RIP1 Inhibitory Compounds and Methods for Preparing and Using the Same

Abstract

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

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of the earlier filing date of U.S. Provisional Application No. 62 / 666,462, filed on May 3, 2018, the entire disclosure of which is incorporated herein by reference. Field of the Invention

[0003] The present disclosure relates to compounds, and methods for preparing and using such compounds, e.g., for inhibiting receptor - interacting protein - 1 kinase (“RIP1”) and for treating diseases and / or disorders associated with RIP1. Background of the Invention

[0004] Receptor - interacting protein - 1 kinase (referred to herein as “RIP1”) belongs to the tyrosine - kinase - like family and is a serine / threonine protein kinase involved in innate immune signaling. RIP1 plays a central role in regulating cell signaling and its role in programmed cell death has been implicated in different inflammatory diseases, such as inflammatory bowel disease, psoriasis, and other diseases and / or disorders associated with inflammation and / or necrotic cell death. Summary of the Invention

[0005] Embodiments of compounds having Formula (I’) are disclosed herein:

[0006]

[0007] or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will understand that compounds within the scope of Formula I also include their stereoisomers, N - oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs.

[0008] Referring to Formula I, Ring B is a 5 - or 6 - membered heteroaryl; L is a heteroatom or R a , provided that 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 C 3-6 cycloalkyl); or R 1 is a halogen, - C≡CH, or - linker - R 6 group, where the linker is R a , provided that R a is not H or D, and R 6 is R b , - C(R f )3, or - C(R f )=C(R f) 2; R 2 and R 3 are independently R a ; R 4 and R 5 are independently R e ; for each occurrence, R a is independently H, D, C 1-10 aliphatic, C 1-10 haloaliphatic, C 5-10 aromatic, or C 3-6 heterocycle; for each occurrence, R b is independently OH, -SH, -OR c , -SR c , -NR d R d , -Si(R a )3, -C(O)OH, -C(O)OR c , or -C(O)NR d R d ; for each occurrence, R c is independently C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl (which may be substituted by 1, 2 or 3 R e groups), or C 5-10 aromatic (which may be substituted by 1, 2 or 3 R e groups); for each occurrence, R d is independently H; C 1-6 alkyl (which may be substituted by 1, 2 or 3 R e groups); C 3-6 cycloalkyl (which may be substituted by 1, 2 or 3 R e groups); C 3-6 heterocycle (which may be substituted by 1, 2 or 3 R e groups); C 5-10 aryl (which may be substituted by 1, 2 or 3 R b groups); C 5-10 heteroaryl (which may be substituted by 1, 2 or 3 R b groups); or two R d groups together with the nitrogen to which they are attached provide a C 3-9 heterocycle (which may be substituted by one or more R e groups) or C 5-10 heteroaryl (which may be substituted by one or more R e groups); for each occurrence, R e is independently halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10Alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-10 heteroaryl, or -OR a ; for each occurrence, R f is independently R a , R b , or R e , or two R f groups together with the carbon atom to which they are attached provide a C 3-6 cycloalkyl group (which may be substituted by one or more R e ) or a C 3-10 heterocycle (which may be substituted by one or more R e ); m is from 1 to 4; n is 0, 1 or 2; and p is 0, 1, 2, 3, 4 or 5.

[0009] The disclosed compounds may have a structure satisfying the following formula:

[0010]

[0011] In any one or all of the above embodiments, ring B may have a structure satisfying the following formula:

[0012]

[0013] wherein at least one W is nitrogen, and each remaining W is selected from carbon, CH, oxygen, sulfur, nitrogen, or NH, and specific ring B embodiments are 1,2,4 - oxadiazole, 1,2,4 - triazole, 1,3,4 - oxadiazole, oxazole, or pyridyl. Suitable exemplary 1,2,4 - triazoles include any one of the following:

[0014]

[0015] Suitable exemplary 1,2,4 - oxadiazoles include any one of the following:

[0016] Or

[0017] Suitable exemplary 1,3,4 - oxadiazoles include any one of the following:

[0018] Or

[0019] Suitable exemplary oxazoles include any one of the following:

[0020]

[0021] Certain disclosed compounds contain an R e group that is an R 5 group, where R eis C1-C4 aliphatic, or halogen, R 2 is R a , where R a is C1-C4 aliphatic, and R 3 is R a , where R a is hydrogen.

[0022] For certain disclosed embodiments, R 1 is linker-R 6 group, where 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. The R 6 group can be R b , where R b is -C(R f )3, where one R f is R e , particularly -OR a , where R a is H; and for each occurrence, each other R f is independently R a , where R a is C 1-4 alkyl, particularly methyl. In a specific embodiment, the C2 group is an alkyne. In any or all of the above embodiments, ring B can be selected from:

[0023]

[0024] In some embodiments, R 6 can be R b , where R b is -C(O)OEt; or R b can be -C(O)NR d R d , where for each occurrence, each R d is independently H, C 5-10 heteroaryl (which can be substituted by 1, 2, or 3 R e ), C 1-6 alkyl (which can be substituted by 1, 2, or 3 R e ), or two R d groups together with the nitrogen to which they are attached provide a C 3-9 heterocycle (which can be substituted by one or more R e ), or C 5-10 heteroaryl (which can be substituted by one or more R e ). More particularly, one R d is H and the other Rd is aromatic, such as

[0025]

[0026] Some compounds may contain an R that is b the R of 6 a group, where R b is -OH; OR c where R c is C 1-10 alkyl (which may be substituted by 1, 2, or 3 Rs e ), C 2-10 alkenyl (which may be substituted by 1, 2, or 3 Rs e ), C 2-10 alkynyl (which may be substituted by 1, 2, or 3 Rs e ), or C 5-10 aromatic (which may be substituted by 1, 2, or 3 Rs e ); or NR d R d where one R d is H and the other R d is C 5-10 aromatic (which may be substituted by 1, 2, or 3 Rs e ). In some embodiments, R b is OR c where R c is C2 alkyl substituted by pyridyl. In some other embodiments, R b may be -NR d R d where one R d is H and the other R d is pyridyl.

[0027] The linker group of the linker-R 6 group may be a C1 group and the corresponding R 6 group is R b where R b is -NR d R d where the two R d groups together with the nitrogen to which they are attached provide a C 3-9 heterocycle (which may be substituted by one or more Rs e ), or a C 5-10 heteroaryl (which may be substituted by one or more Rs e ), especially where the two R d groups together with the nitrogen to which they are attached provide a C e heterocycle substituted by one R 3-9 In such embodiments, R ecan be C 5-10 a heteroaryl, such as pyridyl. In other embodiments, the two R d groups together with the nitrogen to which they are attached can provide a C e heteroaryl which may optionally be substituted by one or more R 5-10 Without R e substituents, the C 5-10 heteroaryl can be

[0028] In some embodiments, R 5 is R e , where R e is a halogen or a methyl. In some embodiments, the linker of the linker-R 6 group is R a , where R a is a C1, C2, C3, or C4 aliphatic group, including an alkyl, alkenyl, or alkynyl group. In some such embodiments, the C2 group contains an alkyne and where R 6 is R b , where R b is -C(R f )3, where one R f is R e , and for each occurrence, each other R f is independently R a , where R a is C 1-4 alkyl. In a specific embodiment, R e is -OR a , where R a is H. In some such embodiments, R a is methyl and ring B is

[0029] R 1 can be located on any suitable one or more carbon atoms of benzene ring A, such as at positions 1, 2, 3, or 4, as illustrated in formula I. Exemplary R 1 groups are as follows:

[0030]

[0031]

[0032] Exemplary compound classes are provided herein.

[0033] The present disclosure also provides embodiments of pharmaceutical compositions that include one compound (or multiple compounds) according to any one of the formulas and / or species disclosed herein (or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof), and at least one additional active agent and / or inactive agent, such as an excipient, therapeutic agent, adjuvant, or a combination thereof.

[0034] The present disclosure also provides methods for using the disclosed compounds. One such embodiment includes contacting receptor-interacting protein-1 (RIP1) kinase with: a compound according to any one of the formulas and / or species 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. The contacting can occur in vitro or in vivo.

[0035] The present disclosure also provides a method for treating a disease in a subject, the method including administering to the subject (i) a therapeutically effective amount of a compound according to any one 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 a pharmaceutical composition described herein; wherein the subject has or is suspected of having or developing the disease, and the disease involves receptor-interacting protein-1 (RIP1) kinase.

[0036] The present disclosure also provides method embodiments for preparing embodiments of the disclosed compounds. In some embodiments, the method can include coupling a starting material having Formula A with an R 1 -containing reagent to form a functionalized product: combining the starting material and the R 1 -containing reagent with a transition metal catalyst, a base, and a solvent, wherein R 1 includes a linker-R 6 group; 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:

[0037]

[0038] The functionalized product has a structure that satisfies Formula B:

[0039]

[0040] and the acid-containing coupling partner has a structure that satisfies Formula C:

[0041] and wherein

[0042] X is a halogen or a triflate;

[0043] PG is an amine protecting group;

[0044] and ring B, L, R 1 , R 2 , R 4 , R 5 , m, n, and p are each as recited for any one or more of the above compound examples.

[0045] The foregoing and other objects and features of the present disclosure will become apparent from the following detailed description. Detailed Description

[0046] I. Overview of Terms

[0047] The following explanations of terms and methods are provided to better describe the present disclosure and to guide one of ordinary skill in the art in practicing the present disclosure. The singular forms "a / an" and "the" refer to one or more than one, unless the context clearly indicates otherwise. The term "or" refers to a single element of the recited alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, "comprising" means "including". Thus, "comprising A or B" means "including A, B, or A and B" without excluding additional elements. All references (including patents and patent applications) cited herein are incorporated by reference.

[0048] Unless otherwise indicated, all numbers expressing amounts of components, molecular weights, percentages, temperatures, times, etc., as used in the specification or claims will be understood to be modified by the term "about". Thus, unless explicitly or implicitly stated otherwise, the numerical parameters set forth are approximations that may depend upon the desired properties and / or the detection limits under standard test conditions / methods. When distinguishing embodiments directly or explicitly from the prior art being discussed, the number of embodiments is not an approximation unless the term "about" is explicitly recited.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the following describes suitable methods and materials. These materials, methods, and examples are illustrative only and are not intended to be limiting.

[0050] When depicting or describing chemical structures, unless otherwise clearly stated, it is assumed that all carbons include hydrogens such that each carbon conforms to the tetravalent valence. For example, in the structure on the left-hand side of the following schematic, nine hydrogen atoms are implied. The nine hydrogen atoms are depicted in the left-hand side structure.

[0051]

[0052] Sometimes a particular atom in a structure is described in the chemical formulas herein as having a hydrogen or hydrogen atoms, such as -CH2CH2-. Those of ordinary skill in the art will understand that the techniques described above are common in the chemical art to provide simplicity and brevity in the description of organic structures.

[0053] If R is depicted as "floating" on a ring system, such as R in the following group for example 1 :

[0054]

[0055] then unless otherwise defined, the substituent R (such as R above 1 ) can be present on any atom of the fused bicyclic system, excluding the atom carrying the bond with the symbol, provided a stable structure can be formed.

[0056] When the group R is depicted as being present on a ring system containing saturated carbons, such as in the following formula:

[0057]

[0058] wherein, in this instance, y can be more than one, assuming each hydrogen currently depicted, implied, or explicitly defined on each alternative ring; then unless otherwise defined, two R' can be present on the same carbon. A simple example is when R is a methyl group. The depicted structure can exist as a gem-dimethyl on the carbon of the depicted ring ("ring" carbon). In another example, two R' on the same carbon (including the same carbon) can be included in the ring, thus resulting in a spiro ring ("spiro group") structure.

[0059] As used herein, the term "substituted" refers to all subsequent modifying portions of the term, such as in the term "substituted aryl C 1-8 alkyl", substitution can occur on the "C 1-8 alkyl" portion, the "aryl" portion, or both portions of the aryl C 1-8 alkyl group.

[0060] When used to modify a specific group or moiety, "substituted" means that at least one, and possibly two or more, hydrogen atoms of the designated group or moiety are independently replaced by the same or different substituent groups as defined below. In specific embodiments, a group, moiety, or substituent may be substituted or unsubstituted, unless explicitly defined as "unsubstituted" or "substituted". Thus, any of the groups designated herein may be unsubstituted or substituted, unless the context otherwise indicates or the specific structural formula excludes substitution. In specific embodiments, a substituent may or may not be explicitly defined as substituted, but is still considered to be optionally substituted. For example, an "aliphatic" or "cyclic" moiety may be unsubstituted or substituted, but an "unsubstituted aliphatic" or "unsubstituted cyclic" is not substituted.

[0061] Unless otherwise specified, a "substituent" or "substituent group" used to replace one or more hydrogen atoms on a saturated carbon atom in a designated group or moiety may be -R 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 , -NR 80 C(O)N(R 70 )2, -NR 70 C(NR 70 and -NR 70 C(NR 70 )N(R 80 )2, where R 60 is C 1-10 aliphatic, heteroaliphatic, or cycloaliphatic, typically, C 1-6 aliphatic, more typically C 1-6 alkyl, where R 60 is optionally substituted; for each occurrence, each R 70 is independently hydrogen or R 60 ; for each occurrence, each R 80 is independently R 70 , or alternatively two R 80 groups together with the nitrogen atom to which they are attached form a 3- to 7-membered heteroalicyclic group, said heteroalicyclic group optionally comprising from 1 to 4 identical or different additional heteroatoms selected from O, N, and S, where N is optionally substituted with R 70 , such as H or C1-C3 alkyl substitution; and each M + is a counterion having a net single positive charge. Each M + is independently, for each occurrence, for example, an alkali metal ion such as K + , Na + , Li + ; an ammonium ion such as + N(R 60 )4; a protonated amino acid ion such as a lysine ion or an arginine ion; or an alkaline earth metal ion (such as [Ca 2+ ) 0.5 , [Mg 2+ ) 0.5 or [Ba 2+ )0.5 (The subscript “0.5” means that, for example, one of the counterions for such divalent alkaline earth ions can be the ionized form of the compound of the present invention, and other typical counterions (such as chloride) or two ionized compounds can act as the counterions for such divalent alkaline earth ions, or a doubly ionized compound can act as the counterion for such divalent alkaline earth ions). As a specific example, -N(R 80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, N-morpholinyl, etc. For example, any two hydrogen atoms on a single carbon can also be replaced by, for example, =O, =NR 70 , =N-OR 70 , =N2 or =S.

[0062] Unless otherwise specified, the substituent groups for replacing hydrogen atoms on unsaturated carbon atoms in groups containing unsaturated carbon are -R 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, where R 60 , R 70 , R 80 and M + are as previously defined. In a separate embodiment, the substituent is not -O - M + , -OR 70 , -SR 70 , or -S - M + .

[0063] Unless otherwise specified, the substituent groups for replacing hydrogen atoms on the nitrogen atoms in groups containing such nitrogen atoms are -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, where R 60 , R 70 , R 80 and M + are as previously defined.

[0064] In one embodiment, the substituted group has at least one substituent, up to as many substituents as may be possible for the particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

[0065] Additionally, in embodiments where a group or moiety is substituted with a substituted substituent, the nesting of such substituted substituents is limited to three to prevent the formation of polymers. Thus, in a group or moiety containing a first group, where the first group is a substituent on a second group, which second group itself is a substituent on a third group, and the group or moiety is attached to a parent structure, the first (outermost) group can only be substituted with an unsubstituted substituent. For example, in a group containing -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with a substituent that is not itself a substituted substituent.

[0066] As will be understood by one of ordinary skill in the art, any group or moiety defined herein can be attached to any other part of the disclosed structure (e.g., a parent or core structure), such as by considering valence rules, comparing to exemplary species, and / or considering functionality, unless the context clearly states or implies the connectivity of the group or moiety to other parts of the structure.

[0067] "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)C1-C6 alkyl, -C(O)C1-C6 haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclic. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0068] "Aliphatic" refers to a group or moiety that is substantially hydrocarbon-based. Aliphatic groups or moieties can be acyclic, including alkyl, alkenyl, or alkynyl groups (and alkylene, alkenylene, or alkynylene groups), their cyclic forms, such as cycloaliphatic groups or moieties, including cycloalkyl, cycloalkenyl, or cycloalkynyl, and further include straight-chain and branched arrangements, as well as all stereoisomers and positional isomers. Unless otherwise explicitly stated, aliphatic groups contain from one to twenty-five carbon atoms (C 1-25 ); for example, for acyclic aliphatic groups or moieties, from one to fifteen (C 1-15 ), from one to ten (C 1-10 ), from one to six (C 1-6 ), or from one to four carbon atoms (C 1-4 ), or for cycloaliphatic groups or moieties, from three to fifteen (C 3-15 ), from three to ten (C 3-10 ), from three to six (C 3-6 ), or from three to four (C 3-4) carbon atoms. The aliphatic group may be substituted or unsubstituted, unless "unsubstituted aliphatic" or "substituted aliphatic" is explicitly mentioned. The aliphatic group may 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 a -C=C- double bond in the aliphatic chain, or up to one substituent for the carbon of a terminal methylene group).

[0069] "Lower aliphatic" refers to an aliphatic group containing from one to ten carbon atoms (C 1-10 ), such as from one to six (C 1-6 ), or from one to four (C 1-4 ) carbon atoms; or for lower cycloaliphatic groups, from three to ten (C 3-10 ), such as from three to six (C 3-6 ) carbon atoms.

[0070] "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 a C 1-6 alkyl group or a C 3-6 cycloalkyl group. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In a substituted alkoxy, R is a substituted alkyl or a substituted cycloalkyl, and examples in the compounds of the present disclosure include haloalkoxy groups, such as -OCF2H.

[0071] "Alkoxyalkyl" refers to the group -alkyl-OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group; -CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl group.

[0072] "Alkyl" refers to a saturated aliphatic hydrocarbon group having from 1 to at least 25 carbon atoms (C 1-25 ), more typically 1 to 10 carbon atoms (C 1-10 ), such as 1 to 6 carbon atoms (C 1-6 ). The alkyl moiety may be substituted or unsubstituted. By way of example, this term includes straight-chain or branched hydrocarbon groups such as methyl (CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)CH2CH3), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), and neopentyl (-CH2C(CH3)3).

[0073] "Amino" refers to the group -NH2, -NHR, or -NRR, where each R is independently selected from H, aliphatic, heteroaliphatic, aromatic (including both aryl and heteroaryl), heterocycloaliphatic, or two R groups together with the attached nitrogen form a heterocycle. Examples of such heterocycles include those in which two R groups together with the attached nitrogen form a -(CH2) 2-5 -ring, which ring is optionally interrupted by one or two heteroatom groups (such as -O- or -N(R g ))), for example in the group , where R g is R 70 , -C(O)R 70 , -C(O)OR 60 or -C(O)N(R 80 )2.

[0074] "Amide" refers to the group -N(R)acyl, where R is hydrogen, heteroaliphatic, or aliphatic, such as alkyl, especially C 1-6 alkyl.

[0075] Unless otherwise specified, "aromatic" refers to a cyclic conjugated group or moiety having from 5 to 15 ring atoms, having a single ring (such as phenyl, pyridyl, or pyrazolyl) or multiple fused rings, in which at least one ring is aromatic (such as naphthyl, indolyl, or pyrazolopyridyl), that is, at least one ring, and optionally multiple fused rings, having a continuous delocalized π electron system. Typically, the number of out-of-plane π electrons corresponds to the Hückel rule (4n + 2). The point of attachment of the parent structure is typically through the aromatic portion of the fused ring system. For example

[0076] However, in certain instances, the context or explicit disclosure may indicate that the point of attachment is through the non-aromatic portion of the fused ring system. For example An aromatic group or moiety may contain only carbon atoms in the ring, such as in an aryl group or moiety, or it may contain one or more ring carbon atoms and one or more ring heteroatoms that contain lone electron pairs (such as S, O, N, P, or Si), such as in a heteroaryl group or moiety. Unless otherwise stated, an aromatic group may be substituted or unsubstituted.

[0077] Unless otherwise indicated, "aryl" refers to an aromatic carbocyclic group having from 6 to 15 carbon atoms, said aromatic carbocyclic group having a monocyclic ring (e.g., phenyl) or multiple fused rings in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodifuran, etc.). If any aromatic ring contains a heteroatom, the group is a heteroaryl and not an aryl. For example, an aryl group can be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, an aryl group can be substituted or unsubstituted.

[0078] "Arylaliphatic" refers to an aryl group attached to the parent via an aliphatic moiety. Arylaliphatic includes aralkyl or arylalkyl groups such as benzyl and phenylethyl.

[0079] "Carboxyl" refers to -CO2H.

[0080] "Formamide" refers to -C(O)amino.

[0081] "Carboxyl ester" (either "Carboxyl ester" or "carboxy ester") refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0082] "Carboxylate" refers to -C(O)O - or a salt thereof.

[0083] "Cyano" refers to the group -CN.

[0084] "Cycloaliphatic" refers to a cycloaliphatic group having a monocyclic ring (e.g., cyclohexyl), or a polycyclic ring (e.g., a fused ring, a bridged ring, or a spiro ring system in which at least one of the rings in the ring or system is aliphatic). Typically, the point of attachment of the parent structure is through the aliphatic portion of the polycyclic system. Cycloaliphatic includes saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. A cycloaliphatic group can contain from three to twenty-five carbon atoms; for example, from three to fifteen, from three to ten, or from three to six carbon atoms. Unless otherwise stated, a cycloaliphatic group can be substituted or unsubstituted. Exemplary cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0085] "Halogen", "halide", or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0086] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CH2F, -CHF2, and -CF3.

[0087] "Heteroaliphatic" means an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., at least one carbon atom from an aliphatic compound or group containing at least two carbon atoms has been replaced by an atom having at least one lone pair of electrons (typically nitrogen, oxygen, phosphorus, silicon, or sulfur). The heteroaliphatic compound or group may be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic, such as a heterocyclic aliphatic group.

[0088] Unless otherwise specified, "heteroaryl" means an aromatic group or moiety having from 5 to 15 ring atoms and containing at least one carbon atom and at least one heteroatom (e.g., N, S, O, P, or Si). The heteroaryl group or moiety may contain a single ring (e.g., pyridyl, pyrimidinyl, or pyrazolyl) or multiple fused rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridyl). For example, the heteroaryl group or moiety may be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, the heteroaryl group or moiety may be substituted or unsubstituted.

[0089] "Heterocyclic group", "heterocycle" ("heterocyclo" and "heterocycle") refers to both aromatic and non-aromatic ring systems, and more specifically refers to a stable three- to fifteen-membered ring moiety containing at least one carbon atom (and typically multiple carbon atoms) and at least one (e.g., from one to five) heteroatom. The one or more heteroatoms can be one or more nitrogen, phosphorus, oxygen, silicon, or sulfur atoms. The heterocyclic group moiety can be a monocyclic moiety, or can contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of these rings contains a heteroatom. Such a polycyclic moiety can include fused or bridged ring systems as well as spiro ring systems; and any nitrogen, phosphorus, carbon, silicon, or sulfur atom in the heterocyclic group moiety can optionally be oxidized to various oxidation states. For convenience, particularly but not exclusively, those defined as cyclic aromatic nitrogens are not meant to include their corresponding N-oxide forms, although not explicitly defined as such in specific instances. Thus, for a compound having, for example, a pyridyl ring; unless the context otherwise explicitly excludes or precludes, the corresponding pyridyl-N-oxide is included as another compound of the present disclosure. In addition, the cyclic nitrogen atom can optionally be quaternized. Heterocycles include heteroaryl moieties and heterocycloalkyl or heterocyclic aliphatic moieties, which are partially or fully saturated heterocyclic group rings. Examples of heterocyclic group radicals include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazole, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridyl, tetrahydropyridyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolinyl, isoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane, diazepinyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothielyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.

[0090] "Hydroxy" refers to the group -OH.

[0091] "Nitro" means the group -NO2.

[0092] "Phosphate ester" means the group -O-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), -O-arylalkyl, or -OR’ is -O - M + , where M + is a counterion with a single positive charge. Each M + can be a basic ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R”)4, where R” is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth metal ion, such as [Ca 2+ 0.5 , [Mg 2+ 0.5 or [Ba 2+ 0.5 . Phosphonoalkyl means the group -alkyl-phosphate ester, such as CH2OP(O)(OH)2, or its salt, such as -CH2OP(O)(O - Na + )2, and (((dialkoxyphosphoryl)oxy)alkyl) means a dialkyl ester of phosphonoalkyl, such as -CH2OP(O)(O-tert-butyl)2.

[0093] "Phosphonate ester" means 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-arylalkyl, or -OR’ is -O - M + , and M + is a counterion with a single positive charge. For example, each M + is a positively charged counterion and can be an alkali metal ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R”)4, where R” is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth metal ion, such as [Ca 2+ 0.5 , [Mg 2+ 0.5 or [Ba​​​​​2+ 0.5 。A phosphonylalkyl refers to the group -alkyl-phosphonate, such as -CH2P(O)(OH)2, or -CH2P(O)(O - Na + )2, and ((dialkoxyphosphonyl)alkyl) refers to the dialkyl ester of phosphonylalkyl, such as -CH2P(O)(O-tert-butyl)2.

[0094] "Patient" or "subject" generally can refer to any living being, but more typically refers to mammals and other animals, especially humans. Thus, the disclosed methods are applicable to both human therapy and veterinary applications.

[0095] "Pharmaceutically acceptable excipient" refers to a substance included in a composition containing an active ingredient in addition to the active ingredient. As used herein, an excipient can be incorporated within the granules of a pharmaceutical composition, or it can be physically mixed with the granules of the pharmaceutical composition. For example, an excipient can be used to dilute the active agent and / or modify the properties of the pharmaceutical composition. Excipients can include, but are not limited to, anti-adhesives, binders, coatings, enteric coatings, disintegrants, flavoring agents, sweetening agents, coloring agents, lubricants, glidants, adsorbents, preservatives, carriers or vehicles. Excipients can be starches and modified starches, celluloses and cellulose derivatives, sugars and their derivatives (such as disaccharides, polysaccharides and sugar alcohols), proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS or TPGS), carboxymethyl cellulose, dipalmitoyl phosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinol palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben, sugars, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite or lanolin.

[0096] "Adjuvant" is a component that modifies the effect of other reagents (typically the active ingredient). Adjuvants are generally pharmaceutical and / or immunological reagents. An adjuvant can improve the action of the active ingredient by increasing the immune response. An adjuvant can also act as a stabilizer for a formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants (such as Freund's complete adjuvant or Freund's incomplete adjuvant). ​

[0097] "Pharmaceutically acceptable carrier" refers to an excipient that serves as a carrier or vehicle, such as a suspending aid, solubilizing aid, or atomizing aid. Remington: The Science and Practice of Pharmacy, Philadelphia College of Pharmacy, editors: Lippincott, Williams, and Wilkins, Philadelphia, Pennsylvania, 21st edition (2005) (incorporated herein by reference), describes exemplary compositions and formulations suitable for the delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0098] Generally, the nature of the carrier will depend on the specific mode of administration employed. For example, parenteral formulations typically include injectable liquids that include pharmaceutically or physiologically acceptable liquids, such as water, saline, balanced salt solutions, aqueous dextrose, glycerol, or the like as vehicles. In some instances, the pharmaceutically acceptable carrier may be sterile to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to the biologically neutral carrier, the pharmaceutical composition to be administered may contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, such as sodium acetate or sorbitan monolaurate.

[0099] "Pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of compounds derived from a variety of organic and inorganic counterions as would be known to one of ordinary skill in the art, and by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium salts, etc.; and when the molecule contains a basic functionality, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological effectiveness of the free base upon formation by an acid moiety. Specifically, the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, hydroxyethanesulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, etc. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" derived from inorganic bases (such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc.). Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include but are not limited to 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, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc.). Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977; 66:1-19, which is incorporated herein by reference). In a specific disclosed embodiment, the compound may be formate, trifluoroacetate, hydrochloride, or sodium salt.

[0100] "Effective amount" with respect to a compound or pharmaceutical composition means an amount of the compound or pharmaceutical composition sufficient to achieve a particular desired result, such as inhibiting a protein or enzyme. In a specific embodiment, the effective amount is an amount sufficient to inhibit RIP1; cause a desired biological or medical response in a tissue, system, subject, or patient; treat a particular disorder or disease; ameliorate or eliminate one or more of its symptoms; and / or prevent the occurrence of a disease or disorder. One of ordinary skill in the art will understand that the amount of the compound that constitutes an "effective amount" can vary depending on the compound, the desired result, the disease state and its severity, the size, age, and sex of the patient to be treated, and the like.

[0101] A "prodrug" is a compound that is converted in vivo to produce a biologically active compound, or a compound that is more biologically active than the parent compound. For example, the in vivo conversion can occur by hydrolysis or enzymatic transformation. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of compounds having an active form with a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the present disclosure include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (e.g., C 1-6 alkyl esters). Other prodrug moieties include phosphate esters, such as -CH2-O-P(O)(OR')2 or its salts, where R' is H or C 1-6 alkyl. Acceptable esters also include cycloalkyl esters and arylalkyl esters, such as, but not limited to, benzyl. Examples of pharmaceutically acceptable amides of the compounds of the present disclosure include, but are not limited to, primary, secondary, and tertiary alkyl amides (e.g., having between about one and about six carbons). The amides and esters of the disclosed exemplary embodiments of the compounds according to the invention can be prepared according to conventional methods. A thorough discussion of prodrugs is provided in the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0102] "Solvate" refers to a complex formed by the combination of solvent molecules with the molecules or ions of a solute. The solvent can be an organic solvent, an inorganic solvent, or a mixture of both. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, and propanol; amides such as N,N-dialiphatic amides such as N,N-dimethylformamide, tetrahydrofuran, alkyl sulfoxides such as dimethyl sulfoxide, water, and combinations thereof. When combined with a pharmaceutically acceptable or unacceptable solvent (such as water, ethanol, etc.), the compounds described herein can exist in both unsolvated and solvated forms. The solvated forms of the compounds of the present disclosure are within the scope of the examples disclosed herein.

[0103] "Sulfonamide" refers to the group or moiety -SO2NH2, or -N(R)SO2, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0104] "Thioalkyl" refers to the group or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic (including both -S-aryl and -S-heteroaryl).

[0105] "Sulfinyl" refers to the group or moiety -S(O)H, -S(O)aliphatic, -S(O)heteroaliphatic, or -S(O)aromatic (including both -S(O)aryl and -S(O)heteroaryl).

[0106] "Sulfonyl" refers to the group: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including both -SO2aryl and -SO2heteroaryl).

[0107] As used herein, "treating" (Treating or treatment) involves treating a disease or disorder of interest in a patient and subject (particularly a human having a disease or disorder of interest), and includes, by way of example and not limitation:

[0108] (i) preventing the occurrence of a disease or disorder in a patient or subject, particularly when such patient or subject is predisposed to the disorder but has not yet been diagnosed as having it;

[0109] (ii) inhibiting the disease or disorder, such as preventing or slowing its development;

[0110] (iii) alleviating the disease or disorder, such as causing a reduction in symptoms or the remission of the disease or disorder or its symptoms; or

[0111] (iv) stabilizing the disease or disorder.

[0112] As used herein, the terms "disease" and "disorder" may be used interchangeably or may be different, as a particular malady or disorder may not have a known causative factor (so the etiology has not been determined) and thus is not yet considered a disease but only an undesirable disorder or syndrome, in which a more or less specific set of symptoms is identified by a clinician.

[0113] The above definitions and the following general chemical formulas are not intended to include non-permissible substitution patterns (e.g., a methyl group substituted by five fluorine groups). Such non-permissible substitution patterns are readily recognizable by one of ordinary skill in the art.

[0114] One of ordinary skill in the art will understand that compounds can exhibit tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds can include one or more chiral centers and / or double bonds and can thus exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof (such as racemic mixtures). As another example, certain disclosed compounds can exist in several tautomeric forms, including enol forms and mixtures thereof. Since the various compound names, chemical formulas, and compound drawings within the specification and claims can represent only one of the possible tautomeric, conformational, optical, or geometric isomeric forms, one of ordinary skill in the art will understand that the disclosed compounds encompass any tautomeric, conformational, optical, and / or geometric isomeric forms of the compounds described herein, along with mixtures of these various different isomeric forms. Techniques known to one of ordinary skill in the art can be used, particularly in light of this disclosure, to separate mixtures of different isomeric forms (including mixtures of enantiomers and / or stereoisomers) to provide each individual enantiomer and / or stereoisomer. Atropisomers are also possible in cases of restricted rotation (e.g., around an amide bond or between two directly attached rings (such as a pyridyl ring, a biphenyl group, etc.)) and are specifically included in the compounds of the present invention.

[0115] In any embodiment, any or all of the hydrogens present in or within a particular group or moiety of the compound can be replaced by deuterium or tritium. Thus, the recitation of an alkyl group includes deuterated alkyl groups in which from one to the maximum number of hydrogens present can be replaced by deuterium. For example, ethyl refers to both C2H5 and C2D x H 5-x in which from 1 to 5 hydrogens are replaced by deuterium, for example.

[0116] II. RIP1-Active Compounds and Pharmaceutical Compositions Comprising RIP1-Active Compounds

[0117] A. Compounds

[0118] The present disclosure relates to compounds that can be used to inhibit RIP1 and / or for the treatment of diseases and / or disorders associated with RIP1, and pharmaceutical compositions comprising such compounds. In some embodiments, the compounds are selective kinase inhibitors. For example, with respect to RIP2, RIP3, or both RIP2 and RIP3, exemplary compounds are capable of selectively inhibiting RIP1. In some embodiments, the compounds of the present disclosure may have a structure that satisfies Formula I:

[0119]

[0120] or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will understand that within its scope, the disclosed general formula includes all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs of compounds that additionally have the structural features required by such formula.

[0121] Referring to Formula I:

[0122] Ring B is a 5- or 6-membered heteroaryl;

[0123] L is a heteroatom or R a , provided that R a is not H or D;

[0124] Z is C 1-10 aliphatic (e.g., C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 3-6 cycloalkyl); or

[0125] R 1 is a halogen, -C≡CH, or -linker-R 6 group, wherein the linker is R a , provided that R a is not H or D, and R 6 is R b , -C(R f )3, or -C(R f )=C(R f )2;

[0126] R 2 and R 3 are independently R a ;

[0127] R 4 and R 5 are independently R e ;

[0128] For each occurrence, R aIndependently H or D (except in the embodiments where L is R a , C 1-10 aliphatic (such as 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 heterocycle;

[0129] For each occurrence, R b independently is 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 ;

[0130] For each occurrence, R c independently is C 1-10 alkyl (which may be substituted by 1, 2 or 3 R e ), C 2-10 alkenyl (which may be substituted by 1, 2 or 3 R e ), C 2-10 alkynyl (which may be substituted by 1, 2 or 3 R e ), C 3-6 cycloalkyl (which may be substituted by 1, 2 or 3 R e ), or C 5-10 aromatic (which may be substituted by 1, 2 or 3 R e );

[0131] For each occurrence, R d independently is H; C 1-6 alkyl (which may be substituted by 1, 2 or 3 R e ); C 3-6 cycloalkyl (which may be substituted by 1, 2 or 3 R e ); C 3-6 heterocycle (which may be substituted by 1, 2 or 3 R e ); C 5-10 aryl (which may be substituted by 1, 2 or 3 R b ); C 5-10 heteroaryl (which may be substituted by 1, 2 or 3 R e ); or two R d groups together with the nitrogen to which they are attached provide C 3-9A heterocycle (which may be substituted by one or more R e substituents) or a C 5-10 heteroaryl (which may be substituted by one or more R e substituents);

[0132] For each occurrence, R e is independently halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-10 heteroaryl, or -OR a ; and

[0133] For each occurrence, R f is independently R a , R b , or R e , or two R f groups together with the carbon atom to which they are attached provide a C 3-6 cycloalkyl group (which may be substituted by one or more R e substituents) or a C 3-10 heterocycle (which may be substituted by one or more R e substituents);

[0134] m is from 1 to 4, such as 1, 2, 3, or 4, where in a specific embodiment it is 1 or 2;

[0135] n is 0, 1, or 2; and

[0136] p is 0, 1, 2, 3, 4, or 5.

[0137] In some embodiments, the compounds of the present disclosure may have a structure satisfying formula IA

[0138]

[0139] or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will understand that within its scope, the disclosed general formula includes all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs of compounds that additionally have the structural features required by such a formula.

[0140] Referring to formula IA:

[0141] Ring B is a 5- or 6-membered heteroaryl;

[0142] L is a heteroatom or R a , provided that R a is not H or D;

[0143] R 1is a halogen, or - linker - R 6 group, where the linker is R a , provided that R a is not H or D, and R 6 is R b , - C(R f )3, or - C(R f ) = C(R f )2;

[0144] R 2 and R 3 are independently R a ;

[0145] R 4 and R 5 are independently R e ;

[0146] For each occurrence, R a is independently H or D (except for the embodiments where 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 heterocycle;

[0147] For each occurrence, R b is independently OH, - SH, - OR c , - SR c , - NR d R d , - Si(R a )3, - C(O)OH, - C(O)OR c , or - C(O)NR d R d ;

[0148] For each occurrence, R c is independently C 1-10 alkyl (which may be substituted by 1, 2, or 3 R e ), C 2-10 alkenyl (which may be substituted by 1, 2, or 3 R e ), C 2-10 alkynyl (which may be substituted by 1, 2, or 3 R e ), C 3-6 cycloalkyl (which may be substituted by 1, 2, or 3 R e ), or C5-10 Aromatic (which may be substituted by 1, 2 or 3 Rs e substituents);

[0149] For each occurrence, R d is independently H; C 1-6 alkyl (which may be substituted by 1, 2 or 3 Rs e substituents); C 3-6 cycloalkyl (which may be substituted by 1, 2 or 3 Rs e substituents); C 3-6 heterocycle (which may be substituted by 1, 2 or 3 Rs e substituents); C 5-10 aryl (which may be substituted by 1, 2 or 3 Rs b substituents); C 5-10 heteroaryl (which may be substituted by 1, 2 or 3 Rs e substituents); or two Rs d groups together with the nitrogen to which they are attached provide a C 3-9 heterocycle (which may be substituted by one or more Rs e substituents) or a C 5-10 heteroaryl (which may be substituted by one or more Rs e substituents);

[0150] For each occurrence, R e is independently halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-10 heteroaryl, or -OR a ; and

[0151] For each occurrence, R f is independently R a , R b , or R e , or two Rs f groups together with the carbon atom to which they are attached provide a C 3-6 cycloalkyl group (and in some embodiments, the C 3-6 cycloalkyl group is substituted by one or more Rs e substituents), or a C 3-10 heterocycle (and in some embodiments, the C 3-10 heterocyclic group is substituted by one or more Rs e substituents);

[0152] m is from 1 to 4, such as 1, 2, 3, or 4, where in specific embodiments it is 1 or 2;

[0153] n is 0, 1 or 2; and

[0154] p is 0, 1, 2, 3, 4 or 5.

[0155] In a specific embodiment of Formula I or IA, the 5-membered heteroaryl may have a structure satisfying the formula wherein at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In some embodiments, the 5-membered heteroaryl group is a diazole, triazole, oxadiazole, or oxazole. Exemplary triazoles include any of the following:

[0156]

[0157] Exemplary diazoles are selected from any of the following:

[0158] Or

[0159] Exemplary oxazoles are selected from any of the following:

[0160] Or

[0161] Exemplary oxadiazoles are selected from any of the following:

[0162] Or

[0163] In a specific embodiment of Formula I or IA, L is oxygen or R a , where R a is C 1- C4 alkyl, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, L is -CH2- or oxygen.

[0164] The R 1 group (where R 1 is linker -R 6 ) of the linker group is a C1, C2, C3, or C4 aliphatic group (such as a C2 alkyl group, alkenyl group, or alkynyl group), or a C1, C2, C3, or C4 haloaliphatic group, such as a C2 haloalkyl group, or haloalkenyl group. In some embodiments, the linker group of R 1 is R a , where R a is C 1- C4 alkyl, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-; or the linker group is C 2-A C4 alkenyl group, such as -CH=CH-, -CH=CHCH2-, -CH2CH=CH-, or -CH2CH=CHCH2-; or the linker group is C 2- A C4 alkynyl group, such as -C≡C-, -C≡CCH2-, -CH2C≡C-, or -CHC≡C-CH2-. In some embodiments, the linker group is C 2- A C4 haloalkenyl group, 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-.

[0165] In some embodiments, R 1 of R 6 group is C(R f )3, where one R f is R e , where R e is -OR a (such as hydroxyl or OMe), and the R f are independently of each other R a , where R a is C 1-4 aliphatic, and preferably the R f are each other R a , where for each occurrence, R a is independently C 1-4 alkyl. In a specific embodiment, the R f are each other R a , where R a is methyl or CD3. In still some other embodiments, R 6 is -C(R f )3, where each R f is R a , where R a is methyl or H, or where each R f is R a (where R a is methyl) or R b (where R b is -C(O)OR c ). In some other embodiments, one R f is R e is -OR a (such as hydroxyl or OMe), and the other two R fThe groups are linked together so as to provide, together with the carbon atoms to which they are attached, a cycloaliphatic group (such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane) or a heterocyclic group (such as an epoxide, oxetane, tetrahydrofuran, tetrahydropyran, or hexahydrofuro[3,2-b]furan). In some such embodiments, the cycloaliphatic and / or heterocyclic group may be substituted, and in some specific embodiments is substituted by one or more hydroxyl groups or benzyl-carbonyl groups.

[0166] Some compound examples have a linker group that is a C 2-4 group (which may include an alkyne). In a specific embodiment, R 1 is the linker R 6 group and the linker is R a , where R a is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, or -C≡C-, or -CH2C≡C-, and R 6 is R b , where R b is -C(O)OEt or -C(O)NR d R d or -NR d R d , where for each occurrence, each R d is independently hydrogen, C 5-10 heteroaryl, C 3-6 cycloalkyl, or two R d groups are linked together so as to provide, together with the nitrogen atom to which they are attached, a heterocyclic group, and in addition to the nitrogen atom to which the R d group is attached, the heterocyclic group may further contain one or more additional heteroatoms. In some embodiments, one R d is hydrogen and the other R d is a C5- 10 heteroaryl, which may be substituted by one or more R e , such as one of the following:

[0167]

[0168] R 6 may also be R b , where R b is -OH or -OR c (where R c is C 1-6 alkyl, and in some embodiments, the C 1-6 alkyl is substituted by C 5-10 heteroaryl (such as pyridyl); or where R c is C5-10 a heteroaryl, such as a quinolinyl), or R b can be -NR d R d , where for each occurrence, R d is independently H, C 5-10 heteroaryl (and in some embodiments, the C 5-10 heteroaryl group is substituted by one or more R e groups), or two R d groups together with the nitrogen to which they are attached provide a C 3-9 heterocycle (and in some embodiments, the C 3-9 heterocycle is substituted by one or more R e groups) or C 5-10 heteroaryl (and in some embodiments, the C 5-10 heteroaryl is substituted by one or more R e groups). In embodiments having R e substitutions, for each occurrence, R e is independently C 5-10 heteroaryl or -OR a , where R a is C 1-10 alkyl.

[0169] Some compounds contain a linker (the linker being a C1 group) and an R b group that is R 6 , where R b is -NR d R d , where one R d is H, and the other R d is pyridinyl, or where two R d groups together with the nitrogen to which they are attached provide a C 5-10 heteroaryl; or R b is OR c , where R c is C 1-4 alkyl substituted by a pyridinyl group. In some embodiments, R b is

[0170]

[0171] In some embodiments, R 1 can be selected from any of the following:

[0172]

[0173]

[0174] In some embodiments, R2 and R 3 each independently in is R a , where upon each occurrence, R a is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In a specific embodiment, R 2 and R 3 each independently in is R a (for each occurrence, it is independently hydrogen, methyl, or ethyl). In an exemplary embodiment, R 2 is methyl and R 3 is hydrogen.

[0175] In some embodiments, each R 4 independently and / or each R 5 independently is R e , where R e is alkyl, alkenyl, alkynyl, chlorine, bromine, iodine, or fluorine. In a specific embodiment, each R 4 and / or each R 5 independently is R e , where R e is lower aliphatic (such as methyl), fluorine, or chlorine.

[0176] In some embodiments, m is 1; n is 0 or 1; and p is 0, 1, or 2. In a specific embodiment, m is 1, n is 0, and p is 0, 1, or 2.

[0177] The compound having formula I or IA may also have a structure satisfying any one or more of formulas II and IIA-IIF.

[0178]

[0179]

[0180] Referring to formulas II and IIA-IIF, each of R 1 and R 5 is as recited above for formula I and / or IA. In a specific embodiment, there are 0, 1, or 2 R 5 groups. R 5 may be R e , where R e is fluorine or chlorine. In other specific embodiments, there is no R 5 . Referring to formulas IIA-IIF, each W is independently nitrogen or oxygen, and particularly nitrogen.

[0181] In some embodiments, the compound having formula I or IA may also have a structure satisfying any one or more of formulas III-VI:

[0182]

[0183]

[0184] Referring to Formulas III - VI, each R 5 may be independently as cited above and in some specific embodiments is lower aliphatic (e.g., methyl) or halogen, such as chlorine or fluorine. Further, Ring B is as cited above and in some embodiments is selected from

[0185]

[0186] R as illustrated in Formulas III - VI 6 is as cited above and in some embodiments is selected from one of the following:

[0187]

[0188] Or

[0189] Within the scope of one or more of Formulas I, IA, II, IIA - IIF, and III - VI, certain exemplary compounds include:

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198] Within the scope of one or more of Formulas I, IA, II, IIA - IIF, and III - VI, exemplary compounds include:

[0199] I - 1: Ethyl (S) - 3 - (3 - (5 - benzyl - 1H - 1,2,4 - triazole - 3 - carboxamido) - 5 - methyl - 4 - oxo - 2,3,4,5 - tetrahydrobenzo[b][1,4]oxazepin - 7 - yl) propionate;

[0200] 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;

[0201] 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;

[0202] 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;

[0203] I-5: Ethyl (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate;

[0204] I-6: (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoic acid;

[0205] 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;

[0206] I-8: Ethyl (S)-3-(3-(1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate:

[0207] I-9: (S)-3-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoic acid;

[0208] 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;

[0209] I-11: (S)-5-Benzyl-N-(5-methyl-7-(3-morpholin-4-yl-3-oxopropyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0210] 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;

[0211] 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;

[0212] 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;

[0213] 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;

[0214] 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;

[0215] 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;

[0216] 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;

[0217] 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;

[0218] 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;

[0219] 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;

[0220] 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;

[0221] 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;

[0222] 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;

[0223] 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;

[0224] 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;

[0225] 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;

[0226] 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;

[0227] 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;

[0228] 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;

[0229] 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;

[0230] 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;

[0231] 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;

[0232] 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;

[0233] 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;

[0234] 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;

[0235] 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;

[0236] 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;

[0237] 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;

[0238] 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;

[0239] 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;

[0240] 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;

[0241] 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;

[0242] 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;

[0243] 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;

[0244] 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;

[0245] 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;

[0246] 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;

[0247] 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;

[0248] 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;

[0249] 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;

[0250] 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;

[0251] 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;

[0252] 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;

[0253] 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;

[0254] I-56: (S)-1-(7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypyridinecarboxamide;

[0255] I-57: (S)-5-Benzyl-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0256] I-58: (S)-1-Benzyl-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0257] 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;

[0258] 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;

[0259] 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;

[0260] 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;

[0261] 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;

[0262] 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;

[0263] 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;

[0264] 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;

[0265] 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;

[0266] 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;

[0267] 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;

[0268] 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;

[0269] 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;

[0270] I-72: (S)-N-(8-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

[0271] I-73: (S)-5-Benzyl-N-(8-((3-hydroxyoxetane-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;

[0272] I-74: (3S,3aR,6R,6aS)-6-(((S)-3-(5-Benzyl-1H-1,2,4-triazole-3-carboxamide)-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;

[0273] 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;

[0274] I-76: Methyl (S)-4-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-ynoate;

[0275] 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;

[0276] 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;

[0277] 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;

[0278] 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;

[0279] 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;

[0280] 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;

[0281] 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;

[0282] 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;

[0283] 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;

[0284] 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;

[0285] 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;

[0286] 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;

[0287] 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;

[0288] 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;

[0289] 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;

[0290] 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;

[0291] 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;

[0292] 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;

[0293] 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;

[0294] I-96: (S)-5-Benzyl-N-(5-methyl-7-(3-morpholinopropyl-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; or

[0295] 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.

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307] In some embodiments, one or more of the compounds may be included in a pharmaceutical composition or a medicament, and in some embodiments, the one or more compounds may be in the form of: a parent compound or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof. The pharmaceutical composition typically includes 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 sections), or any combination thereof.

[0308] Pharmaceutically acceptable excipients may be included in pharmaceutical compositions for various purposes, such as for diluting a pharmaceutical composition to be delivered to a subject, for facilitating formulation, for providing favorable material properties to the formulation, for facilitating dispersion of a delivery device, for stabilizing the formulation (such as antioxidants or buffers), for providing a satisfactory or palatable taste or consistency to the formulation, and the like. The one or more pharmaceutically acceptable excipients may include one or more pharmaceutically acceptable carriers. Exemplary excipients include, but are not limited to: monosaccharides, disaccharides, and polysaccharides, sugar alcohols and other polyols, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitol, dipalmitoyl phosphatidylcholine, and lecithin; swelling agents; buffers, such as phosphate and citrate buffers; anti-adhesion agents, such as magnesium stearate; binders, such as saccharides (including disaccharides, such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose esters (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coatings (such as cellulose ethers, including hydroxypropyl methylcellulose, shellac, zein, and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, croscarmellose sodium, and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavoring agents and sweetening agents (such as mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla); lubricants (such as mineral oil, exemplified as talc or silica, fats (exemplified as vegetable stearin), magnesium stearate or stearic acid); preservatives (such as antioxidants, exemplified as vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids (exemplified as cysteine and methionine), citric acid and sodium citrate, parabens (exemplified as methyl paraben and propyl paraben); colorants; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0309] B. Combinations of Therapeutic Agents

[0310] The compounds described herein can be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to or in combination with other established therapies. The one or more compounds or compositions comprising the one or more compounds can be administered once or administered multiple times. In some embodiments, the compounds of the 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, in any sequential order, by the same route of administration as the compounds disclosed herein or by a different route. For sequential administration, the one or more compounds and the one or more therapeutic agents can be administered such that the effective time period of at least one compound and therapeutic agent overlaps with the effective time period of at least one other compound and / or therapeutic agent. In an exemplary embodiment of a combination comprising four components, the effective time period of the first component administered can overlap with the effective time periods of the second, third, and fourth components, but the effective time periods of the second, third, and fourth components can independently overlap or not overlap with each other. In another exemplary embodiment of a combination comprising four components, the effective time period of the first component administered overlaps with the effective time period of the second component, but does not overlap with the effective time periods of the third or fourth components; the effective time period of the second component overlaps with the effective time periods of the first and third components; and the effective time period of the fourth component overlaps only with the effective time period of the third component. In some embodiments, the effective time periods of all compounds and / or therapeutic agents overlap with each other.

[0311] In some embodiments, the compounds are administered in combination with another therapeutic agent (e.g., an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase C agonist, an incretin, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof). The anti-inflammatory agent can be a steroid or a non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent is selected from the group consisting of aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an anti-lymphocyte globulin, an anti-thymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0312] In some embodiments, the compounds of the invention can be used in combination with an anti-cancer agent or a cytotoxin agent. Various types of anti-cancer agents and anti-tumor compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkaloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureases, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents (e.g., DNMT inhibitors such as azacitidine and decitabine). Exemplary alkylating agents include, but are not limited to, nitrogen mustards, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, by way of example but not limitation, the folic acid analogue methotrexate; the pyrimidine analogues fluorouracil, cytarabine; the purine analogues mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkaloids include, by way of example but not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example but not limitation, actinomycin D, daunorubicin, and bleomycin. Exemplary enzymes effective as anti-tumor agents include L-asparaginase. Exemplary coordination compounds include, by way of example but not limitation, cisplatin and carboplatin. Exemplary sex hormones and hormone-related compounds include, by way of example but not limitation, adrenocortical steroids (prednisone and dexamethasone); aromatase inhibitors (aminoglutethimide, formestane, and anastrozole); progesterone compounds (hydroxyprogesterone caproate, medroxyprogesterone); and antiestrogen compounds tamoxifen.

[0313] These and other useful anti-cancer agent compounds are described in the Merck Index, 13th Edition, (edited by O'Neil M.J. et al.) Merck Publishing Group (2001); and Goodman and Gilman, The Pharmacological Basis of Therapeutics, 12th Edition, edited by Brunton L.L., Chapters 60 - 63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0314] An example of a CTLA4 antibody that can be used in combination with the inhibitors of the present disclosure is ipilimumab, sold by Bristol-Myers Squibb for

[0315] Other chemotherapeutic agents for combination include immuno-oncology agents such as checkpoint pathway inhibitors, for example PD-1 inhibitors (such as nivolumab and lambrolizumab) and PD-L1 inhibitors (such as pembrolizumab, MEDI-4736 and MPDL3280A / RG7446). Additional checkpoint inhibitors for combination with the compounds disclosed herein include anti-LAG-3 agents such as BMS-986016 (MDX-1408).

[0316] Other chemotherapeutic agents for combination with the inhibitors of the present disclosure include anti-SLAMF7 agents (such as the humanized monoclonal antibody elotuzumab (BMS-901608)), anti-KIR agents (such as the anti-KIR monoclonal antibody lirilumab (BMS-986015)) and anti-CD137 agents (such as the fully human monoclonal antibody urelumab (BMS-663513).

[0317] The compounds of the present disclosure can also be advantageously used in combination with CAR-T therapy. Examples of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

[0318] Additional anti-proliferative compounds useful in combination with the compounds of the present invention include, by way of example but not limitation, antibodies against growth factor receptors (such as anti-Her2); and cytokines (such as interferon-α and interferon-γ, interleukin-2 and GM-CSF).

[0319] Other chemotherapeutic agents useful in combination with the compounds of the present invention include proteasome inhibitors such as bortezomib, carfilzomib, marizomib, etc.

[0320] Examples of kinase inhibitors useful in combination with the compounds of the present disclosure, 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.

[0321] In other embodiments, the second therapeutic agent can be selected from any of the following:

[0322] Analgesics - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, pethidine, pentazocine, dextromoramide, dipipanone;

[0323] Antibiotics - Aminoglycosides (such as amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromomycin), carbapenems (such as ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (such as cephalexin, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefibuten, cefotaxime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (such as teicoplanin, vancomycin, and telavancin), lincosamides (such as clindamycin and lincomycin), lipopeptides (such as daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin, and spectinomycin), monobactams (such as aztreonam), nitrofurans (such as furazolidone and nitrofurantoin), penicillins (such as amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), penicillin combinations (such as amoxicillin / clavulanic acid, ampicillin / sulbactam, piperacillin / tazobactam, and ticarcillin / clavulanic acid), polypeptides (such as bacitracin, colistin, and polymyxin B), quinolones (such as ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (such as sulfamylon, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim - sulfamethoxazole), tetracyclines (such as demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), anti - mycobacterial compounds (such as clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin), and others (such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinupristin / dalfopristin, rifaximin, thiamphenicol, tigecycline, and tinidazole);

[0324] Antibodies - Anti - TNF - α antibodies, such as infliximab (Remicade TM) 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, crisaborole, clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zilucoplan;

[0325] Anticoagulants - warfarin (Coumadin TM ), acenocoumarol, phenprocoumon, dicumarol, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatroban, dabigatran, ximelagatran, batroxobin, defibrase;

[0326] Anti-inflammatory agents - steroids (e.g., budesonide), non-steroidal anti-inflammatory agents (e.g., aminosalicylates (e.g., sulfasalazine, mesalazine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin);

[0327] Immunosuppressants - mercaptopurine, corticosteroids (such as dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisolone), alkylating agents (e.g., cyclophosphamide), calcineurin inhibitors (e.g., cyclosporine, sirolimus, and tacrolimus), inosine monophosphate dehydrogenase (IMPDH) inhibitors (e.g., mycophenolate mofetil, mycophenolic acid, and azathioprine), and agents designed to inhibit cellular immunity while leaving 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 under the trade name Azasan from Salix Pharmaceuticals; mercaptopurine is currently available under the trade name Purinethol from Gate Pharmaceuticals; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available under the trade name Rapamune from Wyeth-Ayerst; tacrolimus is currently available under the trade name Prograf from Fujisawa; cyclosporine is currently available under the trade names Sandimmune from Novartis and Gengraf from Abbott; IMPDH inhibitors (e.g., mycophenolate mofetil and mycophenolic acid) are currently available under the trade name Cellcept from Roche and under the trade name Myfortic from Novartis; azathioprine is currently available under the trade name Imuran from Glaxo Smith Kline; and antibodies are currently available under the trade name Orthoclone from Ortho Biotech, under the trade name Simulect (basiliximab) from Novartis, and under the trade name Zenapax (daclizumab) from Roche; and

[0328] Guanylate cyclase C receptor agonists or incretins - such as linaclotide sold under the name Linzess.

[0329] These different agents can be used according to their standard or conventional dosages, as specified in the prescribing information accompanying the commercially available forms of these drugs (see also, prescribing information in the 2006 version of The Physician’s Desk Reference), the disclosure of which is incorporated herein by reference.

[0330] III. Method for Preparing Compounds

[0331] The compounds can be prepared by any suitable method understood by those of ordinary skill in the art. For the specific compounds in the following reference examples, an exemplary suitable method is provided, and may include the following first reaction step according to Scheme 1.

[0332]

[0333] Scheme 1

[0334] Referring to Scheme 1, a metal-mediated cross-coupling reaction can be used to couple a protected amine precursor 100 with an R 1 group 102 (which contains an "R 6 linker" group as illustrated in Scheme 1) to provide a cross-coupled product 104. In some embodiments, a transition metal catalyst, such as a palladium catalyst, can be used for the metal-mediated cross-coupling reaction. Exemplary palladium catalysts include, but are not limited to, Pd(0) catalysts (such as Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, etc.) or Pd(II) catalysts (such as XPhos Pd Generation 2 or Generation 3, PdCl2, Pd(OAc)2, etc.). In some embodiments, a palladium catalyst can be used in combination with another cocatalyst, such as CuI, to facilitate the cross-coupling reaction, for example, in the Sonogoshira reaction. The metal-mediated cross-coupling reaction includes the use of a base (such as an amine base (such as Et3N) or an inorganic base (such as Cs2CO3, Na2CO3, K2CO3, etc.)), and a solvent (such as dimethylformamide). Referring to Scheme 1, X is a group suitable for the metal-mediated cross-coupling, such as a halogen or a triflate group, and PG is an amine protecting group, which can be selected from, but not limited to, 9-fluorenylmethoxycarbonyl ("Fmoc") group, tert-butyloxycarbonyl ("Boc") group, trityl ("Tr") group, allyloxycarbonyl ("Alloc") group, benzyloxycarbonyl ("Cbz") group, etc.

[0335] Representative examples of the method steps shown in Scheme 1 are provided below in Schemes 2A-2F. By replacing the propargyl alcohol in Scheme 2A with the corresponding alkyne group that produces each of Compounds I-14 to I-17 and I-35, a method similar to that described in Scheme 2A can be used to prepare Compounds I-14 to I-17 and I-35; further modifications that can be used to achieve the final structures of Compounds I-14 to I-17 are discussed below.

[0336]

[0337] Scheme 2A

[0338]

[0339] Scheme 2B

[0340]

[0341] Scheme 2C

[0342]

[0343] Scheme 2D

[0344]

[0345] Scheme 2E

[0346]

[0347] Scheme 2F

[0348] Once the cross-coupled product 104 is prepared, it can be subjected to an optional linker group reduction step, in which a linker group containing one or more unsaturated sites can be reduced to a saturated linker group and / or a linker group with less unsaturation. If a linker reducing group is used, a deprotection step can then follow, and then an amide formation step, as illustrated in Scheme 3. Alternatively, if the linker group reduction step is not used, the cross-coupled product 104 can be deprotected and converted to an amide compound 302.

[0349]

[0350] Scheme 3

[0351] Referring to Scheme 3, an optional linker reduction step can be carried out. For example, if the linker contains unsaturated sites (e.g., double bonds or triple bonds), the unsaturated sites can be reduced such that it becomes fully saturated (e.g., reducing a double bond and / or triple bond to a single bond), or such that it has less unsaturation (e.g., reducing a triple bond to a double bond). In the context of the present disclosure, those of ordinary skill in the art will recognize suitable reagents for carrying out such an optional linker reduction step; however, an exemplary set of conditions includes exposing the cross-coupled product 104 to H2 in the presence of palladium on carbon. Since these steps are optional, they need not be carried out in all embodiments. Instead, in some embodiments, the cross-coupled product 104 can be deprotected to provide an amine, which is then converted to an amide compound 302 by reacting the amine with a suitable acid coupling partner 300, as illustrated in Scheme 3.

[0352] Representative examples of the method steps shown in Scheme 3 are provided below in Schemes 4A - 4M. A method similar to that described in Scheme 4A can be used to prepare Compounds I - 14 to I - 17. Compounds I - 16 and I - 17 can be further functionalized as discussed below.

[0353]

[0354] Scheme 4A

[0355]

[0356] Scheme 4B

[0357]

[0358] Scheme 4C

[0359]

[0360] Scheme 4D

[0361]

[0362] Scheme 4E

[0363]

[0364] Scheme 4F

[0365]

[0366] Scheme 4G

[0367]

[0368] Scheme 4H

[0369]

[0370] Scheme 4I

[0371]

[0372] Scheme 4J

[0373]

[0374] Scheme 4K

[0375]

[0376] Scheme 4L

[0377]

[0378] Scheme 4M

[0379] In some embodiments, the method may further comprise performing one or more additional modifications on the amide compound 302 to provide amide compound 500, such as modifying the R 6 group to form a different R 6 group, as illustrated in Scheme 5.

[0380]

[0381] Scheme 5

[0382] Referring to Scheme 5, one or more modifications of the R 6 group can be performed. For example, if R 6 is an ester group, it can be converted to a carboxylic acid or to a primary alcohol. In light of the benefits of the present disclosure, those of ordinary skill in the art will recognize suitable reagents for performing such an optional modification step; however, an exemplary set of conditions includes exposing the R 6 ester group to LiOH to provide the corresponding acid, e.g., as illustrated in Schemes 6A - 6E. By using suitable amide coupling conditions (such as those described above) in combination with an amine coupling partner, the resulting acid can even be further modified to provide an amide-containing product, e.g., as illustrated in Schemes 6A - 6E. Similar methods can be used to prepare Compounds I-10, I-11, I-13, I-18, I-19, I-26, I-27, I-33, I-34, and I-22 and I-23 (where the double bond of the linker group is not first reduced prior to coupling). In still further embodiments, Compounds I-16 and I-17 can be prepared by converting the terminal alcohol obtained in the above method to a functionalized alcohol (such as Compound I-16) or to an amine (such as Compound I-17).

[0383]

[0384] Scheme 6A

[0385]

[0386] Scheme 6B

[0387]

[0388] Scheme 6C

[0389]

[0390] Scheme 6D

[0391]

[0392] Scheme 6E IV. Methods of Using the Compounds

[0393] A. Disease / Disorder

[0394] The disclosed compounds, as well as their combinations and / or pharmaceutical compositions, can be used to inhibit RIP1 kinase by contacting a kinase in vivo or in vitro with one or more compounds of the present disclosure, or a composition comprising one or more compounds of the present disclosure. One or more compounds of the present disclosure, or a composition comprising one or more compounds of the present disclosure, can also be used to alleviate, treat, or prevent various diseases and / or disorders. In specific embodiments, the disclosed compounds, combinations of the disclosed compounds, or their pharmaceutical compositions can be used to treat conditions in which inhibiting RIP1 or involving the RIP1 pathway is therapeutically useful. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds can be used to treat autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancer, ischemic conditions, erythrocyte deficiency, lung and brain injury (e.g., induced by ischemia reperfusion or cisplatin and / or cerebrovascular accident), and bacterial and viral infections.

[0395] In some embodiments, the disclosed compounds, combinations of the disclosed compounds, or their pharmaceutical compositions can be used to treat or prevent allergic diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, or asthma.

[0396] The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can also be used to treat immunomodulatory disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory or immunomodulatory disorders that can be treated with the compounds (or their pharmaceutical compositions or combinations) include, but are not limited to, transplantation of organs or tissues, graft-versus-host disease resulting from transplantation, autoimmune syndromes, including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases (including rheumatic fever and post-infectious glomerulonephritis), inflammatory and proliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpes keratitis, keratoconus, corneal epithelial dystrophy, leukoma cornea, ocular pemphigus, corneal erosive ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway diseases, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or intractable asthma, late-phase asthma, and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular injury caused by ischemic diseases and thrombosis, ischemic bowel disease, ischemia-reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, polyneuropathy, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythrogenesis imperfecta, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortic syndrome, polyarteritis nodosa, cardiomyopathy or myocardial infarction, scleroderma (including systemic scleroderma), antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, obesity, eosinophilic fasciitis,Lesions of the gingiva, periodontal tissue, alveolar bone, and cementum (substantia osseadentis), glomerulonephritis, male pattern baldness or senile alopecia by preventing hair loss or providing hair growth and / or promoting hair generation and hair growth, muscular dystrophy, pyoderma, and Sézary's syndrome, Addison's disease, ischemia-reperfusion injury occurring after organ preservation, transplantation or ischemic diseases, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxicosis caused by pulmonary oxygen or drugs, lung cancer, emphysema, cataract, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scar, alkaline corneal burn, dermatitis, erythema multiforme, linear IgA bullous dermatitis, and intractable dermatitis, gingivitis, periodontitis, septicemia, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, cancer metastasis, and hypobaropathy, diseases caused by histamine or leukotriene-C4 release, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute hepatic necrosis, necrosis caused by toxins, viral hepatitis, shock, or anoxia, hepatitis B virus, non-A / non-B hepatitis, cirrhosis, alcoholic liver disease (including alcoholic cirrhosis), alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), autoimmune hepatobiliary diseases, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, late-onset liver failure, "acute-on-chronic" liver failure, chronic kidney disease, kidney damage / injury (caused by, for example, nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs, acute kidney injury), increased chemotherapy efficacy, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, Parkinson's disease, trauma, or chronic bacterial infection.,

[0397] In certain embodiments, the compounds of the invention can be used to treat neuropathic pain, including pain caused by neuropathy and inflammation.

[0398] In certain embodiments, the compounds can be used to treat interleukin-1 converting enzyme-related fever syndromes, tumor necrosis factor receptor-associated periodic syndromes, NEMO deficiency syndromes, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndromes, lysosomal storage diseases (such as Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, sialidosis, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease).

[0399] In certain embodiments, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be used to treat and / or prevent rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis (especially pustular psoriasis), type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia and periodic fever syndromes, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout attacks, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptor antagonist), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0400] Proliferative diseases that can be treated by the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof include benign or malignant tumors, solid tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, gastric tumors, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, urogenital cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, malignant glioma, neuroblastoma, multiple myeloma, gastrointestinal cancer (especially colon cancer or colorectal adenoma), head and neck tumors, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, 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-driven disorders, MyD88-driven disorders (such as ABC diffuse large B-cell lymphoma (DLBCL), Waldenström macroglobulinemia( macroglobulinemia), Hodgkin's lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), smoldering or asymptomatic multiple myeloma, or hematological malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, or intravascular large B-cell lymphoma). Specifically, the compounds of the present disclosure can be used to treat drug-resistant malignancies, such as those resistant to the JAK inhibitor ibrutinib, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenström macroglobulinemia.

[0401] Examples of allergic disorders that can be treated using the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof include, but are not limited to, asthma (e.g., allergic asthma, atopic asthma, atopic bronchial IgE-mediated asthma, non-allergic asthma, bronchial asthma, non-atopic asthma, idiopathic asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, idiopathic asthma of unknown or obscure origin, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, extrinsic asthma caused by environmental factors, cold air-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoal, or viral infections, early asthma, asthmatic infant syndrome, bronchiolitis, cough variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, nasal discharge, purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis).

[0402] As another example, rheumatoid arthritis (RA) typically results in swelling, pain, loss of motion, and tenderness of systemic target joints. RA is characterized by chronic inflammatory synovium with dense lymphocytes. The synovium, typically one cell layer thick, becomes hypercellular and assumes a form similar to lymphoid tissue (including dendritic cells, T cells, B cells, and NK cells, macrophages, and clusters of plasma cells). This process, along with numerous immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, ultimately leads to destruction of the integrity of the joint, which results in deformity at or near the joint, permanent loss of function, and / or bone erosion. The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be used to treat, alleviate, or prevent any one, several, or all of these RA symptoms. Thus, in the context of RA, a compound is considered to provide a therapeutic benefit when any symptom commonly associated with RA is reduced or alleviated, regardless of whether the treatment results in a reduction in the amount of circulating rheumatoid factor ("RF") and / or combination therapy for RA below.

[0403] The American College of Rheumatology (ACR) has developed criteria for defining improvement and clinical remission in RA. Once such parameters, ACR20 (ACR criteria for 20% clinical improvement) requires a 20% improvement in the counts of tender and swollen joints, and a 20% improvement in 3 of the following 5 parameters: patient global assessment, physician global assessment, patient pain assessment, disability level, and acute phase reactant level. These criteria are increased to 50% and 70% in ACR50 and ACR70, respectively. Other criteria include Paulu's criteria and radiological progression (such as the Sharp score).

[0404] In some embodiments, patients suffering from RA obtain a therapeutic benefit when they exhibit ACR20. In a specific embodiment, an ACR improvement of ACR50 or even ACR70 can be achieved.

[0405] B. Formulation and Administration

[0406] A pharmaceutical composition comprising one or more active compounds of the present invention can be manufactured by any suitable method, such as mixing, dissolving, granulating, sugarcoating, grinding, emulsifying, encapsulating, entrapping, or lyophilization processes. These pharmaceutical compositions can be formulated using one or more physiologically acceptable excipients (such as diluents, carriers, or adjuvants), one or more adjuvants, or a combination thereof to provide a pharmaceutically usable formulation.

[0407] One or more active compounds per se can be formulated as a pharmaceutical composition, or in the form of a pharmaceutically acceptable salt, stereoisomer, N - oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts can also be formed that have lower solubility than the corresponding free acids and bases.

[0408] The pharmaceutical compositions of the present invention can take almost any mode suitable for administration, including, for example, topical, ocular, oral, buccal, systemic, intranasal, injection (such as intraperitoneal or intravenous), transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0409] For topical administration, the one or more active compounds, pharmaceutically acceptable salts, stereoisomers, N - oxides, tautomers, hydrates, solvates, isotopes, or prodrugs can be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art.

[0410] Systemic formulations include those designed for administration by injection (such as subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), along with those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0411] Useful injectable formulations include sterile suspensions, solutions, or emulsions of one or more active compounds in aqueous or oily vehicles. These pharmaceutical compositions can also contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. These formulations for injection can be in unit dosage forms, for example, in ampoules or in multi - dose containers, and can contain added preservatives.

[0412] Alternatively, before use, the injectable formulation can be provided in the form of a powder for reconstitution with a suitable vehicle, which includes but is not limited to sterile, pyrogen-free water, buffers, glucose solutions, etc. To this end, the one or more active compounds can be dried by any technique known in the art (such as lyophilization) and reconstituted before use.

[0413] For transmucosal administration, permeation enhancers suitable for the barrier to be penetrated are used in the formulation. Such permeation enhancers are known in the art.

[0414] For oral administration, the pharmaceutical composition can take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients (such as binders (such as pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (such as lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (such as magnesium stearate, talc or silica); disintegrants (such as potato starch or sodium starch glycolate); and / or wetting agents (such as sodium lauryl sulfate)). These tablets can be coated by methods well known in the art, such as with sugar, film or enteric coatings.

[0415] Liquid preparations for oral administration can take the form of, for example, elixirs, solutions, syrups or suspensions, or they can exist as a dry product to be compounded with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable excipients (such as suspending agents (such as sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (such as lecithin or gum arabic); non-aqueous vehicles (such as almond oil, esters of fatty acids, ethanol, cremophore TM or fractionated vegetable oils); and preservatives (such as methyl paraben or propyl paraben or sorbic acid)). These preparations can also optionally contain buffer salts, preservatives, flavoring agents, coloring agents and sweetening agents.

[0416] As is well known, preparations for oral administration can be suitably formulated to give controlled release of the active compound.

[0417] For buccal administration, these pharmaceutical compositions can take the form of tablets or lozenges formulated in a conventional manner.

[0418] For rectal and vaginal routes of administration, the one or more active compounds can be formulated as solutions (for retention enemas), suppositories or ointments containing conventional suppository bases (such as cocoa butter or other glycerides).

[0419] For nasal administration or administration by inhalation or insufflation, the one or more active compounds, pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs can be conveniently delivered in the form of a spray from a pressurized package or nebulizer using a suitable propellant, which is, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluorocarbons, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules or cartridges (e.g., capsules and cartridges comprising gelatin) can be formulated for use in an inhaler or insufflator, which contain a powder mixture of the compound and a suitable powder matrix (e.g., lactose or starch).

[0420] Specific examples of aqueous suspension formulations suitable for nasal administration using commercially available nasal spray devices include the following components: active compound (0.5 - 20 mg / ml); benzalkonium chloride (0.1 - 0.2 mg / mL); polysorbate 80( 80; 0.5 - 5 mg / ml); sodium carboxymethylcellulose or microcrystalline cellulose (1 - 15 mg / ml); phenethyl alcohol (1 - 4 mg / ml); and glucose (20 - 50 mg / ml). The pH of the final suspension can be adjusted to a range from about pH 5 to pH 7, with a typical pH being about 5.5.

[0421] Another specific example of an aqueous suspension suitable for administering the compound by inhalation contains 20 mg / mL of one or more of the disclosed compounds, 1% (v / v) polysorbate 80( 80), 50 mM citric acid, and / or 0.9% sodium chloride.

[0422] For ocular administration, the one or more active compounds can be formulated as solutions, emulsions, suspensions, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Patent Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851, which are incorporated herein by reference.

[0423] For extended delivery, the one or more active compounds may be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient may be formulated with a suitable polymer or a hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or may be formulated as a sparingly soluble derivative, e.g., as a sparingly soluble salt. Alternatively, a transdermal delivery system in the form of an adhesive disk or patch manufactured to slowly release one or more active compounds for transdermal absorption may be used. For this purpose, a penetration enhancer may be used to facilitate the transdermal penetration of the one or more active compounds. Suitable transdermal patches are described, for example, in U.S. Patent Nos. 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which are incorporated herein by reference.

[0424] Alternatively, other drug delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver the one or more active compounds. Certain organic solvents (such as dimethyl sulfoxide (DMSO)) may also be employed, although usually at the cost of greater toxicity.

[0425] If desired, the pharmaceutical composition may be presented in a package or dispenser device that may comprise one or more unit dosage forms containing the one or more active compounds. The package may, for example, comprise a metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for administration.

[0426] C. Dosage

[0427] The disclosed compounds, pharmaceutical compositions, or combinations of the disclosed compounds will generally be used in an amount effective to achieve the intended result, e.g., in an amount effective to inhibit RIP1 kinase and / or effective to treat, prevent, or alleviate a specific disorder. The one or more disclosed compounds or their pharmaceutical compositions may be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. A therapeutic benefit means the eradication or alleviation of the underlying disorder being treated and / or the eradication or alleviation of one or more symptoms associated with the underlying disorder such that, although the patient may still be afflicted with the underlying disorder, the patient reports a reduction in feeling or condition. For example, administering a compound to a patient suffering from allergies provides a therapeutic benefit not only when the underlying allergic response is eradicated or alleviated, but also when the patient reports a reduction in the severity or duration of allergy-related symptoms after exposure to an allergen. As another example, a therapeutic benefit in the context of asthma includes improvement in breathing after the onset of an asthma attack or a decrease in the frequency or severity of asthma attacks. Whether or not improvement is achieved, a therapeutic benefit also includes the halt or slowdown of the progression of the disease.

[0428] As is known to those of ordinary skill in the art, the preferred dosage of the disclosed compounds may depend on various factors, including the age, weight, general health, and severity of the disorder of the patient or subject being treated. When administered by inhalation, the dosage may also need to be adjusted to accommodate the sex of the individual and / or the lung capacity of the individual. The dosage may also be adjusted to accommodate an individual suffering from more than one disorder or having additional disorders (e.g., emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and respiratory infections) that affect lung capacity and normal breathing ability. The dosage and frequency of administration of the one or more disclosed compounds or their pharmaceutical compositions will also depend on whether the one or more disclosed compounds are formulated for the treatment of an acute episode of a disorder or for prophylactic treatment of a disorder. A person skilled in the art or one of ordinary skill will be able to determine the optimal dosage for a particular individual.

[0429] For prophylactic administration, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a patient or subject at risk of developing one of the previously described conditions. For example, if it is not known whether a patient or subject is allergic to a particular drug, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered prior to administration of the drug to avoid or mitigate an allergic reaction to the drug. Alternatively, prophylactic administration can be used to avoid or mitigate the onset of symptoms in a patient diagnosed with the underlying disorder. For example, prior to the anticipated exposure to an allergen, one or more of the disclosed compounds, or pharmaceutical compositions thereof, can be administered to an allergy sufferer. The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can also be prophylactically administered to a healthy individual to prevent the onset of the disorder, the healthy individual being repeatedly exposed to an agent known to cause one of the above diseases. For example, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a healthy individual who is repeatedly exposed to an allergen (such as latex) known to cause allergies in an attempt to prevent the individual from developing allergies. Alternatively, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a patient with asthma prior to participating in an activity that triggers an asthma attack to reduce the severity of the asthma attack or to completely avoid the asthma attack.

[0430] An effective dose can be initially estimated from in vitro assays. For example, an initial dose for a subject can be formulated to achieve a circulating blood or serum concentration of the active compound equal to or higher than the IC 50 or EC 50 of a particular compound as measured in an in vitro assay. Taking into account the bioavailability of the particular compound, the dose can be calculated to achieve such a circulating blood or serum concentration. Fingl and Woodbury, “General Principles”, in: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, Pergamon Press, and the references cited therein, provide additional guidance on effective doses.

[0431] In some embodiments, the disclosed compounds have an EC 50 from greater than 0 to 20 μM (such as from greater than 0 to 10 μM, from greater than 0 to 5 μM, from greater than 0 to 1 μM, from greater than 0 to 0.5 μM, from greater than 0 to 0.1 μM, or from greater than 0 to 0.05 μM).

[0432] Initial doses can also be estimated from in vivo data such as animal models. Animal models for testing the efficacy of a compound in treating or preventing the various diseases described above are well known in the art. Suitable animal models for hypersensitivity or allergic reactions are described in: Foster, (1995) Allergy, 50 (Suppl 21): 6-9, discussion 34-38; and Tumas et al., (2001), J. Allergy Clin. Immunol. 107(6):1025-1033. Suitable animal models for allergic rhinitis are described in: Szelenyi et al., (2000), Arzneimittelforschung 50(11):1037-42; Kawaguchi et al (1994), Clin. Exp. Allergy 24(3):238-244; and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7. One of ordinary skill in the art can adjust such information to determine a dose suitable for human administration.

[0433] In some embodiments, assays suitable for determining RIP1 activity can be used. Such assay methods can be used to evaluate the efficacy of the compound embodiments disclosed herein, and / or can be used to determine the amount / dose of a compound embodiment that can provide the desired efficacy. In some embodiments, the assay can be the ADP-Glo TM assay for evaluating the ability of a compound embodiment to inhibit RIP1. In other embodiments, whole cell assays using necrosis assays of mouse and / or human cells (such as U937 and / or L929 cells) can be performed to determine the effective dose of a compound for use in human in vivo studies. Using whole cell assays, the activity of a compound against human and / or murine RIP1 can be evaluated in an in vitro context, which then allows one of ordinary skill in the art to determine a safe and effective dose for in vivo use. Yet another assay that can be used to evaluate the activity of the compound embodiments described herein in treating diseases or disorders involving RIP1 is the acute hypothermic mouse model, which evaluates the ability of a compound to inhibit TNF-α-induced hypothermia. Each of these assays, and the different results from using these assays, are described in detail in the Examples section of the present disclosure.

[0434] The dosage of the disclosed compounds will typically range from greater than 0 mg / kg / day (e.g., 0.0001 mg / kg / day or 0.001 mg / kg / day or 0.01 mg / kg / day) up to at least about 100 mg / kg / day. More typically, the dosage (or effective amount) can range from about 0.0025 mg / kg to about 1 mg / kg, such as from 0.01 mg / kg to about 0.5 mg / kg, or from about 0.05 mg / kg to about 0.15 mg / kg, administered at least once a day. The total daily dosage typically ranges from about 0.1 mg / kg to about 5 mg / kg or up to about 20 mg / kg per day, such as from 0.5 mg / kg to about 10 mg / kg per day or from about 0.7 mg / kg to about 2.5 mg / kg per day. Among other factors, the dosage can be higher or lower, depending on the activity of the disclosed compounds, their bioavailability, the mode of administration, and the various factors discussed above.

[0435] The dosage and dosage interval can be adjusted for an individual to provide a plasma level of the disclosed compounds sufficient to maintain a therapeutic or prophylactic effect. For example, the compounds can be administered once a day, multiple times a day, once a week, multiple times a week (e.g., every other day), once a month, multiple times a month, or once a year, among other things, depending on the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. Without undue experimentation, one of ordinary skill in the art can optimize the effective topical dosage.

[0436] A pharmaceutical composition comprising one or more of the disclosed compounds typically comprises from greater than 0 up to 99% of one or more of the disclosed compounds, and / or other therapeutic agents (by weight percentage). More typically, a pharmaceutical composition comprising one or more of the disclosed compounds comprises from about 1 to about 20 total weight percentage of the disclosed compounds and other therapeutic agents, and from about 80 to about 99 weight percentage of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition can further comprise an adjuvant.

[0437] Preferably, the disclosed compounds, combinations of the disclosed compounds, or their pharmaceutical compositions will provide a therapeutic or prophylactic benefit without causing substantial toxicity. The toxicity of the disclosed compounds can be determined using standard pharmaceutical procedures. The dosage ratio between toxicity and therapeutic (or prophylactic) effect is the therapeutic index. Disclosed compounds exhibiting a high therapeutic index are preferred.

[0438] V. Examples

[0439] Example 1

[0440] The compounds of the present disclosure can be prepared using suitable starting compounds (e.g., compound 200 or compound 206) described in the above schemes. A representative method for preparing compound 200 is illustrated in Scheme 7A, and a representative method for preparing compound 206 is illustrated in Scheme 7B.

[0441]

[0442] Scheme 7A

[0443]

[0444] Scheme 7B

[0445] Spectral characterization of 3-(S)-N-trityl-amino-7-bromo-5-methyl-4-oxobenzoxazepine (200): 1 H nmr (400 MHz, CDCl3) δ 7.41 - 7.38 (6H, m, 6H of C(C6H5)3), 7.25 - 7.15 (10H, m, oxobenzoxazapine H-8, 9H of 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, J11.5, 7.5 Hz, oxobenzoxazapine H-3), 3.30 (1H, br s, NH), 2.87 (3H, s, NCH3).

[0446] Characterization data and specific methods for preparing representative compounds disclosed herein are provided below.

[0447] Example 2

[0448]

[0449] Synthesis of (S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydro-1,4-benzoxazepin-4(5H)-one: A mixture of bromooxazepine (0.210 g, 0.410 mmol, 1.0 equiv), potassium carbonate (0.566 g, 4.101 mmol, 10.0 equiv), and copper(I) iodide (0.008 g, 0.041 mmol, 0.1 equiv) in dimethylformamide (3.0 mL) was degassed by bubbling argon for five minutes. 2-Methyl-2-hydroxybut-3-yne (0.052 g, 0.060 mL, 0.615 mmol, 1.5 equiv) and tetrakis(triphenylphosphine)palladium (0.024 g, 0.021 mmol, 0.05 equiv) were added, and the reaction was sealed and then heated in a microwave to 120 °C for 1 hour. The reaction was partitioned between EtOAc (80 mL) and water (80 mL). The organic layer was washed with brine (80 mL), water (80 mL), and brine (80 mL), dried (Na2SO4), and concentrated under reduced pressure. MPLC (10→80% EtOAc-hexanes) gave the starting material (0.091 g) and the title compound as a colorless oil (0.079 g); 1 1H NMR (400 MHz, CDCl3) δ 7.40 - 7.38 (6H, m, 6H of C(C6H5)3), 7.24 - 7.14 (9H, m, 9H of C(C6H5)3), 7.13 (1H, dd, J 8.0, 2.0 Hz, benzoxazepine H-8), 6.96 (1H, d, J 8.0 Hz, benzoxazepine H-9), 6.95 (1H, d, J 2.5 Hz, benzoxazepine H-6), 4.48 (1H, dd, J 10.0, 7.5 Hz, 1H of benzoxazepine H-2), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H of benzoxazepine H-2), 3.55 (1H, dd, J 11.5, 7.5 Hz, benzoxazepine H-3), 2.78 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2); m / z: 555 [M+K] + , 243 [C(C6H5)3] + .

[0450]

[0451] Deprotection of the trityl group: To a solution of trityl-protected amine (0.079 g, 0.153 mmol, 1.0 equiv) in dioxane (2.0 mL) was added a solution of hydrogen chloride (0.15 mL of a 4 M solution in dioxane, 0.614 mmol, 4.0 equiv). The reaction was stirred at room temperature for 6 h, then concentrated to dryness to afford a white solid that was used without purification; m / z: 275 [M+H] + 。

[0452]

[0453] (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 synthesis: To a solution of aminooxybenzoxazepine hydrochloride (0.076 mmol, 1.0 equiv) and benzotriazolecarboxylic acid (0.017 g, 0.084 mmol, 1.1 equiv) in dimethylformamide (1.0 mL) was added diisopropylamine (0.025 g, 0.033 mL, 0.190 mmol, 2.5 equiv), followed by HATU (0.032 g, 0.084 mmol, 1.1 equiv). The reaction was stirred at room temperature for 4 h and partitioned between EtOAc-CH2Cl2 (5:1, 60 mL) and NaHCO3 (60 mL). The organic layer was washed with brine (50 mL), water (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH-CH2Cl2) gave the title compound as a white solid; 1 Hnmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.30 - 7.22 (7H, m, 7 x ArH), 7.11 (1H, d, J9.0 Hz, benzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, benzoxazepine H-3), 4.68 (1H, dd, J 10.0, 7.5 Hz, 1H of benzoxazepine H-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H of benzoxazepine H-2), 4.14 (2H, s, CC H 2C6H5), 3.40 (3H, s, NCH3), 1.63 (6H, s, C(C H 3)2OH); m / z: 442 [M+H-H2O] + 。

[0454] Steps similar to those of Example 2 above can be used to prepare Compounds I-14, I-17, and I-35.

[0455] Example 3

[0456]

[0457] Synthesis of ethyl (S,E)-3-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)acrylate: A suspension of tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (0.500 g, 1.35 mmol, 1.0 equiv) in dimethylformamide (8 mL) was degassed by bubbling argon for five minutes. Ethyl acrylate (0.270 g, 0.29 mL, 2.70 mmol, 2.0 equiv) and triethylamine (0.272 g, 0.37 mL, 2.0 equiv) were added, followed by tetrakis(triphenylphosphine) (0.156 g, 0.14 mmol, 0.1 equiv). The reaction was sealed and heated in a microwave to 100 °C for 1 hour and then to 120 °C for 1 hour. The reaction was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (70 mL), water (100 mL), and brine (70 mL), dried (Na2SO4), and concentrated under reduced pressure. Column chromatography (10% → 40% EtOAc-hexane) gave the title compound as a yellow foam (0.250 g, %). 1 H nmr (400 MHz, CDCl3) δ 7.62 (1H, d, J 16.0 Hz, ArCH=C H CO), 7.35 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazepine H-8), 7.33 (1H, d, J 2.0 Hz, oxobenzoxazepine H-6), 7.14 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 6.37 (1H, d, J 16.0 Hz, ArC H =CHCO), 5.49 (1H, d, J 7.0 Hz, NH), 4.65 (1H, dt, J 11.0, 7.0 Hz, oxobenzoxazepine H-3), 4.57 (1H, dd, J 9.5, 7.0 Hz, 1H of oxobenzoxazepine H-2), 4.27 (2H, q, J 7.0 Hz, OC H2CH3), 4.19 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.41 (3H, s, NCH3), 1.39 (9H, s, C(CH3)3), 1.34 (3H, t, J 7.0 Hz, OCH2C H 3); m / z: 291 [M + H - CO2 - C4H8] + 。

[0458]

[0459] Synthesis of ethyl (S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate: To a solution of the α,β-unsaturated ester (0.25 g, 0.64 mmol, 1.0 equiv) in ethyl acetate (20 mL) was added palladium on carbon (0.23 g). The reaction was purged with hydrogen and stirred under a hydrogen atmosphere for 14 h. The reaction was purged with nitrogen and filtered, eluting with ethyl acetate (2 x 20 mL). The filtrate was concentrated under reduced pressure; filtered, eluting with ethyl acetate (2 x 20 mL). The filtrate was concentrated under reduced pressure; 1 1H NMR (400 MHz, CDCl3) δ 7.04 - 6.82 (3H, m, oxobenzoxazepine H-6, H-8, H-9), 5.50 (1H, d, J 7.5 Hz, NH), 4.61 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.52 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.14 - 4.07 (1H, m, 1H of oxobenzoxazepine H-2), 4.12 (2H, q, J 7.0 Hz, OCH2CH3), 3.36 (3H, s, NCH3), 2.91 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 2.59 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 1.37 (9H, s, C(CH3)3), 1.23 (3H, t, J 7.0 Hz, OCH2CH3); m / z: 337 [M + H - C4H8] + , 293 [M + H - CO2 - C4H8] + 。The crude material was dissolved in dichloromethane (10 mL). Hydrogen chloride (0.80 mL of a 4 M solution in dioxane, 3.21 mmol, 5.0 equiv). The reaction was stirred at room temperature for 14 h, after which an additional hydrogen chloride solution (0.8 mL, 5.0 equiv) was added. After stirring for an additional 2 h, the reaction was concentrated under reduced pressure and dried in vacuo to afford a brown solid. The crude material was used without further purification; m / z: 293 [M + H]+ 。

[0460]

[0461] Synthesis of ethyl (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate: Fluorobenzyltriazole (0.116 g, 0.525 mmol, 1.1 eq) was added to a solution of ethyl (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propionate (0.140 g, 0.477 mmol, 1.0 eq) and diisopropylethylamine (0.154 g, 0.21 mmol, 2.5 eq) in dimethylformamide (5.0 eq). HATU (0.199 g, 0.525 mmol, 1.1 eq) was added and the reaction was stirred at 0 °C for 1 h and at room temperature for 1 h. The reaction was partitioned between EtOAc (120 mL) and NaHCO3 - water (1:1, 120 mL). The organic layer was washed with brine (100 mL), water (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (40→80% EtOAc - hexane) gave the title compound (0.138 mg) as a white solid; 1 1H nmr (400 MHz, CDCl3) δ 8.11 (1H, s, triazole H-5), 8.05 (1H, d, 7.0 Hz, NH), 7.38 - 7.30 (2H, m, 2H of C6H4F), 7.26 - 7.07 (6H, m, 2H of C6H4F, oxobenzoxazepine H-6, H-7, H-8, H-9), 5.42 (2H, s, C H 2C6H4F), 5.08 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.24 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.42 (3H, s, NCH3); 13C NMR (100 MHz, CDCl₃) δ 168.9, 160.6 (d, J 248.5 Hz), 158.3, 156.7, 150.1, 144.1 (d, J 2.0 Hz), 136.0, 131.1 (d, J 8.5 Hz), 130.9 (d, J 2.5 Hz), 127.6, 125.7, 124.9 (d, J Hz), 123.3, 123.1, 121.2 (d, J 14.0 Hz), 115.8 (d, J 21.5 Hz), 77.3, 49.2, 47.9 (d, J 4.0 Hz), 35.5; 19 F NMR (380 MHz, CDCl₃) δ -118.1; m / z: 518 [M+Na] + , 496 [M+H] + (Found [M+H] + , 496.1991, C 25 H 26 FN₅O₅ requires [M+H] + 496.1973).

[0462] Steps similar to those above for Example 3 and those below for Examples 4 and 5 can be used to prepare Compounds I-10, I-11, I-13, I-18, I-19, I-26, I-27, I-33, I-34, and I-22 and I-23 (where the double bond of the linker group is not reduced prior to coupling).

[0463] Example 4

[0464]

[0465] (S)-3-(3-(1-(2-Fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoic acid synthesis: To a solution of the ethyl ester (0.103 g, 0.208 mmol, 1.0 equiv) in tetrahydrofuran (3 mL) was added aqueous lithium hydroxide (0.017 g, 0.416 mmol, 2.0 equiv, in 1 mL of water). The reaction was stirred at room temperature for 3 h, 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 brine (80 mL), dried (Na₂SO₄), and concentrated under reduced pressure. Column chromatography (0 → 10% MeOH-CH₂Cl₂) gave the title compound as a white solid (0.054 g, %). 11H NMR (400 MHz, CDCl3) δ 8.12 (1H, s, triazole H-5), 8.04 (1H, d, J 7.5 Hz, NH), 7.40 - 7.30 (2H, m, 2 x ArH), 7.16 (1H, dd, J 7.5, 1.0 Hz, 1 x ArH), 7.14 - 7.10 (2H, m, 2 x ArH), 7.07 (2H, m, 2 x ArH), 5.43 (2H, s, NC H 2C6H5F), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.22 (1H, dd, J 11.0, 9.5 Hz, 1H of oxabenzoxazepine H-2), 3.41 (3H, s, NCH3), 2.96 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 2.70 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO); 19 19F NMR (CDCl3) δ -118.1 (dd, J 16.5, 7.0 Hz); m / z: 468 [M+H] + (found [M+H] + , 468.1688, C 23 H 22 FN5O5 requires [M+H] + 468.1678).

[0466] Example 5

[0467]

[0468] 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: A solution of (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoic acid (0.049 g, 0.105 mmol, 1.0 equiv) and 6-aminoindazole (0.017 g, 0.126 mmol, 1.2 equiv) in dimethylformamide (10 mL) was cooled to 0 °C. Diisopropylethylamine (0.027 g, 0.036 mL, 0.210 mmol, 2.0 equiv) was added, followed by HATU (0.048 g, 0.126 mmol, 1.2 equiv), and the reaction was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction was partitioned between EtOAc (50 mL) and NaHCO3 (50 mL). The organic layer was washed with brine (50 mL). The combined aqueous phases were extracted with EtOAc (20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (0 → 10% MeOH-CH2Cl2) gave the title compound as a white solid (0.xx g, %). 1 H nmr (400 MHz, CDCl3) δ 8.12 (1H, s, triazole H-5), 8.00 (1H, d, J 7.5 Hz, NH), 7.94 (1H, d, J 0.5 Hz, indazole H-3), 7.90 (1H, s, NH), 7.83 (1H, m, indazole H-7), 7.57 (1H, d, J 9.0 Hz, indazole H-4), 7.37 - 7.30 (2H, m, 2H of C6H4F), 7.13 (1H, td, J 7.5, 1.0 Hz, 1H of C6H4F), 7.09 - 7.00 (5H, m, indazole H-5, 1H of C6H4F, oxobenzoxazepine H-6, H-7, H-9), 5.40 (2H, s, NC H 2C6H4F), 5.02 (1H, td, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.63 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.23 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.29 (3H, s, NCH3), 3.03 (2H, t, J 7.0 Hz, ArC H2CH2CON), 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] + (Found [M+H] + , 583.2205, C 30 H 27 FN8O4 requires [M+H] + 583.2212).

[0469] Example 6

[0470]

[0471] 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)propionate: 1 H nmr(400MHz, CDCl3) δ 8.02(1H, d, J 7.0Hz, NH), 7.96(1H, s, triazole H-5), 7.42(2H, m, 2 x ArH), 7.32(1H, dd, J 9.0, 7.0Hz, 1 x ArH), 7.10(1H, m, 1 x ArH), 7.06(2H, dd, J 6.0, 2.0Hz, 2 x ArH), 5.70(2H, s, CH2C6H3Cl2), 5.07(1H, dt, J 11.0, 7.5Hz, oxobenzoxazepine H-3), 4.74(1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazepine H-2), 4.21(1H, dd, J 11.0, 9.5Hz, 1H of oxobenzoxazepine H-2), 4.14(2H, q, J 7.0Hz, OC H2CH3), 3.41 (3H, s, NCH3), 2.95 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 2.63 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 1.24 (3H, t, J 7.0 Hz, OCH2C H 3); 13 C nmr (100 MHz, CDCl3) δ 172.5, 168.9, 158.3, 156.5, 148.4, 143.9, 138.4, 136.9, 135.8, 131.4, 129.1, 128.9, 127.5, 123.2, 122.9, 77.2, 60.6, 49.4, 49.3, 35.7, 35.5, 30.3, 14.2; m / z: 548, 546 [M+H] + (Found [M+H] + , 546.1291, C 25 H 25 Cl2N5O5 requires [M+H] + 546.1306).

[0472] Example 7

[0473]

[0474] (S)-3-(3-(5-Benzyl-1H-1,2,4-triazole-3-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoic acid: 1 H nmr (400 MHz, CDCl3) δ 8.13 (1H, d, J 7.5 Hz, NH), 7.32 - 7.22 (5H, m, 5 x ArH), 7.08 - 7.06 (3H, m, 3 x ArH), 4.97 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.62 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.24 (1H, dd, J11.0, 9.5 Hz, 1H of oxabenzoxazepine H-2), 4.13 (2H, s, C H 2C6H5), 3.38 (3H, s, NCH3), 2.94 (2H, m, ArC H 2C H 2CO2H's 2H), 2.70 (2H, m, ArC H 2C H 2CO2H's 2H); 19 F nmr (CDCl3) δ -118.1; m / z: 450 [M+H]+ (Found [M+H] + ,450.1760,C 23 H 23 N5O5 requires [M+H] + 450.1772).

[0475] Example 8

[0476]

[0477] (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: 1 H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.29 - 7.21 (5H, m, 5 x ArH), 7.10 - 7.07 (3H, m, 3 x ArH), 5.05 (1H, dt, J11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.22 (1H, dd, J 11.0, 9.5 Hz, 1H of benzoxazepine 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, J7.5 Hz, 2H of ArCH2CH2CO), 2.57 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 1.92 (2H, m, 2H of pyrrolidine), 1.83 (2H, m, 2H of pyrrolidine); 13 C nmr (100 MHz, CDCl3) δ 170.4, 168.9, 158.5, 148.2, 139.5, 135.9, 135.7, 128.9, 128.8, 127.6, 127.1, 123.5, 122.7, 77.1.49.2, 46.6, 45.8, 36.6, 35.5, 33.2, 30.4, 26.0, 24.4; m / z: 503 [M+H] + (Found [M+H] + ,503.2403,C 27 H 30 N6O4 requires [M+H] + 503.2401).

[0478] Example 9

[0479]

[0480] (S,E)-3-(5-Methyl-4-oxo-3-(tritylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)acrylamide Synthesis: To a mixture of bromobenzoxazepine (0.300 g, 0.586 mmol, 1.0 equiv) and acrylamide (0.062 g, 0.879 mmol, 1.5 equiv) was added dimethylformamide (5 mL), and the mixture was degassed by bubbling argon for five minutes. Triethylamine (0.178 g, 0.24 mL, 1.758 mmol, 3.0 equiv) was added, followed by X-PhosPdG2 (0.046 g, 0.059 mmol, 0.1 equiv), and the reaction was sealed and heated in a microwave to 120 °C for 1 hour. The reaction was partitioned between EtOAc (100 mL) and NaHCO3 (100 mL). The organic layer was washed with brine (80 mL), water (100 mL) and brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0 → 10% MeOH-CH2Cl2) gave the title compound as a pale yellow solid (0.267 g, 91%); 1 H nmr (400 MHz, CDCl3) δ 7.55 (1H, d, J 15.5 Hz, ArCH=C H CO), 7.39 - 7.36 (7H, m, 6H of C(C6H5)3, benzoxazepine H-8), 7.25 - 7.13 (9H, m, 9H of C(C6H5)3), 7.01 (1H, d, J 8.5 Hz, benzoxazepine eH-9), 6.97 (1H, d, J 2.0 Hz, benzoxazepine eH-6), 6.39 (1H, d, J 15.5 Hz, ArC H =CHCO), 5.95 (2H, br s, NH2), 4.51 (1H, dd, J9.5, 7.0 Hz, 1H of benzoxazepine eH-2), 4.39 (1H, dd, J 11.5, 9.5 Hz, 1H of benzoxazepine eH-2), 3.54 (1H, dt, J 11.5, 7.5 Hz, benzoxazepine 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] + .

[0481]

[0482] (S)-3-(3-Amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanamide synthesis: A solution of α,β-unsaturated formamide (0.267 g, 0.532 mmol, 1.0 equiv) in ethyl acetate - methanol (5:2, 7 mL) was purged with nitrogen, and palladium on carbon (0.100 g) was added. The reaction was purged with hydrogen and stirred under a hydrogen atmosphere for 2 h. The reaction was purged with nitrogen and filtered through celite, eluting with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in dioxane (5 mL), and hydrogen chloride (0.66 mL of a 4 M solution in dioxane, 2.659 mmol, 5.0 equiv) was added. The reaction was stirred at room temperature for 6 h, forming a white solid. The reaction was concentrated to dryness and used without purification; m / z: 265 [M+H] + 。

[0483]

[0484] (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 synthesis: To a mixture of aminooxybenzoxazepine hydrochloride (0.134 mmol, 1.0 equiv) and benzotriazolecarboxylic acid (0.033 g, 0.161 mmol, 1.2 equiv) in dimethylformamide (1.0 mL) was added diisopropylethylamine (0.043 g, 0.058 mL, 0.335 mmol, 2.5 equiv), followed by HATU (0.102 g, 0.268 mmol, 2.0 equiv). The reaction was stirred at room temperature for 4 h and partitioned between EtOAc - CH2Cl2 (5:1, 60 mL) and water (60 mL). The organic layer was washed with brine (50 mL), water (60 mL), and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. MPLC (0 → 10% MeOH - CH2Cl2) gave the title compound as a white solid; 11H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.36 - 7.28 (5H, m, 5 x ArH), 7.11 - 7.06 (3H, m, 3 x ArH), 5.44 (2H, br s, CONH2), 5.02 (1H, dt, J 11.0, 7.5 Hz, benzoxazepine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H of benzoxazepine H-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H of benzoxazepine H-2), 4.17 (2H, s, C H 2C6H5), 3.41 (3H, s, NCH3), 2.99 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 2.54 (2H, t, J 7.5 Hz, 2H of ArCH2CH2CO); m / z: 449 [M+H] + 。

[0485] Example 10

[0486]

[0487] (S)-7 - ((5,6 - Dihydro - [1,2,4]triazolo[1,5 - a]pyrazin - 7(8H)-yl)methyl)-5 - methyl - 3 - (tritylamino)-2,3 - dihydrobenz[b][1,4]oxazepin - 4(5H)-one formation: Add dioxane (4 mL) and water (2 mL) to a mixture of bromobenzoxazepine (0.270 g, 0.527 mmol, 1.0 equiv), 7 - ((trifluoro - λ 4 -boranyl)methyl)-5,6,7,8 - tetrahydro - [1,2,4]triazolo[1,5 - a]pyrazine potassium salt (0.180 g, 0.738 mmol, 1.4 equiv) and cesium carbonate (0.515 g, 1.581 mmol, 3.0 equiv). Degas the reaction by bubbling argon through for ten minutes. Add X-PhosPd G2 (0.021 g, 0.026 mmol, 0.05 equiv), and seal the reaction and heat in a microwave to 140 °C for 45 minutes. Partition the reaction between EtOAc (80 mL) and NaHCO3 (80 mL). Wash the organic layer with brine (80 mL), dry (Na2SO4), and concentrate under reduced pressure. MPLC (0 → 10% MeOH[2M NH3]-CH2Cl2) gives the title compound as a yellow oil (0.255 g, %). 11H 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, 9H of C(C6H5)3), 7.02 (1H, dd, J 8.0, 2.0 Hz, oxabenzoxazepine H-8), 6.97 (1H, d, J 8.0 Hz, oxabenzoxazepine H-9), 6.87 (1H, d, J 2.0 Hz, oxabenzoxazepine H-6), 4.50 (1H, dd, J 10.0, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.36 (1H, dd, J 11.5, 10.0 Hz, 1H of oxabenzoxazepine 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, oxabenzoxazepine 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] + 。

[0488]

[0489] Deprotection of the trityl group: To a solution of trityl-protected amine (0.255 g, 0.447 mmol, 1.0 equiv) in dioxane (4.0 mL) was added hydrogen chloride (0.56 mL of a 4 M solution in dioxane, 2.237 mmol, 5.0 equiv). A white precipitate formed. The reaction was stirred at room temperature for 14 h. The reaction was concentrated to dryness and used without purification; m / z: 329 [M+H] + 。

[0490]

[0491] Formation 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 aminooxobenzoxazepine hydrochloride (0.377 mmol, 1.0 equiv) and benzotriazolecarboxylic acid (0.077 g, 0.377 mmol, 1.0 equiv) in dimethylformamide (4.0 mL) was added diisopropylethylamine (0.122 g, 0.16 mL, 0.943 mmol, 2.5 equiv). The reaction was cooled to 0 °C and HATU (0.143 g, 0.377 mmol, 1.0 equiv) was added. The reaction was stirred at 0 °C for 2 h and at room temperature for 18 h. The reaction was partitioned between EtOAc-CH2Cl2 (9:1, 60 mL) and NaHCO3-water (1:1, 60 mL). The organic layer was washed with brine (60 mL). The combined aqueous phases were back-extracted with EtOAc (30 mL). The combined organic layers were washed with water (90 mL) and brine (90 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→8% MeOH-CH2Cl2) gave the title compound as a white solid; 1 1H 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 x ArH), 7.16 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.10 (1H, oxobenzoxazepine H-3), 4.74 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28 (1H, t, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.21 (2H, t, J 5.5 Hz, 2H of NCH2CH2N), 4.15 (2H, s, NC H 2C6H5), 3.84, 3.78 (2H, 2d AB system, J 15.5 Hz, ArCH2N or NCH2C), 3.77, 3.73 (2H, 2d AB system, J 13.5 Hz, ArCH2N or NCH2C), 3.40 (3H, s, NCH3), 3.02 (2H, t, J 5.5 Hz, 2H of NCH2CH2N); m / z: 514 [M+H] + (found [M+H] + , 514.2324, C 26 H 27 N9O3 requires [M+H] + 514.2310).

[0492] Additional exemplary compound embodiments are described below.

[0493]

[0494] (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

[0495] 1 H nmr (400 MHz, D6DMSO) δ 7.83 (1H, d, J 8.0 Hz, NH), 7.45 (1H, d, J 2.0 Hz, oxobenzoxazepine H-6), 7.25 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazepine H-8), 7.20 - 7.15 (5H, m, 4H of C6H5 of oxobenzoxazepine H-9), 7.09 - 7.04 (1H, m, 1H of C6H5), 5.47 (1H, br s, OH), 4.81 - 4.74 (1H, m, oxobenzoxazepine H-3), 4.39 - 4.36 (2H, m, 2H of oxobenzoxazepine H-2), 3.84 (2H, s, C H 2C6H5), 3.28 (3H, s, NCH3), 1.44 (6H, s, C(C H 3)2OH); m / z: 442 [M + H] + 。

[0496]

[0497] (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

[0498] 11H NMR (400 MHz, CDCl3) δ 8.76 (1H, dd, J 4.0, 1.5 Hz, quinoline H-2), 8.03 (2H, m, NH, quinoline H-4), 8.01 (1H, d, J 9.5 Hz, quinoline H-8), 7.99 (1H, s, triazole H-5), 7.40 (1H, dd, J 9.0, 3.0 Hz, quinoline H-7), 7.37 - 7.33 (4H, m, 4H of C6H5, oxabenzoxazepine H-6, H-8), 7.28 - 7.24 (3H, m, 3H of C6H5, oxabenzoxazepine H-6, H-8), 7.12 (1H, d, J 2.5 Hz, quinoline H-5), 7.10 (1H, d, J 8.0 Hz, oxabenzoxazepine H-9), 5.36 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.75 (1H, dd, J 10.0, 7.5 Hz, 1H of oxabenzoxazepine 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 oxabenzoxazepine H-2), 3.39 (3H, s, NCH3), 2.98 (2H, t, J 7.0 Hz, CC H 2CH2O); m / z: 573 [M + H] + (found [M + H] + , 573.2244, C 33 H 28 N6O4 requires [M + H] + 573.2245).

[0499]

[0500] (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

[0501] 11H 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, oxabenzoxazepine H-8), 7.25 - 7.20 (6H, m, C6H5, oxabenzoxazepine H-7), 7.11 (1H, d, J 3.0 Hz, quinoline H-5), 7.09 (1H, d, J 8.0 Hz, oxabenzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine 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 oxabenzoxazepine H-2), 4.14 (2H, s, C H 2C6H5), 3.37 (3H, s, NCH3), 2.98 (2H, t, J 7.0 Hz, CC H 2CH2O); 13 13C NMR (100 MHz, CDCl3) δ 168.7, 156.6, 149.7, 148.0, 144.3, 136.0, 134.9, 131.0, 130.8, 129.2, 128.8 (2C), 128.6, 127.1, 126.5, 123.1, 122.4, 121.4, 121.0, 106.3, 86.6, 80.7, 77.2, 66.2, 49.1, 35.4, 33.4, 20.4,; m / z: 573 [M + H] + (found [M + H] + , 573.2262, C 33 H 28 N6O4 requires [M + H] + 573.2245).

[0502]

[0503] (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

[0504] 1 H nmr(400MHz,CDCl3)δ8.04(1H,d,J 7.5Hz,NH),8.00(1H,s,triazole H-5),7.38-7.33(3H,m,3H of C6H5),7.27-7.24(2H,m,2H of C6H5),7.19(2H,m,oxobenzoxazepine H-6,H-8),7.15(1H,d,J 8.0Hz,oxobenzoxazepine H-9),5.35(2H,s,NC H 2C6H5),5.09(1H,dt,J11.0,7.5Hz,oxobenzoxazepine H-3),4.73(1H,dd,J 9.5,7.5Hz,1H of oxobenzoxazepine H-2),4.26-4.21(3H,m,1H of oxobenzoxazepine H-2,2H of NCH2CH2N),3.87(2H,s,2H of ArCH2NCH2C),3.75(2H,s,2H of ArCH2NCH2C),3.40(3H,s,NCH3),3.01(2H,td,J 5.0,1.5Hz,2H of NCH2CH2N); 13 C nmr(100MHz,CDCl3)δ168.8,158.4,156.6,153.5(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,J270.5Hz),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] + (found [M+H] + ,582.2188,C 27 H 26 F3N9O3 requires [M+H] + 582.2183).

[0505]

[0506] (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

[0507] 1 1H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.27 - 7.21 (6H, m, C6H5, oxobenzoxazepine H-8), 7.21 (1H, dd, J 7.5, 2.0 Hz, oxobenzoxazepine H-8), 7.15 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.29 - 4.23 (3H, m, 1H of oxobenzoxazepine H-2, 2H of NCH2CH2N), 4.12 (2H, s, C H 2C6H5), 3.86 (2H, s, 2H of ArCH2NCH2C), 3.76 (2H, s, 2H of ArCH2NCH2C), 3.39 (3H, s, NCH3), 3.03 (2H, t, J 5.5 Hz, 2H of NCH2CH2N); 13 13C NMR (100 MHz, CDCl3) δ 168.8, 158.7, 153.4 (q, J 39.5 Hz), 152.2, 149.6, 136.3, 135.7, 134.6, 128.8, 128.7, 127.9, 127.1, 123.4, 123.2, 123.1, 119.2 (q, J 269.5 Hz), 77.1, 60.7, 50.4, 49.4, 48.6, 47.1, 35.6, 33.0; 19 19F NMR (380 MHz, CDCl3) δ -65.3; m / z: 582 [M + H] + (found [M + H] + , 582.2167, C 27 H 26 F3N9O3 requires [M + H] + 582.2183).

[0508]

[0509] (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

[0510] 1 H nmr(400MHz,CDCl3)δ8.75(1H,dd,J 4.5,2.0Hz,quinoline H-2),8.09-8.06(2H,m,NH,quinoline H-4),7.70(1H,d,J 9.0Hz,quinoline H-5),7.50(1H,d,J 2.5Hz,quinoline H-8),7.27-7.17(9H,m,quinoline H-3,H-6,oxobenzoxazepine H-6,H-8,C6H5),7.07(1H,d,J 8.5Hz,oxobenzoxazepine H-9),5.00(1H,dt,J 11.0,7.5Hz,oxobenzoxazepine H-3),4.66(1H,dd,J 9.5,7.5Hz,1H of oxobenzoxazepine H-2),4.31(2H,td,J 7.0,2.5Hz,OC H 2CH2C),4.24(1H,dd,J 11.0,9.5Hz,1H of oxobenzoxazepine H-2),4.13(2H,s,C H 2C6H5),3.36(3H,s,NCH3),2.97(2H,t,J7.0Hz,OCH2C H 2C); 13 C nmr(100MHz,CDCl3)δ168.7,159.6,158.6,150.3,149.6,149.5,136.0(2C),135.9,131.0,128.9,128.8,128.7,127.0,126.5,123.7,123.0,121.0,120.1,119.1,107.9,86.8,80.6,77.2,66.1,49.2,35.5,33.2,20.3;m / z:573[M+H] + (Found [M+H] + ,573.2269,C 33 H 28 N6O4 requires [M+H] + 573.2245).

[0511]

[0512] (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

[0513] 1 1H NMR (400 MHz, CDCl3) δ 8.20 (1H, dd, J 4.5, 2.0 Hz, quinoline H-2), 8.06 (1H, dd, J 8.0, 1.5 Hz, quinoline H-4), 8.03 (1H, d, J 7.0 Hz, NH), 7.99 (1H, s, triazole H-5), 7.70 (1H, d, J 9.0 Hz, quinoline H-5), 7.45 (1H, d, J 2.5 Hz, quinoline H-8), 7.37 - 7.33 (3H, m, 3H of C6H5, oxobenzoxazepine H-6), 7.27 - 7.22 (6H, m, quinoline H-6, H-3, oxobenzoxazepine H-8, 3H of C6H5, oxobenzoxazepine H-6), 7.09 (1H, dd, J 8.0, 0.5 Hz, oxobenzoxazepine H-9), 5.35 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.33 (2H, t, J 7.0 Hz, OC H 2CH2C), 4.23 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 3.39 (3H, s, NCH3), 2.98 (2H, t, J 7.0 Hz, OCH2C H 2C); 13 13C NMR (100 MHz, CDCl3) δ 168.8, 159.4, 158.4, 156.6, 150.6, 149.8, 149.7, 143.9, 135.9, 135.7, 133.7, 130.9, 129.2, 128.9, 128.2, 126.5, 123.7, 123.1, 121.0, 119.9, 119.1, 108.2, 86.6, 80.7, 77.1, 66.1, 54.3, 49.1, 38.6, 35.5, 20.3; m / z: 573 [M + H] + (found [M + H] + , 573.2249, C 33 H 28 N6O4 requires [M + H] + 573.2245).

[0514]

[0515] (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

[0516] 1 H nmr(400MHz,CDCl3)δ8.05(1H,d,J 7.5Hz,NH),7.27 - 7.20(3H,m,oxobenzoxazepine H-6,H-8,1H of C6H3F2),7.10(1H,d,J 9.0Hz,oxobenzoxazepine H-9),6.82 - 6.74(2H,m,2H of C6H3F2),4.99(1H,dt,J 11.0,7.5Hz,oxobenzoxazepine H-3),4.66(1H,dd,J 10.0,7.5Hz,1H of oxobenzoxazepine H-2),4.27(1H,dd,J 11.0,10.0Hz,1H of oxobenzoxazepine H-2),4.12(2H,s,C H 2C6H3F2),3.39(3H,s,NCH3),1.61(6H,s,C(C H 3)2OH); 19 F nmr(380MHz,CDCl3)δ - 111.2; - 113.2;m / z:478[M + H - H2O] + (Found[M + H] + ,496.1795,C 25 H 23 F2N5O4 requires[M + H] + 496.1791).

[0517]

[0518] (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

[0519] 11H 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, oxabenzoxazepine H-6), 7.26 - 7.22 (4H, m, oxabenzoxazepine H-8, 3H of C6H5, oxabenzoxazepine H-6), 7.09 (1H, d, J 8.0 Hz, oxabenzoxazepine 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, oxabenzoxazepine H-3), 4.73 (1H, dd, J 10.0, 7.5 Hz, 1H of oxabenzoxazepine 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 oxabenzoxazepine H-2), 3.37 (3H, s, NCH3), 3.03 (2H, t, J 7.0 Hz, OCH2C H 2C); m / z: 573 [M + H] + (found [M + H] + , 573.2251, C 33 H 28 N6O4 requires [M + H] + 573.2245).

[0520]

[0521] (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

[0522] 11H 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, oxabenzoxazepine H-6, H-8), 7.08 (1H, d, J 8.0 Hz, oxabenzoxazepine 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, oxabenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine 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 oxabenzoxazepine H-2), 4.13 (2H, s, C H 2C6H5), 3.36 (3H, s, NCH3), 3.04 (2H, t, J 7.0 Hz, OCH2C H 2C); 13 13C NMR (100 MHz, CDCl3) δ 168.7, 158.5, 153.9, 150.6, 149.7, 148.9, 136.0, 131.0, 130.9, 129.4, 128.8, 128.7, 127.0, 126.5, 123.1, 121.8, 121.0, 120.9, 120.3, 105.4, 86.7, 80.7, 77.2, 49.1, 35.5, 33.2, 20.5; m / z: 573 [M + H] + (found [M + H] + , 573.2266, C 33 H 28 N6O4 requires [M + H] + 573.2245).

[0523]

[0524] (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

[0525] 1 H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 8.02 (1H, s, triazole H-5), 7.39 - 7.35 (3H, m, 3 x ArH), 7.29 - 7.7.26 (2H, m, 2 x ArH), 7.20 (2H, m, 2 x ArH), 7.17 (1H, d, J 8.0 Hz, oxabenzoxazepine H-9), 5.38 (2H, s, NC H 2C6H5), 5.12 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxabenzoxazepine H-2), 4.15 (2H, t, J 5.5 Hz, 2H of NCH2CH2N), 3.98, 3.93 (2H, 2d AB system, J 15.5 Hz, 2H of ArCH2NCH2), 3.76 (2H, s, 2H of ArCH2NCH2), 3.42 (3H, s, NCH3), 2.96 (2H, dt, J 4.0, 5.5 Hz, 2H of NCH2CH2N); 19 F NMR (380 MHz, CDCl3) δ -63.2; m / z: 582 [M + H] + (Found [M + H] + , 582.2173, C 27 H 26 F3N9O3 requires [M + H] + 582.2183).

[0526]

[0527] (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

[0528] 11H NMR (400 MHz, CDCl3) δ 8.01 (1H, d, J 7.0 Hz, NH), 7.27 - 7.19 (7H, m, C6H5, benzoxazepine H-6, H-8), 7.16 (1H, d, J 8.0 Hz, benzoxazepine H-9), 5.09 (1H, dt, J 10.5, 7.5 Hz, benzoxazepine H-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, one H of benzoxazepine H-2), 4.28 (1H, dd, J 10.5, 10.0 Hz, one H of benzoxazepine H-2), 4.14 (4H, m, 2H of NCH2CH2N), 2H of 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 13.5 Hz, 2H of ArCH2NCH2), 3.40 (3H, s, NCH3), 2.97 (2H, t, J 5.5 Hz, 2H of NCH2CH2N); 13 13C NMR (100 MHz, CDCl3) δ 168.8, 158.6, 152.0, 149.6, 143.4 (q, J 40.0 Hz), 136.4, 135.8, 134.3, 128.8, 128.7, 127.9, 127.1, 126.9, 123.4, 123.2, 118.3 (q, J 270.5 Hz), 77.2, 60.8, 49.5, 49.4, 43.6, 35.6, 33.1; 19 19F NMR (380 MHz, CDCl3) δ -63.2; m / z: 582 [M + H] + (found [M + H] + , 582.2208, C 27 H 26 F3N9O3 requires [M + H] + 582.2183).

[0529]

[0530] (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

[0531] 11H NMR (400 MHz, CDCl3) δ 8.04 (1H, d, J 7.0 Hz, NH), 8.01 (1H, s, triazole H-5), 7.40 - 7.36 (3H, m, 3H of C6H5), 7.29 - 7.23 (4H, m, 2H of C6H5, oxobenzoxazepine H-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.38 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.76 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3); m / z: 458 [M+H] + (found [M+H] + , 458.2205, C 26 H 27 N5O3 requires [M+H] + 458.2187).

[0532]

[0533] (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

[0534] 1 1H NMR (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26 - 7.21 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.07 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.26 (1H, dd, J Hz, 1H of oxobenzoxazepine H-2), 4.15 (2H, s, C H 2C6H5), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3); 1313C NMR (100 MHz, CDCl3) δ 168.7, 158.5, 149.2, 135.9, 135.8, 130.9, 128.8, 128.7, 127.0, 126.4, 122.8, 121.8, 99.4, 77.6, 77.2, 49.1, 35.5, 33.2, 30.9, 27.9; m / z: 458 [M+H] + (found [M+H] + , 458.2200, C 26 H 27 N5O3 requires [M+H] + 458.2187).

[0535]

[0536] (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

[0537] 1 1H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.99 (1H, s, triazole H-5), 7.38 - 7.34 (3H, m, 3H of C6H5), 7.29 - 7.25 (4H, m, 2H of C6H5, oxobenzoxazepine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.36 (2H, s, NC H 2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.25 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.40 (3H, s, NCH3), 2.55 - 2.49 (2H, m, cBuH-2, 2H of H-4), 2.33 (2H, m, cBuH-2, 2H of H-4), 1.87 (2H, m, cBuH-3); m / z: 472 [M+H] + , 454 [M+H - H2O] + (found [M+H] + , 472.1994, C 26 H 25 N5O4 requires [M+H] + 472.1979).

[0538]

[0539] (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

[0540] 1 H nmr(400MHz,CDCl3)δ8.10(1H,d,J 7.5Hz,NH),7.29 - 7.20(7H,m,C6H5,2H of oxobenzoxazepine H-6,H-8,H-9),7.10(1H,dd,J 7.5,1.0Hz,1H of oxobenzoxazepine H-6,H-8,H-9),5.01(1H,dt,J 11.0,7.5Hz,oxobenzoxazepine H-3),4.66(1H,dd,J 9.5,7.5Hz,1H of oxobenzoxazepine H-2),4.28(1H,dd,J 11.0,9.5Hz,1H of oxobenzoxazepine H-2),4.15,4.11(2H,2d AB system,J 16.0Hz,C H 2C6H5),3.39(3H,s,NCH3),2.57 - 2.50(2H,m,cBuH-2,2H of H-4),2.35(2H,m,cBuH-2,2H of H-4),1.92 - 1.84(2H,m,cBuH-3); 13 C(100MHz,CDCl3)δ168.7,158.7,149.9,136.0,135.8,131.0,128.8,128.7,127.0,126.5,123.0,120.4,93.4,81.9,76.9,68.2,49.1,38.5,35.5,33.0,13.0;m / z:454[M + H - H2O] + (Found [M + H] + ,472.1999,C 26 H 25 N5O4 requires [M + H] + 472.1979).

[0541]

[0542] (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

[0543] 1 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, oxabenzoxazepine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, oxabenzoxazepine H-9), 5.36 (2H, s, NCH2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H of oxabenzoxazepine H-2), 3.40 (3H, s, NCH3), 2.08 - 1.99 (4H, m, c-pentane H-2, H-5), 1.90 - 1.84 (2H, m, 2H of c-pentane H-3, H-4), 1.83 - 1.76 (2H, m, 2H of c-pentane H-3, H-4); m / z: 486 [M + H] + , 468 [M + H - H2O] + (found [M + H] + , 486.2122, C 27 H 27 N5O4 requires [M + H] + 486.2136).

[0544]

[0545] (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

[0546] 1 1H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31 - 7.23 (7H, m, C6H5, oxabenzoxazepine H-6, H-7), 7.10 (1H, d, J 9.0 Hz, oxabenzoxazepine H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H of oxabenzoxazepine H-2), 4.14 (2H, s, C H2C6H5), 3.39 (3H, s, NCH3), 2.08 - 1.97 (4H, m, c-pentane H-2, H-5), 1.90 - 1.85 (2H, m, 2H of c-pentane H-3, H-4), 1.82 - 1.76 (2H, m, 2H of c-pentane H-3, H-4); m / z: 468 [M + H - H2O] + (Found [M + H] + , 486.2154, C 27 H 27 N5O4 requires [M + H] + 486.2136).

[0547]

[0548] (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

[0549] 1 H nmr (400 MHz, CDCl3) δ 8.03 (1H, d, J 7.0 Hz, NH), 8.02 (1H, s, triazole H-5), 7.39 - 7.35 (3H, m, 3H of C6H5), 7.31 - 7.27 (4H, m, 2H of C6H5, oxobenzoxazepine H-6, H-8), 7.14 (1H, dd, J 8.0, 1.0 Hz, oxobenzoxazepine H-9), 5.37 (2H, s, NC H 2C6H5), 5.08 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.95 (2H, dt, J 12.0, 4.5 Hz, 2H of pyran H-2, H-6), 3.72 (2H, ddd, J 12.0, 9.0, 3.0 Hz, 2H of pyran H-2, H-6), 3.42 (3H, s, NCH3), 2.07 - 2.02 (2H, m, 2H of pyran H-3, H-5), 1.89 (2H, ddd, J 13.0, 9.0, 4.0 Hz, 2H of pyran H-3, H-5); m / z: 502 [M + H] + , 484 [M + H - H2O] + (Found [M + H] + , 502.2105, C27 H 27 N5O5 requires [M+H] + 502.2085).

[0550]

[0551] (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

[0552] 1 H nmr (400 MHz, CDCl3) δ 8.07 (1H, d, J 6.5 Hz, NH), 7.28 - 7.19 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.09 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.00 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.64 (1H, dd, J 9.0, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.27 (1H, t, J 10.5 Hz, one H of oxobenzoxazepine H-2), 4.12 (2H, s, CH2C6H5), 3.93 (2H, dt, J12.0, 4.5 Hz, two Hs of pyran H-2, H-6), 3.70 (2H, ddd, J 11.5, 9.0, 2.5 Hz, two Hs of pyran H-2, H-6), 3.37 (3H, s, NCH3), 2.03 (2H, m, two Hs of pyran H-3, H-5), 1.88 (2H, ddd, J13.0, 9.0, 4.0 Hz, two Hs of pyran H-3, H-5); 13 C nmr (100 MHz, CDCl3) δ 168.6, 158.7, 150.1, 136.1, 135.7, 131.1, 128.9, 128.8, 127.1, 126.6, 123.2, 120.0, 92.3, 83.4, 77.3, 66.1, 64.8, 49.1, 39.9, 35.6, 33.1; m / z: 484 [M+H-H2O] + (Found [M+H] + , 502.2080, C 27 H 27 N5O5 requires [M+H] + 502.2085).

[0553]

[0554] (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-phenoxypyridinecarboxamide

[0555] 1 H 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, H-6, H-8 of oxobenzoxazepine, 1H of C6H5), 7.10 (1H, d, J 9.0 Hz, H-9 of oxobenzoxazepine), 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, H-3 of oxobenzoxazepine), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of H-2 of oxobenzoxazepine), 4.28 (1H, dd, J11.0, 9.5 Hz, 1H of H-2 of oxobenzoxazepine), 3.41 (3H, s, NCH3), 1.61 (6H, s, C(C H 3)2OH); 13 C nmr (100 MHz, CDCl3) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1, 150.0, 136.2, 130.8, 130.3, 126.4, 125.6, 123.0, 120.7, 120.3, 114.4, 110.6, 94.4, 80.7, 77.2, 65.6, 49.3, 35.4, 31.4; m / z: 472 [M + H] + (Found [M + H] + , 472.1891, C 27 H 25 N3O5 requires [M + H] + 472.1867).

[0556]

[0557] (S)-5-Benzyl-N-(7-((3-hydroxyoxet-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

[0558] 11H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.33 - 7.26 (7H, m, C6H5, benzoxazepine H-6, H-8), 7.14 (1H, d, J 9.0 Hz, benzoxazepine H-9), 5.03 (1H, dt, J 11.0, 7.5 Hz, benzoxazepine 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 benzoxazepine H-2), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H of benzoxazepine H-2), 4.16 (2H, s, C H 2C6H5), 3.41 (3H, s, NCH3), 2.98 (1H, br s, OH); m / z: 474 [M + H] + (found [M + H] + , 474.1789, C 25 H 23 N5O5 requires [M + H] + 474.1772).

[0559]

[0560] (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

[0561] 1 1H NMR (400 MHz, CDCl3) δ 8.03 (1H, d, J 7.0 Hz, NH), 8.01 (1H, s, triazole H-5), 7.37 (3H, m, 3H of C6H5), 7.28 - 7.25 (4H, m, 2H of C6H5, benzoxazepine H-6, H-8), 7.12 (1H, d, J8.5 Hz, benzoxazepine H-9), 5.35 (2H, s, NC H2C6H5), 5.04 (1H, dt, J 11.5, 7.5 Hz, oxabenzoxazepine H-3), 4.89 (2H, dd, J 7.0, 1.0 Hz, oxetane H-2, 2H of H-4), 4.78 (2H, ddd, J 6.5, 2.0, 1.0 Hz, oxabenzoxazepine H-2D 2H, H-4), 4.72 (1H, dd, J 10.0, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.26 (1H, dd, J 11.5, 9.5 Hz, 1H of oxabenzoxazepine H-2), 3.53 (1H, s, OH), 3.38 (3H, s, NCH3); 13 C nmr (100 MHz, CDCl3) δ 168.7, 158.4, 156.5, 150.4, 144.0, 136.1, 133.7, 130.9, 129.2, 129.0, 128.2, 126.6, 123.4, 119.5, 88.9, 84.5, 77.1, 67.3, 54.4, 53.4, 49.1, 35.5; m / z: 474 [M + H] + 。

[0562]

[0563] (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

[0564] 1 H nmr (400 MHz, CDCl3) δ 8.09 (1, d, J 7.5 Hz, NH), 7.27 (2H, t, J 7.0 Hz, 2H of C6H5), 7.20 - 7.15 (5H, m, 3H of C6H5, oxabenzoxazepine H-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxabenzoxazepine H-9), 5.41 (1H, q, J 1.0 Hz, 1H of =CH2), 5.32 (1H, m, 1H of =CH2), 5.01 (1H, dt, J11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.63 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of oxabenzoxazepine H-2), 4.12 (2H, s, C H 2C6H5), 3.38 (3H, s, NCH3), 1.98 (3H, t, J Hz, C(C H3)=CH2); 13 C NMR (100 MHz, CDCl3) δ 168.7, 158.7, 154.6, 149.8, 136.0, 135.9, 130.9, 128.8, 128.7, 127.0, 126.4 (2C), 123.1, 122.6, 121.0, 91.3, 86.7, 77.2, 49.2, 35.5, 33.0, 23.3; m / z: 464 [M+Na] + , 442 [M+H] + (found [M+H] + , 442.1869, C 25 H 23 (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 requires [M+H] + 442.1874).

[0565]

[0566] (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

[0567] 1 H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.29 - 7.19 (5H, m, C6H5), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 7.03 (1H, d, J 2.0 Hz, oxobenzoxazepine H-6), 7.00 (1H, m, oxobenzoxazepine H-8), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.22 (1H, dd, J11.0, 10.0 Hz, one H of oxobenzoxazepine H-2), 4.14 (2H, s, C H 2C6H5), 3.39 (3H, s, NCH3), 2.60 (2H, m, C H 2CH2CH(CH3)2), 1.60 (1H, m, CH2CH2C H (CH3)2), 1.52 - 1.46 (2H, m, CH2C H 2CH(CH3)2), 0.94 (6H, d, J6.5 Hz, CH2CH2CH(C H 3)2); m / z: 448 [M+H] + (found [M+H]+ ,448.2335,C 25 H 29 N5O3 requires [M+H] + 448.2343).

[0568]

[0569] (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

[0570] 1 H nmr(400MHz,CDCl3)δ8.09(1H,d,J 7.5Hz,NH),7.28-7.25(2H,m,2H of C6H5),7.19(5H,m,3H of C6H5,H-6,H-8 of oxobenzoxazepine),7.09(1H,d,J 8.0Hz,H-9 of oxobenzoxazepine),5.01(1H,dt,J 11.0,7.5Hz,H-3 of oxobenzoxazepine),4.63(1H,dd,J9.0,8.0Hz,1H of H-2 of oxobenzoxazepine),4.26(1H,dd,J 10.5,9.5Hz,1H of H-2 of oxobenzoxazepine),4.12(2H,s,C H 2C6H5),3.43(3H,s,NCH3H or OCH3),3.39(3H,s,NCH3 or OCH3),1.54(6H,s,C(C H 3)2OCH3); m / z: 474 [M+H] + ,442 [M+H-CH3OH] + (Found [M+H] + ,474.2138,C 26 H 27 N5O4 requires [M+H] + 474.2136).

[0571]

[0572] (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

[0573] 11H NMR (400 MHz, CDCl3) δ 8.01 (1H, d, J 7.5 Hz, NH), 8.00 (1H, s, triazole H-5), 7.39 - 7.34 (3H, m, 3H of C6H5), 7.27 - 7.23 (4H, m, 2H of C6H5, oxobenzoxazepine H-8, H-9), 7.12 (1H, d, J 8.0 Hz, oxobenzoxazepine H-6), 5.36 (2H, s, NC H 2C6H5), 5.05 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.23 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 3.39 (3H, s, NCH3), 1.61 (6H, s, C(C H 3)2OH); m / z: 460 [M + H] + , 442 [M + H - H2O] + (found [M + H] + , 460.1968, C 25 H 25 N5O4 requires [M + H] + 460.1979).

[0574]

[0575] (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

[0576] 1 1H NMR (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26 - 7.18 (7H, m, C6H5, oxobenzoxazepine H-7, H-9), 7.11 (1H, d, J 8.0 Hz, oxobenzoxazepine H-6), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.62 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.24 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.14, 4.10 (2H, 2d, J 16.0 Hz, C H 2C6H5), 3.37 (3H, s, NCH3), 1.61 (6H, s, C(CH 3) 2OH); 13 C nmr (100 MHz, CDCl3) δ 168.7, 158.7, 149.5, 136.1, 135.9, 129.0, 128.8, 128.7, 127.0, 126.0, 123.1, 122.2, 95.1, 80.6, 76.9, 65.5, 49.2, 35.4, 33.0, 31.4 (2C); m / z: 442 [M + H - H2O] + (Found [M + H] + , 460.1972, C 25 H 25 N5O4 requires [M + H] + 460.1979).

[0577]

[0578] (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-phenoxypyridinecarboxamide

[0579] 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, oxobenzoxazepine H-7, H-9), 7.13 (1H, d, J 8.0 Hz, oxobenzoxazepine H-6), 7.07 - 7.04 (2H, m, 2H of C6H5), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyridine H-4), 5.01 (1H, dt, J11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.40 (3H, s, NCH3), 1.61 (6H, s, C(C H 3) 2OH); 1313C NMR (100 MHz, CDCl3) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1, 149.6, 136.4, 130.3, 128.9, 126.0, 125.7, 123.0, 122.0, 120.7, 114.4, 110.6, 94.9, 80.6, 77.2, 65.6, 49.4, 35.3, 31.4; m / z: 472 [M+H] + (found [M+H] + , 472.1873, C 27 H 25 N3O5 requires [M+H] + 472.1867).

[0580]

[0581] (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

[0582] 1 1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.33 - 7.29 (3H, m, 3H of C6H3Cl2, oxobenzoxazepine H-6), 7.226 - 7.24 (1H, m, 1H of C6H3Cl2, oxobenzoxazepine H-6), 7.18 - 7.15 (1H, m, oxobenzoxazepine H-8)), 7.10 (1H, d, J 8.5 Hz, oxobenzoxazepine H-9), 5.00 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.67 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.48 (2H, s, C H 2C6H3Cl2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine 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] + (found [M+H] + , 528.1201, C 25 H 23 Cl2N5O4 requires [M+H] +528.1200)

[0583]

[0584] (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

[0585] 1 H NMR (400 MHz, CDCl3) δ 8.04 (1H, d, J 7.5 Hz, NH), 7.30 - 7.17 (8H, m, C6H5, oxobenzoxazepine H-6, H-7, H-9), 5.08 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.30 - 4.25 (3H, m, 1H of oxobenzoxazepine H-2, NCH2CH2N), 4.14 (2H, s, CH2C6H5), 3.88, 3.83 (2H, 2d AB system, J16.0 Hz, 2H of ArCH2NCH2), 3.76 (2H, s, ArCH2NCH2), 3.40 (3H, s, NCH3), 3.09 - 3.02 (2H, m, NCH2CH2N); 19 F NMR (380 MHz, CDCl3) δ -65.3; m / z: 604 [M+Na] + 582 [M+H] + 。

[0586]

[0587] (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

[0588] 11H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J 7.0 Hz, NH), 8.00 (1H, s, triazole H-5), 7.39 - 7.35 (3H, m, 3H of C6H5, H-6, H-7, H-9 of oxabenzoxazepine), 7.28 - 7.25 (2H, m, 2H of C6H5, H-6, H-7, H-9 of oxabenzoxazepine), 7.23 - 7.17 (3H, m, 3H of C6H5, H-6, H-7, H-9 of oxabenzoxazepine), 5.37 (2H, s, NC H 2C6H5), 5.11 (1H, dt, J 11.0, 7.5 Hz, H-3 of oxabenzoxazepine), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of H-2 of oxabenzoxazepine), 4.28 - 4.23 (3H, m, 1H of H-2 of oxabenzoxazepine, 2H of NCH2CH2N), 3.90, 3.86 (2H, 2d AB system, J 16.0 Hz, 2H of ArCH2NCH2), 3.79, 3.75 (2H, 2d AB system, J 13.5 Hz, 2H of ArCH2NCH2), 3.42 (3H, s, NCH3), 3.10 - 3.02 (2H, m, 2H of NCH2CH2N); 19 19F NMR (380 MHz, CDCl3) δ -65.4; m / z: 604 [M + Na] + , 582 [M + H] + 。

[0589]

[0590] (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

[0591] 11H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyH-3), 7.60 (1H, d, J 2.5 Hz, pyH-4), 7.42 - 7.38 (2H, m, 2H of C6H5), 7.27 - 7.22 (3H, m, 3H of C6H5, oxabenzoxazepine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxabenzoxazepine H-9), 7.10 - 7.05 (2H, m, 2H of C6H5, oxabenzoxazepine 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, oxabenzoxazepine H-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.28 (1H, dd, J 11.5, 10.0 Hz, 1H of oxabenzoxazepine H-2), 3.41 (3H, s, NCH3); m / z: 478 [M + H] + , 460 [M + H - H2O] + (Found [M + H] + , 478.2255, C 27 H 19 D6N3O4 requires [M + H] + 478.2244).

[0592]

[0593] (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

[0594] 1 1H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28 - 7.21 (7H, m, C6H5, oxabenzoxazepine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, oxabenzoxazepine H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxabenzoxazepine H-2), 4.14 (2H, s, C H2C6H5), 3.39 (3H, s, NCH3); 13 C nmr (100 MHz, CDCl3) δ 168.6, 158.5, 149.9, 136.0, 135.8, 131.0, 128.8 (2C), 127.1 (2C), 126.5, 123.1, 120.5, 94.6, 80.6, 77.2, 65.3, 49.1, 35.5, 33.2, 30.5 (m); m / z: 466 [M+H] + , 448 [M+H - H2O] + (Found [M+H] + , 466.2356, C 25 H 19 (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 + 466.2356).

[0595]

[0596] (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

[0597] [α] 589 20.2 +135.9 (CHCl3, c 0.54); 1 H nmr (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.30 - 7.23 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, one H of oxobenzoxazepine H-2), 4.15 (2H, s, C H 2C6H5), 3.40 (3H, s, NCH3), 1.63 (6H, s, C(CH3)2OH); m / z: 460 [M+H] + , 442 [M+H - H2O] + (Found [M+H] + , 460.1985, C 25 H 25 N5O4 requires [M+H] +460.1979)

[0598]

[0599] (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

[0600] 1 H nmr(400MHz,CDCl3)δ7.99(1H,d,J 6.5Hz,NH),7.36 - 7.29(7H,m,C6H5,oxobenzoxazepine H-6,H-8),7.13(1H,d,J 9.0Hz,oxobenzoxazepine H-9),4.97(1H,ddd,J 11.0,7.5,7.0Hz,oxobenzoxazepine H-3),4.72(1H,dd,J 9.5,7.5Hz,1H of oxobenzoxazepine H-2),4.27(1H,m,1H of oxobenzoxazepine H-2),4.26(2H,s,C H 2C6H5),3.43(3H,s,NCH3),1.63(6H,s,C(CH3)2);m / z:484[M+Na] + ,443[M+H - H2O] + (found [M+H] + ,443.1727,C 25 H 24 N4O5 requires [M+H - H2O] + 443.1714).

[0601]

[0602] (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

[0603] 11H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.42 - 7.39 (2H, m, 2H of C6H5), 7.31 (1H, dd, J 8.0, 2.0 Hz, benzoxazepine H-7), 7.27 - 7.22 (2H, m, 1H of C6H5, benzoxazepine H-9), 7.17 (1H, d, J 8.0 Hz, benzoxazepine 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, benzoxazepine H-3), 4.93 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.79 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of benzoxazepine H-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H of benzoxazepine H-2), 3.42 (3H, s, NCH3); m / z: 486 [M+H] + (found [M+H] + , 486.1674, C 23 H 23 N3O6 requires [M+H] + 486.1660).

[0604]

[0605] (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

[0606] 11H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.97 (1H, s, OH), 7.32 - 7.22 (6H, m, C6H5, oxabenzoxazepine H-7), 7.20 (1H, d, J 2.0 Hz, oxabenzoxazepine H-9), 7.14 (1H, d, J 8.5 Hz, 1H of oxabenzoxazepine H-6), 4.99 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.92 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.79 (2H, d, J 6.5 Hz, 2H of oxetane H-2, H-4), 4.64 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.25 (1H, dd, J 11.0, 9.5 Hz, 1H of oxabenzoxazepine H-2), 4.14 (2H, s, C H 2C6H5), 3.40 (3H, s, NCH3); m / z: 474 [M + H] + , 456 [M + H - H2O] + (found [M + H] + , 474.1784, C 25 H 23 N5O5 requires [M + H] + 474.1772).

[0607]

[0608] (3S, 3aR, 6R, 6aS)-6-(((S)-3-(5-Benzyl-1H-1,2,4-triazole-3-carboxamide)-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

[0609] 1 1H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.5 Hz, NH), 8.03 (2H, m, 2H of COC6H5), 7.59 (1H, tt, J 7.5, 1.0 Hz, 1H of COC6H5), 7.45 (2H, t, J 7.5 Hz, 2H of COC6H5), 7.32 - 7.23 (7H, m, CH2C6 H5, Oxabenzoxazepine H-6, H-8), 7.12 (1H, d, J 8.5 Hz, Oxabenzoxazepine H-9), 5.23 (1H, d, J 3.0 Hz, Isosorbide H-6), 5.02 (1H, dt, J 11.0, 7.5 Hz, Oxabenzoxazepine H-3), 4.87, 4.83 (2H, 2d AB system, J 4.5 Hz, Isosorbide H-3a, H-6a), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of Oxabenzoxazepine H-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H of Oxabenzoxazepine H-2), 4.25 - 4.20 (2H, m, Isosorbide H-5), 4.15 (2H, s, C H 2C6H5), 4.04, 3.95 (2H, 2d AB system, J9.5 Hz, Isosorbide H-2), 3.40 (3H, s, NCH3),; m / z: 650 [M + H] + (Found [M + H] + , 650.2283, C 35 H 31 N5O8 requires [M + H] + 650.2245).

[0610]

[0611] 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

[0612] 11H NMR (400 MHz, CD3OD) δ 7.51 (1H, d, J 2.0 Hz, benzoxazepine H-6), 7.36 (1H, dd, J 8.0, 2.0 Hz, benzoxazepine H-8), 7.33 - 7.23 (5H, m, C6H5), 7.19 (1H, d, J 8.0 Hz, benzoxazepine H-9), 5.01 (1H, dd, J 11.5, 7.5 Hz, benzoxazepine H-3), 4.65, 4.54 (2H, 2d AB system, J 4.5 Hz, isosorbide H-3a, H-6a), 4.60 (1H, dd, J 10.0, 7.5 Hz, 1H of benzoxazepine H-2), 4.41 (1H, dd, J 11.5, 10.0 Hz, 1H of benzoxazepine H-2), 4.24 (1H, d, J 2.5 Hz, isosorbide H-6), 4.15 (2H, s, C H 2C6H5), 3.99 - 3.91 (2H, m, 2H of isosorbide H-5), 3.93, 3.71 (2H, 2d AB system, J 8.5 Hz, isosorbide H-2), 3.40 (3H, s, NCH3); 13 13C NMR (100 MHz, CD3OD) δ 169.1, 150.3, 136.5, 130.7, 128.4, 128.3, 126.8, 126.6, 122.7, 119.9, 110.0, 89.5, 88.6, 87.1, 83.7, 78.1, 77.8, 77.5, 74.4, 49.1, 34.4, 33.2; m / z: 546 [M + H] + (found [M + H] + , 546.2007, C 28 H 27 N5O7 requires [M + H] + 546.1983).

[0613]

[0614] 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

[0615] 11H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31 - 7.23 (7H, m, C6H5, benzoxazepine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, benzoxazepine H-9), 5.02 (1H, dt, J 11.0, 7.5 Hz, benzoxazepine H-3), 4.68 (1H, dd, J 10.0, 7.5 Hz, one H of benzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, one H of benzoxazepine H-2), 4.16 (2H, s, CH2C6H5), 3.78 (3H, s, OCH3), 3.41 (3H, s, NCH3), 1.58 (6H, s, C(CH3)2); m / z: 502 [M + H] + (found [M + H] + , 502.2107, C 27 H 27 N5O4 requires [M + H] + 502.2085).

[0616]

[0617] (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

[0618] 1 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, benzoxazepine H-6, H-8), 7.28 - 7.21 (4H, m, 4H of C6H5, pyrazole H-4 or H-5, benzoxazepine H-6 or H-8), 7.12 (1H, d, J 9.0 Hz, benzoxazepine 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, benzoxazepine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, one H of benzoxazepine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, one H of benzoxazepine H-2), 3.42 (3H, s, NCH3), 1.62 (6H, s, C(C H3) 2OH); m / z: 459 [M+H] + , 441 [M+H - H2O] + (Found [M+H] + , 459.2040, C 26 H 26 N4O4 requires [M+H] + 459.2027).

[0619]

[0620] (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

[0621] 1 H nmr (400 MHz, CDCl3) δ 8.10 (1H, d, J 7.0 Hz, NH), 7.28 (2H, m, oxobenzoxazepine H-6, H-8), 7.21 (1H, m, 1H of C6H4F), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 7.01 (1H, br d, J 8.0 Hz, 1H of C6H4F), 6.96 (1H, br d, J 9.5 Hz, 1H of C6H4F), 6.90 (1H, td, J 8.5, 2.5 Hz, 1H of C6H4F), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J10.0, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.29 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.15 (2H, s, C H 2C6H4F), 3.40 (3H, s, NCH3), 1.62 (6H, s, C(C H 3) 2OH); 13 C nmr (100 MHz, CD3OD) δ 168.5, 164.0, 161.6, 149.9, 138.5, 135.9, 131.0, 130.2 (d, J 8.5 Hz), 128.8, 126.5, 124.5 (d, J 2.5 Hz), 123.0, 120.5, 115.8 (d, J 22.0 Hz), 113.9 (d, J 21.5 Hz), 94.6, 80.6, 76.9, 65.6, 49.2, 35.5, 32.9, 31.4; 1919F NMR (380 MHz, CDCl3) δ -112.6; m / z: 460 [M+H-H2O] + (Found [M+H] + , 478.1901, C 25 H 24 FN5O4 requires [M+H] + 478.1885).

[0622]

[0623] (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

[0624] 1 1H NMR (400 MHz, CDCl3) δ 8.11 (1H, d, J 7.5 Hz, NH), 7.27 - 7.25 (2H, m, benzoxazepine H-6, H-8), 7.17 (2H, dd, J 8.5, 5.5 Hz, 2H of C6H4F), 7.09 (1H, d, J 9.0 Hz, benzoxazepine H-9), 6.90 (2H, t, J 8.5 Hz, 2H of C6H4F), 4.99 (1H, dt, J 11.5, 7.5 Hz, benzoxazepine H-3), 4.64 (1H, dd, J 10.0, 7.5 Hz, 1H of benzoxazepine H-2), 4.29 (1H, dd, J 11.5, 10.0 Hz, 1H of benzoxazepine H-2), 4.09 (2H, s, C H 2C6H4F), 3.39 (3H, s, NCH3), 1.62 (6H, s, C(C H 3)2OH); 19 19F NMR (380 MHz, CDCl3) δ -115.6; m / z: 478 [M+H] + 460 [M+H-H2O] + (Found [M+H] + , 478.1902, C 25 H 24 FN5O4 requires [M+H] + 478.1885).

[0625]

[0626] (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

[0627] 1 H nmr(400MHz,CDCl3)δ8.08(1H,d,J 7.5Hz,NH),7.26 - 7.16(3H,m,oxobenzoxazepine H-6,H-8,1H of C6H4F),7.09(1H,d,J 9.0Hz,oxobenzoxazepine H-9),7.01(1H,td,J7.5,1.0Hz,1H of C6H4F),7.00 - 6.96(1H,m,1H of C6H4F),5.00(1H,dt,J 11.0,7.5Hz,oxobenzoxazepine H-3),4.65(1H,dd,J 9.5,7.5Hz,1H of oxobenzoxazepine H-2),4.27(1H,dd,J11.0,9.5Hz,1H of oxobenzoxazepine H-2),4.17(2H,s,C H 2C6H4F),3.38(3H,s,NCH3),1.62(6H,s,C(C H 3)2OH); 13 C nmr(100MHz,CDCl3)δ168.7,160.7(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,J4.0Hz),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] + (Found[M + H] + ,478.1895,C 25 H 24 FN5O4 requires[M + H] + 478.1885).

[0628]

[0629] (S)-7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

[0630] 1 H nmr (400 MHz, CDCl3) δ 7.40 - 7.38 (6H, m, 3 x 2H of C6H5), 7.24 - 7.20 (6H, m, 3x2H of C6H5), 7.18 - 7.12 (4H, m, 3x1H of C6H5, 1H of oxabenzoxazepine H-6, H-8, H-9), 6.97 - 6.95 (2H, m, 2H of oxabenzoxazepine H-6, H-8, H-9), 4.48 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.37 (1H, dd, J 11.5, 9.5 Hz, 1H of oxabenzoxazepine H-2), 3.55 (1H, dt, J11.5, 7.5 Hz, oxabenzoxazepine 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] - 。

[0631]

[0632] (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

[0633] 1 H nmr (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.33 - 7.31 (2H, m, oxabenzoxazepine H-8, H-9), 7.25 - 7.20 (5H, m, C6H5), 7.09 (1H, d, J 9.0 Hz, oxabenzoxazepine H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxabenzoxazepine H-2), 4.15 (2H, s, C H2C6H5), 3.40(3H, s, NCH3), 0.26(9H, s, Si(CH3)3); m / z: 474[M+H] + (Found [M+H] + , 474.1981, C 25 H 27 N5O3Si requires [M+H] + 474.1956).

[0634]

[0635] (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

[0636] 1 H nmr(400MHz, CDCl3) δ 8.06(1H, d, J Hz, NH), 7.36(1H, dd, J Hz, oxobenzoxazepine H-8), 7.35 - 7.26(6H, m, C6H5, oxobenzoxazepine H-6), 7.14(1H, d, J 8.5Hz, oxobenzoxazepine H-9), 5.04(1H, dt, J 11.0, 7.5Hz, oxobenzoxazepine H-3), 4.71(1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazepine H-2), 4.29(1H, dd, J 11.0, 9.5Hz, 1H of oxobenzoxazepine 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] + (Found [M+H] + , 402.1561, C 22 H 19 N5O3 requires [M+H] + 402.1576).

[0637]

[0638] (S)-3-Amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

[0639] 1 H nmr(400MHz,CDCl3)δ7.24(1H,d,J 2.0Hz,oxobenzoxazepine H-6),7.22(1H,dd,J 8.0,2.0Hz,oxobenzoxazepine H-8),7.06(1H,d,J 8.0Hz,oxobenzoxazepine H-9),4.41(1H,dd,J 10.0,7.5Hz,1H of oxobenzoxazepine H-2),4.12(1H,dd,J 11.5,10.0Hz,1H of oxobenzoxazepine H-2),3.72(1H,dd,J 11.5,7.5Hz,oxobenzoxazepine H-3);m / z:275[M+H] + (found [M+H] + ,275.1390,C 15 H 18 N2O3 requires [M+H] + 275.1404).

[0640]

[0641] (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

[0642] 1 H nmr(400MHz,CDCl3)δ8.03(1H,d,J 7.0Hz,NH),7.83(1H,s,triazole H-5),7.32 - 7.21(5H,m,5H of C6H4,oxobenzoxazepine H-6),7.16(1H,dd,J 9.0,2.0Hz,oxobenzoxazepine H-8),7.12(1H,d,J 9.0Hz,oxobenzoxazepine H-9),5.37(2H,s,NC H2C6H4CH3), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazepine H-2), 3.41 (3H, s, NCH3), 2.27 (3H, s, C6H4C H 3), 1.62 (6H, s, C(C H 3)2OH); 13 C nmr (100 MHz, CDCl3) δ 168.8, 158.4, 156.5, 149.9, 143.8, 136.8, 136.0, 131.4, 131.1, 130.9, 129.7, 129.4, 126.8, 126.5, 123.2, 120.4, 94.5, 80.6, 77.1, 65.5, 52.6, 49.1, 35.5, 31.4, 19.0; m / z: 474 [M + H] + , 456 [M + H - H2O] +

[0643]

[0644] (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

[0645] 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 C6H4C6H5), 7.45 - 7.42 (2H, m, 2H of C6H4C6H5), 7.38 - 7.34 (3H, m, 3H of C6H4C6H5), 7.28 - 7.26 (2H, m, oxobenzoxazepine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.41 (2H, s, NC H2C6H4Ph), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of benzoxazepine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxabenzoxazepine H-2), 3.41 (3H, s, NCH3), 1.62 (6H, s, C(C H 3)2OH); 13 C nmr (100 MHz, CDCl3) δ 169.1, 158.7, 157.0, 150.3, 144.3, 142.3, 140.4, 136.3, 132.9, 131.2, 129.2, 129.0, 128.2, 128.0, 127.4, 126.8, 123.5, 120.7, 94.9, 80.9, 77.5, 65.9, 54.4, 49.4, 35.8, 31.7; m / z: 536 [M + H] + , 518 [M + H - H2O] +

[0646]

[0647] (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

[0648] 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, 3H of oxabenzoxazepine H-6, H-8, H-9, C6 H 3(CH3)2), 7.13 - 7.10 (3H, m, 3H of oxabenzoxazepine H-6, H-8, H-9, C6H3(C H 3)2), 5.41 (2H, s, NC H 2C6H3(CH3)2), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxabenzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H of oxabenzoxazepine H-2),

[0649] 3.41 (3H, s, NCH3), 2.30 (6H, s, C6H3(C H 3)2), 1.62 (6H, s, C(C H 3)2OH); 13 C nmr (100 MHz, CDCl3) δ 168.8, 158.5, 156.5, 149.9, 143.1, 138.1, 136.0, 130.9, 129.6, 129.0 (2C), 126.5, 123.2, 120.4, 94.5, 80.6, 77.1, 65.5, 49.1, 49.0, 35.5, 31.4, 19.6; m / z: 488 [M+H] + , 470 [M+H-H2O] + (found [M+H] + , 488.2292, C 27 H 29 N5O4 requires [M+H] + 488.2292).

[0650]

[0651] (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

[0652] 1 H nmr (400 MHz, CDCl3) δ 8.04 (1H, s, triazole H-5), 8.03 (1H, d, J 7.0 Hz, NH), 7.29 - 7.26 (2H, m, oxobenzoxazepine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.06 (1H, ddd, J 11.0, 7.5, 7.0 Hz, oxobenzoxazepine H-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, one H of oxobenzoxazepine 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, 1.0 Hz, CH(C H3)2); 13 C nmr(100MHz,CDCl3)δ168.9,158.5,156.5,149.9,144.3,136.0,130.9,126.5,123.2,120.4,94.5,80.6,77.1,65.5,57.6,49.1,35.5,31.4,29.0,19.7;m / z:426[M+H] + ,408[M+H-H2O] + (found [M+H] + ,426.2126,C 22 H 27 N5O4 requires [M+H] + 426.2136).

[0653]

[0654] (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

[0655] 1 H nmr(400MHz,CDCl3)δ7.30 - 7.18(5H,m,5H of C6H5, H-6, H-8, H-9 of oxobenzoxazepine),7.13 - 7.06(3H,m,3H of C6H5, H-6, H-8, H-9 of oxobenzoxazepine),6.85 - 6.77(0.66H,m, major H-3 of oxobenzoxazepine),5.34 - 5.27(0.33H,m, minor H-3 of oxobenzoxazepine),4.94(0.33H,dd,J 12.0,10.5Hz, minor H-3 of oxobenzoxazepine),4.84(0.66H,dd,J12.0,9.5Hz, major H-3 of oxobenzoxazepine),4.55(0.66H,dd,J 9.5,7.5Hz, 1H major of H-2 of oxobenzoxazepine),4.50(0.33H,m, 1H minor of H-2 of oxobenzoxazepine),4.11(0.66H,s,C H 2C6H5 minor),4.05(1.32H,q,J7.0Hz,NC H 2CH3 major),3.91,3.84(1.32H,2dAB system,J 15.5Hz,C H 2C6H5 major),3.50(0.66H,q,J 7.0Hz,NC H2CH3 (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] + (Found [M+H] + , 488.2291, C 27 H 29 N5O4 requires [M+H] + 488.2292).

[0656]

[0657] (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

[0658] 1 H nmr (400MHz, CDCl3) δ 8.10 (1H, d, J Hz, NH), 7.33 (1H, m, oxobenzoxazepine H-6), 7.31 (1H, dd, J 8.0, 2.5Hz, oxobenzoxazepine H-8), 7.15 (5H, br s, C6H5), 7.02 (1H, dd, J8.0, 1.0Hz, oxobenzoxazepine 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] + (Found [M+H] + , 458.0651, C 20 H 18 BrN5O3 requires [M+H] + 458.0645).

[0659]

[0660] (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

[0661] 1 H nmr(400MHz,CDCl3)δ7.72(1H,d,J 7.0Hz,NH),7.36 - 7.21(7H,m,C6H5,oxobenzoxazepine H-6,H-8),7.11(1H,d,J 9.0Hz,oxobenzoxazepine H-9),6.30(1H,br s,isoxazole H-5),4.99(1H,dt,J 11.0,7.0Hz,oxobenzoxazepine H-3),4.70(1H,dd,J 9.5,7.5Hz,1H of oxobenzoxazepine H-2),4.26(1H,dd,J 11.0,10.0Hz,1H of oxobenzoxazepine H-2),4.10(2H,s,C H 2C6H5),3.41(3H,s,NCH3),1.62(6H,s,C(C H 3)2OH); 13 C nmr(100MHz,CDCl3)δ174.1,168.4,158.5,157.9,149.9,136.0,135.2,130.9,128.9,128.7,127.4,126.5,123.1,120.4,101.6,94.6,80.6,76.9,65.6,49.2,35.5,33.2,31.4,;m / z:460[M + H] + ,442[M + H - H2O] + (found[M + H] + ,460.1884,C 26 H 25 N3O5 requires[M + H] + 460.1867).

[0662]

[0663] (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

[0664] 11H NMR (400 MHz, CD3OD) δ 7.71 (1H, dd, J 5.5, 3.0 Hz, 1 x ArH), 7.20 (1H, dd, J 5.5, 3.0 Hz, 1 x ArH), 7.59 (1H, d, J 2.0 Hz, 1 x ArH), 7.44 (1H, td, J 8.5, 2.0 Hz, 1 x ArH), 7.41 (1H, br s, 1 x ArH), 7.33 - 7.23 (6H, m, 6 x ArH), 5.03 (1H, dd, J 11.5, 7.5 Hz, oxabenzoxazepine H-3), 4.60 (1H, dd, J 9.5, 7.5 Hz, 1H of oxabenzoxazepine H-2), 4.45 (1H, dd, J 11.5, 9.5 Hz, 1H of oxabenzoxazepine H-2), 4.35 (2H, s, isoquinoline H-1), 4.16 (2H, s C H 2C6H5), 3.50 (2H, t, J 6.5 Hz, isoquinoline H-3 or H-4), 3.42 (3H, s, NCH3), 3.13 (2H, dd, J 7.0, 6.0 Hz, isoquinoline H-3 or H-4); m / z: 533 [M+H] + (found [M+H] + , 533.2296, C 31 H 28 N6O3 requires [M+H] + 533.2296).

[0665]

[0666] (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

[0667] 11H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.0 Hz, NH), 7.26 - 7.19 (4H, m, H-6, H-7 of benzoxazepine, 2H of C6H4F), 7.08 (1H, d, J 9.0 Hz, H-9 of benzoxazepine), 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, H-3 of benzoxazepine), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H of H-2 of benzoxazepine), 4.25 (1H, dd, J 11.0, 10.0 Hz, 1H of H-2 of benzoxazepine), 4.19 (2H, s, C H 2C6H4F), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3); 13 13C NMR (100 MHz, CDCl3) δ 168.8, 160.7 (d, J 245.5 Hz), 158.5, 149.2, 135.8, 131.0 (d, J 4.0 Hz), 130.9, 128.9 (d, J 8.5 Hz), 126.4, 124.3 (d, J 4.0 Hz), 123.1 (d, J 15.0 Hz), 122.8, 121.8, 115.3 (d, J 21.5 Hz), 99.4, 77.6, 77.0, 49.2, 35.5, 30.9, 27.9, 26.3; m / z: 476 [M + H] + (found [M + H] + , 476.2100, C 25 H 26 (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 requires [M + H] + 476.2092).

[0668]

[0669] (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

[0670] 11H 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, benzoxazepine H-6, H-8, C6H3(CH3)2 H-4), 7.12 (2H, d, J 7.5 Hz, C6H3(CH3)2 H-3, H-5), 7.09 (1H, d, J 9.0 Hz, benzoxazepine H-9), 5.42 (2H, s, NC H 2C6H3(CH3)2), 5.06 (1H, dt, J 11.0, 7.5 Hz, benzoxazepine H-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H of benzoxazepine H-2), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H of benzoxazepine H-2), 3.42 (3H, s, NCH3), 2.31 (6H, s, C6H3(CH3)2, 1.32 (9H, s, C(CH3)3); m / z: 486 [M + H] + (found [M + H] + , 486.2506, C 28 H 31 N5O3 requires [M + H] + 486.2500).

[0671]

[0672] (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

[0673] 1 1H NMR (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.33 - 7.26 (7H, m, C6H5, benzoxazepine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, benzoxazepine H-9), 4.99 (1H, dt, J 11.0, 7.5 Hz, benzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H of benzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H of benzoxazepine H-2), 4.21 - 4.11 (1H, m, NC H 1H of 2CH3), 4.16 (2H, s, NC H2C6H5), 3.66(1H, septet, J 7.0Hz, NC H 2CH3's 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 - H2O] + (Found [M + H] + , 474.2143, C 26 H 27 N5O4 requires [M + H] + 474.2136).

[0674]

[0675] (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

[0676] 1 H nmr(400MHz, CDCl3) δ 8.09(1H, d, J 7.5Hz, NH), 7.30 - 7.28(2H, m, oxobenzoxazepine H-6, H-8), 7.26 - 7.21(1H, m, 1H of C6H4F), 7.12(1H, d, J 8.5Hz, oxobenzoxazepine H-9), 7.03(1H, br d, J 7.5Hz, 1H of C6H4F), 6.98(1H, br d, J 9.5Hz, 1H of C6H4F), 6.92(1H, td, J8.5, 2.5Hz, 1H of C6H4F), 4.97(1H, dt, J 11.0, 7.5Hz, oxobenzoxazepine H-3), 4.65(1H, dd, J9.5, 7.5Hz, 1H of oxobenzoxazepine H-2), 4.27(1H, dd, J 11.0, 10.5Hz, 1H of oxobenzoxazepine H-2), 4.22 - 4.10(1H, m, NC H 2CH3's 1H), 4.14(2H, s, C H 2C6H4F), 3.66(1H, septet, J7.0Hz, NC H 2CH3's 1H), 1.63(6H, s, C(C H 3)2OH), 1.19(3H, t, J 7.0Hz, NCH2C H 3); 1919F NMR (380 MHz, CDCl3) δ -112.6; m / z: 474 [M + H - H2O] + (found [M + H] + , 492.2047, C 26 H 26 FN5O4 requires [M + H] + 492.2042).

[0677]

[0678] (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

[0679] 1 1H NMR (400 MHz, CDCl3) δ 8.01 (1H, d, J 7.0 Hz, 1 x NH), 7.54 (1H, s, 1 x NH), 7.35 - 7.24 (6H, m, C5H5, oxobenzoxazepine H-8), 7.10 (1H, d, J 8.5 Hz, oxobenzoxazepine H-9), 7.09 (1H, m, oxobenzoxazepine H-6), 5.40 (1H, brs, 1H of C=CH2), 5.32 (1H, br s, 1H of C=CH2), 5.08 (1H, m, oxobenzoxazepine H-3), 4.76 (1H, dd, J 10.0, 6.0 Hz, 1H of oxobenzoxazepine H-2), 4.33 (1H, t, J 10.5 Hz, 1H of oxobenzoxazepine H-2), 4.18 (2H, s, C H 2C6H5), 1.98 (3H, s, CCH3); m / z: 428 [M + H] + (found [M + H] + , 428.1709, C 24 H 21 N5O3 requires [M + H] + 428.1717).

[0680]

[0681] (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

[0682] 11H NMR (400 MHz, CD3OD) δ 7.32 - 7.21 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.00 (1H, dd, J 10.5, 6.5 Hz, oxobenzoxazepine H-3), 4.61 (1H, dd, J 10.5, 6.5 Hz, 1H of oxobenzoxazepine H-2), 4.40 (1H, t, J 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.15 (2H, s, CH2C6H5); m / z: 444, 442 [M+H] + (found [M+H] + , 444.0492, C 19 H 16 BrN5O3 requires [M+H] + 444.0489).

[0683]

[0684] (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 1H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.41 - 7.39 (2H, m, oxobenzoxazepine H-6, H-8), 7.29 - 7.22 (5H, m, C6H5), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 6.31 (1H, s, CH=CCl), 5.05 (1H, dt, J11.5, 7.5 Hz, oxobenzoxazepine H-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepine H-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazepine H-2), 4.14 (2H, s, C H 2C6H5), 3.43 (3H, s, NCH3), 1.57 (6H, s, C(CH3)2OH); 1313C NMR (100 MHz, CDCl3) δ 168.7, 158.9, 158.4, 154.3, 150.2, 136.5, 135.9, 135.7, 135.7, 130.1, 128.9, 128.8, 127.2, 125.8, 122.8, 121.8, 77.2, 71.2, 49.1, 35.6, 33.2, 29.4; m / z: 480, 478 [M + H - H2O] + ; m / z: 496, 494 [M - H] - (Found [M + H] + , 496.1743, C 25 H 26 ClN5O4 requires [M + H] + 496.1746).

[0685]

[0686] (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

[0687] 1 1H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.28 - 7.20 (7H, m, oxobenzoxazepine H-6, H-8, C6H5), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazepine H-9), 5.02 (1H, dt, J11.0, 7.5 Hz, oxobenzoxazepine H-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, one H of oxobenzoxazepine H-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, one H of oxobenzoxazepine H-2), 4.14 (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] + (Found [M + H] + , 485.2322, C 27 H 28 N6O3 requires [M + H] + 485.2296).

[0688]

[0689] (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

[0690] 1 H nmr(400MHz,CDCl3)δ8.08(1H,d,J 7.0Hz,NH),7.29 - 7.7.27(2H,m,oxobenzoxazepine H-6,H-8),7.25 - 7.18(5H,m,C6H5),7.10(1H,d,J 9.0Hz,oxobenzoxazepine H-9),5.02(1H,dt,J 11.0,7.0Hz,oxobenzoxazepine H-3),4.65(1H,dd,J 9.5,7.5Hz,1H of oxobenzoxazepine H-2),4.27(1H,t,J 10.5Hz,1H of oxobenzoxazepine H-2),4.13(2H,s,C H 2C6H5),3.78,3.76(4H,2d AB system,J 4.5Hz,4H of morpholine),3.50(2H,s,CCH2N),3.39(3H,s,NCH3),2.65,2.63(4H,2d AB system,J 4.5Hz,4H of morpholine);m / z:501[M + H] + (found [M + H] + ,501.2245,C 27 H 28 N6O4 requires [M + H] + 501.2245).

[0691] Example 11

[0692] In this example, ADP - Glo TM technology was used to evaluate the compounds of the present disclosure using biochemical assays.

[0693] The ADP - Glo TM (Promega, Madison, Wisconsin, USA) reagent was thawed at ambient temperature. A kinase assay reagent was prepared by mixing kinase assay buffer with a lyophilized kinase assay substrate.

[0694] Prepare a 5X reaction kinase buffer with a stock solution volume of 500 ml by mixing 1000 μl of 1 M MgCl2, 500 μl of 1 M Tris-HCL pH 7.4, 0.5 mg / ml (25 mg) of BSA, and 3475 μl of distilled H2O. Prepare a final volume of 3 ml of the 2X working stock solution of the reaction kinase buffer containing 100 μM DTT and 4 mM MnCl2.

[0695] On ice, thaw the components of the RIPK1 enzyme (Igel Pharmaceuticals, South San Francisco, CA, USA). Prepare diluted RIPK1 in 1X kinase reaction buffer (diluted from 2X buffer) to 31 ng / well. Prepare a 166 μM working stock ATP assay solution in 1X kinase reaction buffer (diluted from 2X buffer).

[0696] In a 96-well plate, serially dilute the compound 4-fold in DMSO from 250 μM and then dilute 1:5 in 2X reaction buffer. In duplicate, add 1.0 μl of the diluted compound to a 384-well plate. Add 2 μl of the diluted active RIPK1 to the 384-well plate (not to column 1), and add 2X rxn buffer to column 1. Combine 150 nM of AKT (Anaspec, Fremont, CA, USA) with the ATP working stock in equal volumes and add 2 μl / well to the 384-well plate. The final reaction volume is 5.0 μl.

[0697] Centrifuge the plate briefly and incubate the reaction at 30 °C for 30 minutes. Add 5 μl of ADP-Glo TM to terminate the reaction. Centrifuge the plate briefly and incubate the reaction at room temperature for 40 minutes. Then add the kinase detection reagent and incubate at room temperature for 30 minutes. Determine the relative light units (RLU) of the kinase reaction by luminescence (fluorescence for 0.1 s) using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA). Table 1 provides the IC 50 values obtained from this example.

[0698]

[0699]

[0700]

[0701]

[0702] Example 12

[0703] In this example, U937 and L929 cells were exposed to the compounds of the present disclosure, and a cell necrosis assay was performed to evaluate the activity of the compounds against human RIP1 and murine RIP1.

[0704] U937 and L929 cells were obtained from the American Type Culture Collection (Manassas, Virginia, USA). Both cell types were maintained in logarithmic growth phase at 37 °C in 5% CO2 in RPMI 1640 medium (Sigma, St. Louis, Missouri, USA) supplemented with 10% fetal bovine serum (Sigma, St. Louis, Missouri, USA). For the necrosis assay, L929 cells were placed at 10K cells / well in 100 μL / well of medium in a Costar 96-well black clear bottom plate (Fisher Scientific, Hampton, New Hampshire, USA) for 18 h; on the day of the assay, U937 cells were plated at 50K cells / well in 50 μL / well of medium containing 60 μM zVAD-fmk (Lonza, Basel, Switzerland). The medium was removed from the L929 cells in the 96-well plate and replaced with 50 μL / well of fresh medium containing 40 μM zVAD-fmk. Each compound of the present disclosure evaluated in this example was serially diluted 4-fold from 2.5 mM in DMSO and then diluted 1:125 in complete medium. Then 50 μL / well of 2x compound was added to the cells in the plate. The cells were pre-incubated with the compound for 1 hour at 37 °C in 5% CO2, and then 10 μL / well of 11x TNFα (Peprotech, Rocky Hill, New Jersey, USA) was added to give a final concentration of TNFα of 2 ng / mL. At 37 °C in 5% CO2, using a Wallac Victor2 luminometer (PerkinElmer, Waltham, Massachusetts, USA), and a luminescent cell viability reagent assay ( Luminescent Cell Viability Reagent Assay) (Promega Corporation, Madison, Wisconsin, USA), added according to the manufacturer's instructions after 18 hours of TNFα stimulation, and the relative amount of necrotic cells was determined by luminescence. The results from this example are summarized in Table 2. This example determined that the examples of the compounds described in the text have unexpectedly potent activity against human RIP1 and murine RIP1, an activity that allows them to be evaluated in an in vivo mouse model of disease. These results can be used to determine safe and effective doses for humans.

[0705]

[0706]

[0707]

[0708]

[0709]

[0710] Example 13

[0711] In this example, an acute hypothermia mouse model assay was used to evaluate the ability of the compounds disclosed herein to inhibit TNF-α-induced hypothermia.

[0712] Female C57BL / 6 mice were randomly grouped and weighed on day -1. On the day of the study (day 0), the vehicle or test article was administered to the mice by oral gavage. Fifteen minutes after oral administration of the test reagent, each mouse was given an intraperitoneal (IP) injection containing a solution of recombinant human tumor necrosis factor α (TNF-α, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured at hour 0 (before IP injection) and hourly via a rectal probe temperature measuring device. Three (3) hours after IP injection of TNF-α and zVAD / FMK, the mice were euthanized by CO2 asphyxiation and blood was collected by cardiac puncture. Serum and plasma were harvested for determination of cytokine and compound levels, respectively. Mice in an individual group (satellite mice) were included to determine the compound levels in plasma when TNFα / zVAD-FMK was administered.

[0713] (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 structure as described below was used as a comparative compound, and the examination was carried out using a protocol similar to that described in WO 2014 / 125444. According to WO 2014 / 125444, at a dose of 30 mg / kg, this comparative compound exhibited 93% inhibition. In contrast, using a similar assay protocol as described above, at a dose of 5 mg / kg, the compound I-30 of the present disclosure achieved greater than 85% inhibition.

[0714]

[0715] Comparative compound

[0716] Given the many possible embodiments to which the principles of the present disclosure may be applied, it should be recognized that the illustrated embodiments are only preferred examples and should not be considered limiting. On the contrary, the scope of the present disclosure is defined by the appended claims. Accordingly, we claim that the whole of the invention falls within the scope and spirit of these claims.

Claims

1. A compound having the following formula or a pharmaceutically acceptable salt thereof, wherein: Ring B has a structure satisfying the formula wherein at least one W is nitrogen and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen or NH; L is O or CH2; R 1 is or - linker - R 6 a group, wherein the linker is -C≡C-, and R 6 is R b , -C(R f )3 or -C(R f )=C(R f )2; R 2 is C 1-10 alkyl; R 3 is H, methyl or ethyl; R 4 and R 5 each independently is halogen, C 1-6 alkyl; For each occurrence, R a independently is H, D, C 1-10 aliphatic, C 1-10 haloaliphatic, C 5-10 aromatic or a C containing at least one heteroatom selected from nitrogen, oxygen and sulfur 3-6 heterocycle; For each occurrence, R b is independently OH, -SH, -OR c , -SR c , -NR d R d , -Si(R a )3, -C(O)OH, -C(O)OR c or -C(O)NR d R d ; For each occurrence, R c is independently C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl or C 5-10 aromatic; For each occurrence, R d is independently H; C 1-6 alkyl; C 3-6 cycloalkyl; C containing at least one heteroatom selected from nitrogen, oxygen and sulfur 3-6 heterocycle; C 5-10 aryl; C containing at least one heteroatom selected from nitrogen, oxygen and sulfur 5-10 heteroaryl; or two R d groups together with the nitrogen to which they are attached provide a C containing at least one heteroatom selected from nitrogen, oxygen and sulfur 3-9 heterocycle, or a C containing at least one heteroatom selected from nitrogen, oxygen and sulfur 5-10 heteroaryl; For each occurrence, R e is independently halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C containing at least one heteroatom selected from nitrogen, oxygen and sulfur 5-10 heteroaryl or -OR a ; For each occurrence, R f independently is R a 、R b or R e , or two R f groups together with the carbon atom to which they are attached provide a C 3-6 cycloalkyl group, or a C 3-10 heterocycle containing at least one heteroatom selected from nitrogen, oxygen and sulfur; m is 1; n is 0; and p is 0, 1 or 2; wherein the following compounds are excluded:

2. The compound according to claim 1, wherein ring B is a diazole, triazole, oxadiazole, oxazole or pyridyl group.

3. The compound according to claim 2, wherein the triazole is The diazole is The oxadiazole is The oxazole is 4. The compound according to claim 1, wherein R 5 is a halogen or a methyl group.

5. The compound according to claim 1, wherein R e is -OR a wherein R a is H.

6. The compound according to claim 1, wherein R a is a methyl group.

7. The compound according to claim 1, wherein ring B is 8. The compound according to claim 1, wherein R 1 is 9. A compound selected from:

10. A compound selected from:

11. A pharmaceutical composition comprising the compound according to any one of claims 1-10, an excipient, a therapeutic agent, or a combination thereof.

12. A method for non-therapeutic and non-diagnostic purposes, comprising contacting receptor-interacting protein-1 (RIP1) kinase with the compound according to any one of claims 1-10 or the pharmaceutical composition according to claim 11.

13. Use of a compound or its pharmaceutical composition in the manufacture of a medicament for treating a disease in a subject, comprising administering to the subject (i) a therapeutically effective amount of the compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof; or (ii) a therapeutically effective amount of the pharmaceutical composition according to claim 11; wherein the subject has, is suspected of having, or is developing the disease, and wherein the disease is a disease involving receptor-interacting protein-1 (RIP1) kinase.

14. The use according to claim 13, wherein the compound is 15. The use according to claim 13, wherein the compound is 16. A method for preparing a compound according to any one of claims 1-10, comprising: By combining a starting material having formula A and an R 1 -containing reagent with a transition metal catalyst, a base, and a solvent, the starting material is coupled with the R 1 -containing reagent to form a functionalized product, where R 1 comprises a linker-R 6 group; deprotecting the amino 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: Formula A; the functionalized product has a structure satisfying Formula B: Formula B; and the acid-containing coupling partner has a structure satisfying Formula C: Formula C; and wherein X is halogen or trifluoromethanesulfonate; PG is an amine protecting group; And rings B, L, R 1 , R 2 , R 4 , R 5 , each of m, n and p is as described in any one of claims 1-10.

17. A compound having the following formula: or a pharmaceutically acceptable salt thereof.

18. A compound having the following formula:

19. A pharmaceutical composition comprising a compound having the following formula: or a pharmaceutically acceptable salt thereof, and at least one excipient.

20. Use of the compound according to claim 17 or claim 18, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease involving receptor-interacting protein-1 (RIP1) kinase in a subject, wherein the disease involving receptor-interacting protein-1 (RIP1) kinase is an autoimmune disease.

21. Use of the compound according to claim 17 or claim 18, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease involving receptor-interacting protein-1 (RIP1) kinase in a subject, wherein the disease involving receptor-interacting protein-1 (RIP1) kinase is psoriasis.

22. Use of the compound according to claim 17 or claim 18, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease involving receptor-interacting protein-1 (RIP1) kinase in a subject, wherein the disease involving receptor-interacting protein-1 (RIP1) kinase is rheumatoid arthritis.

23. Use of the compound according to claim 17 or claim 18, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease involving receptor-interacting protein-1 (RIP1) kinase in a subject, wherein the disease involving receptor-interacting protein-1 (RIP1) kinase is atopic dermatitis.

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