml). The aqueous phase was extracted with EtOAc (2x60 ml). The combined organic layers were washed with brine (80 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. Column chromatography (0^10% MeOH-CH ₂ Cl ₂ ) gave the title compound (0.054 g) as a white solid; ^1H NMR (400 MHz, CDCl3) δ 8.12 (1H, s, triazole H-5), 8.04 (1H, d, J=7.5 Hz, NH), 7.40-7.30 ( 2H, m, 2 x ArH), 7.16 (1H, dd, J=7.5, 1.0 Hz, 1 x ArH), 7.14-7.10 (2H, m, 2 x ArH), 7.07 (2H, m, 2 x ArH), 5.43 (2H, s, NCH2C6H5F), 5.07 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazepine H-3), 4 .73 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazepine H-2), 4.22 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazepine H-2) , 3.41 (3H, s, NCH3), 2.96 (2H, t, J=7.5 Hz, 2H ArCH2CH2CO), 2.70 (2H, t, J=7.5 Hz, 2H ArCH2CH2CO); ¹⁹ F NMR (CDCl3) δ -118.1 (dd, J=16.5, 7.0 Hz); m/z: 468 [M+H] ⁺ (found [M+H] ⁺ , 468.1688, C ₂₃ H ₂₂ FN ₅ O ₅ requires [M+H] ⁺ 468.1678).

- 111 045696

Example 5.

Synthesis of (S)-N-(7-(3-((1H-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-1 -(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid: solution of ^)-3-(3-(1-(2-fluorobenzyl )-III-1,2,4-triazol-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoic acid (0.049 g, 0.105 mmol, 1.0 eq.) and 6-aminoindazole (0.017 g, 0.126 mmol, 1.2 eq.) in dimethylformamide (10 ml) were cooled to 0°C. Diisopropylethylamine (0.027 g, 0.036 mL, 0.210 mmol, 2.0 eq) was added followed by HATU (0.048 g, 0.126 mmol, 1.2 eq) and the reaction mixture was stirred at 0°C for 1 h and room temperature for 2 hours. The reaction mixture was partitioned between EtOAc (50 ml) and NaHCO ₃ (50 ml). The organic layers were washed with brine (50 ml). The combined aqueous phase was extracted with EtOAc (20 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Column chromatography (0^10% MeOHCH ₂ Cl ₂ ) gave the title compound as a white solid; ^1H NMR (400 MHz, CDCl3) δ 8.12 (1H, s, triazole H-5), 8.00 (1H, d, J=7.5 Hz, NH), 7.94 (1H, d, J 0.5 Hz, indazole H-3), 7.90 (1H, s, NH), 7.83 (1H, m, indazole H-7), 7.57 (1H, d, J=9.0 Hz, indazole H-4), 7.37-7.30 (2H, m, 2H C6H4F), 7.13 (1H, td, J=7.5, 1.0 Hz, 1H C6H4F), 7.09 -7.00 (5H, m, indazole H-5, 1H C6H4F, oxobenzoxazepine H-6, H-7, H9), 5.40 (2H, eNCH2C6H4F), 5.02 (1H, td, J=H, 5, 7.5 Hz, oxobenzoxazepine H-3), 4.63 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazepine H-2), 4.23 (1H, dd, J=11 ,5, 9.5 Hz, 1H oxobenzoxazepine H-2), 3.29 (3H, s, NCH3), 3.03 (2H, t, J=7.0 Hz, ArCH2CH2CON), 2.68 (2H, m, ArCH2CH2CON); ¹³ C NMR (CDCl3) δ 170.6, 168.7, 160.7 (d, J 248.5 Hz), 158.8, 156.4, 148.4, 144.4, 140.6, 138, 5, 136.3, 135.9, 134.3, 131.2 (d, J=8.5 Hz), 131.0 (d, J 3.0 Hz), 127.5, 124.9 (d , J=4.0 Hz), 123.4, 122.9, 121.1, 121.0, 120.3, 115.8 (d, J=20.5 Hz), 115.3, 101.1 , 77.2, 49.1, 48.0 (d, J=4.0 Hz), 39.3, 35.3, 31.1; ¹⁹ F NMR (CDCl ₃ ) δ -118.0; m/z: 583 [M+H]+ (found [M+H]+, 583.2205, C ₃₀ H ₂₇ FN ₈ O ₄ requires [M+H]+ 583.2212).

Example 6.

Cl

Ethyl-(S)-3-(3-(1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-ethyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionic acid: 1H NMR (400 MHz, CDCl ₃ ) δ 8.02 (1H, d, J=7.0 Hz, NH), 7 .96 (1H, s, triazole H-5), 7.42 (2H, m, 2 x ArH), 7.32 (1H, dd, J=9.0, 7.0 Hz, 1 x ArH), 7.10 (1H, m, 1 x ArH), 7.06 (2H, dd, J=6.0, 2.0 Hz, 2 x ArH), 5.70 (2H, s, CH2C6H3CI2), 5, 07 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.74 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazepine H-2), 4 .21 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazepine H-2), 4.14 (2H, k, J=7.0 Hz, OCH ₂ CH ₃ ), 3.41 ( 3H, s, NCH ₃ ), 2.95 (2H, t, J 7.5 Hz, 2H ArCH ₂ CH ₂ CO), 2.63 (2H, t, J=7.5 Hz, 2H ArCH ₂ CH ₂ CO), 1.24 (3H, t, J=7.0 Hz, OCH ₂ CH ₃ ); ¹³ s NMR (100 MHz, CDCl ₃ ) δ 172.5, 168.9, 158.3, 156.5, 148.4, 143.9, 138.4, 136.9, 135.8, 131.4 , 129.1, 128.9, 127.5, 123.2, 122.9, 77.2, 60.6, 49.4, 49.3, 35.7, 35.5, 30.3, 14 ,2; m/z: 548, 546 [M+H]+ (found _[ M+H]+, _546.1291 , _{C25H25Cl2N5O5 requires} [M+ _H ]+546.1306).

Example 7.

(S)-3-(3-(5-Benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-7-yl)propionic acid: 1H NMR (400 MHz, CDCl ₃ ) δ 8.13 (1H, d, J=7.5 Hz, NH), 7.32-7.22 (5H , m, 5 x ArH), 7.08-7.06 (3H, m, 3 x ArH), 4.97 (1H, dt, J=11.0, 7.5 Hz), oxobenzoxazapine H3), 4 .62 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.24 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2) , 4.13 (2H, s, CH ₂ C ₆ H ₅ ), 3.38 (3H, s, NCH ₃ ), 2.94 (2H, m, 2H AgCH ₂ CH ₂ CO ₂ H), 2.70 (2H, m, 2H AgCH ₂ CH ₂ CO ₂ H); ¹⁹ f NMR (CDCl ₃ ) δ -118.1; m/z: 450 [M+H]+ (found _[ M+H]+, _450.1760 , _{C23H23N5O5 requires} [M+H]+ 450.1772).

Example 8.

(S)-5-benzyl-N-(5 -methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1 -yl)propyl)-2,3,4,5-tetrahydroben

- 112 045696 zo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide: 1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (1H, d , J=7.5 Hz, NH), 7.29-7.21 (5H, m, 5 x ArH), 7.10-7.07 (3H, m, 3 x ArH), 5.05 (1H , dt, J=11.0, 7.5 Hz), oxobenzoxazapine H-3), 4.66 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.22 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.15 (2H, s, CH ₂ Ph), 3.45 (2H, t, J=7.0 Hz , 2H pyrrolidine), 3.38 (3H, s, NCH3), 3.35 (2H, m, 2H pyrrolidine), 2.97 (2H, t, J=7.5 Hz, 2H AgODODSO), 2.57 (2H, t, J=7.5 Hz, 2H AgODODSO), 1.92 (2H, m, 2H pyrrolidine), 1.83 (2H, m, 2H pyrrolidine); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.4, 168.9, 158.5, 148.2, 139.5, 135.9, 135.7, 128.9, 128.8, 127.6 , 127.1, 123.5, 122.7, 77.1. 49.2, 46.6, 45.8, 36.6, 35.5, 33.2, 30.4, 26.0, 24.4; m/z: 503 [M+H] ⁺ (found [M+H]+, 503.2403, C27H30N6O4 requires [M+H]+ 503.2401).

Example 9.

Synthesis of (S,E)-3-(5-methyl-4-oxo-3-(tritylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7yl)acrylamide: to a mixture of bromoxobenzoxazapine (0.300 g, 0.586 mmol, 1.0 eq.) and acrylamide (0.062 g, 0.879 mmol, 1.5 eq.), dimethylformamide (5 ml) was added and the mixture was degassed by bubbling argon for 5 min. Triethylamine (0.178 g, 0.24 mL, 1.758 mmol, 3.0 eq) was added, followed by X-PhosPd G2 (0.046 g, 0.059 mmol, 0.1 eq), the reaction mixture was sealed and heated to 120°C in microwave for 1 hour. The reaction mixture was partitioned between EtOAc (100 ml) and NaHCO ₃ (100 ml). The organic layers were washed with brine (80 ml), water (100 ml) and brine (80 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. HPLC (0^10% MeOHCH ₂ Cl ₂ ) gave the title compound (0.267 g, 91%) as a pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.55 (1H, d, J 15.5 Hz, ArCH=CHCO), 7.39-7.36 (7H, m, 6H C(C6H5)z, oxobenzoxazapine H- 8), 7.25-7.13 (9H, m, 9H C(C6H5)z), 7.01 (1H, d, J=8.5 Hz, oxobenzoxazepine H-9), 6.97 (1H, d, J=2.0 Hz, oxobenzoxazepine H-6), 6.39 (1H, d, J 15.5 Hz, AgCH=CHCO), 5.95 (2H, br. s, NH ₂ ), 4, 51 (1H, dd, J=9.5, 7.0 Hz, 1H oxobenzoxazepine H-2), 4.39 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazepine H-2), 3.54 (1H, d, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 3.31 (1H, d, J=8.5 Hz, NH), 2.94 (3H, s , NCH ₃ ); m/z: 526 [M+Na] ⁺ , 243 [C(C6H5)z] ⁺ .

Synthesis of (S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanamide: solution α,β - unsaturated carboxamide (0.267 g, 0.532 mmol, 1.0 eq.) in ethyl acetate-methanol (5:2, 7 ml) was purged with nitrogen and palladium on carbon (0.100 g) was added. The reaction mixture was purged with hydrogen and stirred under hydrogen for 2 hours. The reaction mixture was purged with nitrogen and filtered through celite, eluting with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in dioxane (5 ml) and hydrogen chloride (0.66 ml of 4M dioxane solution, 2.659 mmol, 5.0 eq.) was added. The reaction mixture was stirred at room temperature for 6 hours, a white precipitate formed. The reaction mixture was concentrated to dryness and used without purification; m/z: 265 [M+H] ⁺ .

Synthesis of (S)-N-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin3-yl)- 5-benzyl-1H-1,2,4-triazole-3-carboxamide:

To a mixture of aminooxobenzoxazapine hydrochloride (0.134 mmol, 1.0 eq.) and benzyltriazolecarboxylic acid (0.033 g, 0.161 mmol, 1.2 eq.) in dimethylformamide (1.0 ml) was added diisopropylethylamine (0.043 g, 0.058 ml, 0.335 mmol, 2.5 eq) followed by the addition of HATU (0.102 g, 0.268 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 4 hours and partitioned between EtOAc-CH ₂ Cl ₂ (5:1, 60 ml) and water (60 ml). The organic layers were washed with brine (50 ml), water (60 ml) and brine (50 ml). The organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. HPLC (0^10% MeOHCH ₂ Cl ₂ ) gave the title compound as a white solid; 1H NMR (400 MHz, CDCb) δ 8.05 (1H, d, J=7.5 Hz, NH), 7.36-7.28 (5H, m, 5 x ArH), 7.11-7, 06 (3H, m, 3 x ArH), 5.44 (2H, br. s, CONH2), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4 .68 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.24 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2) , 4.17 (2H, s, CH ₂ s ₆ H ₅ ), 3.41 (3H, s, NCH3), 2.99 (2H, t, J=7.5 Hz, 2H ArCH ₂ CH ₂ CO) , 2.54 (2H, t, J=7.5 Hz, 2H ArCH2CH2CO); m/z: 449 [M+H]+.

Example 10.

Formation of (S)-7-((5,6-dihydro[1,2,4]mriazol[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-3-(trityl

- 113 045696 amino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one:

Dioxane (4 ml) and water (2 ml) were added to a mixture of bromobenzoxazapine (0.270 g, 0.527 mmol, 1.0 eq), 7-((trifluoro-λ ⁴ -boranyl)methyl)-5,6,7,8 -tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, potassium salt (0.180 g, 0.738 mmol, 1.4 eq.), and cesium carbonate (0.515 g, 1.581 mmol, 3.0 eq. .). The reaction mixture was degassed by bubbling argon for ten minutes. X-PhosPd G2 (0.021 g, 0.026 mmol, 0.05 eq.) was added, the reaction mixture was sealed and microwaved to 140°C for 45 min. The reaction mixture was partitioned between EtOAc (80 ml) and NaHCO3 (80 ml). The combined organic layers were washed with brine (80 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. HPLC (0^10% MeOH [2M NH3]-CH2Cl2) gave the title compound (0.255 g) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.88 (1H, s, triazole H-3), 7.387.35 (6H, m, 6H C(C6H5)3), 7.21-7.11 (9H, m , 9Н С(С6Н5)3), 7.02 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine Н8), 6.97 (1H, d, J=8.0 Hz, oxobenzoxazapine Н- 9), 6.87 (1H, d, J=2.0 Hz, oxobenzoxazapine H-6), 4.50 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.36 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.16 (2H, t, J=5.5 Hz, 2H NCH2CH2N), 3.82 (2H , s, ArCH2N or NCH2CN), 3.69 (2H, s, ArCHA or NCH2CN), 3.51 (1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 2.91 ( 2H, t, J=5.5 Hz, 2H ArC^C^N), 2.88 (3H, s, NCH3); m/z: 593 [M+Na] ⁺ , 243 [C(C6H ₅ ) ₃ ] ⁺ .

Deprotection of the trityl group: to a solution of trityl-protected amine (0.255 g, 0.447 mmol, 1.0 eq.) in dioxane (4.0 ml) was added hydrogen chloride (0.56 ml of a 4M solution in dioxane, 2.237 mmol, 5.0 eq. ). A white precipitate formed. The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated to dryness and used without purification; m/z: 329 [M+H] ⁺ .

Formation of (S)-5-benzyl-N-(7-((5,6-dihydro[1,2,4]triazolo[1,5-a]nirazin-7(8H)-yl)methyl)-5methyl- 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxylic acid: to a solution of aminooxobenzoxazapine hydrochloride (0.377 mmol , 1.0 eq.) and benzyltriazolecarboxylic acid (0.077 g, 0.377 mmol, 1.0 eq.) in dimethylformamide (4.0 ml) was added diisopropylethylamine (0.122 g, 0.16 ml, 0.943 mmol, 2.5 eq. ). The reaction mixture was cooled to 0°C and HATU (0.143 g, 0.377 mmol, 1.0 eq.) was added. The reaction mixture was stirred at 0°C for 2 hours and at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc-CH ₂ Cl ₂ (9:1, 60 ml) and NaHCO ₃ -water (1:1, 60 ml ). The organic layers were washed with brine (60 ml). The combined aqueous phase was re-extracted with EtOAc (30 ml). The combined organic layers were washed with water (90 ml) and brine (90 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. HPLC (0^8% MeOH-CH ₂ Cl ₂ ) gave the title compound as a white solid; ^1H NMR (400 MHz, CDCl3) δ 7.90 (1H, b.m., NH), 7.75 (1H, s, triazole H-3), 7.29-7.21 (7H, m, 7 x ArH), 7.16 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 5.10 (1H, oxobenzoxazapine H-3), 4.74 (1H, dd, J=9.5 , 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, t, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.21 (2H, t, J=5.5 Hz, 2H NCH2CH2N ), 4.15 (2H, s, nch2c6H5), 3.84, 3.78 (2H, 2d system AB, J 15.5 Hz, ArCH2 N or NCH2C), 3.77, 3.73 (2H, 2d AB system, J 13.5 Hz, ArCH2N or NCH2C), 3.40 (3H, s, NCH3), 3.02 (2H, t, J=5.5 Hz, 2H NCH2CH2N); m/z: 514 [M+H] ⁺ (found [M+H] ⁺ , 514.2324, C26H ₂₇ N ₉ O ₃ requires [M+H] ⁺ 514.2310).

Additional illustrative embodiments of the connections are described below.

(S)-5-benzyl-3-((7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3-yl)carbamoyl)-1,2,4-triazol-1-ide

1H NMR (400 MHz, D6-DMSO) δ 7.83 (1H, d, J=8.0 Hz, NH), 7.45 (1H, d, J=2.0 Hz, oxobenzoxazapine H-6), 7.25 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.20-7.15 (5H, m, oxobenzoxazapine H-9, 4H C6H5), 7.09- 7.04 (1H, m, 1H C6H5), 5.47 (1H, br s, OH), 4.81-4.74 (1H, m, oxobenzoxazapine H-3), 4.394.36 (2H, m, 2H oxobenzoxazapine H-2), 3.84 (2H, s, CH ₂ C _b H ₅ ), 3.28 (3H, s, NCH3), 1.44 (6H, s, C (CH ₃ ) ₂ OH) ; m/z: 442 [M+H] ⁺ .

- 114 045696 (S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-in-1-yl)-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.76 (1H, dd, J=4.0, 1.5 Hz, quinoline H-2), 8.03 (2H, m, NH, quinoline H-4) , 8.01 (1H, d, J=9.5 Hz, quinoline H-8), 7.99 (1H, s, triazole H-5), 7.40 (1H, dd, J=9.0, 3.0 Hz, quinoline H-7), 7.37-7.7.33 (4H, m, 4H C ₆ H ₅ , oxobenzoxazapine H-6, H-8), 7.28-7.24 (3H , m, 3Н С _{6 Н5} , oxobenzoxazapine Н-6, Н-8), 7.12 (1H, d, J=2.5 Hz, quinoline Н-5), 7.10 (1H, d, J= 8.0 Hz, oxobenzoxazapine H-9), 5.36 (2H, s, NCH2C6H5), 5.06 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.75 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.30 (2H, t, J=7.0 Hz, statio), 4.24 (1H, dd, J =11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.39 (3H, s, NCH ₃ ), 2.98 (2H, t, J = 7.0 Hz, CCH ₂ CH ₂ O) ; m/z: 573 [M+H] ⁺ (found [M+H] ⁺ , 573.2244, C ₃₃ H ₂₈ N ₆ O ₄ requires [M+H] ⁺ 573.2245).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.73 (1H, dd, J=4.0, 1.5 Hz, quinoline H-2), 8.05 (2H, m, NH, quinoline H-4) , 8.00 (1H, d, J=9.5 Hz, quinoline H-8), 7.40 (1H, dd, J=9.5, 3.0 Hz, quinoline H-7), 7.34 (1H, m, quinoline H-3), 7.25 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.25-7.20 (6H, m, C ₆ H ₅ , oxobenzoxazapine H-7), 7.11 (1H, d, J 3.0 Hz, quinoline H-5), 7.09 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.67 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2) , 4.29 (2H, t, J=7.0 Hz, CCH ₂ CH ₂ O), 4.26 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4 .14 (2H, s, CH ₂ C ₆ H ₅ ), 3.37 (3H, s, NCH ₃ ), 2.98 (2H, t, J = 7.0 Hz, CCH ₂ CH ₂ O); ¹³ C NMR (100 MHz, CDCl3) δ 168.7, 156.6, 149.7, 148.0, 144.3, 136.0, 134.9, 131.0, 130.8, 129.2, 128.8 (2C), 128.6, 127.1, 126.5, 123.1, 122.4, 121.4, 121.0, 106.3, 86.6, 80.7, 77.2 , 66.2, 49.1, 35.4, 33.4, 20.4; m/z: 573 [M+H] ⁺ (found [M+H] ⁺ , 573.2262, C33H ₂₈ N ₆ O ₄ requires [M+H] ⁺ 573.2245).

(S)-1-benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazine7 (8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.04 (1H, d, J=7.5 Hz, NH), 8.00 (1H, s, triazole H-5), 7.38-7.33 ( 3H, m, 3H C ₆ H ₅ ), 7.27-7.24 (2H, m, 2H C ₆ H ₅ ), 7.19 (2H, m, oxobenzoxazapine H-6, H-8), 7, 15 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 5.35 (2H, s, NCH ₂ C ₆ H ₅ ), 5.09 (1H, dt, J=11.0, 7 .5 Hz, oxobenzoxazapine H-3), 4.73 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26-4.21 (3H, m, 1H oxobenzoxazapine H-2), 2H NCH2CH2N), 3.87 (2H, s, 2H ArCH2NCH2C), 3.75 (2H, s, 2H ArCH2NCH2C), 3.40 (3H, s, NCH3), 3.01 (2H, td, J=5.0, 1.5 Hz, 2H from NCH ₂ CH ₂ N); ¹³ C NMR (100 MHz, CDCl3) δ 168.8, 158.4, 156.6, 153.5 (k, J=39.5 Hz), 152.2, 149.6, 143.9, 136, 4, 134.5, 133.7, 129.2, 129.0, 128.2, 127.8, 123.4, 123.3, 119.2 (k, J=270.5 Hz), 77, 2, 60.6, 54.3, 50.7, 49.2, 48.4, 47.1, 35.6; ¹⁹ F NMR (380 MHz, CDCl3) δ -65.4 m/z: 582 [M+H] ⁺ ₍ found [M+H] ⁺ _{, 582.2188} , _{C27H26F3N9O3 requires} [ M+H] ⁺ 582.2183).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazine7 (8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.02 (1H, d, J=7.5 Hz, NH), 7.27-7.21 (6H, m, C6H5, oxobenzoxazapine H8), 7.21 ( 1H, dd, J=7.5, 2.0 Hz, oxobenzoxazapine H-8), 7.15 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 5.07 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.29-4.23 (3H, m, 1H oxobenzoxazapine H-2, 2H NCH2CH2N), 4.12 (2H, s, CH ₂ C ₆ H ₅ ), 3.86 (2H, s, 2HArCH2NCH2C), 3.76 (2H, s, 2H Ar^NC^C), 3.39 (3H, s, NCH3), 3.03 (2H, t, J=5.5 Hz, 2H from NCH ₂ CH ₂ N); ¹³ C NMR (100 MHz, CDCl3) δ 168.8, 158.7, 153.4 (k, J=39.5 Hz), 152.2, 149.6, 136.3, 135.7, 134, 6, 128.8, 128.7, 127.9, 127.1, 123.4, 123.2, 123.1, 119.2 (k, J 269.5 Hz), 77.1, 60.7 , 50.4, 49.4, 48.6, 47.1, 35.6, 33.0; ¹⁹ F NMR (380 MHz, CDCl3) δ -65.3 m/z: 582 [M+H]+ (found [M+H] ⁺ , 582.2167, C ₂ 7H ₂ 6F ₃ N<>O ₃ requires [M+H] ⁺ 582.2183).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

- 115 045696 ^1H NMR (400 MHz, CDCl3) δ 8.75 (1H, dd, J=4.5, 2.0 Hz, quinoline H-2), 8.09-8.06 (2H, m, NH, quinoline H-4), 7.70 (1H, d, J=9.0 Hz, quinoline H-5), 7.50 (1H, d, J=2.5 Hz, quinoline H-8), 7.27-7.17 (9H, m, quinoline H-3, H-6, oxobenzoxazapine H-6, H-8, C6H5), 7.07 (1H, d, J=8.5 Hz, oxobenzoxazapine H -9), 5.00 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.31 (2H, td, J=7.0, 2.5 Hz, OCH2CH2C), 4.24 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H- 2), 4.13 (2H, s, CH2C6H5), 3.36 (3H, s, NCH3), 2.97 (2H, t, J=7.0 Hz, basic2CH2S); ¹³ C NMR (100 MHz, CDCl3) δ 168.7, 159.6, 158.6, 150.3, 149.6, 149.5, 136.0 (2C), 135.9, 131.0, 128 ,9, 128.8, 128.7, 127.0, 126.5, 123.7, 123.0, 121.0, 120.1, 119.1, 107.9, 86.8, 80.6 , 77.2, 66.1, 49.2, 35.5, 33.2, 20.3; m/z: 573 [M+H] ⁺ (found [M+H] ⁺ , 573.2269, C33H28N6O4 requires [M+H] ⁺ 573.2245).

(S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5tetrahydrobenzo [ b] [1,4]oxazepin-3-yl)-1 H-1,2,4-triazol-3-carboxamide ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (1H, dd, J=4 .5, 2.0 Hz, quinoline H-2), 8.06 (1H, dd, J=8.0, 1.5 Hz, quinoline H-4), 8.03 (1H, d, J=7 ,0 Hz, NH), 7.99 (1H, s, triazole H-5), 7.70 (1H, d, J=9.0 Hz, quinoline H-5), 7.45 (1H, d, J=2.5 Hz, quinoline H-8), 7.37-7.33 (3H, m, 3H C ₆ H ₅ , oxobenzoxazapine H-6), 7.27-7.22 (6H, m, quinoline H-6, H-3, oxobenzoxazapine H-8, 3H C ₆ H ₅ , oxobenzoxazapine H-6), 7.09 (1H, dd, J=8.0, 0.5 Hz, oxobenzoxazapine H-9), 5.35 (2H, s, nch ₂ s ₆ h ₅ ), 5.06 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.75 (1H, dd, J =9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.33 (2H, t, J=7.0 Hz, OCH ₂ CH ₂ C), 4.23 (1H, dd, J=9 ,5, 7.5 Hz, 1H oxobenzoxazapine H-2), 3.39 (3H, s, NCH3), 2.98 (2H, t, J=7.0 Hz, OCH ₂ CH ₂ C); ¹³ C NMR (100 MHz, CDCl3) δ 168.8, 159.4, 158.4, 156.6, 150.6, 149.8, 149.7, 143.9, 135.9, 135.7, 133.7, 130.9, 129.2, 128.9, 128.2, 126.5, 123.7, 123.1, 121.0, 119.9, 119.1, 108.2, 86, 6, 80.7, 77.1, 66.1, 54.3, 49.1, 38.6, 35.5, 20.3; m/z: 573 [M+H] ⁺ (found [M+H] ⁺ , 573.2249, C33H28N6O4 requires [M+H] ⁺ 573.2245).

(S)-5-(2,4-difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4 ,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4-triazol-3-carboxamide ^1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J =7.5 Hz, NH), 7.27-7.20 (3H, m, oxobenzoxazapine H-6, H8, 1H C6H3F2), 7.10 (1H, d, J=9.0 Hz, oxobenzoxazapine H- 9), 6.82-6.74 (2H, m, 2H C6H3F2), 4.99 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.12 ( 2H, s, (H-C4GG), 3.39 (3H, s, NCH3), 1.61 (6H, s,C(CH3)2OH); ¹⁹ f NMR (380 MHz, CDCl3) δ -111.2 ; -113.2; m/z: 478 [M+HH ₂ O] ⁺ (found [M+H] ⁺ , 496.1795, C25H23F2N5O4 requires [M+H] ⁺ 496.1791).

(S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-yn-1-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-H-1,2,4-triazol-3-carboxamide ^1H NMR (400 MHz, CDCl ₃ ) δ 8.89 (1H, dd, J=4.0, 2.0 Hz, quinoline H-2), 8.63 (1H, ddd, J=8.5, 2.0, 1.0 Hz, quinoline H-4), 8.02 ( 1H, d, J=7.5 Hz, NH), 7.99 (1H, s, triazole H-5), 7.70 (1H, d, J=8.5 Hz, quinoline H8), 7.59 (1H, dd, J=8.5, 7.5 Hz, quinoline H-7), 7.38-7.33 (4H, m, quinoline H-3, 3H C ₆ H ₅ , oxobenzoxazapine H-6) , 7.26-7.22 (4H, m, oxobenzoxazapine H-8, 3H C _{6 H5} , oxobenzoxazapine H-6), 7.09 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9) , 6.89 (1H, dd, J=7.5, 0.5 Hz, quinoline H-6), 5.35 (2H, s, NCH ₂ C6H ₅ ), 5.06 (1H, dt, J= 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.73 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.35 (2H, t, J =7.0 Hz, OCH ₂ CH ₂ C), 4.24 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.37 (3H, s, NCH3), 3.03 (2H, t, J=7.0 Hz, OCH ₂ CH2C); m/z: 573 [M+H]+ (found [M+H] ⁺ , 573.2251, C33H28N6O4, requires [M+H] ⁺ 573.2245).

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5 -yloxy)but-1 -yn-1 -yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-H-1,2,4-triazol-3-carboxamide ^1H NMR (400 MHz, CDCl ₃ ) δ 8.85 (1H, dd, J=4.0, 2.0 Hz, quinoline H-2), 8.64 (1H, ddd, J=8.5, 2.0, 1.0

- 116 045696

Hz, quinoline H-4), 8.07 (1H, d, J=7.5 Hz, NH), 7.69 (1H, d, J=8.5 Hz, quinoline H-8), 7.59 (1H, dd, J=8.5, 7.5 Hz, quinoline H-3), 7.26-7.17 (7H, m, C ₆ H ₅ oxobenzoxazapine H-6, H-8), 7, 08 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 6.90 (1H, dd, J=8.0, 0.5 Hz, quinoline H-6), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H3)), 4.66 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.36 (2H, t, J=7.0 Hz, OCH2CH2C), 4.25 (1H, dd, J=11.0, 10.0 Hz), 1H oxobenzoxazapine H-2), 4.13 (2H, s, sn ₂ s ₆ H ₅ ), 3.36 (3H, s, NCH3), 3.04 (2H, t, J=7.0 Hz, OCH ₂ CH ₂ C); ¹³ s NMR (100 MHz, CDCl3) δ 168.7, 158.5, 153.9, 150.6, 149.7, 148.9, 136.0, 131.0, 130.9, 129.4, 128.8, 128.7, 127.0, 126.5, 123.1, 121.8, 121.0, 120.9, 120.3, 105.4, 86.7, 80.7, 77, 2, 49.1, 35.5, 33.2, 20.5; m/z: 573 [M+H]+ (found [M+H] ⁺ , 573.2266, C33H ₂₈ N ₆ O ₄ , requires [M+H] ⁺ 573.2245).

(S)-1-Benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]nirasin7 (8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.06 (1H, d, J=7.5 Hz, NH), 8.02 (1H, s, triazole H-5), 7.39-7.35 ( 3H, m, 3 x ArH), 7.29-7.7.26 (2H, m, 2 x ArH), 7.20 (2H, m, 2 x ArH), 7.17 (1H, d, J =8.0 Hz, oxobenzoxazapine H-9), 5.38 (2H, s, NCH ₂ C ₆ H ₅₎ , 5.12 (1H, d, J = 11.0, 7.5 Hz, oxobenzoxazapine H- 3), 4.76 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.15 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 2H, t, J=5.5 Hz, 2H NCH2CH2N), 3.98, 3.93 (2H, 2d system AB, J 15.5 Hz, 2H ArCH2NCH2), 3.76 (2H, s, 2H ArCHNCH), 3.42 (3H, s, NCH ₃ ), 2.96 (2H, dt, J=4.0, 5.5 Hz, 2H NCH ₂ CH ₂ N); ¹⁹ F NMR (380 MHz, CDCl3) δ -63.2; m/z: 582 [M+H] ⁺ (found [M+H] ⁺ , 582.2173, C27H26F ₃ N9O ₃ requires [M+H] ⁺ 582.2183).

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]nirasin7 (8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.01 (1H, d, J=7.0 Hz, NH), 7.27-7.19 (7H, m, C ₆ H ₃ , oxobenzoxazapine H6, H- 8), 7.16 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 5.09 (1H, dt, J=10.5, 7.5 Hz, oxobenzoxazapine H3), 4.70 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=10.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 4 .14 (4H, m, 2H NCH2CH2N), 2H ArCH ₂ NCH ₂ or CH ₂ C ₆ H ₅ ), 3.93 (2H, s, 2H ArCH ₂ NCH ₂ or CH ₂ SbH ₅ ) ₍ 3.78, 3 .74 (2H, 2d system AB, J 13.5 Hz, 2H ArCH ₂ NCH ₂ ), 3.40 (3H, s, NCH ₃ ), 2.97 (2H, t, J=5.5 Hz, 2H NCH ₂ CH ₂ N); ¹³ C NMR (100 MHz, CDCl3) δ 168.8, 158.6, 152.0, 149.6, 143.4 (k, J 40.0 Hz), 136.4, 135.8, 134.3, 128.8, 128.7, 127.9, 127.1, 126.9, 123.4, 123.2, 118.3 (k, J=270.5 Hz), 77.2, 60.8, 49.5, 49.4, 43.6, 35.6, 33.1; ¹⁹ F NMR (380 MHz, CDCl3) δ -63.2; m/z: 582 [M +H] ⁺ (found [M+H] ⁺ , 582.2208, C ₂ 7H ₂₆ F ₃ N9O ₃ requires [M+H] ⁺ 582.2183).

(S)-1-Benzyl-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.04 (1H, d, J=7.0 Hz, NH), 8.01 (1H, s, triazole H-5), 7.40-7.36 ( 3H, m, 3H C ₆ H ₅ ), 7.29-7.23 (4H, m, 2H C ₆ H ₅ , oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J=9 .0 Hz, oxobenzoxazapine H-9), 5.38 (2H, s, NCH ₂ C ₆ H ₅ ), 5.06 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3) , 4.76 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.24 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H- 2), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)z); m/z: 458 [M+H] ⁺ (found [M+H] ⁺ , 458.2205, C26H27N5O ₃ requires [M+H] ⁺ 458.2187).

(S)-5-Benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (1H, d, J=7.5 Hz, NH), 7.26-7.21 (7H, m, C ₆ H ₅ , oxobenzoxazapine H6, H- 8), 7.07 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H3), 4.66 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J Hz, 1H oxobenzoxazapine H-2)), 4.15 (2H, s, CH ₂ SbH ₅ ), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH _h ) _h ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 158.5, 149.2, 135.9, 135.8, 130.9, 128.8, 128.7, 127.0, 126.4 , 122.8, 121.8, 99.4, 77.6, 77.2, 49.1, 35.5, 33.2, 30.9, 27.9; m/z: 458 [M+H] ⁺ (found [M+H] ⁺ , 458.2200, C26H27N5O3 requires [M+H] ⁺ 458.2187).

- 117 045696

[ Ji \ΝΗ Nr (S)-1-Benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4] oxazepin-3 -yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.02 (1H, d, J=7.5 Hz, NH), 7.99 (1H, s, triazole H-5), 7.38-7.34 ( 3H, m, 3H C ₆ H ₅ ), 7.29-7.25 (4H, m, 2H C ₆ H ₅ , oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J=9 .0 Hz, oxobenzoxazapine H-9), 5.36 (2H, s, NCH ₂ C ₆ H ₅ ), 5.06 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3) , 4.75 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.25 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H- 2), 3.40 (3H, s, NCH ₃ ), 2.55-2.49 (2H, m, 2H cBuH-2, H-4), 2.33 (2H, m, 2H cBuH-2, H-4), 1.87 (2H, m, cBuH-3); m/z: 472 [M+H]+, 454 [M+H-H2O]+ (found [M+H] ⁺ , 472.1994, C26H25N5O4 requires [M+H]+ 472.1979).

a / γ j I jVjf y'NH N ^NH (S)-5-Benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide ^1H NMR (400 MHz, CDCl3) δ 8.10 (1H, d, J=7, 5 Hz, NH), 7.29-7.20 (7H, m, C6H5, 2H oxobenzoxazapine H-6, H-8, H-9), 7.10 (1H, dd, J=7.5, 1 ,0 Hz, 1H oxobenzoxazapine H-6, H-8, H-9), 5.01 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.15, 4.11 (2H, 2d system AB, J=16.0 Hz, CH2SbH5), 3.39 (3H, s, NCH3), 2.57-2.50 (2H, m, 2H CBuH-2, H- 4), 2.35 (2H, m, 2H cBuH-2, H-4), 1.92-1.84 (2H, m, cBuH-3); ¹³ C (100 MHz, CDCl3) δ 168.7, 158.7, 149.9, 136.0, 135.8, 131.0, 128.8, 128.7, 127.0, 126.5, 123 ,0, 120.4, 93.4, 81.9, 76.9, 68.2, 49.1, 38.5, 33.0, 35.5; m/z: 454 [M+HH ₂ O]+ (found [M+H] ⁺ , 472.1999, C ₂₆ H ₂₅ N ₅ O ₄ requires [M+H]+ 472.1979).

(S)-1-benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.02 (1H, d, J=7.0 Hz, NH), 7.99 (1H, s, triazole H-5), 7.38-7.34 ( 3H, m, 3H C ₆ H ₅ ), 7.28-7.26 (4H, m, 2H C ₆ H ₅ , oxobenzoxazapine H-6, H-8), 7.10 (1H, d, J=9 .0 Hz, oxobenzoxazapine H-9), 5.36 (2H, s, NCH2C6H5), 5.06 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.75 ( 1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.24 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3, 40 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3H, s, NCH ₃ ), 2.08-1.99 (4H, m, cyclopentane H-2, H -5), 1.901.84 (2H, m, 2H cyclopentane H-3, H-4), 1.83-1.76 (2H, m, 2H cyclopentane H-3, H-4); m/z: 486 [M+H]+, 468 [M+H-H2O]+ (found [M+H] ⁺ , 486.2122, C27H27N5O4 requires [M+H]+486.2136).

(S)-5-Benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J=7.5 Hz, NH), 7.31-7.23 (7H, m, C6H5, oxobenzoxazapine H6, H-7), 7 .10 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 5.01 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H3), 4.68 (1H, dd , J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.14 (2H , s, CH ₂ C ₆ H ₅ ), 3.39 (sn, s, NCH ₃ ), 2.08-1.97 (4H, m, cyclopentane H-2, H-5), 1.90-1 .85 (2H, m, 2H cyclopentane H-3, H-4), 1.82-1.76 (2H, m, 2H cyclopentane H-3, H-4); m/z: 468 [M+HH ₂ O]+ (found [M+H]+, 486.2154, C ₂₇ H ₂₇ N ₅ O ₄ requires [M+H]+ 486.2136).

- 118 045696 (S)-1-Benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide ^1H NMR (400 MHz, CDO3) δ 8.03 (1H, d, J=7, 0 Hz, NH), 8.02 (1H, s, triazole H-5), 7.39-7.35 (3H, m, 3H C ₆ H ₅ ), 7.31-7.27 (4H, m , 2Н С _{6 Н5} , oxobenzoxazapine Н-6, Н-8), 7.14 (1H, dd, J=8.0, 1.0 Hz, oxobenzoxazapine Н-9), 5.37 (2Н, s, NCH2C6H5), 5.08 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H -2), 4.27 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.95 (2H, dt, J=12.0, 4.5 Hz, 2H pirana H-2, H-6), 3.72 (2H, ddd, J=12.0, 9.0, 3.0 Hz, 2H pirana H-2, H-6), 3.42 (3H, s, NCH3), 2.07-2.02 (2H, m, 2H pyran H-3, H-5), 1.89 (2H, dd, J 13.0, 9.0, 4.0 Hz, 2H pyran N-3, N-5); m/z: 502 [M+H]+, 484 [M+H-H2O]+ (found [M+H] ⁺ , 502.2105, C27H27N5O5 requires [M+H]+502.2085).

(S)-5-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J=6.5 Hz, NH), 7.28-7.19 (7H, m, C6H ₅ , oxobenzoxazapine H6, H-8), 7.09 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 5.00 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H3), 4.64 (1H, dd, J=9.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, t, J=10.5 Hz, 1H oxobenzoxazapine H-2), 4.12 (2H, s, CH2C6H5), 3.93 (2H, dt, J=12.0, 4.5 Hz, 2H pyran H-2, H-6), 3.70 (2H, dd, J=11.5, 9.0 , 2.5 Hz, 2H pyran H-2, H-6), 3.37 (3H, s, NCH3), 2.03 (2H, m, 2H pyran H-3, H-5), 1.88 (2H, dd, J 13.0, 9.0, 4.0 Hz, 2H pyran H-3, H-5); ¹³ C NMR (100 MHz, CDC^) δ 168.6, 158.7, 150.1, 136.1, 135.7, 131.1, 128.9, 128.8, 127.1, 126.6 , 123.2, 120.0, 92.3, 83.4, 77.3, 66.1, 64.8, 49.1, 39.9, 35.6, 33.1; m/z: 484 [M+H-H2O] ⁺ (found [M+H] ⁺ , 502.2080, C27H27N5O5 requires [M+H] ⁺ 502.2085).

(S)-u-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-4-phenoxypicolinamide ^1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.42 (1H, d, J= 5.5 Hz, ruN-6), 7.60 (1H, d, J=2.5 Hz, ruN-3), 7.40 (2H, m, 2H C6H5), 7.27-7.22 ( 3H, m, oxobenzoxazapine H-6, H-8, 1H C6H5), 7.10 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.05 (2H, m, 2H C6H5), 6.93 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.01 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4 .70 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2) , 3.41 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2OH); ¹³ s NMR (100 MHz, CDCl3) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1, 150.0, 136.2, 130.8, 130.3, 126.4, 125.6, 123.0, 120.7, 120.3, 114.4, 110.6, 94.4, 80.7, 77.2, 65.6, 49.3, 35, 4, 31.4; m/z: 472 [M+H]+ (found [M+H] ⁺ , 472.1891, C27H25N3O5 requires [M+H]+ 472.1867).

(S)-5-Benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ] oxazepin-3 -yl)- 1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J=7.5 Hz, NH), 7.33-7.26 (7H, m, C6H5, oxobenzoxazapine H6, H-8), 7 .14 (1H, d, J=9.0 Hz, oxobenzoxazapine N-9), 5.03 (1H, d, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.93 (2H , d, J=7.0 Hz, 2H oxetane H-2, H-4), 4.80 (2H, d, J=7.0 Hz, 2H oxetane H-2, H-4), 4.70 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4 .16 (2H, s, CH ₂ SbH ₅ ), 3.41 (3H, s, NCH3), 2.98 (1H, sh. s, OH); m/z: 474 [M+H] ⁺ (found [M+H] ⁺ , 474.1789, C25H23N5O5 requires [M+H] ⁺ 474.1772).

(S)-1-Benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ] oxazepin-3 -yl)- 1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.03 (1H, d, J=7.0 Hz, NH), 8.01 (1H, s, triazole H-5), 7.37 (3H, m, 3H C6H5), 7.28-7.25 (4H, m, 2H, C6H5, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J=8.5 Hz, oxobenzoxazapine

- 119 045696

H-9), 5.35 (2H, s, NCH ₂ C6H ₅ ), 5.04 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.89 (2H, dd, J=7.0, 1.0

Hz, 2H oxetane H-2, H-4), 4.78 (2H, ddd, J=6.5, 2.0, 1.0 Hz, 2H oxobenzoxazapine H-2, H-4), 4.72 (1H, dd,

J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.53 (1H, s, OH), 3.38 (3H, s, NCH3); ¹³ C NMR (100 MHz, CDCl3) δ 168.7, 158.4, 156.5, 150.4, 144.0, 136.1, 133.7,

130.9, 129.2, 129.0, 128.2, 126.6, 123.4, 119.5, 88.9, 84.5, 77.1, 67.3, 54.4, 53, 4, 49.1, 35.5; m/z: 474 [M+H]+.

(S)-5-Benzyl-N-(5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl3) δ 8.09 (1, d, J=7.5 Hz, NH), 7.27 (2H, t, J=7.0 Hz, 2H C6H5), 7.20- 7.15 (5H, m, 3H C ₆ H ₅ , oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 5.41 (1H , d, J 1.0 Hz, 1H = CH2), 5.32 (1H, m, 1H = CH2), 5.01 (1H, dt, J = 11.0, 7.5 Hz, oxobenzoxazapine H-3 ), 4.63 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H -2), 4.12 (2H, s, CH ₂ SbH ₅₎ , s, s8 (sn, s, NCH3), 1.98 (3H, t, J Hz, C(CH ₃ ) = CH ₂ ); ¹³ s NMR (100 MHz, CDCl ₃ ) δ 168.7, 158.7, 154.6, 149.8, 136.0, 135.9, 130.9, 128.8, 128.7, 127.0 , 126.4 (2C), 123.1, 122.6, 121.0, 91.3, 86.7, 77.2, 49.2, 35.5, 33.0, 23.3; m/z: 464 [M+Na] ⁺ , 442 [M+H]+ (found [M+H]+, 442.1869, C25H23N5O3 requires [M+H]+ 442.1874).

(S)-5-Benzyl-N-(7-isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H1,2 ,4-triazole-3-carboxamide

1H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J=7.5 Hz, NH), 7.29-7.19 (5H, m, C6H5), 7.06 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 7.03 (1H, d, J=2.0 Hz, oxobenzoxazapine H-6), 7.00 (1H, m, oxobenzoxazapine H8), 5.04 ( 1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.22 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.14 (2H, s, CH ₂ SbH ₅ ), 3.39 (sn, s, NCH3), 2, 60 (2H, m, CH2CH ₂ CH(CH3) ₂ ), 1.60 (1H, m, CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 1.52-1.46 (2H, m, CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 0.94 (6H, d, J=6.5 Hz,CH ₂ CH ₂ CH(CH ₃ ) ₂ ); m/z: 448 [m+n] ⁺ (found _[ M+H]+, _448.2335 , _{C25H29N5O3 requires} [M+H]+ 448.2343).

(S)-5-Benzyl-N-(7-(3-methoxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetraαhydrobenzo[b ][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (1H, d, J=7.5 Hz, NH), 7.28-7.25 (2H, m, 2H C ₆ H ₅ ), 7.19 (5H, m, 3H C ₆ H ₅ , oxobenzoxazapine H-6, H-8), 7, 09 (1H, d, J=8.0 Hz, oxobenzoxazapine N-9), 5.01 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.63 (1H, dd, J=9.0, 8.0 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=10.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.12 ( 2H, s, CH ₂ C ₆ H ₅ ), 3.43 (sn, s, NCH3 or OCH3), 3.39 (3H, s, NCH3 or OCH3), 1.54 (6H, s, C(CH3) 2OSN ₃ ); m/z: 474 [M+H]+, 442 [M+H-CH _h OH] ⁺ (found [M+H]+, 474.2138, C26H27N5O4 requires [M+H]+ 474.2136).

(S)-1-Benzyl-N-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-III-1,2,4-triazole-3-carboxamide

1H NMR (400 MHz, CDCl3) δ 8.01 (1H, d, J=7.5 Hz, NH), 8.00 (1H, s, triazole H-5), 7.39-7.34 (3H , m, 3H C ₆ H ₅ ), 7.27-7.23 (4H, m, 2H C ₆ H ₅ , oxobenzoxazapine H-8, H-9), 7.12 (1H, d, J=8, 0 Hz, oxobenzoxazapine H-6), 5.36 (2H, s, NCH ₂ C ₆ H ₅ ), 5.05 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.73 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.23 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2 ), 3.39 (3H, s, NCH3), 1.61 (6H, s, C( _CH3 )2OH); m/z: 460 [M+H]+, 442 [M+H-H2O]+ (found [M+H]+, 460.1968, C25H25N5O4 requires [M+H]+ 460.1979).

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(S)-5-benzyl-N-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1-H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl3) δ 8.08 (1H, d, J=7.5 Hz, NH), 7.26-7.18 (7H, m, SSH, oxobenzoxazapine H7, H-9), 7 .11 (1H, d, J=8.0 Hz, oxobenzoxazapine H-6), 5.00 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H3), 4.62 (1H, dd , J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.24 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.14, 4 .10 (2H, 2d, J=16.0 Hz, CH ₂ C ₆ H ₅ ), 3.37 (3H, s, NCH ₃ ), 1.61 (6H, s, C(CH ₃ ) ₂ OH) ; ¹³ s NMR (100 MHz, CDCl3) δ 168.7, 158.7, 149.5, 136.1, 135.9, 129.0, 128.8, 128.7, 127.0, 126.0, 123.1, 122.2, 95.1, 80.6, 76.9, 65.5, 49.2, 35.4, 33.0, 31.4 (2C); m/z: 442 [M+H-H2O]+ (found [M+H] ⁺ , 460.1972, C25H ₂₅ N ₅ O ₄ requires [M+H]+ 460.1979).

(S)-N-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1, 4]oxazepin-3-yl)-4-phenoxypicolinamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.83 (1H, d, J=7.5 Hz, NH), 8.42 (1H, d, J=5.5 Hz, pyridine H-3), 7 .60 (1H, d, J=2.5 Hz, pyridine H-6), 7.42-7.38 (2H, m, 2H C ₆ H ₅ ), 7.28-7.22 (3H, m , 1H C ₆ H ₅ , oxobenzoxazapine H-7, H-9), 7.13 (1H, d, J=8.0 Hz, oxobenzoxazapine H-6), 7.07-7.04 (2H, m, 2H C ₆ H ₅ ), 6.93 (1H, dd, J=5.5, 2.5 Hz, pyridine H-4), 5.01 (1H, dt, J=11.0, 7.5 Hz , oxobenzoxazapine H-3), 4.68 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.40 (3H, s, NCH ₃ ), 1.61 (6H, s, C(CH ₃ ) ₂ OH); ¹³ s NMR(100 MHz, CDCl3) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1, 149.6, 136.4, 130.3, 128.9, 126.0, 125.7, 123.0, 122.0, 120.7, 114.4, 110.6, 94.9, 80.6, 77.2, 65.6, 49.4, 35, 3, 31.4; m/z: 472 [M+H]+ (found [M+H] ⁺ , 472.1873, C27H ₂₅ N ₃ O ₅ requires [M+H]+ 472.1867).

(S)-5-(2,6-dichlorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1 H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.05 (1H, d, J=7.5 Hz, NH), 7.33-7.29 (3H, m, 3H C ₆ H ₃ Cl ₂ , oxobenzoxazapine H -6), 7.226-7.24 (1H, m, 1H C ₆ H ₃ Cl ₂ , oxobenzoxazapine H-6), 7.18-7.15 (1H, m, oxobenzoxazapine H-8), 7.10 ( 1H, d, J=8.5 Hz, oxobenzoxazapine H-9), 5.00 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.67 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.48 (2H, s, CH ₂ C ₆ H ₃ C1 ₂ ), 4.27 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.39 (3H, s, NCH ₃ ), 1.61 (6H, s, C(CH ₃ ) ₂ ); m/z: 532, 530, 528 [M+H]+ 514, 512, 510 [M+HH ₂ O]+ (found [M+H]+, 528.1201, C ₂₅ H ₂₃ Cl ₂ N ₅ O ₄ requires [M+H]+ 528.1200).

(S)-5-benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazine7 (8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide ¹ H NMR ( 400 MHz, CDCl3) δ 8.04 (1H, d, J=7.5 Hz, NH), 7.30-7.17 (8H, m, C6H5, oxobenzoxazapine H6, H-7, H-9), 5.08 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2) , 4.30-4.25 (3H, m, 1H oxobenzoxazapine H-2, NCH2CH2N), 4.14 (2H, s, CH2C6H5), 3.88, 3.83 (2H, 2d AB system, J=16 .0 Hz, 2H ArCH2NCH2), 3.76 (2H, s, ArCHNCH), 3.40 (3H, s, NCH3), 3.093.02 (2H, m, NCH2CH2N); ¹⁹ F NMR (380 MHz, CDCl3) δ -65.3; m/z: 604 [M+Na] ⁺ 582 [M+H] ⁺ .

(S)-1-Benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazine7 (8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.05 (1H, d, J=7.0 Hz, NH), 8.00 (1H, s, triazole H-5), 7.39-7.35 ( 3H, m, 3H C ₆ H ₅ , oxobenzoxazapine H-6, H-7, H-9), 7.28-7.25 (2H, m, 2H C ₆ H ₅ , oxobenzoxazapine H-6, H-7 , H-9), 7.23-7.17 (3H, m, 3H C ₆ H ₅ , oxobenzoxazapine H-6, H-7, H-9), 5.37 (2H, s, NCH2C6H5), 5 .11 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28-4.23 (3H, m,

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1H oxobenzoxazapine H-2, 2H NCH2CH2N), 3.90, 3.86 (2H, 2d system AB, J=16.0 Hz, 2H ArC^NC^),

3.79, 3.75 (2H, 2d system AB, J 13.5 Hz, 2H ArC^NC^), 3.42 (3H, s, NCH3), 3.10-3.02 (2H, m, 2H

NCH2CH2N); ¹⁹ F NMR (380 MHz, CDC13) δ -65.4; m/z: 604 [M+Na] ⁺ , 582 [M+H] ⁺ .

(S)-N-(7-(3-Hydroxy-3-(methyl-d3)but-1-in-1-yl-4,4,4-d3)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[B][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

1H NMR (400 MHz, CDC13) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-3), 7.60 (1H, d, J=2.5 Hz, runH-4), 7.42-7.38 (2H, m, 2H C6H5), 7.27-7.22 (3H, m, 3H C ₆ H5, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.10-7.05 (2H, m, 2H C ₆ H ₅ , oxobenzoxazapine N-6, N-8), 6.93 (1H, dd, J=5.5, 2.5 Hz, ruN-6), 5.01 (1H, dt, J=11.5, 7.5 Hz), oxobenzoxazapine H-3), 4.70 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.5, 10 .0 Hz, 1H oxobenzoxazapine H-2), 3.41 (3H, s, NCH ₃ ); m/z: 478 [M+H] ⁺ , 460 [M+H-H2O] ⁺ (found [M+H] ⁺ , 478.2255, C27H ₁₉ D ₆ N ₃ O ₄ requires [M+H] ⁺ 478 ,2244).

(S)-5-benzyl-N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4- oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.09 (1H, d, J=7.5 Hz, NH), 7.28-7.21 (7H, m, C6H5, oxobenzoxazapine H6, H-8), 7.10 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 5.01 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H3), 4.66 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.14 ( 2H, s, CH ₂ C ₆ H ₅ ), 3.39 (3H, s, NCH3); ¹³ C NMR (100 MHz, CDCI3) δ 168.6, 158.5, 149.9, 136.0, 135.8, 131.0, 128.8 (2C), 127.1 (2C), 126, 5, 123.1, 120.5, 94.6, 80.6, 77.2, 65.3, 49.1, 35.5, 33.2, 30.5, (m); m/z: 466 [M+H] ⁺ , 448 [M+H-H2O] ⁺ (found [M+H] ⁺ , 466.2356, C25H ₁₉ D ₆ N ₅ O ₄ requires [M+H] ⁺ 466 ,2356).

(R)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

[α]589 ^{20 2} +135.9 (CHC13, s 0.54); 1H NMR (400 MHz, CDC1 ₃ ) δ 8.08 (1H, d, J=7.5 Hz, NH), 7.30-7.23 (7H, m, C6H5, oxobenzoxazapine H-6, H-8 ), 7.11 (1H, d, J=9.0 Hz, oxobenzoxazapine N-9), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4, 68 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.15 (2H, s, CH ₂ SbH5), 3.40 (3H, s, NCH ₃ ), 1.63 (6H, s, C(CH3)2OH); m/z: 460 [M+H] ⁺ , 442 [M+HH2O] ⁺ (found [M+H] ⁺ , 460.1985, C25H25N5O4 requires [M+H] ⁺ 460.1979).

(S)-5-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1,3,4-oxadiazol-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.99 (1H, d, J=6.5 Hz, NH), 7.36-7.29 (7H, m, C6H5, oxobenzoxazapine H6, H-8), 7.13 (1H, d, J=9.0 Hz, oxobenzoxazapine N-9), 4.97 (1H, ddd, J=11.0, 7.5, 7.0 Hz, oxobenzoxazapine N-3), 4.72 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, m, 1H oxobenzoxazapine H2), 4.26 (2H, s, CH ₂ SbH ₅ ), 3.43 (3H, s, NCH3), 1.63 (6H, s, C(CH ₃ )2); m/z: 484 [M+Naf, 443 [M+H-H2O] ⁺ (found [M+H] ⁺ , 443.1727, C ₂₅ H ₂₄ N ₄ O ₅ requires [M+HH ₂ O] ⁺ 443 ,1714).

(S)-N-(8-((3-Hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[B][1,4]oxazepine-3 -yl)-4-phenoxypicolinamide

1H NMR (400 MHz, CDCI3) δ 8.84 (1H, d, J=7.5 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7.60 (1H, d,

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J=2.5 Hz, ruN-3), 7.42-7.39 (2H, m, 2H C ₆ H ₅ ), 7.31 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine H-7), 7.27-7.22 (2H, m, 1H C ₆ H ₅ , oxobenzoxazapine H-9), 7.17 (1H, d, J=8.0 Hz, oxobenzoxazapine H-6) , 7.07-7.05 (2H, m, 2H C ₆ H ₅ ), 6.93 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.93 (2H, d, J=7.0 Hz, 2H oxetane H-2, H-4), 4.79 (2H , d, J=7.0 Hz, 2H oxetane H-2, H-4), 4.69 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.29 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH ₃ ); m/z: 486 [M+H]+, (found [M+H]+, 486.1674, C ₂₃ H ₂₃ N ₃ O ₆ requires [M+H]+486.1660).

(S)-5-benzyl-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.07 (1H, d, J=7.5 Hz, NH), 7.97 (1H, s, OH), 7.32-7.22 (6H, m , C ₆ H ₅ , oxobenzoxazapine H-7), 7.20 (1H, d, J=2.0 Hz, oxobenzoxazapine H-9), 7.14 (1H, d, J=8.5 Hz, 1H oxobenzoxazapine N-6), 4.99 (1H, d, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.92 (2H, d, J=7.0 Hz, 2H oxetane N-2 , Н-4), 4.79 (2Н, d, J=6.5 Hz, 2Н oxetane Н-2, Н-4), 4.64 (1H, dd, J=9.5, 7.5 Hz , 1H oxobenzoxazapine H-2), 4.25 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.14 (2H, s, CH ₂ SbH ₅ ), 3, 40 (3H, s, NCH ₃ ); m/z: 474 [M+H] ⁺ , 456 [M+H-H2O] ⁺ (found [M+H] ⁺ , 474.1784, C25H23N5O5 requires [M+H] ⁺ 474.1772).

(3S,3aR,6R,6aS)-6-(((S)-3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)-6-hydroxyhexahydrofuro[3,2-6]furan-3-ylbenzoate ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (1H, d, J=7.5 Hz, NH), 8.03 (2H, m, 2H SOS _{6 H5} ), 7.59 (1H, tt, J=7.5, 1.0 Hz, 1H SOS6H5), 7.45 (2H, t, J=7.5 Hz, 2H SOS6H5), 7.32-7.23 (7H, m, CH ₂ SbH ₅ oxobenzoxazapine H-6, H-8) , 7.12 (1H, d, J=8.5 Hz, oxobenzoxazapine H-9), 5.23 (1H, d, J 3.0 Hz, isosorbate H-6), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.87, 4.83 (2H, 2d AB system, J=4.5 Hz, isosorbate H-3a, H-6a), 4, 69 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.25-4.20 (2H, m, isosorbateH-5), 4.15 (2H, s, CH ₂ SbH ₅ ), 4.04, 3.95 (2H, 2d system AB, J = 9.5 Hz, isosorbate H-2), 3.40 (3H, s, NCH3), ; m/z: 650 [M+H]+ (found [M+H] ⁺ , 650.2283, C35H31N5O8 requires [M+H]+ 650.2245).

5-Benzyl-N-((S)-7-(((3R,3aS,6S,6aR)-3,6-dihydroxyhexahydrofuro[3,2-6]furan-3-yl)ethynyl)-5methyl-4- okso-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

1H NMR (400 MHz, CD ₃ OD) δ 7.51 (1H, d, J=2.0 Hz, oxobenzoxazapine H-6), 7.36 (1H, dd, J=8.0, 2.0 Hz , oxobenzoxazapine H-8), 7.33-7.23 (5H, m, C ₆ H ₅ ), 7.19 (1H, g, J=8.0 Hz, oxobenzoxazapine H-9), 5.01 ( 1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.65, 4.54 (2H, 2d AB system, J=4.5 Hz, isosorbate H-3a, H-6a ), 4.60 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.41 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H -2), 4.24 (1H, d, J=2.5 Hz, isosorbate H-6), 4.15 (2H, s, CH ₂ C ₆ H ₅ ), 3.99-3.91 (2H , m, 2H isosorbate H-5), 3.93, 3.71 (2H, 2d system AB, J=8.5 Hz, isosorbate H-2), 3.40 (3H, s, NCH3); ¹³ C NMR (100 MHz, CD3OD) δ 169.1, 150.3, 136.5, 130.7, 128.4, 128.3, 126.8, 126.6, 122.7, 119.9, 110.0, 89.5, 88.6, 87.1, 83.7, 78.1, 77.8, 77.5, 74.4, 49.1, 34.4, 33.2; m/z: 546 [M+H] ⁺ (found [M+H] ⁺ , 546.2007, C28H27N5O7 requires [M+H] ⁺ 546.1983).

Methyl-(S)-4-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-inoate

1H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J=7.5 Hz, NH), 7.31-7.23 (7H, m, C6H5, oxobenzoxazapine H6, H-8), 7 .10 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H3), 4.68 (1H, dd , J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.16 (2H , s, CH ₂ C ₆ H ₅ ), 3.78 (3H, s, OCH ₃ ), 3.41 (3H, s, NCH ₃ ), 1.58 (6H, s, C(CH ₃ ) ₂ ) ; m/z: 502 [M+H] ⁺ ( _{found [} M+H] ⁺ , 502.2107, _{C27H27N5O4 requires} [M+H] ⁺ 502.2085).

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(S)-1-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide 'H NMR (400 MHz, CDCI3) δ 7.79 (1H, d, J=7.0 Hz, NH), 7 ,38-7.32 (4H, m, 4H or C ₆ H ₅ , pyrazole H-4 or H-5, oxobenzoxazapine H-6, H-8), 7.28-7.21 (4H, m, 4H C ₆ H ₅ , pyrazole H-4 or H-5, oxobenzoxazapine H-6 or H-8), 7.12 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 6.74 (1H , d, J=2.5 Hz, pyrazole H-4 or H5), 5.31 (2H, s, KSN ₂ SbH ₅ ), 5.05 (1H, dt, J=11.0, 7.0 Hz , oxobenzoxazapine H-3), 4.73 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH ₃ ), 1.62 (6H, s, C(CH3) ₂ OH); m/z: 459 [M+H]+, 441 [M+HH ₂ O] ⁺ (found [M+H] ⁺ , 459.2040, C ₂₆ H ₂₆ N ₄ O ₄ requires [M+H] ⁺ 459 ,2027).

___,F

Λ·ΝΗ hT ^NH (S)-5-(3-Fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide 'H NMR (400 MHz, CDCl ₃ ) δ 8.10 ( 1H, d, J=7.0 Hz, NH), 7.28 (2H, m, oxobenzoxazapine H-6, H-8), 7.21 (1H, m, 1H C ₆ H ₄ F), 7, 10 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.01 (1H, br. d, J=8.0 Hz, 1H C6H ₄ F), 6.96 (1H, br. d, J=9.5 Hz, 1H C ₆ H ₄ F), 6.90 (1H, width d, J=9.5 Hz, 1H, td, J=8.5, 2.5 Hz, 1H C ₆ H ₄ F), 5.00 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J=10.0, 7.5 Hz , 1H oxobenzoxazapine H-2), 4.29 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.15 (2H, s, CH ₂ C ₆ H ₄ F) , 3.40 (3H, s, NCH ₃ ), 1.62 (6H, s, C(CH3) ₂ OH); » _with NMR (100 MHz, CD3OD) δ 168.5, 164.0, 161.6, '49.9, '38.5, 135.9, 131.0, 130.2 (d, J=8, 5 Hz), 128.8, 126.5, 124.5 (d, J=2.5 Hz), 123.0, 120.5, 115.8 (d, J 21.9 Hz), 121.03 (r, J 21.5 Hz), 94.6, 80.6, 76.9, 65.6, 49.2, 35.5, 32.9, 31.4; '9F NMR (380 MHz, CDCI3) δ -112.6; m/z: 460 [M+HH ₂ O] ⁺ (found [M+H] ⁺ , 478.1901, C ₂₅ H ₂₄ FN ₅ O ₄ , requires [M+H] + 478.1885).

ΓΥ y nh 1T ^NH (S)-5-(4-Fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 'H NMR (400 MHz, CDCI3) δ 8.11 (1H , d, J=7.5 Hz, NH), 7.27-7.25 (2H, m, oxobenzoxazapine H-6, H8), 7.17 (2H, dd, J=8.5, 5.5 Hz, 2H QH4F), 7.09 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 6.90 (2H, t, J=8.5 Hz, 2H C ₆ H ₄ F), 4.99 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.64 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2) , 4.29 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.09 (2H, s, CH ₂ C ₆ H ₄ F), 3.39 (3H, s, NCH3), 1.62 (6H, s, C(CH ₃ ) ₂ OH); ¹⁹ f NMR (380 MHz, CDCI3) δ -115.6; m/z: 478 [M+H] ⁺ 460 [M+H-H2O] ⁺ (found [M+H] ⁺ , 478.1902, C25H ₂ 4FN5O4 requires [M+H] ⁺ 478.1885).

(S)-5-(2-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide 'H NMR (400 MHz, CDCl ₃ ) δ 8.08 (1H, d, J =7.5 Hz, NH), 7.26-7.16 (3H, m, oxobenzoxazapine H-6, H8, 1H C ₆ H ₄ F), 7.09 (1H, d, J = 9.0 Hz , oxobenzoxazapine N-9), 7.01 (1H, td, J=7.5, 1.0 Hz, 1H C ₆ H ₄ F), 7.006.96 (1H, m, 1H C6H ₄ F), 5, 00 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.65 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4 .27 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.17 (2H, s, CHgSbNT), 3.38 (3H, s, NCH3), 1.62 (6H, s, C(CH ₃ ) ₂ OH). ' ³ s NMR (100 MHz, CDCI3) δ 168.7, 160.7 (d, J 246.3 Hz), 158.5, 149.9, 136.0, 131.0 (d, J=4, 0 Hz), 131.0, 129.1, 129.0 (d, J=8.5 Hz), 126.5, 126.3, 124.4 (d, J=4.0 Hz) ), 123 ,1, 120.4, 115.4 (d, J=12.0 Hz), 94.6, 80.6, 76.9, 65.6, 49.1, 35.5, 31.4, 26 ,3; '9F NMR (380 MHz, CDCI3) δ -117.5; m/z: 460 [M+H-H2O] (found [M+H] ⁺ , 478.1895, C25H ₂ 4FN5O4, requires [M+H] ⁺ 478.1885).

- 124 045696 (S)-7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo [b][1,4] OK-

sazepin-4(5H)-one

1H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.38 (6H, m, 3 x 2H C ₆ H ₅ ), 7.24-7.20 (6H, m, 3 x 2H C ₆ H ₅ ), 7.18-7.12 (4H, m, 3 x 1H C ₆ H ₅ , 1H oxobenzoxazapine H-6, H-8, H-9), 6.97-6.95 (2H, m, 2H oxobenzoxazapine H-6, H8, H-9), 4.48 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.37 (1H, dd, J=11, 5, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.55 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 3.28 (1H, dt, J=8 .5 Hz, NH), 2.88 (3H, s, NCH ₃ ), 1.63 (6H, s, C(CH ₃ ) ₂ OH); m/z- 561 [M-H+HCO2H] ^- .

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 -yl )-1H-1,2,4-triazole-3-carboxamide

1H NMR (400 MHz, CDCI3) δ 8.09 (1H, d, J=7.5 Hz, NH), 7.33-7.31 (2H, m, oxobenzoxazapine H-8, H9), 7.25 -7.20 (5H, m, C ₆ H ₅ ), 7.09 (1H, d, J = 9.0 Hz, oxobenzoxazapine H-9), 5.01 (1H, dt, J = 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, dd, J=11.0 , 10.0 Hz, 1H oxobenzoxazapine H-2), 4.15 (2H, s, CH ₂ SbH ₅ ), 3.40 (3H, s, NCH ₃ ), 0.26 (9H, s, Si(CH ₃ ) ₃ ); m/z: 474 [M+H] ⁺ (found [M+H] ⁺ , 474.1981, C25I Ι2-\5Ο> requires [M+H] ⁺ 474.1956).

(S)-5-Benzyl-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-1 ,2,4 triazole-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.06 (1H, d, J Hz, NH), 7.36 (1H, dd, J Hz, oxobenzoxazapine H-8), 7.357.26 (6H, m, C ₆ H ₅ , oxobenzoxazapine H-6), 7.14 (1H, d, J=8.5 Hz, oxobenzoxazapine H-9), 5.04 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.29 (1H, dd, J=11.0, 9.5 Hz , 1H oxobenzoxazapine H-2), 4.17 (2H, s, CH ₂ SbH5), 3.42 (3H, s, NCH ₃ ), 3.12 (1H, s, HCC); ¹³ C NMR (100 MHz, CDCI3) δ 168.6, 150.4, 136.1, 131.5, 128.9 (2C), 127.3, 127.0, 123.3, 119.8, 82 ,0, 78.1, 77.2, 49.1, 35.5, 33.5; m/z: 402 [M+H] ⁺ (found [M+H] ⁺ , 402.1561, C ₂₂ H ₁₉ N ₅ O ₃ requires [M+H] ⁺ 402.1576).

(S)-3-Amino-7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine4(5H)- He

1H NMR (400 MHz, CDCI3) δ 7.24 (1H, d, J=2.0 Hz, oxobenzoxazapine H-6), 7.22 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.06 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 4.41 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2 ), 4.12 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.72 (1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine H- 3); m/z: 275 [M+H] ⁺ (found [M+H] ⁺ , 275.1390, C ₁₅ H ₁₈ N ₂ O ₃ requires [M+H] ⁺ 275.1404).

(S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-1 -(2-methylbenzyl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCI3) δ 8.03 (1H, d, J=7.0 Hz, NH), 7.83 (1H, s, triazole H-5), 7.32-7.21 (5H , m, 5Н С _{6 Н4} , oxobenzoxazapine Н-6), 7.16 (1H, dd, J=9.0, 2.0 Hz, oxobenzoxazapine Н-8), 7.12 (1H, d, J= 9.0 Hz, oxobenzoxazapine H-9), 5.37 (2H, s, NCH ₂ C6H ₄ CH ₃ ), 5.07 (1H, d, J=11.0, 7.5 Hz, oxobenzoxazapine H-3 ), 4.76 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H -2), 3.41 (3H, s, NCH ₃ ), 2.27 (3H, s, SbH ₄ CH ₃ ), 1.62 (6H, s, C(CH ₃ ) ₂ OH); ¹³ C NMR (100 MHz, CDCl3) δ 168.8, 158.4, 156.5, 149.9, 143.8, 136.8, 136.0, 131.4, 131.1, 130.9, 129.7, 129.4, 126.8, 126.5, 123.2, 120.4, 94.5, 80.6, 77.1, 65.5, 52.6, 49.1, 35, 5, 31.4, 19.0; m/z: 474 [M+H] ⁺ , 456 [M+H-H2O] ⁺ .

- 125 045696

(S)-1-([1,1'-Biphenyl]-4-ylmethyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4- oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4-triazole-3-carboxamide

1H NMR (400 MHz, CDCi ₃ ) δ 8.07 (1H, s, triazole H-5), 8.06 (1H, d, J=7.0 Hz, NH), 7.60-7.55 ( 4H, m, 4H C6H4C6H5), 7.45-7.42 (2H, m, 2H C6H4C6H5), 7.38-7.34 (3H, m, 3H C6H4C6H5), 7.28-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 5.41 (2H, s, NCH ₂ C6H ₄ Ph), 5, 07 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4 .27 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.41 (3H, s, NCH3), 1.62 (6H, s, C(CH ₃ ) ₂ He); ¹³ s NMR (100 MHz, CDCl3) δ 169.1, 158.7, 157.0, 150.3, 144.3, 142.3, 140.4, 136.3, 132.9, 131.2, 129.2, 129.0, 128.2, 128.0, 127.4, 126.8, 123.5, 120.7, 94.9, 80.9, 77.5, 65.9, 54, 4, 49.4, 35.8, 31.7; m/z: 536 [M+H]+, 518 [M+H-H2O] ⁺ .

(S)-1-(2,6-dimethylbenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide 'H NMR (400 MHz, CDCi ₃ ) δ 8.02 (1H, d , J=7.0 Hz, NH), 7.59 (1H, s, triazole H-5), 7.28-7.21 (3H, m, 3H from oxobenzoxazapine H-6, H-8, H- 9, SbZz(CHz)2), 7.13-7.10 (3H, m, 3H from oxobenzoxazapine H-6, H-8, H-9, SbZz(CHz) ₂ ), 5.41 (2H, s , NCH ₂ SbH ₃ (CH ₃ ) ₂ ), 5.06 (1H, dt, J = 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J = 9.5 , 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.41 (3H, s, NCH ₃ ) , 2.30 (6H, s, C ₆ H ₃ (CH ₃ )2), '.62 (6H, s, C(CH ₃ ) ₂ OH); ¹³ s NMR (100 MHz, CDCi ₃ ) δ 168.8, 158.5, 156.5, 149.9, 143.1, 138.1, 136.0, 130.9, 129.6, 129.0 (2C), 126.5, 123.2, 120.4, 94.5, 80.6, 77.1, 65.5, 49.1, 49.0, 35.5, 31.4, 19, 6; m/z: 488 [M+H] ⁺ , 470 [M+H-H2O] ⁺ (found [M+H] ⁺ , 488.2292, C27H29N5O4 requires [M+H] ⁺ 488.2292).

(S)-N-(7-(3-Hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-1-isobutyl-1H-1,2,4-triazol-3-carboxamide 'H NMR (400 MHz, CDCi ₃ ) δ 8.04 (1H, s, triazole H-5) , 8.03 (1H, d, J=7.0 Hz, NH), 7.29-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J =9.0 Hz), oxobenzoxazapine N-9), 5.06 (1H, dd, J=11.0, 7.5, 7.0 Hz, oxobenzoxazapine H-3), 4.75 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.98 (2H, d, J=7.0 Hz, NCH ₂ CH(CH ₃ ) ₂ ), 3.41 (3H, s, NCH ₃ ), 2.30-2.23 (1H, m, CH(CH3)2), 1.62 (6H, s, C(CH ₃ ) ₂ OH), 0.91 (6H, dd, J=6.5, 1.0 Hz, CH(CH3) ₂ ); ¹³ s NMR (100 MHz, CDCi3) δ '68.9, 158.5, '56.5, 149.9, 144.3, 136.0, 130.9, 126.5, 123.2, 120, 4, 94.5, 80.6, 77.1, 65.5, 57.6, 49.1, 35.5, 31.4, 29.0, '9.7; m/z: 426 [M+H] ⁺ , 408 M+H-H2O] ⁺ (found [M+H] ⁺ , 426.2126, C ₂₂ H ₂₇ N ₅ O ₄ requires [M+H] ⁺ 426, 2136).

(S)-5-Benzyl-N-ethyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide 'H NMR (400 MHz, CDCi ₃ ) δ 7.30-7.18 (5H , m, 5Н С ₆ Н ₅ , oxobenzoxazapine Н-6, Н-8, Н-9), 7.13-7.06 (3H, m, 3H C ₆ H ₅ , oxobenzoxazapine Н-6, Н-8) , N-9), 6.85-6.77 (0.66H, m, oxobenzoxazapine N-3, side), 5.34-5.27 (0.33H, m, oxobenzoxazapine N-3, side), 4.94 (0.33Н, dd, J=12.0, 10.5 Hz, oxobenzoxazapine Н-3, side)), 4.84 (0.66Н, dd, J=12.0, 9.5 Hz , oxobenzoxazapine N-3, main), 4.55 (0.66Н, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine Н-2, main), 4.50 (0.33Н, m, 1H oxobenzoxazapine H-2, side), 4.11 (0.66H, s, CH ₂ SbH5, side), 4.05 (1.32H, d, J=7.0 Hz, NCH ₂ CH ₃ main), 3 .91, 3.84 (1.32N, 2d system AB, J 15.5 Hz, CH ₂ C ₆ H ₅ , main), 3.50 (0.66N, d, J=7.0 Hz, nch ₂ CH ₃ , side), 3.28 (1H, s, NCH ₃ , side), 3.25 (2H, s, NCH ₃ , main), 1.61 (2H, s, C(CH ₃ ) ₂ OH, side), 1.57 (4H, s, C(CH3)2OH, main), 1.20 (3H, t, J=7.0 Hz, nch ₂ ch ₃ ); m/z: 488 [M+H] ⁺ , 470 [M+H-H2O] ⁺ (found [M+H] ⁺ , 488.2291, C27H29N5O4 requires [M+H] ⁺ 488.2292).

- 126 045696

(S)-5-Benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetraαhydrobenzo[b][1,4]oxαzepin-3-yl)-1H-1 ,2,4triazole-3-carboxamide

1H NMR (400 MHz, CDCI3) δ 8.10 (1H, d, J Hz, NH), 7.33 (1H, m, oxobenzoxazapine H-6), 7.31 (1H, dd, J=8.0 , 2.5 Hz, oxobenzoxazapine H-8), 7.15 (5H, br s, C ₆ H ₅ ), 7.02 (1H, dd, J=8.0, 1.0 Hz, oxobenzoxazapine H-9 ), 4.10 (2H, s, CH ₂ SbH ₅ ), 3.36 (3H, s, NCH ₃ ); ¹³ C (100 MHz, 100 MHz) δ 168.7, 158.9, 149.1, 137.4, 135.8, 130.6, 128.8, 128.7, 127.1, 126.4, 118.1, 77.2, 49.2, 35.5, 32.9; m/z: 458, 456 [M+H]+ (found [ _M +H] ⁺ , _458.0651 , _{C20H18BrN5O3 requires} [M+H]+ 458.0645).

(S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4] oxazepin-3 -yl)isoxazol-3-carboxamide ¹ H NMR (400 MHz, CDCl3) δ 7.72 (1H, d, J=7.0 Hz, NH), 7.36-7 .21 (7H, m, C6H5, oxobenzoxazapine H6, H-8), 7.11 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 6.30 (1H, br. s, isoxazole H -5), 4.99 (1H, dt, J=11.0, 7.0 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.10 (2H, s, CH2C6H5), 3.41 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2OH); ¹³ s NMR (100 MHz, CDCl3) δ 174.1, 168.4, 158.5, 157.9, 149.9, 136.0, 135.2, 130.9, 128.9, 128.7, 127.4, 126.5, 123.1, 120.4, 101.6, 94.6, 80.6, 76.9, 65.6, 49.2, 35.5, 33.2, 31, 4; m/z: 460 [M+H] ⁺ , 442 [M+HH2O] ⁺ (found [M+H] ⁺ , 460.1884, C26H25N3O5 requires [M+H]+ 460.1867).

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)ethynyl)-2,3,4,5-tetrahydrobenzo [ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CD3OD) δ 7.71 (1H, dd, J=5.5, 3.0 Hz, 1 x ArH), 7.20 (1H, dd, J=5.5, 3.0 Hz, 1 x ArH), 7.59 (1H, d, J=2.0 Hz, 1 x ArH), 7.44 (1H, td, J=8.5, 2.0 Hz, 1 x ArH) , 7.41 (1H, br. s, 1 x ArH), 7.337.23 (6H, m, 6 x ArH), 5.03 (1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine H -3), 4.60 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.45 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.35 (2H, s, isoquinoline H-1), 4.16 (2H, s CH ₂ s ₆ H ₅ ), 3.50 (2H, t, J=6.5 Hz, isoquinoline H-3 or H-4), 3.42 (3H, s, NCH ₃ ), 3.13 (2H, dd, J=7.0, 6.0 Hz, isoquinoline H-3 or H-4) ; m/z: 533 [M+H]+ (found _[ M+H] ⁺ , _533.2296 , _{C31H28N6O3 requires} [M+H]+ 533.2296).

(S)-N-(7-(3,3-Dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4] Oxazepin-3yl)-5-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (1H, d, J=7.0 Hz, NH), 7.26-7.19 (4H, m, oxobenzoxazapine H-6, H7, 2H C6H4F), 7.08 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7 .06-7.02 (1H, m, 1H C6H4F), 7.03-6.99 (1H, m, 1H C ₆ H ₄ F), 5.01 (1H, dt, J = 11.0, 7 .5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.25 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.19 (2H, s, CH ₂ s ₆ h ₄ F), 3.40 (3H, s, NCH3), 1.32 (9H, s, C( СНз)з); ¹³ C NMR (100 MHz, CDCl3) δ 168.8, 160.7 (d, J 245.5 Hz), 158.5, 149.2, 135.8, 131.0 (d, J=4.0 Hz), 130.9, 128.9 (d, J=8.5 Hz), 126.4, 124.3 (d, J=4.0 Hz), 123.1 (d, J=4.0 Hz), 123.1 (d, J=4.0 Hz), g, J 15.0 Hz), 122.8, 121.8, 115.3 (d, J 21.5 Hz), 99.4 , 77.6, 77.0, 49.2, 35.5, 30.9, 27.9, 26.3; m/z: 476 [M+H]+ (found [M+H] ⁺ , 476.2100, C25H26FN5O3 requires [M+H]+ 476.2092).

(S)-1-(2,6-dimethylbenzyl)-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.02 (1H, d, J=7.5 Hz, NH), 7.59 (1H, s, triazole H-5), 7.26-7.22 ( 3H, m,

- 127 045696 oxobenzoxazapine N-6, H-8, SbHz(CHz)2H-4), 7.12 (2H, d, J=7.5 Hz, SbHz(CHz)2H-3, N-5), 7 .09 (1H, d, J=9.0

Hz, oxobenzoxazapine H-9), 5.42 (2H, s, NCH ₂ C ₆ Hz(CH ₃ ) ₂ ), 5.06 (1H, dt, J = 11.0, 7.5 Hz, oxobenzoxazapine

H-3), 4.76 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.24 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 2.31 (6H, s, C6H3(CH3)2, 1.32 (9H, s, C(CH3)3); m/z : 486 [M+H] ⁺ (found

[M+H] ⁺ , 486.2506, C ₂₈ H ₃₁ N ₅ O ₃ requires [M+H] ⁺ 486.2500).

(S)-5-benzyl-N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (1H, d, J=7.5 Hz, NH), 7.33-7.26 (7H, m, C ₆ H ₅ , oxobenzoxazapine H6, H- 8), 7.12 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 4.99 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H3), 4.66 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4 .21-4.11 (1H, m, 1H nch ₂ ch ₃ ), 4.16 (2H, c^CH ₂ C ₆ H ₅ ), 3.66 (1H, heptet, J = 7.0 Hz, 1H NCH ₂ CH ₃ ), 1.63 (6H, s, C(CH3) ₂ OH), 1.19 (3H, t, J=7.0 Hz, CHCH ₂ CH3); m/z: 456 [M+H-H2O] ⁺ (found _[ M+H] ⁺ , 474.2143, _{C26H27N5O4 requires} [M+H] ⁺ 474.2136).

(S)-N-(5-Ethyl-7-(3-hydroxy-3-methylbut-1-in-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-5-(3-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide ¹ H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J= 7.5 Hz, NH), 7.30-7.28 (2H, m, oxobenzoxazapine H-6, H8), 7.26-7.21 (1H, m, 1H C6H4F), 7.12 (1H, d, J=8.5 Hz, oxobenzoxazapine H-9), 7.03 (1H, wd, J=7.5 Hz, 1H C6H4F), 6.98 (1H, wd, J=9, 5 Hz, 1H C6H4F), 6.92 (1H, td, J=8.5, 2.5 Hz, 1H C6H4F), 4.97 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.65 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, dd, J=11.0, 10.5 Hz, 1H oxobenzoxazapine H-2), 4.22-4.10 (1H, m, 1H NCH2CH3), 4.14 (2H, s, CH ₂ SbH ₄ P), 3.66 (1H, heptet, J=7, 0 Hz, 1H NCH2CH3), 1.63 (6H, s, C(CH3) ₂ OH), 1.19(3H, t, J=7.0 Hz, NCH2CH3); 19F NMR (380 MHz, CDCl ₃ ) δ -112.6; m/z: 474 [M+HH ₂ O]+ (found [M+H]+, 492.2047, C ₂₆ H2 ₆ FN ₅ C ₄ requires [M+H]+ 492.2042).

(S)-5-Benzyl-N-(7-(3-methylbut-3-en-1-in-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo [b][1, 4] oxazepin-3 yl)- 1H-1,2,4-triazole-3-carboxamide ¹ H NMR (400 MHz, CDCl3) δ 8.01 (1H, d, J=7.0 Hz, 1 x NH) , 7.54 (1H, s, 1 x NH), 7.35-7.24 (6H, m, C5H5, oxobenzoxazapine H-8), 7.10 (1H, d, J=8.5 Hz), oxobenzoxazapine H-9), 7.09 (1H, m, oxobenzoxazapine H-6), 5.40 (1H, br s, 1H C=CH2), 5.32 (1H, br s, 1H C=CH2), 5.08 (1H, m, oxobenzoxazapineH-3), 4.76 (1H, dd, J=10.0, 6.0 Hz, 1H oxobenzoxazapineH-2), 4.33 (1H, t, J=10 .5 Hz, 1H oxobenzoxazapine H-2), 4.18 (2H, s, CH2CbH5), 1.98 (3H, s, CCH3); m/z: 428 [M+H] ⁺ (found [M+H] ⁺ , 428.1709, C24H ₂₁ N ₅ O ₃ requires [M+H] ⁺ 428.1717).

(S)-5-Benzyl-N-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazenin-3-yl)-1H-1,2,4 -triazole-3carboxamide ^1H NMR (400 MHz, CD3OD) δ 7.32-7.21 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.06 (1H, d, J=8, 0 Hz, oxobenzoxazapine H-9), 5.00 (1H, dd, J=10.5, 6.5 Hz, oxobenzoxazapine H-3), 4.61 (1H, dd, J=10.5, 6, 5 Hz, 1H oxobenzoxazapine H-2), 4.40 (1H, t, J=9.5 Hz, 1H oxobenzoxazapine H-2), 4.15 (2H, s, CH2C6H5); m/z: 444, 442 [M+H] ⁺ (found [M+H] ⁺ , 444.0492, C19H ₁₆ BrN ₅ O ₃ requires [M+H] ⁺ 444.0489).

(S,Z)-5-Benzyl-N-(7-(2-chloro-3-hydroxy-3-methylbut-1-en-1-yl)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide ^1H NMR (400 MHz, CDCl ₃ ) δ 8.09 (1H, d , J=7.5 Hz, NH), 7.41-7.39 (2H, m, oxobenzoxazapine H-6, H8), 7.29-7.22 (5H, m, C ₆ H ₅ ), 7 .15 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 6.31 (1H, s, CH=CCl), 5.05 (1H,

- 128 045696 dt, J=ll.5, 7.5 Hz, oxobenzoxazapine N-3), 4.67 (1H, dd, >9.5, 7.5 Hz, 1H from oxobenzoxazapine N-2), 4, 28 (1H, dd, >11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.14 (2H, s, CHgCeHs), ZDZ (ZN, s, NCH ₃ ), 1.57 (6H, With,

C(CH ₃ ) ₂ OH); ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 168.7, 158.9, 158.4, 154.3, 150.2, 136.5, 135.9, 135.7, 135.7,

130.1, 128.9, 128.8, 127.2, 125.8, 122.8, 121.8, 77.2, 71.2, 49.1, 35.6, 33.2, 29, 4; m/z: 480, 478 [M+H-H ₂ O] ⁺ ;

m/z: 496, 494 [MH]' (found [Μ+Η] ⁺ , 496.1743, C ₂₅ H ₂₆ C1N ₅ O ₄ requires [M+H] ⁺ 496.1746).

(8)-5-benzyl-N(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-in-1-yl)-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide ^! H NMR (400 MHz, CDC13) δ 8.07 (1H, d, J=7.5 Hz, NH), 7.28-7.20 (7H, m, oxobenzoxazapine H-6, H8, C6H5), 7 .09 (1H, d, >9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, >11.0, 7.5 Hz, oxobenzoxazapine H3), 4.66 (1H, dd, > 9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, >11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.14 (2H, s, CH2C6H5 )5 3.62 (2H, s, CCH2N), 3.38 (3H, s, NCH3), 2.73-2.70 (4H, m, pyrrolidine 4H), 1.86-1.82 (4H, m, 4H pyrrolidine); m/z: 485 [M+H] ⁺ (found [M+H] ⁺ , 485.2322, C27H ₂₈ N ₆ O ₃ requires [M+H] ⁺ 485.2296).

(8)-5-benzyl->(5-methyl-7-(3-morpholinoprop-1-in-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-1 Η-1,2,4-triazol-3-carboxamide ^! H NMR (400 MHz, CDC13) δ 8.08 (1H, d, J=7.0 Hz, NH), 7.29-7.7.27 (2H, m, oxobenzoxazapine H-6, H-8) , 7.25-7.18 (5H, m, C6H5), 7.10 (1H, g, J=9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, >11.0, 7.0 Hz, oxobenzoxazapine H-3), 4.65 (1H, dd, >9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, t, J 10.5 Hz, 1H oxobenzoxazapine H-2), 4.13 (2H, s, CH2C6n5), 3.78, 3.76 (4H, 2d system AB, J 4.5 Hz, 4H morpholine), 3.50 (2H, s, CCH2N), 3.39 (ZH, s, NCH3), 2.65, 2.63 (4H, 2d system AB, J 4.5 Hz, 4H morpholine); m/z: 501 [M+H] ⁺ (found [M+H] ⁺ , 501.2245, C27H ₂₈ N ₆ O ₃ , requires [M+H] ⁺ 501.2245).

The following examples provide a synthetic protocol for the preparation of embodiments of the pyridine-containing compounds disclosed herein.

Example 11.

Scheme 9 proposes a method for the preparation of 4-phenoxypicolinonitrile and 4-phenoxypyridine-2carboxylic acid.

Scheme 9

For Scheme 9, cesium carbonate (20.58 g, 63.1 mmol, 1.1 eq) was added to a solution of 4fluoropicolinonitrile 90 (7.00 g, 57.4 mmol, 1.0 eq) and phenol 92 ( 5.66 g, 60.2 mmol, 1.05 eq) in dimethylformamide (90 ml). The reaction mixture was heated to 80°C for 8 hours and cooled. The reaction mixture was poured into ice water (1 L).

A precipitate formed and was isolated by filtration to give 4-phenoxypicolinonitrile 94 (10.7 g, 95%) as a white solid; ^! H NMR (400 MHz, CDC1 ₃ ) δ 8.52 (1H, d, J=6.0 Hz, ruH-6), 7.50-7.45 (2H, m, 2H C ₆ H ₅ ), 7 .33 (1H, tt, >7.5, 1.0 Hz, 1H C ₆ H ₅ ), 7.20 (1H, d, J = 2.0 Hz, ruH-3), 7.11-7, 08 (2H, m, 2H C ₆ H ₅ ), 7.02 (1H, dd, >5.5, 2.5 Hz, ruH-5); m/z: 197 [M+H] ⁺ .

Example 12.

This example proposes a method for preparing 4-phenoxypyridine-2-carboxylic acid 96 from 4phenoxypicolinonitrile 94. A suspension of picolinonitrile 94 (10.7 g, 54.6 mmol) in hydrochloric acid (6M, 100 ml) was heated to 100°C for 8 h. The reaction mixture was cooled to room temperature to form a precipitate, which was isolated by filtration. The filtrate was cooled to provide additional solid, which was isolated by filtration and added to the first batch. The solid was dried in vacuo to give a white solid, 4-phenoxypyridine-2-carboxylic acid 96 (12.6 g, 92%); ^! H NMR (400 MHz, O ₆ -DMSO) δ 8.64 (1H, d, >6.0 Hz, ruN-6), 7.57-7.53 (ZN, m, ruN-3, 2H C ₆ H ₅ ), 7.38 (1H, tt, >7.5, 1.0 Hz, 1H C ₆ H ₅ ), 7.33 (1H, dd, >6.0 2.5 Hz, ruN-5) , 7.28-7.26 (2H, m, 2H C ₆ H ₅ ); m/z: 216 [M+H] ⁺ .

Example 13.

This example concerns methods for the preparation of 5-(4-fluorophenoxy)pyridine-2-carboxylic acid. Nmethylpyrrolidinone (5 ml) was added to a mixture of methyl fluoropicolate (0.400 g, 2.58 mmol, 1.0 eq.), 4fluorophenol (0.318 g, 2.84 mmol, 1.1 eq.) and cesium carbonate (0.925 g, 2.0 eq. 84 mmol, 1.1 eq.). Reactionary

- 129045696 the mixture was stirred at 95°C for 75 hours. The reaction mixture was cooled and added to ice water (150 ml) to form a precipitate. After stirring for 15 minutes, the precipitate was isolated by filtration (0.540 g, 85%) as a white solid; 1H NMR(400 MHz, CDCl3) δ 8.46 (1H, dd, J 3.0, 0.5 Hz, ruH-6), 8.09 (1H, dd, J=9.0 0.5 Hz, runN-2), 7.24 (1H, dd, J=9.0, 3.0 Hz, runN-4), 7.14-7.04 (4H, m, C6H4F), 3.99 (3H, s, OCH3); ¹⁹ F NMR (380 MHz, CDCh) δ -117.0; m/z: 248 [M+H]+.

An aqueous solution of lithium hydroxide (0.14 g in 5 ml water, 3.28 mmol, 1.5 eq.) was added to a solution of methyl ether (0.54 g, 2.19 mmol, 1.0 eq.) in tetrahydrofuran ( 12 ml). The reaction mixture was stirred at room temperature for 35 minutes and concentrated to remove organic matter. The solution was diluted with water (5 ml) and hydrochloric acid (3M, ~1 ml) was added to pH~3. A white precipitate formed, which was separated by filtration. An additional amount of hydrochloric acid (3M, 10 drops) was added to the filtrate, forming an additional precipitate, which was separated by filtration. The precipitates were combined and dried in vacuo to give the title compound (0.49 g, 75%) as a white solid; ^1H NMR (400 MHz, D ₆ -DMSO) δ 8.43 (1H, dd, J 3.0, 0.5 Hz, ruH-6), 8.02 (1H, dd, J=8.5 0 .5 Hz, ruN-2), 7.39 (1H, dd, J=8.5, 3.0 Hz, ruN-4), 7.33-7.22 (4H, m, C6H4F); ¹⁹ F NMR (380 MHz, D6-DMSO) δ -117.7; m/z: 234 [M+H] ⁺ .

Example 14.

This example concerns a process for the preparation of 4-cyclobutyloxypyridine-2-carboxylic acid, as shown in Scheme 10 below.

Scheme 10

A solution of cyclobutanol 102 (0.30 mL, 3.84 mmol, 1.2 eq.) in tetrahydrofuran (20 mL) was cooled to 0°C. Sodium hydride (0.154 g of 60% suspension, 3.84 mmol, 1.2 eq.) was added and the reaction mixture was stirred at 0°C for 25 minutes. Fluoropicolinonitrile 100 (0.390 g, 3.20 mmol, 1.0 eq.) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding NH ₄ Cl (5 ml). The reaction mixture was diluted with EtOAc (80 ml) and washed with NaHCO ₃ (80 ml). The aqueous phase was extracted with EtOAc (30 ml). The combined organic layers were washed with brine (60 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. HPLC (10 >60% EtOAc-hexane) gave 4-cyclobutyloxypicolinitrile 104 (0.487 g, 88%) as a colorless oil. 1H NMR (400 MHz, CDCl ₃ ) δ 8.46 (1H, d, J=5.5 Hz, runH-6), 7.10 (1H, d, J=2.5 Hz, runH-3), 6.88 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 4.72 (1H, pentet, J=7.0 Hz, cBuH-1), 2.53-2, 46 (2H, m, 2H cBuH-2, H-4), 2.26-2.16 (2H, m, 2H cBuH-2, H-4), 1.98-1.89 (1H, m, 1H cBuH-3), 1.82-1.71 (1H, m, 1H cBuH-3).

Hydrochloric acid (6M, 7 ml) was added to 4-cyclobutyloxypicolinonitrile 104 (0.487 g, 2.80 mmol) and the reaction mixture was heated to 100°C for 18 hours. The reaction was cooled, but no precipitate formed. The solution was concentrated to dryness to give a beige solid, 4-cyclobutyloxypyridine-2-carboxylic acid 106, which was used without further purification. 1H NMR (400 MHz, D6-DMSO) δ 8.66 (1H, d, J=6.5 Hz, ruH-6), 7.69 (1H, dd, J=2.5 Hz, ruH-3) , 7.50 (1H, dd, J=6.5, 2.5 Hz, ruH-5), 5.12 (1H, pentet, J=7.0 Hz, cBuH-1), 2.53-2 .46 (2H, m, 2H cBuH-2, H-4), 2.19-2.09 (2H, m, 2H cBuH-2, H-4), 1.88-1.80 (1H, m , 1H cBuH-3), 1.75-1.65 (1H, m, 1H cBuH-3); m/z: 194 [M+H] ⁺ .

Example 15.

This example relates to a process for the preparation of (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-4-phenoxypicolinamide according to scheme 11.

- 130 045696

Scheme 11

Dimethylformamide (80 ml) was added to a mixture of bromoxobenzoxazapine 1100 (8.36 g, 16.3 mmol, 1.0 eq) and copper iodide (0.31 g, 1.6 mmol, 0.1 eq). The mixture was degassed by bubbling argon for five minutes. Triethylamine (11.4 mL, 81.6 mmol, 5.0 eq) was added, followed by hydroxyethyl oxetane 1102 (3.20 g, 32.7 mmol, 2.0 eq) and tetrakis(triphenylphosphine)palladium (0.94 g, 0.8 mmol, 0.05 eq.). The resulting brown solution was heated to 80°C for 4 hours. The reaction mixture was cooled and partitioned between EtOAc (200 ml) and water (200 ml). The organic layers were washed with brine (150 ml), water (200 ml) and brine (150 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. HPLC (10 >70% EtOAc-hexane) gave 1104 (6.18 g, 72%) as a yellow solid. Ή NMR(400 MHz, CD ₃ Cl) δ 7.41-7.39 (6H, m, 6H C(C ₆ H ₅ ) ₃ ), 7.25-7.15 (10H, m, 9H C(C ₆ H ₅ ) ₃ , oxobenzoxazapine H-8), 7.00-6.98 (2H, m, oxobenzoxazapine H-6, H-9), 4.94 (2H, d, J=7.0 Hz, 2H oxetane H-2, H-4), 4.80 (2H, d, J=7.5 Hz, 2H oxetane H-2, H-4), 4.50 (1H, dd, J=10.0, 7.0 Hz, 1H oxobenzoxazapine H-2), 4.39 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.59-3.52 (1H, m, oxobenzoxazapineH-3), 3.29 (1H, d, J=9.0 Hz, NH), 2.89 (3H, s, NCH3).

Formic acid (50 ml) was added to trityl protected amine 1104 (7.49 g, 14.1 mmol, 1 eq.) and the mixture was stirred at room temperature for 4 hours. Water (50 ml) was added and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated to remove some formic acid before diluting with water (100 ml). The organic layers were extracted with EtOAc (50 ml) and set aside. The aqueous phase was neutralized by adding NaOH (5M, in portions up to approximately 40 ml). The organic layers were extracted with EtOAc (4x150 ml). The combined neutralized organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give (S)-3-amino-7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3dihydrobenzo[b ][1,4]oxazepin-4(5H)-one 1106 (3.78 g, 93%) as a yellow solid, which was used without further purification. 1H NMR(400 MHz, D ₆ -DMSO) δ 7.51 (1H, d, J=2.0 Hz, oxobenzoxazapine H-6), 7.29 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.14 (1H, d, J=8.0 Hz, oxobenoxazapine H-9), 4.74 (2H, d, J=7.0 Hz, 2H oxetane H-2, Н-4), 4.58 (2Н, d, J=7.0 Hz, 2Н oxetane Н-2, Н-4), 4.25 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.01 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.59 (1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 3.28 (3H, s, NCH3); ¹³ C NMR (100 MHz, D6DMSO) δ 173.7, 150.7, 137.7, 130.2, 126.2, 126.6, 123.3, 119.1, 90.9, 84.5, 83.7, 80.3, 66.3, 51.1, 35.1; m/z: 289 [M+H]+.

A solution of aminooxobenzoxazapine 1106 (3.78 g, 13.13 mmol, 1.0 eq.) in dimethylformamide (70 ml) was degassed by bubbling nitrogen for five minutes. 4-Phenoxypyridine2-carboxylic acid hydrochloride 1108 (3.30 g, 13.13 mmol, 1.0 eq) was added and the solution was cooled to 0°C before adding diisopropylethylamine (5.7 ml, 32.81 mmol, 2. 5 eq.). HATU (5.49 g, 14.44 mmol, 1.1 eq.) was added portionwise and the reaction mixture was stirred at 0°C for 1 hour and at room temperature for 15 hours. The reaction mixture was poured into ice water (500 ml) with the formation of a precipitate, which, after stirring for 15 minutes, was separated by filtration. The filtrate was extracted with EtOAc (150 ml). The organic extracts were washed with brine (100 ml), water (150 ml) and brine (100 ml), combined with the isolated residue, dried (Na2SO4) and concentrated under reduced pressure. HPLC (30>70% EtOAc-hexane) gave (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-4-phenoxypicolinamide I-110 (5.20 g, 82%) as a white foam. IR (film) v 3357, 2941, 2875, 1662, 1582, 1501, 1488, 1469, 1388, 1360, 1291, 1214, 1192, 1020, 979, 838, 730 cm ^-1 ; ^1H NMR (400 MHz, CDCi ₃ ) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7 .61 (1H, d, J=2.5 Hz, ruH-3), 7.44-7.40 (2H, m, 2H C ₆ H5), 7.32-7.29 (2H, m, 2H C ₆ H5 or oxobenzoxazapine H-6, H-8), 7.27-7.23 (1H, m, 1H C ₆ H ₅ or oxobenzoxazapine H-6, H-8), 7.15 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.08-7.06 (2H, m, 2H C6H5 or oxobenzoxazapine H-6, H-8), 6.50 (1H, dd,

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J=5.5, 2.5 Hz, ruH-5), 5.04 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.93 (2H, dd, J =4.0, 0.5 Hz, oxetane Н-2, Н-4), 4.79 (2Н, dt, J=6.5, 1.0 Hz, oxetane Н-2, Н-4), 4 .71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.32 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2) , 3.42 (3H, s, NCH ₃ ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.9, 166.1, 163.7, 153.7, 151.2, 150.5, 150.1, 136.4, 130.9, 130.3 , 126.5, 125.7, 123.3, 120.7, 119.3, 114.5, 110.7, 88.6, 84.8, 84.5, 77.2, 67.4, 49 ,3, 35.4; m/z: 486 [M+H]+(found [M+H]+, 486.1651, C27H23N3O6 requires [M+H]+ 486.1660).

Example 16.

This example describes a method for preparing embodiments of azetidinylacetylene compounds according to Synthesis Scheme 12 below.

Scheme 12

A. Synthesis of tert-butyl-3-ethynyl-3-hydroxyazetidine-1-carboxylate

Scheme 13

A solution of (trimethylsilyl)acetylene 1302 (0.71 g, 1.00 ml, 6.28 mmol, 1.1 eq.) in tetrahydrofuran (30 ml) was cooled to -78°C and butyllithium (2.51 ml 2, A 5 M solution in hexane, 6.28 mmol, 1.1 eq.) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour before adding Boc-azetidinone 1300 (0.98 g, 5.71 mmol, 1.0 eq.). The reaction mixture was stirred at -78°C to room temperature for 20 hours before quenching by adding NH ₄ Cl (20 ml). The reaction mixture was partitioned between EtOAc (100 ml) and NH4Cl-water (1:1, 100 ml).

The organic layers were washed with brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure.

The residue containing 1304 was dissolved in tetrahydrofuran (30 ml) and cooled to 0°C before adding tetrabutylammonium fluoride trihydrate (1.80 g, 5.71 mmol, 1.0 eq.). The reaction mixture was stirred at 0°C for 3 hours before adding NH ₄ Cl (20 ml). The reaction mixture was partitioned between EtOAc (100 ml) and NH ₄ Cl-water (1:1, 100 ml). The organic layers were washed with NH ₄ Cl (100 ml) and brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1306 as a pale yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ 4.20 (2H, dd, J=9.0, 1.0 Hz, 2H azetidine H-2, H-4), 4.02 (2H, dd, J= 9.0, 1.0 Hz, 2H azetidine H-2, H-4), 2.68 (1H, s, CCH), 1.44 (9H, s, C(CH ₃ ) ₃ ).

B. Formation of (S)-3-hydroxy-3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine- 7-yl)ethynyl)azetidine-1-carboxylate

1312 Vos ¹³¹⁴

Add dimethylformamide (3.0 mL) to a mixture of bromoxobenzoxazapine 1312 (0.141 g, 0.301 mmol, 1.0 eq.) and tert-butyl-3-ethynyl-3-hydroxyazetidine-1-carboxylate 1306 (0.089 g, 4.52 mmol , 1.5 eq.) and

- 132 045696 copper iodide (0.006 g, 0.030 mmol, 0.1 eq.). The reaction mixture was degassed by bubbling argon for five minutes. Triethylamine (0.21 mL, 1.506 mmol, 5.0 eq.) was added to form a clear solution, to which tetrakis(triphenylphosphine) palladium (0.017 g, 0.015 mmol, 0.05 eq.) was added. A brown solution was obtained which was heated to 80°C for 6 hours. The reaction mixture was cooled and partitioned between EtOAc (50 ml) and water (50 ml). The organic layers were washed with brine (50 ml), water (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. HPLC (30^80% EtOAc-hexane) provided starting material (0.050 g) and compound 1314 (0.090 g, 51%); ^1H NMR (400 MHz, CDCl ₃ ) δ 8.87 (1H, d, J=7.5 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7 .61 (1H, d, J=2.5 Hz, ruH-3), 7.44-7.39 (2H, m, 2H C6H5), 7.31-728 (2H, m, oxobenzoxazapine H-6, Н-8), 7.27-7.23 (1H, m, 1H С6Н5), 7.15 (1H, d, J=9.0 Hz, oxobenzoxazapine Н-9), 7.08-7.06 ( 2H, m, 2H C6H5), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.05 (1H, dt, J=11.5, 7.5 Hz , oxobenzoxazapine H-3), 4.69 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.31 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.29-4.26 (2H, m, 2H azetidine H-2, H-4), 4.12-4.09 (2H, m, 2H azetidine H-2, H-4), 3.42 (3H, s, NCH3), 1.45 (9H, s, C(CH3)z); m/z: 585 [M+H]+, 529 [M+H-C^G, 485 [M+H-C4H8-CO2L

C. (S)-N-(7-((3-Hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenoxypicolinamide

Hydrogen chloride (0.12 ml of 4M solution in dioxane, 0.462 mmol, 3.0 eq.) was added to a solution of Boc-protected azetidine 1316 (0.090 g, 0.154 mmol, 1.0 eq.) in ethyl acetate (1.5 ml) at room temperature. The reaction mixture was stirred at room temperature for 6 hours. Additional hydrogen chloride (0.12 mL 4M dioxane, 0.462 mmol, 3.0 eq.) was added and the reaction mixture was stirred for an additional 16 hours before concentration under reduced pressure. . The residue was partitioned between EtOAc (30 ml) and NaHCO ₃ (30 ml). The aqueous phase was extracted with EtOAc (30 ml) and CH ₂ Cl ₂ (3x30 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. HPLC (0^15% MeOH [NH ₃ ]-CH ₂ Cl ₂ ) gave compound 1318 (0.026 g, 39%) as a white solid; 1H NMR (400 MHz, CDCD δ 8.86 (1H, d, J=7.0 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7.61 ( 1H, d, J=2.5 Hz, рН -3), 7.43-7.39 (2H, m, 2H C ₆ H ₅ ), 7.31-7.29 (2H, m, oxobenzoxazapine H- 6, H-8), 7.27-7.22 (1H, m, 1H C ₆ H ₅ ), 7.13 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 7.08 -7.05 (2H, m, 2H C6H5), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.5 , 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J=11, 5, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.05 (2H, d, J=9.0 Hz, 2H azetidine-2, H-4), 3.83 (2H, d, J=9 .5 Hz, 2H azetidine-2, H-4), 3.42 (3H, s, NCH3); m/z: 485 [M+H] ⁺ (found [M+H] ⁺ , 485.1826, C27H24N4O5 requires [M+H] ⁺ 485.1819).

D. (S)-N-(7-((3-Hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide

H 1320 /

An aqueous solution of formaldehyde (0.005 mL of 37% aqueous solution, 0.071 mmol, 1.5 eq.) was added to azetidine 1320 (0.023 g, 0.048 mmol, 1.0 eq.) in methanol (0.5 mL). The reaction was equilibrated at room temperature for 15 min before adding sodium triacetoxyborohydride (0.015 g, 0.071 mmol, 1.5 eq.). After stirring at room temperature for 45 min, the reaction mixture was quenched by adding Rochelle salt (1 ml). The mixture was stirred for 1 hour and partitioned between NaHCO3 (40 ml) and CH2Cl2 (40 ml). The aqueous phase was extracted with CH2Cl2 (2x40 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. HPLC (0^15% MeOH [2M NH ₃ ]-CH ₂ Cl ₂ ) gave compound 1322 as a white solid. 1H NMR (400 MHz, CDCl ₃ ) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7, 61 (1H, d, J=2.5 Hz, ruH-3), 7.43-7.39 (2H, m, 2H C6H5), 7.32-7.29 (2H, m, oxobenzoxazapine H-6 , Н-8), 7.27-7.23 (1H, m, 1H С6Н5), 7.13 (1H, d, J=8.5 Hz, oxobenzoxazapine Н-9), 7.08-7.06 (2H, m, 2H C ₆ H ₅ ), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J Hz, 11, 5, 10.0 N oxobenzoxazapine H-2), 3.70 (2H, w.d, J=9.5 Hz, 2H azetidine H-2, H-4), 3.44 (2H, d, J= 9.0 Hz, 2H azetidine H-2, H-4), 3.41 (3H, s, CONCH3), 2.43 (3H, s, NCH ₃ ); m/z: 499 [M+H] ⁺ (found [M+H] ⁺ , 499.1988, C28H26N4O5 requires [M+H] ⁺ 499.1976).

E. Fluorination of tert-butyl-(S)-3-fluoro-3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[b][1,4] Oxazepin-7-yl)ethynyl)azetidine-1-carboxylate

- 133 045696

Vos 1324 Vos 1326

To a solution of tert-butyl-(S)-3-hydroxy-3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -7-yl)ethynyl)azetidine-1-carboxylate 1324 (0.055 g, 0.094 mmol, 1.0 eq.) in dichloromethane (1.0 ml) at -78°C was added dropwise [bis(2-methoxyethylamino)] sulfur trifluoride (0.031 g, 0.026 ml, 0.141 mmol, 1.5 eq.). The reaction mixture was stirred at -78°C for 3 hours and at 0°C for 45 minutes before quenching with NaHCO ₃ (5 ml). The reaction mixture was added to NaHCO ³ (20 ml) and the organic layers were extracted with CH2Cl2 (3x20 ml). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give compound 1326 as a yellow oil. The raw material was used without purification; 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, runH-3), 7.44-7.40 (2H, m, 2H C6H 5), 7.35-7.32 (2H, m, oxobenzoxazapine H-6 , Н-8), 7.27-7.24 (1H, m, 1H С6Н5), 7.17 (1H, d, J=9.0 Hz, oxobenzoxazapine Н-9), 7.08-7.06 (2H, m, 2H C6H5), 6.95 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.04 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.72 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.35-4.30 (5H, m, 1H oxobenzoxazapine H- 2, azetidine H-2, H-4), 3.44 (3H, s, NCH3), 1.47 (9H, s, C(CH2)z); ¹⁹ F NMR (380 MHz, CDCl3) δ -141.4 (t, J=19.0 Hz); m/z: 587 [M+H]+, 531 [M+H-C^G, 487 [M+H-C4H8-CO2L

Example 17.

This example proposes a method for the preparation of N-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamides by forming the intermediate pyrazole-1-carbonyl chloride according to Scheme 14.

Scheme 14

“And Doyoin tysh. _14SH to eogsh. pace. 14"

_{Added i} -Pr ₂ NEt (5-9 equiv.) over time (15 min/mmol). The red reaction solution was stirred at 0°C for 1 h, warmed to room temperature (2 h), analyzed for 4-[(aryl)methyl]-1H-pyrazole by LC/MS and concentrated to dryness to give 1402. Red semi-solid concentrate was added to 1404 or the corresponding amine or salt thereof (1 eq.) and DMAP (0.1 eq.) and cooled in an ice bath under nitrogen. CH ₂ Cl ₂ (15 ml/mmol) was added to the flask, stirred for 15 min, and the red solution was treated with i'-Pr ₂ NEt (5-9 eq.) for a period of time (15 min/mmol) while stirring. The ice bath was removed after 1 hour and the reaction solution was allowed to warm to room temperature. After analyzing the progress of the reaction, the reaction solution was concentrated to dryness, diluted with water and extracted with either EtOAc or CH ₂ Cl ₂ . Purification by flash column chromatography on silica gel of the crude concentrate gave the desired N-substituted-4-[(aryl)methyl]-1H-pyrazole-1carboxylic acid 1406 (Yield: 20-75%).

Example 18.

This example proposes a method for the preparation of N-substituted-4-[(aryl)methyl]-1H-pyrazole-1carboxamides by the formation of an intermediate isocyanate according to Scheme 15.

Scheme 15

i-Pr2NEt (10-15 eq.) was added over time (20 min/mmol) to a stirred heterogeneous mixture of compound 1420 or its corresponding amine, or its salt (1 eq.) and triphosgene (2.3 eq.) in CH ₂ Cl ₂ (15 ml/mmol) in a nitrogen atmosphere at 0°C. The pale yellow reaction solution was stirred at 0°C for 1 hour, warmed to room temperature (2 hours), the corresponding amine consumption was analyzed by LC/MS and concentrated to dryness. To the red semi-solid concentrate containing compound 1422, 4-[(aryl)methyl]-1H-pyrazole hydrochloride 1424 (0.9 eq) and DMAP (0.1 eq) were added and cooled in an ice bath under nitrogen. CH2Cl2 (15 ml/mmol) was added to the flask, stirred for 15 min and the stirred red solution was treated with i-Pr ₂ NEt (10-15 eq) over time (15 min/mmol). The ice bath was removed after 1 hour and the reaction solution was allowed to warm to room temperature (6-8 hours). After progress analysis, the reaction solution was concentrated to dryness, diluted with water and extracted using either EtOAc or

- 134 045696

CH2C12. Purification by flash column chromatography on silica gel of the resulting crude product gave the desired N-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamide 1426 (Yield: 19-73%).

Example 19.

This example provides a method for preparing embodiments of the disclosed alkynyl-substituted compounds according to Scheme 16.

Scheme 16

Through a stirred solution of aryl halide 1440 (1 eq.) and CuI (0.1-0.2 eq.), Pd(PPh ₃ ) ₄ (0.05-0.1 eq.) in dry DMF (3-4 ml/ mmol) nitrogen was bubbled into the vessel for 3 minutes. NEt ₃ (10 eq.) was then added to the dark reaction solution, followed by rapid addition of the corresponding alkyne 1442 (1.5-3 eq.). Nitrogen was bubbled through the reaction mixture for 2 minutes, the vessel was closed, and the reaction mixture was stirred at 70-75°C for 5-6 hours. The dark reaction solution was concentrated to dryness after analyzing the progress of the reaction using LC/MS analysis. The crude residue was diluted with ice water, sonicated, and the suspension was warmed to room temperature. The resulting gray/dark solid was collected by filtration, suction dried, dissolved in THF (20 ml), filtered through a pad of celite®/silica gel and the layer washed with THF. After concentrating the filtrate, the crude material was purified by flash chromatography to obtain alkynyl-substituted analogues 1444 (Yield: 25-69%).

Example 20.

This example provides a method for preparing the disclosed embodiments of 4-[(aryl)methyl]-1H-pyrazole compounds according to Scheme 17.

Scheme 17 /U ^- Ν] 4.QN HCl in 1,4-dnoisane I

ABOUT

1450 1454 СН _g С1 _g .™ш™.

V

Stirred mixture of 1-Boc-pyrazole-4-boronic acid pinacol ester 1450 (1 mmol), (chloromethyl)arene/hetetoarene (1.3 mmol) 1452, XPhos-Pd-G2 (0.05 mmol) and K ₂ CO ₃ (3-4 mmol) in 1,4dioxane:H ₂ O (9:1, 10 ml/mmol) was degassed under high vacuum and back purged with argon in a balloon in three cycles for 5-10 min and heated at 70-75°C in for 2-6 hours. The reaction mixture was cooled and concentrated to dryness. The crude residue was diluted with EtOAc (or CH ₂ Cl ₂ ), water and saturated aq. Na ₂ CO ₃ (6 ml/mmol). The organic layer was separated and the aqueous layer was extracted with EtOAc (or CH ₂ Cl ₂ ). The combined organic layers were washed with aq. NaCl, stirred over anhydrous Na ₂ SO ₄ and filtered through celite®. After concentrating the filtrate, the crude product was purified by silica gel chromatography to give tert-butyl-4-[(aryl)methyl]-1H-pyrazole-1carboxylic acid (49-85% yield) 1454. 4.0 N HCl in 1. 4-dioxane (5-7 eq.) was added to a stirred solution of 4-[(aryl)methyl]-1I-pyrazole (1 eq.) in CH ₂ Cl ₂ (3-6 ml/mmol) at room temperature. The reaction mixture was stirred until tert-butyl-4-[(aryl)methyl]-1H-pyrazole-1carboxylic acid was consumed and concentrated to dryness. The crude solid was sonicated in EtOAc (6-7 ml/mmol), filtered, washed with EtOAc on a funnel and briefly dried by suction. Thus, the collected half-dried solid was further dried under high vacuum and obtained as 4-[(aryl)methyl]-1Hpyrazole hydrochloride salt 1456 (80-98%) and used in the next step without further purification (purity >95%) .

Example 21.

This example provides a general method for the preparation of (S)-N-(5-methyl-7-(3-methyl-3morpholinobut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-206), as shown in Scheme 18.

Scheme 18

(S)-N-(5-Methyl-7-(3-methyl-3-morpholinobut-1-in-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-4-phenoxypicolinamide (I-206): to a solution of (S)-N-(7-bromo-5-methyl-4-okCO-2,3,4,5tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide 1800 (46.8 mg, 0.1 mmol), 4-(2methylbut-3-in-2-yl)morpholine 1802 (30.6 mg, 0. 2 mmol), CuI (1.9 mg, 0.01 mmol) and Pd(PPh ₃ ) ₄ (11.6 mg,

- 135 045696

0.01 mmol) in anhydrous DMF (1 ml), triethylamine (40.5 mg, 56 μl, 0.4 mmol) was added. The reaction solution was purged with nitrogen for 1 minute, sealed and heated at 70°C for 16 hours. The reaction solution was cooled to ambient temperature and diluted with ethyl acetate (100 ml). The solution was washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0 to 100% ethyl acetate in hexane. The desired fractions were combined and concentrated under reduced pressure. The resulting product was not sufficiently pure and was further purified by reverse phase HPLC using a gradient of 15 to 65% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined, diluted with ethyl acetate, washed with saturated sodium hydrogencarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in a mixture of acetonitrile and water (1/1) and lyophilized to give (S)-N-(5-methyl-7-(3-methyl-3-morpholinobut-1-yn-1-yl)-4 -oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide I-206 (27.9 mg, 52%) in the form of a white foam; m/z: 541.1 [M+H]+.

Example 22.

This example provides a general method for the preparation of (S)-N-(7-((4-hydroxy-1,1dioxidotetrahydro-2H-thiopyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-207), as shown in Scheme 19.

Scheme 19

4-Ethynyl-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide 1904

A solution of ethynylmagnesium bromide 1902 in THF (12 ml, 0.5 M, 6 mmol). The resulting solution was stirred at this temperature for 90 minutes, then heated to ambient temperature. The solution was cooled again to -78°C and saturated aqueous ammonium chloride (40 ml) was added. The solution was extracted with ethyl acetate (2x100 ml). The combined organic layer was washed with saturated aqueous ammonium chloride (30 mlx2), brine (30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Dichloromethane was added to the resulting solid, and the solid was partially precipitated and filtered. The solid was saved and the filtrate was further concentrated under reduced pressure. Further solids precipitated, filtered and washed with a small amount of dichloromethane. The combined solid was dried to give 4-ethynyl-4hydroxytetrahydro-2H-thiopyran 1,1-dioxide 1904 (492 mg, 56%) as a white solid.

(S)-N-(7-((4-Hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-207)

To a solution of (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4phenoxypicolinamide 1906 (46, 8 mg, 0.1 mmol), 4-ethynyl-4-hydroxytetrahydro-2H-thiopyran 1,1 dioxide 1904 (34.8 mg, 0.2 mmol), CuI (1.9 mg, 0.01 mmol) and Pd (PPh ₃ ) ₄ (11.6 mg, 0.01 mmol) in anhydrous DMF (1 ml) was added triethylamine (40.5 mg, 56 μl, 0.4 mmol). The reaction solution was purged with nitrogen for 1 minute, then sealed and heated at 70°C for 16 hours. The reaction solution was cooled to ambient temperature and diluted with ethyl acetate (100 ml). The solution was washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel using a gradient of 0 to 50% acetone in hexane. The desired fractions were combined and concentrated under reduced pressure to give (S)-N-(7-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4yl)ethynyl)-5-methyl-4-oxo-2. 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I207) (51 mg, 91%) as a white solid; m/z: 562.1 [M+H] ⁺ .

Example 23.

This example provides a general method for the preparation of (S)-N-(7-((3-hydroxy-1,1-dioxidothietane3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I209), as shown in Scheme 20.

- 136 045696

Scheme 20

-((Trimethylsilyl)ethynyl)thietan-3-ol (2004):

To a solution of ethynyltrimethylsilane 2002 (1.46 g, 2.1 mL, 14.8 mmol) in anhydrous THF (33 mL) at 78°C was added n-BuLi (6.6 mL, 2.5 M in hexane, 16. 5 mmol) dropwise over 20 minutes. The reaction solution was stirred at this temperature for 5 minutes, then heated to -20°C and cooled again to -78°C. A solution of thietan-3-one 2000 (1.02 g, 11.3 mmol) in anhydrous THF (5 ml) was added dropwise over 10 min and the reaction mixture was stirred at this temperature for 90 min, then warmed to ambient temperature . Saline solution (40 ml) was added. The solution was extracted with ethyl acetate (2x60 ml). The organic layer was combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 3((trimethylsilyl)ethynyl)thiethan-3-ol 2004 (2.02 g, 96%) as a brown solid, which was used directly for next stage without cleaning.

3-Hydroxy-3-((trimethylsilyl)ethynyl)thietane 1,1-dioxide 11 and 3-hydroxy-3-((trimethylsilyl)ethynyl)thietane 1-oxide 2008:

To a solution of 3-((trimethylsilyl)ethynyl)thietan-3-ol 2004 (1.54 g, 8.27 mmol) in anhydrous dichloromethane (80 ml) at 0°C was added m-CPBA (4.08 g, 77% , 18.19 mmol). The resulting solution was then stirred at ambient temperature for 2 hours. Water (50 ml) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2x80 ml). The combined organic layer was washed with semisaturated sodium carbonate solution (2x50 ml), saturated sodium hydrogen carbonate solution (50 ml), brine (2x50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0 to 70% ethyl acetate in hexane. The desired fractions were combined and concentrated under reduced pressure to give 3-hydroxy-3((trimethylsilyl)ethynyl)thietane 1,1-dioxide 2006 (1.57 g, 87%) as a white solid and 3hydroxy-3-((trimethylsilyl )ethynyl)thietane 1-oxide 2008 (130 mg, 11%) as a white solid.

-Ethynyl-3-hydroxythiethane-1-oxide 2010:

To a solution of 3-hydroxy-3-((trimethylsilyl)ethynyl)thietane 1-oxide 2008: (125 mg, 0.57 mmol) in anhydrous THF (6 mL) at 0°C was added TBAF (0.58 mL, 1. 0M in THF, 0.58 mmol). The resulting solution was stirred at this temperature for 10 minutes. Water (20 ml) and ethyl acetate (100 ml) were added. The organic layer was separated, washed with brine (2x15 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0 to 100% ethyl acetate in hexane. The desired fractions were combined and concentrated under reduced pressure to give 3-ethynyl-3hydroxythiethane 1-oxide 2010 (15.9 mg, 19%) as a white solid.

(S)-N-(7-((3-hydroxy-l-oxidotetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-4-phenoxypicolinamide (I-208):

To a solution of (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4phenoxypicolinamide 2012 (51 mg , 0.11 mmol), 3-ethynyl-3-hydroxythiethane 1-oxide 2010 (15.9 mg, 0.12 mmol), CuI (2.0 mg, 0.011 mmol) and Pd(PPh ₃ ) ₄ (12, 6 mg, 0.011 mmol) in anhydrous DMF (1 ml) was added triethylamine (44.1 mg, 61 μl, 0.44 mmol). The reaction solution was purged with nitrogen for 1 minute, then sealed and heated at 70°C for 16 hours. The reaction solution was cooled to ambient temperature and diluted with ethyl acetate (100 ml). The solution was washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 70% acetone in hexane to give the desired product, which was not sufficiently pure, and further purified by reverse phase HPLC using a gradient of 25 to 75% acetonitrile in 0% buffered water. .1% formic acid. The desired fractions were combined, diluted with ethyl acetate (100 ml), washed with saturated sodium hydrogen carbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in a mixture of acetonitrile and water (1/1) and lyophilized to give (S)-N-(7-((3-hydroxy-1-oxidothietane-3-yl)ethynyl)-5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide I-208 (14.5 mg, 26%) as a white foam; m/z: 518.1 [M+H]+.

(S)-N-(7-((3-hydroxy-1,1-dioxidothietane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide I-209:

To a solution of (S)-N-(7-((3-hydroxy-1-oxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-4-phenoxypicolinamide I-208 (11.3 mg, 0.022 mmol) in anhydrous dichloromethane (1 ml) at 0°C was added m-CPBA (5 mg, 77%, 0.022 mmol). The resulting solution was stirred at ambient temperature for 2.5 hours. Two drops of water were added to quench the reaction. All solvents were removed under reduced pressure. The resulting residue was purified by reverse phase HPLC using a gradient of 20 to 80% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined, diluted with ethyl acetate (100 ml), washed with saturated sodium hydrogencarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in a mixture of acetonitrile and water (1/1) and lyophilized to give (S)-N(7-((3-hydroxy-1,1-dioxidothietane-3-yl)ethynyl)-5-methyl-4 -oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide I-209 (11 mg, 95%) as a white foam; m/z: 534.0 [M+1] ⁺ .

Example 24.

This example provides a general method for the preparation of (S)-N-(5-methyl-7-(3-methyl-3-(pyrrolidin1 -yl)but-1 -in-1-yl)-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I210), as shown in Scheme 21.

Scheme 21

(S)-N-(5-Methyl-7-(3-methyl-3-(nirrolidin-1-yl)but-1-in-1-yl)-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-210): solution of (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4 ,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 2100 (46.8 mg, 0.1 mmol), pyrrolidine 2104 (107 mg, 124 µl, 1.5 mmol), potassium carbonate (34.5 mg, 0.25 mmol), CuI (1.9 mg, 0.01 mmol) and Pd(PPh ₃ ) ₄ (11.6 mg, 0.01 mmol) in anhydrous DMF (1 ml) were purged nitrogen for 1 min, and then 3-chloro-3-methylbut-1-yne 2102 (51.3 mg, 56 μL, 0.5 mmol) was added. The reaction vessel was sealed and heated at 70°C for 16 hours. The reaction solution was cooled to ambient temperature and diluted with ethyl acetate (100 ml). The solution was washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 5% methanol in dichloromethane buffered with 0.1% NH ₃ . The desired fractions were combined and concentrated under reduced pressure. The resulting product was dissolved in a mixture of acetonitrile and water (1/1) and lyophilized to obtain (S)N-(5-methyl-7-(3-methyl-3-(pyrrolidin-1-yl)but-1)-in- 1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide I-210 (28.7 mg, 55%) as white foamy solid; m/z: 525.2 [M+H] ⁺ .

Example 25.

This example provides a general method for the preparation of (S)-N-(7-(3-(1,1-dioxidothiomorpholino)-3methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-211), as shown in Scheme 22.

Scheme 22

2200 2202 2204 1-211 (S)-N-(7-(3-(1,1-dioxidothiomorpholino)-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-211): solution of (S)-N-(7-bromo-5-methyl-4-oxo2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 2200 (46.8 mg, 0.1 mmol), thiomorpholine 1,1-dioxide 2204 (135 mg, 1 mmol), potassium carbonate (34.5 mg, 0.25 mmol), CuI (1.9 mg, 0.01 mmol) and Pd(PPh ₃ ) ₄ (11.6 mg, 0.01 mmol) in anhydrous DMF (1 mL) was purged with nitrogen for 1 min and then 3-chloro-3-methylbut-1-yne 2202 (51.3 mg, 56 μL, 0.5 mmol) was added. The reaction vessel was sealed and heated at 70°C for 16 hours. The reaction solution was cooled to ambient temperature and diluted with ethyl acetate (100 ml). The solution was washed with saline (20 ml), dried over

- 138 045696 anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0 to 80% ethyl acetate in hexane to obtain the desired product. The product was not sufficiently pure and was further purified by reverse phase HPLC using a gradient of 40 to 70% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined, diluted with ethyl acetate (100 ml), washed with saturated sodium hydrogencarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in a mixture of acetonitrile and water (1/1) and lyophilized to give (S)-N(7-(3-(1,1-dioxidothiomorpholino)-3-methylbut-1-in-1-yl)- 5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide I-211 (12.5 mg, 21%) as white foam solid; m/z: 589.2 [M+H]+.

Example 26.

This example provides a method for producing 2-ethynylspiro[3.3]heptan-2-ol, shown below.

_Solid h -Bu ₄ NF.3H ₂ O immediately. After 2 hours, the clear pale brown reaction solution was quenched with saturated aqueous NH ₄ Cl (10 ml), warmed slowly to room temperature over 10 minutes, diluted with H2O (6 ml) and Et2O (20 ml). After separation of the organic layer, the aqueous layer was extracted with additional Et ₂ O (3x20 ml). After successively washing the combined organic layers with water (10 ml), aqueous NaHCO ₃ (10 ml) and brine, the organic layer was separated, stirred over anhydrous Na ₂ SO ₄ , purified by filtration, concentrated and ethynylspiro[3.3]heptan-2-ol ( 1.11 g, 99%) was obtained as a pale brown liquid. The title compound thus obtained was used in the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 2.582.46 (m, 3H), 2.43 (br s, 1H), 2.30-2.21 (m, 2H), 2.16-2, 06 (m, 2H), 2.09-1.95 (m, 2H), 1.89-1.76 (m, 2H). (To monitor the progress of the reaction, PMA, KMnO ₄ and ammonium molybdate dyes were used).

Example 27.

This example provides a method for producing 2-((trimethylsilyl)ethynyl)spiro-[3.3]heptan-2ol, shown below.

A two-neck flask containing a stirrer was heated, cooled to room temperature in a vacuum, and again filled with argon from a cylinder. Trimethylsilylacetylene (1.4 ml, 1.0 g, 10.2 mmol) followed by the addition of dry THF was transferred to the flask and cooled to -78°C. n-BuLi (1.6 M hexane solution, 7.0 mL, 11.2 mmol) was added dropwise over 15 min to the stirred solution above. After 30 min, spiro[3.3]heptanone (1.0 mL, 1.0 g, 9.09 mmol) was added to the reaction solution for 15 min, stirred for 1 h at the same temperature and at 0°C for 1 h The reaction solution was slowly quenched with ice-cold aq. NH ₄ Cl (5 ml), concentrated to remove volatiles, diluted with Et ₂ O (30 ml) and H ₂ O (10 ml). After separation of the organic layer, the aqueous layer was extracted with additional Et ₂ O (2x20 ml). The combined organic layers were washed with brine (15 ml), stirred over anhydrous Na ₂ SO ₄ , filtered and concentrated. Drying the crude concentrate under high vacuum provided 2-((trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol (1.71 g, 81%) as a white solid, which was used in the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 2.54-2.43 (m, 2H), 2.26-2.19 (m, 2H), 2.12 (s, 1H), 2.12- 2.07 (m, 2H), 2.04-1.93 (m, 2H), 1.88-1.75 (m, 2H), 0.15 (s, 9H). (PMA, KMnO4 and ammonium molybdate dyes were used to monitor the progress of the reaction).

Example 28.

This example concerns the process for preparing 6-ethynyl-2-oxaspiro[3.3]heptan-6-ol shown below.

6-Ethynyl-2-oxaspiro[3.3]heptan-6-ol was prepared similarly to the preparation of 2-ethynylspiro[3.3]heptan2-ol and was obtained as a pale brown solid and used in the next step for further purification. 1H NMR (400 MHz, chloroform-d) δ 4.74 (s, 2H), 4.66 (s, 2H), 2.76-2.67 (m, 2H), 2.50 (s, 1H) , 2.48-2.39 (m, 2H), 2.24 (s, 1H).

Example 29.

This example concerns a method for the preparation of 6-((trimethylsilyl)ethynyl)-2-oxaspiro[3.3]heptane-6

- 139 045696 ola pictured below.

Similar to the preparation of 2-((trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol, 6-((trimethylsilyl)ethynyl)-2-oxaspiro[3.3]heptan-6-ol was prepared by the reaction of lithium trimethylsilylacetylide with 2oxaspiro[3.3] heptan-6-one as a crude pale brown solid and was used in the next step without further purification. 1H NMR(400 MHz, chloroform-d) δ 4.75-4.62 (m, 4H), 2.77-2.60 (m, 2H), 2.47-2.36 (m, 2H), 2.23 (s, 1H), 0.14 (s, 9H).

Example 30.

This example proposes a method for the preparation of 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine according to a modified method of Imada, Y.; Yurasa, M.; Nakamura, I.; Murahashi, S.-i. J.Org.Chem. 1998, 63, 2342-2347.

To a stirred pale green solution of CuCl (0.10 g, 10 mmol) in dry THF under argon at room temperature, 1-methylpiperazine (1.10 g, 1.22 ml, 11 mmol), NEt ₃ (1. 11 g, 1.53 ml, 11 mmol) over 20 min. After stirring the blue heterogeneous mixture for 10 min, 2-methylbut-3-yn-2-yl acetate (1.27 g, 10 mmol) was added (Lepronier, A.; Achard, T.; Giordano, L.; Tenaglia, A. Buono, G.; Clavier, H. Adv. Synth. Catal. 2016. 358 (4), 631-642. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi, M. ; Rinaldi, S.; Sambri, L. Synlett 2003, 39-42.) in dry THF (5 ml) was added slowly over 20 min and a moderate exothermic effect was observed. The reaction mixture was stirred for 30 minutes, heated at 58°C for 7 hours and cooled. The brownish-red reaction mixture was diluted with Et ₂ O (70 ml) and aqueous NaHCO ₃ (40 ml). After separation of the organic layer, the heterogeneous red aqueous layer was extracted with Et ₂ O (3x75 ml). The combined pale green organic layers were washed with aqueous NaHCO ₃ (40 ml), then successively with aqueous NaCl, stirred over anhydrous Na ₂ SO ₄ and filtered through celite®. The filtrate was concentrated to give the title compound as a crude yellow solid (1.16 g). Further purification by chromatography on silica gel (Combiflash® Teledyne RediSep® 12G gold column. A: CH ₂ Cl ₂ B B: 20% MeOH/CH ₂ Cl ₂ at 15% B/A. Detection at λ 220 and 230 nm) gave a white solid substance with a metallic tint (0.54 g, yield 33%). 1H NMR (400 MHz, chloroform-d) δ 2.67 (br s, 4H), 2.46 (br s, 4H), 2.26 (approx. s, 4H), 1.37 (s, 6H). ¹³ C NMR (101 MHz, chloroform-d) δ 85.55, 71.50, 55.45, 53.82, 46.64, 45.88, 27.71.

Illustrative examples of embodiments of the compounds of the present invention were prepared in accordance with the disclosed synthesis schemes, and data on the characteristics of such compounds are presented below.

(S)-4-(4-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-100).

1H NMR (400 MHz, CDCl ₃ ) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=6.0 Hz, ruH-6), 7, 57 (1H, d, J=2.5 Hz, рН -5), 7.27 (2H, d, J=7.5 Hz, 2H C6H4F), 7.13-7.08 (3H, m, 2H C6H4F, 1H oxobenzoxazapine H-6, H-8, H-9), 7.06-7.02 (2H, m, 1H oxobenzoxazapine H-6, H-8, H-9), 6.92 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.02 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine N-3), 4.70 (1H, dd , J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.29 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H , s, NCH ₃ ), 1.62 (6H, s, C (CH _{3) 2} he); ¹³ s NMR (100 MHz, CDCl3) δ 168.9, 166.1, 163.5, 160.1 (d, J 244.5 Hz), 151.4, 150.2, 150.0, 149.5 (d, J=2.5 Hz), 136.2, 130.8, 126.5, 123.0, 122.4 (g, J=8.5 Hz), 120.3, 117.0 (g , J 23.5 Hz), 114.2, 110.2, 94.5, 80.7, 77.2, 65.6, 49.4, 35.4, 31.4; ¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -116.6; m/z: 490 [M+H]+ (found [M+H] ⁺ , 490.1793, C25H24FN3O5 requires [M+H] ⁺ 490.1773).

(S)-N-(7-(3,3-Dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4] Oxazepin-3yl)-4-(4-fluorophenoxy)picolinamide (I-101).

1H NMR(400 MHz, CDCl ₃ ) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7, 57 (1H, d, J=2.5 Hz, рН-5), 7.33-7.23 (3H, m, 3Н C6H4F, oxobenzoxazapine Н-6, Н-8, Н-9), 7.13 -7.04 (4H, m, 4H

- 140 045696

C6H4F, oxobenzoxazapine H-6, H-8, H-9), 6.93 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.01 (1H, dt, J= 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, dd, J =11.0, 9.5

Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH ₃ ), 1.32 (9H, s, C(CH ₃ ) ₃ ); ¹⁹ F NMR (380 MHz, CDCl3) δ 116.6; m/z: 488 [M+H]+(found [M+H] ⁺ , 488.1985, C28H ₂₆ FN ₃ O ₄ requires [M+H] ⁺ 488.1980).

(S)-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4] Oxazepin-3yl)-4-(2-fluorophenoxy)picolinamide (I-102).

1H NMR (400 MHz, CDCl ₃ ) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.46 (1H, d, J=6.0 Hz, PYH-6), 7, 57 (1H, d, J=2.5 Hz, RUN -3), 7.25-7.21 (4H, m, 4H, C6H4F, oxobenzoxazapine H-6, H-8), 7.19-7, 16 (2H, m, 2H C6H4F, oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 6.96 (1H, dd, J= 5.5, 2.5 Hz, ruH-5), 5.01 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.70 (1H, dd, J=9 ,5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH ₃ ), 1.32 (9H, s, C(CH ₃ ) ₃ ); ¹⁹ F NMR (380 MHz, CDCl3) δ -128.9; m/z: 488 [M+H] ⁺ (found [M+H] ⁺ , 488.1997, C28H ₂₆ FN ₃ O ₄ requires [M+H] ⁺ 488.1980).

(S)-4-(2-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-103).

'H NMR (400 MHz, CDCl ₃ ) δ 8.87 (1H, d, J=7.0 Hz, NH), 8.46 (1H, d, J=6.0 Hz, ruH-6), 7 .60 (1H, d, J=2.5 Hz, ruH-3), 7.28-7.16 (6H, m, oxobenzoxazapine H-6, H-8, C ₆ H ₄ F), 7.12 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 6.96 (1H, dt, J=5.5, 2.5 Hz, ruH-5), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.29 (1H, dd , J=11.0, 9.5 Hz, 1H oxobenzoxazapine H2), 3.42 (3H, s, NCH ₃ ), 1.62 (6H, s, C(CH ₃ ) ₂ OH); ¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -128.9; m/z: 490 [M+H] ⁺ (found [M+H] ⁺ , 490.1768, C27H24FN3O5 requires [M+H] ⁺ 490.1773).

(S)-4-(2,4-Difluorophenoxy)-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-104).

1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J=7.0 Hz, NH), 8.47 (1H, d, J=5.5 Hz, ruH-6), 7.54 (1H, d, J=2.5 Hz, ruH-3), 7.25-7.22 (2H, m, oxobenzoxazapine H-6, H-8), 7.15 (1H, td, J=9 ,0, 5.5 Hz, 1H C6H3F2), 7.09 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.01-6.90 (3H, ruH-5, 2H C6H3F2) , 5.00 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2 ), 4.27 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH ₃ ), 1.32 (9H, s, C( CH ₃ ) ₃ ); ¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -111.8, -123.7; m/z: 506 [M+H] ⁺ .

(S)-4-(2,4-difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-105).

'H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J=7.0 Hz, NH), 8.46 (1H, d, J=5.5 Hz, ruH-6), 7, 54 (1H, d, J=2.5 Hz, рН-3), 7.28-7.26 (2Н, m, oxobenzoxazapine Н-6, Н-8), 7.15 (1H, td, J= 9.0, 5.5 Hz, 1H C6H3F2), 7.00-6.90 (3H, m, ruH-5, 2H C6H3F2), 5.01 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.0, 9, 5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2OH); ¹³ C NMR (100 MHz, CDCl3) δ 168.9, 165.5, 163.4, 160.1 (dd, J=248.5, 10.5 Hz), 154.4 (dd, J=253, 5, 12.5 Hz), 151.5, 150.2, 150.0, 136.9 (dd, J=12.5, 4.0 Hz), 136.2, 130.8, 126.4, 124.1 (dd, 10.0, 1.5 Hz), 123.0, 120.3, 113.5, 112.1 (dd, J=23.0, 4.0 Hz), 109.4, 106.0 (dd, J=26.5, 22.0 Hz) ), 94.5, 80.7, 77.1, 65.6, 49.4, 35.4, 31.4; ¹⁹ F NMR (380 MHz, CDCl3) δ -111.7, -123.7; m/z: 508 [M+H] ⁺ , 490 [M+H-H2O] ⁺ (found [M+H] ⁺ , 508.1671, C27H23F2N3O5 requires [M+H] ⁺ 508.1679).

(S)-N-(7-(3,3-Dimethylbut-1 -yn-1 -yl)-5 -methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4] Oxazepin-3 yl)-4-(3-fluorophenoxy)picolinamide (I-106).

- 141 045696

1H NMR (400 MHz, CDC13) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.47 (1H, d, J=5.5 Hz, ruH-6), 7.62 (1H, d, J=2.5 Hz, ruH-3), 7.37 (1H, td, J=8.0, 6.5 Hz, C ₆ H ₄ F N-5), 7.26- 7.23 (2Н, m, oxobenzoxazapine Н-6, Н-8), 7.09 (1H, d, J=9.0 Hz, oxobenzoxazapine Н-9), 6.98 (1H, dd, J=5 ,5, 2.5 Hz, ruN-5), 6.96 (1H, dd, J=8.0, 2.5, 1.0 Hz, C6H4F Н-4 or Н-6), 6.86 ( 1H, dd, J=8.0, 2.5 Hz, C6H4F Н-4 or Н-6), 6.81 (1H, dt, J=9.5, 2.5 Hz, C6H4F Н-2), 5.01 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2) , 4.28 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 1.32 (9H, s, C(CH ₃ ) ₃ ); ¹³ C NMR (100 MHz, CDCl3) δ 169.0, 165.4, 163.5 (d, J=249.0 Hz), 163.4, 154.8, 151.6, 150.2, 149, 4, 136.0, 131.1 (d, J=9.5 Hz), 130.8, 126.3, 122.8, 121.7, 116.3 (d, J 3.2 Hz), 114 ,7, 112.7 (d, J=20.5 Hz), 110.8, 108.6 (d, J 24.0 Hz), 99.3, 77.6, 77.2, 49.4, 35.4, 30.9, 27.9; ¹⁹ F NMR (380 MHz, CDCl3) δ -109.5; m/z: 488 [M+H]+.

(S)-4-(3-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-107).

'H NMR (400 MHz, CDCl ₃ ) δ 8.86 (1H, d, J=7.0 Hz, NH), 8.47 (1H, d, J=5.5 Hz, ruH-6), 7 .62 (1H, d, J=2.5 Hz, ruH-3), 7.36 (1H, dt, J=8.0, 6.5 Hz, C6H4F H-5), 7.27-7, 25 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 6.98 (1H, dd, J=5.5 , 2.5 Hz, ruH-5), 6.96-6.93 (1H, m, C6H4F Н-4 or Н-6), 6.86 (1H, dd, J=8.0, 2.5 Hz, C6H4F Н-4 or Н-6), 6.80 (1H, dt, J=9.5, 2.5 Hz, C6H4F Н-2), 5.02 (1H, dt, J=11.0 , 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.29 (1H, dd, J=11, 0, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 1.62 (6H, s, C(ch ₃ ) ₂ he); ¹³ C NMR (100 MHz, CDCl3) δ 168.9, 165.4, 163.5 (d, J=249.0 Hz), 163.5, 154.9 (d, J=10.5 Hz), 151.5, 150.3, 150.0, 136.2, 131.2 (d, J=9.5 Hz), 130.8, 126.5, 123.0, 120.3, 116.3 ( d, J=3.5 Hz), 114.7, 112.7 (d, J=20.5 Hz), 110.8, 108.6 (d, J=24.5 Hz), 94.5, 80.6, 77.2, 65.5, 49.4, 35.4, 31.4; ¹⁹ F NMR (380 MHz, CDCI3) δ -109.5; m/z: 490 [M+H] ⁺ , 472 [M+H-H2O] ⁺ (found [M+H] ⁺ , 490.1766, C27H24FN3O5 requires [M+H] ⁺ 490.1773).

(S)-N-(7-Isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-108 ).

'H NMR (400 MHz, CDCl ₃ ) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7 .61 (1H, d, J=2.5 Hz, ruH-3), 7.43-7.39 (2H, m, 2H C ₆ H ₅ ), 7.27-7.23 (1H, m, 1H C ₆ H ₅ ), 7.09-7.03 (4H, m, 2H C ₆ H ₅ , oxobenzoxazapine H-8 or H-9), 7.01 (1H, br. s, oxobenzoxazapine H-6) , 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.05 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine N-3), 4.69 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H2), 4.25 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH ₃ ), 2.63-2.59 (2H, MSn ₂ CH ₂ CH (CH ₃ ) ₂ ), 1.61 (1H, heptet, J=6.5 Hz, CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 1.52-1.47 (2H, m, CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 0.95 (6H, d, J=6.5 Hz, CH ₂ CH ₂ CH(CH3) ₂ ); m/z: 460 [M+H] ⁺ .

(S)-N-(7-((3-Hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-4-phenoxypicolinamide (I-110).

IR (film) v 3357, 2941,2875, 1662, 1582, 1501, 1488, 1469, 1388, 1360, 1291, 1214, 1192, 1020, 979, 838, 730 cm ^-1 ; 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.44-7.40 (2H, m, 2H C6H5), 7.32-7.29 (2H, m, 2H C6H5 or oxobenzoxazapine H -6, H-8), 7.27-7.23 (1H, m, 1H C6H5 or oxobenzoxazapine H- 6, H-8), 7.15 (1H, d, J=9.0 Hz, oxobenzoxazapine H -9), 7.08-7.06 (2H, m, 2H C6H5 or oxobenzoxazapine H-6, H-8), 6.50 (1H, dd, J=5.5, 2.5 Hz, run- 5), 5.04 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.93 (2H, dd, J=4.0, 0.5 Hz, oxetane H- 2, Н-4), 4.79 (2Н, dt, J=6.5, 1.0 Hz, oxetane Н-2, Н-4), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.32 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH3); ¹³ C NMR (100 MHz, CDCl3) δ 168.9, 166.1, 163.7, 153.7, 151.2, 150.5, 150.1, 136.4, 130.9, 130.3, 126.5, 125.7, 123.3, 120.7, 119.3, 114.5, 110.7, 88.6, 84.8, 84.5, 77.2, 67.4, 49, 3, 35.4; m/z: 486 [M+H] ⁺ (found [M+H] ⁺ , 486.1651, C27H23N3O6 requires [M+H] ⁺ 486.1660).

(S)-4-(4-Fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)picolinamide (I-111).

- 142 045696

1H NMR (400 MHz, CDC13) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7.57 (1H, J=2.5 Hz, рН-3), 7.32-7.30 (2Н, m, 2Н C6H4F, oxobenzoxazapine Н-6, Н-8, Н-9), 7.15 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.13-7.09 (2H, m, 2H C6H4F, oxobenzoxazapine H-6, H-8, H-9), 7.06-7, 02 (2H, m, 2H C6H4F, oxobenzoxazapine H-6, H-8), 6.93 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt , J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, ddd, J=6.5, 3.0, 0.5 Hz, 2H oxetane H-2, H-4 ), 4.79 (2H, dt, J=6.5, 1.0 Hz, 2H oxetane H-2, H-4), 4.71 (1H, dd, J=9.5, 7.5 Hz , 1H oxobenzoxazapine H-2), 4.31 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH ₃ ); ¹⁹ F NMR (380 MHz, CDC13) δ -116.5; m/z: 504 [M+H] ⁺ (found [M+H] ⁺ , 504.1568, C ₂ 7H ₂₂ FN ₃ O ₆ requires [M+H] ⁺ 504.1565).

(S)-4-(2-Fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)picolinamide (I-112).

1H NMR (400 MHz, CDCI3) δ 8.87 (1H, d, J=7.0 Hz, NH), 8.46 (1H, d, J=5.5 Hz, ruH-6), 7.58 (1H, d, J=2.5 Hz, ruH-3), 7.32-7.29 (2H, m, 2H C6H4F, oxobenzoxazapine H-6, H-8), 7.26-7.16 ( 4H, m, 4H C6H4F, oxobenzoxazapine H-6, H-8), 7.15 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 6.95 (1H, dd, J=5, 5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.92 (2H, ddd, J=6.5 , 3.0, 1.0 Hz, 2H oxetane H-2, H-4), 4.79 (2H, ddd, J=6.5, 1.5, 1.0 Hz, 2H oxetane H-2, H-4), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.31 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH ₃ ); ¹⁹ F NMR (380 MHz, CDCI3) δ -128.9; m/z: 504 [M+H]+ (found [M+H] ⁺ , 504.1564, C27H22FN3O6 requires [M+H]+ 504.1565).

(R)-N-(7-(3-Hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[B][1, 4]oxazepin-3-yl)-4-phenoxypicolinamide (I-113).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.86 (1H, d, J=7.0 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7, 61 (1H, d, J=2.0 Hz, ruH-3), 7.41 (2H, t, J=8.0 Hz, 2H C ₆ H ₅ ), 7.27-7.23 (3H, m, 1H C ₆ H ₅ , oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.06 (2H, d, J=7 .5 Hz, 2H C6H5), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.02 (1H, dt, J=11.0, 7.0 Hz , oxobenzoxazapine H-3), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.29 (1H, t, J=10.5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH ₃ ), 1.62 (6H, s, C(CH3)2OH); m/z: 472 [M+H]+ (found [M+H] ⁺ , 472.1860, C27H25N3O5 requires [M+H] ⁺ 472.1867).

(S)-4-(2,4-Difluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)picolinamide (I-114).

1H NMR (400 MHz, CDCI3) δ 8.87 (1H, d, J=7.5 Hz, NH), 8.47 (1H, d, J=6.0 Hz, ruH-6), 7.55 (1H, d, J=2.5 Hz, ruH-3), 7.33-7.30 (2H, m, oxobenzoxazapine H-6, H-8), 7.19-7.13 (1H, m , 1H C6H3F2), 7.16 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.01-6.91 (2H, m, 2H C6H3F2), 6.95 (1H, dd, J=6.0, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine N-3), 4.93 (2H, m, 2H oxetane H-2, H-4), 4.80 (2H, d, J=6.5 Hz, 2H oxetane H-2, H-4), 4.72 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.31 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH3); ¹⁹ F NMR (380 MHz, CDCI3) δ -111.7, -123.7; m/z: 522 [M+H] ⁺ (found [M+H] ⁺ , 522.1484, C27H21F2N3O6 requires [M+H] ⁺ 522.1471).

(S)-4-(3-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)picolinamide (I-115).

1H NMR(400 MHz, CDCI3) δ 8.87 (1H, d, J=7.5 Hz, NH), 8.48 (1H, d, J=5.5 Hz, ruH-6), 7.63 (1H, d, J=2.5 Hz, ruH-3), 7.37 (1H, td, J=8.0, 6.5 Hz, C6H4F H-5), 7.32-7.30 ( 2H, m, oxobenzoxazapine N-6, N-8),

- 143 045696

7.15 (1H, d, J=9.0 Hz, oxobenzoxazapine N-9), 6.98 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 6.96 (1H , dd, J=8.5, 2.5, 1.0 Hz, 1H C6H4F), 6.86 (1H, dd, J=8.0, 2.5 Hz, 1H C6H4F), 6.81 (1H , dt, J=9.5, 2.5 Hz, 1H C6H4F), 5.04 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.93 (2H, ddd , J=6.5, 2.5, 0.5 Hz, 2H oxetane H-2, H-4), 4.79 (2H, d, J=6.5 Hz, 2H oxetane H-2, H- 4), 4.72 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.32 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH3); ¹⁹ F NMR (380 MHz, CDO3) δ -109.5; _m /z: 504 [M+H]+ (found _[ M+H] ⁺ , 504.1574, _{C27H22FN3O6 requires} [M+H]+ 504.1565).

(S)-N-(5-Methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-116).

1H NMR (400 MHz, CDCl ₃ ) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7, 60 (1H, d, J=2.0 Hz, ruH-3), 7.43-7.39 (2H, m, 2H C6H5), 7.29-7.23 (3H, m, 1H C6H5, oxobenzoxazapine Н-6, Н-8), 7.11 (1H, d, J=9.0 Hz, oxobenzoxazapine Н-9), 7.08-7.06 (2Н, m, 2Н С _{6 Н5} ), 6 .94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine N-3), 4, 70 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.29 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.62 (2H, s, CCH ₂ N), 3.42 (3H, s, NCH3), 2.72-2.68 (4H, m, pyrrolidine 4H), 1.86-1.83 (4H, m, 4H pyrrolidine); m/z: 497 [M+H]+ ( _{found [} M+H] ⁺ , 497.2209, _{C29H28N4O4 requires} [M+H]+ 497.2183).

(S)-N-(5-Methyl-7-(3-morpholinoprop-1-in-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin- 3yl)-4-phenoxypicolinamide (I-117).

1H NMR(400 MHz, CDCl ₃ ) δ 8.85 (1H, d, J=7.0 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7, 60 (1H, d, J=2.5 Hz, ruH-3), 7.43-7.39 (2H, m, 2H C6H5), 7.30-7.23 (3H, m, 1H C6H5, oxobenzoxazapine Н-6, Н-8), 7.12 (1H, d, J=9.0, Hz, oxobenzoxazapine Н-9), 7.08-7.05 (2Н, m, 2Н С6Н5), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine N-3), 4.70 ( 1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.29 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 3, 78, 3.77 (4H, 2d system AB, J=4.5 Hz, 4H morpholine), 3.50 (2H, s, NCH2C), 3.42 (3H, s, NCH3), 2.65, 2 .63 (4H, 2d AB system, J=4.5 Hz, 4H morpholine); m/z: 513 [M+H]+ ( _{found [} M+H] ⁺ , 513.2183, _{C29H28N4O5 requires} [M+H]+ 513.2132).

(S)-4-(2,6-Difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-118).

1H NMR (400 MHz, CDCl ₃ ) δ 8.07 (1H, d, J=7.0 Hz, NH), 8.48 (1H, d, J=5.5 Hz, ruH-6), 7, 57 (1H, d, J=2.5 Hz, ruH-3), 7.27-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.24-7.18 (1H, m, 1H C6H3F2), 7.11 (1H, d, J Hz, oxobenzoxazapine H-9), 7.03 (2H, dd, J=8.5, 8.0 Hz, 2H C6H3F2), 7.00 ( 1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.01 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H , dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H2), 4.28 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H , s, NCH ₃ ), 1.61 (6H, s, C(CH ₃ ) ₂ OH); ¹⁹ F NMR (380 MHz, CDCl3) δ -126.0; m/z: 508 [M+H] ⁺ , 490 [M+H-H2O]+ (found [M+H]+, 508.1670, C ₂₇ H ₂₃ F ₂ N ₃ O ₅ requires [M+H] +508.1679).

(S)-N-(7-(3-Hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-6-methyl-4-phenoxypicolinamide (I-119).

1H NMR (400 MHz, CDCl3) δ 8.89 (1H, d, J=7.5 Hz, NH), 7.44 (1H, d, J=2.0 Hz, ruH-3), 7.42 -7.38 (2H, m, 2H C6H5), 7.28-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 725-7.22 (1H, m, 1H C6H5), 7 .12 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.06-7.04 (2H, m, 2H C ₆ H ₅ ), 6.75 (1H, d, J=2 ,0 Hz, ruH-5), 5.03 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine N-3), 4.71 (1H, dd, J=9.5, 7, 5 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 2.52 (3H, s, NCH3), 1.62 (6H, s, s(CH ₃ ) ₂ he); m/z: 486 [M+H]+ (found [M+H] ⁺ , 486.2022, C28H27N3O5 requires [M+H]+ 486.2023).

(S)-N-(7-((1-Hydroxycyclobutyl)ethunyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 4-phenoxypicolinamide (I-120).

- 144 045696

1H NMR (400 MHz, CDCI3) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.43-7.39 (2H, m, 2H SL/), 7.31-7.23 (3H, m, 1H C6H5, oxobenzoxazapine Н-6, Н-8), 7.13 (1H, d, J=9.0 Hz, oxobenzoxazapine Н-9), 7.08-7.06 (2Н, m, 2Н С6Н5), 6.94 ( 1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.0, 7.5 Hz), oxobenzoxazapine H-3), 4.71 ( 1H, dd, J=9.5, 7.0 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3, 43 (3H, s, NCH ₃ ), 2.57-2.51 (2H, m, 2H cBu), 2.39-2.31 (2H, m, 2H cBu), 1.93-1.86 ( 2H, m, 2H cBu); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1 (2C), 136.2, 130.9, 130.3, 126.5, 125.7, 123.1, 120.7, 120.3, 114.4, 110.6, 93.2, 82.0, 77.2, 68.3, 49.4, 38, 5, 35.4, 13.0; m/z: 484 [M+H]+ (found _{[M+H]+, 484.1873, C28H25N3O5 requires [ M} +H]+ 484.1867).

(S)-N-(7-(3-Hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-5-phenoxypicolinamide (I-121).

'11 NMR (400 MHz, CDCl ₃ ) δ 8.71 (1H, d, J=7.0 Hz, NH), 8.34 (1H, d, J=2.5 Hz, ruH-6), 8 .03 (1H, d, J=8.5 Hz, ruH-3), 7.42-7.38 (2H, m, 2H C ₆ H ₅ ), 7.30-7.26 (3H, m, runH-4, oxobenzoxazapine N-6, N-8), 7.247.20 (1H, m, 1H C6H5), 7.12 (1H, d, J=9.0 Hz, oxobenzoxazapine N-9), 7.07 -7.04 (2H, m, 2H C6H5), 5.05 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.72 (1H, dd, J=9, 5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH ₃ ), 1.62 (6H, s, C(CH ₃ ) ₂ )OH); m/z: 490 [M+H]+, 472 [M+H-H2O]+ (found [M+H]+, 490.1854, C27H25N3O5 requires [M+H]+ 490.1867).

(S)-5-(4-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-122).

Ή NMR (400 MHz, CDCl ₃ ) δ 8.69 (1H, d, J=7.5 Hz, NH), 8.31 (1H, d, J=2.5 Hz, ruH-6), 8, 03 (1H, d,

J=8.5 Hz, ruH-3), 7.28-7.24 (3H, m, 3 x ArH), 7.13-7.01 (5H, m, 5 x ArH), 5.05 ( 1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.72 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.29 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 1.62 (6H, s, C(CH ₃ ) ₂ )OH ); ¹⁹ f NMR (380 MHz, CDCl3) δ 117.4 (tt, J=8.0, 4.0 Hz); m/z: 528 [M+H]+, 510 [M+H-H2O]+ (found [M+H]+, 490.1772, C27H24FN3O5 requires [M+H]+ 490.1773).

(S-N-(7-((4-Hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine- 3-yl)-4-phenoxypicolinamide (I-123).

1H NMR (400 MHz, CDCl ₃ ) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7, 61 (1H, d, J=2.5 Hz, ruH-3), 7.43-7.39 (2H, m, 2H C6H5), 7.31-7.23 (3H, m, 1H C6H5, Bz oxazapine N-6, N-8), 7.13 (1H, d, J=9.0 Hz, Bz oxazapine N-9), 7.08-7.05 (2H, m, 2H C ₆ H ₅ ) , 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.70 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.31 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazapine H-2 ), 3.95 (2H, dt, J=12.5, 4.5 Hz, 2H pyran H-2, H-6), 3.71 (2H, ddd, J=12.0, 9.0, 3.0 Hz, 2H pyran H-2, H-6), 3.43 (3H, s, NCH ₃ ), 2.08-2.00 (2H, m, 2H pyran H-3, H-5) , 1.89 (2H, dd, J=13.0, 9.0, 4.0 Hz, 2H pyran H-3, H-5); m/z: 514 [M+H]+ (found [M+H]+, 514.1973, C29H27N3O6 requires [M+H]+ 514.1973).

(S)-N-(8-((3-Hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin3-yl) -4-phenoxypicolinamide

1H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J=7.5 Hz, NH), 8.42 (1H, d, J=5.5 Hz, ruH-6), 7.60 (1H, d, J=2.0 Hz, run-3), 7.42-7.38 (2H, m, 2H C ₆ H ₅ ), 7.29-7.20 (4H, m, 1H C ₆ H ₅ , Bz azapine H-6, H-8, H-9), 7.077.05 (2H, m, 2H C ₆ H ₅ ), 6.92 (1H, dd, J = 5.5, 2, 5 Hz, ruN-5), 4.93 (2H, d, J=7.0 Hz, 2H oxetane N-2, N-4), 4.79

- 145 045696 (2H, dd, J=7.0, 1.0 Hz, 2H oxetane N-2, N-4), 4.60 (1H, td, J=11.0, 7.5 Hz, Bz azapine N-3), 3.42 (3H, s,

NCH ₃ ), 2.95-2.86 (1H, m, 1H Bz azapine H-5), 2.75-2.63 (2H, m, 1H Bz azapine H-5, 1H Bz azapine H-4) ,

2.12-2.04 (1H, m, 1H Bz azapine H-4); m/z: 484 [M+H] ⁺ (found [M+H] ⁺ , 484.1867, C ₂₈ H ₂₅ N ₃ O ₅ requires

[M+H] ⁺ 484.1867).

(S)-4-(2,6-Dimethylphenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-124).

'H NMR (400 MHz, CDC13) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.38 (1H, d, J=6.0 Hz, ruH-6), 7, 48 (1H, d, J=2.5 Hz, run-3), 7.27-7.24 (3H, m, oxobenzoxazapine H-6, H-8, C ₆ H ₃ (CH ₃ ) ₂ H- 4), 7.11 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.08 (2H, s, C6H ₃ (CH ₃ )2H-2, H-6), 6.74 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.01 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine N-3), 4.69 ( 1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 3, 41 (3H, s, NCH3), 2.05 (6H, s, 2 x ArCH ₃ ), 1.61 (6H, s, C(CH ₃ ) ₂ OH); ¹³ C NMR (100 MHz, CDCI3) δ 169.0, 165.3, 163.8, 151.4, 150.2, 150.0, 149.6, 136.2, 130.8, 130.7, '29.3, '26.4, '26.1, '23.0, '20.3, 112.5, 109.3, 94.4, 80.7, 77.2, 65.6, 49 ,3, 35,4,31,4, 16,1; m/z: 500 [M+H] ⁺ .

(S)-4-(4-Fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-125).

1H NMR(400 MHz, CDCl ₃ ) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.47 (1H, d, J=5.0 Hz, ruH-6), 7, 90 (1H, d, J 1.0 Hz, ruH-3), 7.28-7.24 (2H, m, oxobenzoxazapine H-6, H-8), 7.17 (1H, dd, J=5 ,0, 2.0 Hz, ruH-5), 7.11 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.11-7.07 (2H, m, 2H C6H4F), 6.97 (2H, tt, J=9.0, 2.0 Hz, 2H C6H4F), 5.03 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4, 70 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.97 (2H, s, (TSLZ;, 3.41 (3H, s, NCH3), 1.61 (6H, s, C(CH ₃ ) ₂ OH); ¹⁹ f NMR (380 MHz, CDCI3) δ -116.0 (tg, J=8.0, 5.5 Hz); m/z: 488 [M+H] ⁺ (found [M+H] ⁺ , 488.1986, C25H26FN3O4 requires [M+H] ^+488.1980 ).

(S)-4-(4-Fluorobenzyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4]oxazepin-3-yl)picolinamide (I-126).

'H NMR (400 MHz, CDCl ₃ ) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.47 (1H, dd, J=5.0, 1.5 Hz, run- 6), 7.90 (1H, br.d, J 1.0 Hz, ruH-3), 7.31-7.29 (2H, m, oxobenzoxazapine H-6, H-8), 7.18 ( 1H, dd, J=5.0, 2.0 Hz, ruH-5), 7.14 (1H, d, J=9.0 Hz, oxobenzoxazapine N-9), 7.11-7.07 (2H , m, 2H C6H4F), 6.96 (2H, t, J=9.0 Hz, 2H C6H4F), 5.04 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3) , 4.91 (2H, dd, J6.5, 4.5 Hz, 2H oxetane H-2, H-4), 4.78 (2H, dd, J=6.5, 2.0, 1.0 Hz, 2H oxteane H-2, H-4), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J=11 .5, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.97 (2H, s, CH2SbH ₄ G), 3.40 (3H, s, NCH3), 3.09 (1H, br. s, OH ); ¹⁹ F NMR (380 MHz, CDCI3) δ -116.0; m/z: 502 [M+H] ⁺ (found [M+H] ⁺ , 502.1787, C ₂₉ H ₂₄ FN ₃ O ₅ requires [M+H] ⁺ 502.1773).

(S)-N-(5-Methyl-7-((3-methyloxetan-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin3-yl )-4-phenoxypicolinamide (I-127).

1H NMR(400 MHz, CDCI3) δ 8.84 (1H, d, J=7.5 Hz, NH), 8.42 (1H, d, J=5.5 Hz, ruH-6), 7.59 (1H, d, J=2.5 Hz, ruH-3), 7.42-7.38 (2H, m, 2H C6H5), 7.26-7.21 (3H, m, 1H C6H5, oxobenzoxazapine H -6, H-8), 7.10 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.06-7.04 (2H, m, 2H C ₆ H ₅ ), 6, 93 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.01 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.90 (2H, d, J=5.5 Hz, 2H oxetane H-2, H-4), 4.69 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4 .46 (2H, d, J=5.5 Hz, 2H oxetane H-2, H-4), 4.28 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine), 3, 41 (3H, s, NCH3), 1.70 (3H, s, CCH3); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1, 149.9, 136.2, 130.7, 130.3 , 126.3, 125.7, 123.0, 120.7, 120.6, 114.4, 110.6, 92.7, 82.9, 82.0, 77.2, 49.3, 35 ,4, 33.7, 25.4; m/z: 484 [M+H]+ (found [M+H] ⁺ , 484.1855, C28H25N3O5 requires [M+H] ⁺ 484.1817).

(S)-N-(7-((3-Methoxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5- 146 045696 tetrahydrobenzo [b][1,4] oxazepine -3-yl)-4-phenoxypicolinamide (I-128).

1H NMR (400 MHz, CDCl ₃ ) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7, 61 (1H, d, J=2.5 Hz, ruH-3), 7.42 (2H, dd, J=8.0, 7.5 Hz, 2H C6H5), 7.35-7.32 (2H , m, 2H С6Н5, oxobenzoxazapine Н-6 or Н-8), 7.27-7.23 (1H, m, 1H С6Н5, oxobenzoxazapine Н-6 or Н-8), 7.16 (1H, d, J =9.0 Hz, oxobenzoxazapine H-9), 7.07 (2H, dd, J=8.5, 1.0 Hz), 2H C ₆ H ₅ ), 6.95 (1H, dd, J=5 ,5, 2.5 Hz, ruH-5), 5.04 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.85 (2H, dt, J=6, 5 Hz, 2H oxetane H-2, H-4), 4.76 (2H, d, J=7.0 Hz, 2H oxetane H-2, H-4), 4.72 (1H, dd, J= 9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.32 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.44 (3H, s, NCH ₃ or OCH ₃ ), 3.42 (3H, s, NCH ₃ or OCH ₃ ); m/z: 500 [M+H] ⁺ .

(S)-N-(7-((3-Fluoroxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl )-4-phenoxypicolinamide (I-129).

1H NMR(400 MHz, CDCl ₃ ) δ 8.56 (1H, d, J=7.0 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7, 61 (1H, d, J=2.5 Hz, run-3), 7.44-7.40 (2H, m, 2H C6H5), 7.36-7.34 (2H, m, oxobenzoxazapine H-6 , Н-8), 7.27-7.23 (1H, m, 1H С6Н5), 7.17 (1H, d, J=9.0 Hz, oxobenzoxazapine Н-9), 7.08-7.06 (2H, m, 2H C6H5), 6.95 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.04 (1H, dt, J=11.5, 7.5 Hz, oxbenzoxazapine H-3), 4.98 (2H, s, 2H oxetane H-2, H-4), 4.93 (2H, s, 2H oxetane H-2, H-4), 4.72 ( 1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.32 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3, 44 (3H, s, NCH ₃ ); ¹⁹ F NMR (380 MHz, CDCl3) δ -140.8 (quintet, J=20.5 Hz); m/z: 488 [M+H] ⁺ (found [M+H] ⁺ , 488.1627, C27H ₂₂ FN ₃ O ₅ requires [M+H] ⁺ 488.1616).

(S)-3-((5-Methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7yl)ethynyl)oxetane-3 -yl (3-morpholinopropyl)carbamate (I-130).

1H NMR (400 MHz, CDCI3) δ 8.85 (1H, d, J=7.0 Hz, Η H CH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7 .60 (1H, d, J=2.5 Hz, ruH-3), 7.43-7.39 (2H, m, 2H C ₆ H ₅ ), 7.34-7.32 (2H, m, oxobenzoxazapine H-6, H-8), 7.27-7.23 (1H, m, 1H C ₆ H ₅ ), 7.13 (1H, d, J=8.5 Hz, oxobenzoxazapine H-9), 7.08-7.05 (2H, m, 2H C ₆ H ₅ ), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 6.23 (1H, t , J=5.5 Hz, CONHCH2), 5.01 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.97 (2H, d, J=7.5 Hz , 2H oxetane H-2, H-4), 4.89 (2H, d, J=7.5 Hz, 2H oxetane H-2, H-4), 4.71 (1H, dd, J=9, 5, 7.0 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.72, 3.71 (4H, 2d system AB, J=4.5 Hz, 4H morpholine), 3.43 (3H, s, NCH ₃ ), 3.31 (2H, k, J=6.0 Hz, CONHCH2CH2CH2N), 2.48-2 .44 (6H, m, 4H morpholine, CONHCH2CH2CH2N), 1.70 (2H, quintet, J=6.0 Hz, CONHCH2CH2CH2N); m/z: 678 [M+Na] ⁺ , 656 [M+H] ⁺ , 329 [M+H] ²⁺ (found [M+H] ⁺ , 656.2740, C ₃₅ H ₃₇ N ₅ O ₈ requires [M+H] ⁺ 656.2465).

(S)-N-(7-((4-hydroxy-1-(4-phenoxypicolinoyl)piperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [b][ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-131).

1H NMR (400 MHz, CDCl ₃ ) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, 1 x ruH-6), 8.42 (1H, d, J=5.5 Hz, 1 x ruN-6), 7.61 (1H, d, J=2.5 Hz, 1 x ruN-3), 7.45-7, 39 (4H, m, 2 x 2H C6H ₅ ), 7.28-23 (4H, m, 2 x 1H C ₆ H ₅ , oxobenzoxazapine H-6, H-8), 7.14-7.05 (6H , m, 2 x 2H C ₆ H ₅ , 1 x ruH-5, oxobenzoxazapine N-9), 6.94 (1H, dd, J=5.5, 2.5 Hz, 1 x ruH-5), 6 .88 (1H, dd, J=5.5, 2.5 Hz, 1 x ruH-5), 5.03 (1H, dt, J Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J Hz, 1H oxobenzoxazapine H2), 4.14-4.10 (1H m, 1H piperidine H-2, H-6), 3, 83 -3.76 (1H, m, 1H piperidine H-2, H-6), 3.75-3.66 (1H, m, 1H piperidine H-2, H-6), 3.60-3, 53 (1H, m, 1H piperidine H-2), H-6), 3.43 (3H, s, NCH ₃ ), 2.48-2.43 (1H, m, 1H piperidine H-3, H- 5), 2.16-2.03 (1H, m, 1H piperidine H-3, H-5), 1.98-1.85 (2H, m, 2H piperidine, H-3, H-5); m/z: 710 [M+H]+, 692 [M+HH ₂ O] ⁺ (found [M+H] ⁺ , 710.2552, C ₄₁ H ₃₅ N ₅ O ₇ requires

- 147 045696

[M+H] ⁺ 710.2609).

(S)-N-(7-((4-hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-4-phenoxypicolinamide (I-132).

1H NMR (400 MHz, CDC13) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=6.0 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.43-7.39 (2H, m, 2H C6H5), 7.30-7.23 (3H, m, oxobenzoxazapine H-6, Н-8, 1H С6Н5), 7.13 (1H, d, J=9.0 Hz, oxobenzoxazapine Н-9), 7.08-7.06 (2Н, m, 2Н С6Н5), 6.94 (1H , dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine N-3), 4.70 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H2), 4.30 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 3.19-3.13 (2H, m, 2H piperidine H-2, H-6), 3.04-2.95 (2H, m, 2H piperidine H-2, H-6) , 2.14-2.04 (2H, m, 2H piperidine H-3, H5), 1.88-1.82 (2H, m, 2H piperidine H-3, H-5); m/z: 513 [M+H]+, 495 [M+HH ₂ O]+ (found [M+H]+, 513.xxxx, C ₂₉ H ₂₈ N ₄ O ₅ requires [M+H]+ 513 .xxxx).

(S)-4-(4-Fluorophenoxy)-N-(7-((4-hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)picolinamide (I-133).

'H NMR (400 MHz, CDCI3) δ 8.84 (1H, d, J=7.5 Hz, NH), 8.42 (1H, d, J=5.5 Hz, ruH-6), 7, 55 (1H, d, J=2.5 Hz, ruH-3), 7.28-7.25 (2H, m, 2H oxobenzoxazapine H-6, N-8), 7.11-7.07 (3H , m, oxobenzoxazapine H-9, 2H C6H4F), 7.04-7.01 (2H, m, 2H C6H4F), 6.91 (1H, dd, J=5.5, 2.5 Hz, ruH-5 ), 5.01 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.68 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H- 2), 4.28 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.40 (3H, s, NCH3), 3.11-3.06 (2H, m, 2H piperidine H-2, H-6), 2.942.87 (2H, m, 2H piperidine H-2, H-6), 2.04-1.97 (2H, m, 2H piperidine H-3, H-5), 1.79-1.72 (2H, m, 2H piperidine, H-3, H-5); ¹³ C NMR (100 MHz, CDCl3) δ 168.9, 166.1, 163.6, 160.1 (d, J 245.0 Hz), 151.4, 150.2, 150.1, 149.5 (d, J=2.5 Hz), 136.3, 130.9, 126.5, 123.1, 122.3 (d, J=8.5 Hz), 120.2, 117.0 (d , J 23.5 Hz), 114.2, 110.3, 93.0, 83.3, 77.1, 67.0, 49.3, 43.5, 40.4, 35.4; ¹⁹ F NMR (380 MHz, CDCl3) δ -116.5; m/z: 531 [M+H] ⁺ (found [M+H] ⁺ , 531.2031, C ₂₉ H ₂₇ FN ₄ O ₅ requires [M+H] ⁺ 531.2038).

(S)-N-(7-(('-Acetyl-4-hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-4-(4-fluorophenoxy)picolinamide (I-134).

'H NMR (400 MHz, CDCls) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, pyridine H-6), 7 .57 (1H, d, J=2.5 Hz, pyridine H-3), 7.29-7.28 (2H, m, 2H oxobenzoxazapine H-6, H-8), 7.14 (1H, d , J=9.0 Hz, oxobenzoxazapine H-9), 7.11-7.08 (2H, m, 2H C6H4F), 7.07-7.02 (2H, m, 2H C6H4F), 6.92 ( 1H, dd, J=5.5, 2.5 Hz, pyridine H-5), 5.03 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.70 ( 1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.31 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4, 05-3.98 (1H, m, 1H piperidine H-2, H-6), 3.74-3.68 (1H, m, 1H piperidine H-2, H-6), 3.54-3, 44 (2H, m, 2H piperidine H-2, H-6), 3.43 (3H, s, NCH3), 2.12 (3H, s, COCH3), 2.09-1.98 (2H, m , 2H piperidine H-3, H-5), 1.89-1.78 (2H, m, 2H piperidine H-3, H-5); ¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -116.5; m/z: 573 [M+H]+ (found [M+H]+, 573.2153, C31H2oFN4O ₆ requires [M+H]+ 573.2144).

(S)-4-(4-Fluorophenoxy)-N-(7-((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-3-yl)picolinamide (I-135).

'H NMR (400 MHz, CDCI3) δ 8.84 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7, 56 (1H, d, J=2.5 Hz, ruH-3), 7.30-7.28 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J= 9.0 Hz, oxobenzoxazapine H-9), 7.12-7.08 (2H, m, 2H C6H4F), 7.05-7.02 (2H, m, 2H C6H4F), 6.92 (1H, dd , J=5.5, 2.5 Hz, ruN-5), 5.02 (1H,

- 148 045696 dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4, 29 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, CONCH3), 2.74-2.66 (2H, m, 2H piperidine H -2, H-6), 2.46-2.39 (2H, m, 2H piperidine H-2, H-6), 2.32 (3H, s, NCH3), 2.09-2.02 ( 2H, m, 2H piperidine H-3, H-5), 1.94 (2H, ddd, J 13.0, 9.0, 3.5 Hz, 2H piperidine H-3, H-5); ¹⁹ F NMR (380 MHz, CDCU) δ

-116.6; m/z: 545 [M+H]+ (found [M+H] ⁺ , 545.2199, C ₃₀ H ₂₉ FN ₄ O ₅ requires [M+H] ⁺ 545.2195).

(S)-N-(7-((3-Hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-4-phenoxypicolinamide (I-136).

1H NMR(400 MHz, CDCl3) δ 8.86 (1H, d, J=7.0 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.43-7.39 (2H, m, 2H C ₆ H ₅ ), 7.31-7.29 (2H, m, oxobenzoxazapine H -6, H-8), 7.27-7.22 (1H, m, 1H C ₆ H ₅ ), 7.13 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 7, 08-7.05 (2H, m, 2H C ₆ H ₅ ), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J =11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.05 (2H, d, J=9.0 Hz, 2H azetidine-2, H-4), 3.83 (2H, d , J=9.5 Hz, 2H osetidine H-2, H-4), 3.42 (3H, s, NCH3); m/z: 485 [M+H] ⁺ (found [M+H] ⁺ , 485.xxxx, C ₂₇ H ₂₄ N ₄ O ₅ requires [M+H] ⁺ 485.xxxx).

(S)-N-(7-((3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4 ] oxazepin-3 -yl)-4-phenoxypicolinamide (I-137).

1H NMR (400 MHz, CDCl ₃ ) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7, 61 (1H, d, J=2.5 Hz, ruH-3), 7.43-7.39 (2H, m, 2H C6H ₅ ), 7.32-7.29 (2H, m, oxobenzoxazapine H- 6, H-8), 7.27-7.23 (1H, m, 1H C6H ₅ ), 7.13 (1H, d, J=8.5 Hz, oxobenzoxazapine H-9), 7.08-7 .06 (2H, m, 2H C6H ₅ ), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J Hz, 11, 5, 10.0 N oxobenzoxazapine H-2), 3.70 (2H, w.d, J=9.5 Hz, 2H azetidine H-2, H-4), 3.44 (2H, d, J= 9.0 Hz, 2H azetidine H-2, H-4), 3.41 (3H, s, CONCH3), 2.43 (3H, s, NCH3); m/z: 499 [M+H] ⁺ (found [M+H] ⁺ , 499.xxxx, C28H26N4O5 requires [M+H] ⁺ 499.xxxx).

(S)-4-(4-Fluorophenoxy)-N-(5-methyl-7-(5-(methylamino)-3-methylenepent-1-yn-1-yl)-4-oxo-2,3,4 ,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-138).

1H NMR(400 MHz, CDCl ₃ ) δ 8.85 (1H, d, J=7.0 Hz, NH), 8.45 (1H, d, J=5.5 Hz, ruH-6), 7, 57 (1H, d, J=2.5 Hz, ruH-3), 7.32-7.29 (2H, m, oxobenzoxazapine H-6, H-8), 7.14 (1H, d, J= 8.5 Hz, oxobenzoxazapine H-9), 7.11 (2H, t, J=8.0 Hz, 2H C ₆ H ₄ F), 7.06-7.03 (2H, m, 2H C ₆ H ₄ F), 6.93 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.51 (1H, d, J=2.0 Hz, 1H CH ₂ =), 5 .41 (1H, d, J=2.0 Hz, 1H CH ₂ =), 5.03 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H , dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.44 (3H, s, CONCH3), 2.87 (2H, t, J=7.0 Hz, 2H CCH2CH2N), 2.49 (3H, s, NCH3), 2.47 (2H, t, J=6, 5 Hz, 2H CCH2CH2N); ¹³ C NMR (100 MHz, CDCl3) δ 168.9, 166.2, 163.6, 160.1 (d, J 245.0 Hz), 151.4, 150.2, 150.0, 149.5 , 136.3, 130.8, 128.9, 126.4, 123.5, 123.1, 122.4 (d, J=8.5 Hz), 120.7, 117.0 (d, J 24.0 Hz), 114.2, 110.3, 89.8, 88.0, 77.2, 49.9, 49.4, 37.2, 36.2, 35.4; ¹⁹ F NMR (380 MHz, CDCl3) δ -116.6; m/z: 515 [M+H]+ (found [M+H] ⁺ , 515.xxxx, C ₂₉ H ₂₇ FN ₄ O ₄ requires [M+H] ⁺ 515).

(S)-N-(7-((3-Hydroxy-1-(2,2,2-trifluoroacetyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-143).

1H NMR (400 MHz, CD3OD) δ 8.50 (1H, d, J=5.5 Hz, ruH-6), 7.59 (1H, d, J=2.0 Hz, ruH-3), 7 ,49-7.42 (4H, m, 2H C ₆ H ₅ , oxobenzoxazapine H-6, H-8), 7.30 (1H, tt, J=7.5, 1.0 Hz, 1H C ₆ H ₅ ), 7.24 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 7.14-7.11 (2H, m, 2H C ₆ H ₅ ), 7.07 (1H, dd , J=5.5, 2.5 Hz, ruH-5), 4.98 (1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine N-3), 4.62 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.42 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.20 (2H, d, J=7.0 Hz, 2H azetidine H-2, H-4), 4.15 (2H,

- 149 045696 d, J=7.5 Hz, 2H azetidine H-2, H-4), 3.41 (3H, s, NCH ₃ ); ^l9 F NMR (380 MHz, CD3OD) δ -138.2 (pentet,

J=17.5 Hz); m/z; 487 [M+H] ⁺ .

(S)-N-(7-((3-Fluoro-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[B][1,4 ]oxazepin-3-yl)-4-phenoxypicolinamide (I-146).

1H NMR (400 MHz, CDC13) δ 8.86 (1H, d, J=7.0 Hz, NH), 8.44 (1H, d, J=6.0 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.44-7.40 (2H, m, 2H C6H5), 7.35-7.33 (2H, m, oxobenzoxazapine H-6, Н-8), 7.27-7.23 (1H, m, 1H С6Н5), 7.15 (1H, d, J=8.5 Hz, oxobenzoxazapine Н-9), 7.08-7.06 ( 2H, m, 2H C6H5), 6.95 (1H, dd, J=6.0, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.5, 7.5 Hz , oxobenzoxazapine H-3), 4.72 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.30 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.79 (2H, dd, J 15.0, 10.0 Hz, 2H azetidine H-2, H-4), 3.56 (2H, dd, J 19.5 , 10.0 Hz, 2H azetidine H-2, H-4), 3.43 (3H, s, CONCH3), 2.47 (3H, s, NCH ₃ ); ¹⁹ F NMR (380 MHz, CDC13) δ -139.9; m/z: 501 [M+H] ⁺ .

(S)-4-((3-((5-Methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[B][1,4]oxazepin-7yl)ethynyl )oxetan-3-yl)oxy)-4-oxobutanoic acid (I-147).

1H NMR (400 MHz, D ₆ -acetone) δ 8.79 (1H, d, J=7.0 Hz, NH), 8.54 (1H, d, J=5.5 Hz, ruH-6), 7.57 (1H, d, J=2.0 Hz), ruH-3), 7.53-7.49 (2H, m, 2H C ₆ H ₅ , 7.48 (1H, d, J=2 .5 Hz, oxobenzoxazapine H-6), 7.39 (1H, dd, J=8.5, 2.0 Hz, oxobenzoxazapine H-8), 7.33 (1H, tt, J=7.5, 1 .0 Hz, 1H C ₆ H ₅ ), 7.25 (1H, d, J=8.5 Hz, oxobenzoxazapine H-9), 7.21-7.19 (2H, m, 2H, C ₆ H5) , 7.11 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 4.97 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine N-3), 4.88 (2H, d, J=7.5 Hz, 2H oxetane H-2, H-4), 4.83 (2H, d, J=7.5 Hz, 2H oxetane H-2, H-4 ), 4.68 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.40 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H -2), 3.44 (3H, s, NCH3), 2.72-2.65 (4H, m, СОНзССЧССН); m/ _z; 586 [M+H] ⁺ .

(S)-N-(7-((3-Hydroxy-1-(2,2,2-trifluoroacetyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-151)

1H NMR (400 MHz, CDCI3) δ 8.87 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, run-3), 7.43-7.40 (2H, m, 2H C ₆ H ₅ ), 7.31-7.23 (3H, m, 1H C _6H5 , 2H oxobenzoxazapine H-6, H-8, H-9), 7.17-7.14 (1H, m, 1H oxobenzoxazapine H- ₆ , H-8, H-9), 7.08- 7.05 (2H, m, 2H C ₆ H ₅ ), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.04 (1H, dt, J=11 ,0, 7.5 Hz, oxobenzoxazapine H-3), 4.72-4.68 (2H, m, 1H oxobenzoxazapine H-2, 1H azetidine H-2, H-4), 4.54 (1H, d , J=10.0 Hz, 1H azetidine H-2, H-4), 4.48 (1H, dd, J=11.0, 7.0 Hz, 1H oxobenzoxazapine H-2), 4.31 (2H , k, J=10.0 Hz, 2H azetidine H-2, H-4), 3.42 (3H, s, NCH ₃ ); ¹⁹ F NMR (380 MHz, CDC13) δ -72.6; m/z; 581 [M+H] ⁺ .

(S)-4-Cyclobutoxy-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ] [ 1,4]oxazepin-3-yl)picolinamide (I-152).

1H NMR (400 MHz, CDC13) δ 8.86 (1H, d, J=7.0 Hz, NH), 8.37 (1H, d, J=6.0 Hz, ruH-6), 7.48 (1H, d, J=2.5 Hz, ruH-3), 7.28-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J=9 ,0 Hz, oxobenzoxazapine N-9), 6.82 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.04 (1H, dt, J=11.5, 7, 5 Hz, oxobenzoxazapine H-3), 4.74 (1H, pentet, J=7.5 Hz, cBuH-1), 4.76-4.69 (1H, m, 1H oxobenzoxazapine H-2), 4, 30 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 2.52-2.44 (2H, m, 2H cBuH- 2, H-4), 2.22-2.12 (2H, m, 2H cBuH-2, H-4), 1.92-1.84 (1H, m, 1H cBuH-3), 1.75 -1.70 (1H, m, cBuH-3); m/z: 450 [M+H]+.

(S)-4-Cyclobutoxy-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[B][1,4 ] oxazepin-3-yl)picolinamide (I-153).

- 150 045696

'H NMR (400 MHz, CDCl ₃ ) δ 8.88 (1H, d, J=7.5 Hz, NH), 8.37 (1H, d, J=6.0 Hz, ruH-6), 7 .49 (1H, d, J Hz, рН-5), 7.32-7.29 (2Н, m, oxobenzoxazapine Н-6, Н-8), 7.15 (1H, d, J=9.0 Hz, oxobenzoxazapine N-9), 6.83 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.05 (1H, dt, J=11.5, 7.5 Hz , oxobenzoxazapine H-3), 4.93 (2H, ddd, J=6.5, 3.5, 0.5 Hz, 2H oxetane H-2, H-4), 4.80-4.78 (2H , m, 2H oxetane H-2, H-4), 4.76-4.70 (2H, m, 1H oxobenzoxazapine H-2, cBuH-1), 4.32 (1H, dd, J=11.0 , 10.0 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH ₃ ), 2.52-2.44 (2H, m, 2H cBuH-2, H-4), 2.22 -2.12 (2H, m, 2H cBuH-2, H-4), 1.92-1.85 (1H, m, 1H cBuH3), 1.77-1.67 (1H, m, 1H cBuH- 3); m/z: 464 [M+H] ⁺ .

(S)-N-(7-((3-methoxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-4-phenoxypicolinamide (I-154).

'H NMR (400 MHz, CDCl ₃ ) δ 8.86 (1H, d, J=7.0 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7 .60 (1H, d, J=2.5 Hz, ruH-3), 7.43-7.39 (2H, m, 2H C6H5), 7.34-7.31 (2H, m, oxobenzoxazapine H- 6, H-8), 7.27-7.7.23 (1H, m, 1H C6H5), 7.14 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.07 ( 2H, dd, J=8.0, 1.0 Hz, 2H CH5), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt , J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.31 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.02-3.82 (4H, shs, azetidine H-2, H-4), 3.43 (3H, s, NCH ₃ or OCH ₃ ), 3.39 (3H, s, NCH ₃ or OCH ₃ ); m/z: 499 [M+H] ⁺ .

(S)-N-(7-((3-Methoxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4 ] oxazepin-3 -yl)-4-phenoxypicolinamide (I-155).

'H NMR (400 MHz, CDCI3) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.44 (1H, dd, J=5.5, 0.5 Hz, ruH-6 ), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.44-7.40 (2H, m, 2H C ₆ H ₅ ), 7.37 (1H, d, J =2.0 Hz, oxobenzoxazapine H-6), 7.36 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.27-7.23 (1H, m, 1H C ₆ H ₅ ), 7.15 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 7.08-7.06 (2H, m, 2H C ₆ H ₅ ), 6.94 ( 1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H , dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.31 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.05 (2H, wd, J=8.0 Hz, 2H azetidine H-2, H-4), 3.60 (2H, d, J=9.0 Hz, 2H azetidine H-2, H-4), 3.44 (3H, s, OCH3 or CONCH3), 3.42 (3H, s, OCH3 or CONCH3), 2.70 (3H, s, NCH3); m/z: 513 [M+H] ⁺ .

(S)-4-(Cyclopentyloxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)picolinamide (I-156).

'H NMR (400 MHz, CDCl ₃ ) δ 8.88 (1H, d, J=7.5 Hz, NH), 8.36 (1H, d, J=5.5 Hz, ruH-6), 7 .56 (1H, d, J=2.5 Hz, ruH-3), 7.28-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J =9.0 Hz, oxobenzoxazapine N-9), 6.86 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.05 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.88-4.85 (1H, m, cyclopentane H-1), 4.72 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine Н-2), 4.30 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine Н-2), 3.42 (3H, s, NCH ₃ ), 1.98-1.89 (2H, m, 2H cyclopentane H-2, H-5), 1.86-1.73 (4H, m, 4H cyclopentane H-2, H-3, H-4, H-5), 1.68 -1.65 (2H, m, 2H cyclopentane H-2, H-3, H-4, H-5), 1.62 (6H, s, C(CH3)gOH); m/z: 464 [M + H] ⁺ .

(S)-4-(Cyclopentyloxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]oxazepin-3-yl)picolinamide (I-157).

'H NMR (400 MHz, CDCI3) δ 8.88 (1H, d, J=7.0 Hz, NH), 8.36 (1H, d, J=5.5 Hz, ruH-6), 7, 56 (1H, d, J=2.5 Hz, ruH-3), 7.33-7.30 (2H, m, oxobenzoxazapine H-6, H-8), 7.16 (1H, d, J= 9.0 Hz, oxobenzoxazapine N-9), 6.87 (1H, dd, J=6.0, 2.5 Hz, ruH-5), 5.06 (1H, dt, J=11.0, 7 .5 Hz, oxobenzoxazapine N-3), 4.93 (2H,

- 151 045696 latitude d, J=6.5 Hz, 2H oxetane H-2, H-4), 4.88-4.85 (1H, m, cyclopentane H-1), 4.80 (2H, d, J=6, 5 Hz, oxetane

Н-2, Н-4), 4.72 (1H, dd, J=9.5, 6.5 Hz, 1H oxobenzoxazapine Н-2), 4.33 (1H, dd, J=11.5, 9 .5 Hz, 1H oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 1.99-1.89 (2H, m, 2H cyclopentane H-2, H-5), 1.86-1 .75 (4H, m, 4H cyclopentane H-2, H-3, H-4, H-5), 1.66-1.62 (2H, m, 2H cyclopentane H-2, H-3, H- 4, N-5); m/z: 478

[M+H] ⁺ .

Methyl (S)-3-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propiolate ( I-159).

1H NMR (400 MHz, CDCI3) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.43 (1H, d, J=5.5 Hz, ruH-6), 7.60 (1H, d, J=2.5 Hz, runH-3), 7.46-7.39 (4H, m, 2H C6H5, oxobenzoxazapine H-6, H-8), 7.24 (1H, tt, J=7.5, 1.5 Hz, 1H C ₆ H ₅ ), 7.19 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7.07-7.05 (2H, m , 2H C ₆ H ₅ ), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-3), 5.03 (1H, dt, J=11.5, 7.5 Hz , oxobenzoxazapine H-3), 4.72 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.34 (1H, dd, J=11.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.84 (3H, s, OCH3), 3.42 (3H, s, NCH3); m/z: 472 [M+H]+.

3-(((S)-5-Methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7yl)ethynyl)oxetane -3 -yl-L-valinate (I-160).

1H NMR (400 MHz, CDCI3) δ 8.85 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.44-7.40 (2H, m, 2H C6H5), 7.31-7.27 (2H, m, oxobenzoxazapine H-6, Н-8), 7.27-7.23 (1H, m, 1H С6Н5), 7.14 (1H, d, J=9.0 Hz, oxobenzoxazapine Н-9), 7.08-7.06 ( 2H, m, 2H C6H5), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.05-4.97 (3H, m, oxobenzoxazapine H-3, 2H oxetane H-2, H-4), 4.89 (2H, t, J=7.0 Hz, 2H oxetane H-2, H-4), 4.71 (1H, dd, J=9.5, 7.0 Hz, 1H oxobenzoxazapine H-2), 4.31 (1H, t, J=11.0 Hz, 1H oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 3.42-3 .39 (1H, m, COCHNH2), 2.18-2.09 (1H, m, CH( _CH3 ) ₂ ), 1.04 (3H, d, J=6.5 Hz, 1 x CH3 CH( CH ₃ ) ₂ ), 0.99 (3H, d, J 6.5 Hz, 1 x CH ₃ CH (CH ₃ ) ₂ ); m/z: 585 [M+H] ⁺ .

(S)-3-(5-Methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7 yl)propiolic acid (I- 161).

'H NMR (400 MHz, CD3OD) δ 8.47 (1H, d, J=6.0 Hz, ruH-6), 7.56 (1H, d, J=2.0 Hz, oxobenzoxazapine H-6) , 7.50 (1H, d, J=2.5 Hz, ruH-3), 7.47-7.41 (3H, m, 2H C ₆ H ₅ , oxobenzoxazapine H-8), 7.28 (1H , latitude, J=7.5 Hz, 1H С6Н5), 7.20 (1H, d, J=8.5 Hz, oxobenzoxazapine Н-9), 7.11-7.09 (2Н, m, 2Н С6Н5 ), 7.04 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 4.98 (1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine N-3) , 4.63 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.38 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H- 2), 3.41 (3H, s, NCH3); m/z: 458 [M+H] ⁺ .

3-(((S)-5-Methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7yl)ethynyl)oxetane-3 -yl-b-valinate salt of benzenesulfonic acid (I-164).

1H NMR (400 MHz, CDCI3) δ 9.06 (1H, d, J=7.0 Hz, NH), 8.62 (1H, d, J=6.0 Hz, ruH-6), 8.40 (2H, br. s, NH ₂ ), 7.85 (2H, d, J Hz, 2H C ₆ H ₅ SO ₃ H) 7.66 (1H, br. s, ruH-3), 7.43 ( 2H, t, J=8.0 Hz, 2H C ₆ H ₅ ), 7.38-7.22 (H, 1H C6H5, 3H C6H5SO3H, oxobenzoxazapine H-6, H-8, H-9), 7, 06 (2H, d, J=8.5 Hz, 2H C6H5), 7.02 (1H, db, J=4.0 Hz, ruH-5), 4.97 (1H, dt, J=11 ,5, 6.5 Hz, oxobenzoxazapine H-3), 4.93-4.84 (4H, m, oxetane H2, H-4), 4.59 (1H, latitude, J=10.0, 7.0 Hz, 1H oxobenzoxazapine H-2), 4.44 (1H, br. d, J=10.5, 9.5 Hz, 1H oxobenzoxazapine H-2), 4.03 (1H, br. with cochnh ₂ ), 3.28 (3H, s, NCH3), 2.36-2.28 (1H, m, n _CH3 ) ₂ ), 1.05-1.02 (6H, m, CH(CH3 ) ₂ ); m/z: 585 [M+H] ⁺ .

(S)-4-((3-((5-Methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7yl)ethynyl )oxetan-3-yl)oxy)-4-oxobutanoic acid 2-amino-2-(hydroxymethyl)propane-1,3-diol salt (I-165).

- 152 045696

1H NMR (400 MHz, D6-DMSO) δ 8.87 (1H, d, J=8.0 Hz, NH), 8.56 (1H, d, J=6.0 Hz, ruH-6), 7 .60 (1H, d, J=2.0 Hz), ruH-3), 7.51-7.46 (2H, m, 2H C6H5), 7.36 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.337.30 (2H, m, 1H C ₆ H ₅ , oxobenzoxazapine H-6), 7.23 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9 ), 7.21-7.18 (3H, m, 2H C ₆ H ₅ , ruH-5), 4.85 (2H, d, J = 7.5 Hz, 2H oxetane H-2, H-4) , 4.81 (1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.78 (2H, dt, J=7.5 Hz, 2H oxetane H-2, H-4 ), 4.57 (1H, dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.45 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H -2), 3.42-3.16 (6H, br. s, C(CH ₂ OH) ₃ ), 3.30 (3H, s, NCH3), 2.56 (2H, dd, J=7, 0, 6.0 Hz, 2H COCH2CH2CO), 2.43 (2H, dd, J=7.0, 6.0 Hz, 2H COCH ₂ CH ₂ CO); m/z: 586 [M+H] ⁺ .

(S)-N-(7-((3-Fluoro-1-isopropylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[B] [1,4 ]oxazepin-3-yl)-4-phenoxypicolinamide (I-166).

1H NMR (400 MHz, CDC13) δ 8.86 (1H, d, J=7.0 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.42 (2H, dd, J=8.0, 7.5 Hz, 2H C6H5), 7.35-7.33 (2H, m, oxobenzoxazapine H-6, H-8), 7.27-7.23 (1H, m, 1H C6H5), 7.14 (1H, d, J=8.5 Hz, oxobenzoxazapine H-9), 7 .07 (2H, d, J=7.5 Hz, 2H C6H5), 6.95 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J Hz, oxobenzoxazapine H-3), 4.72 (1H, dd, J Hz, 1H oxobenzoxazapine H-2), 4.31 (1H, dd, J Hz, 1H oxobenzoxazapine H-2), 3.73 (2H , dd, J 15.5, 9.0 Hz, 2H azetidine H-2, H-4), 3.53 (2H, dd, J 20.5, 9.5 Hz, 2H azetidine H-2, H- 4), 3.43 (3H, s, NCH3), 2.45 (1H, d, J=6.0 Hz, NCH(CH ₃ ) ₂₎ , 0.99 (6H, d, J=6.0 Hz, CH(CH ₃ ) ₂ ); ¹⁹ f NMR (380 MHz, CDC13) δ - 139.3; m/z: 529 [M+H] ⁺ .

(S)-N-(7-((3 -Fluoro-1 -(2,2,2-trifluoroethyl)azetidin-3 -yl)ethynyl)-5 -methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-168).

1H NMR (400 MHz, CDCI3) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.44-7.40 (2H, m, 2H C ₆ H ₅ ), 7.35-7.33 (2H, m, oxobenzoxazapine H -6, H-8), 7.27-7.24 (1H, m, 1H C ₆ H ₅ ), 7.16 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 7, 08-7.06 (2H, m, 2H C ₆ H ₅ ), 6.95 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J =11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.72 (1H, dd, J=9.5, 7.0 Hz, 1H oxobenzoxazapine H-2), 4.32 (1H, dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.94 (2H, dd, J=16.5, 9.5 Hz, 2H azetidine H-2, H-4), 3, 88 (2H, dd, J=10.0, 9.5 Hz, 2H azetidine H-2, H-4), 3.44 (3H, s, NCH3), 3.15 (2H, k, J=9 ,0 Hz, NCH2CF3); ¹⁹ F NMR (380 MHz, CDCI3) δ -71.0, -138.8; m/z: 569 [M+H]+.

(S)-N-(7-((1 -(Cyclopropylmethyl)-3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[B] [1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-169).

1H NMR (400 MHz, CDC13) δ 8.86 (1H, d, J=7.0 Hz, NH), 8.44 (1H, d, J=5.5 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.44-7.39 (2H, m, 2H C6H5), 7.36-7.33 (2H, m, oxobenzoxazapine H-6, H-8), 7.28-7.24 (1H, m, 1H C ₆ H ₅ ), 7.15 (1H, d, J=8.5 Hz, oxobenzoxazapine H-9), 7.09-7 .06 (2H, m, 2H C ₆ H ₅ ), 6.95 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11, 0, 7.5 Hz, oxobenzoxazapine H-3), 4.73 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.31 (1H, dd, J=11 ,0, 9.5 Hz, 1H oxobenzoxazapine H-2), 3.88-3.80 (2H, m, 2H azetidine H-2, H-4), 3.62 (2H, dd, J=9, 5, 8.5 Hz, 2H azetidine H-2, H-4), 3.43 (3H, s, NCH3), 2.48 (2H, d, J Hz, NCH ₂ cPr), 0.89-0 .84 (1H, cPrH-1), 0.53-0.48 (2H, m, 2H cPrH-2, H-3), 0.17-0.13 (2H, m, 2H cPrH-2, N -3); ¹⁹ F NMR (380 MHz, CDCI3) δ -139.1; m/z: 541 [M+H] ⁺ .

(S)-4-(4-Fluorobenzyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1 H-pyrazol-1-carboxamide (I-175).

- 153 045696

1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.2 Hz, 1H), 7.85 (t, J=0.9 Hz, 1H), 7.45 (d, J =0.8 Hz, 1H), 7.34-7.27 (m, 2H), 7.18-7.08 (m, 3H), 7.03-6.92 (m, 2H), 4, 88 (dt, J=11.3, 7.3 Hz, 1H), 4.69 (dd, J=9.8, 7.3 Hz, 1H), 4.32 (dd, J=11.3, 9.8 Hz, 1H), 3.96 (dt, J=11.9, 4.5 Hz, 2H), 3.78 (s, 2H), 3.72 (ddd, J=11.8, 8 ,9, 3.0 Hz, 2H), 3.43 (s, 3H), 2.14 (s, 1H), 2.06 -2.01 (m, 2H), 1.90 (ddd, J= 13.0, 9.0, 3.9 Hz, 2H). ¹⁹ F NMR (376 MHz, chloroform-d) δ -116.72 (ddd, J=13.9, 8.9, 5.3 Hz). LC/MS: purity 99%, MS (m/e) 519 (MH+).

(S)-4-(4-Fluorobenzyl)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1Hbenzo [ b]azepin-3-yl)-1 H-pyrazol-1-carboxamide (I-178)

Path 3. 1H NMR (400 MHz, chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.85 (k, J=0.9 Hz, 1H), 7.46 ( d, J=0.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.19-7.08 (m, 3H), 7.02-6.92 (m, 2H) , 4.94 (d, J=6.9 Hz, 2H), 4.91-4.83 (m, 1H), 4.80 (dd, J=6.6, 0.9 Hz, 2H), 4.70 (dd, J=9.8, 7.2 Hz, 1H), 4.33 (dd, J=11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3 .43 (s, 3H), 2.60 (s, 1H). LC/MS: purity 94%, MS (m/e) 491 (M+H)+.

(S)-1-Benzyl-4-fluoro-N-(5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide (I-179).

1H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J=6.8 Hz, 1H), 7.61-7.56 (m, 1H), 7.50-7.44 (m, 2H ), 7.37 (d, J=7.0 Hz, 4H), 7.22 (dd, J=12.4, 6.2 Hz, 3H), 7.20-7.11 (m, 2H) , 5.23 (s, 2H), 5.08 (dt, J=12.6, 7.0 Hz, 1H), 4.81 (dd, J=9.7, 7.0 Hz, 1H), 4.29 (t, J=10.4 Hz, 1H), 3.45 (d, J=1.6 Hz, 3H), 2.60 (d, J=1.6 Hz, 3H). HRMS (TOFMS ES+) exact mass of C ₂₉ H ₂₄ FN ₅ O ₃ 509.1863, found 510.1930.

(S)-1-Benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide (I-181).

MS (IER, m/e): calculated 533.2438; Found 534.1 M+H]+.

(±)-4-Benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H -benzo[b]azepin-3-yl)-1-pyrazole-1-carboxamide (racemic variant I-182)

Path 1. 1H NMR (400 MHz, Methanol-d ₄ ) δ 7.87 (k, J=0.8 Hz, 1H), 7.51 (s, 1H), 7.31-7.23 (m, 2H), 7.267.14 (m, 3H), 7.10 (d, J=8.1 Hz, 1H), 6.45-6.35 (m, 2H), 4.38 (dd, J=11 ,4, 7.7 Hz, 1H), 3.82 (s, 2H), 3.66 (d, J=4.3 Hz, 8H), 3.37 (s, 3H), 2.74 (td , J=13.3, 7.6 Hz, 1H), 2.63-2.42 (m, 2H), 2.15-1.98 (m, 1H), 1.87-1.80 (m , 4H). LC/MS: purity 99%, MS (m/e) 500 (M+H)+.

(S)-4-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-pyrazolepyrazole-1-carboxamide (I-184)

Path 2. 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.5 Hz, 1H), 7.85 (k, J=0.9 Hz, 1H), 7.45 ( d, J=0.9 Hz, 1H), 7.17-7.08 (m, 2H), 7.07-6.92 (m, 3H), 6.28 (dd, J=8.6, 2.7 Hz, 1H), 6.21 (d, J=2.7 Hz, 1H), 4.90 (dt, J=11.0, 7.5 Hz, 1H), 4.61 (dd, J=9.7, 7.6 Hz, 1H), 4.20 (dd, J=11.1, 9.8 Hz, 1H), 3.78 (s, 2H), 3.71-3.61 (m, 8H), 3.40 (s, 3H), 1.86 (t, J=5.3 Hz, 4H). LC/MS: purity 97%, MS (m/e) 520 (M+H)+.

(S)-5-Benzyl-N-(7-(3-chloro-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3 -yl)-1H-1,2,4-triazol-3-carboxamide (I-187)

- 154 045696

1H NMR (400 MHz, CDCI3) δ 8.09 (1H, d, J=7.5 Hz, NH), 7.41-7.39 (2H, m, oxobenzoxazapine H-6, H8), 7.29 -7.22 (5H, m, C6H5), 7.15 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 6.31 (1H, s, CH=CCl), 5.05 ( 1H, dt, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.67 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.28 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.14 (2H, s, QhCdb), 3.43 (3H, _s , NCH ₃ ), 1.57 ( 6H, s, C(CH3)2OH); ¹³ C NMR (100 MHz, CDCI3) δ 168.7, 158.9, 158.4, 154.3, 150.2, 136.5, 135.9, 135.7, 135.7, 130.1, 128.9, 128.8, 127.2, 125.8, 122.8, 121.8, 77.2, 71.2, 49.1, 35.6, 33.2, 29.4; m/z: 480, 478 [M+H-H2O]+; m/z: 496, 494 [MH]' (found [M+H]+, 496.1743, C25H26CIN5O4 requires [M+H]+ 496.1746).

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-in-1-yl)-2,3,4,5- tetraαhydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide (I-188)

1H NMR (400 MHz, CDCI3) δ 8.07 (1H, d, J=7.5 Hz, NH), 7.28-7.20 (7H, m, oxobenzoxazapine H-6, H8, C ₆ H ₅ ), 7.09 (1H, g, J=9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J=11.0, 7.5 Hz, oxobenzoxazapine H3), 4.66 ( 1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.26 (1H, dd, J=11.0, 10.0 Hz, 1H oxobenzoxazapine H-2), 4, 14 (2H, s, sn ₂ s ₆ H ₅ ), 3.62 (2H, s, CCH2N), 3.38 (3H, s, NCH ₃ ), 2.73-2.70 (4H, m, 4H pyrrolidine), 1.86-1.82 (4H, m, 4H pyrrolidine); m/z: 485 [M+H]+ (found _[ M+H]+, _485.2322 , _{C27H28N6O3 requires} [M+H]+ 485.2296).

(S)-5-Benzyl-N-(5-methyl-7-(3-morpholinoprop-1-in-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-1 H-1,2,4-triazol-3-carboxamide (I-189)

1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (1H, d, J=7.0 Hz, NH), 7.29-7.7.27 (2H, m, oxobenzoxazapine H-6, H-8 ), 7.25-7.18 (5H, m C6H5), 7.10 (1H, d, J=9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J=11.0 , 7.0 Hz, oxobenzoxazapine H-3), 4.65 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.27 (1H, t, J=10, 5 Hz, 1H oxobenzoxazapine H-2), 4.13 (2H, s,CH ₂ C ₆ H ₅ ), 3.78, 3.76 (4H, 2d AB system, J=4.5 Hz, 4H morpholine) , 3.50 (2H, s, CCH2N), 3.39 (3H, s, NCH ₃ ), 2.65, 2.63 (4H, 2d AB system, J=4.5 Hz, 4H morpholine); m/z: 501 [M+H]+ (found [M+H]+, 501.2245, C ₂₇ H ₂₈ N ₆ O ₃ , requires [M+H]+ 501.2245).

(S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-4-(phenoxy-b5)picolinamide (I-190)

1H NMR (400 MHz, CDCI3) δ 8.86 (1H, d, J=7.5 Hz, NH), 8.44 (1H, d, J=6.0 Hz, ruH-6), 7.61 (1H, d, J=2.5 Hz, ruH-3), 7.32-7.29 (2H, m, oxobenzoxazapine H-6, H-8), 7.14 (1H, d, J=9 ,0 Hz, oxobenzoxazapine N-9), 6.94 (1H, dd, J=5.5, 2.5 Hz, ruH-5), 5.03 (1H, dt, J=11.0, 7, 5 Hz, oxobenzoxazapine H-3), 4.92 (2H, dd, J=6.5, 4.0 Hz, 2H oxetane H-2, H-4), 4.78 (2H, dd, J=6 .5, 1.0 Hz, 2H oxetane H-2, H-4), 4.71 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.31 (1H , dd, J=11.0, 9.5 Hz, 1H oxobenzoxazapine), 3.42 (3H, s, NCH ₃ ), 3.16 (1H, s, OH); m/z: 491 [M+H]+ (found [M+H]+, 491.xxxx, C ₂₇ H ₁₈ D ₅ N ₃ O ₆ requires [M+H]+ 491.1973).

(S)-N-(7-((1-acetyl-3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-4-phenoxypicolinamide (I-191)

3-(((S)-5-Methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxαzepin-7yl)ethynyl)oxetane-3 -yl-L-alaninate salt of trifluoroacetic acid (I-194)

- 155 045696

t/r. 557 [M + N] ⁺ .

(S)-N-(7-((3-Hydroxy-1-isopropylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4 ] oxazepin-3 -yl)-4-phenoxypicolinamide (I-195)

t/y. 527 [M + H] ⁺ (S)-N-(7-((1-(Cyclopropylmethyl)-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-196)

mz\ 539 [M + H] ⁺ .

(S)-N-(7-((1-Acetyl-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4 ] oxazepin-3 -yl)-4-phenoxypicolinamide (I-197)

(S)-N-(7-((1-(Ethylcarbamoyl)-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [ 1 ,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-198)

(S)-3-((5-Methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7yl)ethynyl)oxetane-3 -ylethylcarbamate (I-199)

(S)-N-(7-((3-Hydroxy-1-neopentyl azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4 ] oxazepin-3 -yl)-4-phenoxypicolinamide (I-200)

(S)-N-(5-Methyl-7-((1-methyl-1H-imidazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-4-phenoxypicolinamide (I-203)

(S)-N-(7-(3-(Butylamino)-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-204)

- 156 045696 (S)-N-(7-(3-((4-Fluorobenzyl)amino)-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-205)

(S)-4-Benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-1 H-pyrazolepyrazole-1-carboxamide (I-212)

Path 1. 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.2 Hz, 1H), 7.86 (k, J=0.8 Hz, 1H), 7.46 ( s, 1H), 7.33-7.14 (m, 7H), 7.13-7.06 (m, 1H), 4.86 (dt, J=11.2, 7.3 Hz, 1H) , 4.67 (dd, J=9.7, 7.3 Hz, 1H), 4.34 - 4.24 (m, 1H), 3.81 (s, 2H), 3.42 (s, 3H ), 1.32 (s, 9H).

LC/MS: purity 99%, MS (m/e) 457 (M+H)+.

(S)-4-Benzyl-N-(7-(3-hydroxy-3-methylbut-'-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1 H-pyrazolepyrazole-1-carboxamide (I-213).

Path 1. 1H NMR (400 MHz, chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.86 (k, J=0.9 Hz, 1H), 7.47 ( d, J=0.9 Hz, 1H), 7.33 - 7.25 (m, 4H), 7.25-7.09 (m, 4H), 4.87 (dt, J=11.2, 7.3 Hz, 1H), 4.69 (dd, J=9.8, 7.3 Hz, 1H), 4.31 (dd, J=11.3, 9.8 Hz, 1H), 3, 81 (s, 2H), 3.42 (s, 3H), 1.63 (s, 6H).

LC/MS: purity 99%, MS (m/e) 459 (M+H)+.

(S)-4-Benzyl-N-(5-methyl-4-oxo-7-(pyridin-3-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin3 -yl) -1H-pyrazolepyrazole-1-carboxamide (I-214)

Path 3. 1H NMR (400 MHz, methylene chloride-d ₂ ) δ 8.78 (s, 1H), 8.60-8.51 (m, 1H), 7.94-7.84 (m, 3H), 7.53-7.47 (m, 2H), 7.49-7.42 (m, 2H), 7.37 (dd, J=8.0, 5.0 Hz, 1H), 7.34- 7.26 (m, 2H), 7.22 (t, J=7.9 Hz, 3H), 4.91 (dt, J=11.2, 7.1 Hz, 1H), 4.73 (ddd , J=9.8, 7.2, 0.9 Hz, 1H), 4.34 (approx. ddd, J=10.9, 9.8, 0.9 Hz, 1H), 3.84 (s , 2H), 3.45 (s, 3H).

LC/MS: purity 99%, MS (m/e) 478 (M+H)+.

(S)-4-Benzyl-N-(5-methyl-4-oxo-7-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin3 -yl) -1 H-pyrazolepyrazole-1-carboxamide (I-215).

Path 3. 1H NMR (400 MHz, methylene chloride^) δ 8.65-8.56 (m, 1H), 7.91 (d, J=7.1 Hz, 1H), 7.88 (s, 1H) , 7.72 (td, J=7.8, 1.8 Hz, 1H), 7.60-7.44 (m, 4H), 7.36-7.15 (m, 7H), 4.91 (dt, J=11.3, 7.1 Hz, 1H), 4.74 (dd, J=9.8, 7.2 Hz, 1H), 4.34 (dd, J=11.2, 9 .8 Hz, 1H), 3.83 (s, 2H), 3.45 (s, 3H).

LC/MS: purity 96%, MS (m/e) 478 (M+H)+.

(S)-4-Benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ] oxazepin-3 -yl)-1 H-pyrazolepyrazole-1-carboxamide (I-216).

Path 3. 1H NMR (400 MHz, chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.86 (k, J=0.9 Hz, 1H), 7.47 ( d, J=0.9 Hz, 1H), 7.35-7.25 (m, 4H), 7.29-7.17 (m, 1H), 7.21-7.12 (m, 3H) , 4.97-4.83 (m, 3H), 4.80 (dt, J=6.5, 0.8 Hz, 2H), 4.69 (dd, J=9.8, 7.3 Hz , 1H), 4.33 (dd, J=11.3, 9.8 Hz, 1H), 3.81 (s, 2H), 3.42 (s, 3H), 2.92 (s, 1H) .

- 157 045696

LC/MS: purity 99%, MS (m/e) 473 (M+H)+.

(S)-4-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1 H-pyrazol-1-carboxamide (I-217)

Path 1. 'H NMR (400 MHz, chloroform-d) δ 7.95 (d, J=7.5 Hz, 1H), 7.86 (t, J=0.9 Hz, 1H), 7.46 (s, 1H), 7.33-7.25 (m, 2H), 7.25-7.12 (m, 3H), 7.03 (d, J=8.7 Hz, 1H), 6, 28 (dd, J=8.7, 2.7 Hz, 1H), 6.21 (d, J=2.6 Hz, 1H), 4.90 (dt, J=11.1, 7.6 Hz , 1H), 4.61 (dd, J=9.7, 7.6 Hz, 1H), 4.20 (dd, J=11.0, 9.8 Hz, 1H), 3.81 (s, 2H), 3.73-3.60 (m, 8H), 3.40 (s, 3H), 1.86 (t, J=5.2 Hz, 4H).

LC/MS: purity 99%, MS (m/e) 502 (M+H)+.

(S)-4-(4-Fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-pyrazol-1-carboxamide (I-218).

Path 3. 'H NMR (400 MHz, chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.85 (k, J=0.9 Hz, 1H), 7.45 (d, J=0.8 Hz, 1H), 7.32-7.25 (m, 2H), 7.16-7.08 (m, 3H), 7.02-6.92 (m, 2H ), 4.87 (dt, J=11.2, 7.3 Hz, 1H), 4.73-4.64 (m, 1H), 4.31 (dd, J=11.3, 9.7 Hz, 1H), 3.78 (s, 2H), 3.42 (s, 3H), 2.02 (s, 1H), 1.63 (s, 6H).

LC/MS: purity 99%, MS (m/e) 459 (M-H ₂ O+H)+.

(S)-4-Benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepine-3 -yl)-1 H-pyrazolpyrazole-1-carboxamide (I-219)

Path 3. 'H NMR (400 MHz, chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.86 (k, J=0.9 Hz, 1H), 7.47 (d, J=0.8 Hz, 1H), 7.34-7.25 (m, 4H), 7.25-7.17 (m, 1H), 7.18 (dt, J=1.3 , 0.6 Hz, 1H), 7.20-7.10 (m, 2H), 4.88 (dt, J=11.3, 7.3 Hz, 1H), 4.69 (dd, J= 9.8, 7.3 Hz, 1H), 4.32 (dd, J=11.3, 9.8 Hz, 1H), 3.81 (s, 2H), 3.43 (s, 3H), 2.60-2.48 (m, 2H), 2.41-2.29 (m, 2H), 2.25 (s, 1H), 1.97-1.82 (m, 2H).

LC/MS: purity 99%, MS (m/e) 471 (M+H)+.

(S)-4-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-5-methyl-1H-pyrazole-1-carboxamide (I-220)

Path 3. 'H NMR (400 MHz, chloroform-d) δ 7.90 (d, J=7.3 Hz, 1H), 7.75 (d, J=1.0 Hz, 1H), 7.32 -7.24 (m, 4H), 7.24-7.16 (m, 1H), 7.20-7.09 (m, 3H), 4.88 (dt, J=11.3, 7. 3 Hz, 1H), 4.68 (dd, J=9.8, 7.3 Hz, 1H), 4.31 (dd, J=11.3, 9.8 Hz, 1H), 3.73 ( s, 2H), 3.42 (s, 3H), 2.15 (approx. s, 3H), 1.63 (s, 6H).

LC/MS: purity 96%, MS (m/e) 473 (M+H)+.

(S)-4-(4-Fluorobenzyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ] oxazepin-3 -yl)-1 H-pyrazol-1-carboxamide (I-221)

Path 3. 'H NMR (400 MHz, chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.85 (d, J=1.1 Hz, 1H), 7.45 (s, 1H), 7.31 (dk, J=4.6, 2.0 Hz, 2H), 7.17-7.09 (m, 3H), 7.03-6.93 (m, 2H ), 4.88 (dt, J=11.2, 7.2 Hz, 1H), 4.69 (dd, J=9.8, 7.3 Hz, 1H), 4.32 (dd, J= 11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.43 (s, 3H), 2.60-2.49 (m, 1H), 2.57-2.50 (m, 2H), 2.36 (cd, J=9.2, 2.7 Hz, 2H), 2.24 (br s, 1H), 1.96-1.85 (m, 2H).

LC/MS: purity 99%, MS (m/e) 489 (M+H)+.

(S)-4-(4-Fluorobenzyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1 H-pyrazol-1-carboxamide (I-222)

Path 3. 1H NMR (400 MHz, chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.85 (k, J=0.9 Hz, 1H), 7.46 ( d, J=0.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.19-7.08 (m, 3H), 7.02-6.92 (m, 2H) , 4.94 (d, J=6.9 Hz, 2H), 4.91-4.83 (m, 1H), 4.80 (dd, J=6.6, 0.9 Hz, 2H), 4.70 (dd, J=9.8, 7.2 Hz, 1H), 4.33 (dd, J=11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3 .43 (s, 3H),

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2.60 (s, 1H).

LC/MS: purity 94%, MS (m/e) 491 (M+H) ⁺ .

(S)-3-(4-Fluorobenzyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ] oxazepin-3 -yl)-1 H-pyrazol-1-carboxamide (I-223)

Path 3. 1H NMR (400 MHz, chloroform-d) δ 8.04-7.97 (approx. m, 2H), 7.35-7.28 (m, 2H), 7.24-7.16 ( m, 2H), 7.20-7.11 (m, 1H), 7.04-6.93 (m, 2H), 6.10 (d, J=2.7 Hz, 1H), 4.91 (dt, J=11.3, 7.2 Hz, 1H), 4.72 (dd, J=9.7, 7.3 Hz, 1H), 4.35 (dd, J=11.3, 9 .7 Hz, 1H), 3.96 (s, 2H), 3.45 (s, 3H), 2.60-2.49 (m, 2H), 2.36 (dt, J=12.2, 9.2 Hz, 2H), 1.97-1.82 (m, 2H). ¹⁹ F NMR (376 MHz, chloroform-d) δ -116.69 (ddd, J=14.2, 8.9, 5.4 Hz).

LC/MS: purity 97%, MS (m/e) 511 (M+Na) ⁺ .

(S)-4-(4-Fluorobenzyl)-N-(7-((2-hydroxyspiro[3.3]heptan-2-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-1-carboxamide (I-224).

Path 3. 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.2 Hz, 1H), 7.84 (k, J=0.9 Hz, 1H), 7.45 ( d, J=0.8 Hz, 1H), 7.31-7.24 (m, 2H), 7.17-7.07 (m, 3H), 7.02-6.92 (m, 2H) , 4.87 (dt, J=11.3, 7.3 Hz, 1H), 4.68 (dd, J=9.8, 7.3 Hz, 1H), 4.31 (dd, J=11 ,3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.41 (s, 3H), 2.66-2.57 (m, 2H), 2.39-2.29 ( m, 2H), 2.202.12 (m, 3H), 2.05 (dd, J=8.1, 6.9 Hz, 2H), 1.92-1.80 (m, 2H). ¹⁹ F NMR (376 MHz, chloroform-d) δ -116.74 (ddd, J=14.2, 8.7, 5.5 Hz).

LC/MS: purity 94%, MS (m/e) 529 (M+H) ⁺ .

(S)-4-(4-Fluorobenzyl)-N-(7-((6-hydroxy-2-oxaspiro[3.3]heptan-6-yl)ethynyl)-5-methyl-4-oxo2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-1-carboxamide (I-225)

Path 3. 1H NMR (400 MHz, methylene chloride-d ₂ ) δ 7.87 (d, J=7.1 Hz, 1H), 7.84 (s, 1H), 7.48 (d, J=0, 8 Hz, 1H), 7.34-7.24 (m, 2H), 7.21-7.12 (m, 3H), 7.04-6.93 (m, 2H), 4.85 (dt , J=11.2, 7.2 Hz, 1H), 4.76 (s, 2H), 4.734.66 (m, 1H), 4.66 (s, 2H), 4.30 (dd, J= 11.3, 9.8 Hz, 1H), 3.80 (s, 2H), 3.39 (s, 3H), 2.84-2.74 (m, 2H), 2.55-2.46 (m, 2H). ¹⁹ F NMR (376 MHz, methylene chloride-d ₂ ) δ -117.74 (ddd, J=14.3, 9.0, 5.4 Hz).

LC/MS: purity 99%, MS (m/e) 531 (M+H)+.

(S)-4-Benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole1 -carboxamide (I-228)

Path 1. 1H NMR (400 MHz, chloroform-d) δ 7.95 (d, J=7.3 Hz, 1H), 7.86 (k, J=0.9 Hz, 1H), 7.47 ( d, J=0.9 Hz, 1H), 7.39-7.33 (m, 2H), 7.33-7.14 (m, 6H), 7.08 (dd, J=8.1, 0.8 Hz, 1H), 4.89 (dt, J=11.3, 7.3 Hz, 1H), 4.724.63 (m, 1H), 4.35-4.25 (m, 1H), 3.81 (s, 2H), 3.42 (s, 3H).

LC/MS: purity 99%, MS (m/e) 456 (M+H) ⁺ .

(S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-fluorobenzyl) - 1Hpyrazole-1-carboxamide (I-229)

Path 2. 1H NMR (400 MHz, chloroform-d) δ 7.95 (d, J=7.3 Hz, 1H), 7.85 (s, 1H), 7.45 (s, 1H), 7, 39 - 7.32 (m, 2H), 7.16-7.04 (m, 3H), 6.97 (t, J=8.6 Hz, 2H), 4.89 (dt, J=11, 2, 7.3 Hz, 1H), 4.67 (dd, J=9.8, 7.4 Hz, 1H), 4.30 (dd, J=11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.42 (s, 3H).

LC/MS: purity 96%, MS (m/e) 474 (M+H) ⁺ .

(S)-4-Benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-methyl -1Hpyrazolepyrazole-1-carboxamide (I-230)

Path 2. 1H NMR (400 MHz, chloroform-d) δ 7.88 (d, J=7.4 Hz, 1H), 7.75 (d, J=1.0 Hz, 1H), 7.39- 7.32 (m, 2H), 7.31-7.24 (m, 2H), 7.23-7.16 (m, 1H), 7.16-7.12 (m, 2H), 7. 07 (d, J=8.4 Hz, 1H), 4.89 (dt, J=11.3, 7.4 Hz,

- 159 045696

1H), 4.66 (dd, J=9.8, 7.4 Hz, 1H), 4.30 (dd, J=11.3, 9.8 Hz, 1H), 3.73 (s, 2H ), 3.42 (s, 3H), 2.15 (s, 3H).

LC/MS: purity 99%, MS (m/e) 470 (M+H) ⁺ .

(S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(4-fluorobenzyl) -1Hpyrazole-1-carboxamide (I-231)

Path 2. 1H NMR (400 MHz, chloroform-d) δ 8.16 (d, J=7.4 Hz, 1H), 7.51-7.46 (m, 1H), 7.38 -7.30 (m, 2H), 7.12 (dd, J=8.3, 5.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.96 (t, J= 8.5 Hz, 2H), 5.94 (s, 1H), 4.88 (dt, J=11.2, 7.3 Hz, 1H), 4.65 (dd, J=9.8, 7 .3 Hz, 1H), 4.30 (approx. m, 1H), 4.27 (s, 2H), 3.41 (s, 3H). LC/MS: purity 94%, MS (m/e) 474 (M+H) ⁺ .

(S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(4-fluorobenzyl) -1Hpyrazole-1-carboxamide (I-232)

Path 2. 1H NMR (400 MHz, chloroform-d) δ 8.00 (d, J=2.7 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.38- 7.32 (m, 2H), 7.19 (approx. dddd, J=8.3, 5.3, 2.1, 1.5 Hz, 2H), 7.08 (dd, J=8.4 , 0.4 Hz, 1H), 7.01-6.93 (m, 2H), 6.10 (d, J=2.7 Hz, 1H), 4.91 (dt, J=11.3, 7.3 Hz, 1H), 4.69 (dd, J=9.8, 7.4 Hz, 1H), 4.33 (dd, J=11.3, 9.8 Hz, 1H), 3, 95 (s, 2H), 3.43 (s, 3H).

LC/MS: purity 95%, MS (m/e) 474 (M+H) ⁺ .

(S)-5-Benzyl-N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ] oxazepin-3 -yl)-1H-1,2,4-triazol-3-carboxamide (I-233)

1H NMR (400 MHz, CD3OD) δ 7.52 (1H, d, J=2.0 Hz, oxobenzoxazapine H-6), 7.39 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.32-7.23 (5H, m, C ₆ H ₅ ), 7.21 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.60 (1H, dd, J=9.5, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.41 (1H , dd, J=11.5, 10.0, Hz, 1H oxobenzoxazapine H-2), 4.35 (2H, d, J=11.5 Hz, 2H azetidine H-2, H-4), 4, 15 (2H, s, CH2QH5), 4.14 (2H, m, 2H azetidineH-2, H-4), 3.40 (3H, s, NCH3); m/z: 473 [M+H] ⁺ .

(S)-5-Benzyl-N-(7-((3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-234)

1H NMR (400 MHz, CD3OD) δ 7.55 (1H, d, J=2.0 Hz, oxobenzoxazapine H-6), 7.39 (1H, dd, J=8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.33-7.24 (5H, m, C ₆ H ₅ ), 7.22 (1H, d, J=8.0 Hz, oxobenzoxazapine H-9), 5.00 (1H, dd, J=11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.59 (1H, dd, J=10.0, 7.5 Hz, 1H oxobenzoxazapine H-2), 4.44 (1H , dd, J=11.5, 10.0 Hz, 1H oxobenzoxazapine H-2), 4.16 (2H, s, CH2C6H5), 4.15 (2H, d, J=9.5 Hz, 2H azetidine H -2, H-4), 3.81 (2H, d, J=10.0 Hz, 2H azetidineH-2, H-4), 3.39 (3H, s, CONCH3), 2.74 (3H, s, NCH ₃ ); m/z: 487 [M+H]+.

(S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(2,4- difluorobenzyl)1H-pyrazole-1-carboxamide (I-237).

1H NMR (400 MHz, chloroform-d) δ 7.95 (d, J=1.3 Hz, 1H), 7.87 (s, 1H), 7.48 (d, J=0.8 Hz, 1H ), 7.397.30 (m, 2H), 7.15-7.03 (m, 2H), 6.84-6.74 (m, 2H), 4.88 (dt, J=11.2, 7 .3 Hz, 1H), 4.67 (dd, J=9.8, 7.4 Hz, 1H), 4.29 (dd, J=11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.41 (s, 3H). ¹³ C NMR (101 MHz, chloroform-d) δ 168.51, 162.57 (dd, J=116.5, 12.0 Hz), 160.84-159.36 (m), 149.18 (d , J=5.4 Hz), 143.12, 137.56, 131.08 (dd, J=9.5, 6.1 Hz), 130.71, 126.89, 126.50, 124.58 , 123.01-122.71 (m), 122.62, 118.23, 111.42 (dd, J=21.1, 3.9 Hz), 104.08 (t, J=25.6 Hz ), 77.32, 50.15, 35.65, 23.33. ¹⁹ F NMR (376 MHz, chloroform-d) δ -112.35 (p, J=7.6 Hz), -113.80 (k, J=8.5 Hz). LC-MS: purity 97%, MS (m/z) 491/493 (M+H) ⁺ .

- 160 045696 (S)-4-(2,4-Difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-pyrazol-1-carboxamide (I-23 8)

^1H NMR (400 MHz, chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.86 (s, 1H), 7.46 (s, 1H), 7.24 ( d, J=7.4 Hz, 2H), 7.12-7.04 (m, 2H), 6.77 (t, J=8.4 Hz, 2H), 4.85 (dt, J=11 ,2, 7.3 Hz, 1H), 4.65 (dd, J=9.8, 7.3 Hz, 1H), 4.29 (dd, J=11.3, 9.8 Hz, 1H) , 3.75 (s, 2H), 3.38 (s, 3H), 1.59 (s, 6H). ¹³ C NMR (101 MHz, chloroform-d) δ 168.41, 162.40 (dd, J=115.8, 11.9 Hz), 159.94 (dd, J=116.6, 11.8 Hz ), 149.80, 149.02, 142.97, 135.99, 131.11-130.79 (m), 126.79, 126.49, 123.04, 122.73 (dd, J=16 ,0, 3.8 Hz), 122.44, 120.49, 111.26 (dd, J=21.0, 3.8 Hz), 103.90 (t, J=25.6 Hz), 94 .77, 80.46, 65.45, 49.98, 35.50, 31.38, 23.15. ¹⁹ F NMR (376 MHz, chloroform-d) δ -112.33 (p, J=1.1 Hz), -113.78 (k, J=8.4 Hz). LC-MS: purity 95%, MS (m/z) 495 (M+H)+.

(S)-4-(2,4-Difluorobenzyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-pyrazol-1-carboxamide (I-239)

^1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.2 Hz, 1H), 7.87 (s, 1H), 7.47 (s, 1H), 7.30- 7.20 (m, 2H), 7.15-7.03 (m, 2H), 6.86-6.75 (m, 2H), 4.85 (dt, J=11.2, 7.3 Hz, 1H), 4.67 (dd, J=9.8, 7.3 Hz, 1H), 4.29 (dd, J=11.3, 9.8 Hz, 1H), 3.77 (s , 2H), 3.50 (s, 2H), 3.41 (s, 3H), 1.30 (s, 6H). ¹³ C NMR (101 MHz, chloroform-d) δ 168.41, 160.61, 149.59, 148.99, 142.94, 135.95, 131.03, 130.99-130.69 (m) , 126.75, 126.56, 122.98, 122.89122.56 (m), 122.43, 121.05, 111.27 (dd, J=21.1, 3.8 Hz), 103, 93 (t, J=25.6 Hz), 95.38, 80.45, 77.16, 71.55, 49.98, 35.51, 34.81, 25.40, 23.19. ¹⁹ F NMR (376 MHz, chloroform-d) δ -112.39 (p, J=1.1 Hz), -113.81 (k, J=8.4 Hz). LC-MS: purity 96%, MS (m/z) 509 (M+H) ⁺ .

tert-Butyl-(S)-(4-(3-(4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamido)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl)carbamate (I-240)

1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.2 Hz, 1H), 7.86 (s, 1H), 7.46 (s, 1H), 7.29 -7 .21 (m, 2H), 7.13-7.03 (m, 2H), 6.77 (t, J=8.5 Hz, 2H), 4.92-4.79 (m, 1H), 4.65 (dd, J=9.8, 7.3 Hz, 1H), 4.28 (dd, J=11.3, 9.8 Hz, 1H), 3.76 (s, 2H), 3 .40 (s, 3H), 3.19 (d, J=6.5 Hz, 2H), 1.43 (s, 9H), 1.27 (s, 6H). ¹³ C NMR (101 MHz, chloroform-d) δ 168.40, 162.41 (dd, J=115.8, 11.9 Hz), 159.94 (dd, J=116.5, 11.9 Hz ), 156.08, 149.56, 148.97, 142.92, 135.94, 132.27-131.80 (m), 131.00, 130.98 - 130.79 (m), 128, 49 (d, J=12.1 Hz), 126.74, 126.51, 122.94, 122.86 - 122.58 (m), 122.41, 121.12, 111.25 (dd, J =21.0, 3.7 Hz), 103.90 (t, J=25.6 Hz), 95.80, 79.85, 79.37, 77.10, 50.84, 49.97, 35 .49, 33.43, 28.34, 26.44, 23.17. ¹⁹ F NMR (376 MHz, chloroform-d) δ -112.37 (p, J=7.5 Hz), -113.81 (k, J=8.5 Hz). LC-MS: purity 98%, MS (m/z) 508 (M-Boc+H) ⁺ .

(S)-N-(7-(4-Amino-3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-(2,4-difluorobenzyl)-1 H-pyrazole-1-carboxamide hydrochloride (I-241)

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (d, J=6.6 Hz, 1H), 8.14 (s, 3H), 7.99 (s, 1H), 7.67 ( s, 1H), 7.61 (s, 1H), 7.38-7.27 (m, 2H), 7.24-7.11 (m, 2H), 6.99 (t, J=8, 6 Hz, 1H), 4.72-4.60 (m, 2H), 4.41 (d, J=5.4 Hz, 1H), 3.78 (s, 2H), 3.27 (s, 3H), 2.91 (s, 2H), 1.32 (s, 6H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -112.67- -112.85 (m), 114.02 (d, J=9.0 Hz). LC-MS: purity 98%, MS (m/z) 508 (M-HC1+H) ⁺ .

(S)-N-(5-Methyl-7-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide (II-27)

^1H NMR (400 MHz, methylene chloride) δ 8.74 (d, J=7.4 Hz, 1H), 8.48 (d, J=5.6 Hz, 1H), 7.57 (d, J= 2.5 Hz, 1H), 7.51-7.41 (m, 2H), 7.34-7.25 (m, 1H), 7.14-7.09 (m, 2H), 7.07 (d, J=8.8 Hz, 1H), 6.99 (dd, J=5.6, 2.6 Hz, 1H), 6.80 (dd, J=8.8, 2.9 Hz, 1H), 6.75 (d, J=2.8 Hz, 1H), 4.97 (dt, J=11.1, 7.4 Hz, 1H), 4.63 (dd, J=9.7 , 7.5 Hz, 1H), 4.16 (dd, J=11.1, 9.7 Hz, 1H), 3.40 (s, 3H), 3.18-3.10 (approx. m, 4H), 2.41-2.34 (approx. m, 4H), 2.26 (s, 3H), 1.66-1.54 (m, 8H). LC-MS: purity 98%, MS (m/e) 556 (M+H) ⁺ .

tert-Butyl-4-benzyl-1 H-pyrazole-1-carboxylate

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1H NMR (400 MHz, chloroform-d) δ 7.82 (d, J=0.9 Hz, 1H), 7.55 (d, J=0.9 Hz, 1H), 7.30 (dd, J =8.1, 6.6 Hz, 2H), 7.26-7.13 (m, 3H), 3.82 (s, 2H), 1.63 (s, 9H).

LC-MS: purity 96%, MS (m/e) 282 (M+Na) ⁺ 4-benzyl-1H-pyrazole hydrochloride

1H NMR (400 MHz, DMSO-d6) δ 10.47 (br s, 2H), 7.65 (s, 2H), 7.36-7.04 (m, 5H), 3.79 (s, 2H).

LC-MS: purity 99%, MS (m/e) 159 (M-HC1+H) ⁺ tert-Butyl-4-benzyl-3,5-dimethyl-1H-pyrazole-1-carboxylate

1H NMR (400 MHz, methylene chloride-d ₂ ) δ 7.31-7.23 (m, 2H), 7.22-7.14 (m, 1H), 7.14-7.07 (m, 2H) , 3.74 (s, 2H), 2.43 (s, 3H), 2.10 (s, 3H), 1.62 (approx. s, 9H).

LC-MS: purity 97%, MS (m/e) 309 (M+Na) ⁺

4-Benzyl-3,5-dimethyl-1H-pyrazole hydrochloride

1H NMR (400 MHz, chloroform-d) δ 7.33-7.24 (m, 2H), 7.27-7.18 (m, 1H), 7.08-7.00 (m, 2H), 3.78 (s, 2H), 2.37 (s, 6H).

LC-MS: purity 99%, MS (m/e) 187 (M-HC1+H) ⁺ tert-Butyl-4-(4-fluorobenzyl)-1 H-pyrazole-1-carboxylate

1H NMR (400 MHz, chloroform-d) δ 7.81 (k, J=0.9 Hz, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.19-7.09 (m, 2H), 7.04-6.93 (m, 2H), 3.79 (s, 2H), 1.63 (s, 9H).

LC-MS: purity 99%, MS (m/e) 177 (M-Boc+H) ⁺

4-(4-Fluorobenzyl)-1H-pyrazole hydrochloride

1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 2H), 7.64 (s, 2H), 7.29-7.14 (m, 2H), 7.14-6.97 ( m, 2H), 3.78 (s, 2H).

LC-MS: purity 99%, MS (m/e) 177 (M-HC1+H) ⁺ tert-Butyl-4-benzyl-3-methyl-1 H-pyrazole-1-carboxylate

1H NMR (400 MHz, chloroform-d) δ 7.71 (s, 1H), 7.32-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.19- 7.12 (m, 2H), 3.75 (s, 2H), 2.18 (s, 3H), 1.62 (s, 9H).

LC-MS: purity 98%, MS (m/e) 295 (M+Na) ⁺

4-Benzyl-5-methyl-1 H-pyrazole

1H NMR (400 MHz, chloroform-d) δ 7.53 (approx. s, 1H), 7.36-7.27 (m, 2H), 7.29-7.21 (m, 1H), 7. 15-7.08 (m, 2H), 3.81 (s, 2H), 2.42 (s, 3H).

LC-MS: purity 98%, MS (m/e) 173 (M-HC1+H) ⁺ .

tert-Butyl-3-(4-fluorobenzyl)-1 H-pyrazole-1-carboxylate

1H NMR (400 MHz, chloroform-d) δ 7.94 (dd, J=2.8, 0.7 Hz, 1H), 7.25-7.12 (m, 2H), 7.06-6, 84 (m, 2H), 6.06 (dd, J=2.8, 0.7 Hz, 1H), 4.00 (s, 2H), 1.64 (d, J=1.1 Hz, 9H ). ¹⁹ F NMR (376 MHz, chloroform-d) δ -116.79 (ddd, J=14.2, 9.0, 5.3 Hz).

LC-MS: purity 95%, MS (m/e) 299 (M+Na) ⁺

3-(4-Fluorobenzyl)-1H-pyrazole

1H NMR (400 MHz, DMSO-d6) δ 9.88 (br s, 2H), 7.77 (d, J=2.2 Hz, 1H), 7.33-7.23 (m, 2H) , 7.16-7.05 (m, 2H), 6.20 (d, J=2.2 Hz, 1H), 3.98 (s, 2H).

LC-MS: purity 96%, MS (m/e) 177 (M-HC1+H) ⁺

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Example 31.

In this example, the compounds of this invention were evaluated by biochemical assay using ADP-Glo™ technology.

ADP-Glo™ reagents (Promega, Madison, WI, USA) were thawed at ambient temperature. Kinase detection reagent was prepared by mixing kinase detection buffer with lyophilized kinase detection substrate.

An initial volume of 500 ml of 5X kinase reaction buffer was prepared by mixing 1000 µl 1 M MgCl2, 500 µl 1 M Tris-HCL pH 7.4, 0.5 mg/ml (25 mg) BSA and 3475 µl distilled H2O. Prepared 3 ml of 2X working volume of the stock kinase reaction buffer containing a final concentration of 100 μM DTT and 4 mM MnCl ₂ .

RIPK1 enzyme components (Rigel Pharmaceuticals, South San Francisco, CA, USA) were thawed on ice. Diluted RIPK1 was prepared in 1X kinase reaction buffer (diluted from 2X buffer) to 31 ng/well. A 166 μM working stock solution for the ATP assay was prepared in 1X kinase reaction buffer (diluted from 2X buffer).

Compounds were serially diluted in DMSO from 250 μM to a 4-fold dilution, then diluted 1:5 in 2X reaction buffer in a 96-well plate. 1.0 μl of diluted compound was added twice to a 384-well plate. 2 µl of diluted Active RIPK1 was added to a 384 well plate (do not add to column 1), 2X buffer rxn was added to column 1. AKT (Anaspec, Fremont, CA, USA) at a concentration of 150 nM was combined with an equal volume of ATP working stock solution and added 2 μl/well to a 384-well plate. The final reaction volume was 5.0 μl.

The plate was quickly centrifuged and the reaction mixture was incubated at 30°C for 30 min. Addition of 5 µl ADP-Glo™ stopped the reaction. The plate was quickly centrifuged and the reaction mixture was incubated at room temperature for 40 min. Kinase detection reagent was then added and incubated at room temperature for 30 min. The relative light unit (RLU) of the kinase reaction was determined by luminescence (0.1 s luminescence) using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA).

The IC ₅₀ values obtained in this example are given in table. 1.

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Table 1

Compound RIPK1 ADP-Glo kinase (ICso) 1-1 0.019 1-2 0.0157 1-3 0.0402 1-4 0.0568 1-5 0.0197 1-6 0.0724 1-7 0.021 1-8 0.0529 1-9 0.1892 1-10 0.0429 1-11 0.0571 1-12 0.052 1-13 0.0539 1-14 0.073 1-15 0.1359 1-16 1.633 1-17 0.4906 1-18 0.1645 1-19 0.1455 1-20 0.1528 1-21 0.077 1-22 0.048 1-23 0.0352 1-24 0.0592 1-25 0.051 1-26 0.0656 1-27 0.1583 1-28 0.0375 1-29 0.0124 1-30 0.0402 1-31 0.0334

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1-32 0.0219 1-33 0.0145 1-34 0.0492 1-35 0.0223 1-36 0.0338 1-37 0.0565 1-38 0.068 1-39 0.0364 1-40 0.0887 1-41 0.08 1-42 0.0477 1-43 0.0854 1-44 0.034 1-45 0.0825 1-46 0.0437 1-47 0.0683 1-48 0.0624 1-49 0.0604 1-50 0.0234 1-51 0.0317 1-52 0.0249 1-53 0.034 1-54 0.0269 1-55 0.0337 1-57 0.0215 1-58 0.011 1-59 0.0579 1-60 0.0644 1-61 0.0654 1-62 0.0355 1-63 0.0303 1-64 0.019

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- 166 045696

1-98 0.0296 1-99 0.1258 I-100 0.0392 1-101 0.1332 1-102 0.3833 1-103 0.049 1-104 0.581 1-105 0.0312 1-106 0.5819 1-107 0.0231 1-108 0.3137 1-109 0.0321 1-110 0.021 1-111 0.0218 1-112 0.0151 1-113 1.002 1-114 0.0202 1-115 0.024 1-116 0.0234 1-117 0.0316 1-118 0.0276 1-119 0.0598 1-120 0.0296 1-121 12.4 1-122 12.3 1-123 0.0357 1-124 0.0935 1-125 0.0262 1-126 0.0246 1-127 0.0296 1-128 0.0197 1-129 0.0352

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1-130 0.0308 1-131 0.4455 1-132 0.0305 1-133 0.1727 1-134 0.0528 1-135 0.1107 1-136 0.0267 1-137 0.0236 1-138 0.0769 1-139 0.0212 1-140 0.1244 1-141 0.4141 1-142 0.0242 1-143 0.0279 1-144 0.022 1-145 0.0275 1-146 0.0173 1-147 0.0173 1-148 0.0337 1-149 0.0396 1-150 0.0447 1-151 0.0554 1-152 0.0103 1-153 0.0326 1-154 0.0267 1-155 0.0246 1-156 0.0273 1-157 0.0316 1-158 0.0147 1-159 0.0175 1-160 0.0253 1-161 0.0362

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1-162 0.0544 1-163 0.5086 1-164 0.0717 1-165 0.0112 1-166 BUT 1-167 0.0175 1-168 BUT 1-169 But 1-170 But 1-171 But 1-172 But 1-173 But 1-174 But 1-175 0.0278 1-190 0.0145 1-191 0.0197 1-206 0.0556 1-207 0.0279 1-208 0.0172 1-209 0.1064 1-193 0.0553 1-194 0.0186 1-195 0.0153 1-210 0.0286 1-196 BUT 1-197 But 1-203 0.0234 1-198 BUT 1-211 But 1-199 But 1-200 But 1-212 0.1535

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1-213 0.0352 1-214 0.0762 1-215 0.0321 1-216 0.0188 1-217 0.0239 1-218 0.0245 1-219 0.0284 1-220 0.0355 1-221 0.0397 1-222 0.0166 1-223 0.1411 1-224 0.3124 1-225 0.0227 1-226 0.033 1-235 0.0621 1-236 0.0559 1-237 0.0431 1-239 0.0434 1-240 0.2653 1-241 0.0501 II-16 0.0452 II-17 0.5184 II-18 0.0518 II-19 0.0349 P-20 0.0403 P-21 0.0409 P-22 0.3104 P-23 1.277 P-24 0.0563 P-25 0.2258 P-26 0.193 P-27 0.0279 P-28 0.0161 P-31 0.0363 P-32 0.0505 P-33 0.1006 P-35 0.0275 P-36 0.0389 P-39 0.023

Example 32.

In this example, U937 and L929 cells were exposed to the compounds of the present invention and a cell necroptosis assay was performed to evaluate the activity of the compounds against human RIP1 and mouse RIP1.

U937 and L929 cells were obtained from the American Type Culture Collection (Manassa, VA, USA). Both cells were maintained in logarithmic growth phase in complete RPMI 1640 medium (Sigma, St. Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, St. Louis, MO, USA) at 37°C with 5% CO ₂ . For the necroptosis assay, L929 cells were seeded for 18 h in 100 μl/well of medium at 10 thousand cells/well in 96-well Costar black transparent bottom plates (Fisher Scientific, Hampton, NH, USA); U937 cells were seeded on the day of analysis in 50 μl/well of medium containing 60 μM zVAD-fmk (Lonza, Basel, Switzerland) at 50 thousand cells/well. L929 cell medium was removed from the 96-well plates and replaced with 50 μl/well of new medium containing 40 μ m zVADfmk. Each compound of the present invention evaluated in this example was serially diluted in DMSO from 2.5 mM into 4-fold dilutions and then diluted 1:125 in complete medium. Then 50

- 170045696 µl/well 2 l/well of compound was added to the cells in the plates. Cells were preincubated with compound for 1 hour at 37°C with 5% CO ₂ before adding 10 μl/well 11x TNFa (Peprotech, Rocky Hill, NJ, USA) to obtain a final concentration of 2 ng/ml TNFa. The relative number of necroptotic cells was determined by luminescence using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA) and CellTiter-Glo® Luminescent Cell Viability Assay Reagent (Promega, Madison, WI, USA) added according to the manufacturer's instructions after 18 h TNFa stimulation at 37°C with 5% CO ₂ . The results of this example are shown in table. 2. This example establishes that embodiments of the compounds described herein have unexpectedly potent activity against human RIP1 and mouse RIP1, allowing them to be evaluated in in vivo mouse models of disease. These results are suitable for determining safe and effective doses for humans.

____________ Table 2

Compound L929-CTGisolation, L929, TNFa+zVAD (IC50) U937 Zvad TNF CTG selection, U937, TNFa+zVAD (IC50) 1-1 2,356 0.0027 1-2 BUT 0.0319 1-3 0.4278 0.0049 1-4 BUT 0.0293 1-5 0.0188 0.0005 1-6 97.54 0.0438 1-7 1.959 0.0009 1-8 0.0092 0.0014 1-9 BUT 0.3623 1-10 11.23 0.0079 1-11 14.1 0.0081 1-12 41.95 0.0053 1-13 BUT 0.0138 1-14 5,878 0.0114 1-15 2.2 0.0048 1-16 5,669 0.0517 1-17 0.3683 0.0024 1-18 0.2797 0.0013 1-19 1,302 0.0027 1-20 53.37 0.0136 1-21 1,306 0.0025 1-22 3,383 0.0048 1-23 14.5 0.0067 1-24 4,608 0.0036 1-25 0.4895 0.0027

- 171 045696

1-26 0.6131 0.0044 1-27 But 0.0697 1-28 0.6735 0.0054 1-29 0.0088 0.0023 1-30 0.0723 0.0036 1-31 BUT 0.0337 1-32 17.74 0.0027 1-33 1.227 0.0015 1-34 9,592 0.0222 1-35 0.0178 0.0031 1-36 0.0014 0.0022 1-37 0.0002 0.001 1-38 0.0005 0.0036 1-39 0.0004 0.0027 1-40 0.0003 0.0023 1-41 0.0016 0.0052 1-42 0.0012 0.0033 1-43 0.0009 0.0038 1-44 0.0002 0.0011 1-45 0.0003 0.0014 1-46 0.0004 0.0012 1-47 0.0015 0.0046 1-48 0.0005 0.0016 1-49 0.0012 0.005 1-50 0.0003 0.0011 1-51 0.0005 0.0017 1-52 0.0003 0.0009 1-53 0.0005 0.0018 1-54 0.0003 0.0009 1-55 0.0006 0.002

- 172045696

1-57 0.0009 0.003 1-58 0.0002 0.0008 1-59 0.0007 0.0019 1-60 0.0024 0.0048 1-61 0.0013 0.0034 1-62 0.0007 0.002 1-63 0.0003 0.001 1-64 0.0001 0.0005 1-65 0.0415 0.042 1-66 0.0949 0.1886 1-67 0.0085 0.0152 1-68 0.0003 0.0007 1-69 0.0009 0.0022 1-70 0.0195 0.1876 1-71 0.0002 0.0009 1-73 0.0027 0.0117 1-74 0.0002 0.0014 1-75 0.0014 0.0083 1-76 0.0024 0.0181 1-77 0.0003 0.0028 1-78 0.0009 0.0025 1-79 0.0008 0.0051 1-80 0.0007 0.0027 1-81 0.0012 0.0042 1-82 0.0003 0.0019 1-83 0.0001 0.001 1-84 0.0122 0.0563 1-85 0.0006 0.0033 1-86 0.0006 0.0041 1-87 0.0292 0.1385

- 173 045696

- 174 045696

1-118 0.083 0.001 1-119 4,054 0.0146 1-120 0.0615 0.0005 1-121 BUT* 30.31 1-122 But* 40.39 1-123 0.0535 0.0006 1-124 2.117 0.0887 1-125 0.1157 0.0098 1-126 0.0553 0.0035 1-127 0.0406 0.0003 1-128 0.0422 0.0006 1-129 0.0241 0.0007 1-130 0.0895 0.0015 1-131 0.0658 0.0037 1-132 4,603 0.0359 1-133 BUT* 0.4924 1-134 0.6079 0.0274 1-135 2.63 0.2241 1-136 4,969 0.0152 1-137 0.3329 0.005 1-138 3.146 0.1223 1-139 0.5384 0.0077 1-140 0.1086 0.0046 1-141 0.1203 0.0022 1-142 0.0773 0.0014 1-143 0.1973 0.0035 1-144 0.1565 0.0012 1-145 3,049 0.0086 1-146 0.0183 0.0004 1-147 0.1537 0.0012

- 175 045696

1-148 0.3591 0.0052 1-149 11.57 0.03 1-150 BUT* 0.0831 1-151 1,081 0.017 1-152 2,509 0.0391 1-153 1.238 0.0161 1-154 0.6564 0.0035 1-155 0.3127 0.0013 1-156 10.26 0.0554 1-157 5,161 0.0255 1-158 1.645 0.0095 1-159 16.07 0.021 1-160 0.0442 0.0009 1-161 5061 0.0455 1-162 HO* 1.656 1-163 But* 3.317 1-164 0.0319 0.0007 1-165 0.0471 0.0009 1-166 0.0277 0.001 1-167 1.211 0.0053 1-168 0.103 0.0009 1-169 0.148 0.0022 1-170 1.835 0.0148 1-171 0.3943 0.0064 1-172 0.8495 0.0221 1-173 2,863 0.0485 1-174 16.52 0.4379 1-175 0.1072 0.009 1-190 0.0205 0.0006 1-191 0.0215 0.0003

- 176 045696

1-206 0.0415 0.0006 1-207 0.1158 0.0005 1-208 0.0975 0.0006 1-209 5001 0.0595 1-193 7,062 0.3612 1-194 0.0325 0.0006 1-195 0.2683 0.0011 1-210 0.4701 0.0042 1-196 0.201 0.0033 1-197 0.0706 0.0007 1-203 0.004 0.0004 1-198 0.0391 0.0009 1-211 0.0448 0.0011 1-212 0.2674 0.0043 1-213 0.0455 0.001 1-214 0.3515 0.004 1-215 0.0209 0.0003 1-216 0.0285 0.0005 1-217 0.5968 0.0005 1-218 0.0758 0.0026 1-219 0.0236 0.0006 1-220 1,921 0.0089 1-221 0.0722 0.0025 1-222 0.0625 0.0014 1-223 10.34 0.6274 1-224 0.2203 0.0015 1-225 0.0325 0.0005 1-226 1.773 0.017 1-235 1,071 0.0132 1-236 0.2583 0.0066 1-237 15.53 0.135 1-239 0.2178 0.0088 1-240 0.9435 0.0151 1-241 2,095 0.0626 II-16 2.122 0.0034 II-17 BUT 1,492 II-18 6,638 0.2864 II-19 2,894 0.0555 P-20 14.62 0.0316 P-21 3,442 0.0143 P-22 55.98 0.5803 P-23 BUT 0.5449 P-24 7,912 0.0166 P-25 0.2023 0.0024 P-26 BUT 0.5101 P-27 10.45 0.0633 P-28 2.22 0.0083 P-31 0.6543 0.008 P-32 0.0574 0.0021 P-33 0.0331 0.0018 P-35 0.1643 0.0007 P-36 0.1316 0.0016 P-39 1,348 0.0018

- 177 045696 * BUT means that no activity was detected or that the inhibition curve shows artifacts. This value does not necessarily indicate an inactive compound, but does indicate that for some reason the experiment did not produce data. For example, an insoluble compound or other experimental artifact may result in an HO value.

Example 33.

In this example, an acute hypothermia mouse model assay was used to evaluate the ability of the compounds disclosed herein to inhibit TNF-alpha-induced hypothermia.

Female C57BL/6 mice were randomly grouped and weighed on day 1. On study day (day 0), mice were gavaged with vehicle or test drug. Fifteen minutes after oral administration of the test agents, each mouse received an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor alpha (TNF-α, 25.0 μg) and zVAD-FMK (200 μg). Body temperature is measured at 0 o'clock (before intraperitoneal injections) and every hour using a device for measuring temperature with a rectal probe. Three (3) hours after intraperitoneal injections of TNF-α and zVAD/FMK, mice were euthanized by CO ₂ asphyxiation and blood was collected by cardiac puncture. Serum and plasma are collected to determine levels of cytokines and compounds, respectively. Separate groups of mice (satellite mice) were included to determine plasma compound levels during TNFa/zVAD-FMK administration.

(S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4 α-triazole-3carboxamide (WO 2014/125444), having the structure illustrated below, was used as a reference compound and tested using a similar protocol as described in WO 2014/125444. This comparative compound showed 93% inhibition at a dose of 30 mg/kg in accordance with WO 2014/125444; however, in the hands of the inventors, the compound inhibited only 70% at 30 mg/kg. In comparison, compound 1-30 of the present invention achieved greater than 85% inhibition at a dose of only 5 mg/kg using a similar assay protocol described above.

Comparative connection

In certain embodiments, the present invention provides a compound, compounds, or compositions thereof for crossing the blood-brain barrier. The disclosed compound and composition embodiments demonstrate sufficient penetration into the brain as a potential therapeutic agent for neurological diseases. Brain penetration can be assessed by assessing the free brain to plasma ratio (Bu/Pu) measured in in vivo pharmacokinetic studies in rodents. Other methods for assessing brain penetration are known to those skilled in the art. See, for example, Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008.

In the table below. 3 provides additional biological data for representative compounds of the present invention.

Table 3

COMPOUND PLASMA BRAIN C.I. Tl/2 Vss PPKo-6 PPKo-6 Attitude (Brain/Plasma) 1-180 151.0 2.3 16.4 103 251 2.44 1-127 94.8 2.1 9.2 164 160 0.98 1-181 16.4 1.1 1.0 1000 456 0.46 1-182 57.7 1.4 5.2 280 157 0.56 1-183 40.7 3.0 5.5 361 326 0.90 1-184 19.0 2.4 2.6 783 731 0.93 1-137 40.6 1.3 4.0 396 - - 1-139 16.9 2.6 2.7 856 1100 1.29 1-185 11.7 2.7 2.6 1140 418 0.37 1-155 64.4 2.3 11.9 220 373 1.70

In view of the many possible embodiments to which the principles of the present disclosure may be applied, it is recognized that the illustrated embodiments are preferred examples only and should not be construed as limiting. Rather, the scope of the present disclosure is defined by the following claims. We therefore declare that everything within the scope and spirit of these claims is our invention.

Claims (13)

1. Connection selected from: I-98: (S)-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-4-phenoxypicolinamide; I-99: (S)-N-(5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b ] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-100: (S)-4-(4-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-101: (S)-N-(7-(3,3-dimethylbum-1-un-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-(4-fluorophenoxy)picolinamide; I-102: (S)-N-(7-(3,3-dimethylbum-1-un-1-ul)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxαzepin-3-yl)-4-(2-fluorophenoxy)picolinamide; I-103: (S)-4-(2-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-104: (S)-4-(2,4-difluorophenoxy)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-105: (S)-4-(2,4-difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2 ,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-106: (S)-N-(7-(3,3-dimethylbut-1-un-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-(3-fluorophenoxy)picolinamide; I-107: (S)-4-(3-fluorophenoxy)-I-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-108: (S)-N-(7-isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide ; I-109: (S)-N-(7-(4-hydroxy-3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-110: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-4-phenoxypicolinamide; I-111: (S)-4-(4-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-112: (S)-4-(2-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-113: (R)-N-(7-(3 -hydroxy-3-methylbut-1 -in-1 -yl)-5 -methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-114: (S)-4-(2,4-difluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4, 5tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-115: (S)-4-(3-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-116: (S)-N-(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-117: (S)-N-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1, 4]oxazepin-3-yl)-4-phenoxypicolinamide; I-118: (S)-4-(2,6-difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2 ,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-119: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-6-methyl-4-phenoxypicolinamide; I-120: (S)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-4-phenoxypicolinamide; I-121: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-122: (S)-4-(3-fluorophenoxy)-I-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-123: (S)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-124: (S)-4-(2,6-dimethylphenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2 ,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-125: (S)-4-(4-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-126: (S)-4-(4-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-127: (S)-N-(5-methyl-7-((3-methyloxetαn-3-ul)ethyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]ok- 179 045696 sazepin-3-yl)-4-phenoxypicolinamide; I-128: (S)-N-(7-((3-methoxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-4-phenoxypicolinamide; I-129: (S)-N-(7-((3-fluoroxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]osazepin-3-yl)-4-phenoxypicolinamide; I-130: (8)-3-((5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein7-yl)ethynyl )oxetan-3-yl(3-morpholinoiroyl)carbamate; I-131: (S)-N-(7-((4-hydroxy-1-(4-phenoxyiicolinoyl)iieridin-4-yl)ethynyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo [b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-132: (S)-N-(7-((4-hydroxyiiieridin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazein-3-yl)-4-phenoxyicolinamide; I-133: (S)-4-(4-fluorophenoxy)-N-(7-((4-hydroxyiiieridin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[ b][1,4]oxazein-3-yl)icolinamide; I-134: (S)-N-(7-((1-acetyl-4-hydroxyiiieridin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-4-(4-fluorophenoxy)icolinamide; I-135: (S)-4-(4-fluorophenoxy)-N-(7-((4-hydroxy-1-methyliieridin-4-yl)ethynyl)-5-methyl-4-oxo2,3,4, 5-tetrahydrobenzo[b][1,4]oxazein-3-yl)icolinamide; I-136: (S)-N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazein-3-yl)-4-phenoxyicolinamide; I-137: (S)-N-(7-((3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-138: (S)-4-(4-fluorophenoxy)-N-(5-methyl-7-(5-(methylamino)-3-methylenient-1 -in-1 -yl)-4-oxo2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)icolinamide; I-139: (S)-N-(7-(3-amino-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-140: (S)-N-(7-(3,3-dimethyl-4-morpholinobut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-141: tert-butyl-((S)-1-((2,2-dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3, 4,5tetrahydrobenzo[b][1,4]oxazein-7-yl)but-3-yn-1-yl)oxy)-1-oxoiroyan-2-yl)-12-azancarboxylate; I-142: 2,2-dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4] oxazein-7-yl)but-3-yn-1-yl-L-alaninate; I-143: (S)-N-(7-((3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazein-3-yl)-4-phenoxyicolinamide; I-144: (S)-4-((2,2-dimethyl-4-(5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazein-7-yl)but-3-in-1-yl)oxy)-4-oxobutanoic acid; I-145: (2R,3R)-2,3-diacetoxy-4-((2,2-dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxyicolinamido)2, 3,4,5-tetrahydrobenzo[b][1,4]oxazein-7-yl)but-3-yn-1-yl)oxy)-4-oxobutanoic acid; I-146: (S)-N-(7-((3-fluoro-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-147: (R)-4-((3-((5-methyl-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein-7yl)ethynyl )oxetan-3-yl)oxy)-4-oxobutanoic acid; I-148: (S)-4-(4-fluorophenoxy)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2 ,3,4,5tetrahydrobenzo[b][1,4]oxazein-3-yl)icolinamide; I-149: (S)-N-(7-((3-oxa-9-azasiiro[5.5]undecan-9-yl)methyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-150: (S)-N-(7-((7-oxa-2-azasiiro[3.5]nonan-2-yl)methyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-151: (S)-N-(7-((3-hydroxy-1-(2,2,2-trifluoroacetyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazein-3-yl)-4-phenoxyicolinamide; I-152: (S)-4-cyclobutoxy-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazein-3-yl)icolinamide; I-153: (S)-4-cyclobutoxy-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)icolinamide; I-154: (S)-N-(7-((3-methoxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazein-3-yl)-4-phenoxyicolinamide; I-155: (S)-N-(7-((3-methoxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-156: (S)-4-(cycloientyloxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4 ,5tetrahydrobenzo[b][1,4]oxazein-3-yl)icolinamide; I-157: (S)-4-(cycloientyloxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazein-3-yl)icolinamide; I-158: (S)-N-(5-methyl-7-(3 -methyl-3-(4-methyliiyerazin-1 -yl)but-1 -in-1 -yl)-4-oxo-2, 3,4,5-tetra- 180 045696 hydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide: I-159: methyl-(S)-3-(5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7 - yl)propiolate; I-160: 3-((^)-5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein7-yl)ethynyl) oxetan-3-yl-b-valinate; I-161: (S)-3-(5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein7-yl)yroiolic acid ; I-162: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazein-3-yl)-4-methoxyicolinamide; I-163: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ] [1,4]oxazein-3-yl)-4-methoxyicolinamide; I-164: 3-(((S)-5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein7-yl)ethynyl )oxetan-3-yl-L-valinate salt of benzenesulfonic acid; I-165: (S)-4-((3-((5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein -7-yl)ethynyl)oxetan-3-yl)oxy)-4-oxobutanoic acid tris salt; I-166: (S)-N-(7-((3-fluoro-1-isoiroylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-167: (S)-N-(7-(3-amino-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-phenoxyiicolinamide hydrochloride; I-168: (S)-N-(7-((3-fluoro-1-(2,2,2-trifluoroethyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-169: (S)-N-(7-((1 -(cycloiroylmethyl)-3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-170: (S)-4-((4-(3-(4-(4-fluorophenoxy)icolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]oxazein-7-yl)-2,2-dimethylbut-3-yn-1-yl)oxy)-4-oxobutanoic acid; I-171: 4-((S)-3-(4-(4-fluorophenoxy)icolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein -7 -yl)-2,2-dimethylbut-3-yn-1 -yl-L-alaninate; I-172: 4-((S)-3-(4-(4-fluorophenoxy)icolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein -7 -yl)-2,2-dimethylbut-3-yn-1 -yl-L-valinate; I-173: (S)-2,2-dimethyl-4-(5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4] oxazein-7-yl)but-3-yn-1-yl dihydrogen phosphate; I-174: (S)-4-(3-(4-(4-fluorophenoxy)icolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein -7-yl)-2,2-dimethylbut-3-yn-1-yl dihydrogen phosphate. I-175: (S)-4-(4-fluorobenzyl)-N-(7-((4-hydroxytetrahydro-2H-iiran-4-yl)ethynyl)-5-methyl-4-oxo2,3,4, 5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yirazol-1-carboxamide; I-177: (S)-N-(5-methyl-7-((6-methyliiridin-2-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazein-3-yl)-4-phenoxyiicolinamide I-178: (S)-4-(4-fluorobenzyl)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5- tetrahydro-1H-benzo[b]azein-3-yl)-1H-irazol-1-carboxamide; I-179: (S)-1-benzyl-4-fluoro-N-(5-methyl-7-((6-methyliiridin-2-yl)ethynyl)-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazein-3-yl)-1 H-yirazol-3-carboxamide; I-180: (S)-4-(4-fluorobenzyl)-N-(5-methyl-7-((3-methyloxetan-3-yl)ethynyl)-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yirazol-1-carboxamide; I-181: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azasiiro[4.5]decan-2-yl)-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yirazol-3-carboxamide; I-182: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(7-oxa-2-azasiiro[3.5]nonan-2-yl)-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yirazol-3-carboxamide; I-183: (S)-4-(4-fluorobenzyl)-N-(5-methyl-7-((6-methyliiridin-2-yl)ethynyl)-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yirazol-1-carboxamide; I-184: (S)-4-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azasiiro[3.5]nonan-2-yl)-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yirazol-1-carboxamide; I-190: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazein-3-yl)-4-(phenoxy-d5)icolinamide; I-191: (S)-N-(7-((1-acetyl-3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-192: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazein-3-yl)-4-((6-methyliiridin-3-yl)oxy)icolinamide; I-193: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-((6-methyliiridin-3-yl)oxy)icolinamide; I-194: 3-(((S)-5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein7-yl)ethynyl )oxetan-3-yl-L-alaninate salt of trifluoroacetic acid; I-195: (S)-N-(7-((3-hydroxy-1-isoiroylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydr- 181 045696 robenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-196: (S)-N-(7-((1-(cycloiroylmethyl)-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-197: (S)-N-(7-((1-acetyl-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-198: (S)-N-(7-((1-(ethylcarbamoyl)-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-199: ^)-3-((5-methyl-4-oxo-3-(4-phenoxyicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein7-yl)ethynyl) oxetan-3-ylethylcarbamate; I-200: (S)-N-(7-((3-hydroxy-1-neoientyl azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-203: (S)-N-(5-methyl-7-(( 1 -methyl-1 H-imidazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-204: (S)-N-(7-(3-(butylamino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-205: (S)-N-(7-(3-((4-fluorobenzyl)amino)-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-206: (S)-N-(5-methyl-7-(3-methyl-3-morpholinobut-1-in-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-207: (S)-N-(7-((4-hydroxy-1,1-dioxidotetrahydro-2H-thioiran-4-yl)ethynyl)-5-methyl-4-oxo2,3,4,5- tetrahydrobenzo[b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-208: (S)-N-(7-((3-hydroxy-1-oxidothietane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-209: (S)-N-(7-((3-hydroxy-1,1-dioxidothietane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b] [1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-210: (S)-N-(5-methyl-7-(3-methyl-3-(iirrolidin-1-yl)but-1-in-1-yl)-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-211: (S)-N-(7-(3-(1,1-dioxidothiomorpholino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; I-212: (S)-4-benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazein-3-yl)-1 H-irazol-1-carboxamide; I-213: (S)-4-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazein-3-yl)-1 H-yirazol-1-carboxamide; I-214: (S)-4-benzyl-N-(5-methyl-4-oxo-7-(iridin-3-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4] oxazein-3-yl)-1 H-irazol-1-carboxamide; I-215: (S)-4-benzyl-N-(5-methyl-4-oxo-7-(iridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4] oxazein-3-yl)-1 H-irazol-1-carboxamide; I-216: (S)-4-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-1 H-irazol-1-carboxamide; I-217: (S)-4-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azasiiro[3.5]nonan-2-yl)-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazein-3-yl)-1 H-yirazol-1-carboxamide; I-218: (S)-4-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yrazol-1-carboxamide; I-219: (S)-4-benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazein-3-yl)-1 H-irazol-1-carboxamide; I-220: (S)-4-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazein-3-yl)-5-methyl-1H-yirazol-1-carboxamide; I-221: (S)-4-(4-fluorobenzyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-1 H-irazol-1-carboxamide; I-222: (S)-4-(4-fluorobenzyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yirazol-1-carboxamide; I-223: (S)-3-(4-fluorobenzyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-1 H-irazol-1-carboxamide; I-224: (S)-4-(4-fluorobenzyl)-N-(7-((2-hydroxysiiro[3,3]geitan-2-yl)ethynyl)-5-methyl-4-oxo-2, 3,4,5tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yrazol-1-carboxamide; I-225: (S)-4-(4-fluorobenzyl)-N-(7-((6-hydroxy-2-oxasiiro[3.3]geitan-6-yl)ethynyl)-5-methyl-4-oxo2, 3,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yirazol-1-carboxamide; I-226: (S)-N-(7-(3-amino-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-(4-fluorobenzyl)-1 H-irazol-1-carboxamide; I-227: (S)-4-(4-fluorobenzyl)-N-(5-methyl-7-(3 -methyl-3 -(4-methyliiyerazin-1 -yl)but-1 -in-1 -yl ))-4oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-1 H-yirazol-1-carboxamide; I-228: (S)-4-benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl) -1H- 182 045696 pyrazole-1-carboxamide; I-229: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-4-( 4-fluorobenzyl)-1 H-pyrazole-1 carboxamide; I-230: (8)-4-benzyl-H-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl) -5methyl-1 H-irazol-1-carboxamide; I-231: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-3-( 4-fluorobenzyl)-1 H-irazol-1-carboxamide; I-232: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-5-( 4-fluorobenzyl)-1H-irazole-1-carboxamide; I-233: (S)-5-benzyl-N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazein-3-yl)-1 H-1,2,4-triazole-3-carboxamide; I-234: (S)-5-benzyl-N-(7-((3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazein-3-yl)-1 H-1,2,4-triazol-3-carboxamide; I-235: (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azasiiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-5-(1-phenylcycloyl)-1,3,4-oxadiazol-2-carboxamide; I-236: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azasiiro[3.5]nonan-2-yl)-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazein-3-yl)-1,3,4-oxadiazol-2-carboxamide; I-237: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)-4-( 2,4-difluorobenzyl)-1H-irazole-1-carboxamide; I-238: (S)-4-(2,4-difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2 ,3,4,5tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yrazol-1-carboxamide; I-239: (S)-4-(2,4-difluorobenzyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo 2,3,4,5tetrahydrobenzo[b][1,4]oxazein-3-yl)-1H-yrazol-1-carboxamide; I-240: tert-butyl-(S)-(4-(3-(4-(2,4-difluorobenzyl)-1H-irazol-1-carboxamido)-5-methyl-4-oxo2,3,4, 5-tetrahydrobenzo[b][1,4]oxazein-7-yl)-2,2-dimethylbut-3-yn-1-yl)carbamate; I-241: (S)-N-(7-(4-amino-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazein-3-yl)-4-(2,4-difluorobenzyl)-1H-yirazol-1-carboxamide hydrochloride; II-16: (S)-N-(5-methyl-4-oxo-8-(iridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein-3yl) -4-phenoxycolinamide; II-17: (S)-4-(4-cyanophenoxy)-N-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazein-3-yl)icolinamide; II-18: (S)-4-(4-cyanophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazein-3-yl)icolinamide; II-19: (S)-4-(4-cyanophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazein-3-yl)icolinamide; II-20: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-phenylicolinamide; II-21: (S)-4-(3-cyanophenoxy)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazein-3-yl)icolinamide; II-22: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-(4-methoxyphenyl)icolinamide; II-23: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-(3-methoxyphenyl)icolinamide; II-24: (S)-N-(7-(3-amino-3-oxoyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazein- 3yl)-4-phenoxyiicolinamide; II-25: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazein-3-yl)-4-phenoxyiicolinamide; II-26: (S)-N-(5-methyl-4-oxo-8-(3-oxa-9-azasiiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; II-27: (S)-N-(5-methyl-7-(9-methyl-3,9-diazasiiro[5.5]undecan-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; II-28: (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azasiiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; II-31: (S)-N-(5-methyl-4-oxo-7-(8-oxa-2-azasiiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; II-32: (S)-N-(7-(3-methoxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazein-3-yl)-4-phenoxyiicolinamide; II-33: (S)-N-(7-((6-cyanoiridin-2-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazein3-yl)-4-phenoxyicolinamide; II-35: (S)-N-(7-(3-hydroxyiroo-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazein-3yl)-4-phenoxyiicolinamide; II-36: (S)-N-(7-(3-(dimethylamino)iroi-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]ok- 183 045696 sazepin-3-yl)-4-phenoxypicolinamide or II-39: N-((3S)-5-methyl-4-oxo-7-(pyrrolidin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin3-yl) -4-phenoxypicolinamide. 2. The connection according to claim 1, which is or a pharmaceutically acceptable salt thereof. 3. The connection according to claim 1, which is or a pharmaceutically acceptable salt thereof. 4. The connection according to claim 1, which is or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition containing a compound according to claim 1, as well as an excipient, a therapeutic agent or combinations thereof. 6. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the treatment of a disease in a subject, wherein the subject has or is suspected of having or developing a disease involving receptor-interacting protein 1 (RIP1) kinase. 7. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the treatment of a disease involving inflammation and/or necroptosis. 8. Use according to claim 7, characterized in that the disease is an inflammatory or immunoregulatory disorder. 9. Use according to claim 7, characterized in that the disease is a senile disorder. 10. Use according to claim 7, characterized in that the disease is selected from amyotrophic lateral sclerosis (ALS), autoimmune syndrome, rheumatoid arthritis, type I diabetes, inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, internal asthma, external asthma, dust asthma, chronic or inveterate asthma, advanced asthma and airway hyperresponsiveness, allergic rhinitis, spondyloarthritis, Ankylosing spondylitis, autoimmune hepatitis, autoimmune diseases of the hepatobiliary system, cerebrovascular accidents, allergic diseases, chronic obstructive pulmonary disease, emphysema, Friedreich's ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr's disease, Menke's disease, disease Wilson, prion disorder, destructive bone diseases, preferably bone resorption disease, multiple myeloma-related bone diseases; benign tumor, proliferative diseases, inflammatory and hyperproliferative skin diseases, epidermal hyperproliferation, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, erythematous dermatitis multiforme, linear IgA bullous dermatitis, cemental dermatitis, gingivitis, periodontitis, gum damage, alveolar bone, bone substance sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, obesity, eosinophilic fasciitis, acne, alopecia areata, alopecia male type, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, alkaline corneal burn, Behçet's disease, uveitis associated with Behçet's disease, keratitis, herpetic keratitis, conical cornea, epithelial corneal dystrophy, corneal leukoma, ocular pemphigus, Moray's ulcer, scleritis, Vogt's syndrome - Koyanagi-Harada, hematological disorders, hematological malignancies, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, ABC diffuse large B-cell lymphoma (DLBCL), macroglobulin Waldenström'semia, primary cutaneous T-cell lymphoma, indolent or indolent multi- - 184 045696 female myeloma, leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymph plasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1 disorders, MyD88 disorders, drug-resistant malignancies, preferably an inhibitor JAK-resistant malignancies and ibrutinib-resistant malignancies, preferably ibrutinib-resistant hematological malignancies, ibrutinib-resistant CLL and ibrutinib-resistant Waldenström macroglobulinemia, acute myelogenous leukemia, chronic myelogenous leukemia; angiogenic disorders, preferably angiogenic disorders including solid tumors, ocular neovascularization, hemangiomas, preferably infantile hemangiomas; sepsis, septic shock, shigellosis; migraine, bronchitis, gastric ulcers, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 conversion-related fever syndrome, periodic syndrome, tumor necrosis factor receptor-associated deficiency syndrome NEMO, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage disease, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, disease Farber's, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, early-life free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipophus scinosis , Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, Wolman disease, Huntington disease, Parkinson disease, neurodegenerative diseases, Huntington disease, Parkinson disease, metastatic melanoma, HIV-associated neurodegeneration and CMV retinitis, preferably associated neurocognitive disorders or dementia, fibrotic conditions, preferably non-alcoholic steatohepatitis, and cardiac conditions, preferably ischemia reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythematosis, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia , Reiter's syndrome, rubella arthritis, acute synovitis, pancreatic β-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis, psoriatic arthritis and other arthritic conditions, cerebral malaria, chronic inflammatory pulmonary disease, silicosis, pulmonary sarcoidosis, pulmonary fibroids, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgia due to infection, keloid formation, formation scar tissue, fever, flu, chronic myelogenous leukemia; angiogenic disorders, including solid tumors; viral diseases, including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), AIDS, ARC or malignancy, herpes; stroke, myocardial infarction, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardial ischemia, ischemia during stroke infarction, organ hypoxia, vascular hyperplasia, reperfusion damage to the heart and kidneys, ischemia-reperfusion damage to organs that occurs during conservation, transplantation or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, prostaglandin endoperoxidase syndase-2-related conditions, pemphigus vulgaris, autoimmune/multiple myositis, dermatomyositis, leukoderma vulgaris, photoallergic sensitivity, ischemia, reperfusion injury, cardiac ischemia , reperfusion injury due to myocardial infarction, multiple system atrophy, Parkinson plus syndromes, frontotemporal dementia, intracranial hemorrhage, cerebral hemorrhage, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, demyelinating diseases, systemic juvenile idiopathic arthritis (JIA) or Still's disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), kidney transplantation, surgery, acute renal failure (AKI), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), COVID-19 ARDS, post-infectious autoimmune diseases, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis , - 185 045696 cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO deficiency syndrome (basic F-kappa B modulator gene deficiency syndrome (also known as IKK gamma or IKKG)), parenchymal organ malignancies, lysosomal diseases storage, glaucoma, retinal degenerative disease, retinal ischemia/reperfusion injury, renal ischemia reperfusion injury, cataracts, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, septic shock caused by lethal anthrax toxin death cells, LPS-induced, infectious encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic scleroderma, macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, toxic retinitis and light-induced toxicity , macular edema, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, ischemic optic neuropathy (preferably anterior ischemic neuropathy with arteritic or non-arteritis and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (preferably Leber optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, dominant no optic neuropathy, syndrome Beer, Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paresis, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, anoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia and hypoxic hypoxia, peritoneal dialysate-induced peritoneal injury (PDF) and side effects associated with PD, glomerular diseases, tubulointerstitial diseases, interstitial nephritis, obstruction, polycystic kidney disease), focal glomerulosclerosis, immune complex nephropathy, diabetic nephropathy, Goodpasture's syndrome, hepatocellular carcinoma, pancreatic cancer, urological cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostate hyperplasia, kidney cancer, renal cancer, liver cancer, adrenal cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, stomach cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, neuroendocrine cancer, central nervous system cancer, brain tumors (preferably brain carcinoma, glioma, anaplastic oligodendroglioma, glioblastoma multiforme adult and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusions, malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblastic neoplasms, epithelial neoplasia, gastric carcinoma, ovarian carcinoma, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, adenoma , adenocarcinomas, keratoantomalics, epidermoid cancer, large -cell cancer, lung non -cell cancer, lymphomas, colon cancer, colorectal adenoma, hemangiopericitis, microdidal carcinoma, coil -cell carcinoma, plane cell cells, and plane cell carcinoma, carcinoma mouth, vulva cancer, adrenal cortex cancer, ACTH-producing tumors and leukemia, respiratory infectious viruses, preferably influenza virus, rhinovirus, corona virus, parainfluenza virus, PC virus, adenovirus, or reovirus), herpes zoster virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infectious diseases, preferably Bacillus cereus, Vibrio parahaemolyticus, enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRS A, Salmonella, Botulinus, Candida, Paget's disease, achondroplasia, osteochondrosis, hyperparathyroidism, osteogenesis imperfecta, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis necrosis, shock necrosis, anoxia necrosis, B viral hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), acetaminophen toxicity , hepatotoxicity, liver failure, fulminant liver failure, late-onset liver failure, acute chronic liver failure, chronic kidney disease, kidney damage/trauma, nephritis-induced kidney damage/trauma, transplant-induced kidney damage/trauma - 186 045696 kidney, kidney damage/trauma caused by surgery, kidney damage/trauma caused by administrative intervention, taking nephrotoxic drugs, increased chemotherapy effect, cytomegalovirus infection, CMV infection, AIDS, cancer, senile dementia, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, hypobaropathy, diseases caused by histamine or leukotriene-C4 release, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure , toxicosis caused by pulmonary oxygen or drugs, congenital hypophosphatasia, fibromatous lesions, fibrous dysplasia, bone metabolism, osteolytic bone disease, treatment of post-traumatic bone surgery, treatment after joint replacement, treatment after plastic surgery on bones, treatment after dental surgery, chemotherapy treatment bone or bone radiation therapy treatment, bone cancer, fragile plaque, disorder, occlusive disorder, stenosis, coronary artery disease, peripheral artery disease, arterial occlusion, neurosm formation, post-traumatic aneurysm formation, restenosis, postoperative graft occlusion, Guillain-Barré syndrome, disease Meniere's, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoito's thyroiditis, myasthenia gravis, cold and heat agglutinin disease, Evan's syndrome, hemolyticouremic syndrome a/thrombotic thrombocytopenic purpura (HUS/TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, or a combination thereof. 11. Use according to claim 7, characterized in that the disease is myelodysplastic syndrome. 12. Use according to claim 7, characterized in that the disease is atopic dermatitis, rheumatoid arthritis or ankylosing spondylitis. 13. Use according to claim 7, characterized in that the disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or multiple sclerosis.