RIP1 inhibitor compounds and methods for making and using same

Abstract

To provide RIP1 inhibitory compounds and methods for making and using the same.SOLUTION: The present invention provides a compound having formula I or a pharmaceutically acceptable salt thereof (where ring B represents a 5-membered or 6-membered heteroaryl).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of earlier-filed U.S. Provisional Patent Application No. 62 / 666,462, filed May 3, 2018, which is incorporated herein by reference in its entirety.

[0002] Field The present disclosure relates to compounds and methods of making and using the compounds, such as for inhibiting receptor-interacting protein kinase-1 ("RIP1") and treating diseases and / or conditions associated with RIP1. [Background technology]

[0003] background Receptor-interacting protein kinase-1 (herein referred to as "RIP1") is a serine / threonine protein kinase that belongs to the tyrosine kinase-like family and is involved in innate immune signaling. RIP1 plays a central role in regulating cell signaling, and its role in programmed cell death has been linked to various inflammatory diseases, such as inflammatory bowel disease, psoriasis, and other diseases, and / or conditions involving inflammation and / or necroptotic cell death. Summary of the Invention [Means for solving the problem]

[0004] overview As used herein, Formula I [ka] or a pharmaceutically acceptable salt thereof. One of ordinary skill in the art will recognize that compounds encompassed within the scope of Formula I also include stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs thereof.

[0005] In Formula I, ring B is a 5- or 6-membered heteroaryl; L is a heteroatom or R a where R a is not H or D; Z is C 1~10 Aliphatic (C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl or C 3~6 cycloalkyl, etc.); or [ka] and;R 1 is a halogen, -C≡CH or -linker -R 6 group, and the linker is R a where R a is not H or D, and R 6 is R b , -C(R f )3 or -C(R f )=C(R f )2;R 2 and R 3 are independently, R a and;R 4 and R 5 are independently, R e and;R a are, in each case independently, H, D, C 1~10 aliphatic, C 1~10 Haloaliphatic, C 5~10 Aromatic or C 3~6 Heterocyclic; R b is, independently in 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 and;R c are, in each case independently, C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~6 Cycloalkyl (which can be one, two, or three Re (which may be substituted with) or C 5~10 Aromatic (which means that one, two or three R e (which may be substituted with); R d are, independently in each case, H;C 1~6 Alkyl (which can be one, two or three R e can be substituted with);C 3~6 Cycloalkyl (which can be one, two, or three R e can be substituted with);C 3~6 Heterocycles (which may contain one, two or three R e can be substituted with);C 5~10 Aryl (which can be one, two, or three R b can be substituted with);C 5~10 Heteroaryl (which can be one, two, or three R b or two R d The groups, together with the nitrogen to which they are attached, form a C 3~9 Heterocycles (which may be one or more R e (which may be substituted with) or C 5~10 Heteroaryl (which may be one or more R e and R e is, independently in each occurrence, a 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 are, in each case independently, R a , R b or R e or two R f The groups, together with the carbon atoms to which they are attached, form a C 3~6 A cycloalkyl group (which may be one or more R e (which may be substituted with) or C 3~10 Heterocycles (which may be one or more R em is 1 to 4; n is 0, 1, or 2; and p is 0, 1, 2, 3, 4, or 5.

[0006] The disclosed compound has the formula: [ka] The structure may satisfy the following.

[0007] In any or all of the above embodiments, ring B is of the formula [ka] wherein at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. Specific embodiments of Ring B are diazole, triazole, oxadiazole, oxazole, or pyridinyl. Examples of suitable triazoles include any of the following: [ka]

[0008] Examples of suitable diazoles include any of the following: [ka]

[0009] Examples of suitable oxadiazoles include any of the following: [ka]

[0010] Examples of suitable oxazoles include any of the following: [ka]

[0011] Certain disclosed compounds are e The group R 5 group, R e is a C1-C4 aliphatic group or halogen, and R 2 is R a and R a is a C1-C4 aliphatic group, and R 3 is R a and R a is hydrogen.

[0012] For certain disclosed embodiments, R 1 Linker-R 6 group, and the linker is R a and R a is a C1, C2, C3, or C4 aliphatic group. The C2 aliphatic group can be an alkyl, alkenyl, or alkynyl group. R 6 The group is R b R b is -C(R f )3 and 1 R f is R e , especially -OR a and R a is H; and each other R f are, in each case independently, R a and R a is C 1~4 In certain embodiments, the C2 group is an alkyne. In any or all of the above embodiments, ring B is [ka] may be selected from:

[0013] In some embodiments, R 6 is R b R b is -C(O)OEt; or R b is -C(O)NR d R d where each R dare, in each case independently, H, C 5~10 Heteroaryl (which can be one, two, or three R e (which may be substituted with), C 1~6 Alkyl (which can be one, two or three R e or two R d The groups, together with the nitrogen to which they are attached, form a C 3~9 Heterocycles (which may be one or more R e (which may be substituted with) or C 5~10 Heteroaryl (which may be one or more R e More particularly, one R d is H and other R d is aromatic, e.g. [ka] is.

[0014] Certain compounds are R b (where R b is -OH); OR c (where R c is C 1~10 Alkyl (which can be one, two or three R e (which may be substituted with), C 2~10 Alkenyl (which is one, two or three R e (which may be substituted with), C 2~10 Alkynyl (which is a group consisting of 1, 2, or 3 R e (which may be substituted with) or C 5~10 Aromatic (which means that one, two or three R e (which may be substituted with); or NR d R d (Here, one R d is H, and the other R d is C 5~10 Aromatic (which means that one, two or three R e R 6 In some embodiments, R b is OR c and R cis a C alkyl substituted with pyridinyl. b is -NR d R d while R d is H, and the other R d is pyridinyl.

[0015] Linker-R 6 The linker group of the group can be a C group, and the corresponding R 6 The group is R b and R b is -NR d R d and two R d The groups, together with the nitrogen to which they are attached, form a C 3~9 Heterocycles (which may be one or more R e (which may be substituted with) or C 5~10 Heteroaryl (which may be one or more R e and in particular, two R d The groups, together with the nitrogen to which they are attached, form one R e C replaced with 3~9 In such embodiments, R e is C 5~10 In other embodiments, two R d The groups, together with the nitrogen to which they are attached, may optionally be one or more R e C can be substituted with 5~10 Heteroaryl may be provided. R e Unsubstituted C 5~10 Heteroaryl is [ka] It could be.

[0016] In some embodiments, R 5 is R e and R e is halogen or methyl. In some embodiments, the linker -R 6 The linker of the group is Ra and R a is a C1, C2, C3, or C4 aliphatic group, including alkyl, alkenyl, or alkynyl groups. In some such embodiments, the C2 group comprises an alkyne, and R 6 is R b and R b is -C(R f )3 and 1 R f is R e and each other R f are, in each case independently, R a and R a is C 1~4 In certain embodiments, R e -OR a and R a is H. In some such embodiments, R a is methyl and ring B is [ka] is.

[0017] R 1 can be located on any suitable carbon atom of the phenyl ring A, for example, at the 1, 2, 3, or 4 position as illustrated in Formula I. Exemplary R 1 The group is shown below. [ka] [ka]

[0018] Exemplary compound classes are presented herein.

[0019] Also disclosed herein are pharmaceutical composition embodiments that include a compound (or compounds) according to any of the formulas and / or compound species disclosed herein (or pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs thereof) and at least one additional active and / or inactive agent, such as an additive, therapeutic agent, adjuvant, or combination thereof.

[0020] Also disclosed herein are method embodiments for using the disclosed compounds. One such embodiment includes contacting a receptor-interacting protein-1 (RIP1) kinase with a compound according to any of the formulas and / or compound classes disclosed herein (or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof), or an embodiment of a pharmaceutical composition described herein. Contacting can occur ex vivo or in vivo.

[0021] Also disclosed are methods for treating a disease in a subject, the method comprising administering to the subject (i) a therapeutically effective amount of a compound according to any of the formulas and / or species disclosed herein (or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof); and / or (ii) a therapeutically effective amount of an embodiment of the pharmaceutical composition described herein, wherein the subject has or is suspected of having or developing a disease involving receptor-interacting protein-1 (RIP1) kinase.

[0022] Also described are methods for preparing embodiments of the compounds disclosed herein. In some embodiments, the methods include reacting a starting material having formula A with a compound having formula R 1 A reagent containing R 1 Linker-R 6 R 1 and a reagent containing the starting material and R 1by combining a reagent containing the formula: with a transition metal catalyst, a base, and a solvent to produce a functionalized product; deprotecting the amine group of the functionalized product to provide an amine compound; and forming an amide bond between the amine compound and an acid-containing coupling partner to provide an amide-containing compound, wherein Formula A is [ka] and the functionalized product is of formula B [ka] and the acid-containing coupling partner has a structure satisfying formula C [ka] having a structure satisfying the formula: X is a halogen or triflate; PG is an amine protecting group; and Ring B, L, R 1 , R 2 , R 4 , R 5 , m, n, and p are as described in any one or more of the compound embodiments above.

[0023] The above and other objects and features of the present disclosure will become more apparent from the detailed description set forth below. DETAILED DESCRIPTION OF THE INVENTION

[0024] Detailed Description I. Terminology Overview The following explanations of terms and methods are provided to more fully describe the present disclosure and to guide those skilled in the art in practicing the present disclosure. The singular forms "a," "an," and "the" mean one or more, unless the context clearly dictates otherwise. The word "or" refers to a single element or a combination of two or more elements of the presented alternative elements, unless the context clearly dictates otherwise. As used herein, "comprises" means "includes." Thus, "comprising A or B" means "including A, B, or A and B," and does not exclude additional elements. All references cited herein, including patents and patent applications, are hereby incorporated by reference.

[0025] Unless otherwise specified, all numbers expressing amounts of ingredients, molecular weights, percentages, temperatures, times, etc. used in the specification or claims should be understood to be modified by the word "about." Thus, unless otherwise specified, either implicitly or explicitly, the numerical parameters recited are approximations that may depend on the desired properties sought and / or the limits of detection under standard testing conditions / methods. When directly and explicitly distinguishing an embodiment from the cited prior art, the numbers of that embodiment are not approximations unless the word "about" is explicitly recited.

[0026] Unless otherwise explained, 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 pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0027] When depicting or describing chemical structures, unless expressly stated otherwise, all carbons are considered to include hydrogens such that each carbon has a valence of 4. For example, in the structure on the left of the following schematic, the presence of 9 hydrogen atoms is implied. In the structure on the right, 9 hydrogen atoms are depicted. [ka]

[0028] Certain atoms within a structure may also be designated by a string of letters, such as -CHCH-, to refer to them as having a hydrogen or hydrogen atom. Those skilled in the art will appreciate that the notation described above is common in the chemical arts as a concise and simple way to represent organic structures.

[0029] The R group is not "fixed" to the ring system, for example, R in the group 1 [ka] Unless otherwise specified, when written as 1 ) is expressed as the symbol [ka] It may be located on any atom of the fused bicyclic ring system except the atom bearing the bond with .

[0030] The R group may be present on a ring system containing saturated carbons, for example, [ka] In this example, y can be greater than 1, assuming replacement of each hydrogen on the ring that is then depicted, implied, or explicitly defined; in that case, unless otherwise specified, two Rs can be located on the same carbon. A simple example is when R is a methyl group. In the depicted structure, it can also exist as a geminal dimethyl on the depicted ring carbon (an "annular" carbon). In another example, two Rs on the same carbon can be included in the ring, including that carbon, thus forming a spiro ring (a "spirocyclic" group) structure.

[0031] As used herein, the term "substituted" refers to any modifier that follows a word, such as "substituted aryl C 1~8 The word "alkyl" is "C 1~8 "Alkyl" moiety, "aryl" moiety or aryl C 1~8 Substitution can occur on both positions of the alkyl group.

[0032] When "substituted" is used to modify a particular group or moiety, it means that at least one hydrogen atom, and optionally two or more hydrogen atoms, of that particular group or moiety have been independently replaced with the same or different substituents, as defined below. In certain embodiments, a group, moiety, or substituent may be substituted or unsubstituted unless expressly defined as either "unsubstituted" or "substituted." Thus, any of the groups defined herein may be substituted or unsubstituted unless the context suggests otherwise or a specific structural formula excludes substitution. In certain embodiments, a substituent may or may not be expressly defined as substituted, but is still considered to be optionally substituted. For example, an "aliphatic" moiety or a "cyclic" moiety may be substituted or unsubstituted, but an "unsubstituted aliphatic" or an "unsubstituted cyclic" is not substituted.

[0033] A "substituent" or "substituent group" that replaces one or more hydrogen atoms on a saturated carbon atom of a particular group or moiety is represented by the radical -R, unless otherwise specified. 60 , halo, =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, and R 60 is C 1~10 Aliphatic, heteroaliphatic or alicyclic, typically C 1~6 Aliphatic, more typically C 1~6 alkyl, and R 60 may be optionally substituted; each R 70 is, independently in each occurrence, hydrogen or R 60 and each R 80 are, in each case independently, R 70 or alternatively, two R 80 The groups, together with the nitrogen atom to which they are attached, form a 3- to 7-membered aliphatic heterocycle optionally containing 1 to 4 identical or different additional heteroatoms selected from O, N and S, of which N is optionally selected from R 70 each M + is a counterion with a net positive charge. + is, independently in each case, for example, an alkali metal ion, e.g., K + , Na + Or Li + ammonium ions, e.g. + N(R 60 ) 4; protonated amino acid ions, such as lysine or arginine ions; or alkaline earth metal ions, 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 to such a divalent alkaline earth metal ion may be the ionized form of a compound of the invention, and the other may be a typical counterion such as chloride, or that a two-ionized compound may serve as the counterion to such a divalent alkaline earth ion, or that a doubly ionized compound may serve as the counterion to such a divalent alkaline earth ion.) Specific examples include -N(R 80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, N-methyl-piperazin-1-yl, N-morpholinyl, etc. Any two hydrogen atoms on a single carbon can be replaced by, for example, =O, =NR 70 , =N-OR 70 , =N2 or =S.

[0034] A substituent replacing a hydrogen atom on an unsaturated carbon atom of a group containing an unsaturated carbon is -R unless otherwise specified. 60 , halo, -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 and R 60 , R 70 , R 80 and M + is as defined above. In an independent embodiment, the substituent is -O - M + , -OR 70 , -SR 70 or -S - M + isn't it.

[0035] The substituent replacing the hydrogen atom on the nitrogen atom of such a nitrogen-containing group is, unless otherwise specified, -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 , -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 and R 60 , R 70 , R 80 and M + is synonymous with the above.

[0036] In one embodiment, a substituted group has at least one substituent up to the number of substituents possible for that particular moiety, for example, 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

[0037] Also, in embodiments where a group or moiety is substituted with substituted substituents, the nesting of such substituted substituents is limited to three, thereby preventing polymer formation. Thus, in a group or moiety that includes a first group that is a substituent on a second group (which is itself a substituent on a third group attached to the parent structure), the first (outermost) group can only be substituted with unsubstituted substituents. For example, in a group that includes -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can itself only be substituted with unsubstituted substituents.

[0038] Any of the groups or moieties defined herein can be attached to any other site on the disclosed structures (e.g., parent or core structures) as understood by one of ordinary skill in the art, e.g., by considering valence rules and / or by considering degree of functionality relative to the illustrated species of compounds, unless it is expressly stated or implied by context that the group or moiety is attached to another site on the structure.

[0039] "Acyl" refers to the group -C(O)R, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl). Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)Ci-C6 alkyl, -C(O)Ci-C6 haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0040] "Aliphatic" refers to a group or moiety that is substantially hydrocarbon-based. Aliphatic groups or moieties can be in their acyclic form, including alkyl, alkenyl, or alkynyl groups (including alkylene, alkenylene, or alkynylene groups), or in their cyclic form (such as alicyclic groups or moieties, including cycloalkyl, cycloalkenyl, or cycloalkynyl), and further include straight-chain and branched-chain configurations and all stereo- and positional isomers. Aliphatic groups, unless expressly stated otherwise, contain from 1 to 25 carbon atoms (C 1~25 For example, in the case of an acyclic aliphatic group or moiety, 1 to 15 (C 1~15 ), 1~10 pieces (C 1~10 ), 1~6 pieces (C 1~6 ) or 1 to 4 (C 1~4 ) carbon atoms, or in the case of an alicyclic group or moiety, 3 to 15 (C 3~15 ), 3~10 pieces (C 3~10 ), 3~6 pieces (C 3~6 ) or 3 to 4 (C 3~4 ) carbon atoms. An aliphatic group can be substituted or unsubstituted, unless expressly referred to as "unsubstituted aliphatic" or "substituted aliphatic." An aliphatic group can be substituted with 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 of the aliphatic chain, or up to one substituent for the carbon of the terminal methine group).

[0041] "Lower aliphatic" refers to a group of 1 to 10 carbon atoms (C 1~10 ), for example, 1 to 6 (C 1~6 ) or 1 to 4 (C 1~4 ) carbon atoms; in the case of a lower alicyclic group, 3 to 10 (C 3~10 ), for example, 3 to 6 (C 3~6 ) refers to an aliphatic group containing carbon atoms.

[0042] "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group. In certain instances, R is C 1~6 Alkyl group or C 3~6and cycloalkyl groups. Exemplary alkoxy groups are methoxy (-OCH3) and ethoxy (-OCH2CH3). In substituted alkoxy, R is substituted alkyl or substituted cycloalkyl, examples of which in the compounds disclosed herein include haloalkoxy groups such as -OCF2H.

[0043] "Alkoxyalkyl" refers to the group -alkyl-OR where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group; an exemplary alkoxyalkyl group is -CH2CH2-O-CH2CH3.

[0044] "Alkyl" means a group having 1 to at least 25 (C 1~25 ) carbon atoms, more typically 1 to 10 (C 1~10 ) carbon atoms, e.g., 1 to 6 (C 1~6 (--) carbon atoms. The alkyl portion can be substituted or unsubstituted. This term includes, for example, straight-chain and branched hydrocarbyl groups such as methyl (CH), ethyl (-CHCH), n-propyl (-CHCHCH), isopropyl (-CH(CH)), n-butyl (-CHCHCHCH), isobutyl (-CHCH(CH)), sec-butyl (-CH(CH)(CHCH), t-butyl (-C(CH)), n-pentyl (-CHCHCHCHCHCH), and neopentyl (-CHC(CH)).

[0045] "Amino" refers to the group -NH, -NHR, or -NRR, where each R is independently selected from H, aliphatic, heteroaliphatic, aromatic (including both aryl and heteroaryl), or heterocycloaliphatic, or two R groups taken together with the nitrogen to which they are attached form a heterocycle. An example of such a heterocycle is when two R groups taken together with the nitrogen to which they are attached form: [ka] group (in the formula, R g is R 70, -C(O)R 70 , -C(O)OR 60 or -C(O)N(R 80 )2) is -O- or -N(R g Optionally interrupted by one or two heteroatom groups such as —(CH) 2~5 Examples include those that form a ring.

[0046] "Amido" refers to an -N(R) acyl group, where R is hydrogen, heteroaliphatic, or aliphatic, e.g., alkyl, especially C 1~6 It is alkyl.

[0047] "Aromatic," unless otherwise specified, refers to a conjugated cyclic group or moiety having 5 to 15 ring atoms, either a single ring (e.g., phenyl, pyridinyl, or pyrazolyl) or multiple fused rings in which at least one ring is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl), i.e., at least one ring, optionally multiple fused rings, has a contiguous, delocalized π-electron system. Typically, the number of out-of-plane π-electrons follows Hückel's rule (4n+2). The point of attachment to the parent structure is typically through the aromatic portion of the fused ring system. Examples are shown below. [ka]

[0048] However, in certain instances, context, or explicit disclosure, the point of attachment may also be suggested to be via the non-aromatic portion of the fused ring system, for example: [ka] An aromatic group or moiety can contain only carbon atoms in the ring, such as, for example, an aryl group or moiety, or it can contain one or more ring carbon atoms and one or more ring heteroatoms (e.g., S, O, N, P, or Si) having an unshared pair of electrons, such as, for example, a heteroaryl group or moiety. Unless otherwise specified, an aromatic group can be substituted or unsubstituted.

[0049] "Aryl," unless otherwise specified, refers to an aromatic carbocyclic group having 6 to 15 carbon atoms, either having a single ring (e.g., phenyl) or having multiple condensed rings in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, and the like). If any portion of the aromatic ring contains a heteroatom, the group is heteroaryl and not aryl. Aryl groups can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, aryl groups can be substituted or unsubstituted.

[0050] "Arylaliphatic" refers to an aryl group that is attached to its parent through an aliphatic moiety. Arylaliphatic groups include aralkyl or arylalkyl groups, such as benzyl and phenylethyl.

[0051] "Carboxyl" refers to -CO2H.

[0052] "Carboxamido" refers to --C(O)amino.

[0053] "Carboxyl ester" or "carboxy ester" refers to the group --C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0054] "Carboxylate" is -C(O)O - Or its salt.

[0055] "Cyano" refers to the radical -CN.

[0056] "Alicyclic" refers to a cycloaliphatic group having a single ring (e.g., cyclohexyl) or multiple rings, such as fused, bridged, or spirocyclic systems, where the ring or at least one of the rings in the system is aliphatic. Typically, the point of attachment to the parent structure is through the aliphatic portion of the multiple ring system. Alicyclic encompasses saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. Alicyclic groups can contain 3 to 25 carbon atoms; e.g., 3 to 15, 3 to 10, or 3 to 6 carbon atoms. Unless otherwise specified, alicyclic groups can be substituted or unsubstituted. Exemplary alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0057] "Halo", "halide" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0058] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CHF, -CHF, and -CF.

[0059] "Heteroaliphatic" refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., an aliphatic compound or group containing at least two carbon atoms, in which at least one carbon atom is replaced by an atom having at least one unshared electron pair, typically nitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroaliphatic compounds or groups can be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic, such as a heteroaliphatic group.

[0060] "Heteroaryl," unless otherwise specified, refers to an aromatic group or moiety having 5 to 15 ring atoms and having at least one carbon atom and at least one heteroatom, such as N, S, O, P, or Si. A heteroaryl group or moiety can contain a single ring (e.g., pyridinyl, pyrimidinyl, or pyrazolyl) or multiple condensed rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). A heteroaryl group or moiety can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, a heteroaryl group or moiety can be substituted or unsubstituted.

[0061] "Heterocyclyl," "heterocyclo," and "heterocycle" refer to both aromatic and non-aromatic ring systems, and more specifically to stable 3- to 15-membered ring moieties containing at least one carbon atom, typically multiple carbon atoms, and at least one, e.g., 1 to 5, heteroatoms. The heteroatom may be a nitrogen, phosphorus, oxygen, silicon, or sulfur atom. A heterocyclyl moiety may be a monocyclic moiety or may contain multiple rings, such as a bicyclic or tricyclic ring system, e.g., when at least one ring contains a heteroatom. Polycyclic moieties of this type may include spirocyclic systems, as well as fused or bridged ring systems; any of the nitrogen, phosphorus, carbon, silicon, or sulfur atoms of the heterocyclyl moiety may be optionally oxidized to various oxidation states. For convenience, references to nitrogens, particularly (but not limited to) nitrogens in aromatic rings, are meant to encompass their corresponding N-oxide forms, even if not explicitly defined as such in specific examples. Thus, for example, in the case of a compound having a pyridinyl ring, the corresponding pyridinyl-N-oxide is included as another compound of the present invention, unless expressly excluded or excluded by context. In addition, the nitrogen atom in the ring can be optionally quaternized. Heterocycles include heteroaryl moieties and heteroalicyclic or heterocyclic aliphatic moieties, which are partially or fully saturated heterocycles.Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, and quinoxalinyl. , quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl , pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphosphoranyl, and oxadiazolyl.

[0062] "Hydroxyl" refers to the group --OH.

[0063] "Nitro" refers to the -NO2 group.

[0064] "Phosphate" refers to the group -OP(O)(OR')2, where each -OR' is independently -OH; -O-aliphatic, e.g., -O-alkyl or -O-cycloalkyl; -O-aromatic (including both -O-aryl and -O-heteroaryl); -O-aralkyl; or -OR' is -O - M + and M + is a counter ion with a single positive charge. + is an alkali ion, e.g., K + , Na + , Li + ammonium ions, e.g. + N(R")4, where R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or alkaline earth metal ions, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 or [Ba 2+ ] 0.5 The phosphonooxyalkyl can be an alkyl-phosphate group, such as —CH2OP(O)(OH)2 or a salt thereof (e.g., —CH2OP(O)(O - Na + )2), and the like, and (((dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ester of a phosphonooxyalkyl group (e.g., —CH2OP(O)(O-tert-butyl)2, and the like).

[0065] "Phosphonate" refers to the group -P(O)(OR')2, where each -OR' is independently -OH; -O-aliphatic, e.g., -O-alkyl or -O-cycloalkyl; -O-aromatic, (including both -O-aryl and -O-heteroaryl); or -O-aralkyl; or -OR' is -O - M + and M + is a counter ion with a single positive charge. + is a positively charged counter ion, for example, an alkali metal ion, e.g., K + , Na + , Li + ammonium ions, e.g.+ N(R")4, where R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or alkaline earth metal ions, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 or [Ba 2+ ] 0.5 A phosphonoalkyl can be an alkyl-phosphonate group, such as —CHP(O)(OH) or —CHP(O)(O - Na + )2 and the like, and ((dialkoxyphosphoryl)alkyl) refers to a dialkyl ester of a phosphonoalkyl group, such as -CH2P(O)(O-tert-butyl)2 and the like.

[0066] "Patient" or "subject" refers generally to any living organism, but more typically to mammals and other animals, particularly humans. Thus, the disclosed methods are applicable to both human therapy and veterinary applications.

[0067] A "pharmaceutically acceptable excipient" refers to a substance other than the active ingredient contained in a composition containing the active ingredient. As used herein, an excipient may be incorporated within or physically mixed with the particles of the pharmaceutical composition. The excipient may be used, for example, to dilute the active agent and / or modify the properties of the pharmaceutical composition. The excipient may include, but is not limited to, an anti-adherent, a binder, a coating, an enteric coating, a disintegrant, a flavoring agent, a sweetener, a coloring agent, a lubricant, a glidant, a sorbent, a preservative, a carrier, or a solvent. The excipient may be starch and modified starch, cellulose 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 additives include, but are not limited to, magnesium stearate, stearic acid, vegetable stearic acid, sucrose, lactose, starch, hydroxypropyl cellulose, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or wool fat.

[0068] An "adjuvant" is an ingredient that modifies the effect of another agent, typically an active ingredient. Adjuvants are often agents that have pharmacological and / or immunological effects. Adjuvants can modify the effect of an active ingredient by augmenting the immune response. Adjuvants can also act as stabilizers for the formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, surfactants, cytokines, paraffin oil, and adjuvant combinations, such as complete Freund's adjuvant or incomplete Freund's adjuvant.

[0069] "Pharmaceutically acceptable carrier" refers to an additive that is a carrier or solvent, such as a suspending aid, a solubilizing aid, or an aerosolizing aid. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21 st Edition (2005), incorporated herein by reference, describes exemplary compositions and formulations suitable for the pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0070] Generally, the nature of the carrier will depend on the particular mode of administration being employed. For example, parenteral formulations usually contain a pharmaceutically and physiologically acceptable fluid, such as an injectable fluid, such as water, physiological saline, balanced salt solution, aqueous dextrose, glycerol, or a solvent. In some cases, the pharmaceutically acceptable carrier can be sterilized to make it suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to a biologically neutral carrier, the administered pharmaceutical composition may contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, and the like, such as sodium acetate or sorbitan monolaurate.

[0071] "Pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of compounds derived from various organic and inorganic counterions, as known to those skilled in the art, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, where the molecule contains a basic functional group, includes salts of organic or inorganic acids, such as hydrochloride, bromate, tartrate, mesylate, acetate, maleate, oxalate, etc. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed with the corresponding acid but retain the biological effectiveness of the free base. In particular, the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, and the like. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" and are derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. 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 primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, e.g., SM 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 a formate, trifluoroacetate, hydrochloride, or sodium salt.

[0072] An "effective amount," with respect to a compound or pharmaceutical composition, refers to the amount of the compound or pharmaceutical composition sufficient to achieve a specific desired result, such as inhibiting a protein or enzyme. In certain embodiments, an "effective amount" is an amount sufficient to inhibit RIP1; to induce a desired biological or medical response in a tissue, system, subject, or patient; to treat a specified disorder or disease; to alleviate or eradicate one or more of its symptoms; and / or to prevent the onset of a disease or disorder. The amount of compound that constitutes an "effective amount" can vary depending on the compound, the desired result, the state of the disease and its severity, the size, age, and sex of the patient being treated, etc., as will be understood by those skilled in the art.

[0073] A "prodrug" refers to a compound that is converted in vivo to a biologically active compound or a compound that is more biologically active than the parent compound. In vivo conversion may occur, for example, by hydrolysis or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of the compound where the activated form bears a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the invention include, but are not limited to, esters of a phosphate group and a carboxylic acid, such as aliphatic esters, particularly alkyl esters (e.g., C 1~6 Other prodrug moieties include phosphate esters, such as -CH2-OP(O)(OR')2 or salts thereof, where R' is H or C1~6

[0033] Further acceptable esters include cycloalkyl esters and arylalkyl esters, such as, but not limited to, benzyl. Examples of pharmaceutically acceptable amides of the compounds of the present invention include, but are not limited to, primary amides and secondary and tertiary alkyl amides (e.g., those having from about 1 to about 6 carbon atoms). Amides and esters of the disclosed exemplary embodiments of the compounds of the present invention can be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0074] "Solvate" refers to a complex formed when solvent molecules combine with solute molecules or ions. 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. The compounds described herein can exist in unsolvated and solvated forms when combined with pharmaceutically acceptable or non-acceptable solvents, such as water and ethanol. Solvated forms of the disclosed compounds are encompassed within the scope of the embodiments disclosed herein.

[0075] "Sulfonamido" refers to a -SO2 amino or -N(R) sulfonyl group or moiety, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0076] "Sulfanyl" refers to an -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic, (including both -S-aryl and -S-heteroaryl) group or moiety.

[0077] "Sulfinyl" refers to a -S(O)H, -S(O)aliphatic, -S(O)heteroaliphatic, or -S(O)aromatic (including both -S(O)aryl and -S(O)heteroaryl) group or moiety.

[0078] "Sulfonyl" refers to a -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including both -SO2aryl and -SO2heteroaryl) group.

[0079] As used herein, "treating" or "treatment" refers to treating a disease or condition of interest in a patient or subject, particularly a human having the disease or condition of interest, including, but not limited to: (i) Preventing the occurrence of a disease or condition in a patient or subject, particularly where such patient or subject has a predisposition to the condition but has not yet been diagnosed as having it; (ii) inhibiting a disease or condition, e.g., halting or slowing its progression; thing; (iii) alleviating the disease or condition, e.g., causing the symptoms to diminish or the disease or condition or its symptoms to regress; or (iv) stabilizing the disease or condition Examples include:

[0080] As used herein, the terms "disease" and "condition" may be used interchangeably, but may differ in that a particular disorder or condition may not have a known causative agent (and thus the etiology is yet to be determined) and is therefore merely an undesirable condition or syndrome not yet recognized as a disease, although a more or less specific set of symptoms may have been identified by clinicians.

[0081] The definitions set forth above and the general formulae set forth below are not intended to encompass impermissible substitution patterns (e.g., methyl substituted with five fluoro groups), which would be readily recognized by one of ordinary skill in the art.

[0082] Those of skill in the art will understand that compounds may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may contain one or more asymmetric centers and / or double bonds and, as a result, may exist as stereoisomers, e.g., double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, e.g., racemic mixtures. As another example, certain disclosed compounds may exist in several tautomeric forms, such as the enol form, the keto form, and mixtures thereof. While the various compound names, formulas, and compound diagrams in the specification and claims may represent only one of the possible tautomers, conformational isomers, optical isomers, or geometric isomers, those of skill in the art will understand that the disclosed compounds also encompass any tautomers, conformational isomers, optical isomers, and / or geometric isomers of the compounds described herein, as well as mixtures of these various different isomers. Mixtures of different isomers, such as mixtures of enantiomers and / or stereoisomers, can be separated using techniques known to those skilled in the art to obtain each separate enantiomer and / or stereoisomer, particularly with the benefit of the present disclosure. For example, when rotation about an amide bond or between two directly bonded rings, such as a pyridinyl ring and a biphenyl group, is restricted, atropisomers are also possible and are likewise specifically encompassed by the compounds of the present invention.

[0083] In any embodiment, any hydrogen present in a compound or in a particular group or portion of a compound can be replaced with deuterium or tritium. Thus, when alkyl is referred to, deuterated alkyl is also included, where one to the maximum number of hydrogens present can be replaced with deuterium. For example, ethyl can be C2H5 or C2H5 in which one to five hydrogens have been replaced with deuterium, e.g., C2D x H 5-x Refers to...

[0084] II. RIP1 Active Compounds and Pharmaceutical Compositions Comprising RIP1 Active Compounds A. Compound Disclosed herein are compounds useful for inhibiting RIP1 and / or treating diseases and / or conditions associated with RIP1, as well as pharmaceutical compositions comprising such compounds. In some embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds have the ability to selectively inhibit RIP1 relative to RIP2, RIP3, or both RIP2 and RIP3. In some embodiments, the disclosed compounds have the formula I [ka] or a pharmaceutically acceptable salt thereof. Those skilled in the art will recognize that the generic formulas disclosed herein encompass within their scope all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes and / or prodrugs of the compounds (having, except for the structural characteristics required by such formulas).

[0085] In Formula I, Ring B is a 5- or 6-membered heteroaryl; L is a heteroatom or R a where R a is not H or D; Z is C 1~10 Aliphatic (e.g., C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl or C3~6 cycloalkyl); or [ka] and; R 1 is a halogen, -C≡CH or -linker -R 6 group, and the linker is R a where R a is not H or D, and R 6 is R b , -C(R f )3 or -C(R f )=C(R f )2; R 2 and R 3 are independently, R a and; R 4 and R 5 are independently, R e and; R a is independently in each occurrence H or D (L is R a C 1~10 Aliphatic (e.g., C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl or C 3~6 cycloalkyl), C 1~10 Haloaliphatic, C 5~10 Aromatic or C 3~6 It is a heterocyclic ring; R b is, independently in 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 and; R c are, in each case independently, C 1~10 Alkyl (which can be one, two or three R e (which may be substituted with), C 2~10Alkenyl (which is one, two or three R e (which may be substituted with), C 2~10 Alkynyl (which is a group consisting of 1, 2, or 3 R e (which may be substituted with), C 3~6 Cycloalkyl (which can be one, two, or three R e (which may be substituted with) or C 5~10 Aromatic (which means that one, two or three R e (which may be replaced by); R d are, independently in each case, H;C 1~6 Alkyl (which can be one, two or three R e can be substituted with);C 3~6 Cycloalkyl (which can be one, two, or three R e can be substituted with);C 3~6 Heterocycles (which may contain one, two or three R e can be substituted with);C 5~10 Aryl (which can be one, two, or three R b can be substituted with);C 5~10 Heteroaryl (which can be one, two, or three R e or two R d The groups, together with the nitrogen to which they are attached, form a C 3~9 Heterocycles (which may be one or more R e (which may be substituted with) or C 5~10 Heteroaryl (which may be one or more R e (which may be replaced by); R e is, independently in each occurrence, a 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 are, in each case independently, R a , R b or R e or two R fThe groups, together with the carbon atoms to which they are attached, form a C 3~6 A cycloalkyl group (which may be one or more R e (which may be substituted with) or C 3~10 Heterocycles (which may be one or more R e (which may be replaced by); m is 1 to 4, e.g., 1, 2, 3, or 4, and in certain embodiments, 1 or 2; n is 0, 1 or 2; and p is 0, 1, 2, 3, 4 or 5.

[0086] In some embodiments, compounds of the present disclosure have formula IA [ka] or a pharmaceutically acceptable salt thereof. Those skilled in the art will understand that the generic formulae disclosed herein encompass within their scope all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes and / or prodrugs (having, except for the structural characteristics required for such formulae).

[0087] In formula IA: Ring B is a 5- or 6-membered heteroaryl; L is a heteroatom or R a where R a is not H or D; R 1 is a halogen, -C≡CH or -linker -R 6 group, and the linker is R a where R a is not H or D, and R 6 is R b , -C(R f )3 or -C(R f )=C(R f )2; R 2 and R 3 are independently, R a and; R 4and R 5 are independently, R e and; R a is independently in each occurrence H or D (L is R a C 1~10 Aliphatic (e.g., C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl or C 3~6 cycloalkyl), C 1~10 Haloaliphatic, C 5~10 Aromatic or C 3~6 It is a heterocyclic ring; R b is, independently in 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 and; R c are, in each case independently, C 1~10 Alkyl (which can be one, two or three R e (which may be substituted with), C 2~10 Alkenyl (which is one, two or three R e (which may be substituted with), C 2~10 Alkynyl (which is a group consisting of 1, 2, or 3 R e (which may be substituted with), C 3~6 Cycloalkyl (which can be one, two, or three R e (which may be substituted with) or C 5~10 Aromatic (which means that one, two or three R e (which may be replaced by); R d are, independently in each case, H;C 1~6 Alkyl (which can be one, two or three R e can be substituted with);C 3~6 Cycloalkyl (which can be one, two, or three R e can be substituted with);C 3~6 Heterocycles (which may contain one, two or three R ecan be substituted with);C 5~10 Aryl (which can be one, two, or three R b can be substituted with);C 5~10 Heteroaryl (which can be one, two, or three R e or two R d The groups, together with the nitrogen to which they are attached, form a C 3~9 Heterocycles (which may be one or more R e (which may be substituted with) or C 5~10 Heteroaryl (which may be one or more R e (which may be replaced by); R e is, independently in each occurrence, a 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 are, in each case independently, R a , R b or R e or two R f The groups, together with the carbon atoms to which they are attached, form a C 3~6 A cycloalkyl group (in some embodiments, C 3~6 A cycloalkyl group can be one or more R e substituted with) or C 3~10 Heterocycles (in some embodiments, C 3~10 A heterocyclic group can be one or more R e (which is replaced by ); m is 1 to 4, e.g., 1, 2, 3, or 4, and in certain embodiments, 1 or 2; n is 0, 1 or 2; and p is 0, 1, 2, 3, 4 or 5.

[0088] In certain embodiments of formula I or IA, the 5-membered heteroaryl group is of the formula [ka] wherein at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In some embodiments, the five-membered heteroaryl group is a diazole, triazole, oxadiazole, or oxazole. Exemplary triazoles include any of the following: [ka]

[0089] Exemplary diazoles are selected from any of the following: [ka]

[0090] Exemplary oxazoles are selected from any of the following: [ka]

[0091] Exemplary oxadiazoles are selected from any of the following: [ka]

[0092] In certain embodiments of formula I or IA, L is oxygen or R a and R a is C1-C4 alkyl, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, L is -CH2- or oxygen.

[0093] R 1 Linker-R 6 If R 1The linker group of the group is a C1, C2, C3, or C4 aliphatic group, such as a C2 alkyl, alkenyl, or alkynyl group, or a C1, C2, C3, or C4 haloaliphatic group, such as a C2 haloalkyl or haloalkenyl group. 1 The linker group in R a and R a is a C1-C4 alkyl, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-; or the linker group is a C2-C4 alkenyl, such as -CH=CH-, -CH=CHCH2-, -CH2CH=CH-, or -CH2CH=CHCH2-; or the linker group is a C2-C4 alkynyl, such as -C≡C-, -C≡CCH2-, -CH2C≡C-, or -CHC≡C-CH2-. In some embodiments, the linker group is a C2-C4 haloalkenyl, such as -CF=CH-, -CCl=CH-, -CH=CCl-, -CH=CF-, -CCl=CCl-, -CF=CF-, or -CCl=CF-, -CF=CCl-. In some embodiments, the linker group is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, -CCl=CH-, -CH=CCl-, or -C≡C-.

[0094] In some embodiments, R 1 R 6 The group is C(R f )3 and 1 R f is R e and R e -OR a (e.g., hydroxyl or OMe), and each other R f are independently, R a and R a is C 1~4 aliphatic, preferably other R f are R a and R a are, in each case independently, C 1~4 In certain embodiments, each other R f is Ra and R a is methyl or CD3. In some further embodiments, R 6 is -C(R f )3, and each R f is R a and R a is methyl or H, or each R f is R a and R a is methyl or R b and R b is -C(O)OR c In some further embodiments, one R f is R e and -OR a (e.g., hydroxyl or OMe), and the other two R f The groups, together with the carbon atoms to which they are attached, provide 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 some such embodiments, the alicyclic and / or heterocyclic groups can be substituted, and some particular embodiments are substituted with one or more hydroxyl or benzylcarbonyl groups.

[0095] Some compound embodiments include C 2~4 In certain embodiments, R 1 -linker-R 6 group, and the linker is R a and R a is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, or -C≡C-, or -CH2C≡C-, and R 6 is R b and R b is —C(O)OEt or —C(O)NR d R d or -NR d R dand R d are, independently in each occurrence, hydrogen, C 5~10 Heteroaryl, C 3~6 cycloalkyl, or both R d The groups, together with the nitrogen atom to which they are attached, provide a heterocyclic group, which is represented by R d The group may further include one or more additional heteroatoms other than the nitrogen atom to which it is attached. d is hydrogen, and other R d is C5 ~10 heteroaryl, which is one or more R e , for example one of the following: [ka] may be substituted with

[0096] R 6 is R b But it's possible, R b is -OH or -OR c and R c is C 1~6 alkyl, and in some embodiments, C 1~6 Alkyl is C such as pyridinyl 5~10 or R c C such as quinolinyl 5~10 heteroaryl or R b is -NR d R d R d are, in each case independently, H, C 5~10 Heteroaryl (in some embodiments, this C 5~10 A heteroaryl group can be one or more R e substituted with two R d The groups, together with the nitrogen to which they are attached, form a C 3~9 Heterocycle (in some embodiments, this C 3~9 The heterocycle may be formed by one or more R e substituted with a group) or C 5~10Heteroaryl (in some embodiments, this C 5~10 Heteroaryl can be one or more R e R e In embodiments having substituents, R e are, in each case independently, C 5~10 Heteroaryl or -OR a and R a is C 1~10 It is alkyl.

[0097] Some compounds have a linker that is a C1 group and an R b is R 6 group, R b is -NR d R d and one R d is H and other R d is pyridinyl, or both R d The groups, together with the nitrogen to which they are attached, form a C 5~10 heteroaryl; or R b is OR c and R c is a C substituted with a pyridinyl group 1~4 In some embodiments, R b teeth, [ka] is.

[0098] In some embodiments, R 1 can be selected from the following: [ka]

[0099] In some embodiments, R 2 and R 3 Each of the following is independently R a and R ais, independently at each occurrence, hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. 2 and R 3 are, in each case independently, R a which is, independently in each occurrence, hydrogen, methyl, or ethyl. In an exemplary embodiment, R 2 is methyl and R 3 is hydrogen.

[0100] In some embodiments, each R 4 are independently, and / or each R 5 are independently, R e and R e is alkyl, alkenyl, alkynyl, chloro, bromo, iodo, or fluoro. 4 and / or each R 5 are independently, R e and R e is lower aliphatic (eg, methyl), fluoro, or chloro.

[0101] In some embodiments, m is 1; n is 0 or 1; and p is 0, 1, or 2. In certain embodiments, m is 1, n is 0, and p is 0, 1, or 2.

[0102] Compounds of formula I or IA may be represented by formulas II and IIA-IIF [ka] In formulas II and IIA to IIF, R 1 and R 5 and each of R is as described above with respect to Formula I and / or IA. In certain embodiments, 0, 1, or 2 R 5 The R group is present. 5 is R e R e is fluoro or chloro. In other particular embodiments, R 5is not present. In formulae IIA to IIF, each W is independently nitrogen or oxygen, particularly nitrogen.

[0103] In some embodiments, the compound of formula I or IA has formula III-VI: [ka] In formulae III to VI, each R 5 can be independently as described above, and in certain embodiments is a lower aliphatic (e.g., methyl) or halogen, such as chloro or fluoro. Similarly, ring B is as described above, and in some embodiments is [ka] is selected from.

[0104] R shown in Formulas III to VI 6 is as described above, and in some embodiments is selected from one of the following: [ka]

[0105] Specific exemplary disclosed compounds falling within the scope of one or more of Formulas I, IA, II, IIA-IIF, and III-VI include those shown below. [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0106] Exemplary compounds encompassed within one or more of Formulas I, IA, II, IIA-IIF, and III-VI include those shown below: 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)propanoate; I-2: (S)—N-(7-(3-((1H-indazol-5-yl)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; I-3: (S)—N-(7-(3-((1H-indazol-6-yl)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; 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)-1H-1,2,4-triazole-3-carboxamide; I-5: ethyl (S)-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)propanoate; I-6: (S)-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)propanoic acid; I-7: (S)—N-(7-(3-((1H-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; I-8: ethyl (S)-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)propanoate; 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; 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)-1H-1,2,4-triazole-3-carboxamide; I-11: (S)-5-benzyl-N-(5-methyl-7-(3-morpholino-3-oxopropyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; I-14: (S)-5-benzyl-N-(7-(3-hydroxypropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-15: (S)-5-benzyl-N-(7-(4-hydroxybutyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; I-24: (S)-5-benzyl-N-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-25: (S)-1-benzyl-N-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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; 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)-1H-1,2,4-triazole-3-carboxamide; 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; 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; 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; 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; 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; 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; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; I-54: (S)-1-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-55: (S)-5-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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-57: (S)-5-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-58: (S)-1-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; I-60: (S)-5-benzyl-N-(7-isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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-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)-1H-1,2,4-triazole-3-carboxamide; 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(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-68: (S)-N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-69: (S)-5-benzyl-N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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; I-72: (S)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; 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)-1H-1,2,4-triazole-3-carboxamide; I-74: (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 benzoate; I-75: 5-benzyl-N-((S)-7-(((3R,3aS,6S,6aR)-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)-1H-1,2,4-triazole-3-carboxamide; I-76: methyl (S)-4-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-ynoate; 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)-1H-pyrazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; I-81: (S)-5-benzyl-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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; 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)-1H-1,2,4-triazole-3-carboxamide; 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; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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)-1H-1,2,4-triazole-3-carboxamide; 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; I-95: (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; 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)-1H-1,2,4-triazole-3-carboxamide; or I-97: (S)-5-benzyl-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0107] In some embodiments, one or more of the compounds can be included in a pharmaceutical composition or medicament, and in some embodiments, the one or more compounds can be in the form of their parent compound or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug. Pharmaceutical compositions typically contain at least one additional component in addition to the one or more disclosed compounds, such as a pharmaceutically acceptable excipient, adjuvant, additional therapeutic agent (described in the following section), or any combination thereof.

[0108] Pharmaceutically acceptable additives may be included in pharmaceutical compositions for various purposes, such as to dilute the pharmaceutical composition for delivery to a subject, to facilitate processing of the formulation, to impart advantageous material properties to the formulation, to facilitate dispersion from a delivery device, to stabilize the formulation (e.g., antioxidants or buffers), to impart a pleasant or palatable taste or consistency to the formulation, etc. Pharmaceutically acceptable additives may include pharmaceutically acceptable carriers.Exemplary additives include, but are not limited to, mono-, di-, 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, diphosphatidylcholine, and lecithin; bulking agents; buffers, such as phosphate and citrate buffers; anti-adherents, such as magnesium stearate; binders, such as sugars (disaccharides, such as sucrose and lactose), polysaccharides (e.g., starch, cellulose, microcrystalline cellulose), cellulose ethers (e.g., hydroxypropyl cellulose), gelatin, synthetic polymers (e.g., polyvinylpyrrolidone, polyalkylene glycols); coatings (e.g., cellulose ethers such as hydroxypropyl methylcellulose, shellac, corn protein zein, and gelatin); release aids ( For example, enteric coatings); disintegrants (e.g., crospovidone, cross-linked sodium carboxymethylcellulose, and sodium starch glycolate); fillers (e.g., dibasic calcium phosphate, vegetable oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavorings and sweeteners (e.g., mint, cherry, anise, peach, apricot, or licorice, raspberry, and vanilla); lubricants (e.g., minerals such as talc or silica, fats such as vegetable stearin, magnesium stearate, or stearic acid); preservatives (e.g., antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids such as cysteine ​​and methionine, citric acid and sodium citrate, parabens such as methylparaben and propylparaben); colorants; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0109] B. Therapeutic Combinations The compounds described herein can be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or adjunctively or in combination with other established therapies. One or more compounds or compositions containing one compound (or compounds) can be administered once or multiple times. In some embodiments, the compounds of the present invention 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 with the disclosed compounds, sequentially in any order, by the same or different routes of administration. When administered sequentially, the compounds and therapeutic agents can be administered such that the duration of effect of at least one compound and therapeutic agent overlaps with the duration of effect of at least one other compound and / or therapeutic agent. In an exemplary embodiment of a combination containing four components, the duration of effect of the first component administered can overlap with the duration of effect of the second, third, and fourth components, but the durations of effect of the second, third, and fourth components may or may not independently overlap with each other. In other exemplary embodiments of combinations comprising four components, the duration of effect of the first component administered overlaps with the duration of effect of the second component but not with the third or fourth; the duration of effect of the second component overlaps with the duration of effect of the first and third components; and the duration of effect of the fourth component overlaps only with that of the third component. In some embodiments, the durations of effect of all compounds and / or therapeutic agents overlap with each other.

[0110] In some embodiments, the compound is administered with other therapeutic agents, such as an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof. The anti-inflammatory agent can be a steroid or a nonsteroidal anti-inflammatory agent. In certain embodiments, the nonsteroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an antilymphocyte globulin, an antithymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0111] In some embodiments, the compounds of the present invention can be used in combination with anticancer or cytotoxic agents. Various classes of anticancer and antineoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and demethylating agents, such as DNMT inhibitors, e.g., azacitidine and decitabine. Exemplary alkylating agents include, but are not limited to, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimine, methylmelamine, alkylsulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, but are not limited to, folic acid analogs such as methotrexate; pyrimidine analogs such as fluorouracil and cytosine albinoside; and purine analogs such as mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkyloids include, but are not limited to, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, but are not limited to, actinomycin D, daunorubicin, and bleomycin. An example of an enzyme effective as an anti-cancer agent includes L-asparaginase. Exemplary coordination compounds include, but are not limited to, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, but are not limited to, the corticosteroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progestin compounds hydroxyprogesterone caproate and medroxyprogesterone; and the anti-estrogen compound tamoxifen. In some embodiments, the compounds of the present invention are used in combination with anti-cancer or cytocidal agents. It is possible.

[0112] These and other useful anticancer compounds are described in The Merck Index, 13th Ed. (O'Neil MJ et al., ed.) Merck Publishing Group (2001) and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Brunton LL ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0113] Among the CTLA 4 antibodies that can be used in combination with the inhibitors disclosed herein is ipilimumab, available commercially from Bristol-Myers Squibb as YERVOY®.

[0114] Other chemotherapeutic agents that may be used in combination include cancer immunotherapeutics, such as PD-1 inhibitors, checkpoint pathway inhibitors such as nivolumab and lambrolizumab, and PD-L1 inhibitors such as pembrolizumab, MEDI-4736, and MPDL3280A / RG7446. Additional checkpoint inhibitors that may be used in combination with the compounds disclosed herein include anti-LAG-3 agents, such as BMS-986016 (MDX-1408).

[0115] Other chemotherapeutic agents that may be used in 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 humanized monoclonal antibody urelumab (BMS-663513).

[0116] The compounds disclosed herein may also be advantageously used in combination with CAR-T therapy. Examples of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

[0117] Examples of other anti-proliferative compounds useful in combination with the compounds of the invention include, but are not limited to, antibodies that target growth factor receptors (e.g., anti-Her2); and cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.

[0118] Other chemotherapeutic agents useful in combination with the compounds of the present invention include proteasome inhibitors such as bortezomib, carfilzomib, and marizomib.

[0119] Examples of kinase inhibitors useful 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 vandetinib; Mek inhibitors, such as trametinib; Raf inhibitors, such as dabrafenib, sorafenib, and vemurafenib. VEGFR inhibitors such as axitinib, lenvatinib, nintedanib, pazopanib; BCR-Abl inhibitors such as bosutinib, dasatinib, imatinib, and nilotinib; FLT-3 inhibitors such as gilteritinib and quizartinib; PI3-kinase inhibitors such as idelalisib; Syk inhibitors such as fostamatinib; and JAK inhibitors such as ruxolitinib and fedratinib.

[0120] In other embodiments, the second therapeutic agent can be selected from any of the following: Painkillers - morphine, fentanyl, hydromorphone, oxycodone, codeine, Cetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone; Antibiotics - aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefazolin, cephalosporins ... ceftizoxime, ceftriaxone, cefepime, and cefobiprole, glycopeptides (e.g., teicoplanin, vancomycin, and telavancin), lincosamides (e.g., clindamycin and incomycin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spectinomycin), monobactams (e.g., aztreonam), nitrofurans (e.g., furazolinone), penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), combined penicillin preparations (e.g., amoxicillin / clavulanic acid, ampicillin / sulbactam, piperacillin / tazobactam, ticarcillin / clavulanic acid), polypeptides (e.g., bacitracin, colistin, and polymyxin), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide, sulfonamide chrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole,trimethoprim and trimethoprim-sulfamethoxazole), tetracyclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), 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 timidazole; Antibodies - anti-TNF-α antibodies such as infliximab (Remicade™), adalimumab, golimumab, certolizumab; anti-B cell antibodies such as rituximab; anti-IL-6 antibodies such as tocilizumab; anti-IL-1 antibodies such as anakinra; anti-PD-1 and / or anti-PD-L1 antibodies such as nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, freticumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab; Anticoagulants - warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrovam, dabigatran, ximelagatran, batroxobin, hementin; Anti-inflammatory agents - steroids such as budesonide, non-steroidal anti-inflammatory agents such as aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin; Immunosuppressants - mercaptopurine, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus, inosine monophosphate dehydrogenase (IMPDH) inhibitors such as mycophenolate, mycophenolate mofetil, and azathioprine, and agents designed to suppress cellular immunity while preserving the recipient's humoral immune response intact, including various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T cell antibody (OKT3)), and radiation). 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 Purinethol; 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 GlaxoSmithKline is available from Kline under the trade name Imuran; antibodies are currently available from Ortho Biotech under the trade name Orthoclone, from Novartis under the trade name Simulect (basiliximab), and from Roche under the trade name Zenapax (daclizumab); and Guanylate cyclase C receptor agonists or intestinal secretagogues, such as linaclotide sold under the name Linzess.

[0121] These various agents may be used according to their standard or conventional doses as prescribed in the package insert accompanying the commercially available form of the drug (see also the package insert in the 2006 edition of The Physician's Desk Reference), the disclosure of which is incorporated herein by reference).

[0122] III. Methods for producing compounds The compounds of the present invention can be prepared by any suitable method, as will be understood by those skilled in the art. One exemplary suitable method is shown in the following examples with reference to specific compounds. This can include a first reaction step according to Scheme 1, as follows: [ka]

[0123] Referring to Scheme 1, the protected amine precursor 100 can be converted to a hydroxy group, "R 6 - R containing a "linker" group 1Coupling with group 102 can provide cross-coupling product 104. In some embodiments, the metal-catalyzed 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 2nd or 3rd generation, PdCl2, Pd(OAc)2, etc.). In some embodiments, the palladium catalyst can be used in conjunction with other co-catalysts, such as CuI, to facilitate the cross-coupling reaction, such as the Sonogashira reaction. The metal-catalyzed 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 group suitable for metal-catalyzed cross-coupling, such as a halogen or triflate group, and PG is an amine protecting group that may be selected from, but is not limited to, a 9-fluorenylmethoxycarbonyl ("Fmoc") group, a t-butyloxycarbonyl ("Boc") group, a trityl ("Tr") group, an allyloxycarbonyl ("Alloc") group, a benzyloxycarbonyl ("Cbz") group, and the like.

[0124] Representative examples of the steps of the process shown in Scheme 1 are shown in the following Schemes 2A-2F. Using methods similar to those shown in Scheme 2A, compounds I-14-I-17 and I-35 can be produced by replacing the propargyl alcohol in Scheme 2A with the corresponding alkyne group to produce compounds I-14-I-17 and I-35, respectively. Further modifications that can be used to arrive at the final structures of compounds I-14-I-17 are described below. [ka] [ka]

[0125] Once cross-coupled product 104 is formed, it can be subjected to an optional linker group reduction step, in which a linker group containing one or more unsaturated sites is reduced to a saturated linker group and / or a linker group with a reduced degree of unsaturation. If a linker reducing group is used, this can be followed by a deprotection step and then an amide formation step, as shown in Scheme 3. Alternatively, if a linker group reduction step is not used, cross-coupled product 104 can be deprotected and converted to amide compound 302. [ka]

[0126] Referring to Scheme 3, an optional linker reduction step can be performed. For example, if the linker contains an unsaturated site (e.g., a double or triple bond), the unsaturated site can be reduced to full saturation (e.g., reducing a double and / or triple bond to a single bond) or to a less unsaturated site (e.g., reducing a triple bond to a double bond). Suitable reagents for performing this type of optional linker reduction step will be recognized by those of skill in the art given the benefit of this disclosure. However, an exemplary set of conditions includes exposing the cross-coupling product 104 to H in the presence of Pd on carbon. Because these steps are optional, they need not be performed in all embodiments. Instead, in some embodiments, the cross-coupling product 104 can be deprotected to provide an amine, which is subsequently converted to amide compound 302 by reaction with a suitable acid, coupling partner 300, as shown in Scheme 3.

[0127] Representative steps of the process shown in Scheme 3 are shown in the following Schemes 4A-4M. Compounds I-14-I-17 can be produced using methods similar to those described in Scheme 4A. Compounds I-16 and I-17 can be further functionalized as described below. [ka] [ka] [ka] [ka] [ka]

[0128] In some embodiments, the method includes further modifying amide compound 302 to form amide compound 500, e.g., by subjecting R 6 Change the group to create a different R 6 The method can further include forming a group. [ka]

[0129] Referring to Scheme 5, R 6 One or more modifications of the groups can be performed. For example, R 6 When R is an ester group, it can be converted to a carboxylic acid or a primary alcohol. While suitable reagents for carrying out this type of optional modification step will be known to those of skill in the art given the benefit of this disclosure, an exemplary set of conditions can be found by reacting R with R as illustrated in the following Schemes 6A-6E. 6This involves exposing the ester group to LiOH to obtain the corresponding acid. The resulting acid can even be further modified with an amine coupling partner under suitable amide coupling conditions (e.g., those described above) to obtain amide-containing products, as shown in Schemes 6A-6E. Similar methods can be used to generate 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 (in which the double bond of the linker group is not first reduced prior to coupling). In yet other embodiments, compounds I-16 and I-17 can be generated by converting the terminal alcohol obtained by the above method to a functionalized alcohol, such as compound I-16, or to an amine, such as compound I-17. [ka] [ka]

[0130] IV. Methods of Use of the Compounds A. Disease / Disorder The disclosed compounds, as well as combinations and / or pharmaceutical compositions thereof, can be used to inhibit RIP1 kinase by contacting the kinase either in vivo or ex vivo with one or more disclosed compounds or compositions comprising one or more disclosed compounds. One or more disclosed compounds or compositions comprising one or more disclosed compounds can also be used to alleviate, treat, or prevent various diseases and / or disorders. In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be useful in treating conditions in which inhibition of RIP1 or inhibition of a pathway involving RIP1 is therapeutically beneficial. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds are useful in treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurological disorders, neurodegenerative diseases, allergic diseases, respiratory diseases, kidney diseases, cancer, ischemic conditions, red blood cell deficiency, lung and brain damage (e.g., caused by ischemia-reperfusion or cisplatin and / or cerebrovascular accidents), and bacterial and viral infections.

[0131] In some embodiments, the disclosed compounds, combinations of 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 1 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' ophthalmopathy, or asthma.

[0132] The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof may also be useful in treating bone marrow-associated immunomodulatory disorders or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunomodulatory disorders that can be treated with the present compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, organ or tissue transplants, transplant-induced graft-versus-host disease, autoimmune syndromes (rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type 1 diabetes, uveitis, posterior uveitis, and the like). , allergic encephalomyelitis, glomerulonephritis, etc.), post-infectious autoimmune diseases (rheumatic fever and post-infectious glomerulonephritis, etc.), inflammatory and proliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal keratoconjunctivitis, bud fever associated with Behçet's disease uveitis, keratitis, herpetic keratitis, keratoconus, corneal epithelial degeneration, corneal leukoplakia, ocular pemphigus, corneal ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada disease, sarcoidosis, hay fever, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular disease due to ischemic disease and thrombosis Injury, ischemic bowel disease, ischemia-reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with 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 anemiaanemia), idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, leukemia chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy or myocardial infarction, scleroderma (including systemic sclerosis), antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, adiposity, eosinophilic Fasciitis, lesions of the gums, periodontium, alveolar bone, dental cementum, glomerulonephritis, male pattern baldness or senile alopecia (by preventing hair loss or promoting hair formation and / or hair regrowth), muscular dystrophy, pyoderma and Sézary syndrome, Addizon disease, ischemia-reperfusion injury occurring during organ preservation, transplantation or ischemic diseases, endotoxin shock, pseudomembranous enterocolitis, drug-induced or radiation-induced enterocolitis, ischemic acute renal failure, chronic renal failure, pulmonary oxygen- or drug-induced intoxication, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, retinal degeneration eczema, retinal detachment, senile macular degeneration, vitreous scar, corneal alkali burn, erythema multiforme, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and altitude sickness, diseases caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune arthritis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock or oxygen deprivation, type B viral hepatitis, non-A non-B hepatitis, liver cirrhosis, Examples of conditions that may be present include alcoholic liver disease (including alcoholic cirrhosis and alcoholic steatohepatitis), non-alcoholic steatohepatitis (NASH), autoimmune hepatobiliary disease, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant hepatitis, delayed-onset liver failure, acute exacerbation of chronic liver failure, chronic kidney disease, kidney damage / injury (e.g., caused by nephritis, kidney transplant, surgery, administration of nephrotoxic drugs, acute kidney injury), enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, psychological trauma, or chronic bacterial infection.

[0133] In certain embodiments, the compounds of the present invention are useful for treating neuralgic pain, including neuropathic pain and inflammation-induced pain.

[0134] In certain embodiments, the compound is used to treat interleukin-1 converting enzyme-associated fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain synthase deficiency syndrome, lysosomal storage diseases (e.g., Gaucher disease, GM2 gangliosidosis, alpha mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, It is useful for the treatment of various conditions, including: rhesus malabsorption, ...

[0135] In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof are useful for the treatment and / or prevention of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, especially pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperglobulinemia and periodic fever syndrome, cryopyrin periodic syndrome, Schnitzler's syndrome, systemic juvenile rheumatoid arthritis, adult-onset Still's disease, gout, gouty attacks, pseudogout, Sapho syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptor antagonist), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0136] Proliferative disorders that can be treated with the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof include benign or malignant tumors of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testes, urogenital tract, esophagus, larynx, skin, bone, or thyroid, solid tumors, carcinomas, sarcomas, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancers, particularly colon cancer or colorectal adenomas, tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, epithelial neoplasms, adenomas, adenocarcinomas, keratoacanthomas, tonsils, thyroid cancers, and the like. squamous cell carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's and non-Hodgkin's, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-induced disorders, disorders caused by MyD88 (including, for example, ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, or chronic lymphocytic leukemia), smoldering or indolent asymptomatic multiple myeloma or hematological malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, ABC and other malignancies, including DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma. In particular, the compounds disclosed herein are useful for treating drug-resistant malignancies, such as ibrutinib-resistant hematological malignancies that have developed resistance to the JAK inhibitor ibrutinib, e.g., ibrutinib-resistant CLL and ibrutinib-resistant Waldenstrom's macroglobulinemia.

[0137] Examples of allergic diseases 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, IgE-mediated atopic bronchial asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiology, essential asthma of unknown or unclear cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, asthma caused by environmental factors, and the like). Examples of asthma include extrinsic asthma caused by or complicated with bacterial, fungal, protozoan or viral infection, cold-induced asthma, occupational asthma, infectious asthma caused by or complicated with bacterial, fungal, protozoan or viral infection, early asthma, wheezing infant syndrome, bronchiolitis, cough-type asthma or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, as well as ethmoid sinusitis, frontal sinusitis, maxillary sinusitis or sphenoid sinusitis.

[0138] As another example, rheumatoid arthritis (RA) typically causes swelling, pain, limited motion, and tenderness in target joints throughout the body. RA is characterized by chronic inflammation of the synovial membrane, where lymphocytes accumulate. The synovial membrane, typically a layer one cell thick, becomes highly cellular and resembles lymphoid tissue, containing populations of dendritic cells, T-, B-, and NK cells, macrophages, and plasma cells. This process, coupled with the overactivity of immunopathological mechanisms, including the formation of antigen-immunoglobulin complexes, ultimately destroys the integrity of the joint, resulting in deformation, permanent loss of function, and / or erosion of bone in or near the joint. The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof, can be used to treat, alleviate, or prevent any one, some, or all of these symptoms of RA. Thus, with respect to RA, a treatment is considered to provide a therapeutic benefit if the compound reduces or alleviates any symptoms commonly associated with RA, regardless of whether the treatment results in concomitant treatment of the underlying RA and / or a reduction in the amount of rheumatoid factor ("RF") in the blood.

[0139] The American College of Rheumatology (ACR) has established criteria for defining improvement and clinical remission in RA. This measure, ACR20 (recognizing a 20% clinical improvement in the ACR criteria), requires a 20% improvement in tender and swollen joint counts, as well as a 20% improvement in three of the following five measures: patient's global assessment, physician's global assessment, patient's pain assessment, physical disability, and acute inflammatory response. These criteria are also extended to ACR50 and ACR70 for 50% and 70% improvement, respectively. Other criteria include Paulu's criteria and radiographic progression (e.g., Sharp score).

[0140] In some embodiments, a therapeutic benefit for a patient with RA is achieved when the patient exhibits an ACR 20. In certain embodiments, an improvement in ACR can achieve an ACR 50 or even an ACR 70.

[0141] B. Formulation and Administration Pharmaceutical compositions containing one or more active compounds of the present invention can be prepared by any suitable method, such as mixing, dissolving, granulating, sugar-coating, mashing, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions can be formulated with one or more physiologically acceptable additives (e.g., diluents, carriers, or adjuvants), one or more adjuvants, or a combination thereof, to obtain pharmaceutically usable preparations.

[0142] The active compound may be formulated in the pharmaceutical composition per se, or in the form of its pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug. Typically, such salts are more soluble in aqueous solution than the corresponding free acids and bases, although salts which are less soluble than the corresponding free acids and bases can also be formed.

[0143] The pharmaceutical compositions of the present invention may be in a form suitable for virtually any mode of administration, such as topical, ocular, oral, buccal, systemic, nasal, parenteral (e.g., intravenous or intraperitoneal), transdermal, rectal, vaginal, or in a form suitable for inhaled or insufflated administration.

[0144] For topical administration, the active compounds, pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs may be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art.

[0145] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, and those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0146] Useful injectable preparations include sterile suspensions, solutions, or emulsions of the active compound in aqueous or oily solvents. Pharmaceutical compositions may also contain formulation aids such as suspending agents, stabilizers, and / or dispersing agents. Injectable preparations may be provided in unit dosage form, for example, in ampoules or in multi-dose containers, and may contain added preservatives.

[0147] Alternatively, the injectable formulations may be provided in powder form for reconstitution with a suitable solvent (including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, etc.) before use. To this end, the active compound can be dried by any known technique, such as lyophilization, and reconstituted prior to use.

[0148] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0149] For oral administration, the pharmaceutical compositions can take the form of, for example, lozenges, tablets, or capsules prepared by conventional means with pharmaceutically acceptable additives such as binders (e.g., pregelatinized maize 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 can be coated, for example, with sugars, films, or enteric coatings by methods well known in the art.

[0150] Liquid preparations for oral administration can take the form of, for example, elixirs, solutions, syrups, or suspensions, or can be provided as a dry product to be constituted with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, 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, oily esters, ethyl alcohol, Cremophore™, or fractionated vegetable oils); and preservatives (e.g., p-hydroxybenzoic acid or methyl or propyl sorbate). The preparations can further contain buffer salts, preservatives, flavoring agents, coloring agents, and sweetening agents, as appropriate.

[0151] Preparations for oral administration can be suitably formulated to give controlled release of the active compound, as is well known.

[0152] For buccal administration, the pharmaceutical compositions can take the form of tablets or lozenges formulated in conventional manner.

[0153] For rectal and vaginal administration routes, the active compounds can be formulated as solutions (for retention enemas), suppositories, or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0154] For nasal administration or administration by inhalation or insufflation, the active compound, pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug can be conveniently delivered in the form of an aerosol spray from a pressurized fill or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbon, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges (e.g., capsules and cartridges comprised of gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0155] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray contains the following ingredients: 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); phenylethanol (1-4 mg / 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 typical pH being about pH 5.5.

[0156] Another specific example of an aqueous suspension suitable for administering a compound by inhalation contains 20 mg / mL of the disclosed compound, 1% (v / v) polysorbate 80 (TWEEN® 80), 50 mM citrate, and / or 0.9% sodium chloride.

[0157] For intraocular administration, the active compound can be formulated into a solution, emulsion, suspension, etc. suitable for intraocular administration. A variety of solvents suitable for intraocular administration of compounds are known in the art. Non-limiting examples are described in U.S. Patent No. 6,261,547; U.S. Patent No. 6,197,934; U.S. Patent No. 6,056,950; U.S. Patent No. 5,800,807; U.S. Patent No. 5,776,445; U.S. Patent No. 5,698,219; U.S. Patent No. 5,521,222; U.S. Patent No. 5,403,841; U.S. Patent No. 5,077,033; U.S. Patent No. 4,882,150; and U.S. Patent No. 4,738,851, which are incorporated herein by reference.

[0158] For sustained delivery of the active compound, it can be formulated as a depot preparation for administration by implantation or intramuscular injection.The active ingredient can be formulated with a suitable polymer or hydrophobic material (for example, as an emulsion in an acceptable oil), or with an ion exchange resin, or as a sparingly soluble derivative, for example, a sparingly soluble salt.Alternatively, a transdermal delivery system can be used, which is manufactured as a circular patch or patch that slowly releases the active compound so that it is absorbed through the skin.For this purpose, a penetration enhancer can be used to promote percutaneous penetration of the active compound. Suitable transdermal patches are described, for example, in U.S. Pat. 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.

[0159] Alternatively, other pharmaceutical delivery systems can be utilized. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compounds. Certain organic solvents such as dimethyl sulfoxide (DMSO) can also be used, although usually at the cost of greater toxicity.

[0160] The pharmaceutical compositions may, if desired, be presented in a pack or dispenser that can contain one or more unit dosage forms containing the active compound. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser may also be accompanied by instructions for administration.

[0161] C. Dosage The disclosed compounds, pharmaceutical compositions, or combinations of disclosed compounds will generally be used in an amount effective to achieve the intended result, e.g., an amount effective to inhibit RIP1 kinase and / or treat, prevent, or alleviate a specific condition. The disclosed compounds or pharmaceutical compositions thereof can be administered therapeutically to achieve a therapeutic effect or prophylactically to achieve a prophylactic effect. A therapeutic effect means eradicating or alleviating the underlying disorder being treated and / or one or more symptoms associated with the underlying disorder, such that the patient reports an improved feeling or condition, regardless of whether the patient may still be afflicted by the underlying disorder. For example, a therapeutic effect is achieved when administering a compound to a patient suffering from an allergy not only eradicates or alleviates the underlying allergic reaction, but also when the patient reports a decrease in the severity or duration of symptoms associated with the allergy after exposure to an allergen. As another example, a therapeutic effect related to asthma may include improved breathing after an asthma attack or a decrease in the frequency or severity of asthma attacks. Benefits of treatment also include halting or slowing the progression of the disease, regardless of whether improvement is realized.

[0162] As known to those skilled in the art, the preferred dosage of the disclosed compounds may depend on various factors, including the age, weight, overall health, and severity of the condition of the patient or subject being treated. The dosage may also need to be adjusted for the individual's gender and / or lung capacity when administered by inhalation. The dosage may also be adjusted for individuals suffering from more than one condition or individuals with additional conditions that adversely affect lung capacity and breathing ability, such as, commonly, emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and respiratory infections. The dosage and frequency of administration of the disclosed compounds or pharmaceutical compositions thereof will also depend on whether the disclosed compounds are prescribed for the treatment of an acute episode of a condition or for the prophylactic treatment of a disorder. Those skilled in the art will be able to determine the optimal dosage for a particular individual.

[0163] In the case of prophylactic administration, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered to patients or subjects at risk of developing one of the above-mentioned conditions. For example, if it is unknown whether a patient or subject is allergic to a particular drug, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered before the drug is administered to avoid or reduce an allergic reaction to the drug. Alternatively, prophylactic administration can be used to avoid or reduce the onset of symptoms in patients diagnosed with an underlying disorder. For example, an allergy patient can be administered the disclosed compounds or pharmaceutical compositions thereof before exposure to an allergen. The disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can also be administered prophylactically to healthy individuals who are repeatedly exposed to a known causative agent of one of the above-mentioned disorders to prevent the onset of the disorder. For example, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered to healthy individuals who are repeatedly exposed to an allergen, such as latex, that is known to induce allergies, in an attempt to prevent the individual from developing the allergy. Alternatively, a patient suffering from asthma can be administered a disclosed compound, a combination of disclosed compounds, or a pharmaceutical composition thereof prior to participating in activities that induce an asthma attack in order to reduce the severity of or completely avoid any asthma symptoms that occur.

[0164] An effective dose can be initially estimated from in vitro testing. For example, the initial dose for use in a subject may be determined based on the IC value of a particular compound determined in in vitro testing, as determined by circulating or serum concentrations of the active compound. 50 or EC 50 The compound can be formulated to reach or exceed a circulating or serum concentration of 100 mg / kg / day. Doses can be calculated to achieve such circulating or serum concentrations, taking into account the bioavailability of the particular compound. Further guidance regarding effective dosages can be found in Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and references cited therein.

[0165] In some embodiments, the EC of the disclosed compounds 50 is greater than 0 to 20 μM, for example, 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.

[0166] The initial dose can also be estimated from in vivo data, such as animal models. Animal models useful for testing the effectiveness of compounds in treating or preventing the various diseases mentioned above are well known in the art. Suitable animal models of hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50 (21Suppl): 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. Those skilled in the art can adapt such information to determine appropriate dosages for administration to humans.

[0167] In some embodiments, a test suitable for determining RIP1 activity can be used. This type of test method can be used to evaluate the efficacy of compound embodiments disclosed herein and / or to determine the amount / dosage of compound embodiments that can provide the desired effect. In some embodiments, the test can be an ADP-Glo™ assay, which evaluates the ability of compound embodiments to inhibit RIP1. In other embodiments, whole-cell assays using mouse and / or human cells, such as U937 and / or L929 cell necroptosis assays, can be performed to determine safe and effective doses of compounds that can be used for in vivo studies. Such whole-cell assays can be used to evaluate the activity of compounds against human and / or mouse RIP1 in in vitro conditions, thereby enabling one of skill in the art to determine safe and effective doses for in vivo use. Yet another test in which compound embodiments described herein can be used to evaluate activity in treating diseases or conditions involving RIP1 is the acute hypothermia mouse model, which evaluates the ability of compounds to inhibit TNF-α-induced hypothermia. Each of these tests and various results obtained using these tests are described in the Examples section of this disclosure.

[0168] Doses of the disclosed compounds will typically be greater than 0 mg / kg / day, e.g., 0.0001 mg / kg / day, or 0.001 mg / kg / day, or in the range of 0.01 mg / kg / day to at least about 100 mg / kg / day. More typically, dosages (or effective amounts) can be administered at least once per day in the range of about 0.0025 mg / kg to about 1 mg / kg, e.g., 0.01 mg / kg to about 0.5 mg / kg, or about 0.05 mg / kg to about 0.15 mg / kg. Total daily doses typically range from about 0.1 mg / kg / day to about 5 mg / kg / day or about 20 mg / kg / day, e.g., 0.5 mg / kg / day to about 10 mg / kg / day, or about 0.7 mg / kg / day to about 2.5 mg / kg / day. Dosages may be higher or lower depending on, among other factors, the activity of the disclosed compound, its bioavailability, the mode of administration, and the various factors noted above.

[0169] Dosage amounts and intervals can be adjusted to provide plasma concentrations sufficient to maintain therapeutic or prophylactic effects of the disclosed compounds in an individual. For example, compounds can be administered once daily, multiple times daily, weekly, multiple times weekly (e.g., every other day), monthly, multiple times monthly, or yearly, depending on, among other things, the mode of administration, the specific target disease being treated, and the judgment of the prescribing physician. One of ordinary skill in the art will be able to optimize effective topical dosages without undue experimentation.

[0170] Pharmaceutical compositions comprising one or more disclosed compounds typically contain greater than 0 to 99% by weight of one or more disclosed compounds and / or other therapeutic agents. More typically, pharmaceutical compositions comprising one or more disclosed compounds contain from about 1 to about 20% by weight of the disclosed compounds and other therapeutic agents in total, and from about 80 to about 99% by weight of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition may further comprise an adjuvant.

[0171] Preferably, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof will exhibit therapeutic or prophylactic effects without significant toxicity. Toxicity of the disclosed compounds can be determined using standard pharmaceutical procedures. The ratio of the dose exhibiting toxic effects to the dose exhibiting therapeutic (or prophylactic) effects is the therapeutic index. Disclosed compounds exhibiting high therapeutic indices are preferred. [Example]

[0172] V. Working Examples Example 1 The disclosed compounds can be prepared as illustrated in the schemes above using a suitable starting compound, such as compound 200 or compound 206. A representative method for producing compound 200 is illustrated in Scheme 7A, and a representative method for producing compound 206 is illustrated in Scheme 7B. [ka] Spectral analysis of 3-(S)-N-trityl-amino-7-bromo-5-methyl-4-oxobenzoxazapine (200): 1 H nmr (400 MHz, CDCl) δ 7.41-7.38 (6H, m, 6H of C(C6H5)3), 7.25-7.15 (10H, m, 9H of oxobenzoxazapine H-8, C(C6H5)3), 7.00 (1H, d, J 2.5 Hz, oxobenzoxazapine H-6), 6.91 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 4.50 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.53 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 3.30 (1H, br s, NH), 2.87 (3H, s, NCH3).

[0173] Characterization data and specific methods of preparation for representative compounds disclosed herein are provided below.

[0174] Example 2 [ka] Synthesis of (S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one: A mixture of bromooxazapine (0.210 g, 0.410 mmol, 1.0 eq), potassium carbonate (0.566 g, 4.101 mmol, 10.0 eq), and copper(I) iodide (0.008 g, 0.041 mmol, 0.1 eq) in dimethylformamide (3.0 mL) was degassed by bubbling argon through it for 5 minutes. 2-Methyl-2-hydroxybut-3-yne (0.052 g, 0.060 mL, 0.615 mmol, 1.5 eq) and tetrakis(triphenylphosphine)palladium (0.024 g, 0.021 mmol, 0.05 eq) were added, and the reaction was sealed and heated in a microwave at 120 °C for 1 h. The reaction was partitioned between EtOAc (80 mL) and water (80 mL). The organics were washed with brine (80 mL), water (80 mL), and brine (80 mL), dried (NaSO), and concentrated under reduced pressure. MPLC (10→80% EtOAc-hexanes) gave the starting material (0.091 g) and the title compound (0.079 g) as a colorless oil. 1 H 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, oxobenzoxazapine H-8), 6.96 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 6.95 (1H, d, J 2.5 Hz, oxobenzoxazapine H-6), 4.48 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.55 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 2.78 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2); m / z: 555 [M+K] + ,243[C(C6H5)3] + .

[0175] [ka] Trityl group deprotection: To a solution of the trityl-protected amine (0.079 g, 0.153 g, 1.0 eq) in dioxane (2.0 mL) was added hydrogen chloride solution (0.15 mL of a 4 M solution in dioxane, 0.614 mmol, 4.0 eq). The reaction was stirred at room temperature for 6 hours and then concentrated to dryness to give a white solid, which was used without further purification. m / z: 275 [M+H] +

[0176] [ka] Synthesis of (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)-1H-1,2,4-triazole-3-carboxamide: To a solution of aminooxobenzoxazapine hydrochloride (0.076 mmol, 1.0 eq) and benzyltriazolecarboxylic acid (0.017 g, 0.084 mmol, 1.1 eq) in dimethylformamide (1.0 mL) was added diisopropylamine (0.025 g, 0.033 mL, 0.190 mmol, 2.5 eq), followed by the addition of HATU (0.032 g, 0.084 mmol, 1.1 eq). The reaction was stirred at room temperature for 4 h and then partitioned between EtOAc-CHCl (5:1, 60 mL) and NaHCO (60 mL). The organics were washed with brine (50 mL), water (50 mL), and brine (50 mL), dried (NaSO), and concentrated under reduced pressure. MPLC (0→10% MeOH-CHCl) afforded the title compound as a white solid. 1H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.30-7.22 (7H, m, 7 × ArH), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.68 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine 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 - HO] + .

[0177] Steps similar to those in Example 2 above can be used to generate compounds I-14, .about.I-17, and I-35.

[0178] Example 3 [ka] 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 eq) in dimethylformamide (8 mL) was degassed by bubbling argon through it for 5 min. Ethyl acrylate (0.270 g, 0.29 mL, 2.70 mmol, 2.0 eq) and triethylamine (0.272 g, 0.37 mL, 2.0 eq) were added, followed by tetrakis(triphenylphosphine) (0.156 g, 0.14 mmol, 0.1 eq). The reaction was sealed and heated in a microwave at 100 °C for 1 h and 120 °C for 1 h. The reaction was partitioned between EtOAc (100 mL) and water (100 mL). The organics were washed with saturated brine (70 mL), water (100 mL), and saturated brine (70 mL), dried (NaSO), and concentrated under reduced pressure. Column chromatography (10→40% EtOAc-hexanes) afforded the title compound (0.250 g, %) as a yellow foam. 1 H nmr(400MHz,CDCl3)δ 7.62(1H,d,J 16.0Hz,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] + .

[0179] [ka] Synthesis of ethyl (S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate: A solution of the α,β-unsaturated ester (0.25 g, 0.64 mmol, 1.0 eq) in ethyl acetate (20 mL) was added to palladium on carbon (0.23 g). The reaction was purged with hydrogen and stirred under a hydrogen atmosphere for 14 hours. The reaction was purged with nitrogen and filtered through Celite®, eluting with ethyl acetate (2 × 20 mL). The filtrate was concentrated under reduced pressure. 1 H 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 7.5Hz,ArCH2CH2CO2H),1.37(9H,s,C(CH3)3),1.23(3H,t,J 7.0Hz,OCH2CH3);m / z:337[M+H-C4H8] + ,293[M+H-CO2-C4H8] +The crude product was dissolved in dichloromethane (10 mL). Hydrogen chloride (0.80 mL of a 4 M solution in dioxane, 3.21 mmol, 5.0 eq). The reaction was stirred at room temperature for 14 hours, after which more hydrogen chloride solution (0.8 mL, 5.0 eq) was added. After stirring for an additional 2 hours, the reaction was concentrated under reduced pressure and dried in vacuo to give a brown solid. The crude product was used without further purification. m / z: 293 [M+H] +

[0180] [ka] Synthesis of ethyl (S)-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)propanoate: Fluorobenzyltriazole (0.116 g, 0.525 mmol, 1.1 eq) was dissolved in ethyl (S)-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)propanoate. To a solution of (dihydrobenzo[b][1,4]oxazepin-7-yl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate (0.140 g, 0.477 mmol, 1.0 eq) and diisopropylethylamine (0.154 g, 0.21 mmol, 2.5 eq) in dimethylformamide (5.0 eq) was added. HATU (0.199 g, 0.525 mmol, 1.1 eq) 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 organics were washed with saturated brine (100 mL), water (100 mL), and saturated brine (100 mL), dried (Na2SO4), and concentrated under reduced pressure. Column chromatography (40→80% EtOAc-hexanes) gave the title compound (0.138 mg) as a white solid. 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 CHF), 7.26-7.07 (6H, m, 2H of CHF, oxobenzoxazapine H-6, H-7, H-8, H-9), 5.42 (2H, s, C H 2C6H4F), 5.08 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.42 (3H, s, NCH3); 13 C nmr(100MHz,CDCl3)δ 168.9,160.6(d,J 248.5Hz),158.3,156.7,150.1,144.1(d,J 2.0Hz),136.0,131.1(d,J 8.5Hz),130.9(d,J 2.5Hz),127.6,125.7,124.9(d,JHz),123.3,123.1,121.2(d,J 14.0Hz),115.8(d,J 21.5Hz),77.3,49.2,47.9(d,J 4.0Hz),35.5; 19 F nmr(380MHz,CDCl3)δ -118.1;m / z:518[M+Na] + ,496[M+H] + (Measured value [M+H] + ,496.1991,C 25 H 26 FN5O5 theoretical value [M+H] + 496.1973).

[0181] Using steps similar to Example 3 above and Examples 4 and 5 below, 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 (in which case the double bond of the linker group is not first reduced prior to coupling) can be produced.

[0182] Example 4 [ka] Synthesis of (S)-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)propanoic acid: To a solution of the ethyl ester (0.103 g, 0.208 mmol, 1.0 eq) in tetrahydrofuran (3 mL) was added aqueous lithium hydroxide (0.017 g, 0.416 mmol, 2.0 eq in 1 mL of water). The reaction was stirred at room temperature for 3 h and then partitioned between EtOAc (80 mL) and NH4Cl (80 mL). The aqueous phase was extracted with EtOAc (2 x 60 mL). The combined organics were washed with saturated brine (80 mL), dried (Na2SO4), and concentrated under reduced pressure. Column chromatography (0→10% MeOH-CH2Cl2) gave the title compound (0.054 g, %) as a white solid. 1 H nmr(400MHz,CDCl3)δ 8.12(1H,s,triazole H-5),8.04(1H,d,J 7.5Hz,NH),7.40-7.30(2H,m,2×ArH),7.16(1H,dd,J 7.5,1.0Hz,1×ArH),7.14-7.10(2H,m,2×ArH),7.07(2H,m,2×ArH),5.43(2H,s,NC H 2C6H5F), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine eH-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 F nmr(CDCl3)δ -118.1(dd,J 16.5,7.0Hz);m / z:468[M+H] + (Measured value [M+H] + ,468.1688,C 23 H 22 FN5O5 theoretical value [M+H] + 468.1678).

[0183] Example 5 [ka] Synthesis of (S)-N-(7-(3-((1H-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide: (S)-3-(3-(1-(2-fluorobenzyl)-1H-1, A solution of 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 eq) and 6-aminoindazole (0.017 g, 0.126 mmol, 1.2 eq) in dimethylformamide (10 mL) was cooled to 0 °C. Diisopropylethylamine (0.027 g, 0.036 mL, 0.210 mmol, 2.0 eq) was added, followed by HATU (0.048 g, 0.126 mmol, 1.2 eq), and the reaction was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction was partitioned between EtOAc (50 mL) and NaHCO (50 mL). The organics were washed with saturated brine (50 mL). The combined aqueous phases were extracted with EtOAc (20 mL). The combined organics were washed with water (50 mL) and saturated brine (50 mL), dried (NaSO), and concentrated under reduced pressure. Column chromatography (0→10% MeOH-CHCl) afforded the title compound (0.xx g, %) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.12 (1H, s, triazole H-5), 8.00 (1H, d, J 7.5 Hz, NH), 7.94 (1H, d, J 0.5 Hz, indazole H-3), 7.90 (1H, s, NH), 7.83 (1H, m, indazole H-7), 7.57 (1H, d, J 9.0 Hz, indazole H-4), 7.37-7.30 (2H, m, 2H of CHF), 7.13 (1H, td, J 7.5, 1.0 Hz, 1H of CHF), 7.09-7.00 (5H, m, indazole H-5, 1H of CHF, 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 C nmr(CDCl3)δ 170.6,168.7,160.7(d,J 248.5Hz),158.8,156.4,148.4,144.4,140.6,138.5,136.3,135.9,134.3,131.2(d,J 8.5Hz),131.0(d,J 3.0Hz),127.5,124.9(d,J 4.0Hz),123.4,122.9,121.1,121.0,120.3,115.8(d,J 20.5Hz),115.3,101.1,77.2,49.1,48.0(d,J 4.0Hz),39.3,35.3,31.1; 19 F nmr(CDCl3)δ -118.0;m / z:583[M+H] + (Measured value [M+H] + ,583.2205,C 30 H 27 FN8O4 theoretical value [M+H] + 583.2212).

[0184] Example 6 [ka] Ethyl (S)-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)propanoate: 1 H nmr (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.96 (1H, s, triazole H-5), 7.42 (2H, m, 2 × ArH), 7.32 (1H, dd, J 9.0, 7.0 Hz, 1 × ArH), 7.10 (1H, m, 1 × ArH), 7.06 (2H, dd, J 6.0, 2.0 Hz, 2 × ArH), 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, oxobenzoxazepine H-2 (1H), 4.14 (2H, q, J 7.0 Hz, OC H 2CH3),3.41(3H,s,NCH3),2.95(2H,t,J 7.5Hz,2H of ArCH2CH2CO),2.63(2H,t,J 7.5Hz,2H of ArCH2CH2CO),1.24(3H,t,J 7.0Hz,OCH2C H 3); 13 C nmr(100MHz,CDCl3)δ 172.5,168.9,158.3,156.5,148.4,143.9,138.4,136.9,135.8,131.4,129.1,128.9,1 27.5,123.2,122.9,77.2,60.6,49.4,49.3,35.7,35.5,30.3,14.2;m / z:548,546[M+H] + (Measured value [M+H] + ,546.1291,C 25 H 25 Cl2N5O5 theoretical value [M+H] + 546.1306).

[0185] Example 7 [ka] (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: 1 H nmr (400 MHz, CDCl3) δ 8.13 (1H, d, J 7.5 Hz, NH), 7.32-7.22 (5H, m, 5 × ArH), 7.08-7.06 (3H, m, 3 × ArH), 4.97 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.62 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.13 (2H, s, C H 2C6H5),3.38(3H,s,NCH3),2.94(2H,m,ArC H 2C H 2CO2H), 2.70 (2H, m, ArC H 2C H 2H of 2CO2H); 19 F nmr(CDCl3)δ -118.1;m / z:450[M+H] + (Measured value [M+H] + ,450.1760,C 23 H 23 N5O5 theoretical value [M+H] + 450.1772).

[0186] Example 8 [ka] (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)-1H-1,2,4-triazole-3-carboxamide: 1H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.29-7.21 (5H, m, 5 × ArH), 7.10-7.07 (3H, m, 3 × ArH), 5.05 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.22 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.15 (2H, s, CH2Ph), 3.45 (2H, t, J 7.0 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(100MHz,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] + (Measured value [M+H] + ,503.2403,C 27 H 30 N6O4 theoretical value [M+H] + 503.2401).

[0187] Example 9 [ka] Synthesis of (S,E)-3-(5-methyl-4-oxo-3-(tritylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)acrylamide: To a mixture of bromooxobenzoxazapine (0.300 g, 0.586 mmol, 1.0 eq) and acrylamide (0.062 g, 0.879 mmol, 1.5 eq) was added dimethylformamide (5 mL), and the mixture was degassed by bubbling argon through it for 5 min. Triethylamine (0.178 g, 0.24 mL, 1.758 mmol, 3.0 eq) was added, followed by X-PhosPd G2 (0.046 g, 0.059 mmol, 0.1 eq). The reaction was sealed and heated in a microwave oven at 120 °C for 1 h. The reaction was partitioned between EtOAc (100 mL) and NaHCO (100 mL). The organics were washed with brine (80 mL), water (100 mL), and brine (80 mL), dried (NaSO), and concentrated under reduced pressure. MPLC (0→10% MeOH-CHCl) afforded the title compound (0.267 g, 91%) as a pale yellow solid. 1 H nmr(400MHz,CDCl3)δ 7.55(1H,d,J 15.5Hz,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 8.5Hz, oxobenzoxazepine H-9), 6.97 (1H,d,J 2.0Hz, oxobenzoxazepine H-6), 6.39 (1H,d,J 15.5Hz, 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] + .

[0188] [ka] Synthesis of (S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanamide: A solution of α,β-unsaturated carboxamide (0.267 g, 0.532 mmol, 1.0 eq) in ethyl acetate-methanol (5:2, 7 mL) was purged with nitrogen and palladium on carbon (0.100 g) was added. The reaction was purged with hydrogen and stirred under a hydrogen atmosphere for 2 hours. 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 a 4 M solution in dioxane, 2.659 mmol, 5.0 eq) was added. The reaction was stirred at room temperature for 6 hours, at which time a white solid formed. The reaction was concentrated to dryness and used without further purification. m / z: 265[M+H] + .

[0189] [ka] Synthesis of (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: To a mixture of aminooxobenzoxazapine hydrochloride (0.134 mmol, 1.0 eq) and benzyltriazolecarboxylic acid (0.033 g, 0.161 mmol, 1.2 eq) in dimethylformamide (1.0 mL) was added diisopropylethylamine (0.043 g, 0.058 mL, 0.335 mmol, 2.5 eq), followed by HATU (0.102 g, 0.268 mmol, 2.0 eq). The reaction was stirred at room temperature for 4 h and then partitioned between EtOAc-CHCl (5:1, 60 mL) and water (60 mL). The organics were washed with brine (50 mL), water (60 mL), and brine (50 mL). The organics were dried (NaSO) and concentrated under reduced pressure. MPLC (0→10% MeOH-CHCl) afforded the title compound as a white solid. 1 H nmr (400 MHz, CDCl3) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.36-7.28 (5H, m, 5 × ArH), 7.11-7.06 (3H, m, 3 × ArH), 5.44 (2H, br s, CONH2), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.17 (2H, s, C H m / z:449[M+H] + .

[0190] Example 10 [ka] Preparation of (S)-7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one: Dioxane (4 mL) and water (2 mL) were dissolved in bromobenzoxazapine (0.270 g, 0.527 mmol, 1.0 eq), 7-((trifluoro-λ 4 To a mixture of (-boraneil)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine potassium salt (0.180 g, 0.738 mmol, 1.4 eq) and cesium carbonate (0.515 g, 1.581 mmol, 3.0 eq) was added. The reaction was degassed by bubbling argon through it for 10 minutes. X-PhosPd G2 (0.021 g, 0.026 mmol, 0.05 eq) was added, the reaction was sealed, and heated in a microwave oven at 140 °C for 45 minutes. The reaction was partitioned between EtOAc (80 mL) and NaHCO3 (80 mL). The organics were washed with saturated brine (80 mL), dried (Na2SO4), and concentrated under reduced pressure. MPLC (0→10% MeOH [2M NH3]—CH2Cl2) gave the title compound (0.255 g, %) as a yellow oil. 1H nmr (400 MHz, CDCl3) δ 7.88 (1H, s, triazole H-3), 7.38-7.35 (6H, m, 6H of C(C6H5)3), 7.21-7.11 (9H, m, 9H of 9HC(C6H5)3), 7.02 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapine H-8), 6.97 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 6.87 (1H, d, J 2.0 Hz, oxobenzoxazapine H-6), 4.50 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.36 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine 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, oxobenzoxazapine 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] + .

[0191] [ka] Deprotection of the trityl group: To a solution of the trityl-protected amine (0.255 g, 0.447 mmol, 1.0 eq) in dioxazine (4.0 mL) was added hydrogen chloride (0.56 mL of a 4 M solution in dioxane, 2.237 mmol, 5.0 eq). A white precipitate formed. The reaction was stirred at room temperature for 14 hours. The reaction was concentrated to dryness and used without further purification. m / z: 329 [M+H] + .

[0192] [ka] Preparation of (S)-5-benzyl-N-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide: To a solution of aminooxobenzoxazapine hydrochloride (0.377 mmol, 1.0 eq) and benzyltriazolecarboxylic acid (0.077 g, 0.377 mmol, 1.0 eq) in dimethylformamide (4.0 mL) was added diisopropylethylamine (0.122 g, 0.16 mL, 0.943 mmol, 2.5 eq). The reaction was cooled to 0 °C, and HATU (0.143 g, 0.377 mmol, 1.0 eq) 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-CHCl (9:1, 60 mL) and NaHCO-water (1:1, 60 mL). The organics were washed with brine (60 mL). The aqueous phases were combined and back-extracted with EtOAc (30 mL). The organics were combined, washed with water (90 mL) and brine (90 mL), dried (NaSO), and concentrated under reduced pressure. MPLC (0→8% MeOH-CHCl) afforded the title compound as a white solid. 1 H nmr (400 MHz, CDCl3) δ 7.90 (1H, br m, NH), 7.75 (1H, s, triazole H-3), 7.29-7.21 (7H, m, 7×ArH), 7.16 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 5.10 (1H, oxobenzoxazapine H-3), 4.74 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, t, 10.0 Hz, 1H of oxobenzoxazapine 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, J 15.5Hz, ArCH2N or NCH2C), 3.77, 3.73 (2H, 2d AB system, J 13.5Hz, ArCH2N or NCH2C), 3.40 (3H, s, NCH3), 3.02 (2H, t, J 5.5Hz, 2H of NCH2CH2N);m / z:514[M+H]+ (Measured value [M+H] + ,514.2324,C 26 H 27 N9O3 theoretical value [M+H] + 514.2310).

[0193] Additional exemplary compound embodiments are shown below. [ka] (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 1 H NMR (400 MHz, D6DMSO) δ 7.83 (1H, d, J 8.0 Hz, NH), 7.45 (1H, d, J 2.0 Hz, oxobenzoxazapine H-6), 7.25 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.20-7.15 (5H, m, oxobenzoxazapine H-9, 4H of CH), 7.09-7.04 (1H, m, 1H of CH), 5.47 (1H, br s, OH), 4.81-4.74 (1H, m, oxobenzoxazapine H-3), 4.39-4.36 (2H, m, 2H of oxobenzoxazapine 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] + .

[0194] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 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 CH, oxobenzoxazapine H-6, H-8), 7.28-7.24 (3H, m, 3H of CH, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J 2.5 Hz, quinoline H-5), 7.10 (1H, d, J 8.0Hz, oxobenzoxazapine H-9), 5.36 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.75 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine 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 oxobenzoxazapine H-2), 3.39 (3H, s, NCH3), 2.98 (2H, t, J 7.0 Hz, CC H 2CH2O); m / z: 573 [M+H] + (Measured value [M+H] + ,573.2244,C 33 H 28 N6O4 theoretical value [M+H] + 573.2245).

[0195] [ka] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H 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, oxobenzoxazapine H-8), 7.25-7.20 (6H, m, CH, oxobenzoxazapine H-7), 7.11 (1H, d, J 3.0 Hz, quinoline H-5), 7.09 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (2H, t, J 7.0 Hz, CCH2C H 2O), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.14 (2H, s, C H 2C6H5),3.37(3H,s,NCH3),2.98(2H,t,J 7.0Hz,CC H 2CH2O); 13 C nmr(100MHz,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] + (Measured value [M+H] + ,573.2262,C 33 H 28 N6O4 theoretical value [M+H] + 573.2245).

[0196] [ka] (S)-1-Benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.04 (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, oxobenzoxazapine H-6, H-8), 7.15 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 5.35 (2H, s, NC H 2C6H5), 5.09 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26-4.21 (3H, m, 1H of oxobenzoxazapine 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(100MHz,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 270.5Hz),77.2,60.6,54.3,50.7,49.2,48.4,47.1,35.6; 19 F nmr(380MHz,CDCl3)δ -65.4 m / z:582[M+H] + (Measured value [M+H] + ,582.2188,C 27 H 26 F3N9O3 theoretical value [M+H] + 582.2183).

[0197] [ka] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.27-7.21 (6H, m, CH, oxobenzoxazapine H-8), 7.21 (1H, dd, J 7.5, 2.0 Hz, oxobenzoxazapine H-8), 7.15 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29-4.23 (3H, m, 1H of oxobenzoxazapine H-2, 2H of NCHCHN), 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 5.5Hz,2H of NCH2CH2N); 13 C nmr(100MHz,CDCl3)δ 168.8,158.7,153.4(q,J 39.5Hz),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 269.5Hz),77.1,60.7,50.4,49.4,48.6,47.1,35.6,33.0; 19 F nmr(380MHz,CDCl3)δ -65.3 m / z:582[M+H] + (Measured value [M+H] + ,582.2167,C 27 H 26F3N9O3 theoretical value [M+H] + 582.2183).

[0198] [ka] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 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, oxobenzoxazapine H-6, H-8, C6H5), 7.07 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 9.5, 7.5Hz, oxobenzoxazapine H-2 (1H), 4.31 (2H, td, J 7.0, 2.5Hz, OC H 2CH2C), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.13 (2H, s, C H 2C6H5),3.36(3H,s,NCH3),2.97(2H,t,J 7.0Hz,OCH2C H 2C); 13 C nmr(100MHz,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 value [M+H]+ ,573.2269,C 33 H 28 N6O4 theoretical value [M+H] + 573.2245).

[0199] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1 H 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, C6H5, 3H, oxobenzoxazapine H-6), 7.27-7.22 (6H, m, quinoline H-6, H-3, oxobenzoxazapine H-8, C6H5, 3H, oxobenzoxazapine H-6), 7.09 (1H, dd, J 8.0, 0.5 Hz, oxobenzoxazapine H-9), 5.35 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine 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 oxobenzoxazapine H-2), 3.39 (3H, s, NCH3), 2.98 (2H, t, J 7.0 Hz, OCH2C H 2C); 13C nmr(100MHz,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. m / z:573[M+H] + (Measured value [M+H] + ,573.2249,C 33 H 28 N6O4 theoretical value [M+H] + 573.2245).

[0200] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.27-7.20 (3H, m, 1H of oxobenzoxazapine H-6, H-8, C6H3F2), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.82-6.74 (2H, m, 2H of C6H3F2), 4.99 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine 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]+ (Measured value [M+H] + ,496.1795,C 25 H 23 F2N5O4 theoretical value [M+H] + 496.1791).

[0201] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.89 (1H, dd, J 4.0, 2.0 Hz, quinoline H-2), 8.63 (1H, ddd, J 8.5, 2.0, 1.0 Hz, quinoline H-4), 8.02 (1H, d, J 7.5 Hz, NH), 7.99 (1H, s, triazole H-5), 7.70 (1H, d, J 8.5 Hz, quinoline 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, oxobenzoxazapine H-6), 7.26-7.22 (4H, m, oxobenzoxazapine H-8, 3H of C6H5, oxobenzoxazapine H-6), 7.09 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 6.89 (1H, dd, J 7.5, 0.5 Hz, quinoline H-6), 5.35 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.73 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine 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 oxobenzoxazapine H-2), 3.37 (3H, s, NCH3), 3.03 (2H, t, J 7.0 Hz, OCH2C H 2C); m / z: 573 [M+H] +(Measured value [M+H] + ,573.2251,C 33 H 28 N6O4 theoretical value [M+H] + 573.2245).

[0202] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 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, oxobenzoxazapine H-6, H-8), 7.08 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 6.90 (1H, dd, J 8.0, 0.5 Hz, quinoline H-6), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.36 (2H, t, J 7.0 Hz, OC H 2CH2C), 4.25 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.13 (2H, s, C H 2C6H5),3.36(3H,s,NCH3),3.04(2H,t,J 7.0Hz,OCH2C H 2C); 13C nmr(100MHz,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 value [M+H] + ,573.2266,C 33 H 28 N6O4 theoretical value [M+H] + 573.2245).

[0203] [ka] (S)-1-Benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 8.02 (1H, s, triazole H-5), 7.39-7.35 (3H, m, 3 × ArH), 7.29-7.26 (2H, m, 2 × ArH), 7.20 (2H, m, 2 × ArH), 7.17 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 5.38 (2H, s, NC H2C6H5), 5.12 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine 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(380MHz,CDCl3)δ -63.2;m / z:582[M+H] + (Measured value [M+H] + ,582.2173,C 27 H 26 F3N9O3 theoretical value [M+H] + 582.2183).

[0204] [ka] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxa Zepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.01 (1H, d, J 7.0 Hz, NH), 7.27-7.19 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.16 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 5.09 (1H, dt, J 10.5, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 10.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.14 (4H, m, 2H of NCH2CH2N), ArCH2NCH2 or C H 2H of 2C6H5), 3.93 (2H, s, ArCH2NCH2 or C H 2H of 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 5.5Hz, 2H of NCH2CH2N); 13 C nmr(100MHz,CDCl3)δ 168.8,158.6,152.0,149.6,143.4(q,J 40.0Hz),136.4,135.8,134.3,128.8,128.7,127.9,127.1,126.9,123.4,123.2,118.3(q,J 270.5Hz),77.2,60.8,49.5,49.4,43.6,35.6,33.1; 19 F nmr(380MHz,CDCl3)δ -63.2;m / z:582[M+H] + (Measured value [M+H] + ,582.2208,C 27 H 26 F3N9O3 theoretical value [M+H] + 582.2183).

[0205] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 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 CH), 7.29-7.23 (4H, m, 2H of CH, oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.38 (2H, s, NC) H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3); m / z: 458 [M+H] + (Measured value [M+H] + ,458.2205,C 26 H 27 N5O3 theoretical value [M+H] + 458.2187).

[0206] [ka] (S)-5-Benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.21 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.07 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J Hz, 1H of oxobenzoxazapine H-2), 4.15 (2H, s, C H 2C6H5),3.40(3H,s,NCH3),1.32(9H,s,C(CH3)3); 13 C nmr(100MHz,CDCl3)δ 168.7,158.5,149.2,135.9,135.8,130.9,128.8,128.7,127.0,126.4,12 2.8,121.8,99.4,77.6,77.2,49.1,35.5,33.2,30.9,27.9;m / z:458[M+H] + (Measured value [M+H] + ,458.2200,C 26 H 27 N5O3 theoretical value [M+H] + 458.2187).

[0207] [ka] (S)-1-Benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 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 CH), 7.29-7.25 (4H, m, 2H of CH, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.36 (2H, s, NC) H2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.25 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.40 (3H, s, NCH3), 2.55-2.49 (2H, H-4 of 2H, m, cBuH-2), 2.33 (2H, H-4 of 2H, m, cBuH-2), 1.87 (2H, m, cBuH-3); m / z: 472 [M+H] + ,454[M+H-H2O] + (Measured value [M+H] + ,472.1994,C 26 H 25 N5O4 theoretical value [M+H] + 472.1979).

[0208] [ka] (S)-5-Benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.10 (1H, d, J 7.5 Hz, NH), 7.29-7.20 (7H, m, C6H5, 2H, H-8, H-9 of oxobenzoxazapine H-6), 7.10 (1H, dd, J 7.5, 1.0 Hz, 1H, H-8, H-9 of oxobenzoxazapine H-6), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.15, 4.11 (2H, 2d AB system, J 16.0Hz,C H2C6H5),3.39(3H,s,NCH3),2.57-2.50(2H,m,cBuH-2's 2H,H-4),2.35(2H,m,cBuH-2's 2H,H-4),1.92-1.84(2H,m,cBuH-3); 13 C(100MHz,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 value [M+H] + ,472.1999,C 26 H 25 N5O4 theoretical value [M+H] + 472.1979).

[0209] [ka] (S)-1-Benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, 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, oxobenzoxazapine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.36 (2H, s, NCH2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, oxobenzoxazapine (1H from H-2), 3.40 (3H, s, NCH3), 2.08-1.99 (4H, m, c from pentane H-2 and H-5), 1.90-1.84 (2H, m, c from pentane H-3 and H-4), 1.83-1.76 (2H, m, 2H from cyclopentane H-3 and H-4); m / z: 486 [M+H] + ,468[M+H-H2O] + (Measured value [M+H] + ,486.2122,C 27 H 27 N5O4 theoretical value [M+H] + 486.2136).

[0210] [ka] (S)-5-Benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31-7.23 (7H, m, C6H5, oxobenzoxazapine H-6, H-7), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.14 (2H, s, C H 2C6H5), 3.39 (3H,s,NCH3), 2.08-1.97 (4H,m,c pentane H-2, H-5), 1.90-1.85 (2H,H-4 of 2H,m,c pentane H-3), 1.82-1.76 (2H,H-4 of 2H,m,c pentane H-3); m / z: 468 [M + H - H2O] + (Measured value [M+H] + ,486.2154,C 27 H 27 N5O4 theoretical value [M+H] + 486.2136).

[0211] [ka] (S)-1-Benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 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 CH), 7.31-7.27 (4H, m, 2H of CH, oxobenzoxazapine H-6, H-8), 7.14 (1H, dd, J 8.0, 1.0 Hz, oxobenzoxazapine H-9), 5.37 (2H, s, NC) H2C6H5), 5.08 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine 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, H-6 of pyran H-2), 3.42 (3H, s, NCH3), 2.07-2.02 (2H, m, 2H, H-5 of pyran H-3), 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] + (Measured value [M+H] + ,502.2105,C 27 H 27 N5O5 theoretical value [M+H] + 502.2085).

[0212] [ka] (S)-5-Benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.07 (1H, d, J 6.5 Hz, NH), 7.28-7.19 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 5.00 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.64 (1H, dd, J 9.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, t, J 10.5 Hz, 1H of oxobenzoxazapine H-2), 4.12 (2H, s, CH2C6H5), 3.93 (2H, dt, J 12.0, 4.5Hz, 2H,H-6 of pyran H-2), 3.70 (2H,ddd,J 11.5, 9.0, 2.5Hz, 2H,H-6 of pyran H-2), 3.37 (3H,s,NCH3), 2.03 (2H,m, 2H,H-5 of pyran H-3), 1.88 (2H,ddd,J 13.0, 9.0, 4.0Hz, 2H,H-5 of pyran H-3); 13 C nmr(100MHz,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] + (Measured value [M+H] + ,502.2080,C 27 H 27 N5O5 theoretical value [M+H] + 502.2085).

[0213] [ka] (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 1H 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, 1H of oxobenzoxazapine H-6, H-8, C6H5), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine 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, oxobenzoxazapine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.41 (3H, s, NCH3), 1.61 (6H, s, C(C H 3)2OH); 13 C nmr(100MHz,CDCl3)δ 169.0,166.1,163.6,153.7,151.3,150.1,150.0,136.2,130.8,130.3,126.4,125.6,12 3.0,120.7,120.3,114.4,110.6,94.4,80.7,77.2,65.6,49.3,35.4,31.4;m / z:472[M+H] + (Measured value [M+H] + ,472.1891,C 27 H 25 N3O5 theoretical value [M+H] + 472.1867).

[0214] [ka] (S)-5-Benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.33-7.26 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.03 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine 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 oxobenzoxazapine H-2), 4.30 (1H, dd, J 11.0, 9.5 Hz, oxobenzoxazapine H-2 (1H), 4.16 (2H, s, C H 2C6H5),3.41(3H,s,NCH3),2.98(1H,br s,OH);m / z:474[M+H] + (Measured value [M+H] + ,474.1789,C 25 H 23 N5O5 theoretical value [M+H] + 474.1772).

[0215] [ka] (S)-1-Benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H 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 CH), 7.28-7.25 (4H, m, 2H of CH, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 5.35 (2H, s, NC) H2C6H5), 5.04 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.89 (2H, dd, J 7.0, 1.0 Hz, 2H, H-4 of oxetane H-2), 4.78 (2H, ddd, J 6.5, 2.0, 1.0 Hz, 2H, H-4 of oxobenzoxazapine H-2), 4.72 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.53 (1H, s, OH), 3.38 (3H, s, NCH3); 13 C nmr(100MHz,CDCl3)δ 168.7,158.4,156.5,150.4,144.0,136.1,133.7,130.9,129.2,129.0,128.2,12 6.6,123.4,119.5,88.9,84.5,77.1,67.3,54.4,53.4,49.1,35.5;m / z:474[M+H] + .

[0216] [ka] (S)-5-Benzyl-N-(5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.09 (1, d, J 7.5 Hz, NH), 7.27 (2H, t, J 7.0 Hz, CH 2H), 7.20-7.15 (5H, m, CH 3H, oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.41 (1H, q, J 1.0 Hz, CH 1H), 5.32 (1H, m, CH 1H), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.63 (1H, dd, J 9.5, 7.5 Hz, oxobenzoxazapine H-2 1H), 4.26 (1H, dd, J 11.0, 10.0 Hz, oxobenzoxazapine H-2 (1H), 4.12 (2H, s, C H 2C6H5),3.38(3H,s,NCH3),1.98(3H,t,JHz,C(C H 3)=CH2); 13 C nmr(100MHz,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] + (Measured value [M+H] + ,442.1869,C 25 H 23 N5O3 theoretical value [M+H] + 442.1874).

[0217] [ka] (S)-5-Benzyl-N-(7-isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.29-7.19 (5H, m, C6H5), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 7.03 (1H, d, J 2.0 Hz, oxobenzoxazapine H-6), 7.00 (1H, m, oxobenzoxazapine H-8), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.22 (1H, dd, J 11.0, 10.0 Hz, oxobenzoxazapine H-2 (1H), 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 6.5Hz,CH2CH2CH(C H 3)2); m / z: 448 [M+H] + (Measured value [M+H] + ,448.2335,C 25 H 29 N5O3 theoretical value [M+H] + 448.2343).

[0218] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28-7.25 (2H, m, 2H of CH), 7.19 (5H, m, 3H of CH, oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.63 (1H, dd, J 9.0, 8.0 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 10.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 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] + (Measured value [M+H] + ,474.2138,C 26 H 27 N5O4 theoretical value [M+H] + 474.2136).

[0219] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1 H 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 CH), 7.27-7.23 (4H, m, 2H of CH, oxobenzoxazapine H-8, H-9), 7.12 (1H, d, J 8.0 Hz, oxobenzoxazapine H-6), 5.36 (2H, s, NC) H2C6H5), 5.05 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.23 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine 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] + (Measured value [M+H] + ,460.1968,C 25 H 25 N5O4 theoretical value [M+H] + 460.1979).

[0220] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.18 (7H, m, C6H5, oxobenzoxazapine H-7, H-9), 7.11 (1H, d, J 8.0 Hz, oxobenzoxazapine H-6), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.62 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.24 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine 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); 13C nmr(100MHz,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] + (Measured value [M+H] + ,460.1972,C 25 H 25 N5O4 theoretical value [M+H] + 460.1979).

[0221] [ka] (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 1 H 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, oxobenzoxazapine H-7, H-9), 7.13 (1H, d, J 8.0 Hz, oxobenzoxazapine 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, oxobenzoxazapine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.40 (3H, s, NCH3), 1.61 (6H, s, C(C H 3)2OH); 13C nmr(100MHz,CDCl3)δ 169.0,166.1,163.6,153.7,151.3,150.1,149.6,136.4,130.3,128.9,126.0,125.7,12 3.0,122.0,120.7,114.4,110.6,94.9,80.6,77.2,65.6,49.4,35.3,31.4;m / z:472[M+H] + (Measured value [M+H] + ,472.1873,C 27 H 25 N3O5 theoretical value [M+H] + 472.1867).

[0222] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 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, oxobenzoxazapine H-6), 7.226-7.24 (1H, m, 1H of C6H3Cl2, oxobenzoxazapine H-6), 7.18-7.15 (1H, m, oxobenzoxazapine H-8), 7.10 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 5.00 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.67 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.48 (2H, s, C H 2C6H3Cl2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 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 value [M+H]+ ,528.1201,C 25 H 23 Cl2N5O4 theoretical value [M+H] + 528.1200).

[0223] [ka] (S)-5-Benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.04 (1H, d, J 7.5 Hz, NH), 7.30-7.17 (8H, m, C6H5, oxobenzoxazapine H-6, H-7, H-9), 5.08 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.30-4.25 (3H, m, 1H of oxobenzoxazapine H-2, NCH2CH2N), 4.14 (2H, s, CH2C6H5), 3.88, 3.83 (2H, 2d, AB system, J 16.0Hz,2H of ArCH2NCH2),3.76(2H,s,ArCH2NCH2),3.40(3H,s,NCH3),3.09-3.02(2H,m,NCH2CH2N); 19 F nmr(380MHz,CDCl3)δ -65.3;m / z:604[M+Na] + 582[M+H] + .

[0224] [ka] (S)-1-Benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J 7.0 Hz, NH), 8.00 (1H, s, triazole H-5), 7.39-7.35 (3H, m, 3H of C6H5, oxobenzoxazapine H-6, H-7, H-9), 7.28-7.25 (2H, m, 2H of C6H5, oxobenzoxazapine H-6, H-7, H-9), 7.23-7.17 (3H, m, 3H of C6H5, oxobenzoxazapine H-6, H-7, H-9), 5.37 (2H, s, NC H 2C6H5), 5.11 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28-4.23 (3H, m, 1H of oxobenzoxazapine 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 F nmr(380MHz,CDCl3)δ -65.4;m / z:604[M+Na] + ,582[M+H] + .

[0225] [ka] (S)-N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 1 H 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, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.10-7.05 (2H, m, 2H of C6H5, oxobenzoxazapine 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, oxobenzoxazapine H-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.41 (3H, s, NCH3); m / z: 478 [M+H] + ,460[M+H-H2O] + (Measured value [M+H] + ,478.2255,C 27 H 19 D6N3O4 theoretical value [M+H] + 478.2244).

[0226] [ka] (S)-5-Benzyl-N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28-7.21 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.14 (2H, s, C H 2C6H5), 3.39(3H,s,NCH3); 13 C nmr(100MHz,CDCl3)δ 168.6,158.5,149.9,136.0,135.8,131.0,128.8(2C),127.1(2C),126.5,12 3.1,120.5,94.6,80.6,77.2,65.3,49.1,35.5,33.2,30.5(m);m / z:466[M+H] + ,448[M+H-H2O] + (Measured value [M+H] + ,466.2356,C 25 H 19 D6N5O4 theoretical value [M+H] + 466.2356).

[0227] [ka] (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)-1H-1,2,4-triazole-3-carboxamide [α] 589 20.2 +135.9(CHCl3,c0.54); 1H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.30-7.23 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine 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] + (Measured value [M+H] + ,460.1985,C 25 H 25 N5O4 theoretical value [M+H] + 460.1979).

[0228] [ka] (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 1 H nmr (400 MHz, CDCl3) δ 7.99 (1H, d, J 6.5 Hz, NH), 7.36-7.29 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 4.97 (1H, ddd, J 11.0, 7.5, 7.0 Hz, oxobenzoxazapine H-3), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, m, 1H of oxobenzoxazapine H-2), 4.26 (2H, s, C H2C6H5),3.43(3H,s,NCH3),1.63(6H,s,C(CH3)2);m / z:484[M+Na] + ,443[M+H-H2O] + (Measured value [M+H] + ,443.1727,C 25 H 24 N4O5 theoretical value [M+H-H2O] + 443.1714).

[0229] [ka] (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 1 H 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, oxobenzoxazapine H-7), 7.27-7.22 (2H, m, 1H of C6H5, oxobenzoxazapine H-9), 7.17 (1H, d, J 8.0 Hz, oxobenzoxazapine 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, oxobenzoxazapine H-3), 4.93 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.79 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.42 (3H, s, NCH3); m / z: 486 [M+H] + ,(Measured value [M+H] + ,486.1674,C 23 H 23N3O6 theoretical value [M+H] + 486.1660).

[0230] [ka] (S)-5-Benzyl-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H 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, oxobenzoxazapine H-7), 7.20 (1H, d, J 2.0 Hz, oxobenzoxazapine H-9), 7.14 (1H, d, J 8.5 Hz, 1H of oxobenzoxazapine H-6), 4.99 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.79 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.64 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.25 (1H, dd, J) 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.14 (2H, s, C) H 2C6H5),3.40(3H,s,NCH3);m / z:474[M+H] + ,456[M+H-H2O] + (Measured value [M+H] + ,474.1784,C 25 H 23 N5O5 theoretical value [M+H] + 474.1772).

[0231] [ka] (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 benzoate 1 H nmr(400MHz,CDCl3)δ 8.07(1H,d,J 7.5Hz,NH),8.03(2H,m,2H of COC6H5),7.59(1H,tt,J 7.5,1.0Hz,1H of COC6H5),7.45(2H,t,J 7.5Hz,2H of COC6H5),7.32-7.23(7H,m,CH2C6 H 5, oxobenzoxazapine H-6, H-8), 7.12 (1H,d,J 8.5Hz, oxobenzoxazapine H-9), 5.23 (1H,d,J 3.0Hz, isosorbate H-6), 5.02 (1H,dt,J 11.0, 7.5Hz, oxobenzoxazapine H-3), 4.87, 4.83 (2H,2d AB series, J 4.5Hz, isosorbate H-3a, H-6a), 4.69 (1H,dd,J 9.5, 7.5Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H,dd,J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.25-4.20 (2H, m, isosorbate H-5), 4.15 (2H, s, C H 2C6H5),4.04,3.95(2H,2d AB series,J 9.5Hz,isosorbate H-2),3.40(3H,s,NCH3),;m / z:650[M+H] + (Measured value [M+H] + ,650.2283,C 35 H 31 N5O8 theoretical value [M+H] + 650.2245).

[0232] [ka] 5-Benzyl-N-((S)-7-(((3R,3aS,6S,6aR)-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)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CD3OD) δ 7.51 (1H, d, J 2.0 Hz, oxobenzoxazapine H-6), 7.36 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.33-7.23 (5H, m, C6H5), 7.19 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 5.01 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.65, 4.54 (2H, 2d AB series, J 4.5 Hz, isosorbate H-3a, H-6a), 4.60 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.41 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.24 (1H, d, J), 2.5 Hz, isosorbate H-6), 4.15 (2H, s, C) H 2C6H5), 3.99-3.91 (2H,m, 2H of isosorbate H-5), 3.93, 3.71 (2H,2d AB system, J 8.5Hz, isosorbate H-2), 3.40 (3H,s,NCH3); 13 C nmr(100MHz,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] + (Measured value [M+H] + ,546.2007,C 28 H 27 N5O7 theoretical value [M+H] + 546.1983).

[0233] [ka] Methyl (S)-4-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-ynoate 1 H nmr (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31-7.23 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.68 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, oxobenzoxazapine H-2 (1H), 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] + (Measured value [M+H] + ,502.2107,C 27 H 27 N5O4 theoretical value [M+H] + 502.2085).

[0234] [ka] (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-pyrazole-3-carboxamide 1H 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, oxobenzoxazapine H-6 or H-8), 7.28-7.21 (4H, m, C6H5, 4H of pyrazole H-4 or H-5, oxobenzoxazapine H-6 or H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.74 (1H, d, J 2.5 Hz, pyrazole H-4 or H-5), 5.31 (2H, s, NC H 2C6H5), 5.05 (1H, dt, J 11.0, 7.0 Hz, oxobenzoxazapine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine 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] + (Measured value [M+H] + ,459.2040,C 26 H 26 N4O4 theoretical value [M+H] + 459.2027).

[0235] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.10 (1H, d, J 7.0 Hz, NH), 7.28 (2H, m, oxobenzoxazapine H-6, H-8), 7.21 (1H, m, 1H of C6H4F), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine 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, oxobenzoxazapine H-3), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J) 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.15 (2H, s, C) H 2C6H4F),3.40(3H,s,NCH3),1.62(6H,s,C(C H 3)2OH); 13 C nmr(100MHz,CD3OD)δ 168.5,164.0,161.6,149.9,138.5,135.9,131.0,130.2(d,J 8.5Hz),128.8,126.5,124.5(d,J 2.5Hz),123.0,120.5,115.8(d,J 22.0Hz),113.9(d,J 21.5Hz),94.6,80.6,76.9,65.6,49.2,35.5,32.9,31.4; 19 F nmr(380MHz,CDCl3)δ -112.6;m / z:460[M+H-H2O] + (Measured value [M+H] + ,478.1901,C 25 H 24 FN5O4 theoretical value [M+H] + 478.1885).

[0236] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.11 (1H, d, J 7.5 Hz, NH), 7.27-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.17 (2H, dd, J 8.5, 5.5 Hz, 2H of CHF), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.90 (2H, t, J 8.5 Hz, 2H of CHF), 4.99 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.64 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.5, 10.0 Hz, oxobenzoxazapine H-2 (1H), 4.09 (2H, s, C H 2C6H4F),3.39(3H,s,NCH3),1.62(6H,s,C(C H 3)2OH); 19 F nmr(380MHz,CDCl3)δ -115.6;m / z:478[M+H] + 460[M+H-H2O] + (Measured value [M+H] + ,478.1902,C 25 H 24 FN5O4 theoretical value [M+H] + 478.1885).

[0237] [ka] (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 1H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.16 (3H, m, 1H of oxobenzoxazapine H-6, H-8, C6H4F), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine 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, oxobenzoxazapine H-3), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, oxobenzoxazapine H-2 (1H), 4.17 (2H, s, C H 2C6H4F),3.38(3H,s,NCH3),1.62(6H,s,C(C H 3)2OH); 13 C nmr(100MHz,CDCl3)δ 168.7,160.7(d,J 246.3Hz),158.5,149.9,136.0,131.0(d,J 4.0Hz),131.0,129.1,129.0(d,J 8.5Hz),126.5,126.3,124.4(d,J 4.0Hz),123.1,120.4,115.4(d,J 12.0Hz),94.6,80.6,76.9,65.6,49.1,35.5,31.4,26.3; 19 F nmr(380MHz,CDCl3)δ -117.5;m / z:460[M+H-H2O] + (Measured value [M+H] + ,478.1895,C 25 H 24 FN5O4 theoretical value [M+H] + 478.1885).

[0238] [ka] (S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 1H nmr (400 MHz, CDCl3) δ 7.40-7.38 (6H, m, 2H of 3 × C6H5), 7.24-7.20 (6H, m, 2H of 3 × C6H5), 7.18-7.12 (4H, m, 1H of 3 × C6H5, 1H of oxobenzoxazapine H-6, H-8, H-9), 6.97-6.95 (2H, m, 2H of oxobenzoxazapine H-6, H-8, H-9), 4.48 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.37 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.55 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine 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] - .

[0239] [ka] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.33-7.31 (2H, m, oxobenzoxazapine H-8, H-9), 7.25-7.20 (5H, m, C6H5), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine 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] + (Measured value [M+H]+ ,474.1981,C 25 H 27 N5O3Si Theoretical value [M+H] + 474.1956).

[0240] [ka] (S)-5-Benzyl-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.06 (1H, d, J Hz, NH), 7.36 (1H, dd, J Hz, oxobenzoxazapine H-8), 7.35-7.26 (6H, m, C6H5, oxobenzoxazapine H-6), 7.14 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.17 (2H, s, C H 2C6H5),3.42(3H,s,NCH3),3.12(1H,s,HCC); 13 C nmr(100MHz,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] + (Measured value [M+H] + ,402.1561,C 22 H 19 N5O3 theoretical value [M+H] + 402.1576).

[0241] [ka] (S)-3-Amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 1 H nmr (400 MHz, CDCl3) δ 7.24 (1H, d, J 2.0 Hz, oxobenzoxazapine H-6), 7.22 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 4.41 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.12 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.72 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3); m / z: 275 [M+H]. + (Measured value [M+H] + ,275.1390,C 15 H 18 N2O3 theoretical value [M+H] + 275.1404).

[0242] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1 H 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 CH4, oxobenzoxazapine H-6), 7.16 (1H, dd, J 9.0, 2.0 Hz, oxobenzoxazapine H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.37 (2H, s, NC) H2C6H4CH3), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine 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(100MHz,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] +

[0243] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1 H 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 CHC6H5), 7.45-7.42 (2H, m, 2H of CHC6H5), 7.38-7.34 (3H, m, 3H of CHC6H5), 7.28-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.41 (2H, s, NC H2C6H4Ph), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.41 (3H, s, NCH3), 1.62 (6H, s, C(C H 3)2OH); 13 C nmr(100MHz,CDCl3)δ 169.1,158.7,157.0,150.3,144.3,142.3,140.4,136.3,132.9,131.2,129.2,129.0,128.2,12 8.0,127.4,126.8,123.5,120.7,94.9,80.9,77.5,65.9,54.4,49.4,35.8,31.7;m / z:536[M+H] + ,518[M+H-H2O] +

[0244] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1 H 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, oxobenzoxazapine H-6, 3H, H-8, H-9, C6 H 3(CH3)2), 7.13-7.10 (3H, m, oxobenzoxazapine H-6 3H, H-8, H-9, C6H3 (C H 3)2),5.41(2H,s,NC H2C6H3(CH3)2), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.41 (3H, s, NCH3), 2.30 (6H, s, CH3(C H 3)2),1.62(6H,s,C(C H 3)2OH); 13 C nmr(100MHz,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] + (Measured value [M+H] + ,488.2292,C 27 H 29 N5O4 theoretical value [M+H] + 488.2292).

[0245] [ka] (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-1H-1,2,4-triazole-3-carboxamide 1H 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, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.06 (1H, ddd, J 11.0, 7.5, 7.0 Hz, oxobenzoxazapine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.98 (2H, d, J 7.0 Hz, 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 6.5,1.0Hz,CH(C H 3)2); 13 C nmr(100MHz,CDCl3)δ 168.9,158.5,156.5,149.9,144.3,136.0,130.9,126.5,123.2,120.4,9 4.5,80.6,77.1,65.5,57.6,49.1,35.5,31.4,29.0,19.7;m / z:426[M+H] + ,408[M+H-H2O] + (Measured value [M+H] + ,426.2126,C 22 H 27 N5O4 theoretical value [M+H] + 426.2136).

[0246] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 7.30-7.18 (5H, m, 5H of C6H5, oxobenzoxazapine H-6, H-8, H-9), 7.13-7.06 (3H, m, 3H of C6H5, oxobenzoxazapine H-6, H-8, H-9), 6.85-6.77 (0.66H, m, oxobenzoxazapine H-3 major), 5.34-5.27 (0.33H, m, oxobenzoxazapine H-3 minor), 4.94 (0.33H, dd, J 12.0, 10.5 Hz, oxobenzoxazapine H-3 minor), 4.84 (0.66H, dd, J 12.0, 9.5 Hz, oxobenzoxazapine H-3 major), 4.55 (0.66 H, dd, J) 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2 major), 4.50 (0.33 H, m, 1H of oxobenzoxazapine H-2 minor), 4.11 (0.66 H, s, C) H 2C6H5 minor), 4.05 (1.32H, q, J 7.0Hz, NC H 2CH 3 major), 3.91, 3.84 (1.32H, 2d AB, J 15.5Hz, C H 2C6H5 major), 3.50 (0.66H, q, J 7.0Hz, 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 7.0Hz, NCH2C H 3); m / z: 488 [M+H] + ,470[M+H-H2O] + (Measured value [M+H] + ,488.2291,C 27 H 29 N5O4 theoretical value [M+H] + 488.2292).

[0247] [ka] (S)-5-Benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H nmr (400 MHz, CDCl3) δ 8.10 (1H, d, J Hz, NH), 7.33 (1H, m, oxobenzoxazapine H-6), 7.31 (1H, dd, J 8.0, 2.5 Hz, oxobenzoxazapine H-8), 7.15 (5H, br s, C6H5), 7.02 (1H, dd, J 8.0, 1.0 Hz, oxobenzoxazapine H-9), 4.10 (2H, s, C H 2C6H5), 3.36(3H,s,NCH3); 13 C(100MHz,100MHz)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 value [M+H] + ,458.0651,C 20 H 18 BrN5O3 theoretical value [M+H] + 458.0645).

[0248] [ka] (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 1H nmr (400 MHz, CDCl3) δ 7.72 (1H, d, J 7.0 Hz, NH), 7.36-7.21 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.30 (1H, br s, isoxazole H-5), 4.99 (1H, dt, J 11.0, 7.0 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine 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(100MHz,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] + (Measured value [M+H] + ,460.1884,C 26 H 25 N3O5 theoretical value [M+H] + 460.1867).

[0249] [ka] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CD3OD) δ 7.71 (1H, dd, J 5.5, 3.0 Hz, 1 × ArH), 7.20 (1H, dd, J 5.5, 3.0 Hz, 1 × ArH), 7.59 (1H, d, J 2.0 Hz, 1 × ArH), 7.44 (1H, td, J 8.5, 2.0 Hz, 1 × ArH), 7.41 (1H, br s, 1 × ArH), 7.33-7.23 (6H, m, 6 × ArH), 5.03 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.60 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.45 (1H, dd, J 11.5, 9.5 Hz, oxobenzoxazapine H-2 (1H), 4.35 (2H,s), isoquinoline H-1 (2H,s), 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] + (Measured value [M+H] + ,533.2296,C 31 H 28 N6O3 theoretical value [M+H] + 533.2296).

[0250] [ka] (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 1H nmr (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.0 Hz, NH), 7.26-7.19 (4H, m, 2H of oxobenzoxazapine H-6, H-7, C6H4F), 7.08 (1H, d, J 9.0 Hz, oxobenzoxazapine 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, oxobenzoxazapine H-3), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.25 (1H, dd, J 11.0, 10.0 Hz, oxobenzoxazapine H-2 (1H), 4.19 (2H, s, C H 2C6H4F),3.40(3H,s,NCH3),1.32(9H,s,C(CH3)3); 13 C nmr(100MHz,CDCl3)δ 168.8,160.7(d,J 245.5Hz),158.5,149.2,135.8,131.0(d,J 4.0Hz),130.9,128.9(d,J 8.5Hz),126.4,124.3(d,J m / z:476[M+H] + (Measured value [M+H] + ,476.2100,C 25 H 26 FN5O3 theoretical value [M+H] + 476.2092).

[0251] [ka] (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 1H 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, oxobenzoxazapine 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, oxobenzoxazapine H-9), 5.42 (2H, s, NC H 2C6H3(CH3)2), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 2.31 (6H, s, C6H3(CH3)2), 1.32 (9H, s, C(CH3)3); m / z: 486 [M+H] + (Measured value [M+H] + ,486.2506,C 28 H 31 N5O3 theoretical value [M+H] + 486.2500).

[0252] [ka] (S)-5-Benzyl-N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.33-7.26 (7H, m, C6H5, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 4.99 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.21-4.11 (1H, m, NC) H 2CH3 1H), 4.16(2H,s,NC H 2C6H5),3.66(1H,heptet,J 7.0Hz,NC H 2CH3 1H), 1.63(6H,s,C(C H 3)2OH),1.19(3H,t,J 7.0Hz,NCH2C H 3); m / z: 456 [M + H - HO] + (Measured value [M+H] + ,474.2143,C 26 H 27 N5O4 theoretical value [M+H] + 474.2136).

[0253] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.30-7.28 (2H, m, oxobenzoxazapines H-6 and H-8), 7.26-7.21 (1H, m, 1H of C6H4F), 7.12 (1H, d, J 8.5 Hz, oxobenzoxazapines 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, oxobenzoxazapine H-3), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 10.5 Hz, 1H of oxobenzoxazapine H-2), 4.22-4.10 (1H, m, NC H 2CH3 1H), 4.14 (2H, s, C H 2C6H4F),3.66(1H,heptet,J 7.0Hz,NC H 2CH3 1H), 1.63(6H,s,C(C H 3)2OH),1.19(3H,t,J 7.0Hz,NCH2C H 3); 19 F nmr(380MHz,CDCl3)δ -112.6;m / z:474[M+H-H2O] + (Measured value [M+H] + ,492.2047,C 26 H 26 FN5O4 theoretical value [M+H] + 492.2042).

[0254] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.01 (1H, d, J 7.0 Hz, 1× NH), 7.54 (1H, s, 1× NH), 7.35-7.24 (6H, m, C5H5, oxobenzoxazapine H-8), 7.10 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 7.09 (1H, m, oxobenzoxazapine H-6), 5.40 (1H, br s, 1H of C=CH2), 5.32 (1H, br s, 1H of C=CH2), 5.08 (1H, m, oxobenzoxazapine H-3), 4.76 (1H, dd, J 10.0, 6.0 Hz, 1H of oxobenzoxazapine H-2), 4.33 (1H, t, J 10.5 Hz, oxobenzoxazapine H-2 (1H), 4.18 (2H, s, C H 2C6H5),1.98(3H,s,CCH3);m / z:428[M+H] + (Measured value [M+H] + ,428.1709,C 24 H 21 N5O3 theoretical value [M+H] + 428.1717).

[0255] [ka] (S)-5-Benzyl-N-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR (400 MHz, CD3OD) δ 7.32-7.21 (7H, m, CH5, oxobenzoxazapine H-6, H-8), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 5.00 (1H, dd, J 10.5, 6.5 Hz, oxobenzoxazapine H-3), 4.61 (1H, dd, J 10.5, 6.5 Hz, 1H of oxobenzoxazapine H-2), 4.40 (1H, t, J 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.15 (2H, s, CH2C6H5); m / z: 444, 442 [M+H]. + (Measured value [M+H] + ,444.0492,C19 H 16 BrN5O3 theoretical value [M+H] + 444.0489).

[0256] [ka] (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 H nmr (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.41-7.39 (2H, m, oxobenzoxazapine H-6, H-8), 7.29-7.22 (5H, m, C6H5), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.31 (1H, s, CH=CCl), 5.05 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.14 (2H, s, C H 2C6H5),3.43(3H,s,NCH3),1.57(6H,s,C(CH3)2OH); 13 C nmr(100MHz,CDCl3)δ 168.7,158.9,158.4,154.3,150.2,136.5,135.9,135.7,135.7,130.1,128.9,128.8,1 27.2,125.8,122.8,121.8,77.2,71.2,49.1,35.6,33.2,29.4;m / z:480,478[M+H-H2O] + ;m / z:496,494[MH] - (Measured value [M+H] + ,496.1743,C 25 H 26 ClN5O4 theoretical value [M+H] + 496.1746).

[0257] [ka] (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 1 H nmr (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.28-7.20 (7H, m, oxobenzoxazapine H-6, H-8, C6H5), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.14 (2H, s, C H 2C6H5), 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 value [M+H] + ,485.2322,C 27 H 28 N6O3 theoretical value [M+H] + 485.2296).

[0258] [ka] (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)-1H-1,2,4-triazole-3-carboxamide 1H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.0 Hz, NH), 7.29-7.27 (2H, m, oxobenzoxazapine H-6, H-8), 7.25-7.18 (5H, m, C6H5), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.02 (1H, dt, J 11.0, 7.0 Hz, oxobenzoxazapine H-3), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, t, J 10.5 Hz, 1H of oxobenzoxazapine H-2), 4.13 (2H, s, C6H5). 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 value [M+H] + ,501.2245,C 27 H 28 N6O4 theoretical value [M+H] + 501.2245).

[0259] Example 11 In this example, the disclosed compounds were evaluated by biochemical analysis using ADP-Glo™ technology.

[0260] ADP-Glo™ (Promega, Madison, WI, USA) reagent was thawed at ambient temperature. Kinase detection reagent was prepared by mixing kinase detection buffer with lyophilized kinase detection substrate.

[0261] A 500 mL 5x stock solution of kinase reaction buffer was made by mixing 1000 μL of 1 M MgCl2, 500 μL of 1 M Tris-HCl (pH 7.4), 25 mg of 0.5 mg / mL BSA, and 3475 μL of distilled water. A 3 mL 2x working solution of kinase reaction buffer containing final concentrations of 100 μM DTT and 4 mM MnCl2 was made.

[0262] RIPK1 enzyme components (Rigel Pharmaceutical, South San Francisco, CA, USA) were thawed on ice. Diluted RIPK1 was prepared at 31 ng / well in 1x kinase reaction buffer (diluted from 2x buffer). A 166 μM ATP assay working solution was prepared in 1x kinase reaction buffer (diluted from 2x buffer).

[0263] Compounds were diluted in DMSO in 4-fold serial dilutions starting from 250 μM in a 96-well plate, then diluted 1:5 with 2× reaction buffer. 1.0 μL of the diluted compounds were added to a 384-well plate in duplicate. 2 μL of diluted active RIPK1 was added to the 384-well plate (not to column 1), and 2× rxn buffer was added to column 1. 150 nM AKT (Anaspec, Fremont, CA, USA) was mixed with an equal volume of ATP working solution and added to the 384-well plate at 2 μL / well. The final reaction volume was 5.0 μL.

[0264] The plate was briefly centrifuged and the reaction was incubated at 30°C for 30 minutes. 5 μl of ADP-Glo™ was added to stop the reaction. The plate was briefly centrifuged and the reaction was incubated at room temperature for 40 minutes. Kinase detection reagent was then added and incubated at room temperature for 30 minutes. The amount of luminescence (light emitted during 0.1 seconds) was measured using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, MA, USA) to determine the relative luminescence units (RLU) from the kinase reaction. The IC obtained in this example 50 The values ​​are shown in Table 1.

[0265] [Table 1]

[0266] [Table 2]

[0267] [Table 3]

[0268] [Table 4]

[0269] Example 12 In this example, U937 and L929 cells were exposed to the disclosed compounds and a cellular necroptosis assay was performed to evaluate the activity of the compounds against human RIP1 and mouse RIP1.

[0270] U937 and L929 cells were obtained from the American Type Culture Collection (Manassa, VA, USA). Both cells were maintained in logarithmic growth phase in complete RPMI 1640 medium (Sigma, St. Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, St. Louis, MO, USA) at 37°C and 5% CO2. For necroptosis assays, L929 cells were plated at 10,000 cells / well in 100 μL / well of medium for 18 hours in Costar 96-well black clear-bottom plates (Fisher Scientific, Hampton, NH, USA). U937 cells were plated at 50,000 cells / well in 50 μL / well of medium containing 60 μM zVAD-fmk (Lonza, Basel, Switzerland) on the day of the assay. The medium was removed from L929 cells in a 96-well plate and replaced with 50 μL / well of fresh medium supplemented with 40 μM zVAD-fmk. In this example, the disclosed compounds were serially diluted in DMSO starting from 2.5 mM in 4-fold dilutions, followed by a 1:125 dilution in complete medium. 2× compound was then added to the plated cells at 50 μL / well. After preincubating the cells with compound at 37°C and 5% CO2 for 1 hour, 11× TNFα (Peprotech, Rocky Hill, NJ, USA) was added at 10 μL / well to achieve a final TNFα concentration of 2 ng / mL. Eighteen hours after TNFα stimulation at 37°C and 5% CO2, CellTiter-Glo® Luminescent Cell Viability Reagent Assay (Promega, Madison, WI, USA) was added according to the manufacturer's instructions, and the relative amount of necroptotic cells was determined from the amount of luminescence using a Wallac Victor 2 Luminometer (PerkinElmer, Waltham, MA, USA). The results of this example are summarized in Table 2. Unexpectedly, this example confirms that embodiments of the compounds described herein exhibit potent activity against human and mouse RIP1, thereby enabling in vivo evaluation in mouse models of disease.These results are useful for determining safe and effective doses in humans.

[0271] [Table 5]

[0272] [Table 6]

[0273] [Table 7]

[0274] [Table 8]

[0275] Example 13 In this example, an acute hypothermia mouse model test was used to assess the ability of compounds disclosed herein to inhibit TNFα-induced hypothermia.

[0276] Female C57BL / 6 mice were randomly assigned to groups and weighed on day -1. On the day of the study (day 0), mice were administered vehicle or test substance by oral gavage. 15 minutes after oral administration of the test drug, each mouse received an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor alpha (TNF-α, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured using a rectal probe thermometer at time 0 (before IP injection) and every hour. Three hours after IP injection of TNF-α and zVAD / FMK, mice were euthanized by CO2 asphyxiation, and blood was collected by cardiac puncture. Serum and plasma were collected for measurement of cytokine and compound concentrations, respectively. A separate group of mice (satellite group mice) was also included to measure plasma compound concentrations during TNFα / zVAD-FMK administration.

[0277] (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (WO 2014 / 125444), having the following exemplary structure, was used as a comparative compound and tested using a procedure similar to that described in WO 2014 / 125444. According to WO 2014 / 125444, this comparative compound showed a 93% inhibition rate at a dose of 30 mg / kg. .child In comparison, the disclosed compound I-30 achieved over 85% inhibition at a dose of only 5 mg / kg using an assay procedure similar to that described above. [ka]

[0278] In view of the many possible embodiments to which the principles of the present disclosure may be applied, the illustrated embodiments should be recognized as merely preferred examples and should not be construed as limiting. Rather, the scope of the present disclosure is defined by the claims that follow. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

1. formula 【Chemical 1】 (In the formula, Ring B is a 5- or 6-membered heteroaryl; L is O or CH ２ and Z is 【Chemistry 2】 and R １ is -linker-R ６ group, and the linker is C １～４ alkyl, and R ６ is R ｂ or -C(R ｆ ) = C(R ｆ ) ２ and R ２ and R ３ is independently H, methyl, or ethyl; R ４ and R ５ are independently R ｅ and R ａ are, independently in each case, H, D, C １ Alkyl, C ２～１０ aliphatic, C １～１０ Haloaliphatic, C ５～１０ Aromatic, or C ３～６ is a heterocyclic ring; R ｂ is, independently in each occurrence, -NR ｄ R ｄ , -C(O)OH, -C(O)OR ｃ or -C(O)NR ｄ R ｄ and R ｃ is, independently in each case, C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, or C ３～６ is cycloalkyl; R ｄ is, independently in each occurrence, H; C ３～６ Cycloalkyl; C ３～６ Heterocycle; C ５～１０ Aryl; C ５～１０ heteroaryl; or two R ｄ The groups, together with the nitrogen to which they are attached, can be one or more R ｅ C, optionally substituted with ３～９ Heterocycle or C ５～１０ providing a heteroaryl; R ｅ is independently in each occurrence a 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 in each occurrence, R ａ , R ｂ or R ｅ or two R ｆ The groups, together with the carbon atoms to which they are attached, form a C ３～６ Cycloalkyl group or C ３～１０ providing a heterocycle; m is 1 to 4; n is 0, 1 or 2; and p is 0, 1, 2, 3, 4 or 5. or a pharmaceutically acceptable salt thereof.

2. formula 【Chemistry 3】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt thereof.

3. formula 【Chemistry 4】 (Wherein, L is O or CH ２ is) 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having a structure satisfying the formula:

4. Ring B is a group represented by the formula 【Chemistry 5】 wherein at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, having a structure satisfying the following formula:

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring B is diazole, triazole, oxadiazole, oxazole or pyridinyl.

6. The triazole is 【Chemistry 6】 Is it; The diazole is 【Chemistry 7】 Is it; The oxadiazole is 【Chemistry 8】 or The oxazole is 【Chemistry 9】 6. The compound of claim 5, wherein:

7. R ５ But, R ｅ and R ｅ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is halogen or methyl.

8. R １ but, 【Chemistry 11】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:

9.

12. 【Chemistry 13】 or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and an excipient, a therapeutic agent, or a combination thereof.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is used to contact receptor-interacting protein-1 (RIP1) kinase with the pharmaceutical composition.

12. A pharmaceutical composition comprising the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt, stereoisomer, N-oxide, hydrate, solvate or deuterated compound thereof for treating a disease in a subject; or the pharmaceutical composition of claim 10, wherein the subject has or is suspected of having or developing the disease, and the disease is a disease involving receptor-interacting protein-1 (RIP1) kinase.

13. The pharmaceutical composition according to claim 12, wherein the disease associated with receptor-interacting protein-1 (RIP1) kinase is ankylosing spondylitis.

14. The pharmaceutical composition according to claim 12, wherein the disease associated with receptor-interacting protein-1 (RIP1) kinase is rheumatoid arthritis.

15. The pharmaceutical composition according to claim 12, wherein the disease associated with receptor-interacting protein-1 (RIP1) kinase is atopic dermatitis.

16. The pharmaceutical composition according to claim 12, wherein the disease involving receptor-interacting protein-1 (RIP1) kinase is psoriasis.

17. A process for producing a compound according to any one of claims 1 to 9, The starting material having formula A is reacted with R １ A reagent containing R １ is the linker-R ６ R １ and a reagent containing the starting material and the R １ by combining a reagent containing the compound with a transition metal catalyst, a base, and a solvent to produce a functionalized product; deprotecting the amine group of the functionalized product to provide an amine compound; forming an amide bond between the amine compound and an acid-containing coupling partner; Providing an amide-containing compound; Including, Formula A is: 【Chemistry 16】 and The functionalized product has the formula B 【Chemistry 17】 and The acid-containing coupling partner has formula C 【Chemistry 18】 having a structure satisfying the formula: X is a halogen or triflate; PG is an amine protecting group; and Ring B, L, R １ , R ２ , R ４ , R ５ , R ６ , m, n, and p are as defined in claim 1.

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