RIP1 Inhibitory Compounds and Methods for Their Preparation and Use

Abstract

Kinase inhibitory compounds are disclosed herein, such as receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and / or combinations can be used to treat or prevent kinase-related diseases or disorders, particularly RIP1-related diseases or disorders.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of the earlier filing dates of U.S. Provisional Application No. 62 / 897,223, filed September 6, 2019; U.S. Provisional Application No. 62 / 932,404, filed November 7, 2019; U.S. Provisional Application No. 63 / 004,290, filed April 2, 2020; U.S. Provisional Application No. 63 / 001,016, filed March 27, 2020; U.S. Provisional Application No. 63 / 004,301, filed April 2, 2020; and U.S. Provisional Application No. 63 / 004,319, filed April 2, 2020.

[0003] Field

[0004] The present disclosure relates to compounds and methods of making and using such compounds, such as for inhibiting receptor - interacting protein - 1 kinase (“RIP1”) and for treating diseases and / or disorders associated with RIP1.

[0005] Background

[0006] 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 regulating cell signaling and its role in programmed cell death has been associated with a variety of inflammatory diseases, such as inflammatory bowel disease, psoriasis, and other diseases and / or disorders associated with inflammation and / or programmed necrotic cell death.

[0007] Summary

[0008] The compounds disclosed according to the present disclosure can have Formula I

[0009]

[0010] or a pharmaceutically acceptable salt, N - oxide, solvate, tautomer, or stereoisomer thereof. Referring to Formula 1, Ring B is a 5 - or 6 - membered heteroaryl, wherein the heteroaryl has at least one ring atom and the remaining ring atoms are carbon; L is a heteroatom or R a , provided that R a is not H or D; Z is C 1-10 an aliphatic group, including an alicyclic group, or an aryl; each R 1 is independently a halogen, - C≡CH or a - linker - R 6 group, wherein the linker is a bond or R a , provided that R a is not H or D, and R 6is a heterocyclic group, R b , -C(R f )3 or -C(R f )=C(R f )2; R 2 is R a ; R 3 is R a ; Each R 4 is independently R e ; R a is independently H or D each time it appears, where L is except for the embodiment of R a , C 1-10 aliphatic group, C 1-10 haloaliphatic group, C 1-10 heteroaliphatic group, C 5-10 aryl, C 3-6 alicyclic group or C 3-6 heteroalicyclic group; R b is independently -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)C 1-10 alkyl, the -OC(O)C 1-10 alkyl is substituted by 1 or 2 NR d R d , carboxyl or a combination thereof, and optionally further substituted by an aromatic group, -SH, -O-acyl or -C(O)NH2; R c is independently C e alkyl optionally substituted by 1, 2 or 3 R 1-10 , C e alkenyl optionally substituted by 1, 2 or 3 R 2-10 , C e alkynyl optionally substituted by 1, 2 or 3 R 2-10 , C e cycloalkyl optionally substituted by 1, 2 or 3 R 3-6 , or C e aromatic group optionally substituted by 1, 2 or 3 R 5-10 ; R d is independently H; optionally substituted by 1, 2 or 3 R e or C 3-9Heterocyclic group-substituted C 1-6 alkyl; C e alkyl which may be substituted by 1, 2 or 3 R 3-6 cycloalkyl; C e cycloalkyl which may be optionally substituted by 1, 2 or 3 R 3-6 heterocyclic group; C b heterocyclic group which may be optionally substituted by 1, 2 or 3 R 5-10 aryl; C e aryl which may be optionally substituted by 1, 2 or 3 R 5-10 heteroaryl; or 2 R d groups together with the nitrogen to which they are attached form a C e heterocyclic group which may be optionally substituted by 1 or more R 3-9 or a C e heteroaryl which may be optionally substituted by 1 or more R 5-10 ; R e is independently at each occurrence halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-10 heteroaryl or -OR a ; and R f is independently at each occurrence -alkyl-phosphate, R a , R b or R e , or 2 R f groups together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C e cycloalkyl which may be optionally substituted by 1 or more R 3-6 or a C e heterocyclic group which may be optionally substituted by 1 or more R 3-10 or acyl; m is 1, 2, 3 or 4; and n is 0, 1 or 2.

[0011] For certain embodiments, the compound is not: I-56 - ( S )-i-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-64 - ( S )- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-68 - ( S )-N -(7-(3-Hydroxy-3-(methyl- d 3)but-1-yn-1-yl-4,4,4- d 3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-72 - ( S )- N -(8-((3-Hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; or I-77 - ( S )-1-benzyl- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -pyrazole-3-carboxamide. In certain other embodiments, the compound is not I-1 to I-97 or I-187 to I-189.

[0012] For certain embodiments, ring B is pyrazolyl or pyridyl. For example, when ring B is pyrazolyl or pyridyl, L can be a heteroatom or C 1-10 aliphatic group; Z can be C 1-10 aliphatic group or aryl; each R 1 can be heterocyclic or C 1-10 aliphatic group; R 2 can be H or C 1-10 aliphatic group; R 3 can be H or C 1-10 aliphatic group; each R 4 can independently be halogen or C 1-10 aliphatic group; m can be 1, 2, 3, or 4; and n can 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 following formula:

[0013] .

[0014] Referring to specific exemplary embodiments of the disclosed pyridine- and pyrazole-type compounds, such compounds can have the formula shown below, including any and all of their stereoisomers:

[0015]

[0016] .

[0017] Referring to each of the above general formulas, the R of a specific compound 2 and / or R 3 is H or C 1-6 alkyl, such as methyl; each R 4 is independently halogen or C 1-6 alkyl, such as chlorine, fluorine or methyl; n is 0, 1 or 2; L is a heteroatom, such as oxygen, or C 1-10 alkyl or C 1-6 alkyl, such as -CH2-; and Z is aryl or C 3-6 cycloalkyl.

[0018] For a specific compound, Z is , where 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 can also be C 1-6 alkyl, such as methyl; or cycloalkyl, such as cyclobutyl or cyclopentyl. For certain embodiments, the -L-Z moiety is phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 2-fluorophenoxy, 2,4-difluorophenoxy, 2,6-difluorophenoxy, 4-fluorobenzyl, 2,6-dimethylphenoxy, cyclobutoxy, cyclopentoxy, methoxy, 4-methylphenoxy or benzyl.

[0019] For a specific compound, each R 1 is independently a heterocyclic group, an unsubstituted C 1-10 aliphatic group or a C 1-10 aliphatic group substituted with 1 or 2 substituents selected from -OH, halogen, carboxyl, carboxyl ester, heterocyclic group, amino, alkoxy, phosphate, cycloalkyl, alkenyl, -OC(O)NH(C 1-4 alkyl)-amino, -OC(O)R 8 , or -OC(O)(CHR 9 )2CO2H. The -OC(O)-R 8 substituent can be derived from an amino acid, particularly a naturally occurring amino acid, where the -OC(O)- moiety of -OC(O)-R 8 corresponds to the acid moiety on the amino acid and R 8 contains -N(R 10 )2 or a nitrogen-containing non-aromatic heterocyclic group, where R 10 is H or carboxyl ester. R 1 can also be C 1-10An alkyne or a substituted alkyne, such as an alkyne substituted with a hydroxyl group, an oxetanyl group, an azetidinyl group, a pyridyl group, a pyrrolidinyl group, a piperidinyl group, a tetrahydropyranyl group, or a phosphate group. R 1 may also be an 8- to 12-membered spiroheterocyclic group.

[0020] Exemplary disclosed compounds include Compounds I-98 to I-211 and II-1 to II-61, and include pyridine amide 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.

[0021] The disclosed embodiments also include pharmaceutical compositions comprising the disclosed compounds. Such compositions may further comprise excipients, additional therapeutic agents, or combinations thereof.

[0022] A method may include administering to a subject one or more of the disclosed compounds or a composition comprising one or more of the disclosed compounds, such as to treat a disease. In certain embodiments, the subject may have, or may be suspected of having or developing, a disease, such as a disease involving receptor-interacting protein-1 (RIP1) kinase. Examples of diseases that may be treated according to embodiments of the method include diseases or disorders associated with inflammation, necroptosis, or both. In certain embodiments, the diseases to be treated with the compounds of the invention are inflammatory or immunomodulatory disorders, including autoimmune and proliferative disorders. Exemplary diseases are disclosed herein.

[0023] The foregoing and other objects and features of the present disclosure will become more apparent from the following detailed description.

[0024] DETAILED DESCRIPTION

[0025] I. Overview of Terms

[0026] The following explanations of terms and methods are provided to better describe the present disclosure and to guide one of ordinary skill in the art in practicing the present disclosure. The singular forms "a," "an," and "the" denote one or more than one, unless the context clearly dictates otherwise. The term "or" denotes a single one of the alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, "comprising" means "including." Thus, "comprising A or B" means "including A, B, or A and B," and does not exclude additional elements.

[0027] Unless otherwise indicated, all numbers expressing quantities of ingredients, molecular weights, percentages, temperatures, times, and the like, used in the specification or claims, are to be understood as being modified by the term "about." Accordingly, unless otherwise implicitly or explicitly stated, the numerical parameters set forth are approximations that may depend upon the desired properties sought and / or the limits of detection under standard test conditions / methods. When embodiments are directly and explicitly distinguished from the prior art being discussed, the numbers for the embodiments are not approximations unless the term "about" is explicitly recited.

[0028] 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 belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0029] When depicting or describing a chemical structure, unless otherwise explicitly stated, it is assumed that all carbons include hydrogens such that each carbon satisfies the tetravalence. For example, in the left structure of the following schematic, the presence of nine hydrogen atoms is implied. Nine hydrogen atoms are depicted in the right structure.

[0030]

[0031] Sometimes, a particular atom in a structure is described in the formulas herein as having one or more hydrogen atoms, such as -CH2CH2-. One of ordinary skill in the art will understand that the techniques described above are common in the chemical arts to provide simplicity and brevity in the description of organic structures.

[0032] If the R group is depicted as "floating" on a ring system, such as R in the following group for example 1 :

[0033]

[0034] then, unless otherwise defined, the substituent R (e.g., R above 1 ) can be present on any atom of the fused bicyclic ring system, excluding the atom bearing the bond with the symbol, so long as a stable structure is formed.

[0035] When the group R is depicted as being present on a ring system containing saturated carbons, such as in the following formula:

[0036]

[0037] Wherein, in this example, y can be more than one, assuming the currently depicted, implied, or explicitly defined hydrogens on each alternative ring; then, unless otherwise defined, two R' can be present on the same carbon. A simple example is when R is a methyl group. The depicted structure can exist as gem-dimethyl on the carbon of the depicted ring ("annular" carbon). In another example, two R' on the same carbon (including that same carbon) can be included in the ring, resulting in a spiro ring ("spiro group") structure.

[0038] As used herein, the term "substituted" refers to all subsequent modifying portions of the term, e.g., in the term "substituted aryl C 1-8 alkyl", substitution can occur on the "C 1-8 alkyl" portion, the "aryl" portion, or both portions of the alkyl group. 1-8

[0039] When used to modify a specified group or moiety, "substituted" means that at least one, and possibly two or more, of the 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 can be substituted or unsubstituted, unless explicitly defined as "unsubstituted" or "substituted". Thus, any of the groups specified herein can be unsubstituted or substituted, unless the context otherwise indicates or a particular structural formula excludes substitution. In a particular embodiment, a substituent may or may not be explicitly defined as substituted, but is still considered to be optionally substituted. For example, an "aliphatic" or "cyclic" moiety can be unsubstituted or substituted, but an "unsubstituted aliphatic" or "unsubstituted cyclic" moiety is unsubstituted.

[0040] Unless otherwise indicated, a "substituent" or "substituent group" used to replace one or more hydrogen atoms on a saturated carbon atom in a specified group or moiety can be -R 60 , halogen, =O, -OR 70 , -SR 70 , -N(R 80 )2, haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -P(O)(O - )2(M +)2, -P(O)(O - )2M 2+ , -P(O)(OR 70 )O - M + , -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 70 CO2 - 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 is a C 1-10 aliphatic group, heteroaliphatic group or cycloaliphatic group, usually a C 1-6 aliphatic group, more usually a C 1-6 alkyl group, where R 60 is optionally substituted; each R 70 is independently hydrogen or R 60 at each occurrence; each R 80 is independently R 70 at each occurrence, or alternatively, 2 R 80The groups, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heteroalicyclic group which optionally includes 1 to 4 additional heteroatoms, the same or different, selected from O, N and S, where N is optionally R 70 substituted, such as H or C1-C3 alkyl substitution; and each M + is a counterion having a net single positive charge. Each M + is, independently at each occurrence, for example, an alkali metal ion such as K + , Na + , Li + ; an 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 of such a divalent alkaline earth metal ion can be the ionized form of the compound of the present disclosure and other typical counterions (such as chloride ions), or two ionized compounds can serve as the counterion of such a divalent alkaline earth metal ion, or a doubly ionized compound can serve as the counterion of such a divalent alkaline earth metal ion). As a specific example, -N(R 80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N -pyrrolidinyl, N -piperazinyl, 4 N -methyl-piperazin-1-yl, N -morpholinyl, etc. Any two hydrogen atoms on a single carbon can also be replaced, for example, by =O, =NR 70 , =N-OR 70 , =N2 or =S.

[0041] Unless otherwise indicated, the substituent groups for replacing hydrogen atoms on unsaturated carbon atoms in groups containing unsaturated carbon are -R 60 , halogen, -O - M + , -OR 70 , -SR 70 , -S - M + , -N(R 80 )2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 - M + ​​​, -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 -2 (M + )2, -PO3 - 2 M 2+ , -P(O)(OR 70 )O - M + , -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)NR 80 R 80 , -C(NR 70 )N(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 70 CO2 - 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 , R 70 , R 80 and M + are as defined previously. In a separate embodiment, the substituent is not -O- M + 、 -OR 70 、 -SR 70 or -S - M + 。

[0042] Unless otherwise indicated, the substituent group used to replace the hydrogen atom on such a nitrogen atom in a group containing a nitrogen atom is -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 、 -PO3 2- (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 、 -CO2R 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 、 -OCO2R 70 、 -OC(S)OR 70 、 -NR 70 C(O)R 70 、 -NR 70 C(S)R 70 、 -NR 70 CO2R 70 、 -NR70 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 defined previously.

[0043] 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.

[0044] Additionally, in embodiments where a group or moiety is substituted with a substituted substituent, the nesting of such substituted substituents is limited to three to prevent polymer formation. Thus, in a group or moiety containing a first group (where the first group is a substituent on a second group, the second group itself is a substituent on a third group, and the third group is attached to the parent structure), the first (outermost) group can only be substituted with an unsubstituted substituent. For example, in a group containing -(aryl - 1)-(aryl - 2)-(aryl - 3), aryl - 3 can only be substituted with its own unsubstituted substituents.

[0045] One of ordinary skill in the art will understand that any group or moiety defined herein can be attached to any other part of the disclosed structure (such as the parent structure or the core structure), such as by considering valence rules, comparing with exemplary species, and / or considering functionality, unless the connectivity of the group or moiety to the other part of the structure is explicitly stated or implied by the context.

[0046] "Acyl" means the group -C(O)R, where R is H, an aliphatic group, a heteroaliphatic group, or an aromatic group (including aryl and heteroaryl). Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C1 - C6 alkyl, -C(O)C1 - C6 haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclic group. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0047] "Aliphatic" means a group or moiety that is substantially hydrocarbon-based. An aliphatic group or moiety can be acyclic, including alkyl, alkenyl, or alkynyl groups (and alkylene, alkenylene, or alkynylene groups), its cyclic forms, such as cycloaliphatic groups or moieties, including cycloalkyl, cycloalkenyl, or cycloalkynyl, and further includes straight-chain and branched arrangements, as well as all stereoisomers and positional isomers. Unless explicitly stated otherwise, an aliphatic group contains 1 to 25 carbon atoms (C 1-25 ); for example, for an acyclic aliphatic group or moiety, 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), 1 to 6 (C 1-6 ), or 1 to 4 carbon atoms (C 1-4 ), or for a cycloaliphatic group or moiety, 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), 3 to 6 (C 3-6 ), or 3 to 4 (C 3-4 ) carbon atoms. An aliphatic group can be substituted or unsubstituted, unless explicitly referred to as an "unsubstituted aliphatic group" or a "substituted aliphatic group". An aliphatic group can be substituted 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 of the terminal methylene group).

[0048] "Lower aliphatic" means an aliphatic group containing 1 to 10 carbon atoms (C 1-10 ), such as 1 to 6 (C 1-6 ), or 1 to 4 (C 1-4 ) carbon atoms; or for a lower cycloaliphatic group, 3 to 10 (C 3-10 ), such as 3 to 6 (C 3-6 ) carbon atoms.

[0049] "Alkoxy" means the group -OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl. In certain instances, R is a C 1-6 alkyl group or a C 3-6 cycloalkyl group. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In a substituted alkoxy, R is a substituted alkyl or a substituted cycloalkyl, examples of which in the compounds disclosed herein include haloalkoxy groups, such as -OCF2H.

[0050] "Alkoxyalkyl" means the group -alkyl-OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group; -CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl group.

[0051] "Alkyl" means a saturated aliphatic hydrocarbon radical having from 1 to at least 25 carbon atoms (C 1-25 ), more usually from 1 to 10 carbon atoms (C 1-10 ), such as from 1 to 6 carbon atoms (C 1-6 ). The alkyl moiety may be substituted or unsubstituted. By way of example, the term includes straight and branched chain hydrocarbon radicals such as methyl (CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3)), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3) and neopentyl (-CH2C(CH3)3).

[0052] "Amino" means the group -NH2, -NHR or -NRR, where each R is independently selected from H, aliphatic groups, heteroaliphatic groups, aromatic groups (including aryl and heteroaryl) or heterocycloaliphatic groups, or two R groups together with the nitrogen to which they are attached form a heterocycle. Examples of such heterocycles include those in which two R groups together with the nitrogen to which they are attached form a -(CH2) 2-5 -ring which is optionally interrupted by one or two heteroatom groups such as -O- or -N(R g ), such as in the groups and wherein R g is R 70 , -C(O)R 70 , -C(O)OR 60 or -C(O)N(R 80 )2.

[0053] "Amide" means the group -N(R)acyl, where R is hydrogen, a heteroaliphatic group or an aliphatic group such as alkyl, especially C 1-6 alkyl.

[0054] Unless otherwise stated, "aromatic" means a cyclic conjugated group or moiety having from 5 to 15 ring atoms, having a single ring (e.g., phenyl, pyridyl or pyrazolyl) or multiple fused rings, in which at least one ring is aromatic (e.g., naphthyl, indolyl or pyrazolopyridyl), that is, at least one ring and optionally multiple fused rings have a continuous delocalized π-electron system. Generally, the number of out-of-plane π electrons corresponds to Hückel's rule (4n + 2). The point of attachment of the parent structure is usually through the aromatic part of the fused ring system. For example, However, in some instances, the context or explicit disclosure may indicate that the point of attachment is through a non-aromatic portion of the fused ring system. For example, An aromatic group or moiety may contain only carbon atoms in the ring, such as in an aryl group or moiety, or it may contain one or more ring carbon atoms and one or more ring heteroatoms containing lone electron pairs (e.g., S, O, N, P, or Si), such as in a heteroaryl group or moiety. Unless otherwise stated, the aromatic group may be substituted or unsubstituted.

[0055] Unless otherwise stated, "aryl" means an aromatic carbocyclic group of 6 to 15 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings, at least one of which is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, etc.). If any aromatic ring moiety contains a heteroatom, the group is heteroaryl and not aryl. An aryl group may be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, the aryl group may be substituted or unsubstituted.

[0056] "Aralkyl" means an aryl group attached to the parent via an aliphatic moiety. Aralkyl groups include aralkyl or arylalkyl groups, such as benzyl and phenylethyl.

[0057] "Carboxyl" means -CO2H.

[0058] "Carboxamide" means -C(O)amino.

[0059] "Carboxyl ester" ("carboxyl ester" or "carboxy ester") means the group -C(O)OR, where R is an aliphatic group, heteroaliphatic group, or aromatic group (including aryl and heteroaryl).

[0060] "Carboxylate" means -C(O)O - or a salt thereof.

[0061] "Cyano" means the group -CN.

[0062] "alicyclic" means a cyclic aliphatic group having a monocyclic (e.g., cyclohexyl) or polycyclic ring, such as in a fused, bridged or spiro ring system, wherein at least one of the rings or the system is aliphatic. Generally, the point of attachment to the parent structure is through the aliphatic portion of the polycyclic system. Alicyclic groups include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl and cycloalkynyl. An alicyclic group may contain from 3 to 25 carbon atoms; for example, 3 to 15, 3 to 10, or 3 to 6 carbon atoms. Unless otherwise indicated, an alicyclic group may be substituted or unsubstituted. Exemplary alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl or cyclohexenyl.

[0063] "halo", "halide" or "halogen" means fluorine, chlorine, bromine or iodine.

[0064] "haloalkyl" means an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CH2F, -CHF2 and -CF3.

[0065] "heteroaliphatic" means an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., at least one carbon atom from an aliphatic compound or group containing at least two carbon atoms has been replaced by an atom having at least one lone pair of electrons (usually nitrogen, oxygen, phosphorus, silicon or sulfur). A heteroaliphatic compound or group may be substituted or unsubstituted, branched or unbranched, chiral or achiral and / or acyclic or cyclic, such as a heteroalicyclic group.

[0066] "heteroaryl" means an aromatic group or moiety which, unless otherwise indicated, has from 5 to 15 ring atoms, said ring atoms comprising 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 a monocyclic ring (e.g., pyridyl, pyrimidinyl or pyrazolyl) or multiple fused rings (e.g., indolyl, benzopyrazolyl or pyrazolopyridinyl). A heteroaryl group or moiety may be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise indicated, a heteroaryl group or moiety may be substituted or unsubstituted.

[0067] "Heterocyclic group", "heterocycle" ("heterocyclo" and "heterocycle") denote aromatic and non-aromatic ring systems, and more specifically denote stable three- to fifteen-membered ring moieties containing at least one carbon atom, and usually multiple carbon atoms and at least one (such as 1 to 5) heteroatom. The heteroatom can be a nitrogen, phosphorus, oxygen, silicon or sulfur atom. The heterocyclic group moiety can be a monocyclic moiety, or can contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such polycyclic moieties can include fused or bridged ring systems as well as spiro ring systems; and any nitrogen, phosphorus, carbon, silicon or sulfur atom in the heterocyclic group moiety can optionally be oxidized to various oxidation states. For convenience, nitrogen, particularly but not exclusively, those defined as cyclic aromatic nitrogen are intended to include their corresponding N-oxide forms, although not explicitly defined as such in a particular instance. Thus, for a compound having, for example, a pyridyl ring, the corresponding pyridyl-N-oxide is included as another compound of the present disclosure, unless explicitly excluded or excluded by context. In addition, the cyclic nitrogen atom can optionally be quaternized. Heterocycles include heteroaryl moieties and heterocycloalkyl or heterocycloaliphatic moieties, which are partially or fully saturated heterocyclic group rings. Examples of heterocyclic group include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridyl, tetrahydropyridyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolinyl, isoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxaphospholanyl and oxadiazolyl.

[0068] "Hydroxyl" means the group -OH.

[0069] "Nitro" means the group -NO2.

[0070] "Phosphate group" means the group -O-P(O)(OR')2, where each -OR' is independently -OH; -O-aliphatic group, such as -O-alkyl or -O-cycloalkyl; -O-aromatic group, including -O-aryl and -O-heteroaryl; -O-arylalkyl; or -OR' is -O - M + , where M + is a counterion with a single positive charge. Each M + can be an alkali metal ion, such as K + , Na + , Li + ; ammonium ion, such as + N(R")4, where R" is H, aliphatic group, heteroaliphatic group or aromatic group (including aryl and heteroaryl); or alkaline earth metal ion, such as [Ca 2+ 0.5 , [Mg 2+ 0.5 or [Ba 2+ 0.5 . Phosphoryloxyalkyl represents the group -alkyl-phosphate, such as, for example, -CH2OP(O)(OH)2 or its salt, such as -CH2OP(O)(O - Na + )2, and (((dialkoxyphosphoryl)oxy)alkyl) represents a dialkyl ester of phosphoryloxyalkyl, such as, for example, -CH2OP(O)(O-tert-butyl)2.

[0071] "Phosphonate group" means the group -P(O)(OR')2, where each -OR' is independently -OH; -O-aliphatic group such as -O-alkyl or -O-cycloalkyl; -O-aromatic group, including -O-aryl and -O-heteroaryl; or -O-arylalkyl; or -OR' is -O - M + , and M + is a counterion with a single positive charge. Each M + is a positively charged counterion and can be, for example, an alkali metal ion, such as K + , Na + , Li + ; ammonium ion, such as + N(R")4, where R" is H, aliphatic group, heteroaliphatic group or aromatic group (including aryl and heteroaryl); or alkaline earth metal ion, such as [Ca 2+ 0.5 , [Mg 2+ ​​​​0.5 or [Ba 2+ 0.5 . Phosphonoalkyl represents the group -alkyl-phosphonate, such as, for example, -CH2P(O)(OH)2, or -CH2P(O)(O - Na + )2, and ((dialkoxyphosphonyl)alkyl) represents the dialkyl ester of phosphonoalkyl, such as, for example, -CH2P(O)(O-tert-butyl)2.

[0072] "Patient" or "subject" generally can represent any living being, but more usually represents mammals and other animals, especially humans. Thus, the disclosed methods are applicable to human therapy and veterinary applications.

[0073] "Pharmaceutically acceptable excipient" represents a substance other than the active ingredient, which is included in a composition containing the active ingredient. As used herein, the excipient can be incorporated within the particles of the pharmaceutical composition, or it can be physically mixed with the particles of the pharmaceutical composition. For example, an excipient can be used to dilute the active agent and / or alter the properties of the pharmaceutical composition. Excipients can include, but are not limited to, anti-adhesives, binders, coating agents, enteric coating agents, disintegrants, flavoring agents, sweetening agents, coloring agents, lubricants, glidants, adsorbents, preservatives, carriers or vehicles. Excipients can be starches and modified starches, celluloses and cellulose derivatives, sugars and their derivatives (such as disaccharides, polysaccharides and sugar alcohols), proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS or TPGS), carboxymethyl cellulose, dipalmitoyl phosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben, sugars, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite or lanolin.

[0074] ​​"Adjuvant" is a component that improves the effect of other reagents (usually the active ingredient). Adjuvants are often pharmacological and / or immunological reagents. Adjuvants can improve the effect of the active ingredient by increasing the immune response. Adjuvants can also act as stabilizers for formulations. Exemplary 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.

[0075] "Pharmaceutically acceptable carrier" refers to an excipient that serves as a carrier or vehicle, such as a suspending aid, solubilizing aid, or atomizing aid. Remington: The Science and Practice of Pharmacy , The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21st Edition (2005) (incorporated herein by reference) describes exemplary compositions and formulations suitable for drug delivery of one or more therapeutic compositions and additional pharmaceutical reagents.

[0076] Generally, the nature of the carrier will depend on the particular mode of administration employed. For example, parenteral formulations typically contain an injectable fluid that includes pharmaceutically and physiologically acceptable fluids such as water, saline, balanced salt solutions, aqueous dextrose solutions, glycerol, etc. as the vehicle. In certain instances, the pharmaceutically acceptable carrier may be sterile to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to the biologically neutral carrier, the pharmaceutical composition to be administered may contain trace amounts of non-toxic auxiliary substances such as wetting agents or emulsifying agents, preservatives, and pH buffering agents, etc., such as sodium acetate or sorbitan monolaurate.

[0077] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable salts of compounds derived from various organic and inorganic counterions as known to those of ordinary skill in the art, and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the molecule contains a basic functional group, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological effectiveness of the free base upon formation by an acid moiety. Specifically, the disclosed compounds form salts with various pharmaceutically acceptable acids, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and 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, etc. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include but are not limited to salts of the following substances: primary amines, secondary amines, 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, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methyl glucosamine, theobromine, purine, piperazine, piperidine, N -ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, e.g., 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 compound may be formate, trifluoroacetate, hydrochloride, or sodium salt.

[0078] "Effective amount" of a compound or pharmaceutical composition means an amount of the compound or pharmaceutical composition sufficient to achieve a particular desired result, such as inhibition of a protein or enzyme. In certain embodiments, an "effective amount" is an amount sufficient to achieve one or more of the following results: inhibition of RIP1; eliciting a desired biological or medical response in a tissue, system, subject, or patient; treating a designated disorder or disease; ameliorating or eradicating one or more of its symptoms; and / or preventing the occurrence of a disease or disorder. As will be understood by those of ordinary skill in the art, the amount of a compound that constitutes an "effective amount" can vary depending on the compound, the desired result, the disease state and its severity, the size, age, and sex of the patient to be treated, etc.

[0079] "Prodrug" means a compound that is converted in vivo to produce a biologically active compound or a compound that is more biologically active than the parent compound. For example, in vivo conversion can occur by hydrolysis or enzymatic transformation. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of compounds having an active form with a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the present disclosure include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (e.g., C 1-6 alkyl esters). Other prodrug moieties include phosphate esters, such as -CH2-O-P(O)(OR')2 or its salts, where R' is H or C 1-6 alkyl. Acceptable esters also include cycloalkyl esters and arylalkyl esters, such as, but not limited to, benzyl esters. Examples of pharmaceutically acceptable amides of the compounds of the present disclosure include, but are not limited to, primary amides, as well as secondary and tertiary alkyl amides (e.g., having from about one to about six carbons). Amides and esters according to the disclosed exemplary embodiments of the compounds of the present disclosure can be prepared according to conventional methods. A comprehensive discussion of prodrugs is provided in the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0080] "Solvate" means a complex formed by the combination of solvent molecules with the molecules or ions of a solute. The solvent can be an organic solvent, an inorganic solvent, or a mixture of both. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, and propanol; amides such as N,N-dialiphatic amides such as N,N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides such as dimethyl sulfoxide; water; and combinations thereof. When combined with a pharmaceutically acceptable or unacceptable solvent (such as water, ethanol, etc.), the compounds described herein can exist in unsolvated as well as solvated forms. The solvated forms of the compounds disclosed herein are within the scope of the embodiments disclosed herein.

[0081] "Sulfonamide" means the group or moiety -SO2NH2 or -N(R)SO2, where R is H, an aliphatic group, a heteroaliphatic group, or an aromatic group (including aryl and heteroaryl).

[0082] "Thiol group" means the group or -SH, -S-aliphatic group, -S-heteroaliphatic group, -S-aromatic group (including -S-aryl and -S-heteroaryl).

[0083] "Sulfinyl group" means the group or moiety -S(O)H, -S(O)aliphatic group, -S(O)heteroaliphatic group, or -S(O)aromatic group (including -S(O)aryl and -S(O)heteroaryl).

[0084] "Sulfonyl group" means the group: -SO2H, -SO2aliphatic group, -SO2heteroaliphatic group, -SO2aromatic group (including -SO2aryl and -SO2heteroaryl).

[0085] As used herein, "treatment" relates to treating a target disease or disorder in a patient or subject (especially a human having the target disease or disorder), and includes, by way of example, but not limited to:

[0086] (i) preventing the occurrence of the disease or disorder in the patient or subject, especially when such patient or subject is predisposed to the disorder but has not been diagnosed as having it;

[0087] (ii) inhibiting the disease or disorder, e.g., preventing or slowing its development;

[0088] (iii) alleviating the disease or disorder, e.g., causing a reduction in symptoms or the regression of the disease or disorder or its symptoms; or

[0089] (iv) stabilizing the disease or disorder.

[0090] The terms "disease" and "disorder" as used herein may be used interchangeably or may be different, as a particular disease or disorder may not have a known causative agent (so the cause is not yet determined) and is thus not yet considered a disease, but only an undesirable disorder or syndrome, in which a more or less specific set of symptoms is identified by a clinician.

[0091] The above definitions and the following general formulas are not intended to include non-permissible substitution patterns (e.g., a methyl group substituted by five fluorine groups). Such non-permissible substitution patterns are readily recognizable by one of ordinary skill in the art.

[0092] One of ordinary skill in the art will appreciate that a compound may exhibit tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may include one or more chiral centers and / or double bonds and may thus exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, certain disclosed compounds may exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Since the various compound names, formulas, and compound drawings within the specification and claims may represent only one of the possible tautomeric, conformational, optical, or geometric isomeric forms, one of ordinary skill in the art will appreciate that the disclosed compounds encompass any tautomeric, conformational, optical, and / or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. Using techniques known to one of ordinary skill in the art, particularly in light of this disclosure, mixtures of different isomeric forms (including mixtures of enantiomers and / or stereoisomers) can be separated to provide each individual enantiomer and / or stereoisomer. Atropisomers are also possible in cases of restricted rotation (e.g., around an amide bond or between two directly linked rings, such as a pyridyl ring, a biphenyl group, etc.) and are also expressly included within the compounds of this disclosure.

[0093] In any embodiment, any or all of the hydrogens present in the compound or in a particular group or moiety within the compound may be replaced by deuterium or tritium. Thus, the description of an alkyl group includes deuterated alkyl groups in which one to the maximum number of hydrogens present may be replaced by deuterium. For example, ethyl represents C2H5 or C2H5 in which 1 to 5 hydrogens are replaced by deuterium, e.g., in C2D x H 5-x In.

[0094] II. RIP1 - Active Compounds and Pharmaceutical Compositions Comprising RIP1 - Active Compounds

[0095] A. Compounds

[0096] Compounds useful for inhibiting RIP1 and / or for treating diseases and / or disorders associated with RIP1, and pharmaceutical compositions containing such compounds, are disclosed herein. In certain embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds are capable of selectively inhibiting RIP1 relative to RIP2, RIP3, or both RIP2 and RIP3.

[0097] In certain embodiments, the compounds of the present disclosure have a structure according to Formula I

[0098]

[0099] or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will appreciate that compounds within the scope of Formula I also include their stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs, unless otherwise indicated. With respect to Formula I, Ring B is a heteroaryl, such as a 5-membered or 6-membered heteroaryl. In certain embodiments, Ring B is a 5-membered or 6-membered heteroaryl having at least one ring nitrogen atom, and possibly 1, 2, or 3 ring nitrogen atoms, and the remaining ring atoms are carbon. In certain embodiments, the B ring does not include 3 ring nitrogen atoms, and Ring B is not a triazole, triazine, or a heteroaryl containing an oxygen or sulfur ring atom, such as oxazole, thiazole, or isoxazole. In certain embodiments, Ring B is pyrazolyl, and in other specific embodiments, Ring B is pyridyl.

[0100] Each R 1 may independently be halogen, -C≡CH, or -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 heterocyclic group, R b , -C(R f )3, or -C(R f )=C(R f )2.

[0101] R 2 is R a .

[0102] R 3 is R a .

[0103] If present, each R 4 is independently R e .

[0104] L is a heteroatom or R a , provided that R a is not H or D.

[0105] If present, Z is an aryl or alicyclic group, including cycloalkyl, such as C 3-6 cycloalkyl;

[0106] m is 1, 2, 3 or 4, and n is 0, 1 or 2.

[0107] R a is independently H or D at each occurrence, where L is R a except for embodiments of, C 1-10 aliphatic group, C 1-10 haloaliphatic group, C 1-10 heteroaliphatic group, C 5-10 aryl, C 3-6 alicyclic group or C 3-6 heteroalicyclic group.

[0108] R b is independently -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)C 1-10 alkyl, said -OC(O)C 1-10 alkyl is substituted by 1 or 2 NR d R d , carboxyl or a combination thereof, and optionally further substituted by an aromatic moiety, -SH, -O-acyl or -C(O)NH2.

[0109] R c is independently C e alkyl which can be substituted by 1, 2 or 3 R 1-10 ; C e alkenyl which can be substituted by 1, 2 or 3 R 2-10 ; C e alkynyl which can be substituted by 1, 2 or 3 R 2-10 ; C e cycloalkyl which can be substituted by 1, 2 or 3 R 3-6 ; or C e aryl which can be substituted by 1, 2 or 3 R 5-10 .

[0110] R dis independently H at each occurrence; can be substituted by 1, 2 or 3 R e or C 3-9 heterocyclic group-substituted C 1-6 alkyl; can be substituted by 1, 2 or 3 R e substituted C 3-6 cycloalkyl; can be substituted by 1, 2 or 3 R e substituted C 3-6 heterocyclic group; can be substituted by 1, 2 or 3 R b substituted C 5-10 aryl; can be substituted by 1, 2 or 3 R e substituted C 5-10 heteroaryl; or 2 R d groups together with the nitrogen to which they are attached form a C that can be substituted by 1 or more R e substituted C 3-9 heterocyclic group, or a C that can be substituted by 1 or more R e substituted C 5-10 heteroaryl.

[0111] R e is independently halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-10 heteroaryl or -OR a .

[0112] and R f is independently -alkyl-phosphate, R a , R b or R e , or 2 R f groups together with the carbon atom to which they are attached form C 2-6 alkenyl, which can be substituted by 1 or more R e substituted C 3-6 cycloalkyl, or a C that can be substituted by 1 or more R e or acyl-substituted C 3-10 heterocyclic group.

[0113] In certain embodiments of Formula I, the compound is not any one of Compounds I-1 to I-97 or I-187 to I-189. In other embodiments, the compound is not:

[0114] I-56: ( S)-i-(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0115] I-64: ( S )- N -(8-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0116] I-68: ( S )- N -(7-(3-Hydroxy-3-(methyl- d 3)but-1-yn-1-yl-4,4,4- d 3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0117] I-72: ( S )- N -(8-((3-Hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; or

[0118] I-77: ( S )-1-Benzyl- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -pyrazole-3-carboxamide.

[0119] In a separate embodiment, the compound is not any of the following:

[0120] (S)-N-(7-(4-(Chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0121] (S)-1-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0122] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;

[0123] (S)-1-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]non-7-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0124] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0125] N-((S)-7-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

[0126] N-((S)-7-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0127] (S)-1-(4-Fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0128] (S)-5-Benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;

[0129] (S)-5-(4-Fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0130] (S)-5-(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)-1H-1,2,4-triazole-3-carboxamide;

[0131] (S)-5-Benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0132] N-((3S)-7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

[0133] (S)-N-(7-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

[0134] ( S )-5-Benzyl- N -(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)-1 H -1,2,4-triazole-3-carboxamide;

[0135] (S)-N-(7-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0136] (S)-5-Benzyl-N-(7-((3-chloropropyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0137] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]dec-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0138] (S)-5-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]dec-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0139] (S)-N-(7-(Azetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0140] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(2-oxa-8-azaspiro[4.5]dec-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0141] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]dec-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0142] (S)-5-Benzyl-N-(7-(2-Benzyl-1-oxo-2,8-diazaspiro[4.5]dec-8-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0143] (S)-5-Benzyl-N-(7-(2-Benzyl-1-oxo-2,9-diazaspiro[5.5]undec-9-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0144] (S)-5-Benzyl-N-(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;

[0145] (S)-5-Benzyl-N-(7-(3,3-difluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; and

[0146] (S)-5-Benzyl-N-(7-(3-fluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

[0147] In certain embodiments of Formula I, ring B is pyridyl or pyrazolyl; L is a heteroatom, such as oxygen, or a C 1-10 aliphatic group, such as a C 1-5 aliphatic group, including -CH2 or a substituted C 1-5 aliphatic group, such as a C 1-5 aliphatic group substituted by an alicyclic group (such as a C 1-5 aliphatic group; Z is aryl, in certain exemplary embodiments phenyl or a substituted phenyl, or a C 1-10 aliphatic group, including an alicyclic group, such as a cycloalkyl, in certain exemplary embodiments a C 3-6 cycloalkyl; each R 1 is a heterocyclic group, or a C 1-10 aliphatic group; R 2 is H or a C 1-10 aliphatic group; R 3 is H or a C 1-10 aliphatic group; each R 4 is independently halogen or a C 1-10 aliphatic group; m is 1, 2, 3, or 4; and n is 0, 1, or 2.

[0148] In certain embodiments, each R 1 is independently a heterocyclic group, an unsubstituted C 1-10 aliphatic group or a C 1-10 aliphatic group substituted by 1 or 2 substituents selected from -OH, halogen, carboxyl, carboxyl ester, heterocyclic group, amino, alkoxy, phosphate, cycloalkyl, alkenyl, -OC(O)NH(C 1-4 alkyl)-amino, -OC(O)R8 or -OC(O)(CHR 9 )2CO2H. -OC(O)-R 8 The moiety can be derived from an amino acid, wherein the -OC(O)- 8 portion of -OC(O)-R corresponds to the acid portion on the amino acid, and R 8 contains -N(R 10 )2 or a nitrogen-containing non-aromatic heterocyclic group, wherein R 10 is H or a carboxyl ester. And each R 9 is independently H or -O-acyl.

[0149] Regarding the -OC(O)-R 8 moiety, the nitrogen-containing non-aromatic heterocyclic group can be a 5- or 6-membered unsaturated nitrogen-containing heterocyclic group, such as, for example, pyrrolidinyl. The amino acid can be any amino acid, such as a naturally occurring amino acid, and can 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 of ordinary skill in the art will understand that if the amino acid contains one or more chiral centers, then all enantiomers, diastereomers and / or mixtures thereof are encompassed. For example, the amino acid can be an L-amino acid, a D-amino acid or a mixture thereof. In certain embodiments, the amino acid is an L-amino acid. And in certain embodiments,

[0150] -OC(O)-R 8 is -OC(O)CH(NH2)R 11 , or -OC(O)-(CH2) 1-2 C(NH2)CO2H, wherein R 11 is an amino acid side chain, and / or can be H, -CH3, isopropyl, -CH2CH(CH3)2, -CH(CH3)Et, -CH2CH2SCH3, , , , -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2CH2NHC(O)(NH)NH2, , -CH2CH2CH2CH2NH2, -CH2CO2H or CH2CH2CO2H.

[0151] Regarding R 1 , at least one R 1 can be an 8- to 12-membered spiro heterocyclic group or C1-10 Alkyne. C 1-10 The alkyne may include substituents, such as 1 or 2 substituents. A particular exemplary substituent may be -OH. In certain embodiments, a substituent is oxetanyl, azetidinyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or phosphate ester, and / or in certain embodiments, a substituent is -OC(O)-R 8 .

[0152] In certain embodiments, m is 1, 2 or 3, and may be 1 or 2, and in certain embodiments, m is 1.

[0153] R 2 may be H or C 1-6 alkyl, such as methyl.

[0154] R 3 may be H or C 1-6 alkyl, and in certain embodiments, R 3 is H.

[0155] Each R 4 may independently be a halogen, such as F, Br, Cl or I, or C 1-10 aliphatic group, such as C 1-6 alkyl. In certain embodiments, each R 4 is independently chlorine, fluorine or methyl.

[0156] In certain embodiments, n is 0, and in other particular embodiments, n is 1.

[0157] 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, such as C 1-6 alkyl, more particularly methylene (-CH2-). Z is C 1-10 aliphatic group or aryl. In certain embodiments, Z is C 3-6 cycloalkyl, such as cyclobutyl or cyclopentyl, or C 1-6 alkyl, such as methyl. In certain embodiments, the -L-Z moiety is phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 2-fluorophenoxy, 2,4-difluorophenoxy, 2,6-difluorophenoxy, 4-fluorobenzyl, 2,6-dimethylphenoxy, cyclobutoxy, cyclopentoxy, methoxy, 4-methylphenoxy or benzyl.

[0158] In certain embodiments of Formula I, the compound may have a structure according to Formula I-1 or I-2:

[0159] .

[0160] In certain embodiments, the compound may have a structure according to one or more of the following formulas

[0161]

[0162]

[0163] .

[0164] With respect to Formulas I-1 to I-20, if present, ring B, L, Z, R 1 , R 2 , R 3 , R 4 , m and n are as defined herein with respect to Formula I.

[0165] In any of the above embodiments involving Formula I and / or Formulas I-1 to I-20, R 1 may be selected from any of the following:

[0166]

[0167]

[0168]

[0169]

[0170] .

[0171] And, in certain embodiments of Formula I and / or Formulas I-1 to I-32, R 1 may be selected from any of the following:

[0172]

[0173]

[0174] .

[0175] In other embodiments of Formula I

[0176]

[0177] ring B is a 5- or 6-membered heteroaryl;

[0178] L is a heteroatom or R a , provided that R a is not H or D;

[0179] Z is C1-10 An aliphatic group (such as C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 3-6 cycloalkyl); or ;

[0180] R 1 is halogen (-F, -Cl, -Br, -I), -C≡CH or a linking group -R 6 group, where the linking group 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;

[0181] R 2 and R 3 are independently R a ;

[0182] R 4 and R 5 are independently R e ;

[0183] R a is independently H or D at each occurrence (except in embodiments where L is R a ), a C 1-10 aliphatic group (such as C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 3-6 cycloalkyl), a C 1-10 haloaliphatic group, a C 5-10 aryl, a C 3-6 alicyclic group or a C 3-6 heteroalicyclic group;

[0184] R b is independently -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 ;

[0185] R c is independently C 1-10alkyl (which may be substituted by 1, 2 or 3 Rs e ), C 2-10 alkenyl (which may be substituted by 1, 2 or 3 Rs e ), C 2-10 alkynyl (which may be substituted by 1, 2 or 3 Rs e ), C 3-6 cycloalkyl (which may be substituted by 1, 2 or 3 Rs e ), or C 5-10 aromatic group (which may be substituted by 1, 2 or 3 Rs e );

[0186] R d , each occurrence of which is independently H; C 1-6 alkyl (which may be substituted by 1, 2 or 3 Rs e ), C 3-6 cycloalkyl (which may be substituted by 1, 2 or 3 Rs e ), C 3-6 heterocyclic group (which may be substituted by 1, 2 or 3 Rs e ), C 5-10 aryl (which may be substituted by 1, 2 or 3 Rs b ), C 5-10 heteroaryl (which may be substituted by 1, 2 or 3 Rs e ), or two Rs d groups together with the nitrogen to which they are attached form a C 3-9 heterocyclic group (which may be substituted by one or more Rs e ), or C 5-10 heteroaryl (which may be substituted by one or more Rs e );

[0187] R e , each occurrence of which is independently halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-10 heteroaryl or -OR a ; and

[0188] R f , each occurrence of which is independently R a , R b or R e , or two Rs f groups together with the carbon atom to which they are attached form a C 3-6 cycloalkyl (which may be substituted by one or more Rs e ), or C 3-10 heterocyclic group (which may be substituted by one or more Rse substituted);

[0189] m is 1 - 4, such as 1, 2, 3, or 4, and in certain embodiments is 1 or 2;

[0190] n is 0, 1, or 2; and

[0191] p is 0, 1, 2, 3, 4, or 5.

[0192] In certain embodiments, the compounds of the present disclosure can have a structure satisfying Formula IA

[0193]

[0194] or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will appreciate that the disclosed general formula includes, within its scope, all stereoisomers, N - oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs of compounds having such structural features of the formula in other respects.

[0195] Regarding Formula IA:

[0196] Ring B is a 5 - membered or 6 - membered heteroaryl;

[0197] L is a heteroatom or R a , provided that R a is not H or D;

[0198] R 1 is a halogen, - C≡CH, or a - linker - R 6 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 )2;

[0199] R 2 and R 3 are independently R a ;

[0200] R 4 and R 5 are independently R e ;

[0201] R a is independently H or D at each occurrence (except in embodiments where L is R a ), a C 1-10 aliphatic group (such as C 1-10 alkyl, C 2-10Alkenyl, C 2-10 alkynyl or C 3-6 alicyclic group such as C 3-6 cycloalkyl), C 1-10 haloaliphatic group, C 1-10 heteroaliphatic group, C 5-10 aryl or C 3-6 heteroalicyclic group such as C 3-6 heterocycloalkyl;

[0202] R b is independently, at each occurrence, -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 ;

[0203] R c is independently, at each occurrence, C 1-10 alkyl (which may be substituted by 1, 2 or 3 R e substituents), C 2-10 alkenyl (which may be substituted by 1, 2 or 3 R e substituents), C 2-10 alkynyl (which may be substituted by 1, 2 or 3 R e substituents), C 3-6 cycloalkyl (which may be substituted by 1, 2 or 3 R e substituents) or C 5-10 aromatic group (which may be substituted by 1, 2 or 3 R e substituents);

[0204] R d is independently, at each occurrence, H; C 1-6 alkyl (which may be substituted by 1, 2 or 3 R e substituents); C 3-6 cycloalkyl (which may be substituted by 1, 2 or 3 R e substituents); C 3-6 heterocyclic group (which may be substituted by 1, 2 or 3 R e substituents); C 5-10 aryl (which may be substituted by 1, 2 or 3 R b substituents); C 5-10 heteroaryl (which may be substituted by 1, 2 or 3 R e substituents); or two R d groups together with the nitrogen to which they are attached form a C 3-9 heterocyclic group (which may be substituted by one or more R e(substituted) or C 5-10 heteroaryl (which may be substituted by one or more R e substituents);

[0205] R e is independently at each occurrence halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-10 heteroaryl or -OR a ; and

[0206] R f is independently at each occurrence R a , R b or R e , or two R f groups together with the carbon atom to which they are attached form a C 3-6 cycloalkyl (and in certain embodiments, the C 3-6 cycloalkyl is substituted by one or more R e substituents) or C 3-10 heterocyclic group (and in certain embodiments, the C 3-10 heterocyclic group is substituted by one or more R e substituents);

[0207] m is 1 - 4, such as 1, 2, 3 or 4, and in certain embodiments is 1 or 2;

[0208] n is 0, 1 or 2; and

[0209] p is 0, 1, 2, 3, 4 or 5.

[0210] In certain embodiments of Formula I or IA, the 5 - membered heteroaryl may have a structure satisfying the formula , where at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen or NH. In certain embodiments, the 5 - membered heteroaryl is a diazole, triazole, oxadiazole or oxazole. Exemplary triazoles include any one of the following:

[0211]

[0212] .

[0213] Exemplary diazoles are selected from any one of the following:

[0214] .

[0215] Exemplary oxazoles are selected from any one of the following:

[0216] .

[0217] The exemplary oxadiazole is selected from any of the following:

[0218] .

[0219] In certain embodiments of Formula I or IA, L is oxygen or R a , where R a is C 1- C4 alkyl, such as -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-. In certain embodiments, L is -CH2- or oxygen.

[0220] The R 1 group (where R 1 is the linking group -R 6 ) is a C1, C2, C3 or C4 aliphatic group, such as C2 alkyl, alkenyl or alkynyl, or a C1, C2, C3 or C4 haloaliphatic group, such as C2 haloalkyl or haloalkenyl. In certain embodiments, the linking group of R 1 is R a , where R a is C 1- C4 alkyl, such as -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-; or the linking group is a C2-C4 alkenyl, such as -CH=CH-, -CH=CHCH2-, -CH2CH=CH- or -CH2CH=CHCH2-; or the linking group is a C2-C4 alkynyl, such as -C≡C-, -C≡CCH2-, -CH2C≡C- or -CHC≡C-CH2-. In certain embodiments, the linking 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 certain embodiments, the linking group is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, -CCl=CH-, -CH=CCl- or -C≡C-.

[0221] In certain embodiments, the R 1 of R 6 group is C(R f )3, where one R f is R e , where R e is -OR a(e.g., hydroxy or OMe) and each other R f is independently R a , where R a is a C 1-4 aliphatic group and preferably each other R f is R a , where R a is independently at each occurrence a C 1-4 alkyl. In certain embodiments, each other R f is R a , where R a is methyl or CD3. In some additional embodiments, R 6 is -C(R f )3, where each R f is R a , where R a is methyl or H, or where each R f is R a , where R a is methyl or R b , where R b is -C(O)OR c . In certain additional embodiments, one R f is R e is -OR a (e.g., hydroxy or OMe) and the other two R f groups are joined to the carbon atom to which they are attached to form an alicyclic group (e.g., cyclopropane, cyclobutane, cyclopentane or cyclohexane) or a heterocyclic group (e.g., epoxide, oxetane, tetrahydrofuran, tetrahydropyran or hexahydrofuro[3,2- b furan). In certain such embodiments, the alicyclic group and / or heterocyclic group may be substituted, in some specific embodiments by one or more hydroxy or benzyl-carbonyl groups.

[0222] Some compound embodiments have a linking group that is a C 2-4 group, and the C 2-4 group may contain an alkyne. In certain embodiments, R 1 is a -linking group-R 6 group and the linking group 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 dR d or -NR d R d , where each R d is, independently upon each occurrence, hydrogen, C 5-10 heteroaryl, C 3-6 cycloalkyl, or two R d groups are joined to the nitrogen atom to which they are attached to form a heterocyclic group, which may further contain one or more additional heteroatoms other than the nitrogen atom to which the R d group is attached. In certain embodiments, one R d is hydrogen and the other R d is C 5-10 heteroaryl, and the C 5-10 heteroaryl may be substituted with one or more R e groups, such as one of the following:

[0223] .

[0224] R 6 may also be R b , where R b is a heterocyclic group, such as pyridyl, which may be substituted or unsubstituted. In other embodiments, R 6 may be R b , where R b is -OH or -OR c (where R c is C 1-6 alkyl, and in certain embodiments, the C 1-6 alkyl is substituted with C 5-10 heteroaryl such as pyridyl; or where R c is C 5-10 heteroaryl, such as quinolinyl), or R b may be -NR d R d , where R d is, independently upon each occurrence, H, C 5-10 heteroaryl (and in certain embodiments, the C 5-10 heteroaryl is substituted with one or more R e groups), or two R d groups together with the nitrogen to which they are attached form a C 3-9 heterocyclic group (and in certain embodiments, the C 3-9 heterocyclic group is substituted with one or more R e groups) or C 5-10 heteroaryl (and in certain embodiments, the C 5-10 heteroaryl is substituted with one or more R e groups). In those having Re In the substituted embodiments, R e is independently, at each occurrence, C 5-10 heteroaryl or -OR a , where R a is C 1-10 alkyl.

[0225] Some compounds contain a linking group that is a C1 group and an R b for R 6 group, where R b is -NR d R d , where one R d is H and the other R d is pyridyl, or where two R d groups together with the nitrogen to which they are attached form a C 5-10 heteroaryl; or R b is OR c , where R c is C 1-4 alkyl substituted with pyridyl. In certain embodiments, R b is

[0226] .

[0227] In certain embodiments, R 1 can be selected from any of the following:

[0228]

[0229] In certain embodiments, each of R 2 and R 3 is independently R a , where R a is independently, at each occurrence, hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain specific embodiments, each of R 2 and R 3 is independently R a , and the R a is independently, at each occurrence, hydrogen, methyl, or ethyl. In an exemplary embodiment, R 2 is methyl and R 3 is hydrogen.

[0230] In certain embodiments, each R 4 independently and / or each R 5 independently is R e , where R e is alkyl, alkenyl, alkynyl, chlorine, bromine, iodine, or fluorine. In certain specific embodiments, each R 4and / or each R 5 is independently R e , where R e is a lower aliphatic group (e.g., methyl), fluorine or chlorine.

[0231] In certain embodiments, m is 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.

[0232] The compounds of formula I or IA may also have a structure satisfying any one or more of formulas II and IIA-IIF.

[0233]

[0234]

[0235] Regarding formulas II and IIA-IIE, each R 1 and R 5 is as described above for formula I and / or IA. In particular embodiments, there are 0, 1 or 2 R 5 groups. R 5 can be R e , particularly where R e is fluorine or chlorine. In other particular embodiments, R 5 is absent. Regarding formulas IIA-IIE, each W is independently nitrogen or oxygen, and in particular nitrogen.

[0236] Certain disclosed embodiments have formula IIF.

[0237]

[0238] Regarding formula IIF, R 1 , R 2 and R 3 are as described above. R 10 is alkyl, cycloalkyl or aryl. More particularly, R 10 is lower alkyl, such as C 1-10 alkyl, more particularly C 1-5 alkyl, including methyl, ethyl, propyl, butyl and pentyl. Cycloalkyl is generally selected from cyclobutyl, cyclopentyl or cyclohexyl, particularly cyclobutyl or cyclopentyl. In certain embodiments, the compounds according to the present disclosure have formula IIG.

[0239]

[0240] For many disclosed embodiments, R 10 is phenyl. Thus, certain disclosed embodiments of the present disclosure have formula IIH.

[0241]

[0242] Regarding formulas IIG and IIH, R 1 and R 5 each is as described above regarding formula I and / or IA. R 5 can be R e . In certain embodiments, there are 0, 1, or 2 R 5 groups. In some embodiments, R 5 is absent or is a halogen, such as fluorine or chlorine, especially fluorine, or C 1-6 alkyl, such as methyl.

[0243] In certain embodiments, the compounds of formula I or IA may also have a structure that satisfies any one or more of formulas III - VI:

[0244] .

[0245] Regarding formulas III - VI, each R 5 independently can be as described above and, in certain specific embodiments, is a lower aliphatic group (e.g., methyl) or a halogen, such as chlorine or fluorine. And, ring B is as described above and, in some embodiments, can be selected from

[0246] .

[0247] The R 6 shown in formulas III - VI is as described above and, in some embodiments, is selected from one of the following:

[0248]

[0249]

[0250]

[0251]

[0252] .

[0253] Some of the disclosed exemplary compounds within the scope of one or more of formulas I, I - 1 to 1 - 35, IA, II, IIA - IIJ, and III - VI include:

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] 。

[0273] Exemplary compounds within the scope of one or more of Formulas I, I-1 to I-32, IA, II, IIA-IIH, and III-VI include:

[0274] I-1: Ethyl (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)propionate;

[0275] I-2:( S )- N -(7-(3-((1 H -indazol-5-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1 H -1,2,4-triazole-3-carboxamide;

[0276] I-3: ( S )- N -(7-(3-((1 H -Indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1 H -1,2,4-triazole-3-carboxamide;

[0277] I-4: ( S )-5-benzyl- N -(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)-1 H -1,2,4-triazole-3-carboxamide;

[0278] I-5: (S)-Ethyl 3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate;

[0279] I-6: ( S )-3-(3-(1-(2-fluorobenzyl)-1 H -1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-7-yl)propanoic acid;

[0280] I-7: ( S )- N -(7-(3-((1 H -Indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1-(2-fluorobenzyl)-1 H -1,2,4-triazole-3-carboxamide;

[0281] I-8: (S)-Ethyl 3-(3-(1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate;

[0282] I-9: ( 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)propanoic acid;

[0283] I-10: ( S )-5-benzyl- N -(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0284] I-11: ( S )-5-benzyl- N -(5-methyl-7-(3-morpholin-3-oxopropyl)-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0285] I-12: ( S )-5-benzyl- N -(5-methyl-4-oxo-7-(3-oxo-3-(quinolin-7-ylamino)propyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0286] I-13: ( S )-5-benzyl- N -(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0287] I-14: ( S )-5-benzyl- N -(7-(3-hydroxypropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0288] I-15: ( S)-5-Benzyl- N -(7-(4-Hydroxybutyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0289] I-16: ( S )-5-Benzyl- N -(5-Methyl-4-oxo-7-(4-(pyridin-2-ylmethoxy)butyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0290] I-17: ( S )-5-Benzyl- N -(5-Methyl-4-oxo-7-(4-(pyridin-2-ylamino)butyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0291] I-18: ( S )-1-(2,6-Dichlorobenzyl)- N -(5-Methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0292] I-19: ( S )- N -(7-(3-(Cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1-(2,6-dichlorobenzyl)-1 H -1,2,4-triazole-3-carboxamide;

[0293] I-20: ( S )-5-Benzyl- N -(5-Methyl-4-oxo-7-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H-1,2,4-Triazole-3-carboxamide;

[0294] I-21: ( S )-1-(2,6-Dichlorobenzyl)- N -(5-Methyl-4-oxo-7-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0295] I-22: ( S , E )-5-Benzyl- N -(5-Methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-1-yl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0296] I-23: ( S , E )-5-Benzyl- N -(7-(3-(Cyclopropylamino)-3-oxoprop-1-en-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0297] I-24: ( S )-5-Benzyl- N -(7-((5,6-Dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8 H )-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0298] I-25: ( S )-1-Benzyl- N -(7-((5,6-Dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8 H )-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H-1,2,4-Triazole-3-carboxamide;

[0299] I-26: ( S )-1-Benzyl- N -(7-(3-(Cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0300] I-27: ( S )- N -(7-(3-(Cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-5-(2,4-difluorobenzyl)-1 H -1,2,4-triazole-3-carboxamide;

[0301] I-28: ( S )-5-Benzyl- N -(7-(3-Hydroxy-3-methylbutyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0302] I-29: (S)-1-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0303] I-30: ( S )-5-Benzyl- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0304] I-31: (S)-N-(7-(3-Amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0305] I-32: (S)-N-(7-(3-Amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0306] I-33: (S)-1-Benzyl-N-(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-triazole-3-carboxamide;

[0307] I-34: (S)-5-(2,4-Difluorobenzyl)-N-(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-triazole-3-carboxamide;

[0308] I-35: (S)-5-Benzyl-N-(7-(5-hydroxypent-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0309] I-36: ( S )-5-Benzyl-3-((7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)carbamoyl)-1,2,4-triazol-1-ide;

[0310] I-37: ( S )-1-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)-1 H -1,2,4-triazole-3-carboxamide;

[0311] I-38: ( 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)-1 H -1,2,4-triazole-3-carboxamide;

[0312] I-39: ( S )-1-Benzyl- N -(5-Methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8 H )-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0313] I-40: ( S )-5-Benzyl- N -(5-Methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5- a pyrazin-7(8 H )-yl)methyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0314] I-41: ( 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)-1 H -1,2,4-Triazole-3-carboxamide;

[0315] I-42: ( S )-1-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)-1 H -1,2,4-Triazole-3-carboxamide;

[0316] I-43: ( S )-5-(2,4-Difluorobenzyl)- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0317] I-44: ( 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-triazole-3-carboxamide;

[0318] I-45: ( 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-triazole-3-carboxamide;

[0319] I-46: ( S )-1-Benzyl- N -(5-Methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8 H )-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0320] I-47: ( S )-5-Benzyl- N -(5-Methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8 H )-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0321] I-48: ( S )-1-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 -1,2,4-triazole-3-carboxamide;

[0322] I-49: ( 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)-1 H-1,2,4-Triazole-3-carboxamide;

[0323] I-50: ( S )-1-Benzyl- N -(7-((1-Hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0324] I-51: ( S )-5-Benzyl- N -(7-((1-Hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0325] I-52: ( S )-1-Benzyl- N -(7-((1-Hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0326] I-53: ( S )-5-Benzyl- N -(7-((1-Hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1 H -1,2,4-Triazole-3-carboxamide;

[0327] I-54: ( S )-1-Benzyl- N -(7-((4-Hydroxytetrahydro-2 H -pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0328] I-55: ( S )-5-Benzyl- N -(7-((4-Hydroxytetrahydro-2 H -pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4-Triazole-3-carboxamide;

[0329] I-56: ( S )-i-(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0330] I-57: ( S )-5-Benzyl- N -(7-((3-Hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0331] I-58: ( S )-1-Benzyl- N -(7-((3-Hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0332] I-59: ( 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)-1 H -1,2,4-triazole-3-carboxamide;

[0333] I-60: ( S )-5-Benzyl- N -(7-Isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0334] I-61: ( S )-5-Benzyl- N -(7-(3-Methoxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0335] I-62: ( S)-1-Benzyl- N -(8-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0336] I-63: ( S )-5-Benzyl- N -(8-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0337] I-64: ( S )- N -(8-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0338] I-65: ( S )-5-(2,6-Dichlorobenzyl)- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0339] I-66: ( S )-5-Benzyl- N -(5-Methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5- a pyrazin-7(8 H )-yl)methyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0340] I-67: ( S )-1-Benzyl- N -(5-Methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5- a pyrazin-7(8 H )-yl)methyl)-2,3,4,5-tetrahydrobenzob [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0341] I-68: ( S )- N -(7-(3-hydroxy-3-(methyl- d 3)but-1-yn-1-yl-4,4,4- d 3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0342] I-69: ( S )-5-benzyl- N -(7-(3-hydroxy-3-(methyl- d 3)but-1-yn-1-yl-4,4,4- d 3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0343] I-70: ( R )-5-benzyl- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0344] I-71: ( S )-5-benzyl- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide;

[0345] I-72: ( S )- N -(8-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0346] I-73: (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)-1 H -1,2,4-triazole-3-carboxamide;

[0347] I-74: Benzoic acid (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-b]furan-3-yl ester;

[0348] I-75: 5-Benzyl- N -(( S )-7-(((3 R ,3a S ,6 S ,6a R )-3,6-Dihydroxyhexahydrofuro[3,2- b furan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0349] I-76: (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-ynoic acid methyl ester;

[0350] I-77: ( S )-1-Benzyl- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -pyrazole-3-carboxamide;

[0351] I-78: ( S )-5-(3-Fluorobenzyl)- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b[1,4]Oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0352] I-79: ( S )-5-(4-fluorobenzyl)- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]Oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0353] I-80: ( S )-5-(2-fluorobenzyl)- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]Oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0354] I-81: ( S )-5-benzyl- N -(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]Oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0355] I-82: ( S )- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]Oxazepin-3-yl)-1-(2-methylbenzyl)-1 H -1,2,4-triazole-3-carboxamide;

[0356] I-83: ( S )-1-([1,1'-biphenyl]-4-ylmethyl)- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]Oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0357] I-84: ( S)-1-(2,6-dimethylbenzyl)- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0358] I-85: ( S )- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1-isobutyl-1 H -1,2,4-triazole-3-carboxamide;

[0359] I-86: ( S )-5-benzyl- N -ethyl- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0360] I-87: ( S )-5-benzyl- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)isoxazole-3-carboxamide;

[0361] I-88: ( 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)-1 H -1,2,4-triazole-3-carboxamide;

[0362] I-89: ( 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)-5-(2-fluorobenzyl)-1H -1,2,4-Triazole-3-carboxamide;

[0363] I-90: ( S )-1-(2,6-Dimethylbenzyl)- 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 -1,2,4-Triazole-3-carboxamide;

[0364] I-91: ( 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)-1 H -1,2,4-Triazole-3-carboxamide;

[0365] I-92: ( S )- 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)-5-(3-fluorobenzyl)-1 H -1,2,4-Triazole-3-carboxamide;

[0366] I-93: ( S )-5-Benzyl- N -(7-(3-Methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide;

[0367] I-94: (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-triazole-3-carboxamide;

[0368] I-95: ( S )-5-Benzyl- N -(5-Methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzob [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0369] I-96: ( S )-5-benzyl- N -(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0370] I-97: ( S )-5-benzyl- N -(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0371] I-98: (S)-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0372] 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;

[0373] I-100: (S)-4-(4-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

[0374] I-101: (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-(4-fluorophenoxy)picolinamide;

[0375] I-102: (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-(2-fluorophenoxy)picolinamide;

[0376] I-103: (S)-4-(2-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide;

[0377] 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)pyridinecarboxamide;

[0378] I-105: (S)-4-(2,4-Difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide;

[0379] I-106: (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)pyridinecarboxamide;

[0380] I-107: (S)-4-(3-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide;

[0381] I-108: (S)-N-(7-Isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide;

[0382] I-109: (S)-N-(7-(4-Hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide;

[0383] 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-phenoxypyridinecarboxamide;

[0384] 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)pyridinecarboxamide;

[0385] 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)pyridinecarboxamide;

[0386] I-113: (R)-N-(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide;

[0387] I-114: (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)pyridinecarboxamide;

[0388] 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)pyridinecarboxamide;

[0389] 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-phenoxypyridinecarboxamide;

[0390] I-117: (S)-N-(5-Methyl-7-(3-morpholinopropyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide:

[0391] I-118: (S)-4-(2,6-Difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide;

[0392] I-119: (S)-N-(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-methyl-4-phenoxypicolinamide;

[0393] I-120: (S)-N-(7-((1-Hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0394] I-121: (S)-N-(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0395] I-122: (S)-4-(3-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

[0396] 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;

[0397] I-124: (S)-4-(2,6-Dimethylphenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

[0398] I-125: (S)-4-(4-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

[0399] I-126: (S)-4-(4-Fluorophenoxy)-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

[0400] I-127: (S)-N-(5-Methyl-7-((3-methyloxetan-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0401] 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;

[0402] I-129: (S)-N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0403] I-130: (S)-3-((5-Methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl (3-morpholinopropyl)carbamate;

[0404] I-131: (S)-N-(7-((4-Hydroxy-1-(4-phenoxypicolyl)piperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0405] I-132: (S)-N-(7-((4-Hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0406] I-133: (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;

[0407] I-134: (S)-N-(7-((1-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;

[0408] I-135: (S)-4-(4-Fluorophenoxy)-N-(7-((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide;

[0409] I-136: (S)-N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide;

[0410] I-137: (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-phenoxypyridinecarboxamide;

[0411] I-138: (S)-4-(4-Fluorophenoxy)-N-(5-methyl-7-(5-(methylamino)-3-methylidenepent-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide;

[0412] I-139: (S)-N-(7-(3-amino-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide;

[0413] 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]oxazepin-3-yl)-4-phenoxypyridinecarboxamide;

[0414] I-141: ((S)-1-((2,2-dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl)oxy)-1-oxopropan-2-yl)-tert-butyl l2-azaneformate;

[0415] I-142: L-Alanine 2,2-dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl ester;

[0416] I-143: (S)-N-(7-((3-Fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0417] I-144: (S)-4-((2,2-Dimethyl-4-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl)oxy)-4-oxobutanoic acid;

[0418] I-145: (2R,3R)-2,3-Diacetoxy-4-((2,2-dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl)oxy)-4-oxobutanoic acid;

[0419] I-146: (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;

[0420] I-147: (R)-4-((3-((5-Methyl-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetidin-3-yl)oxy)-4-oxobutanoic acid;

[0421] I-148: (S)-4-(4-Fluorophenoxy)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

[0422] I-149: (S)-N-(7-((3-Oxa-9-azaspiro[5.5]undecan-9-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0423] I-150: (S)-N-(7-((7-Oxa-2-azaspiro[3.5]nonan-2-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0424] I-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)-4-phenoxypicolinamide;

[0425] I-152: (S)-4-Cyclobutoxy-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

[0426] I-153: (S)-4-Cyclobutoxy-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

[0427] I-154: (S)-N-(7-((3-Methoxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0428] I-155: (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;

[0429] I-156: (S)-4-(Cyclopentyloxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

[0430] I-157: (S)-4-(Cyclopentyloxy)-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;

[0431] I-158: (S)-N-(5-Methyl-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide:

[0432] I-159: Methyl (S)-3-(5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propiolate;

[0433] I-160: L-Valine 3-(((S)-5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl ester;

[0434] I-161: (S)-3-(5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propioic acid;

[0435] I-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-methoxypyridinecarboxamide;

[0436] I-163: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-methoxypyridinecarboxamide;

[0437] I-164: L-Valine 3-(((S)-5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl ester benzenesulfonate;

[0438] I-165: (S)-4-((3-((5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl)oxy)-4-oxobutanoic acid tris salt;

[0439] I-166: (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-phenoxypyridinecarboxamide;

[0440] I-167: (S)-N-(7-(3-Amino-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide hydrochloride;

[0441] 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]oxazepin-3-yl)-4-phenoxypicolinamide;

[0442] I-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)-4-phenoxypicolinamide;

[0443] I-170: (S)-4-((4-(3-(4-(4-Fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl)oxy)-4-oxobutanoic acid;

[0444] I-171: L-Alanine 4-((S)-3-(4-(4-Fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl ester;

[0445] I-172: L-Valine 4-((S)-3-(4-(4-Fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl ester;

[0446] I-173: (S)-2,2-Dimethyl-4-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl dihydrogen phosphate;

[0447] I-174: (S)-4-(3-(4-(4-Fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl dihydrogen phosphate.

[0448] I-175: (S)-4-(4-Fluorobenzyl)-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-pyrazole-1-carboxamide;

[0449] I-177: (S)-N-(5-Methyl-7-((6-methylpyridin-2-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

[0450] I-178: (S)-4-(4-Fluorobenzyl)-N-(8-((3-hydroxyoxetane-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide;

[0451] I-179: (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)-1H-pyrazole-3-carboxamide;

[0452] I-180: (S)-4-(4-Fluorobenzyl)-N-(5-methyl-7-((3-methyloxetane-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0453] I-181: (S)-1-Benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]dec-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide;

[0454] I-182: (S)-1-Benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide;

[0455] I-183: (S)-4-(4-Fluorobenzyl)-N-(5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0456] I-184: (S)-4-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0457] I-187: (S)-5-Benzyl-N-(7-(3-chloro-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0458] I-188: (S)-5-Benzyl-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)-1H-1,2,4-triazole-3-carboxamide;

[0459] I-189: (S)-5-Benzyl-N-(5-methyl-7-(3-morpholinopropyl-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0460] I-190: (S)-N-(7-((3-Hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(phenoxy-d5)picolinamide;

[0461] I-191: (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;

[0462] I-194: L-Alanine 3-(((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl ester trifluoroacetate;

[0463] I-195: (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;

[0464] I-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)-4-phenoxypicolinamide;

[0465] 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;

[0466] 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;

[0467] I-199: (S)-3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetane-3-yl ethylcarbamate;

[0468] I-200: (S)-N-(7-((3-hydroxy-1-neopentylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0469] I-203: (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;

[0470] 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]oxazepin-3-yl)-4-phenoxypicolinamide;

[0471] I-205: (S)-N-(7-(3-((4-Fluorobenzyl)amino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0472] I-206: (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;

[0473] I-207: (S)-N-(7-((4-Hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0474] I-208: (S)-N-(7-((3-Hydroxy-1-oxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0475] I-209: (S)-N-(7-((3-Hydroxy-1,1-dioxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0476] I-210: (S)-N-(5-methyl-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0477] I-211: (S)-N-(7-(3-(1,1-Dioxidomorpholinyl)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0478] 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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0479] 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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0480] I-214: (S)-4-Benzyl-N-(5-methyl-4-oxo-7-(pyridin-3-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0481] I-215: (S)-4-Benzyl-N-(5-methyl-4-oxo-7-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0482] I-216: (S)-4-Benzyl-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0483] I-217: (S)-4-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0484] 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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0485] I-219: (S)-4-Benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0486] 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]oxazepin-3-yl)-5-methyl-1H-pyrazole-1-carboxamide;

[0487] I-221: (S)-4-(4-Fluorobenzyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0488] 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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0489] I-223: (S)-3-(4-Fluorobenzyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0490] I-224: (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-pyrazole-1-carboxamide;

[0491] I-225: (S)-4-(4-Fluorobenzyl)-N-(7-((6-hydroxy-2-oxospiro[3.3]heptan-6-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0492] I-226: (S)-N-(7-(3-Amino-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-fluorobenzyl)-1H-pyrazole-1-carboxamide;

[0493] I-227: (S)-4-(4-Fluorobenzyl)-N-(5-methyl-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

[0494] I-228: ( S )-4-Benzyl- N -(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b[1,4]oxazepin-3-yl)-1 H -pyrazole-1-carboxamide;

[0495] I-229: ( S )- N -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-4-(4-fluorobenzyl)-1 H -pyrazole-1-carboxamide;

[0496] I-230: ( S )-4-benzyl- N -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-5-methyl-1 H -pyrazole-1-carboxamide;

[0497] I-231: ( S )- N -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b ;[1,4]oxazepin-3-yl)-3-(4-fluorobenzyl)-1 H -pyrazole-1-carboxamide;

[0498] I-232: ( S )- N -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-5-(4-fluorobenzyl)-1 H -pyrazole-1-carboxamide;

[0499] I-233: (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-triazole-3-carboxamide;

[0500] 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]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0501] I-235: (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide;

[0502] I-236: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide;

[0503] I-237: ( S )- N -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-4-(2,4-difluorobenzyl)-1 H -pyrazole-1-carboxamide;

[0504] I-238 : (S )-4-(2,4-difluorobenzyl)- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -pyrazole-1-carboxamide;

[0505] I-239: ( S )-4-(2,4-difluorobenzyl)- N -(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -pyrazole-1-carboxamide;

[0506] I-240: (S)-(tert-butyl ((4-(3-(4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl)amino)carbamate);

[0507] (S)-N-(7-(4-amino-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamide hydrochloride;

[0508] II-16: (S)-N-(5-methyl-4-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide;

[0509] II-17: (S)-4-(4-cyanophenoxy)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide;

[0510] II-18: (S)-4-(4-cyanophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide;

[0511] 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]oxazepin-3-yl)pyridinecarboxamide;

[0512] II-20: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenylpyridinecarboxamide;

[0513] 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]oxazepin-3-yl)pyridinecarboxamide;

[0514] II-22: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-methoxyphenyl)pyridinecarboxamide;

[0515] II-23: (S)-N-(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-methoxyphenyl)picolinamide;

[0516] II-24: (S)-N-(7-(3-Amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0517] II-25: (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-phenoxypicolinamide;

[0518] II-26: (S)-N-(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;

[0519] II-27: (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;

[0520] II-28: (S)-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)-4-phenoxypicolinamide;

[0521] II-31: (S)-N-(5-Methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0522] II-32: (S)-N-(7-(3-Methoxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0523] II-33: (S)-N-(7-((6-cyanopyridin-2-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0524] II-35: (S)-N-(7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0525] II-36: (S)-N-(7-(3-(dimethylamino)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; or

[0526] II-39: N-((3S)-5-methyl-4-oxo-7-(pyrrolidin-2-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide.

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[0556] In certain embodiments, one or more compounds may be included in a pharmaceutical composition or a medicament, and in certain embodiments, the one or more compounds may be in the form of a parent compound or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof. The pharmaceutical composition generally includes at least one additional component in addition to the disclosed one or more compounds, such as a pharmaceutically acceptable excipient, adjuvant, additional therapeutic agent (described in the following section), or any combination thereof.

[0557] Pharmaceutically acceptable excipients can be included in a pharmaceutical composition for a variety of purposes, such as to dilute the pharmaceutical composition for delivery to a subject, to facilitate processing of the formulation, to provide favorable material properties to the formulation, to facilitate dispersion from a delivery device, to stabilize the formulation (e.g., antioxidants or buffers), to provide a pleasant or palatable taste or consistency to the formulation, and the like. Pharmaceutically acceptable excipients can include pharmaceutically acceptable carriers. Exemplary excipients include, but are not limited to: monosaccharides, disaccharides and polysaccharides, sugar alcohols and other polyols, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitol, dipalmitoyl phosphatidylcholine, and lecithin; bulking agents; buffers, such as phosphate and citrate buffers; anti-adhesion agents, such as magnesium stearate; binders, such as sugars (including disaccharides, such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coating agents (such as cellulose ethers, including hydroxypropyl methyl cellulose, shellac, zein and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, croscarmellose sodium, and sodium starch glycolate); filling agents (such as calcium hydrogen phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavoring agents and sweeteners (such as mint, cherry, star anise, peach, apricot, or licorice, raspberry, and vanilla); lubricants (such as minerals, e.g., talc or silica, fats, e.g., vegetable stearin, magnesium stearate, or stearic acid); preservatives (such as antioxidants, e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids, e.g., cysteine and methionine, citric acid and sodium citrate, parabens, e.g., methyl paraben and propyl paraben); coloring agents; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0558] B. Combinations of Therapeutic Agents

[0559] The compounds described herein can be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as adjuncts to or in combination with other established therapies. The one or more compounds or compositions comprising the one or more compounds can be administered once or administered multiple times. In certain embodiments, the compounds of the present disclosure can be used in combination with other therapeutic agents useful for the disorder or condition being treated. These other therapeutic agents can be administered simultaneously, sequentially in any order, by the same route of administration as the compounds disclosed herein or by a different route. For sequential administration, the one or more compounds and the one or more therapeutic agents can be administered such that the effective period of at least one compound and therapeutic agent overlaps with the effective period of at least one other compound and / or therapeutic agent. In one exemplary embodiment of a combination comprising four components, the effective period of the first component administered can overlap with the effective periods of the second, third, and fourth components, but the effective periods of the second, third, and fourth components can independently overlap with each other or not. In another exemplary embodiment of a combination comprising four components, the effective period of the first component administered overlaps with the effective period of the second component, but not with the effective periods of the third or fourth components; the effective period of the second component overlaps with the effective periods of the first and third components; and the effective period of the fourth component overlaps only with the effective period of the third component. In certain embodiments, the effective periods of all compounds and / or therapeutic agents overlap with each other.

[0560] In certain embodiments, the compound is administered together with another therapeutic agent such as an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an incretin, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof. The anti-inflammatory agent can be a steroid or a non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In certain embodiments, the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, antilymphocyte globulin, antithymocyte globulin, an anti-T-cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0561] In certain embodiments, the compounds of the invention can be used in combination with an anti-cancer agent or cytotoxic agent. Classes of anti-cancer and anti-tumor compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkaloids, 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. Exemplary alkylating agents include, but are not limited to, nitrogen mustards, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimine, methylmelamine, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, by way of example and not limitation, the folic acid analogue methotrexate; the pyrimidine analogues fluorouracil, cytarabine; the purine analogues mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkaloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. Exemplary enzymes effective as anti-tumor agents include L-asparaginase. Exemplary coordination compounds include, by way of example and not limitation, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, by way of example and not limitation, the adrenocortical steroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progesterone compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

[0562] These and other useful anti-cancer compounds are described in Merck Index, 13th Edition (O'Neil M. J. et al., eds.) Merck Publishing Group (2001) and Goodman&Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Brunton L.L., eds., Chapters 60 - 63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0563] Among CTLA 4 antibodies, ipilimumab, which is sold by Bristol-Myers Squibb as YERVOY ® can be used in combination with the inhibitors disclosed herein.

[0564] Other chemotherapeutic agents for combination include immuno-oncology agents such as checkpoint pathway inhibitors, e.g., PD-1 inhibitors such as nivolumab and pembrolizumab (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).

[0565] Other chemotherapeutic agents for combination with the 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).

[0566] The compounds disclosed herein can also be advantageously used in combination with CAR-T therapy. Examples of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

[0567] Additional anti-proliferative compounds that can be used in combination with the compounds of the present disclosure include, by way of example and not limitation, antibodies against growth factor receptors (e.g., anti-Her2); and cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.

[0568] Other chemotherapeutic agents that can be used in combination with the compounds of the present invention include proteasome inhibitors such as bortezomib, carfilzomib, marizomib, etc.

[0569] Examples of kinase inhibitors that can be used in combination with the compounds disclosed herein, particularly in the treatment of malignancies, include: Btk inhibitors such as ibrutinib; CDK inhibitors such as palbociclib; EGFR inhibitors such as afatinib, erlotinib, gefitinib, lapatinib, osimertinib, and vandetanib; 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.

[0570] In other embodiments, the second therapeutic agent can be selected from any of the following:

[0571] Analgesics - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, pethidine, pentazocine, dextromoramide, dipipanone;

[0572] Antibiotics - Aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromomycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cefalotin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, cefotaxime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, and telavancin), lincosamides (e.g., clindamycin and incomysin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin, and spectinomycin), monobactams (e.g., aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin), penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), penicillin combinations (e.g., amoxicillin / clavulanate, ampicillin / sulbactam, piperacillin / tazobactam, and ticarcillin / clavulanate), polypeptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., sulfamylon, sulfacridine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim - sulfamethoxazole), tetracyclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), anti - mycobacterial compounds (e.g., 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, platensimycin, quinupristin / dalfopristin, rifaximin, thiamphenicol, tigecycline, and tinidazole;

[0573] Antibodies - Anti - TNF - α antibodies, e.g., infliximab (Remicade TM) Adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g., rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1 antibodies, e.g., anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, e.g., nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ibritumomab, brodalumab, ofatumumab, sirukumab, crisaborole, clazakizumab, fezakinumab, flecainide, maprilimumab, ocrelizumab, sarilumab, secukinumab, tolitumomab, zanolimumab;

[0574] Anticoagulants - warfarin (Coumadin TM ) acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin;

[0575] Anti-inflammatory agents - steroids, e.g., budesonide, non-steroidal anti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine, mesalazine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

[0576] Immunosuppressive agents - mercaptopurine, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus and tacrolimus, inosine monophosphate dehydrogenase inhibitors (IMPDH) such as mycophenolate mofetil, mycophenolic acid and azathioprine, and agents designed to inhibit cellular immunity while maintaining the integrity of the recipient's humoral immunological response, including various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibody (OKT3)) and irradiation. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trade name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name Mercaptopurine; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune; tacrolimus is currently available from Fujisawa under the trade name Prograf; cyclosporine is currently available from Novartis under the trade name Sandimmune and from Abbott under the trade name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the trade name Cellcept and from Novartis under the trade name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the trade name Imuran; and antibodies are currently available from OrthoBiotech under the trade name Orthoclone, from Novartis under the trade name Simulect (basiliximab) and from Roche under the trade name Zenapax (daclizumab); and

[0577] Guanylate cyclase-C receptor agonists or incretins, such as linaclotide, which is sold under the name Linzess.

[0578] These different agents can be used according to their standard or conventional dosages, as specified in the prescribing information of the commercially available forms of the accompanying drugs (see also, the prescribing information in the 2006 edition of The Physician's Desk Reference), the disclosure of which is incorporated herein by reference.

[0579] III. Methods for Preparing Compounds

[0580] The disclosed embodiments of the compounds of the present invention can be prepared by any suitable method understood by a person of ordinary skill in the art. An exemplary suitable method is provided in the following reference examples for specific compounds and may include the following first reaction step according to Scheme 1.

[0581]

[0582] Referring to Scheme 1, using a metal-mediated cross-coupling reaction, a protected amine precursor 100 can be coupled with an R 1 group 102, where the R 1 group 102 contains an “R 6 -linker” group as shown in Scheme 1, to provide a cross-coupled product 104. In certain embodiments, the metal-mediated cross-coupling reaction can be carried out using a transition metal catalyst, such as a palladium catalyst. Exemplary palladium catalysts include, but are not limited to, Pd(0) catalysts (e.g., Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, etc.) or Pd(II) catalysts (e.g., XPhos Pd Generation 2 or 3, PdCl2, Pd(OAc)2, etc.). In certain embodiments, the palladium catalyst can be used in combination with another cocatalyst (such as CuI) to facilitate the cross-coupling reaction, such as in the Sonogoshira reaction. The metal-mediated cross-coupling can also include the use of a base, such as an amine base (e.g., Et3N) or an inorganic base (e.g., Cs2CO3, Na2CO3, K2CO3, etc.) and a solvent (e.g., dimethylformamide). Referring to Scheme 1, X is a suitable group for the metal-mediated cross-coupling, such as a halogen or a trifluoromethanesulfonate group, and PG is an amine protecting group, which can be selected from, but is not limited to, 9-fluorenylmethoxycarbonyl (“Fmoc”) group, tert-butyloxycarbonyl (“Boc”) group, trityl (“Tr”) group, allyloxycarbonyl (“Alloc”) group, benzyloxycarbonyl (“Cbz”) group, etc.

[0583] Representative examples of the method steps shown in Scheme 1 are provided below in Schemes 2A-2F. Compounds I-14 to I-17 and I-35 can be prepared using a method similar to that shown in Scheme 2A by replacing the propargyl alcohol in Scheme 2A with the corresponding alkynyl group that gives rise to each of Compounds I-14 to I-17 and I-35; further modifications that can be used to obtain the final structures of Compounds I-14 to I-17 are discussed below.

[0584]

[0585] Once the cross-coupled product 104 is generated, an optional linker reduction step can be performed, in which a linker containing one or more unsaturated sites can be reduced to a saturated linker and / or a linker with fewer degrees of unsaturation. If a linker reducing group is used, a deprotection step can follow it, and then an amide formation step, as shown in Scheme 3. Alternatively, if the linker reduction step is not used, the cross-coupled product 104 can be deprotected and converted to an amide compound 302.

[0586]

[0587] Referring to Scheme 3, an optional linker reduction step can be performed. For example, if the linker contains unsaturated sites (e.g., double bonds or triple bonds), the unsaturated sites can be reduced such that it becomes fully saturated (e.g., reducing a double bond and / or triple bond to a single bond), or it has fewer degrees of unsaturation (e.g., reducing a triple bond to a double bond). One of ordinary skill in the art, benefiting from this disclosure, will recognize suitable reagents for performing such an optional linker reduction step; however, an exemplary set of conditions includes exposing the cross-coupled product 104 to H2 in the presence of carbon-supported Pd. Since these steps are optional, they need not be performed in all embodiments. Instead, in certain embodiments, the cross-coupled product 104 can be deprotected to provide an amine, which is then converted to an amide compound 302 by reacting the amine with a suitable acid coupling partner 300, as shown in Scheme 3.

[0588] Representative examples of the method steps shown in Scheme 3 are provided in Schemes 4A - 4M below. Compounds I-14 to I-17 can be prepared using methods similar to those described for Scheme 4A. Compounds I-16 and I-17 can be further functionalized as discussed below.

[0589]

[0590]

[0591]

[0592]

[0593]

[0594] In certain embodiments, the method can further include performing one or more additional modifications on the amide compound 302 to provide an amide compound 500, such as modifying the 6 R group to form a different 6 R group, as shown in Scheme 5.

[0595]

[0596] Referring 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. Those of ordinary skill in the art will recognize suitable reagents for carrying out such optional modification steps from the present disclosure; however, a set of exemplary conditions includes exposing the R 6 ester group to LiOH to provide the corresponding acid, as shown in Schemes 6A - 6E below. By using suitable amide coupling conditions (such as those described above) in combination with an amine coupling partner, the resulting acid can even be further modified to provide an amide-containing product, as shown in Schemes 6A - 6E. Similar methods can be used to prepare 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 is not first reduced prior to coupling). In other embodiments, Compounds I-16 and I-17 can be prepared as follows: converting the terminal alcohol obtained in the methods described above into a functionalized alcohol (such as for Compound I-16) or into an amine (such as for Compound I-17).

[0597]

[0598]

[0599] Many of the exemplary disclosed compounds are alkynyl-substituted analogs. These compounds can be prepared using the metal-mediated coupling strategy referred to in Scheme 1 as discussed above. Scheme 7 illustrates a more detailed general method for preparing alkynyl-substituted analogs according to the present disclosure (including but not limited to Examples 21 and 22).

[0600]

[0601] Referring to Scheme 7, nitrogen was bubbled through a stirred solution of aryl halide (1 equiv), Compound 700, CuI (0.1 - 0.2 equiv), and Pd(PPh3)4 (0.05 - 0.1 equiv) in dry DMF (3 - 4 mL / mmol) in a flask for 3 minutes. Subsequently, NEt3 (10 equiv) was added to the dark reaction solution, followed immediately by the addition of the corresponding alkyne (1.5 - 3 equiv), i.e., Compound 702. Nitrogen was bubbled through the reaction mixture for 2 minutes and the flask was capped. The reaction mixture was stirred at an effective reaction temperature (such as 70 - 90 °C) for an effective reaction period, such as 3 - 6 hours. Alternatively, the reaction mixture can be heated in a microwave reactor (30 - 45 minutes) until the aryl halide 700 is depleted. The dark reaction solution was worked up by one of the following methods: a) workup with ice water / organic solvent dilution; b) concentration to dryness followed by workup after dilution with ice water / organic solvent; or c) dilution of the crude residue with ice water, sonication, and warming of the slurry to room temperature. The resulting gray / dark solid was collected by filtration, suction dried, dissolved in THF (20 mL), filtered through a celite® / silica gel pad, and the pad was washed with THF. Subsequently, the crude material was purified by reverse-phase column chromatography or by normal-phase silica gel flash column chromatography to afford the corresponding alkynyl-substituted analog (yield: 25 - 69%), i.e., Compound 704.

[0602] IV. Methods of Using the Compounds

[0603] A. Diseases / Disorders

[0604] The disclosed compounds, their combinations and / or pharmaceutical compositions can be used to inhibit RIP1 kinase by contacting RIP1 kinase in vivo or in vitro with one or more compounds of the present disclosure, or a composition comprising one or more compounds of the present disclosure. One or more disclosed compounds, or a composition comprising one or more disclosed compounds, can also be used to ameliorate, treat, or prevent a variety of diseases and / or disorders. In certain embodiments, the disclosed compounds, combinations of the disclosed compounds, or their pharmaceutical compositions can be used to treat conditions in which inhibition of RIP1 or a pathway comprising RIP1 is therapeutically useful. In certain embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds can be used to treat autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancer, ischemic conditions, erythrocyte deficiencies, lung and brain injuries (e.g., induced by ischemia-reperfusion or cisplatin and / or cerebrovascular accident), and bacterial and viral infections.

[0605] In certain embodiments, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be used to treat or prevent allergic diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, 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.

[0606] The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can also be used to treat immunomodulatory disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunomodulatory disorders that can be treated with the compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, transplantation of organs or tissues, graft-versus-host disease caused by transplantation, autoimmune syndromes, including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes, 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, uveitis associated with Behçet's disease, keratitis, herpes keratitis, keratoconus, corneal epithelial dystrophy, leukoma cornea, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway diseases, bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, dust asthma, chronic or refractory asthma, late asthma and airway hyperreactivity, bronchitis, gastric ulcer, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, ischemia-reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, intestinal injury 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, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythrogenesis imperfecta, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa,Cardiomyopathy or myocardial infarction, scleroderma (including systemic scleroderma), antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, obesity, eosinophilic fasciitis, lesions of the gingiva, periodontal tissue, alveolar bone, and cementum, glomerulonephritis, male pattern hair loss or senile alopecia (by preventing hair loss or providing hair germination and / or promoting hair production and hair growth), muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, ischemia-reperfusion injury of organs occurring after preservation, transplantation, or ischemic diseases, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxicosis caused by pulmonary oxygen or drugs, lung cancer, emphysema, cataract, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scar formation, corneal alkali burn, erythema multiforme dermatitis, linear IgA bullous dermatitis, and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, cancer metastasis, and hypobaropathy, diseases caused by the release of histamine or leukotriene-C4, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute hepatic necrosis, necrosis caused by toxins, viral hepatitis, shock, or anoxia, hepatitis B virus, 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, "chronic plus acute" liver failure, chronic kidney disease, renal damage / injury (caused by, for example, nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs, acute kidney injury), increased chemotherapy efficacy, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, Parkinson's disease, trauma, or chronic bacterial infection.,

[0607] In certain embodiments, the compounds of the present invention can be used to treat neuropathic pain, including neuropathic pain and inflammation-induced pain.

[0608] In certain embodiments, the compounds can be used to treat interleukin-1 converting enzyme-related fever syndrome, tumor necrosis factor receptor-related periodic syndrome, NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases (e.g., Gaucher disease, GM2 gangliosidosis, α-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, sialidosis, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease).

[0609] In certain embodiments, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be used to treat and / or prevent rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis (especially pustular psoriasis), type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia d and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, acute gout attack, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptor antagonist), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0610] The combined use of the compounds of the present invention with other therapies is particularly useful in treating hyperproliferative disorders. The compounds of the present invention can be used in combination with standard of care to treat disorders such as cancer, leukemia, and lymphoma. As an example, myelodysplastic syndrome (MDS) can be treated with the compounds disclosed herein in combination with standard of care. Therapeutic agents for use in combination with the compounds of the present 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 therapies can also be used in combination with the compounds of the present invention for the treatment of MDS.

[0611] Proliferative diseases that can be treated by the disclosed compounds, combinations of the disclosed compounds, or their pharmaceutical compositions include benign or malignant tumors, solid tumors, cancers of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone, or thyroid, sarcomas, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancers, particularly colon cancer or colorectal adenomas, tumors of the neck and head, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenomas, adenocarcinomas, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphomas, such as Hodgkin's and non-Hodgkin's lymphomas, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disorders, hematopoietic tissue tumors, such as the lymphomas described above, MyD88-driven disorders (such as ABC diffuse large B-cell lymphoma (DLBCL) and Waldenström's macroglobulinemia), Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, or chronic lymphocytic leukemia), indolent or asymptomatic multiple myeloma, or hematological malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi sarcoma, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). Specifically, the compounds disclosed herein can be used to treat drug-resistant malignancies, such as JAK inhibitor-resistant malignancies, ibrutinib-resistant malignancies, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenström's macroglobulinemia.

[0612] Examples of allergic disorders that can be treated using the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, idiopathic asthma, true asthma, endogenous asthma caused by pathophysiological disorders, idiopathic asthma of unknown or undetermined cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, exogenous asthma caused by environmental factors, cold air-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoal, or viral infections, incipient asthma, wheezy infant syndrome, 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, and ethmoiditis, frontal sinusitis, maxillary sinusitis, or sphenoid sinusitis).

[0613] As another example, rheumatoid arthritis (RA) typically results in swelling, pain, loss of mobility, and tenderness in target joints throughout the body. RA is characterized by a chronically inflamed synovium with dense lymphocytes. The synovium, which is normally one cell layer thick, becomes cell-dense and assumes a form similar to lymphoid tissue, including dendritic cells, T cells, B cells, and NK cells, macrophages, and clusters of plasma cells. This process, along with numerous immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, ultimately leads to the destruction of joint integrity, resulting in deformities, permanent loss of function, and / or bone erosion at or near the joints. The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be used to treat, ameliorate, or prevent any one, several, or all of these symptoms of RA. Thus, in the context of RA, a compound is considered to provide a therapeutic benefit when any symptom commonly associated with RA is reduced or ameliorated, regardless of whether the treatment results in a concomitant treatment of underlying RA and / or a reduction in the amount of circulating rheumatoid factor (“RF”).

[0614] The American College of Rheumatology (ACR) has developed criteria for defining improvement and clinical remission in RA. One such parameter, the ACR20 (ACR criteria for 20% clinical improvement), requires a 20% improvement in the count of tender and swollen joints, as well as a 20% improvement in 3 of the following 5 parameters: patient global assessment, physician global assessment, patient pain assessment, disability level, and acute phase reactant level. These criteria are expanded to 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include Paulu's criteria and radiographic progression (e.g., Sharp score).

[0615] In certain embodiments, a treatment benefit is achieved in patients suffering from RA when the patient exhibits ACR20. In a specific embodiment, an ACR improvement of ACR50 or even ACR70 can be achieved.

[0616] In one embodiment, the compounds disclosed herein can be used to slow the onset of the consequences of aging. For example, the compounds of the invention mitigate the exacerbation of chronic inflammation associated with advanced age (“inflammaging”). Numerous symptoms and disorders are associated with inflammaging, and by way of example, such disorders that can be treated with the compounds of the invention include neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, hematopoietic tissue tumors, and myeloproliferative disorders. Other disorders that can be treated or ameliorated with the compounds of the invention include those described in 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 the invention can be used to reduce the aging effects on the reproductive system. For example, Li et al. eLife 2017;6:e27692 and Chaudhary et al. Journal of Biomedical Science (2019) 26:11 have shown that necroptosis induced by RIP1 signaling is associated with the aging of reproductive organs, and thus the compounds of the invention can be used to treat aging-related symptoms such as reduced testosterone levels, reduced fertility, and prostate hyperplasia.

[0617] Additional diseases or disorders that can be treated and / or prevented using the compounds and compositions of the present invention include amyotrophic lateral sclerosis (ALS), autoimmune syndromes, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, 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, endogenous asthma, exogenous asthma, dust asthma, chronic or refractory asthma, late-stage asthma and airway hyperreactivity, allergic rhinitis, spondyloarthritis, ankylosing spondylitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, cerebrovascular accident, allergic diseases, chronic obstructive pulmonary disease, emphysema, Friedreich's ataxia, Lewy body dementia, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr disease, Menke's disease, Wilson's disease, prion disorders, destructive bone disorders such as bone resorption diseases, multiple myeloma-related bone disorders; benign tumors, proliferative disorders, inflammatory and hyperproliferative skin disorders, epidermal hyperplasia, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, erythema multiforme dermatitis, linear IgA bullous dermatitis, cement dermatitis, gingivitis, periodontitis, injury to the gingiva, alveolar bone, and cementum, sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, obesity, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burn, Behçet's disease, uveitis associated with Behçet's disease, keratitis, herpes simplex keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Vogt-Koyanagi-Harada syndrome, hematological disorders, hematological malignancies, lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, ABC diffuse large B-cell lymphoma (DLBCL), Waldenström's macroglobulinemia, primary cutaneous T-cell lymphoma, indolent or asymptomatic multiple myeloma, leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS),Myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1-driven disorders, MyD88-driven disorders, drug-resistant malignancies such as JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies, e.g., ibrutinib-resistant hematological malignancies, ibrutinib-resistant CLL and ibrutinib-resistant Waldenström macroglobulinemia, acute myeloid leukemia, chronic myeloid 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 injury associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 converting enzyme-related 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, Gaucher disease, GM2 gangliosidosis, α-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, sialidosis, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, Wolman disease, Huntington disease, Parkinson's disease, neurodegenerative diseases, Huntington disease, Parkinson's disease, metastatic melanoma, neurodegeneration associated with HIV infection and CMV retinitis (such as associated with neurocognitive disorder or dementia), fibrotic disorders such as non-alcoholic steatohepatitis, and cardiac disorders such as ischemia reperfusion; allergic reactions, 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 syndrome, rubella arthritis, acute synovitisPancreatic β-cell diseases; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis, psoriatic arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgia caused by infection, keloid formation, scar tissue formation, fevers, influenza, chronic myeloid leukemia; angiogenic disorders including solid tumors; viral diseases including acute hepatitis infections (including hepatitis A, B and C), AIDS, ARC or malignancy, herpes; stroke, myocardial infarction, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardial ischemia, ischemia in stroke heart attacks, organ hypoxia, angiogenesis, cardiac and renal reperfusion injury, ischemia-reperfusion injury of organs occurring after preservation, transplantation or ischemic diseases, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions associated with prostaglandin endoperoxide synthase-2, pemphigus vulgaris, autoimmune / dermatomyositis, polymyositis, vitiligo vulgaris, photoallergic sensitivity, ischemia-reperfusion injury, myocardial ischemia-reperfusion injury caused by myocardial infarction, multiple system atrophy, parkinsonism plus syndrome, frontotemporal dementia, intracranial hemorrhage, cerebral hemorrhage, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, demyelinating diseases, systemic-onset juvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), renal transplantation, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), ARDS caused by COVID-19, post-infectious autoimmune diseases, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO-deficiency syndrome (deficiency of the F-κ-B essential modulator gene (also known as IKKγ or IKKG)), solid organ malignancies, lysosomal storage diseases, glaucoma, retinal degenerative diseases, retinal ischemia / reperfusion injury, renal ischemia / reperfusion injury, cataracts, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scar formation, septic shock induced by anthrax lethal toxin,LPS-induced cell death, infectious encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, segmental 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 chorioretinopathy, 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 neuropathy, central retinal artery occlusion, ischemic optic neuropathy (e.g., arteritic or non-arteritic anterior ischemic optic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, marked optic atrophy, Behr syndrome, Creutzfeldt-Jakob disease, progressive supranuclear palsy, hereditary spastic paraplegia, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, hypoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia and hypoxic hypoxia, peritoneal injury caused by peritoneal dialysis fluid (PDF) and PD-related side effects, glomerular disease, tubulointerstitial disease, interstitial nephritis, obstruction, polycystic kidney disease, focal segmental glomerulosclerosis, immune complex nephropathy, diabetic nephropathy, Goodpasture syndrome, hepatocellular carcinoma, pancreatic cancer, urinary tract cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostatic hyperplasia, renal cancer, kidney cancer, liver cancer, adrenal cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, neuroendocrine cancer, central nervous system cancer, brain tumor (e.g., brain cancer, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, nephroblastoma, trophoblastic tumor, epithelioma formation, gastric cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancerSkin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, colon cancer, colorectal adenoma, hemangiopericytoma, mucinous carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, vulvar cancer, adrenocortical cancer, ACTH-producing tumors and leukemia, respiratory infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, adenovirus, reovirus, etc.), herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infectious diseases such as Bacillus cereus ( Bacillus cereus ), Vibrio parahaemolyticus ( Vibrio parahaemolyticus ), enterohemorrhagic Escherichia coli ( Enterohemorrhagic Escherichia coli ), Staphylococcus aureus ( Staphylococcus aureus ), methicillin-resistant Staphylococcus aureus (MRSA), Salmonella spp. ( Salmonella ), Clostridium botulinum ( Botulinus ), Candida spp. ( Candida), Paget's disease, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, partial hepatectomy, acute hepatic necrosis, necrosis caused by toxins, necrosis caused by viral hepatitis, necrosis caused by shock, necrosis caused by hypoxia, hepatitis B virus, 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, "chronic plus acute" liver failure, chronic kidney disease, kidney damage / injury, kidney damage / injury caused by nephritis, kidney damage / injury caused by renal transplantation, kidney damage / injury caused by surgery, kidney damage / injury caused by administration of nephrotoxic drugs, enhanced chemotherapy effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, decompression sickness, diseases caused by histamine or leukotriene-C4 release, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by pulmonary oxygen or drugs, congenital hypophosphatasia, fibromatous lesion, fibrous dysplasia, bone turnover, osteolytic bone disease, orthopedic surgery after treatment of trauma, arthroscopic surgery after treatment of repair, orthopedic surgery after treatment of plastic surgery, surgical operation after treatment of teeth, bone chemotherapy treatment or bone radiotherapy treatment, bone cancer, vulnerable plaque, disorder, occlusive disorder, stenosis, coronary artery disorder, peripheral arterial disorder, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, graft occlusion after surgery, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoto's thyroiditis, myasthenia gravis, cold and warm agglutinin diseases, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoiesis imperfecta, and combinations thereof.

[0618] For certain embodiments, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject having or likely to develop atopic dermatitis. In another particular embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject having or likely to develop rheumatoid arthritis. In another particular embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject having or likely to develop ankylosing spondylitis. In another particular embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject having or likely to develop myelodysplastic syndrome.

[0619] B. Formulations and Administration

[0620] A pharmaceutical composition comprising one or more active compounds of the present disclosure can be prepared by any suitable method, such as mixing, dissolving, granulating, sugarcoating, milling, emulsifying, encapsulating, entrapping, or lyophilization processes. The pharmaceutical composition can be formulated using one or more physiologically acceptable excipients (e.g., diluents, carriers, or adjuvants), one or more adjuvants, or combinations thereof to provide a pharmaceutically usable article.

[0621] One or more active compounds can be formulated in a pharmaceutical composition in their own right or in the form of their pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs. Generally, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts may also be formed that have lower solubility than the corresponding free acids and bases.

[0622] The pharmaceutical compositions of the present disclosure can take forms suitable for substantially any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection (such as intravenous or intraperitoneal), transdermal, rectal, vaginal, etc., or forms suitable for inhalation or insufflation administration.

[0623] For topical administration, one or more active compounds, pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs can be formulated into solutions, gels, ointments, creams, suspensions, etc., well known in the art.

[0624] Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0625] Useful injectable preparations include sterile suspensions, solutions or emulsions of one or more active compounds in an aqueous or oily vehicle. The pharmaceutical composition may also contain formulating agents such as suspending agents, stabilizers and / or dispersing agents. Preparations for injection may be in unit dosage forms, for example, in ampoules or in multi-dose containers, and may contain added preservatives.

[0626] Alternatively, the injectable preparation may be provided in powder form, which is reconstituted with a suitable vehicle before use, the vehicle including, but not limited to, sterile, pyrogen-free water, buffer solutions, dextrose solutions, etc. For this purpose, one or more active compounds may be dried by any technique known in the art, such as lyophilization, and reconstituted before use.

[0627] For transmucosal administration, permeating agents suitable for the barrier to be permeated are used in the preparation. Such permeating agents are known in the art.

[0628] For oral administration, the pharmaceutical composition may be in the form of, for example, lozenges, tablets or capsules, which are prepared by conventional means with pharmaceutically acceptable excipients such as: binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art, for example, with sugar, film or enteric coatings.

[0629] Liquid preparations for oral administration may be in the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as dry products to be constituted with water or other suitable vehicles before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable excipients such as: suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, esters of fatty acids, ethanol, cremophore TM. or fractionated vegetable oils); and preservatives (e.g., methylparaben or propylparaben or sorbic acid). The preparation may also contain suitable buffer salts, preservatives, flavoring agents, coloring agents and sweetening agents.

[0630] As is well known, preparations for oral administration may be suitably formulated to provide controlled release of the active compound.

[0631] For buccal administration, the pharmaceutical composition may be in the form of tablets or lozenges formulated by conventional means.

[0632] For rectal and vaginal administration routes, one or more active compounds can be formulated as a solution (for retention enemas), suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0633] For nasal administration or administration by inhalation or insufflation, the one or more active compounds, pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes or prodrugs can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, which is for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluorocarbons, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, the dose unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges (such as capsules and cartridges containing gelatin) for use in an inhaler or insufflator can be formulated, which contain a powder mixture of the compound and a suitable powder matrix such as lactose or starch.

[0634] Specific examples of aqueous suspension formulations suitable for nasal administration using commercially available nasal spray devices include the following components: active compound (0.5 - 20 mg / ml); benzalkonium chloride (0.1 - 0.2 mg / mL); polysorbate 80 (TWEEN ® 80; 0.5 - 5 mg / ml); sodium carboxymethylcellulose or microcrystalline cellulose (1 - 15 mg / ml); phenyl ethanol (1 - 4mg / ml); and dextrose (20 - 50 mg / ml). The pH of the final suspension can be adjusted to a range of about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

[0635] Another specific example of an aqueous suspension suitable for inhalation of the compound contains 20 mg / mL of one or more of the disclosed compounds, 1% (v / v) polysorbate 80 (TWEEN ® 80), 50 mM citrate and / or 0.9% sodium chloride.

[0636] For ocular administration, one or more active compounds can be formulated as solutions, emulsions, suspensions, etc. suitable for administration to the eye. A variety of vehicles suitable for administration of compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Patent Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851, which are incorporated herein by reference.

[0637] For extended delivery, one or more active compounds can be formulated into a depot preparation for administration by implantation or intramuscular injection. The active ingredient can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, e.g., a sparingly soluble salt. Alternatively, a transdermal delivery system can be used, which is manufactured as an adhesive disk or patch that slowly releases one or more active compounds for percutaneous absorption. For this purpose, permeation enhancers can be used to facilitate the transdermal permeation of one or more active compounds. Suitable transdermal patches are described, for example, in U.S. Patent Nos. 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which are incorporated herein by reference.

[0638] Alternatively, other drug delivery systems can be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver one or more active compounds. Certain organic solvents such as dimethyl sulfoxide (DMSO) can also be employed, although usually at the cost of greater toxicity.

[0639] If desired, the pharmaceutical composition can be presented in a package or dispenser device that can contain one or more unit dosage forms, each unit dosage form containing one or more active compounds. The package can comprise, for example, a metal or plastic foil, such as a blister pack. The package or dispenser device can be accompanied by instructions for administration.

[0640] There are several approaches for transporting 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 for transporting compounds across the blood-brain barrier include, but are not limited to, completely bypassing the blood-brain barrier and / or creating openings in the blood-brain barrier. Bypass methods include, but are not limited to, direct injection (e.g., 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 delivery devices in the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003). Openings in the blood-brain barrier include, but are not limited to, ultrasound, osmotic pressure (e.g., by administration of hypertonic mannitol), and permeabilization with, e.g., bradykinin or permeabilizer A-7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416). Compounds can also be encapsulated in liposomes conjugated to antibody-binding fragments that bind to receptors on the vascular endothelium of the blood-brain barrier.

[0641] For certain embodiments, the compound can be administered continuously by infusion into a fluid reservoir of the central nervous system or by bolus injection. The compound can be administered using an indwelling catheter and a continuous administration device such as a pump or by implantation of a sustained-release vehicle. For example, these compounds can be injected by long-term implanted cannulas or by long-term infusion with the aid of an osmotic minipump. A subcutaneous pump can deliver the compound to the cerebral ventricle.

[0642] C. Dosage

[0643] The disclosed compounds, pharmaceutical compositions, or combinations of the disclosed compounds are generally used in an amount effective to achieve the desired result, e.g., in an amount effective to inhibit RIP1 kinase and / or effective to treat, prevent, or ameliorate a particular disorder. The disclosed compounds or their pharmaceutical compositions can be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated, and / or the eradication or amelioration of one or more symptoms associated with the underlying disorder, such that although the patient may still be afflicted with the underlying disorder, the patient reports an improvement in how they feel or their condition. For example, the administration of a compound to a patient suffering from an allergy will provide a therapeutic benefit not only when the underlying allergic reaction is eradicated or ameliorated, but also when the patient reports a reduction in the severity or duration of allergy-related symptoms upon exposure to an allergen. As another example, a therapeutic benefit in the context of asthma includes an improvement in breathing following the onset of an asthma attack or a reduction in the frequency or severity of asthma attacks. A therapeutic benefit also includes halting or slowing the progression of the disease, whether or not an improvement is achieved.

[0644] As is known to those of ordinary skill in the art, the preferred dosage of the disclosed compounds can depend on a variety of factors, including the age, weight, general health, and the severity of the disorder of the patient or subject being treated. When administered by inhalation, it may also be necessary to adjust the dosage to accommodate the sex of the individual and / or the individual's lung capacity. The dosage can also be adjusted to accommodate individuals suffering from more than one disorder or those with additional disorders that affect lung capacity and normal breathing ability (e.g., emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and respiratory infections). The dosage and frequency of administration of the disclosed compounds or their pharmaceutical compositions will also depend on whether the disclosed compound is formulated for the treatment of an acute episode of a disorder or for the prophylactic treatment of a disorder. Those of ordinary skill in the art will be able to determine the optimal dosage for a particular individual.

[0645] For prophylactic administration, the disclosed compounds, combinations of the 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 not known whether a patient or subject is allergic to a particular drug, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered prior to administration of the drug to avoid or ameliorate an allergic reaction to the drug. Alternatively, prophylactic administration can be used to avoid or ameliorate the onset of symptoms in a patient diagnosed with an underlying disorder. For example, prior to an anticipated exposure to an allergen, the disclosed compounds or pharmaceutical compositions thereof can be administered to an allergic patient. The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can also be administered prophylactically to a healthy individual to prevent the onset of the disorder, the healthy individual being repeatedly exposed to a factor known to be associated with one of the above diseases. For example, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a healthy individual repeatedly exposed to an allergen (such as latex) known to induce allergy in an attempt to prevent the individual from developing an allergy. Alternatively, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a patient with asthma prior to participating in an activity that triggers an asthma attack to reduce the severity of the asthma attack or to avoid the asthma attack altogether.

[0646] The effective dose can be initially estimated from in vitro assays. For example, an initial dose for a subject can be formulated to achieve a circulating blood or serum concentration of the active compound equal to or higher than the IC 50 or EC 50 of a particular compound as measured in an in vitro assay. Taking into account the bioavailability of the particular compound, the dose can be calculated to achieve such a circulating blood or serum concentration. Fingl and Woodbury, “General Principles”, see: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, Pergamon Press, and references cited therein, provide additional guidance on effective doses.

[0647] In certain embodiments, the disclosed compounds have an EC 50 greater than 0 to 20 μM, such as 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, greater than 0 to 0.1 μM, or greater than 0 to 0.05 μM.

[0648] Initial doses can also be estimated from in vivo data such as animal models. Animal models that can be used to test the efficacy of a compound in treating or preventing the various diseases described above are well known in the art. Suitable animal models of hypersensitivity or allergy 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 in: 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. One of ordinary skill in the art can adjust such information to determine a dose suitable for human administration.

[0649] In certain embodiments, assays suitable for determining RIP1 activity can be used. Such assay methods can be used to evaluate the efficacy of the compound embodiments disclosed herein, and / or can be used to determine the amount / dose of the compound embodiments that can provide the desired efficacy. In certain embodiments, the assay can be an ADP-Glo TM assay, which assesses the ability of a compound embodiment to inhibit RIP1. In other embodiments, whole cell assays using mouse and / or human cells, such as the U937 and / or L929 necroptosis assays, can be performed to determine the safe and effective dose of a compound for use in human in vivo studies. Using these whole cell assays, the activity of a compound against human and / or murine RIP1 can be evaluated in an in vitro context, which then allows one of ordinary skill in the art to determine the safe and effective dose for in vivo use. Another assay that can be used to evaluate the activity of the compound embodiments described herein in treating diseases or disorders involving RIP1 is the acute hypothermic mouse model, which assesses the ability of a compound to inhibit TNF-α-induced hypothermia. Each of these assays and the different results from using these assays are described in detail in the Examples section of the present disclosure.

[0650] The dose of the disclosed compounds is generally in the range of greater than 0 mg / kg / day (such as 0.0001 mg / kg / day or 0.001 mg / kg / day or 0.01 mg / kg / day) up to at least about 100 mg / kg / day. More typically, the dose (or effective amount) can be in the range of about 0.0025 mg / kg to about 1 mg / kg administered at least once a day, such as 0.01 mg / kg to about 0.5 mg / kg or about 0.05 mg / kg to about 0.15 mg / kg. The total daily dose is generally in the range of about 0.1 mg / kg to about 5 mg / kg or up to about 20 mg / kg per day, such as 0.5 mg / kg to about 10 mg / kg per day or about 0.7 mg / kg / day to about 2.5 mg / kg / day. The dose can be higher or lower, depending, among other factors, on the activity of the disclosed compound, its bioavailability, the mode of administration, and the various factors discussed above.

[0651] The dose and dose interval can be adjusted for an individual to provide a plasma level of the disclosed compound sufficient to maintain a therapeutic or prophylactic effect. For example, the compound can be administered once a day, multiple times a day, once a week, multiple times a week (e.g., every other day), once a month, multiple times a month, or once a year, depending, among other factors, on the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. Without undue experimentation, one of ordinary skill in the art can optimize the effective topical dose.

[0652] A pharmaceutical composition comprising one or more of the disclosed compounds generally comprises greater than 0 up to 99% of the one or more disclosed compounds and / or other therapeutic agents (by total weight). More typically, a pharmaceutical composition comprising one or more of the disclosed compounds comprises about 1 to about 20 total weight % of the disclosed compounds and other therapeutic agents, and about 80 to about 99 weight % of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition can further comprise an adjuvant.

[0653] Preferably, the disclosed compounds, combinations of the disclosed compounds, or their pharmaceutical compositions will provide a therapeutic or prophylactic benefit without causing substantial toxicity. The toxicity of the disclosed compounds can be determined using standard pharmaceutical procedures. The dose ratio between toxicity and therapeutic (or prophylactic) effect is the therapeutic index. Disclosed compounds exhibiting a high therapeutic index are preferred.

[0654] V. Examples

[0655] Example 1

[0656] The compounds of the present disclosure can be prepared using suitable starting compounds such as compound 200 or compound 206 shown in the above schemes. A representative method for preparing compound 200 is exemplified in Scheme 8A, and a representative method for preparing compound 206 is exemplified in Scheme 8B.

[0657]

[0658]

[0659] 3-( S )- N Spectral characterization of 3-trityl-amino-7-bromo-5-methyl-4-oxobenzoxazepine (200): 1 H nmr (400 MHz, CDCl3) δ 7.41 - 7.38 (6H, m, 6H of C(C6H5)3), 7.25 - 7.15 (10H, m, oxobenzoxazepine H-8, 9H of C(C6H5)3), 7.00 (1H, d, J 2.5 Hz, oxobenzoxazepine H-6), 6.91 (1H, d, J 8.5 Hz, oxobenzoxazepine H-9), 4.50 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.37 (1H, dd, J 11.5, 10.0Hz, 1H of oxobenzoxazepine H-2), 3.53 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 3.30 (1H, br s, NH), 2.87 (3H, s, NCH3).

[0660] Characterization data and specific methods for preparing representative compounds disclosed herein are provided below.

[0661] Example 2

[0662]

[0663] ( S )-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo b [1,4]oxazepin-4(5 H)-Ketone Synthesis: A mixture of bromooxaazepine (0.210 g, 0.410 mmol, 1.0 equiv), potassium carbonate (0.566 g, 4.101 mmol, 10.0 equiv), and copper(I) iodide (0.008 g, 0.041 mmol, 0.1 equiv) in dimethylformamide (3.0 mL) was degassed by bubbling argon through it for 5 minutes. 2-Methyl-2-hydroxybut-3-yne (0.052 g, 0.060 mL, 0.615 mmol, 1.5 equiv) and tetrakis(triphenylphosphine)palladium (0.024 g, 0.021 mmol, 0.05 equiv) were added, and the reaction mixture was sealed and then heated in a microwave to 120 °C for 1 hour. The reaction was partitioned between EtOAc (80 mL) and water (80 mL). The organic layer was washed with brine (80 mL), water (80 mL), and brine (80 mL), dried (Na2SO4), and concentrated under reduced pressure. MPLC (10→80% EtOAc - hexane) gave the starting material (0.091 g) and the title compound (0.079 g) as a colorless oil; 1 1H nmr (400 MHz, CDCl3) δ 7.40 - 7.38 (6H, m, 6H of C(C6H5)3), 7.24 - 7.14 (9H, m, 9H of C(C6H5)3), 7.13 (1H, dd, J 8.0, 2.0 Hz, oxabenzoxaazepine H-8), 6.96 (1H, d, J 8.0 Hz, oxabenzoxaazepine H-9), 6.95 (1H, d, J 2.5 Hz, oxabenzoxaazepine H-6), 4.48 (1H, dd, J 10.0, 7.5 Hz, 1H of oxabenzoxaazepine H-2), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H of oxabenzoxaazepine H-2), 3.55 (1H, dd, J 11.5, 7.5 Hz, oxabenzoxaazepine H-3), 2.78 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2); m / z : 555 [M+K] + , 243 [C(C6H5)3] + .

[0664]

[0665] Deprotection of trityl: To a solution of trityl-protected amine (0.079 g, 0.153 g, 1.0 equiv) in dioxane (2.0 mL) was added hydrochloric acid solution (0.15 mL of 4 M solution in dioxane, 0.614 mmol, 4.0 equiv). The reaction was stirred at room temperature for 6 h and then concentrated to dryness to afford a white solid, which was used without purification; m / z : 275 [M+H] + .

[0666]

[0667] ( S )-5-benzyl- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide synthesis: To a solution of aminooxobenzoxazepine hydrochloride (0.076 mmol, 1.0 equiv) and benzyltriazolecarboxylic acid (0.017 g, 0.084 mmol, 1.1 equiv) in dimethylformamide (1.0 mL) was added diisopropylamine (0.025 g, 0.033 mL, 0.190 mmol, 2.5 equiv), followed by HATU (0.032 g, 0.084 mmol, 1.1 equiv). The reaction was stirred at room temperature for 4 h and partitioned between EtOAc-CH2Cl2 (5:1, 60 mL) and NaHCO3 (60 mL). The organic layer was washed with brine (50 mL), water (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH-CH2Cl2) gave the title compound as a white solid; 11H NMR (400 MHz, CDCl3) 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, oxobenzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.68 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.14 (2H, s, CC H 2C6H5), 3.40 (3H, s, NCH3), 1.63 (6H, s, C(C H 3)2OH); m / z : 442 [M + H - H2O] + 。

[0668] Steps similar to those described above for Example 2 can be used to prepare Compounds I-14 to I-17 and I-35.

[0669] Example 3

[0670]

[0671] Synthesis of ethyl (S,E)-3-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)acrylate: A suspension of tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (0.500 g, 1.35 mmol, 1.0 equiv) in dimethylformamide (8 mL) was degassed by bubbling argon through it for 5 minutes. Ethyl acrylate (0.270 g, 0.29 mL, 2.70 mmol, 2.0 equiv) and triethylamine (0.272 g, 0.37 mL, 2.0 equiv) were added, followed by tetrakis(triphenylphosphine)palladium(0) (0.156 g, 0.14 mmol, 0.1 equiv). The reaction was sealed and heated in a microwave to 100 °C for 1 hour and 120 °C for 1 hour. The reaction was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (70 mL), water (100 mL) and brine (70 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (10→40% EtOAc-hexanes) gave the title compound as a yellow foam (0.250 g, %); 1 H nmr (400 MHz, CDCl3) δ 7.62 (1H, d, J 16.0 Hz, ArCH=C H CO), 7.35 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazepine H-8), 7.33 (1H, d, J 2.0 Hz, oxobenzoxazepine H-6), 7.14 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 6.37 (1H, d, J 16.0 Hz, ArC H =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 of oxobenzoxazepine H-2), 4.27 (2H, q, J 7.0 Hz, OC H2CH3), 4.19 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.41 (3H, s, NCH3), 1.39 (9H, s, C(CH3)3), 1.34 (3H, t, J 7.0 Hz, OCH2C H 3); m / z : 291 [M+H-CO2-C4H8] + 。

[0672]

[0673] (S)-Ethyl 3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate synthesis: To a solution of α,β-unsaturated ester (0.25 g, 0.64 mmol, 1.0 equiv) in ethyl acetate (20 mL) was added palladium on carbon (0.23 g). The reaction was purged with hydrogen and stirred under a hydrogen atmosphere for 14 h. The reaction was purged with nitrogen and filtered through celite®, eluting with ethyl acetate (2 x 20 mL). The filtrate was concentrated under reduced pressure; 1 1H NMR (400 MHz, CDCl3) 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 of oxobenzoxazepine H-2), 4.14 - 4.07 (1H, m, 1H of oxobenzoxazepine H-2), 4.12 (2H, q, J 7.0 Hz, OCH2CH3), 3.36 (3H, s, NCH3), 2.91 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 2.59 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 1.37 (9H, s, C(CH3)3), 1.23 (3H, t, J 7.0 Hz, OCH2CH3); m / z : 337 [M+H-C4H8] + , 293 [M+H-CO2-C4H8] +The crude material was dissolved in dichloromethane (10 mL). Hydrogen chloride (0.80 mL of a 4 M solution in dioxane, 3.21 mmol, 5.0 equiv) was added. The reaction was stirred at room temperature for 14 h, then additional hydrogen chloride solution (0.8 mL, 5.0 equiv) was added. After stirring for an additional 2 h, the reaction was concentrated under reduced pressure and dried in vacuo to afford a brown solid. The crude material was used without further purification; m / z : 293 [M+H] + 。

[0674]

[0675] (S)-Ethyl 3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate synthesis: Fluorobenzyltriazole (0.116 g, 0.525 mmol, 1.1 equiv) was added to a solution of (S)-ethyl 3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate (0.140 g, 0.477 mmol, 1.0 equiv) and diisopropylethylamine (0.154 g, 0.21 mmol, 2.5 equiv) in dimethylformamide (5.0 equiv). HATU (0.199 g, 0.525 mmol, 1.1 equiv) was added and the reaction was stirred at 0 °C for 1 h and at room temperature for 1 h. The reaction was partitioned between EtOAc (120 mL) and NaHCO3 - water (1:1, 120 mL). The organic layer was 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 as a white solid (0.138 mg); 1 1H nmr (400 MHz, CDCl3) δ 8.11 (1H, s, triazole H-5), 8.05 (1H, d, 7.0 Hz, NH), 7.38 - 7.30 (2H, m, 2H of C6H4F), 7.26 - 7.07 (6H, m, 2H of C6H4F, oxobenzoxazepine H-6, H-7, H-8, H-9), 5.42 (2H, s, C H2C6H4F), 5.08 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine 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 FN5O5 requires [M+H] + 496.1973).

[0676] Similar steps to those described above for Example 3 and those described below for Examples 4 and 5 can be used to prepare 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 is not first reduced before coupling).

[0677] Example 4

[0678]

[0679] ( S )-3-(3-(1-(2-Fluorobenzyl)-1 H -1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzob Synthesis of [[1,4]oxazepin-7-yl)propionic acid: To a solution of the ethyl ester (0.103 g, 0.208 mmol, 1.0 equiv) in tetrahydrofuran (3 mL) was added an aqueous lithium hydroxide solution (0.017 g, 0.416 mmol, 2.0 equiv in 1 mL of water). The reaction was stirred at room temperature for 3 hours and then partitioned between EtOAc (80 mL) and NH4Cl (80 mL). The aqueous phase was extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (0→10% MeOH-CH2Cl2) gave the title compound as a white solid (0.054 g,%); 1 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, NC H 2C6H5F), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.22 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.41 (3H, s, NCH3), 2.96 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 2.70 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO); 19 19F 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 FN5O5 requires [M+H] + 468.1678).

[0680] Example 5

[0681]

[0682] ( S )- N -(7-(3-((1 H -Indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1-(2-fluorobenzyl)-1 H -1,2,4-triazole-3-carboxamide synthesis: A solution of ([[]] S S )-3-(3-(1-(2-fluorobenzyl)-1 H -1,2,4-triazole-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 equiv) and 6-aminoindazole (0.017 g, 0.126 mmol, 1.2 equiv) in dimethylformamide (10 mL) was cooled to 0 °C. Diisopropylethylamine (0.027 g, 0.036 mL, 0.210 mmol, 2.0 equiv) was added, followed by HATU (0.048 g, 0.126 mmol, 1.2 equiv), and the reaction was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction was partitioned between EtOAc (50 mL) and NaHCO3 (50 mL). The organic layer was washed with brine (50 mL). The combined aqueous phases were extracted with EtOAc (20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (0 → 10% MeOH-CH2Cl2) gave the title compound as a white solid (0.xx g,%); 11H 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 of C6H4F), 7.13 (1H, td, J 7.5, 1.0 Hz, 1H of C6H4F), 7.09 - 7.00 (5H, m, indazole H-5, 1H of C6H4F, oxobenzoxazepine H-6, H-7, H-9), 5.40 (2H, s, NC H 2C6H4F), 5.02 (1H, td, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.63 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.23 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.29 (3H, s, NCH3), 3.03 (2H, t, J 7.0 Hz, ArC H 2CH2CON), 2.68 (2H, m, ArCH2C H 2CON); 13 13C 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 19F NMR (CDCl3) δ -118.0; m / z : 583 [M+H] + (found [M+H] + , 583.2205, C30 H 27 FN8O4 requires [M+H] + 583.2212).

[0683] Example 6

[0684]

[0685] (S)-Ethyl 3-(3-(1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate: 1 H nmr (400 MHz, CDCl3) δ8.02 (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 xArH), 5.70 (2H, s, CH2C6H3Cl2), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.74 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.21 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.14(2H, q, J 7.0 Hz, OC H 2CH3), 3.41 (3H, s, NCH3), 2.95 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 2.63 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 1.24 (3H, t, J 7.0 Hz, OCH2C H 3); 13 C nmr (100 MHz, CDCl3) 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] + (Measured [M+H] + , 546.1291,C 25 H 25 Cl2N5O5 requires [M+H] + 546.1306).

[0686] Example 7

[0687]

[0688] ( S )-3-(3-(5-Benzyl-1 H -1,2,4-triazol-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-7-yl)propanoic acid: 1 H nmr (400 MHz, CDCl3) 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, oxobenzoxazepine H-3), 4.62 (1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazepine H-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.13 (2H, s, C H 2C6H5), 3.38 (3H, s, NCH3), 2.94 (2H, m, ArC H 2C H 2CO2H's 2H), 2.70 (2H, m, ArC H 2C H 2CO2H's 2H); 19 F nmr (CDCl3) δ -118.1; m / z :450 [M+H] + (Measured [M+H] + , 450.1760, C 23 H 23 N5O5 requires [M+H] + 450.1772).

[0689] Example 8

[0690]

[0691] ( S )-5-Benzyl- N -(5-Methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide: 1 H nmr (400 MHz, CDCl3) 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, oxobenzoxazepine H-3), 4.66(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.22 (1H, dd, J 11.0,9.5 Hz, 1H of oxobenzoxazepine H-2), 4.15 (2H, s, CH2Ph), 3.45 (2H, t, J7.0 Hz, 2H of pyrrolidine), 3.38 (3H, s, NCH3), 3.35 (2H, m, 2H of pyrrolidine), 2.97 (2H, t,J 7.5 Hz, 2H of ArCH2CH2CO), 2.57 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 1.92 (2H, m, 2H of pyrrolidine), 1.83 (2H, m, 2H of pyrrolidine); 13 C nmr (100 MHz, CDCl3) 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, C 27 H 30 N6O4 requires [M+H] + 503.2401).

[0692] Example 9

[0693]

[0694] ( S , E )-3-(5-Methyl-4-oxo-3-(tritylamino)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-7-yl)acrylamide synthesis: To a mixture of bromooxobenzoxazepine (0.300 g, 0.586 mmol, 1.0 equiv) and acrylamide (0.062 g, 0.879 mmol, 1.5 equiv) was added dimethylformamide (5 mL), and the mixture was degassed by bubbling argon through it for 5 minutes. Triethylamine (0.178 g, 0.24 mL, 1.758 mmol, 3.0 equiv) was added, followed by X-PhosPd G2 (0.046 g, 0.059 mmol, 0.1 equiv), and the reaction was sealed and heated in a microwave to 120 °C for 1 hour. The reaction was partitioned between EtOAc (100 mL) and NaHCO3 (100 mL). The organic layer was washed with brine (80 mL), water (100 mL), and brine (80 mL), dried (Na2SO4), and concentrated under reduced pressure. MPLC (0→10% MeOH-CH2Cl2) gave the title compound as a pale yellow solid (0.267 g, 91%); 1 H nmr (400 MHz, CDCl3) δ 7.55 (1H, d, J 15.5 Hz, ArCH=C H CO), 7.39 - 7.36 (7H, m, 6H of C(C6H5)3, oxobenzoxazepine H-8), 7.25 - 7.13 (9H, m, 9H of C(C6H5)3), 7.01 (1H, d, J 8.5 Hz, oxobenzoxazepin-9H), 6.97 (1H, d, J 2.0 Hz, oxobenzoxazepin-6H), 6.39 (1H, d, J 15.5 Hz, ArC H=CHCO), 5.95(2H, br s, NH2), 4.51 (1H, dd, J 9.5, 7.0 Hz, 1H of oxobenzoxazepine H-2), 4.39 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.54 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 3.31 (1H, d, J 8.5 Hz, NH), 2.94 (3H, s, NCH3); m / z : 526 [M+Na] + , 243 [C(C6H5)3] + 。

[0695]

[0696] ( S )-3-(3-Amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-7-yl)propanamide synthesis: A solution of α,β-unsaturated carboxamide (0.267 g, 0.532 mmol, 1.0 equiv) in ethyl acetate - methanol (5:2, 7 mL) was purged with nitrogen and palladium on carbon (0.100 g) was added. The reaction was purged with hydrogen and stirred under a hydrogen atmosphere for 2 h. The reaction 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 4 M solution in dioxane, 2.659 mmol, 5.0 equiv) was added. The reaction was stirred at room temperature for 6 h to form a white solid. The reaction was concentrated to dryness and used without purification; m / z : 265 [M+H] + 。

[0697]

[0698] ( S )- N -(7-(3-Amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-5-benzyl-1 HSynthesis of 1,2,4-triazole-3-carboxamide: Diisopropylethylamine (0.043 g, 0.058 mL, 0.335 mmol, 2.5 equiv) was added to a mixture of aminooxobenzoxazepine hydrochloride (0.134 mmol, 1.0 equiv) and benzyltriazolecarboxylic acid (0.033 g, 0.161 mmol, 1.2 equiv) in dimethylformamide (1.0 mL), followed by the addition of HATU (0.102 g, 0.268 mmol, 2.0 equiv). The reaction was stirred at room temperature for 4 h and partitioned between EtOAc-CH2Cl2 (5:1, 60 mL) and water (60 mL). The organic layer was washed with brine (50 mL), water (60 mL), and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH-CH2Cl2) gave the title compound as a white solid; 1 1H NMR (400 MHz, CDCl3) 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, oxobenzoxazepine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.17 (2H, s, C H 2C6H5), 3.41 (3H, s, NCH3), 2.99 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 2.54 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO); m / z : 449 [M+H] + .

[0699] Example 10

[0700]

[0701] ( S )-7-((5,6-dihydro-[1,2,4]triazolo[1,5- a pyrazin-7(8 H )-yl)methyl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzob [1,4]Oxazepin-4(5 H )-one formation: Dioxane (4 mL) and water (2 mL) were added to a mixture of bromobenzoxazepine (0.270 g, 0.527 mmol, 1.0 equiv), 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 equiv) and cesium carbonate (0.515 g, 1.581 mmol, 3.0 equiv). The reaction was degassed by bubbling argon through it for 10 minutes. X-PhosPdG2 (0.021 g, 0.026 mmol, 0.05 equiv) was added and the reaction was sealed and heated in a microwave to 140 °C for 45 minutes. The reaction was partitioned between EtOAc (80 mL) and NaHCO3 (80 mL). The organic layer was washed with brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH [2M NH3]-CH2Cl2) gave the title compound as a yellow oil (0.255 g,%); 1H NMR (400 MHz, CDCl3) δ 7.88 (1H, s, triazole H-3), 7.38 - 7.35 (6H, m, 6H of C(C6H5)3), 7.21 - 7.11 (9H, m, 9H of C(C6H5)3), 7.02 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazepine H-8), 6.97 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 6.87 (1H, d, J 2.0 Hz, oxobenzoxazepine H-6), 4.50 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.36 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.16 (2H, t, J 5.5 Hz, 2H of NCH2CH2N), 3.82 (2H, s, ArCH2N or NCH2CN), 3.69 (2H, s, ArCH2N or NCH2CN), 3.51 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 2.91 (2H, t, J 5.5 Hz, 2H of ArCH2CH2N), 2.88 (3H, s, NCH3); m / z : 593 [M+Na] + , 243[C(C6H5)3] + 。

[0702]

[0703] Deprotection of trityl: To a solution of trityl - protected amine (0.255 g, 0.447 mmol, 1.0 equiv) in dioxazne (4.0 mL) was added hydrogen chloride (0.56 mL of 4 M solution in dioxazne, 2.237 mmol, 5.0 equiv). A white precipitate formed. The reaction was stirred at room temperature for 14 h. The reaction was concentrated to dryness and used without purification; m / z : 329 [M+H] + 。

[0704]

[0705] ( S ) - 5 - benzyl - N -(7 - ((5,6 - dihydro - [1,2,4]triazolo[1,5 - a]pyrazin - 7(8 H)-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide formation: Diisopropylethylamine (0.122 g, 0.16 mL, 0.943 mmol, 2.5 equiv) was added to a solution of aminooxobenzoxazepine hydrochloride (0.377 mmol, 1.0 equiv) and benzyltriazolecarboxylic acid (0.077 g, 0.377 mmol, 1.0 equiv) in dimethylformamide (4.0 mL). The reaction was cooled to 0 °C and HATU (0.143 g, 0.377 mmol, 1.0 equiv) was added. The reaction was stirred at 0 °C for 2 h and at room temperature for 18 h. The reaction was partitioned between EtOAc-CH2Cl2 (9:1, 60 mL) and NaHCO3-water (1:1, 60 mL). The organic layer was washed with brine (60 mL). The combined aqueous layers were back-extracted with EtOAc (30 mL). The combined organic layers were washed with water (90 mL) and brine (90 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→8% MeOH-CH2Cl2) gave the title compound as a white solid; 1 Hnmr (400 MHz, CDCl3) δ 7.90 (1H, br 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, oxobenzoxazepine H-9), 5.10 (1H, oxobenzoxazepine H-3), 4.74 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28 (1H,t, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.21 (2H, t,J 5.5 Hz, 2H of NCH2CH2N), 4.15 (2H, s, NC H 2C6H5), 3.84, 3.78 (2H, 2d AB system, J15.5 Hz, ArCH2N 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 of NCH2CH2N); m / z : 514 [M+H] +(Measured [M+H] + , 514.2324, C 26 H 27 N9O3 requires [M+H] + 514.2310).

[0706] Additional exemplary compound embodiments are described below.

[0707]

[0708] ( S )-5-Benzyl-3-((7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)carbamoyl)-1,2,4-triazol-1-ide

[0709] 1 H nmr (400 MHz, D6DMSO) δ 7.83 (1H, d, J 8.0 Hz, NH), 7.45 (1H,d, J 2.0Hz, oxobenzoxazepine H-6), 7.25 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazepine H-8), 7.20-7.15 (5H, m, oxobenzoxazepine H-9, 4H of C6H5), 7.09-7.04 (1H,m, 1H of C6H5), 5.47 (1H, br s, OH), 4.81-4.74 (1H, m, oxobenzoxazepine H-3),4.39-4.36 (2H, m, 2H of oxobenzoxazepine H-2), 3.84 (2H, s, C H 2C6H5), 3.28(3H, s, NCH3), 1.44 (6H, s, C(C H 3)2OH); m / z : 442 [M+H] + .

[0710]

[0711] ( S )-1-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)-1 H -1,2,4-triazole-3-carboxamide

[0712] 1 1H NMR (400 MHz, CDCl3) 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 - 7.33 (4H, m, 4H of C6H5, oxobenzoxazepine H-6, H-8), 7.28 - 7.24 (3H, m, 3H of C6H5, oxobenzoxazepine H-6, H-8), 7.12 (1H, d, J 2.5 Hz, quinoline H-5), 7.10 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.36 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.75 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.30 (2H, t, J 7.0 Hz, CCH2C H 2O), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.39 (3H, s, NCH3), 2.98 (2H, t, J 7.0 Hz, CC H 2CH2O); m / z : 573 [M+H] + (found [M+H] + , 573.2244, C 33 H 28 N6O4 requires [M+H] + 573.2245).

[0713]

[0714] ( 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)-1 H -1,2,4-triazole-3-carboxamide

[0715] 1 H NMR (400 MHz, CDCl3) 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, oxobenzoxazepine H-8), 7.25 - 7.20 (6H, m, C6H5, oxobenzoxazepine H-7), 7.11 (1H, d, J 3.0 Hz, quinoline H-5), 7.09 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.29 (2H, t, J 7.0 Hz, CCH2C H 2O), 4.26 (1H, dd, J11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.14 (2H, s, C H 2C6H5), 3.37 (3H, s, NCH3), 2.98 (2H, t, J 7.0 Hz, CC H 2CH2O); 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, C 33 H 28 N6O4 requires [M + H] + 573.2245).

[0716]

[0717] ( S )-1-Benzyl- N -(5-Methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8 H ))-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide

[0718] 1 H nmr (400 MHz, CDCl3) δ 8.04 (1H, d, J 7.5 Hz, NH), 8.00 (1H,s, triazole H-5), 7.38 - 7.33 (3H, m, 3H of C6H5), 7.27 - 7.24 (2H, m, 2H of C6H5), 7.19 (2H, m, oxobenzoxazepine H-6, H-8), 7.15 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9),5.35 (2H,s, NC H 2C6H5), 5.09 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.26 - 4.21(3H,m, 1H of oxobenzoxazepine H-2, 2H of NCH2CH2N), 3.87 (2H, s, 2H of ArCH2NCH2C),3.75 (2H, s, 2H of ArCH2NCH2C), 3.40 (3H, s, NCH3), 3.01 (2H, td, J 5.0, 1.5 Hz, 2H of NCH2CH2N); 13 C nmr (100 MHz, CDCl3) δ 168.8, 158.4, 156.6, 153.5 (q, J 39.5Hz), 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 (q,J 270.5 Hz), 77.2, 60.6, 54.3, 50.7, 49.2, 48.4, 47.1,35.6; 19F NMR (380 MHz, CDCl3) δ -65.4 m / z : 582 [M+H] + (Measured [M+H] + , 582.2188, C 27 H 26 F3N9O3 requires [M+H] + 582.2183).

[0719]

[0720] ( S )-5-Benzyl- N -(5-Methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5- a pyrazin-7(8 H )-yl)methyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0721] 1 H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.27 - 7.21(6H, m, C6H5, oxobenzooxazepine H-8), 7.21 (1H, dd, J 7.5, 2.0 Hz, oxobenzooxazepine H-8), 7.15 (1H, d, J 8.0 Hz, oxobenzooxazepine H-9), 5.07 (1H, dt, J11.0, 7.5 Hz, oxobenzooxazepine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzooxazepine H-2), 4.29 - 4.23(3H, m, 1H of oxobenzooxazepine H-2, 2H of NCH2CH2N), 4.12 (2H, s, C H 2C6H5), 3.86 (2H, s, 2H of ArCH2NCH2C), 3.76 (2H, s, 2H of ArCH2NCH2C), 3.39 (3H, s, NCH3), 3.03 (2H, t, J 5.5 Hz, 2H of NCH2CH2N); 13Cnmr (100 MHz, CDCl3) δ 168.8, 158.7, 153.4 (q, 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 (q, 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] + (Measured [M+H] + , 582.2167, C 27 H 26 F3N9O3 requires [M+H] + 582.2183).

[0722]

[0723] ( 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)-1 H -1,2,4-Triazole-3-carboxamide

[0724] 1 H 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, oxobenzoxazepine H-6, H-8, C6H5), 7.07 (1H, d, J 8.5 Hz, oxobenzoxazepine H-9), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.31 (2H, td, J 7.0, 2.5 Hz, OC H2CH2C), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.13 (2H, s, C H 2C6H5), 3.36 (3H, s, NCH3), 2.97 (2H, t, J 7.0 Hz, OCH2C H 2C); 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] + (Measured [M+H] + , 573.2269, C 33 H 28 N6O4 requires [M+H] + 573.2245).

[0725]

[0726] ( S )-1-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)-1 H -1,2,4-Triazole-3-carboxamide

[0727] 11H NMR (400 MHz, CDCl3) 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 of C6H5, oxobenzoxazepine H-6), 7.27 - 7.22 (6H, m, quinoline H-6, H-3, oxobenzoxazepine H-8, 3H of C6H5, oxobenzoxazepine H-6), 7.09 (1H, dd, J 8.0, 0.5 Hz, oxobenzoxazepine H-9), 5.35 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.33 (2H, t, J 7.0 Hz, OC H 2CH2C), 4.23 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 3.39 (3H, s, NCH3), 2.98 (2H, t, J 7.0 Hz, OCH2C H 2C); 13 13C 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, C 33 H 28 N6O4 requires [M+H] +573.2245).

[0728]

[0729] ( S )-5-(2,4-difluorobenzyl)- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0730] 1 H nmr (400 MHz, CDCl3) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.27 - 7.20(3H, m, oxobenzoxazepine H-6, H-8, 1H of C6H3F2), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 6.82 - 6.74 (2H, m, 2H of C6H3F2), 4.99 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.12(2H, s, C H 2C6H3F2), 3.39 (3H, s, NCH3), 1.61 (6H, s, C(C H 3)2OH); 19 F nmr (380MHz, CDCl3) δ -111.2; -113.2; m / z : 478 [M + H - H2O] + (found [M + H] + , 496.1795, C 25 H 23 F2N5O4 requires [M + H] + 496.1791).

[0731]

[0732] ( 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-triazole-3-carboxamide

[0733] 1 H nmr (400 MHz, CDCl3) δ 8.89 (1H, dd, J 4.0, 2.0Hz, 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 H-8), 7.59 (1H, dd, J 8.5, 7.5 Hz, quinoline H-7), 7.38 - 7.33(4H, m, quinoline H-3, 3H of C6H5, oxobenzoxazepine H-6), 7.26 - 7.22(4H, m, oxobenzoxazepine H-8, 3H of C6H5, oxobenzoxazepine H-6), 7.09(1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 6.89 (1H, dd, J 7.5, 0.5 Hz, quinoline H-6), 5.35 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.73 (1H, dd,J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.35(2H, t, J 7.0 Hz, OC H 2CH2C), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.37 (3H, s, NCH3), 3.03 (2H, t, J 7.0 Hz, OCH2C H 2C); m / z : 573 [M+H] + (Found [M+H] + , 573.2251, C 33 H 28 N6O4 requires [M+H] + 573.2245).

[0734]

[0735] ( 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-triazole-3-carboxamide

[0736] 1 H NMR (400 MHz, CDCl3) 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 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, C6H5, oxobenzoxazepine H-6, H-8), 7.08 (1H, d, J 8.0 Hz, oxobenzoxazepine 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, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.36 (2H, t, J 7.0 Hz, OC H 2CH2C), 4.25 (1H, dd, J 11.0, 10.0 Hz, one H of oxobenzoxazepine H-2), 4.13 (2H, s, C H 2C6H5), 3.36 (3H, s, NCH3), 3.04(2H, t, J 7.0 Hz, OCH2C H 2C); 13 C 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] + (Measured [M+H] + , 573.2266, C 33 H 28 N6O4 requires [M+H] + 573.2245).

[0737]

[0738] ( S )-1-Benzyl- N -(5-Methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8 H ))-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide

[0739] 1 H nmr (400 MHz, CDCl3) 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, 2x ArH), 7.17 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.38 (2H, s,NC H 2C6H5), 5.12 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.76 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0Hz, 1H of oxobenzoxazepine H-2), 4.15 (2H, t, J 5.5 Hz, 2H of NCH2CH2N), 3.98,3.93 (2H, 2d AB system, J 15.5 Hz, 2H of ArCH2NCH2), 3.76 (2H, s, 2H of ArCH2NCH2),3.42 (3H, s, NCH3), 2.96 (2H, dt, J 4.0, 5.5 Hz, 2H of NCH2CH2N); 19 F nmr (380 MHz, CDCl3) δ -63.2; m / z: 582 [M+H] + (Measured [M+H] + , 582.2173, C 27 H 26 F3N9O3 requires [M+H] + 582.2183).

[0740]

[0741] ( S )-5-Benzyl- N -(5-Methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8 H )-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide

[0742] 1 H nmr (400 MHz, CDCl3) δ 8.01 (1H, d, J 7.0 Hz, NH), 7.27-7.19(7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.16 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.09 (1H, dt, J 10.5, 7.5 Hz, oxobenzoxazepine H-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28 (1H, dd, J 10.5, 10.0Hz, 1H of oxobenzoxazepine H-2), 4.14 (4H, m, 2H of NCH2CH2N), 2H of ArCH2NCH2 or C H 2C6H5), 3.93 (2H, s, 2H of ArCH2NCH2 or C H 2C6H5), 3.78, 3.74 (2H, 2d AB system, J 13.5Hz, 2H of ArCH2NCH2), 3.40 (3H, s, NCH3), 2.97 (2H, t, J 5.5 Hz, 2H of NCH2CH2N); 13C nmr (100 MHz, CDCl3) δ 168.8, 158.6, 152.0, 149.6, 143.4 (q, 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 (q, 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] + (Measured [M+H] + , 582.2208, C 27 H 26 F3N9O3 requires [M+H] + 582.2183).

[0743]

[0744] ( S )-1-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 -1,2,4-Triazole-3-carboxamide

[0745] 1 H nmr (400 MHz, CDCl3) δ 8.04 (1H, d, J 7.0 Hz, NH), 8.01 (1H, s, triazole H-5), 7.40 - 7.36 (3H, m, 3H of C6H5), 7.29 - 7.23 (4H, m, 2H of C6H5, oxobenzoxazepine H-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.38 (2H, s, NC H2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.76 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3); m / z : 458 [M+H] + (Found [M+H] + , 458.2205, C 26 H 27 N5O3 requires [M+H] + 458.2187).

[0746]

[0747] ( 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)-1 H -1,2,4-Triazole-3-carboxamide

[0748] 1 H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26 - 7.21(7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.07 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.26 (1H, dd, J Hz, oxobenzoxazepine H-2), 4.15 (2H, s, C H 2C6H5), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) 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] + (Measured [M+H] + , 458.2200, C 26 H 27 N5O3 requires [M+H] + 458.2187).

[0749]

[0750] ( S )-1-Benzyl- N -(7-((1-Hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide

[0751] 1 H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.99 (1H, s, triazole H-5), 7.38 - 7.34 (3H, m, 3H of C6H5), 7.29 - 7.25 (4H, m, 2H of C6H5, oxobenzoxazepine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.36 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.25 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.40 (3H, s, NCH3), 2.55 - 2.49 (2H, m, 2H of cBuH-2, H-4), 2.33 (2H, m, 2H of cBuH-2, H-4), 1.87 (2H, m, cBuH-3); m / z : 472 [M+H]+ ,454 [M+H-H2O] + (Measured [M+H] + , 472.1994, C 26 H 25 N5O4 requires [M+H] + 472.1979).

[0752]

[0753] ( S )-5-Benzyl- N -(7-((1-Hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide

[0754] 1 H nmr (400 MHz, CDCl3) δ 8.10 (1H, d, J 7.5 Hz, NH), 7.29 - 7.20(7H, m, C6H5, 2H of oxobenzoxazepine H-6, H-8, H-9), 7.10 (1H, dd, J 7.5, 1.0 Hz, 1H of oxobenzoxazepine H-6, H-8, H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2),4.28 (1H,dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.15, 4.11 (2H,2d AB system, J 16.0 Hz, C H 2C6H5), 3.39 (3H, s, NCH3), 2.57 - 2.50 (2H, m, cBuH-2, H-4's 2H), 2.35 (2H, m, cBuH-2, H-4's 2H), 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, 35.5, 33.0, 13.0;m / z : 454 [M + H - H2O] + (Measured [M + H] + , 472.1999, C 26 H 25 N5O4 requires [M + H] + 472.1979).

[0755]

[0756] ( S )-1-benzyl- N -(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0757] 1 H nmr (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.99 (1H,s, triazole H-5), 7.38 - 7.34 (3H, m, 3H of C6H5), 7.28 - 7.26 (4H, m, 2H of C6H5, oxobenzoxazepine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.36 (2H,s,NCH2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.75 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.24 (1H, dd, J 11.0, 9.5Hz, 1H of oxobenzoxazepine H-2), 3.40 (3H, s, NCH3), 2.08 - 1.99 (4H, m, cyclopentane H-2, H-5), 1.90 - 1.84 (2H, m, 2H of cyclopentane H-3, H-4), 1.83 - 1.76 (2H, m, 2H of cyclopentane H-3, H-4); m / z : 486 [M + H] + , 468 [M + H - H2O] + (Measured [M + H] + , 486.2122, C 27 H 27 N5O4 requires [M + H] + 486.2136).

[0758]

[0759] ( S )-5-Benzyl- N -(7-((1-Hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide

[0760] 1 H nmr (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31 - 7.23(7H, m, C6H5, oxobenzoxazepene H-6, H-7), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazepene H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepene H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepene H-2), 4.26 (1H, dd, J 11.0, 9.5Hz, 1H of oxobenzoxazepene H-2), 4.14 (2H, s, C H 2C6H5), 3.39 (3H, s, NCH3), 2.08 - 1.97 (4H, m, cyclopentane H-2, H-5), 1.90 - 1.85 (2H, m, 2H of cyclopentane H-3, H-4), 1.82 - 1.76 (2H, m, 2H of cyclopentane H-3, H-4); m / z : 468 [M + H - H2O] + (Found [M + H] + , 486.2154, C 27 H 27 N5O4 requires [M + H] + 486.2136).

[0761]

[0762] ( S )-1-Benzyl- N -(7-((4-Hydroxytetrahydro-2 H -pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-Triazole-3-carboxamide

[0763] 1 H NMR (400 MHz, CDCl3) δ 8.03 (1H, d, J 7.0 Hz, NH), 8.02 (1H, s, triazole H-5), 7.39 - 7.35 (3H, m, 3H of C6H5), 7.31 - 7.27 (4H, m, 2H of C6H5, oxobenzoxazepine H-6, H-8), 7.14 (1H, dd, J 8.0, 1.0 Hz, oxobenzoxazepine H-9), 5.37 (2H, s, NC H 2C6H5), 5.08 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.95 (2H, dt, J 12.0, 4.5 Hz, 2H of pyran H-2, H-6), 3.72 (2H, ddd, J 12.0, 9.0, 3.0 Hz, 2H of pyran H-2, H-6), 3.42 (3H, s, NCH3), 2.07 - 2.02 (2H, m, 2H of pyran H-3, H-5), 1.89 (2H, ddd, J 13.0, 9.0, 4.0 Hz, 2H of pyran H-3, H-5); m / z : 502 [M + H] + , 484 [M + H - H2O] + (found [M + H] + , 502.2105, C 27 H 27 N5O5 requires [M + H] + 502.2085).

[0764]

[0765] ( S )-5-benzyl- N -(7-((4-hydroxy - tetrahydro - 2 H -pyranyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0766] 11H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 6.5 Hz, NH), 7.28 - 7.19 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.09 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.00 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.64 (1H, dd, J 9.0, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.27 (1H, t, J 10.5 Hz, one H of oxobenzoxazepine H-2), 4.12 (2H, s, CH2C6H5), 3.93 (2H, dt, J 12.0, 4.5 Hz, 2H of pyran H-2, H-6), 3.70 (2H, ddd, J 11.5, 9.0, 2.5 Hz, 2H of pyran H-2, H-6), 3.37 (3H, s, NCH3), 2.03 (2H, m, 2H of pyran H-3, H-5), 1.88 (2H, ddd, J 13.0, 9.0, 4.0 Hz, 2H of pyran H-3, H-5); 13 13C NMR (100 MHz, CDCl3) 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, C 27 H 27 N5O5 requires [M + H] + 502.2085).

[0767]

[0768] ( S )-i-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

[0769] 11H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5 Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.40 (2H, m, 2H of C6H5), 7.27 - 7.22 (3H, m, oxobenzoxazepine H-6, H-8, 1H of C6H5), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 7.05 (2H, m, 2H of C6H5), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.41 (3H, s, NCH3), 1.61 (6H, s, C(C H 3)2OH); 13 13C 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, C 27 H 25 N3O5 requires [M+H] + 472.1867).

[0770]

[0771] ( S )-5-benzyl- N -(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0772] 1 1H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.33 - 7.26 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.03 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.93 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.80 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.16 (2H, s, C H 2C6H5), 3.41 (3H, s, NCH3), 2.98 (1H, br s, OH); m / z : 474 [M+H] + (found [M+H] + , 474.1789, C 25 H 23 N5O5 requires [M+H] + 474.1772).

[0773]

[0774] ( 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)-1 H -1,2,4-triazole-3-carboxamide

[0775] 11H NMR (400 MHz, CDCl3) δ 8.03 (1H, d, J 7.0 Hz, NH), 8.01 (1H, s, triazole H-5), 7.37 (3H, m, 3H of C6H5), 7.28 - 7.25 (4H, m, 2H of C6H5, oxobenzoxazepine H-6, H-8), 7.12 (1H, d, J 8.5 Hz, oxobenzoxazepine H-9), 5.35 (2H, s, NC H 2C6H5), 5.04 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.89 (2H, dd, J 7.0, 1.0 Hz, 2H of oxetane H-2, H-4), 4.78 (2H, ddd, J 6.5, 2.0, 1.0 Hz, 2H of oxobenzoxazepine H-2, H-4), 4.72 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.53 (1H, s, OH), 3.38 (3H, s, NCH3); 13 13C 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] + 。

[0776]

[0777] ( 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)-1 H -1,2,4-triazole-3-carboxamide

[0778] 11H NMR (400 MHz, CDCl3) δ 8.09 (1, d, J 7.5 Hz, NH), 7.27 (2H, t, J 7.0 Hz, 2H of C6H5), 7.20 - 7.15 (5H, m, 3H of C6H5, H-6, H-8 of oxobenzoxazepine), 7.09 (1H, d, J 9.0 Hz, H-9 of oxobenzoxazepine), 5.41 (1H, q, J 1.0 Hz, 1H of =CH2), 5.32 (1H, m, 1H of =CH2), 5.01 (1H, dt, J 11.0, 7.5 Hz, H-3 of oxobenzoxazepine), 4.63 (1H, dd, J 9.5, 7.5 Hz, 1H of H-2 of oxobenzoxazepine), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of H-2 of oxobenzoxazepine), 4.12 (2H, s, C H 2C6H5), 3.38 (3H, s, NCH3), 1.98 (3H, t, J Hz, C(C H 3)=CH2); 13 13C NMR (100 MHz, CDCl3) 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, C 25 H 23 N5O3 requires [M+H] + 442.1874).

[0779]

[0780] ( S ) - 5 - benzyl - N -(7 - isopentyl - 5 - methyl - 4 - oxo - 2,3,4,5 - tetrahydrobenzo[b][1,4]oxazepin - 3 - yl) - 1 H -1,2,4 - triazole - 3 - carboxamide

[0781] 1 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, oxobenzoxazepine H-9), 7.03 (1H, d, J 2.0 Hz, oxobenzoxazepine H-6), 7.00 (1H, m, oxobenzoxazepine H-8), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.22 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.14 (2H, s, C H 2C6H5), 3.39 (3H, s, NCH3), 2.60 (2H, m, C H 2CH2CH(CH3)2), 1.60 (1H, m, CH2CH2C H (CH3)2), 1.52 - 1.46 (2H, m, CH2C H 2CH(CH3)2), 0.94 (6H, d, J 6.5 Hz, CH2CH2CH(C H 3)2); m / z : 448 [M + H] + (found [M + H] + , 448.2335, C 25 H 29 N5O3 requires [M + H] + 448.2343).

[0782]

[0783] ( S )-5-Benzyl- N -(7-(3-Methoxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0784] 11H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28 - 7.25 (2H, m, 2H of C6H5), 7.19 (5H, m, 3H of C6H5, H-6, H-8 of oxobenzoxazepine), 7.09 (1H, d, J 8.0 Hz, H-9 of oxobenzoxazepine), 5.01 (1H, dt, J 11.0, 7.5 Hz, H-3 of oxobenzoxazepine), 4.63 (1H, dd, J 9.0, 8.0 Hz, 1H of H-2 of oxobenzoxazepine), 4.26 (1H, dd, J 10.5, 9.5 Hz, 1H of H-2 of oxobenzoxazepine), 4.12 (2H, s, C H 2C6H5), 3.43 (3H, s, NCH3 or OCH3), 3.39 (3H, s, NCH3 or OCH3), 1.54 (6H, s, C(C H 3)2OCH3); m / z : 474 [M + H] + , 442 [M + H - CH3OH] + (Found [M + H] + , 474.2138, C 26 H 27 N5O4 requires [M + H] + 474.2136).

[0785]

[0786] ( S )-1-Benzyl- N -(8-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0787] 11H 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 of C6H5), 7.27 - 7.23 (4H, m, 2H of C6H5, oxobenzoxazepine H-8, H-9), 7.12 (1H, d, J 8.0 Hz, oxobenzoxazepine H-6), 5.36 (2H, s, NC H 2C6H5), 5.05 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.23 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.39 (3H, s, NCH3), 1.61 (6H, s, C(C H 3)2OH); m / z : 460 [M + H] + , 442 [M + H - H2O] + (Found [M + H] + , 460.1968, C 25 H 25 N5O4 requires [M + H] + 460.1979).

[0788]

[0789] ( S )-5-Benzyl- N -(8-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0790] 11H NMR (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26 - 7.18 (7H, m, C6H5, oxobenzoxazepine H-7, H-9), 7.11 (1H, d, J 8.0 Hz, oxobenzoxazepine H-6), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.62 (1H, dd, J 9.5, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.24 (1H, dd, J 11.5, 9.5 Hz, one H of oxobenzoxazepine H-2), 4.14, 4.10 (2H, 2d, J 16.0 Hz, C H 2C6H5), 3.37 (3H, s, NCH3), 1.61 (6H, s, C(C H 3)2OH); 13 13C 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, C 25 H 25 N5O4 requires [M + H] + 460.1979).

[0791]

[0792] ( S ) - N -(8-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

[0793] 11H NMR (400 MHz, CDCl3) 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 of C6H5), 7.28 - 7.22 (3H, m, 1H of C6H5, oxobenzoxazepine H-7, H-9), 7.13 (1H, d, J 8.0 Hz, oxobenzoxazepine H-6), 7.07 - 7.04 (2H, m, 2H of C6H5), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyridine H-4), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.40 (3H, s, NCH3), 1.61 (6H, s, C(C H 3)2OH); 13 13C 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, C 27 H 25 N3O5 requires [M + H] + 472.1867).

[0794]

[0795] ( S ) - 5 - (2,6 - dichlorobenzyl) - N - (7 - (3 - hydroxy - 3 - methylbut - 1 - yn - 1 - yl) - 5 - methyl - 4 - oxo - 2,3,4,5 - tetrahydrobenzo[b][1,4]oxazepin - 3 - yl) - 1 H-1,2,4-Triazole-3-carboxamide

[0796] 1 H nmr (400 MHz, CDCl3) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.33 - 7.29 (3H, m, 3H of C6H3Cl2, H - 6 of oxobenzoxazepine), 7.226 - 7.24 (1H, m, 1H of C6H3Cl2, H - 6 of oxobenzoxazepine), 7.18 - 7.15 (1H, m, H - 8 of oxobenzoxazepine)), 7.10 (1H, d, J 8.5 Hz, H - 9 of oxobenzoxazepine), 5.00 (1H, dt, J 11.5, 7.5 Hz, H - 3 of oxobenzoxazepine), 4.67 (1H, dd, J 10.0, 7.5 Hz, 1H of H - 2 of oxobenzoxazepine), 4.48 (2H, s, C H 2C6H3Cl2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of H - 2 of oxobenzoxazepine), 3.39 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2); m / z : 532, 530, 528 [M + H] + 514, 512, 510 [M + H - H2O] + (Measured [M + H] + , 528.1201, C 25 H 23 Cl2N5O4 requires [M + H] + 528.1200).

[0797]

[0798] ( S ) - 5 - Benzyl - N - (5 - Methyl - 4 - oxo - 8 - ((2 - (trifluoromethyl) - 5,6 - dihydro - [1,2,4]triazolo[1,5 - a pyrazin - 7(8 H ) - yl)methyl) - 2,3,4,5 - tetrahydrobenzo b [1,4]oxazepin - 3 - yl) - 1 H - 1,2,4 - Triazole - 3 - carboxamide

[0799] 11H NMR (400 MHz, CDCl3) δ 8.04 (1H, d, J 7.5 Hz, NH), 7.30 - 7.17 (8H, m, C6H5, oxobenzoxazepine H-6, H-7, H-9), 5.08 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.30 - 4.25 (3H, m, 1H of oxobenzoxazepine H-2, NCH2CH2N), 4.14 (2H, s, CH2C6H5), 3.88, 3.83 (2H, 2d AB system, J 16.0 Hz, 2H of ArCH2NCH2), 3.76 (2H, s, ArCH2NCH2), 3.40 (3H, s, NCH3), 3.09 - 3.02 (2H, m, NCH2CH2N); 19 19F NMR (380 MHz, CDCl3) δ -65.3; m / z : 604 [M+Na] + 582 [M+H] + 。

[0800]

[0801] ( S )-1-Benzyl- N -(5-Methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5- a pyrazin-7(8 H )-yl)methyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0802] 11H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J 7.0 Hz, NH), 8.00 (1H, s, triazole H-5), 7.39 - 7.35 (3H, m, 3H of C6H5, oxobenzoxazepine H-6, H-7, H-9), 7.28 - 7.25 (2H, m, 2H of C6H5, oxobenzoxazepine H-6, H-7, H-9), 7.23 - 7.17 (3H, m, 3H of C6H5, oxobenzoxazepine H-6, H-7, H-9), 5.37 (2H, s, NC H 2C6H5), 5.11 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28 - 4.23 (3H, m, 1H of oxobenzoxazepine H-2, 2H of NCH2CH2N), 3.90, 3.86 (2H, 2d AB system, J 16.0 Hz, 2H of ArCH2NCH2), 3.79, 3.75 (2H, 2d AB system, J 13.5 Hz, 2H of ArCH2NCH2), 3.42 (3H, s, NCH3), 3.10 - 3.02 (2H, m, 2H of NCH2CH2N); 19 19F NMR (380 MHz, CDCl3) δ -65.4; m / z : 604 [M+Na] + , 582 [M+H] + 。

[0803]

[0804] ( S )- N -(7-(3-hydroxy-3-(methyl- d 3)but-1-yn-1-yl-4,4,4- d 3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-4-phenoxypicolinamide

[0805] 11H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyH-3), 7.60 (1H, d, J 2.5 Hz, pyH-4), 7.42 - 7.38 (2H, m, 2H of C6H5), 7.27 - 7.22 (3H, m, 3H of C6H5, oxobenzoxazepine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 7.10 - 7.05 (2H, m, 2H of C6H5, oxobenzoxazepine H-6, H-8), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyH-6), 5.01 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.41 (3H, s, NCH3); m / z : 478 [M+H] + , 460 [M+H - H2O] + (Measured [M+H] + , 478.2255, C 27 H 19 D6N3O4 requires [M+H] + 478.2244).

[0806]

[0807] ( S ) - 5 - benzyl - N - (7 - (3 - hydroxy - 3 - (methyl - d 3)but - 1 - yn - 1 - yl - 4,4,4 - d 3) - 5 - methyl - 4 - oxo - 2,3,4,5 - tetrahydrobenzo b [1,4]oxazepin - 3 - yl) - 1 H - 1,2,4 - triazole - 3 - carboxamide

[0808] 11H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28 - 7.21 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.14 (2H, s, C H 2C6H5), 3.39 (3H, s, NCH3); 13 13C NMR (100 MHz, CDCl3) 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, C 25 H 19 D6N5O4 requires [M + H] + 466.2356).

[0809]

[0810] ( R ) - 5 - benzyl - N - (7 - (3 - hydroxy - 3 - methylbut - 1 - yn - 1 - yl) - 5 - methyl - 4 - oxo - 2,3,4,5 - tetrahydrobenzo b [1,4]oxazepin - 3 - yl) - 1 H - 1,2,4 - triazole - 3 - carboxamide

[0811] [α] 589 20.2 +135.9 (CHCl3, c 0.54); 11H NMR (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.30 - 7.23 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, one H of oxobenzoxazepine H-2), 4.15 (2H, s, C H 2C6H5), 3.40 (3H, s, NCH3), 1.63 (6H, s, C(CH3)2OH); m / z : 460 [M+H] + , 442 [M+H - H2O] + (found [M+H] + , 460.1985, C 25 H 25 N5O4 requires [M+H] + 460.1979).

[0812]

[0813] ( S ) - 5 - benzyl - N -(7-(3 - hydroxy - 3 - methylbut - 1 - yn - 1 - yl)-5 - methyl - 4 - oxo - 2,3,4,5 - tetrahydrobenzo b [1,4]oxazepin - 3 - yl)-1,3,4 - oxadiazole - 2 - carboxamide

[0814] 11H NMR (400 MHz, CDCl3) δ 7.99 (1H, d, J 6.5 Hz, NH), 7.36 - 7.29 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 4.97 (1H, ddd, J 11.0, 7.5, 7.0 Hz, oxobenzoxazepine H-3), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, m, 1H of oxobenzoxazepine H-2), 4.26 (2H, s, C H 2C6H5), 3.43 (3H, s, NCH3), 1.63 (6H, s, C(CH3)2); m / z : 484 [M+Na] + , 443 [M+H-H2O] + (Found [M+H] + , 443.1727, C 25 H 24 N4O5 requires [M+H-H2O] + 443.1714).

[0815]

[0816] ( 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

[0817] 11H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.42 - 7.39 (2H, m, 2H of C6H5), 7.31 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazepine H-7), 7.27 - 7.22 (2H, m, 1H of C6H5, oxobenzoxazepine H-9), 7.17 (1H, d, J 8.0 Hz, oxobenzoxazepine H-6), 7.07 - 7.05 (2H, m, 2H of C6H5), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.93 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.79 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.42 (3H, s, NCH3); m / z : 486 [M+H] + , (found [M+H] + , 486.1674, C 23 H 23 N3O6 requires [M+H] + 486.1660).

[0818]

[0819] ( 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)-1 H -1,2,4-triazole-3-carboxamide

[0820] 11H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.97 (1H, s, OH), 7.32 - 7.22 (6H, m, C6H5, oxobenzoxazepine H-7), 7.20 (1H, d, J 2.0 Hz, oxobenzoxazepine H-9), 7.14 (1H, d, J 8.5 Hz, 1H of oxobenzoxazepine H-6), 4.99 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.92 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.79 (2H, d, J 6.5 Hz, 2H of oxetane H-2, H-4), 4.64 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.25 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.14 (2H, s, C H 2C6H5), 3.40 (3H, s, NCH3); m / z : 474 [M + H] + , 456 [M + H - H2O] + (found [M + H] + , 474.1784, C 25 H 23 N5O5 requires [M + H] + 474.1772).

[0821]

[0822] (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]oxazepine-7-yl)ethynyl)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl benzoate

[0823] 11H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.5 Hz, NH), 8.03 (2H, m, 2H of COC6H5), 7.59 (1H, tt, J 7.5, 1.0 Hz, 1H of COC6H5), 7.45 (2H, t, J 7.5 Hz, 2H of COC6H5), 7.32 - 7.23 (7H, m, CH2C6 H 5, oxobenzoxazepine H-6, H-8), 7.12 (1H, d, J8.5 Hz, oxobenzoxazepine H-9), 5.23 (1H, d, J 3.0 Hz, isosorbide H-6), 5.02(1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.87, 4.83 (2H, 2d AB system, J 4.5 Hz, isosorbide H-3a, H-6a), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.25 - 4.20(2H, m, isosorbide H-5), 4.15 (2H, s, C H 2C6H5), 4.04, 3.95 (2H,2d AB system, J 9.5 Hz, isosorbide H-2), 3.40 (3H, s, NCH3); m / z : 650 [M+H] + (found [M+H] + , 650.2283, C 35 H 31 N5O8 requires [M+H] + 650.2245).

[0824]

[0825] 5-Benzyl- N -(( S )-7-(((3 R ,3a S ,6 S ,6a R )-3,6-Dihydroxyhexahydrofuro[3,2- b furan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b(1,4)oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0826] 1 H nmr (400 MHz, CD3OD) δ 7.51 (1H, d, J 2.0 Hz, oxobenzoxazepine H-6), 7.36 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazepine H-8), 7.33 - 7.23 (5H, m, C6H5), 7.19 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.01 (1H, dd, J11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.65, 4.54 (2H, 2d AB system, J 4.5 Hz, isosorbide H-3a, H-6a), 4.60 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.41 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.24(1H, d, J 2.5 Hz, isosorbide H-6), 4.15 (2H, s, C H 2C6H5), 3.99 - 3.91 (2H, m, 2H of isosorbide H-5), 3.93, 3.71 (2H, 2d AB system, J8.5 Hz, isosorbide 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, C 28 H 27 N5O7 requires [M+H] + 546.1983).

[0827]

[0828] (S)-Methyl 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-ynoate

[0829] 1 1H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31 - 7.23 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.68 (1H, dd, J 10.0, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, one H of oxobenzoxazepine H-2), 4.16 (2H, s, CH2C6H5), 3.78 (3H, s, OCH3), 3.41 (3H, s, NCH3), 1.58 (6H, s, C(CH3)2); m / z : 502 [M+H] + (found [M+H] + , 502.2107, C 27 H 27 N5O4 requires [M+H] + 502.2085).

[0830]

[0831] ( S )-1-Benzyl- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -pyrazole-3-carboxamide

[0832] 11H NMR (400 MHz, CDCl3) δ 7.79 (1H, d, J 7.0 Hz, NH), 7.38 - 7.32 (4H, m, 4H or C6H5, pyrazole H-4 or H-5, oxobenzoxazepine H-6, H-8), 7.28 - 7.21 (4H, m, 4H of C6H5, pyrazole H-4 or H-5, oxobenzoxazepine H-6 or H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 6.74 (1H, d, J 2.5 Hz, pyrazole H-4 or H-5), 5.31 (2H, s, NC H 2C6H5), 5.05 (1H, dt, J 11.0, 7.0 Hz, oxobenzoxazepine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.42 (3H, s, NCH3), 1.62 (6H, s, C(C H 3)2OH); m / z : 459 [M+H] + , 441 [M+H - H2O] + (found [M+H] + , 459.2040, C 26 H 26 N4O4 requires [M+H] + 459.2027).

[0833]

[0834] ( S ) - 5 - (3 - fluorobenzyl) - N - (7 - (3 - hydroxy - 3 - methylbut - 1 - yn - 1 - yl) - 5 - methyl - 4 - oxo - 2,3,4,5 - tetrahydrobenzo b [1,4]oxazepin - 3 - yl) - 1 H - 1,2,4 - triazole - 3 - carboxamide

[0835] 11H NMR (400 MHz, CDCl3) δ 8.10 (1H, d, J 7.0 Hz, NH), 7.28 (2H, m, oxobenzoxazepine H-6, H-8), 7.21 (1H, m, 1H of C6H4F), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 7.01 (1H, br d, J 8.0 Hz, 1H of C6H4F), 6.96 (1H, br d, J 9.5 Hz, 1H of C6H4F), 6.90 (1H, td, J 8.5, 2.5 Hz, 1H of C6H4F), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.29 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.15 (2H, s, C H 2C6H4F), 3.40 (3H, s, NCH3), 1.62 (6H, s, C(C H 3)2OH); 13 13C NMR (100 MHz, CD3OD) δ 168.5, 164.0, 161.6, 149.9, 138.5, 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 22.0 Hz), 113.9 (d, J 21.5 Hz), 94.6, 80.6, 76.9, 65.6, 49.2, 35.5, 32.9, 31.4; 19 19F NMR (380 MHz, CDCl3) δ -112.6; m / z : 460 [M+H-H2O] + (found [M+H] + , 478.1901, C 25 H 24 FN5O4 requires [M+H] + 478.1885).

[0836]

[0837] ( S)-5-(4-Fluorobenzyl)- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0838] 1 H nmr (400 MHz, CDCl3) δ 8.11 (1H, d, J 7.5 Hz, NH), 7.27 - 7.25(2H, m, oxobenzoxazepine H-6, H-8), 7.17 (2H, dd, J 8.5, 5.5 Hz, 2H of C6H4F), 7.09(1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 6.90 (2H, t, J 8.5 Hz, 2H of C6H4F),4.99 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.64 (1H, dd, J10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.29 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.09 (2H, s, C H 2C6H4F), 3.39 (3H, s, NCH3), 1.62(6H, s, C(C H 3)2OH); 19 F nmr (380 MHz, CDCl3) δ -115.6; m / z : 478 [M+H] + 460 [M+H-H2O] + (Measured [M+H] + , 478.1902, C 25 H 24 FN5O4 requires [M+H] + 478.1885).

[0839]

[0840] ( S )-5-(2-Fluorobenzyl)- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1H -1,2,4-Triazole-3-carboxamide

[0841] 1 H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26 - 7.16 (3H, m, oxobenzoxazepine H-6, H-8, 1H of C6H4F), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 7.01 (1H, td, J 7.5, 1.0 Hz, 1H of C6H4F), 7.00 - 6.96 (1H, m, 1H of C6H4F), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.65 (1H, dd, J9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.17 (2H, s, C H 2C6H4F), 3.38 (3H, s, NCH3), 1.62(6H, s, C(C H 3)2OH); 13 C nmr (100 MHz, CDCl3) 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; 19 F nmr (380 MHz, CDCl3) δ -117.5; m / z :460 [M + H - H2O] + (found [M + H] + , 478.1895, C 25 H 24 FN5O4 requires [M + H] + 478.1885).

[0842]

[0843] ( S )-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo b [1,4]oxazepin-4(5 H )-one

[0844] 1 H nmr (400 MHz, CDCl3) δ 7.40 - 7.38 (6H, m, 2H of 3 x C6H5), 7.24 - 7.20(6H, m, 2H of 3 x C6H5), 7.18 - 7.12 (4H, m, 1H of 3 x C6H5, 1H of oxobenzoxazepine H-6, H-8, H-9), 6.97 - 6.95 (2H, m, 2H of oxobenzoxazepine H-6, H-8, H-9), 4.48(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.37 (1H, dd, J 11.5,9.5 Hz, 1H of oxobenzoxazepine H-2), 3.55 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 3.28 (1H,d, J 8.5 Hz, NH), 2.88 (3H, s, NCH3), 1.63 (6H,s, C(C H 3)2OH); m / z : 561 [M - H+HCO2H] - 。

[0845]

[0846] ( S )-5-benzyl- N -(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0847] 11H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.33 - 7.31 (2H, m, oxobenzoxazepine H-8, H-9), 7.25 - 7.20 (5H, m, C6H5), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.15 (2H, s, C H 2C6H5), 3.40 (3H, s, NCH3), 0.26 (9H, s, Si(CH3)3); m / z : 474 [M+H] + (found [M+H] + , 474.1981, C 25 H 27 N5O3Si requires [M+H] + 474.1956).

[0848]

[0849] ( S )-5-Benzyl- N -(7-Ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0850] 11H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J Hz, NH), 7.36 (1H, dd, J Hz, oxobenzoxazepine H-8), 7.35 - 7.26 (6H, m, C6H5, oxobenzoxazepine H-6), 7.14 (1H, d, J 8.5 Hz, oxobenzoxazepine H-9), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.17 (2H, s, C H 2C6H5), 3.42 (3H, s, NCH3), 3.12 (1H, s, HCC); 13 13C NMR (100 MHz, CDCl3) 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 N5O3 requires [M + H] + 402.1576).

[0851]

[0852] ( S )-3 - Amino - 7-(3 - hydroxy - 3 - methylbut - 1 - yn - 1 - yl)-5 - methyl - 2,3 - dihydrobenzo b [1,4]oxazepine - 4(5 H )-one

[0853] 11H NMR (400 MHz, CDCl3) δ 7.24 (1H, d, J 2.0 Hz, oxobenzoxazepine H-6), 7.22 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazepine H-8), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 4.41 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.12 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.72 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazepine H-3); m / z : 275 [M+H] + (found [M+H] + , 275.1390, C 15 H 18 N2O3 requires [M+H] + 275.1404).

[0854]

[0855] ( S )- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1-(2-methylbenzyl)-1 H -1,2,4-triazole-3-carboxamide

[0856] 1 1H NMR (400 MHz, CDCl3) δ 8.03 (1H, d, J 7.0 Hz, NH), 7.83 (1H, s, triazole H-5), 7.32 - 7.21 (5H, m, 5H of C6H4, oxobenzoxazepine H-6), 7.16 (1H, dd, J 9.0, 2.0 Hz, oxobenzoxazepine H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.37 (2H, s, NC H2C6H4CH3), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.41 (3H, s, NCH3), 2.27 (3H, s, C6H4C H 3), 1.62 (6H, s, C(C H 3)2OH); 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] +

[0857]

[0858] ( S )-1-([1,1'-biphenyl]-4-ylmethyl)- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepinetrione-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0859] 11H NMR (400 MHz, CDCl3) δ 8.07 (1H, s, triazole H-5), 8.06 (1H, d, J 7.0 Hz, NH), 7.60 - 7.55 (4H, m, 4H of C6H4C6H5), 7.45 - 7.42 (2H, m, 2H of C6H4C6H5), 7.38 - 7.34 (3H, m, 3H of C6H4C6H5), 7.28 - 7.26 (2H, m, oxobenzoxazepine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.41 (2H, s, NC H 2C6H4Ph), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.41 (3H, s, NCH3), 1.62 (6H, s, C(C H 3)2OH); 13 13C 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] +

[0860]

[0861] ( S )-1-(2,6-dimethylbenzyl)- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0862] 1 1H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.59 (1H, s, triazole H-5), 7.28 - 7.21 (3H, m, 3H of oxobenzoxazepine H-6, H-8, H-9, C6 H 3(CH3)2), 7.13 - 7.10 (3H, m, 3H of oxobenzoxazepine H-6, H-8, H-9, C6H3(C H 3)2), 5.41 (2H, s, NC H 2C6H3(CH3)2), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.76(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.41 (3H, s, NCH3), 2.30 (6H, s, C6H3(C H 3)2), 1.62 (6H, s, C(C H 3)2OH); 13 13C NMR (100 MHz, CDCl3) 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, C 27 H 29 N5O4 requires [M + H] + 488.2292).

[0863]

[0864] ( S ) - N -(7-(3 - hydroxy - 3 - methylbut - 1 - yn - 1 - yl)-5 - methyl - 4 - oxo - 2,3,4,5 - tetrahydrobenzo b[1,4]oxazepin-3-yl)-1-isobutyl-1 H -1,2,4-triazole-3-carboxamide

[0865] 1 H nmr (400 MHz, CDCl3) δ 8.04 (1H, s, triazole H-5), 8.03 (1H, d, J 7.0 Hz, NH), 7.29 - 7.26 (2H, m, oxobenzoxazepine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.06 (1H, ddd, J 11.0, 7.5, 7.0 Hz, oxobenzoxazepine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.98 (2H, d, J 7.0Hz, NC H 2CH(CH3)2), 3.41 (3H, s, NCH3), 2.30 - 2.23 (1H, m, C H (CH3)2), 1.62 (6H, s, C(C H 3)2OH), 0.91 (6H, dd, J 6.5, 1.0 Hz, CH(C H 3)2); 13 C nmr (100 MHz, CDCl3) δ 168.9, 158.5, 156.5, 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, 19.7; m / z : 426 [M + H] + , 408 [M + H - H2O] + (found [M + H] + , 426.2126, C 22 H 27 N5O4 requires [M + H] + 426.2136).

[0866]

[0867] ( S )-5-benzyl-N -Ethyl- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0868] 1 H nmr (400 MHz, CDCl3) δ 7.30 - 7.18 (5H, m, 5H of C6H5, H-6, H-8, H-9 of oxobenzoxazepine), 7.13 - 7.06 (3H, m, 3H of C6H5, H-6, H-8, H-9 of oxobenzoxazepine), 6.85 - 6.77 (0.66H, m, H-3 of oxobenzoxazepine, major), 5.34 - 5.27 (0.33H, m, H-3 of oxobenzoxazepine, minor), 4.94 (0.33H, dd, J 12.0, 10.5 Hz, H-3 of oxobenzoxazepine, minor), 4.84 (0.66H, dd, J 12.0, 9.5 Hz, H-3 of oxobenzoxazepine, major), 4.55 (0.66H, dd, J 9.5, 7.5 Hz, 1H of H-2 of oxobenzoxazepine, major), 4.50 (0.33H, m, 1H of H-2 of oxobenzoxazepine, minor), 4.11 (0.66H, s, C H 2C6H5, minor), 4.05 (1.32H, q, J 7.0 Hz, NC H 2CH3, major), 3.91, 3.84 (1.32H, 2d AB system, J 15.5 Hz, C H 2C6H5, major), 3.50 (0.66H, q, J 7.0 Hz, NC H 2CH3, minor), 3.28(1H, s, NCH3, minor), 3.25 (2H, s, NCH3, major), 1.61 (2H, s, C(CH3)2OH, minor),1.57 (4H, s, C(CH3)2OH, major), 1.20 (3H, t, J 7.0 Hz, NCH2C H 3); m / z : 488 [M+H] + ,470 [M+H-H2O] + (Found [M+H]+ , 488.2291, C 27 H 29 N5O4 requires [M+H] + 488.2292).

[0869]

[0870] ( S )-5-Benzyl- N -(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b )[1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0871] 1 H nmr (400 MHz, CDCl3) δ 8.10 (1H, d, J Hz, NH), 7.33 (1H, m, oxobenzoxazepine H-6), 7.31 (1H, dd, J 8.0, 2.5 Hz, oxobenzoxazepine H-8), 7.15 (5H, br s, C6H5), 7.02 (1H, dd, J 8.0, 1.0 Hz, oxobenzoxazepine H-9), 4.10 (2H, s, C H 2C6H5), 3.36 (3H, s, NCH3); 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] + (Measured [M+H] + , 458.0651, C 20 H 18 BrN5O3 requires [M+H] + 458.0645).

[0872]

[0873] ( S )-5-Benzyl- N -(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b(1,4)oxazepin-3-yl)isoxazole-3-carboxamide

[0874] 1 H NMR (400 MHz, CDCl3) δ 7.72 (1H, d, J 7.0 Hz, NH), 7.36 - 7.21 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 6.30 (1H, br s, isoxazole H-5), 4.99 (1H, dt, J 11.0, 7.0 Hz, oxobenzoxazepine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.10 (2H, s, C H 2C6H5), 3.41 (3H, s, NCH3), 1.62 (6H, s, C(C H 3)2OH); 13 C 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 + H - H2O] + (found [M + H] + , 460.1884, C 26 H 25 N3O5 requires [M + H] + 460.1867).

[0875]

[0876] ( 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)-1 H-1,2,4-Triazole-3-carboxamide

[0877] 1 H 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), 7.33 - 7.23 (6H, m, 6 x ArH),5.03 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.60 (1H, dd, J 9.5,7.5 Hz, 1H of oxobenzoxazepine H-2), 4.45 (1H,dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.35 (2H, s, isoquinoline H-1), 4.16 (2H, s C H 2C6H5), 3.50(2H, t, J 6.5 Hz, isoquinoline H-3 or H-4), 3.42 (3H, s, NCH3), 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, C 31 H 28 N6O3 requires [M + H] + 533.2296).

[0878]

[0879] ( S )- N -(7-(3,3 - dimethylbut - 1 - yn - 1 - yl)-5 - methyl - 4 - oxo - 2,3,4,5 - tetrahydrobenzo b [1,4]oxazepine - 3 - yl)-5-(2 - fluorobenzyl)-1 H -1,2,4 - Triazole - 3 - carboxamide

[0880] 1H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.0 Hz, NH), 7.26 - 7.19 (4H, m, oxobenzoxazepine H-6, H-7, 2H of C6H4F), 7.08 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 7.06 - 7.02 (1H, m, 1H of C6H4F), 7.03 - 6.99 (1H, m, 1H of C6H4F), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.25 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.19 (2H, s, C H 2C6H4F), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3); 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 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, C 25 H 26 FN5O3 requires [M+H] + 476.2092).

[0881]

[0882] ( S )-1-(2,6-dimethylbenzyl)- 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-Triazole-3-carboxamide

[0883] 1 H nmr (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.59 (1H, s, triazole H-5), 7.26 - 7.22 (3H, m, oxobenzoxazepine H-6, H-8, C6H3(CH3)2H-4), 7.12 (2H, d, J 7.5 Hz, C6H3(CH3)2H-3, H-5), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.42 (2H, s, NC H 2C6H3(CH3)2), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.24(1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine 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 N5O3 requires [M+H] + 486.2500).

[0884]

[0885] ( 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)-1 H -1,2,4-Triazole-3-carboxamide

[0886] 11H NMR (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.33 - 7.26 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 4.99 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, one H of oxobenzoxazepine H-2), 4.21 - 4.11 (1H, m, NC H one H of 2CH3), 4.16 (2H, s, NC H 2C6H5), 3.66 (1H, septet, J 7.0 Hz, NC H one H of 2CH3), 1.63 (6H, s, C(C H 3)2OH), 1.19 (3H, t, J 7.0 Hz, NCH2C H 3); m / z : 456 [M + H - H2O] + (found [M + H] + , 474.2143, C 26 H 27 N5O4 requires [M + H] + 474.2136).

[0887]

[0888] ( S ) - 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) - 5 - (3 - fluorobenzyl) - 1 H - 1,2,4 - triazole - 3 - carboxamide

[0889] 11H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.30 - 7.28 (2H, m, oxobenzoxazepine H-6, H-8), 7.26 - 7.21 (1H, m, 1H of C6H4F), 7.12 (1H, d, J 8.5 Hz, oxobenzoxazepine H-9), 7.03 (1H, br d, J 7.5 Hz, 1H of C6H4F), 6.98 (1H, br d, J 9.5 Hz, 1H of C6H4F), 6.92 (1H, td, J 8.5, 2.5 Hz, 1H of C6H4F), 4.97 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 10.5 Hz, 1H of oxobenzoxazepine H-2), 4.22 - 4.10 (1H, m, 1H of NC H 2CH3), 4.14 (2H, s, C H 2C6H4F), 3.66 (1H, septet, J 7.0 Hz, 1H of NC H 2CH3), 1.63 (6H, s, C(C H 3)2OH), 1.19 (3H, t, J 7.0 Hz, NCH2C H 3); 19 19F NMR (380 MHz, CDCl3) δ -112.6; m / z : 474 [M + H - H2O] + (Found [M + H] + , 492.2047, C 26 H 26 FN5O4 requires [M + H] + 492.2042).

[0890]

[0891] ( S )-5-Benzyl- N -(7-(3-Methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0892] 1 1H NMR (400 MHz, CDCl3) δ 8.01 (1H, d, J 7.0 Hz, 1 x NH), 7.54 (1H, s, 1x NH), 7.35 - 7.24 (6H, m, C5H5, oxobenzoxazepine H-8), 7.10 (1H, d, J 8.5 Hz, oxobenzoxazepine H-9), 7.09 (1H, m, oxobenzoxazepine H-6), 5.40 (1H, br s, 1H of C=CH2), 5.32 (1H, br s, 1H of C=CH2), 5.08 (1H, m, oxobenzoxazepine H-3), 4.76 (1H, dd, J 10.0, 6.0 Hz, 1H of oxobenzoxazepine H-2), 4.33 (1H, t, J 10.5 Hz, 1H of oxobenzoxazepine H-2), 4.18 (2H, s, C H 2C6H5), 1.98 (3H, s, CCH3); m / z : 428 [M+H] + (Found [M+H] + , 428.1709, C 24 H 21 N5O3 requires [M+H] + 428.1717).

[0893]

[0894] ( S )-5-Benzyl- N -(7-Bromo-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0895] 11H NMR (400 MHz, CD3OD) δ 7.32 - 7.21 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.00 (1H, dd, J 10.5, 6.5 Hz, oxobenzoxazepine H-3), 4.61 (1H, dd, J 10.5, 6.5 Hz, 1H of oxobenzoxazepine H-2), 4.40 (1H, t, J 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.15 (2H, s, CH2C6H5); m / z : 444, 442 [M+H] + (found [M+H] + , 444.0492, C 19 H 16 BrN5O3 requires [M+H] + 444.0489).

[0896]

[0897] (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-triazole-3-carboxamide 1 1H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.41 - 7.39 (2H, m, oxobenzoxazepine H-6, H-8), 7.29 - 7.22 (5H, m, C6H5), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 6.31 (1H, s, CH=CCl), 5.05 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28(1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.14 (2H, s, C H 2C6H5), 3.43 (3H, s, NCH3), 1.57 (6H, s, C(CH3)2OH); 13C NMR (100 MHz, CDCl3) 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 [M - H] - (Measured [M + H] + , 496.1743, C 25 H 26 ClN5O4 requires [M + H] + 496.1746).

[0898]

[0899] ( S )-5-Benzyl- 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)-1 H -1,2,4-triazole-3-carboxamide

[0900] 1 H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.28 - 7.20 (7H, m, oxobenzoxazepine H-6, H-8, C6H5), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.14 (2H, s, C H2C6H5), 3.62 (2H, s, CCH2N), 3.38 (3H, s, NCH3), 2.73 - 2.70 (4H, m, 4H of pyrrolidine), 1.86 - 1.82 (4H, m, 4H of pyrrolidine); m / z : 485 [M + H] + (Measured [M + H] + , 485.2322, C 27 H 28 N6O3 requires [M + H] + 485.2296).

[0901]

[0902] ( S ) - 5 - benzyl - N -(5 - methyl - 7 - (3 - morpholinoprop - 1 - yn - 1 - yl) - 4 - oxo - 2,3,4,5 - tetrahydrobenzo b [1,4]oxazepin - 3 - yl) - 1 H -1,2,4 - triazole - 3 - carboxamide

[0903] 1 1H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.0 Hz, NH), 7.29 - 7.7.27 (2H, m, oxobenzoxazepine H - 6, H - 8), 7.25 - 7.18 (5H, m, C6H5), 7.10 (1H, d, J 9.0Hz, oxobenzoxazepine H - 9), 5.02 (1H, dt, J 11.0, 7.0 Hz, oxobenzoxazepine H - 3), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H - 2), 4.27 (1H, t, J 10.5 Hz, 1H of oxobenzoxazepine H - 2), 4.13 (2H, s, C H 2C6H5), 3.78, 3.76 (4H, 2d AB system, J 4.5 Hz, 4H of morpholine), 3.50 (2H, s, CCH2N), 3.39 (3H, s, NCH3), 2.65, 2.63 (4H, 2d AB system, J 4.5 Hz, 4H of morpholine); m / z : 501 [M + H] + (Measured [M + H] + , 501.2245, C27 H 28 N6O4 requires [M+H] + 501.2245).

[0904] The following examples provide synthetic schemes for preparing the embodiments of the pyridine-containing compounds disclosed in the present application.

[0905] Example 11

[0906] Scheme 9 provides a method for preparing 4-phenoxypyridinecarbonitrile and 4-phenoxypyridine-2-carboxylic acid.

[0907]

[0908] Referring to Scheme 9, cesium carbonate (20.58 g, 63.1 mmol, 1.1 equiv) was added to a solution of 4-fluoropyridinecarbonitrile 90 (7.00 g, 57.4 mmol, 1.0 equiv) and phenol 92 (5.66 g, 60.2 mmol, 1.05 equiv) in dimethylformamide (90 mL). The reaction was heated to 80 °C for 8 hours and cooled. The reaction was poured into ice water (1 L). A precipitate formed, which was separated by filtration to give 4-phenoxypyridinecarbonitrile 94 (10.7 g, 95%) as a white solid; 1 H nmr (400 MHz, CDCl3) δ 8.52 (1H, d, J 6.0 Hz, pyH-6), 7.50 - 7.45 (2H, m, 2H of C6H5), 7.33 (1H, tt, J 7.5, 1.0 Hz, 1H of C6H5), 7.20 (1H, d, J 2.0 Hz, pyH-3), 7.11 - 7.08 (2H, m, 2H of C6H5), 7.02 (1H, dd, J 5.5, 2.5 Hz, pyH-5); m / z : 197 [M+H] + .

[0909] Example 12

[0910] This example relates to a method for preparing 4-phenoxypyridine-2-carboxylic acid 96 from 4-phenoxypyridinecarbonitrile 94. A suspension of pyridinecarbonitrile 94 (10.7 g, 54.6 mmol) in hydrochloric acid (6M, 100 mL) was heated to 100 °C and maintained for 8 hours. The reaction was cooled to room temperature to form a precipitate, which was separated by filtration. The filtrate was cooled to yield additional solid, which was separated by filtration and added to the first batch. The solid was dried under vacuum to obtain the white solid 4-phenoxypyridine-2-carboxylic acid 96 (12.6 g, 92%); 1 H nmr (400 MHz, D6-DMSO) δ 8.64 (1H, d, J 6.0 Hz, pyH-6), 7.57 - 7.53 (3H, m, pyH-3, 2H of C6H5), 7.38 (1H, tt, J 7.5, 1.0 Hz, 1H of C6H5), 7.33 (1H, dd, J 6.0 2.5 Hz, pyH-5), 7.28 - 7.26 (2H, m, 2H of C6H5); m / z : 216 [M+H] + .

[0911] Example 13

[0912] This example relates to a method for preparing 5-(4-fluorophenoxy)pyridine-2-carboxylic acid. N-Methylpyrrolidone (5 mL) was added to a mixture of methyl fluoropicolate (0.400 g, 2.58 mmol, 1.0 equivalent), 4-fluorophenol (0.318 g, 2.84 mmol, 1.1 equivalents), and cesium carbonate (0.925 g, 2.84 mmol, 1.1 equivalents). The reaction was stirred at 95 °C for 75 minutes. The reaction was cooled and added to ice water (150 mL) to form a precipitate. After stirring for 15 minutes, the precipitate was separated by filtration to obtain a white solid (0.540 g, 85%); 1H nmr (400 MHz, CDCl3) δ 8.46 (1H, dd, J 3.0, 0.5 Hz, pyH-6), 8.09 (1H, dd, J 9.0 0.5 Hz, pyH-2), 7.24 (1H, dd, J 9.0, 3.0 Hz, pyH-4), 7.14 - 7.04 (4H, m, C6H4F), 3.99 (3H, s, OCH3); 19F nmr (380 MHz, CDCl3) δ -117.0; m / z: 248 [M+H]+.

[0913] Aqueous lithium hydroxide (0.14 g in 5 mL of water, 3.28 mmol, 1.5 eq) was added to a solution of the methyl ester (0.54 g, 2.19 mmol, 1.0 eq) in tetrahydrofuran (12 mL). The reaction was stirred at room temperature for 35 minutes and concentrated to remove the organics. The solution was diluted with water (5 mL) and hydrochloric acid (3 M, ~1 mL) was added to pH ~3. A white precipitate formed, which was separated by filtration. Additional hydrochloric acid (3 M, 10 drops) was added to the filtrate, forming an additional precipitate, which was separated by filtration. The precipitates were combined and dried under vacuum to give the title compound as a white solid (0.49 g, 75%); 1H nmr (400 MHz, D6-DMSO) δ 8.43 (1H, dd, J 3.0, 0.5 Hz, pyH-6), 8.02 (1H, dd, J 8.5 0.5 Hz, pyH-2), 7.39 (1H, dd, J 8.5, 3.0 Hz, pyH-4), 7.33 - 7.22 (4H, m, C6H4F); 19F nmr (380 MHz, D6-DMSO) δ -117.7; m / z: 234 [M+H]+.

[0914] Example 14

[0915] This example relates to a method for preparing 4-cyclobutoxypyridine-2-carboxylic acid as shown in Scheme 10 below.

[0916]

[0917] 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 a 60% suspension, 3.84 mmol, 1.2 eq) was added and the reaction was stirred at 0 °C for 25 minutes. 4-Fluoropyridinecarbonitrile 100 (0.390 g, 3.20 mmol, 1.0 eq) was added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by the addition of NH4Cl (5 mL). The reaction was diluted with EtOAc (80 mL) and washed with NaHCO3 (80 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organics were washed with brine (60 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (10→60% EtOAc - hexanes) gave 4-cyclobutoxypyridinecarbonitrile 104 as a colorless oil (0.487 g, 88%). 11H NMR (400 MHz, CDCl3) δ 8.46 (1H, d, J 5.5 Hz, pyH-6), 7.10 (1H, d, J 2.5 Hz, pyH-3), 6.88 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 4.72 (1H, pentet, J 7.0 Hz, cBuH-1), 2.53 - 2.46 (2H, m, 2H of cBuH-2 and H-4), 2.26 - 2.16 (2H, m, 2H of cBuH-2 and H-4), 1.98 - 1.89 (1H, m, 1H of cBuH-3), 1.82 - 1.71 (1H, m, 1H of cBuH-3).

[0918] Hydrochloric acid (6 M, 7 mL) was added to 4-cyclobutoxypicolinonitrile 104 (0.487 g, 2.80 mmol) and the reaction was heated to 100 °C for 18 h. The reaction was cooled, but no precipitate was formed. The solution was concentrated to dryness to give the beige solid 4-cyclobutoxypyridine-2-carboxylic acid 106, which was used without further purification. 1 1H NMR (400 MHz, D6-DMSO) δ 8.66 (1H, d, J 6.5 Hz, pyH-6), 7.69 (1H, dd, J 2.5 Hz, pyH-3), 7.50 (1H, dd, J 6.5, 2.5 Hz, pyH-5), 5.12 (1H, pentet, J 7.0 Hz, cBuH-1), 2.53 - 2.46 (2H, m, 2H of cBuH-2 and H-4), 2.19 - 2.09 (2H, m, 2H of cBuH-2 and H-4), 1.88 - 1.80 (1H, m, 1H of cBuH-3), 1.75 - 1.65 (1H, m, 1H of cBuH-3); m / z : 194 [M+H] + .

[0919] Example 15

[0920] This example relates to a method for preparing ( S )- N -(7-((3-Hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide according to Scheme 11.

[0921]

[0922] Dimethylformamide (80 mL) was added to a mixture of bromooxobenzoxazepine 1100 (8.36 g, 16.3 mmol, 1.0 equiv) and copper(I) iodide (0.31 g, 1.6 mmol, 0.1 equiv). The mixture was degassed by bubbling argon through it for 5 minutes. Triethylamine (11.4 mL, 81.6 mmol, 5.0 equiv) was added, followed by hydroxyethynyl oxetane 1102 (3.20 g, 32.7 mmol, 2.0 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.94 g, 0.8 mmol, 0.05 equiv). The resulting brown solution was heated to 80 °C for 4 hours. The reaction was cooled and partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was washed with brine (150 mL), water (200 mL), and brine (150 mL), dried (Na2SO4), and concentrated under reduced pressure. MPLC (10→70% EtOAc - hexanes) gave compound 1104 as a yellow solid (6.18 g, 72%). 1H nmr (400 MHz, CD3Cl) δ 7.41 - 7.39 (6H, m, 6H of C(C6H5)3), 7.25 - 7.15 (10H, m, 9H of C(C6H5)3, H-8 of oxobenzoxazepine), 7.00 - 6.98 (2H, m, H-6, H-9 of oxobenzoxazepine), 4.94 (2H, d, J 7.0 Hz, 2H of H-2, H-4 of oxetane), 4.80 (2H, d, J 7.5 Hz, 2H of H-2, H-4 of oxetane), 4.50 (1H, dd, J 10.0, 7.0 Hz, 1H of H-2 of oxobenzoxazepine), 4.39 (1H, dd, J 11.5, 10.0 Hz, 1H of H-2 of oxobenzoxazepine), 3.59 - 3.52 (1H, m, H-3 of oxobenzoxazepine), 3.29 (1H, d, J 9.0 Hz, NH), 2.89 (3H, s, NCH3).

[0923] Formic acid (50 mL) was added to triphenylmethyl-protected amine 1104 (7.49 g, 14.1 mmol, 1 equiv), and the mixture was stirred at room temperature for 4 h. Water (50 mL) was added, and the reaction was stirred at room temperature for 15 h. The reaction was concentrated to remove some formic acid and then diluted with water (100 mL). The organic matter was extracted with EtOAc (50 mL) and set aside. The aqueous phase was neutralized by adding NaOH (5 M, portionwise to about 40 mL). The organic matter was extracted with EtOAc (4 x 150 mL). The combined neutralized organic matter was dried (Na2SO4) and concentrated under reduced pressure to afford (S)-3-amino-7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[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, D6-DMSO) δ 7.51 (1H, d, J 2.0 Hz, oxobenzoxazepine H-6), 7.29 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazepine H-8), 7.14 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 4.74 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.58 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.25 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.01 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.59 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 3.28 (3H, s, NCH3); 13C nmr (100 MHz, D6-DMSO) 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]+.

[0924] A solution of aminooxobenzoxazepine 1106 (3.78 g, 13.13 mmol, 1.0 equiv) in dimethylformamide (70 mL) was degassed by bubbling nitrogen through it for 5 minutes. 4-Phenoxypyridine-2-carboxylic acid hydrochloride 1108 (3.30 g, 13.13 mmol, 1.0 equiv) was added and the solution was cooled to 0 °C, then diisopropylethylamine (5.7 mL, 32.81 mmol, 2.5 equiv) was added. HATU (5.49 g, 14.44 mmol, 1.1 equiv) was added portionwise and the reaction was stirred at 0 °C for 1 hour and at room temperature for 15 hours. The reaction was poured into ice water (500 mL) to form a precipitate, which was stirred for 15 minutes and then separated by filtration. The filtrate was extracted with EtOAc (150 mL). The organic extract was washed with brine (100 mL), water (150 mL) and brine (100 mL), combined with the separated precipitate, dried (Na2SO4) and concentrated under reduced pressure. MPLC (30→70% EtOAc-hexanes) gave (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypyridinecarboxamide I-110 (5.20 g, 82%) as a white foam.IR (thin film) ν 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, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44 - 7.40 (2H, m, 2H of C6H5), 7.32 - 7.29 (2H, m, 2H of C6H5 or H-6, H-8 of oxobenzoxazepine), 7.27 - 7.23 (1H, m, 1H of C6H5 or H-6, H-8 of oxobenzoxazepine), 7.15 (1H, d, J 9.0 Hz, H-9 of oxobenzoxazepine), 7.08 - 7.06 (2H, m, 2H of C6H5 or H-6, H-8 of oxobenzoxazepine), 6.50 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.04 (1H, dt, J 11.0, 7.5 Hz, H-3 of oxobenzoxazepine), 4.93 (2H, dd, J 4.0, 0.5 Hz, H-2, H-4 of oxetane), 4.79 (2H, dt, J 6.5, 1.0 Hz, H-2, H-4 of oxetane), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of H-2 of oxobenzoxazepine), 4.32 (1H, dd, J 11.0, 9.5 Hz, 1H of H-2 of oxobenzoxazepine), 3.42 (3H, s, NCH3); 13C 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, required [M+H]+ 486.1660 for C27H23N3O6).

[0925] Example 16

[0926] This example describes a method for the embodiment of preparing an azetidinyl-acetylene compound according to the following synthetic scheme 12.

[0927]

[0928] A. Synthesis of tert-Butyl 3-Ethynyl-3-Hydroxyazetidine-1-Carboxylate

[0929]

[0930] 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 n-butyllithium (2.51 mL of a 2.5 M solution in hexane, 6.28 mmol, 1.1 eq) was added dropwise. The reaction was stirred at -78 °C for 1 hour, then Boc-azetidinone 1300 (0.98 g, 5.71 mmol, 1.0 eq) was added. The reaction was stirred between -78 °C and room temperature for 20 hours and then quenched by the addition of NH4Cl (20 mL). The reaction was partitioned between EtOAc (100 mL) and NH4Cl-water (1:1, 100 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure.

[0931] The residue containing 1304 was dissolved in tetrahydrofuran (30 mL) and cooled to 0 °C, then tetrabutylammonium fluoride trihydrate (1.80 g, 5.71 mmol, 1.0 eq) was added. The reaction was stirred at 0 °C for 3 hours and then NH4Cl (20 mL) was added. The reaction was partitioned between EtOAc (100 mL) and NH4Cl-water (1:1, 100 mL). The organic layer was washed with NH4Cl (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to give 1306 as a pale yellow oil. 1 Hnmr (400 MHz, CDCl3) δ 4.20 (2H, dd, J 9.0, 1.0 Hz, 2H of azetidine H-2, H-4), 4.02 (2H, dd, J 9.0, 1.0 Hz, 2H of azetidine H-2, H-4), 2.68 (1H, s, CCH), 1.44 (9H, s, C(CH3)3).

[0932] B. ( S)-3-Hydroxy-3-((5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo b [1,4]oxazepin-7-yl)ethynyl)azetidine-1-carboxylate formation

[0933]

[0934] Dimethylformamide (3.0 mL) was added to a mixture of bromooxobenzoxazepine 1312 (0.141 g, 0.301 mmol, 1.0 equiv), tert-butyl 3-ethynyl-3-hydroxyazetidine-1-carboxylate 1306 (0.089 g, 4.52 mmol, 1.5 equiv), and copper(I) iodide (0.006 g, 0.030 mmol, 0.1 equiv). The reaction was degassed by bubbling argon through it for 5 minutes. Triethylamine (0.21 mL, 1.506 mmol, 5.0 equiv) was added to form a clear solution, to which tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol, 0.05 equiv) was added. A brown solution was produced and heated to 80 °C for 6 hours. The reaction was cooled and partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), water (50 mL), and brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. MPLC (30→80% EtOAc-hexanes) gave the starting material (0.050 g) and compound 1314 (0.090 g, 51%); 11H NMR (400 MHz, CDCl3) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44 - 7.39 (2H, m, 2H of C6H5), 7.31 - 7.28 (2H, m, oxobenzoxazepine H-6, H-8), 7.27 - 7.23 (1H, m, 1H of C6H5), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 7.08 - 7.06 (2H, m, 2H of C6H5), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.05 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.31 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.29 - 4.26 (2H, m, 2H of azetidine H-2, H-4), 4.12 - 4.09 (2H, m, 2H of azetidine H-2, H-4), 3.42 (3H, s, NCH3), 1.45 (9H, s, C(CH3)3); m / z : 585 [M+H] + , 529 [M+H - C4H8] + , 485 [M+H - C4H8 - CO2] + 。

[0935] C. (S)-N-(7-((3-Hydroxyazetidin-3-Yl)Ethynyl)-5-Methyl-4-Oxo-2,3,4,5-Tetrahydro Benzo[b][1,4]Oxazepin-3-Yl)-4-Phenoxypyridinecarboxamide

[0936]

[0937] At room temperature, hydrogen chloride (0.12 mL of a 4 M solution in dioxane, 0.462 mmol, 3.0 equiv) was added to a solution of Boc-protected azetidine 1316 (0.090 g, 0.154 mmol, 1.0 equiv) in ethyl acetate (1.5 mL). The reaction mixture was stirred at room temperature for 6 h. Additional hydrogen chloride (0.12 mL of a 4 M solution in dioxane, 0.462 mmol, 3.0 equiv) was added, and the reaction was stirred for an additional 16 h and then concentrated under reduced pressure. The residue was partitioned between EtOAc (30 mL) and NaHCO3 (30 mL). The aqueous phase was extracted with EtOAc (30 mL) and CH2Cl2 (3 x 30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→15% MeOH[NH3]-CH2Cl2) gave compound 1318 (0.026 g, 39%) as a white solid; 1 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.43 - 7.39 (2H, m, 2H of C6H5), 7.31 - 7.29 (2H, m, oxobenzoxazepine H-6, H-8), 7.27 - 7.22 (1H, m, 1H of C6H5), 7.13 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 7.08 - 7.05 (2H, m, 2H of C6H5), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.30 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.05 (2H, d, J 9.0 Hz, 2H of azetidine-2, H-4), 3.83 (2H, d, J 9.5 Hz, 2H of ozetidine H-2, H-4), 3.42 (3H, s, NCH3); m / z : 485 [M+H]+ + (found [M+H]+ + , 485.1826, C27 H 24 N4O5 requires [M+H] + 485.1819).

[0938] 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-Phenoxypyridinecarboxamide

[0939]

[0940] Aqueous formaldehyde solution (0.005 mL of 37% aqueous solution, 0.071 mmol, 1.5 equiv) was added to a solution of azetidine 1320 (0.023 g, 0.048 mmol, 1.0 equiv) in methanol (0.5 mL). The reaction was equilibrated at room temperature for 15 minutes, then sodium triacetoxyborohydride (0.015 g, 0.071 mmol, 1.5 equiv) was added. After stirring at room temperature for 45 minutes, the reaction was quenched by the addition of Rochelle's 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 (2 x 40 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→15% MeOH [2M NH3]-CH2Cl2) gave compound 1322 as a white solid. 11H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.43 - 7.39 (2H, m, 2H of C6H5), 7.32 - 7.29 (2H, m, oxobenzoxazepine H-6, H-8), 7.27 - 7.23 (1H, m, 1H of C6H5), 7.13 (1H, d, J 8.5 Hz, oxobenzoxazepine H-9), 7.08 - 7.06 (2H, m, 2H of C6H5), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.30 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.70 (2H, br d, J 9.5 Hz, 2H of azetidine H-2, H-4), 3.44 (2H, d, J 9.0 Hz, 2H of azetidine H-2, H-4), 3.41 (3H, s, CONCH3), 2.43 (3H, s, NCH3); m / z : 499 [M+H] + (Found [M+H] + , 499.1988, C 28 H 26 N4O5 requires [M+H] + 499.1976).

[0941] E. Fluorination of (S)-3-Fluoro-3-((5-Methyl-4-Oxo-3-(4-Phenoxypyridinecarboxamido)-2,3,4,5-Tetrahydrobenzo [b][1,4]Oxazepin-7-Yl)Ethynyl)Azetidine-1-Carboxylate tert-Butyl Ester

[0942]

[0943] At -78 °C, [bis(2-methoxyethylamino)]sulfur trifluoride (0.031 g, 0.026 mL, 0.141 mmol, 1.5 equiv) was added dropwise to a solution of tert-butyl (S)-3-hydroxy-3-((5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)azetidine-1-carboxylate 1324 (0.055 g, 0.094 mmol, 1.0 equiv) in dichloromethane (1.0 mL). The reaction was stirred at -78 °C for 3 h and at 0 °C for 45 min, then quenched with NaHCO3 (5 mL). The reaction was added to NaHCO3 (20 mL) and the organics were extracted with CH2Cl2 (3 x 20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the compound 1326 as a yellow oil. The crude material was used without purification; 1 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5 Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44 - 7.40 (2H, m, 2H of C6H5), 7.35 - 7.32 (2H, m, oxobenzoxazepine H-6, H-8), 7.27 - 7.24 (1H, m, 1H of C6H5), 7.17 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 7.08 - 7.06 (2H, m, 2H of C6H5), 6.95 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.35 - 4.30 (5H, m, 1H of oxobenzoxazepine H-2, azetidine H-2, H-4), 3.44 (3H, s, NCH3), 1.47 (9H, s, C(CH3)3); 19 19F NMR (380 MHz, CDCl3) δ -141.4 (t, J 19.0 Hz); m / z : 587 [M+H] + , 531 [M+H-C4H8] + , 487 [M+H-C4H8-CO2]+ .

[0944] Example 17

[0945] This example provides a method for preparing N -substituted-4-[(aryl)methyl]-1 H -pyrazole-1-carboxamide via the formation of intermediate pyrazole-1-carbonyl chloride according to Scheme 14.

[0946]

[0947] Under nitrogen, at 0 °C, H -Pr2NEt (5 - 9 equivalents) was added over time (15 min / mmol) to a stirred heterogeneous mixture of 4-[(aryl)methyl]-1 i -pyrazole hydrochloride 1400 (1 equivalent) and triphosgene (1.5 equivalents) in CH2Cl2 (15 mL / mmol). The red reaction solution was stirred at 0 °C for 1 h, warmed to room temperature (2 h), and the consumption of 4-[(aryl)methyl]-1 H -pyrazole was analyzed by LC / MS and concentrated to dryness to afford 1402. The red semi-solid concentrate was added to 1404 or the corresponding amine or its salt (1 equivalent) and DMAP (0.1 equivalent) 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 over time (15 min / mmol) with i -Pr2NEt (5 - 9 equivalents). After 1 h, the ice bath was removed and the reaction solution was warmed to room temperature. After analyzing the reaction progress, the reaction solution was concentrated to dryness, diluted with water and worked up by extraction with EtOAc or CH2Cl2. Flash column chromatography on silica gel of the crude concentrate provided the desired N -substituted-4-[(aryl)methyl]-1 H -pyrazole-1-carboxamide 1406 (Yield: 20 - 75%).

[0948] Example 18

[0949] This example provides a method for preparing N -substituted-4-[(aryl)methyl]-1 H -pyrazole-1-carboxamide via the formation of intermediate isocyanate according to Scheme 15.

[0950]

[0951] Under nitrogen, at 0 °C, over time (20 min / mmol), i-Pr2NEt (10 - 15 equivalents) was added to a stirred heterogeneous mixture of compound 1420 or its corresponding amine or its salt (1 equivalent) and triphosgene (2.3 equivalents) in CH2Cl2 (15 mL / mmol). The pale yellow reaction solution was stirred at 0 °C for 1 hour, warmed to room temperature (2 hours), analyzed by LC / MS for consumption of the corresponding amine and concentrated to dryness. To the red semi-solid concentrate containing compound 1422 was added 4-[(aryl)methyl]-1 H -pyrazole hydrochloride 1424 (0.9 equivalent) and DMAP (0.1 equivalent) and the mixture was cooled in an ice bath under nitrogen. CH2Cl2 (15 mL / mmol) was added to the flask, stirred for 15 minutes and the stirred red solution was treated over time (15 min / mmol) with i -Pr2NEt (10 - 15 equivalents). After 1 hour the ice bath was removed and the reaction solution was warmed to room temperature (6 - 8 hours). After analysis, the reaction solution was concentrated to dryness, diluted with water and worked up by extraction with EtOAc or CH2Cl2. Flash column chromatography of the resulting crude material on silica gel provided the desired N -substituted-4-[(aryl)methyl]-1 H -pyrazole-1-carboxamide 1426 (Yield: 19 - 73%).

[0952] Example 19

[0953] This example provides a method for the embodiment of preparing the disclosed alkynyl-substituted compounds according to Scheme 16.

[0954]

[0955] Nitrogen was bubbled through a stirred solution of aryl halide 1440 (1 equivalent), CuI (0.1 - 0.2 equivalent), Pd(PPh3)4 (0.05 - 0.1 equivalent) in dry DMF (3 - 4 mL / mmol) in a flask for 3 minutes. Subsequently, NEt3 (10 equivalents) was added to the dark reaction solution, followed immediately by the corresponding alkyne 1442 (1.5 - 3 equivalents). Nitrogen was bubbled through the reaction mixture for 2 minutes, the flask was capped and the reaction mixture was stirred at 70 - 75 °C for 5 - 6 hours. After analyzing the reaction progress by LC / MS, the dark reaction solution was concentrated to dryness. The crude residue was diluted with ice wat...

Claims

1. A compound selected from: I-98: (S)-N-(7-((1-Hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-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-yn-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-Dimethylbut-1-yn-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-Dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(2-fluorophenoxy)picolinamide; I-103: (S)-4-(2-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-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-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-106: (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-107: (S)-4-(3-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; I-109: (S)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; 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-phenoxypyridinecarboxamide; 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)pyridinecarboxamide; 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)pyridinecarboxamide; I-114: (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)pyridinecarboxamide; 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)pyridinecarboxamide; 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-phenoxypyridinecarboxamide; I-117: (S)-N-(5-methyl-7-(3-morpholinopropyl-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; I-118: (S)-4-(2,6-difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; I-119: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-methyl-4-phenoxypyridinecarboxamide; I-120: (S)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; I-121: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; I-122: (S)-4-(3-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; 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-phenoxypyridinecarboxamide; I-124: (S)-4-(2,6-dimethylphenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; I-125: (S)-4-(4-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; I-126: (S)-4-(4-fluorophenoxy)-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; I-127: (S)-N-(5-Methyl-7-((3-methyloxetan-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-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-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-130: (3-Morpholinopropyl)carbamic acid (S)-3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl ester; I-131: (S)-N-(7-((4-Hydroxy-1-(4-phenoxypicolyl)piperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-132: (S)-N-(7-((4-Hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-133: (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-134: (S)-N-(7-((1-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-135: (S)-4-(4-Fluorophenoxy)-N-(7-((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-136: (S)-N-(7-((3-Hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-137: (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-138: (S)-4-(4-Fluorophenoxy)-N-(5-methyl-7-(5-(methylamino)-3-methylidenepent-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-139: (S)-N-(7-(3-Amino-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; 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]oxazepin-3-yl)-4-phenoxypicolinamide; I-141: ((S)-1-((2,2-Dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl)oxy)-1-oxopropan-2-yl)-N2-tert-butyl-1,2-diazane-carboxylate; I-142: L-Alanine 2,2-dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl ester; I-143: (S)-N-(7-((3-Fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-144: (S)-4-((2,2-Dimethyl-4-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-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-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-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]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; I-147: (R)-4-((3-((5-methyl-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetane-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-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; I-149: (S)-N-(7-((3-oxa-9-azaspiro[5.5]undecan-9-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; I-150: (S)-N-(7-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; I-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)-4-phenoxypyridinecarboxamide; I-152: (S)-4-cyclobutoxy-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; I-153: (S)-4-cyclobutoxy-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; I-154: (S)-N-(7-((3-methoxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-155: (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-156: (S)-4-(cyclopentyloxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-157: (S)-4-(cyclopentyloxy)-N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-158: (S)-N-(5-methyl-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-159: (S)-methyl 3-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propiolate; I-160: L-valine 3-(((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetidin-3-yl ester; I-161: (S)-3-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)prop-2-ynoic acid; I-162: (S)-N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-methoxypicolinamide; I-163: (S)-N-(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-methoxypicolinamide; I-164: L-Valine 3-(((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl ester benzenesulfonate; I-165: (S)-4-((3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl)oxy)-4-oxobutanoic acid tris salt; I-166: (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-167: (S)-N-(7-(3-Amino-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 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]oxazepin-3-yl)-4-phenoxypicolinamide; I-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)-4-phenoxypicolinamide; I-170: (S)-4-((4-(3-(4-(4-Fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl)oxy)-4-oxobutanoic acid; I-171: L-Alanine 4-((S)-3-(4-(4-fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl ester; I-172: L-Valine 4-((S)-3-(4-(4-fluorophenoxy)pyridinecarboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl ester; I-173: (S)-2,2-Dimethyl-4-(5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl dihydrogen phosphate; I-174: (S)-4-(3-(4-(4-fluorophenoxy)pyridinecarboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl dihydrogen phosphate; I-175: (S)-4-(4-fluorobenzyl)-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-pyrazole-1-carboxamide; I-177: (S)-N-(5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; 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]azepin-3-yl)-1H-pyrazole-1-carboxamide; I-179: (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)-1H-pyrazole-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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-181: (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)-1H-pyrazole-3-carboxamide; I-182: (S)-1-Benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide; I-183: (S)-4-(4-Fluorobenzyl)-N-(5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-184: (S)-4-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-190: (S)-N-(7-((3-Hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(phenoxy-d5)pyridinecarboxamide; I-191: (S)-N-(7-((1-Acetyl-3-fluorazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; I-192: (S)-N-(7-((3-Hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)oxy)pyridinecarboxamide; I-193: (S)-N-(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)oxy)pyridinecarboxamide; I-194: L-Alanine 3-(((S)-5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetane-3-yl ester trifluoroacetate; I-195: (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-phenoxypyridinecarboxamide; I-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)-4-phenoxypyridinecarboxamide; 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-phenoxypyridinecarboxamide; 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-phenoxypyridinecarboxamide; I-199: (S)-3-((5-methyl-4-oxo-3-(4-phenoxypyridinecarboxamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetane-3-yl ethylcarbamate; I-200: (S)-N-(7-((3-hydroxy-1-neopentylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; I-203: (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-phenoxypyridinecarboxamide; 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]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; I-205: (S)-N-(7-(3-((4-Fluorobenzyl)amino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-206: (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-207: (S)-N-(7-((4-Hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-208: (S)-N-(7-((3-Hydroxy-1-oxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-209: (S)-N-(7-((3-Hydroxy-1,1-dioxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-210: (S)-N-(5-methyl-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-211: (S)-N-(7-(3-(1,1-Dioxidomorpholinyl)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; 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]oxazepin-3-yl)-1H-pyrazole-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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-214: (S)-4-Benzyl-N-(5-methyl-4-oxo-7-(pyridin-3-yl ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-215: (S)-4-Benzyl-N-(5-methyl-4-oxo-7-(pyridin-2-yl ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-216: (S)-4-Benzyl-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-219: (S)-4-Benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-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]oxazepin-3-yl)-5-methyl-1H-pyrazole-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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-222: (S)-4-(4-Fluorobenzyl)-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-224: (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-pyrazole-1-carboxamide; I-225: (S)-4-(4-Fluorobenzyl)-N-(7-((6-hydroxyl-2-oxaspiro[3.3]heptan-6-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-226: (S)-N-(7-(3-Amino-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-fluorobenzyl)-1H-pyrazole-1-carboxamide; I-227: (S)-4-(4-Fluorobenzyl)-N-(5-methyl-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-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]oxazepin-3-yl)-1H-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]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-238: (S)-4-(2,4-Difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-239: (S)-4-(2,4-Difluorobenzyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-240: tert-Butyl ((S)-(4-(3-(4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl)amino)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]oxazepin-3-yl)-4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamide hydrochloride; II-16: (S)-N-(5-Methyl-4-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; II-17: (S)-4-(4-Cyanophenoxy)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; II-18: (S)-4-(4-Cyanophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridinecarboxamide; 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]oxazepin-3-yl)pyridinecarboxamide; II-20: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenylpyridinecarboxamide; 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]oxazepin-3-yl)pyridinecarboxamide; II-22: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-methoxyphenyl)pyridinecarboxamide; II-23: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-methoxyphenyl)pyridinecarboxamide; II-25: (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-phenoxypyridinecarboxamide; II-32: (S)-N-(7-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; II-33: (S)-N-(7-((6-cyanopyridin-2-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; II-35: (S)-N-(7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; II-36: (S)-N-(7-(3-(dimethylamino)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide; or II-39: N-((3S)-5-methyl-4-oxo-7-(pyrrolidin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide.

2. A compound of the following formula or a pharmaceutically acceptable salt thereof:

3. The compound according to claim 2, wherein the compound is:

4. A pharmaceutical composition comprising the compound according to any one of claims 1 - 3.

5. The composition according to claim 4, wherein the composition comprises an excipient, a therapeutic agent, or a combination thereof.

6. Use of a compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating 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 according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease involving inflammation, necroptosis or both.

8. Use according to claim 7, wherein the disease is an inflammatory or immunomodulatory disorder.

9. Use according to claim 7, wherein the disease is an aging disorder.

10. Use according to claim 7, wherein the disease is amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease or Alzheimer's disease.

11. Use according to claim 7, wherein the disease is atopic dermatitis, rheumatoid arthritis or ankylosing spondylitis.

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