Rip1k inhibitors

Abstract

To provide: kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds; and pharmaceutical compositions and combinations comprising such inhibitory compounds.SOLUTION: The invention provides compounds according to the formula in the figure. In the formula, ring B is 5- or 6-membered heteroaryl; X is CH2 or O; L is a heteroatom or Ra, provided that Ra is not hydrogen; Z is C1-10 aliphatic (such as C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-6 cycloalkyl), aryl or heteroaryl, each optionally substituted with one or more R5 groups.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the earlier filing date of U.S. Provisional Application No. 63 / 004,404, filed April 2, 2020.

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

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

[0004] Disclosed herein are compounds according to formula I, [ka] wherein Ring B is a 5- or 6-membered heteroaryl; X is CH2 or O; L is a heteroatom or R a where R a is not hydrogen, Z is C 1-10 Aliphatic (C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 cycloalkyl, each of which optionally contains one or more R 5 aryl or heteroaryl substituted with a group; R 1 is, independently for each occurrence, -NR d R d where two R d The groups, together with the nitrogens to which they are attached, are C 3-10 Heterocyclic group, -C≡CH, or -linker -R 6 and the linker is a divalent C 1-10 Aliphatic moiety (C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, etc.) or C 1-10 is an alicyclic moiety, R 6 is R b , -C(R f )3, or -C(R f )=C(R f 2, each linker optionally having one or more halo, R a , or C replaced by 5-10 Aromatic or C 3-6 is heterocyclic, R 2 and R 3 are independently a and in some embodiments, R 2 is H or C 1-6 Hydrogen or C such as alkyl 1-10 aliphatic, and in certain embodiments, R 2 C such as CH3 or CD3 1-6 is alkyl, R 4 and R 5 is calculated independently for each occurrence, R e and R a are independently defined for each occurrence as hydrogen, C 1-10 Aliphatic (C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 Cycloalkyl, etc.), C 1-10 Haloaliphatic, C 5-10 Aromatic, or C 3-6 is heterocyclic, R b independently for each occurrence: -OH, -SH, -ORc , -SR c , -NR e R e , -Si(R a )3, -C(O)OH, -C(O)OR c or -C(O)NR e R e and R c independently for each occurrence (1, 2, or 3 R e Optionally substituted with C 1-10 Alkyl, (1, 2, or 3 R e Optionally substituted with C 2-10 alkenyl, (1, 2 or 3 R e Optionally substituted with C 2-10 Alkynyl, (1, 2 or 3 R e Optionally substituted with C 3-6 Cycloalkyl, or (1, 2, or 3 R e Optionally substituted with C 5-10 It is aromatic, R d is 1, 2, or 3 R a , R b and / or R e C optionally substituted with a group 1-9 It is aliphatic, R e is independently for each occurrence oxo (=O), -OR a , N(R a )2, Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or two R e The groups are bonded together to form two R e C with nitrogen to which the group is attached 3-10 providing a heterocyclic group, m is 1 to 4; n is 0, 1, or 2.

[0005] The foregoing and other objects, features, and advantages of the present invention will become more apparent from the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] I. Terminology Overview The following explanations of terms and methods are provided to better describe the present disclosure and guide those skilled in the art in the practice of the present disclosure. The singular forms "a," "an," and "the" refer to one or more, unless the context clearly dictates otherwise. The term "or" refers to a single element of the described alternative elements or a combination of two or more elements, unless the context clearly dictates otherwise. As used herein, "comprises" means "includes." Thus, "including A or B" means "including A, B, or A and B," without excluding additional elements. All references cited herein, including patents and patent applications, are incorporated by reference.

[0007] Unless otherwise indicated, all numbers expressing amounts of components, molecular weights, percentages, temperatures, times, and the like used in the specification or claims are to be understood as being modified by the term "about." Thus, unless otherwise indicated, implicitly or explicitly, the numerical parameters recited are approximations that may depend on the desired properties sought and / or the limits of detection under standard testing conditions / methods. In directly and explicitly distinguishing the embodiments from the prior art discussed, the numerical values ​​of the embodiments are not approximations unless the word "about" is explicitly recited.

[0008] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled 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 this disclosure, suitable methods and materials are described below. These materials, methods, and examples are illustrative only and are not intended to be limiting.

[0009] As used herein, for example, "substituted aryl C 1-8The term "substituted" in the term "alkyl" refers to all subsequent modifiers, and substitution is 1-8 The alkyl group, "C 1-8 It may occur in the "alkyl" portion, the "aryl" portion, or both portions.

[0010] "Substituted", when used to modify a named group or moiety, means that at least one, possibly more than one, hydrogen atom of the named group or moiety is independently replaced with the same or different substituents as defined below. In certain embodiments, a group, moiety, or substituent may be substituted or unsubstituted unless otherwise expressly defined as either "unsubstituted" or "substituted". Thus, any of the groups specified herein may be unsubstituted or substituted unless the context indicates otherwise or a particular structural formula excludes substitution. In certain embodiments, a substituent may or may not be expressly defined as substituted, but is still intended 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.

[0011] "Substituents" or "substituent groups" for replacing one or more hydrogen atoms on a saturated carbon atom of a specified group or moiety are defined as -R, unless otherwise specified. 60 , halo, =O, -OR 70 , -SR 70 , -N(R 80 )2, haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -P(O)(O - )2(M + )2, -P(O)(O - )2M 2+, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)N(R 80 )2, -C(NR 70 )(R 80 )2, -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )N(R 80 )2, R 60 But, C 1-10 Aliphatic, heteroaliphatic, or alicyclic, typically C 1-6 Aliphatic, more typically C 1-6 is alkyl, R 60 may be optionally substituted, and each R 70 may independently represent at each occurrence a halogen or R 60 And each R 80 But for each occurrence, R 70 or two R 80The group, together with the nitrogen atom attached thereto, optionally forms a 3-7 membered heteroalicyclic ring containing 1-4 identical or different additional heteroatoms selected from O, N, and S, where N is optionally H or an R group such as a C1-C3 alkyl group. 70 Each M + is a counterion with a net single positive charge. + is expressed independently for each occurrence, e.g., K + , Na + , Li + Alkali metal ions such as + N(R 60 ) 4, protonated amino acid ions such as lysine ion or arginine ion, or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 (The subscript "0.5" means, for example, that one of the counterions of such divalent alkaline earth ions may be the ionized form of the compound of the invention, and that other typical counterions such as chloride, or a two-ionized compound may serve as the counterion of such divalent alkaline earth ion, or a doubly-ionized compound may serve as the counterion of such divalent alkaline earth ion.) 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. Any two hydrogen atoms on a single carbon can also be replaced by, for example, =O, =NR 70 , =N-OR 70 , =N2, or =S.

[0012] Substituents for replacing a hydrogen atom on an unsaturated carbon atom of a group containing an unsaturated carbon are, unless otherwise specified, -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 , -NR 80 )2, -NR 70 C(NR 70 )R 70 , and -NR 70C(NR 70 )N(R 80 )2, and R 60 , R 70 , R 80 , and M + is as defined above. In an independent embodiment, the substituent is -O - M + , -OR 70 , -SR 70 , or -S - M + isn't it.

[0013] Substituents for replacing a hydrogen atom on a nitrogen atom of such nitrogen-containing groups are, unless otherwise specified, -R 60 , -O - M + , -OR 70 , -SR 70 , -S - M + , -N(R 80 )2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R 70 , -SO3 - M + , -SO3R 70 , -OS(O)2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 2- (M + )2, -PO3 2- M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70, -OC(S)R 70 , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )N(R 80 )2, and R 60 , R 70 , R 80 , and M + is as defined above.

[0014] In one embodiment, a substituted group has at least one substituent, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents, up to the maximum number of substituents possible for a particular moiety.

[0015] In addition, in embodiments where a group or moiety is substituted with a substituted substituent, the nesting of such substituted substituents is limited to three, thereby preventing the formation of a polymer. Thus, in a group or moiety that includes a first group that is a substituent of a second group that is itself a substituent of a third group, attached to a parent structure, the first (outermost) group can only be substituted with unsubstituted substituents. For example, in a group that includes -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with a substituent that is itself unsubstituted.

[0016] Any group or moiety defined herein may be connected to any other portion of the disclosed structures, such as a parent or core structure, as would be understood by one of skill in the art, such as by considering valence rules and / or considering functionality, as compared to exemplary species, unless the connectivity of the group or moiety to other portions of the structure is explicitly stated or implied by context.

[0017] "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)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0018] "Aliphatic" refers to a substantially hydrocarbon-based group or moiety. An aliphatic group or moiety may be acyclic, including alkyl, alkenyl, or alkynyl groups (as well as alkylene, alkenylene, or alkynylene groups), cycloalkyl, cycloalkenyl, or cycloalkynyl, including linear and branched chain configurations, as well as all stereoisomers and positional isomers, and may be cyclic versions thereof, such as alicyclic groups or moieties. Unless expressly stated otherwise, an aliphatic group is an acyclic aliphatic group or moiety having 1 to 25 carbon atoms (C 1-25 ), for example, 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), 1 to 6 (C 1-6 ), or 1 to 4 carbon atoms (C 1-4 ), or in an alicyclic group or moiety, 3 to 15 (C 3-15 ), 3~10(C 3-10 ), 3~6(C 3-6 ), or 3 to 4 carbon atoms (C 3-4). An aliphatic group may be substituted or unsubstituted, unless expressly referred to as "unsubstituted aliphatic" or "substituted aliphatic". An aliphatic group may be substituted with one or more substituents (up to two substituents for each methylene carbon of the aliphatic chain, or up to one substituent for each carbon of the -C=C- double bond of the aliphatic chain, or up to one substituent for the carbon of the terminal methine group).

[0019] "Lower aliphatic" refers to 1-6(C 1-6 ), or 1-4(C 1-4 1 to 10 carbon atoms (C 1-10 ), or in the case of a lower alicyclic group, 3 to 6 (C 3-6 ) with 3 to 10 carbon atoms (C 3-10 ) refers to an aliphatic group containing

[0020] "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 1-6 Alkyl group or C 3-6 Cycloalkyl groups. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In substituted alkoxy, R is substituted alkyl or substituted cycloalkyl, examples of which in the compounds of the present disclosure include haloalkoxy groups such as -OCF2H.

[0021] "Alkoxyalkyl" refers to the group -alkyl-OR where R is a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl group, where -CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl group.

[0022] "Alkyl" is a group consisting of 1 to at least 25 (C 1-25 ) carbon atoms, more typically 1 to 6 (C 1-6 ) carbon atoms, such as 1 to 10 (C 1-10(-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), t-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), and neopentyl (-CH2C(CH3)3).

[0023] "Amino" refers to the groups -NH2, -NHR, or -NRR, where each R is independently selected from H, aliphatic, heteroaliphatic, aromatic, including both aryl and heteroaryl, or heteroalicyclic, or two R groups taken together with the nitrogen to which they are attached form a heterocyclic ring. Examples of such heterocyclic rings include those in which two R groups taken together with the nitrogen to which they are attached optionally form the group [ka] In the above, -O- or -N(R g ), interrupted by one or two heteroatom groups such as -(CH2) 2-5 - forms a ring, R g But R 70 , -C(O)R 70 , -C(O)OR 60 , or -C(O)N(R 80 )2.

[0024] An "amide" is an amide group in which R is hydrogen, heteroaliphatic, or alkyl, particularly C 1-6 Refers to the group -N(R) acyl, which is an aliphatic group such as alkyl.

[0025] "Aromatic", unless otherwise specified, refers to a cyclic conjugated group or moiety of 5-15 ring atoms having a single ring (e.g., phenyl, pyridinyl, or pyrazolyl) or multiple fused rings in which at least one ring is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl), i.e., at least one ring, and optionally multiple fused rings, have a contiguous delocalized pi-electron system. Typically, the number of out-of-plane pi-electrons corresponds to Hückel's rule (4n+2). The point of attachment to the parent structure is typically through the aromatic portion of the fused ring system. For example, [ka] However, in certain instances, the context or explicit disclosure may dictate that the point of attachment is through the non-aromatic portion of the fused ring system. For example, [ka] An aromatic group or moiety may contain only carbon atoms in the ring, such as an aryl group or moiety, or may contain one or more ring carbon atoms and one or more ring heteroatoms (e.g., S, O, N, P, or Si) that contain lone pairs of electrons, such as a heteroaryl group or moiety. Unless otherwise stated, an aromatic group may be substituted or unsubstituted.

[0026] "Aryl" refers to an aromatic carbocyclic group of 6 to 15 carbon atoms (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, etc.) having a single ring (e.g., phenyl) or multiple condensed rings in which at least one ring is aromatic, unless otherwise specified. If any aromatic ring moiety contains a heteroatom, the group is heteroaryl and not aryl. Aryl groups can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, aryl groups can be substituted or unsubstituted.

[0027] "Aliphatic" refers to an aryl group attached to a parent through an aliphatic moiety. Aliphatic includes aralkyl or arylalkyl groups such as benzyl and phenylethyl.

[0028] "Carboxyl" refers to -CO2H.

[0029] "Carboxamide" refers to --C(O)amino.

[0030] A "carboxyl ester" or "carboxy ester" refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0031] "Carboxylate" is -C(O)O - Or its salt.

[0032] "Cyano" refers to the group --CN.

[0033] "Alicyclic" refers to a cyclic aliphatic group having a single ring (e.g., cyclohexyl) or multiple rings, such as in a fused, bridged, or spirocyclic system, where the ring or at least one of the rings of the system is aliphatic. Typically, the point of attachment to the parent structure is through the aliphatic portion of the polycyclic system. Alicyclics include saturated and unsaturated systems including cycloalkyl, cycloalkenyl, and cycloalkynyl. Alicyclic groups can contain 3 to 25 carbon atoms, e.g., 3 to 15, 3 to 10, or 3 to 6 carbon atoms. Unless otherwise stated, alicyclic groups can be substituted or unsubstituted. Exemplary alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0034] "Halo," "halide," or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0035] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CH2F, -CHF2, and -CF3.

[0036] "Heteroaliphatic" refers to 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 is replaced with an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroaliphatic compounds or groups, such as heteroalicyclic groups, can be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic.

[0037] "Heteroaryl" refers to an aromatic group or moiety having 5-15 ring atoms, including at least one carbon atom and at least one heteroatom such as N, S, O, P, or Si, unless otherwise specified. A heteroaryl group or moiety can contain a single ring (e.g., pyridinyl, pyrimidinyl, or pyrazolyl) or multiple condensed rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). A heteroaryl group can contain one or more non-aromatic rings fused to an aromatic moiety, and such heteroaryl groups can be attached to the remainder of the molecule through an aromatic or non-aromatic ring. A heteroaryl group or moiety can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, a heteroaryl group or moiety can be substituted or unsubstituted.

[0038] "Heterocyclyl", "heterocyclo", and "heterocycle" refer to both aromatic and non-aromatic ring systems, and more specifically to stable 3- to 15-membered ring moieties containing at least one carbon atom, typically multiple carbon atoms, and at least one heteroatom, such as 1 to 5. The heteroatom may be a nitrogen, phosphorus, oxygen, silicon, or sulfur atom. A heterocyclyl moiety may be a monocyclic moiety or may contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such polycyclic moieties may include fused or bridged ring systems, as well as spirocyclic systems, in which any nitrogen, phosphorus, carbon, silicon, or sulfur atom of the heterocyclyl moiety may be optionally oxidized to various oxidation states. For convenience, nitrogens, specifically, but not limited to, those defined as cyclic aromatic nitrogens, are meant to include their corresponding N-oxide forms, even if not expressly defined as such in specific instances. Thus, for example, for compounds having a pyridinyl ring, the corresponding pyridinyl-N-oxide is included as another compound of the invention unless expressly excluded or excluded by context. In addition, the ring nitrogen atom may be optionally quaternized. Heterocycles include heteroaryl moieties and heteroalicyclyl or heteroalicyclic moieties, which are partially or fully saturated heterocyclyl rings.Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, naphthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoaryl, and aryl groups. Quinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl nyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazebicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieryl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphosphoranyl, and oxadiazolyl.

[0039] "Hydroxyl" refers to the group --OH.

[0040] "Nitro" refers to the group --NO.sub.2.

[0041] A "phosphate" refers to an aryl group in which each -OR' is independently -OH; O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; -O-aralkyl; or -OR' is M + is a single positively charged counterion -O - M + Each M + is K + , Na + , Li + Alkaline ions such as + Ammonium ions such as N(R")4 (where R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl), or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The phosphonooxyalkyl can be, for example, -CH2OP(O)(O - Na + (((dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ester of a phosphonooxyalkyl group, such as, for example, -CH2OP(O)(O-tert-butyl)2.

[0042] A "phosphonate" refers to an aryl group in which each -OR' is independently -OH; -O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; or -O-aralkyl; - M + And M + refers to the group -P(O)(OR')2, which is a counter ion having a single positive charge. + is a positively charged counterion, e.g., K + , Na + , Li + Alkali metal ions such as +Ammonium ions such as N(R")4 (where R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl), or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The phosphonoalkyl can be, for example, -CH2P(O)(OH)2, or -CH2P(O)(O - Na + ((dialkoxyphosphoryl)alkyl) refers to a dialkyl ester of a phosphonoalkyl group such as, for example, -CH2P(O)(O-tert-butyl)2.

[0043] A "patient" or "subject" may generally refer to any organism, but more typically refers to mammals and other animals, particularly humans. Thus, the disclosed methods are applicable to both human therapy and veterinary applications.

[0044] A "pharmaceutical acceptable excipient" refers to a substance, other than an active ingredient, that is included in a composition that includes an active ingredient. As used herein, an excipient may be incorporated within or physically mixed with a particle of a pharmaceutical composition. An excipient may be used, for example, to dilute an active agent and / or to modify the properties of a pharmaceutical composition. Excipients may include, but are not limited to, anti-adherents, binders, coatings, enteric coatings, disintegrants, flavors, sweeteners, colorants, lubricants, glidants, adsorbents, preservatives, carriers, or vehicles. Excipients may be starches and modified starches, cellulose and cellulose derivatives, sugars and derivatives of sugars 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 methylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), carboxymethylcellulose, dipalmitoyl phosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

[0045] An "adjuvant" is a component that modifies the effect of another agent, typically an active ingredient. Adjuvants are often pharmacological and / or immunological agents. Adjuvants can modify the effect of an active ingredient by increasing the immune response. Adjuvants can also act as stabilizers of the 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 or incomplete adjuvants.

[0046] "Pharmaceutically acceptable carrier" refers to an excipient that is a carrier or vehicle, such as a suspending aid, solubilizing aid, or aerosolizing aid. See Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21, incorporated herein by reference. st Edition (2005) describes exemplary compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0047] Generally, the nature of the carrier will depend on the particular mode of administration used. For example, parenteral formulations usually contain an injectable fluid, which includes pharma- ceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol, etc., as a vehicle. In some instances, the pharma-ceutically acceptable carrier can be sterilized so as to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical compositions to be administered may contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, for example, sodium acetate or sorbitan monolaurate.

[0048] "Pharmaceutically acceptable salts" refers to pharma-ceutically acceptable salts of a compound derived from a variety of organic and inorganic counterions, as would be known to one of ordinary skill in the art, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, where the molecule contains a basic functional group, 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 are formed with acid partners while retaining the biological effectiveness of the free base. In particular, the disclosed compounds form salts with a variety of pharma- ceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, and the like. A "pharma-ceutically acceptable base addition salt" is a subset of "pharma-ceutically acceptable salts" derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharma- ceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.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 particularly disclosed embodiments, the compound may be a formate, trifluoroactate, hydrochloride, or sodium salt.

[0049] An "effective amount" of a compound or pharmaceutical composition refers to an amount of the compound or pharmaceutical composition sufficient to achieve a particular desired result, such as inhibiting a protein or enzyme. In certain embodiments, an "effective amount" is an amount sufficient to inhibit RIP1, elicit a desired biological or medical response in a tissue, system, subject, or patient, treat a specified disorder or disease, improve or eradicate one or more of its symptoms, and / or prevent the occurrence of a disease or disorder. The amount of a compound that constitutes an "effective amount" can vary depending on the compound, the desired result, the condition and its severity, the size, age, and sex of the patient being treated, etc., as will be understood by those skilled in the art.

[0050] "Prodrug" refers to a compound that is biologically active or that is converted in vivo to yield a compound that is more biologically active than the parent compound. In vivo conversion can occur, for example, by hydrolysis or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of a compound having an active form that bears a carboxylic acid moiety. Examples of pharma- ceutically acceptable esters of the compounds of the invention include, but are not limited to, aliphatic esters, particularly alkyl esters (e.g., C 1-6 Other prodrug moieties include phosphate ester groups and carboxylate esters, such as alkyl esters (alkyl esters), where R' is H or C. 1-6and phosphate esters or salts thereof, such as -CH2-OP(O)(OR')2, which is an alkyl group. Acceptable esters also include, but are not limited to, cycloalkyl esters and arylalkyl esters, such as benzyl. Examples of pharma- ceutically acceptable amides of the compounds of the invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (e.g., having about 1 to about 6 carbons). 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 T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated by reference for all purposes.

[0051] "Solvate" refers to a complex formed by the combination of a solvent molecule with a molecule or ion of a solute. The solvent may 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, propanol, amides such as N,N-dialiphatic amides such as N,N-dimethylformamide, alkyl sulfoxides such as tetrahydrofuran, dimethyl sulfoxide, water, and combinations thereof. The compounds described herein may exist in unsolvated as well as solvated forms when combined with pharma- ceutically acceptable or non-acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds of the present disclosure are within the scope of the embodiments disclosed herein.

[0052] "Sulfonamido" refers to the group or moiety -SO2amino, or -N(R)sulfonyl, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0053] "Sulfanyl" refers to the groups or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic (including both -S-aryl and -S-heteroaryl).

[0054] "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).

[0055] "Sulfonyl" refers to the groups: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including both -SO2aryl and -SO2heteroaryl).

[0056] As used herein, "treating" or "treatment" relates to the treatment of a disease or condition of interest in a patient or subject, particularly a human having the disease or condition of interest, and includes, by way of example and not limitation, the following: (i) specifically, to prevent a disease or condition from occurring in a patient or subject, where such patient or subject is susceptible to the condition but has not yet been diagnosed as having the disease or condition; (ii) inhibiting a disease or condition, e.g., preventing or delaying its onset; (iii) alleviating the disease or condition, e.g., reducing the symptoms thereof or causing regression of the disease or condition or its symptoms; or (iv) stabilizing a disease or condition.

[0057] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular disease or condition may not have a known causative agent (and thus the etiology has not yet been determined) and therefore is not yet recognized as a disease, but only as an undesirable state or syndrome in which a more or less specific set of symptoms has been identified by clinicians.

[0058] The above definitions and the general formula below are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups) that would be readily recognized by one of ordinary skill in the art.

[0059] Those skilled in the art will understand that compounds may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may contain one or more chiral centers and / or double bonds, and may therefore exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, certain disclosed compounds may exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. As the various compound names, formulae, and compound diagrams in the specification and claims may represent only one of the possible tautomeric, conformational, optical, or geometric isomeric forms, those skilled in the art will understand that the disclosed compounds encompass any tautomeric, conformational, optical, and / or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. Using techniques known to those skilled in the art, particularly those having the benefit of this disclosure, mixtures of different isomeric forms, including mixtures of enantiomers and / or stereoisomers, can be separated to provide each separate enantiomer and / or stereoisomer. In cases of restricted rotation, e.g., around an amide bond or between two directly bonded rings such as a pyridinyl ring, a biphenyl group, etc., atropisomers are also possible and are also specifically included in the compounds of the invention.

[0060] As will be appreciated by those skilled in the art, hydrogen can exist in any of the three isotopes, namely protium, deuterium, and tritium. In certain embodiments, any or all hydrogen present in a compound, or in a particular group or moiety within a compound, can be enriched in deuterium or tritium relative to the natural abundance of such isotopes. Thus, the description of an alkyl includes compounds that are enriched in deuterium relative to protium. A deuterated alkyl group can have one or more protium atoms replaced by deuterium. For example, C2D x H 5-x When one to five hydrogens in, etc. are replaced with deuterium, ethyl refers to both C2H5 or C2H5.

[0061] II. RIP1-ACTIVE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING RIP1-ACTIVE COMPOUNDS A. Compound Disclosed herein are compounds and pharmaceutical compositions comprising such compounds that are useful for inhibiting RIP1 and / or treating diseases and / or conditions associated with RIP1. In some embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds inhibit RIP1 over RIP2, RIP3, or both RIP2 and RIP3. In some embodiments, the compounds of the present disclosure have the formula I [ka] It is possible to have a structure that satisfies the above.

[0062] One of ordinary skill in the art will understand that the formulas disclosed herein include within their scope all hydrates, solvates, physical forms, stereoisomers, N-oxides, tautomers, and prodrugs of the exemplified compounds.

[0063] With reference to formula I: Ring B is a 5- or 6-membered heteroaryl; X is CH2 or O; L is a heteroatom or R a where R ais not hydrogen, Z is C 1-10 Aliphatic (C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 cycloalkyl, each of which optionally contains one or more R 5 aryl or heteroaryl substituted with a group; R 1 is, independently for each occurrence, -NR d R d where two R d The groups, together with the nitrogens to which they are attached, are C 3-10 Heterocyclic group, -C≡CH, or -linker -R 6 and the linker is a divalent C 1-10 Aliphatic moiety (C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, etc.) or C 1-10 is an alicyclic moiety, R 6 is R b , -C(R f )3, or -C(R f )=C(R f 2, each linker optionally having one or more halo, R a , or C replaced by 5-10 Aromatic or C 3-6 is heterocyclic, R 2 and R 3 are independently a and in some embodiments, R 2 is H or C 1-6 Hydrogen or C such as alkyl 1-10 aliphatic, and in certain embodiments, R 2 C such as CH3 or CD3 1-6 is alkyl, R 4 and R 5 is calculated independently for each occurrence, R e and R a are independently defined for each occurrence as hydrogen, C 1-10 Aliphatic (C 1-10Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 Cycloalkyl, etc.), C 1-10 Haloaliphatic, C 5-10 Aromatic, or C 3-6 is heterocyclic, R b independently for each occurrence: -OH, -SH, -OR c , -SR c , -NR e R e , -Si(R a )3, -C(O)OH, -C(O)OR c or -C(O)NR e R e and R c independently for each occurrence (1, 2, or 3 R e Optionally substituted with C 1-10 Alkyl, (1, 2, or 3 R e Optionally substituted with C 2-10 alkenyl, (1, 2 or 3 R e Optionally substituted with C 2-10 Alkynyl, (1, 2 or 3 R e Optionally substituted with C 3-6 Cycloalkyl, or (1, 2, or 3 R e Optionally substituted with C 5-10 It is aromatic, R d is 1, 2, or 3 R a , R b and / or R e C optionally substituted with a group 1-9 It is aliphatic, R e is independently for each occurrence oxo (=O), -OR a , N(R a )2, Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or two R e The groups are bonded together to form two Re C with nitrogen to which the group is attached 3-10 providing a heterocyclic group, m is 1 to 4; n is 0, 1, or 2.

[0064] In certain embodiments, R 1 But -NR d R d where two R d The groups, together with the nitrogen to which they are attached, are 3-10 When providing a heterocyclic group, C 3-10 The heterocyclic group optionally contains one, two or three additional heteroatoms selected from nitrogen and oxygen. In some embodiments, C 3-10 The heterocyclic groups are joined together by C 3-10 One or more R providing a heterocyclic group e This C is substituted with 3-10 Heterocyclic rings are R b Together with the group, a spirocyclic group or a bridged or unbridged bicyclic group can be provided.

[0065] R 1 can be located on any suitable carbon atom of the phenyl ring A, for example, at the 1, 2, 3, or 4 positions, as shown in Formula I. In some embodiments, one R 1 is R a where R a is C 1- C 10 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl), and the second R 1 is R b where R b is a halogen (e.g., Br, F, I, or Cl) or -NR d R d and two R d The groups, together with the nitrogens to which they are attached, are C 4-9 In some embodiments, C 4-9 A heterocyclic group can be formed by one or more R egroup and / or both R d In addition to the nitrogen to which the group is attached, there are one or more additional heteroatoms. b At least one R 1 R b -NR d R d (i) each R d are independently a Or R e or (ii) two R d The groups, together with the nitrogens to which they are attached, are C 4-9 In some embodiments, R b -NR d R d where one R d is R a and R a is H and the other R d is R e and R e is C 1-6 In some embodiments, the heterocyclic group is a heterocyclic group having one or two heteroatoms (R b Particular heterocyclic groups include those having a nitrogen atom of R b The heterocyclic group in some compound embodiments includes the nitrogen atom of the group and either an oxygen atom or an additional nitrogen atom. b In some embodiments, the heterocyclic group is attached to the phenyl ring of ring A of formula I through a nitrogen atom of the R e is substituted with an R e independently for each occurrence, C 1-6 Haloalkyl (e.g., -CH2Cl) or C 1-6 Heteroalkyl (e.g., CHOH). The heterocyclic group is a 6- or 7-membered heterocyclic group. In an exemplary embodiment, the heterocyclic group is [ka] and where each n is independently an integer ranging from 0 to 4, such as 0, 1, 2, 3, or 4; R6 is hydrogen, C 1-10 Aliphatic, such as aliphatic, C 5-10 Aromatic, such as aromatic, or C 1-10 Heteroaliphatic, such as heteroaliphatic.

[0066] In some embodiments, R 1 is R b and R b -NR d R d and both R d The groups, together with the nitrogens to which they are attached, must have at least two R e C substituted with a group 4-9 Provide a heterocyclic group, and two R e The groups are bonded together to the R b C having a group 3-10 In such embodiments, two R e The groups can be joined together to provide a bicyclic or spirocyclic group (one ring of the bicyclic or spirocyclic group is R b The other ring of the bicyclic or spirocyclic group is provided by two R e In embodiments that include a spirocyclic group, each ring of the spirocyclic group can have the same number of atoms or a different number of atoms. In certain embodiments, the spirocyclic group includes at least two rings, and the first and second rings of the spirocyclic group have a different number of carbon atoms, a different number of heteroatoms, or both. In some embodiments, the two rings of the spirocyclic group include the same number of carbon atoms, the same number of heteroatoms, or both. In some embodiments, each ring of the spirocyclic group includes a heteroatom in the ring, and the heteroatoms can be the same in each ring, or each ring of the spirocyclic group can have a different heteroatom in the ring. The spirocyclic group can include a first ring bonded to a carbon atom of the ring A phenyl group, the first ring having 3 to 7 atoms, and the second ring having 3 to 7 atoms. In some embodiments, the spirocyclic group can include a ... bIn addition to the nitrogen atom of the group, the spirocyclic group contains at least one oxygen atom. The spirocyclic group can contain more than 7 total atoms in the spiro ring system, with certain embodiments containing 9 total atoms in the spiro ring system. In an exemplary embodiment, R b There are two R e Together with the radical, it forms a spiro ring: [ka] We can provide In the formula, R 6 is hydrogen, C 1-10 Aliphatic, such as aliphatic, C 5-10 Aromatic, such as aromatic, or C 1-10 Heteroaliphatic, such as heteroaliphatic.

[0067] As an example of such a moiety, in certain embodiments, R 1 teeth, [ka] is selected from where each n is independently an integer ranging from 0 to 4, such as 0, 1, 2, 3, or 4; R 6 are independently hydrogen, C 1-10 Aliphatic, such as aliphatic, C 5-10 Aromatic, such as aromatic, or C 1-10 Heteroaliphatic, such as heteroaliphatic.

[0068] In certain embodiments, R 1 is C 2-10 -Linker-R, such as an alkynyl moiety 6 Such a C 2-10 The alkynyl moiety may be linear, branched, and / or cyclic and has one, two, or three substituents. Exemplary substituents include cycloalkyl and OH. In some embodiments, one substituent is oxetanyl, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, amino, or phosphate, and / or in some embodiments, one substituent is -OC(O)-R.8 C 2-10 Alkynes are [ka] Some compounds may include linear and / or branched portions and cyclic portions, such as C groups and linkers, R b R 6 and R b But -NR d R d and one R d is H and other R d is pyridinyl or both R d The groups, together with the nitrogen to which they are attached, form a C 5-10 or R b But, OR c and R c C substituted with a pyridinyl group 1-4 In some embodiments, R b teeth, [ka] It is.

[0069] In some embodiments, R 1 is one of the following: [ka] [ka] may be selected from:

[0070] In certain embodiments, R 1 teeth, [ka] , is selected from.

[0071] In some embodiments, R 2 and R 3 Each of the groups independently represents Ra and R a is, independently at each occurrence, hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, R 2 and R 3 Each occurrence is independently hydrogen, methyl, or ethyl; a In an exemplary embodiment, R 2 is methyl, R 3 is hydrogen.

[0072] For each of the above embodiments, X is CH2 or O.

[0073] In certain embodiments of formula I, including those described above, the B-ring heteroaryl group is 5-membered. Such 5-membered heteroaryl groups have the formula [ka] wherein at least one W is nitrogen and each remaining W is independently C, -C(R a )-, CH, oxygen, sulfur, nitrogen, or NH. In some embodiments, the 5-membered heteroaryl group is a diazole, oxazole, or oxadiazole, such as triazole, imidazole, or pyrazole.

[0074] Exemplary diazoles include any of the following: [ka] Examples include:

[0075] Exemplary oxazoles include any of the following: [ka] Examples include:

[0076] In other embodiments, B is a 6-membered heteroaryl, such as pyridine, pyridazine, pyrimidine, or pyrazine.

[0077] In certain embodiments, L is C 1- Divalent C, such as a C4 alkylene linker (e.g., -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2) 1-10 In some embodiments, L is -CH2-.

[0078] With continued reference to Formula I, Z can be an aryl, such as phenyl, or a heteroaryl. In any embodiment, Z is a heteroaryl, and Z can be a 5- or 6-membered nitrogen-containing heteroaryl, such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, or triazolyl. In certain such embodiments, Z is a 6-membered nitrogen-containing heteroaryl, and can be pyridinyl, pyrimidinyl, or pyridazinyl.

[0079] In certain embodiments, Z is [ka] and the like, wherein R 5 is calculated independently for each occurrence, R e and p is 0, 1, 2, 3, 4, or 5. In other embodiments, Z is [ka] Certain disclosed compounds are heteroaryls such as R a The group R 5 R a is C1-C4 aliphatic or R b is a group, R b is a halogen, such as fluoro, and R 2 is R a and R a is C1-C4 aliphatic, R 3 is R a and R a is hydrogen.

[0080] Compounds of formula I can also have a structure satisfying any one or more of formulas II, IIA-IIF, IIG, and IIH. [ka] [ka]

[0081] With respect to Formulas II and IIA-IIH, R 1 , X, W and R 5 Each of R is as recited above for formula I. In certain embodiments, 0, 1, or 2 R 5 R 5 is R e R e is fluoro or chloro. In other particular embodiments, R 5 is not present. For formulas IIA-IIF, each W is independently nitrogen or oxygen, specifically nitrogen. In certain embodiments, formula IIE has formula IIK: [ka] where W is O or N. As will be appreciated by one of skill in the art, when W is N in formula IIK, N has an open valence and can be hydrogen or R with respect to formula I. e By way of example, suitable Re groups for substitution of the nitrogen in such cases include C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Examples include cycloalkyl.

[0082] Specific exemplary compounds within one or more of Formulas I, II, and IIA-IIG, IIH, and IIK include the following: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0083] In some embodiments, one or more of the compounds may be included in a pharmaceutical composition or medicament, and in some embodiments, the compound or compounds may be in the form of a parent compound, or a pharma- ceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof. Pharmaceutical compositions typically include at least one additional component other than the disclosed compound or compounds, such as a pharma- ceutically acceptable excipient, an adjuvant, an additional therapeutic agent (described in the following section), or any combination thereof.

[0084] Pharmaceutically acceptable excipients may be included in pharmaceutical compositions for a variety of purposes, such as diluting the pharmaceutical composition for delivery to a subject, facilitating processing of the formulation, providing advantageous material properties to the formulation, facilitating dispersion from a delivery device, stabilizing the formulation (e.g., antioxidants or buffers), providing a pleasant or palatable taste or consistency to the formulation, etc. Pharmaceutically acceptable excipients may include pharma- ceutically acceptable carriers.Exemplary excipients include, but are not limited to, mono-, di-, and polysaccharides, sugar alcohols, and other polyols such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants such as sorbitol, diphosphatidylcholine, and lecithin; bulking agents; buffers such as phosphate and citrate buffers; anti-adherents such as magnesium stearate; binders such as sugars (including disaccharides such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coatings (such as hydroxypropyl methylcellulose, shellac, corn protein zein, and cellulose ethers including gelatin); release aids (such as enteric coatings); disintegrants (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavors and sweeteners (such as mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla); lubricants (such as minerals exemplified by talc or silica, vegetable stearin, magnesium stearate, or fats exemplified by stearic acid); preservatives (such as antioxidants exemplified by vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids exemplified by cysteine ​​and methionine, citric acid and sodium citrate, parabens exemplified by methylparaben and propylparaben); colorants; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0085] III. Methods of Using the Compounds A. Disease / Disorder The disclosed compounds, as well as combinations and / or pharmaceutical compositions thereof, can be used to inhibit RIP1 kinase by contacting the kinase either in vivo or ex vivo with the disclosed compound or compounds, or a composition comprising the disclosed compound or compounds. The disclosed compounds or compounds, or a composition comprising the disclosed compound or compounds, can also be used to ameliorate, treat, or prevent a variety of diseases and / or disorders. In certain embodiments, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be useful for treating conditions in which inhibition of RIP1 or a pathway involving RIP1 is therapeutically useful. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds are useful for treating autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancer, ischemic conditions, red blood cell deficiencies, lung and brain injuries (e.g., induced by ischemia-reperfusion, or cisplatin, and / or cerebrovascular accidents), and bacterial and viral infections.

[0086] In some embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof may be used to treat or prevent allergic diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmyopathy, or asthma.

[0087] The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof may also be useful for treating immune dysregulation disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immune dysregulation disorders that can be treated with the compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, autoimmune disorders including organ or tissue transplantation, graft-versus-host disease resulting from transplantation, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, gravitational myasthenia, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, and glomerulonephritis. Immune syndromes, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus , dystrophic epithelial cornea, corneal leukemia, ocular pemphigus, Mooren's ulcer, scleritis, malignant exophthalmos, Falk-Koyanagi-Harada disease, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular damage caused by ischemic disease and thrombosis, ischemic bowel disease, ischemic reperfusion injury, inflammation Intestinal 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 uraemic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuropathy, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, hypoplastic anemiaanemia), idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, albinism, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy or cardiomyopathic infection, scleroderma (including systemic scleroderma), antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, adiposity, eosinophilic fasciitis, gingiva , lesions of periodontium, alveolar bone, dental cementum, glomerulonephritis, male pattern baldness or alopecia due to prevention of hair loss or provision of hair growth and / or promotion of hair growth and hair growth, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, ischemia-reperfusion injury of organs occurring during storage, transplantation, or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary hypertension or drug-induced hypertension, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, retinal Degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, corneal alkali burn, erythematous polymorphous dermatitis, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and altitude sickness, diseases caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock or anoxia, viral hepatitis type B, non-A / Alcoholic liver disease including non-B hepatitis, cirrhosis, alcoholic cirrhosis, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH), autoimmune hepatic and biliary diseases, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed onset liver failure, acute exacerbation of chronic liver failure, chronic kidney disease, kidney damage / injury (caused, for example, by nephritis, kidney transplant, surgery, administration of nephrotoxic drugs, acute kidney injury), enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, or chronic bacterial infection.

[0088] In certain embodiments, the compounds are useful for treating neuropathic pain, including inflammation-induced pain.

[0089] In certain embodiments, the compound is used to treat interleukin-1 converting enzyme-associated associated fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases (e.g., Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Fatty acidosis, Fibroblast disease ... Barr disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, polysulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pyknodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease).

[0090] In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof are useful for the treatment and / or prevention of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, particularly pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia d and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout flare, pseudogout, Saffo's syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptor antagonist), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0091] Proliferative diseases that may be treated by the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof include benign and malignant tumors, solid tumors, carcinomas of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, urogenital tract, esophagus, larynx, skin, bone, or thyroid, sarcomas, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancers, particularly colon carcinomas or colorectal adenomas, tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, epithelial neoplasms, adenomas, adenocarcinomas, keratoacanthomas, and the like. , epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin and non-Hodgkin, breast carcinoma, follicular carcinoma, anaplastic carcinoma, papillary carcinoma, seminoma, melanoma, disorders caused by IL-1, disorders caused by MyD88 (ABC diffuse large B-cell lymphoma (DLBCL) Waldenstrom's macroglobulinemia, Hodgkin lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), smoldering or asymptomatic multiple myeloma, or hematological malignancies (leukemia, acute myeloid leukemia (AML), DLBCL, ABC Myelodysplastic / myeloproliferative neoplasms (MDS / MPN) such as DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, chronic myelogenous leukemia (CML), primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, chronic myelomonocytic leukemia (CMML including CMML-0, CMML-1 and CMML-2), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds of the present disclosure are useful for treating drug-resistant malignancies such as those resistant to the JAK inhibitor ibrutinib-resistant malignancies, including ibrutinib-resistant hematological malignancies such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenstrom's macroglobulinemia.

[0092] Although CMML has certain clinical and pathological features of both myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDS), it is classified by the World Health Organization (WHO) as a separate category of MDS / MPN overlap group. (Arber et al. “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia” Blood, vol. 127, number 20, pages 2391-2405, May 19, 2016.) According to the WHO, CMML currently has a prevalence of ≥ 1 × 10 9 Both the presence of persistent peripheral blood monocytosis of >1×10 / L and monocytes accounting for >10% of the white blood cell (WBC) differential count are required. Furthermore, CMML can only be diagnosed according to the definition if PDGFRA, PDGFRB, or FGFR1 gene rearrangements have been excluded, with the 2016 update adding the PCM1-JAK2 fusion gene as an exclusion criterion. In some embodiments, the methods for treating CMML include those that meet the WHO diagnostic criteria (i.e., >1×10 9 and identifying a subject with persistent peripheral blood monocytosis of ≥ 10% (persistent peripheral blood monocytosis of ≥ 10% / L and monocytes accounting for ≥ 10% of the white blood cell differential count), ruling out rearrangements in the PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 genes, and treating the subject by administering a RIP1 inhibitor disclosed herein, combinations of such compounds, and / or compositions thereof.

[0093] Examples of allergic disorders that may be treated using the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by a pathophysiological disorder, essential asthma of unknown or undetermined cause, emphysema-like asthma, exercise-induced asthma, emotion-induced asthma, asthma caused by environmental factors, and the like). asthma caused by or associated with bacterial, fungal, protozoan, or viral infections, incipient asthma, wheezing infant syndrome, bronchitis, cough variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis.

[0094] As another example, rheumatoid arthritis (RA) typically results in generalized swelling, pain, loss of motion, and tenderness of target joints. RA is characterized by a chronically inflamed synovium that is densely packed with lymphocytes. The synovium, typically one cell layer thick, appears to be cellular and similar in morphology to lymphoid tissue, including clusters of dendritic cells, T, B, and NK cells, macrophages, and plasma cells. This process, as well as a number of immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, ultimately results in the destruction of joint integrity, resulting in deformity, permanent loss of function, and / or bone erosion at or near the joint. The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof, may be used to treat, ameliorate, or prevent any one, some, or all of these symptoms of RA. Thus, in the context of RA, a compound is considered to provide a therapeutic benefit if it achieves a reduction or amelioration of any of the symptoms commonly associated with RA, regardless of whether the treatment results in a treatment associated with the underlying RA and / or a reduction in the amount of circulating rheumatoid factor ("RF").

[0095] The American College of Rheumatology (ACR) has developed criteria to define improvement and clinical remission in RA. Such parameters, ACR20 (ACR criteria for 20% clinical improvement), require a 20% improvement in tender and swollen joint counts, and a 20% improvement in three of the following five parameters: patient's global assessment, physician's global assessment, patient's pain assessment, degree of disability, and level of acute phase reactants. These criteria are expanded to 50% and 70% improvement, respectively, with ACR50 and ACR70. Other criteria include Paulu's criteria and radiographic progression (e.g., Sharp score).

[0096] In some embodiments, therapeutic benefit in a patient with RA is achieved when the patient exhibits an ACR20. In certain embodiments, an ACR improvement of ACR50 or even ACR70 can be achieved.

[0097] B. Therapeutic Combinations The compounds described herein may be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to or in combination with other established therapies. The compound or compounds, or compositions containing the compound (or compounds), may be administered once or multiple times. In some embodiments, the compounds of the present invention may be used in combination with other therapeutic agents useful for the disorder or condition being treated. These other therapeutic agents may be administered simultaneously, sequentially in any order, by the same route of administration as the compounds of the present disclosure, or by different routes. In sequential administration, the compounds and therapeutic agents may be administered such that the effective period of at least one compound and therapeutic agent overlaps with the effective period of at least one other compound and / or therapeutic agent. In an exemplary embodiment of a combination containing four components, the effective period of the first component administered may overlap with the effective periods of the second, third, and fourth components, but the effective periods of the second, third, and fourth components may or may not overlap with each other independently. In another exemplary embodiment of a combination comprising four components, the effective period of the first component administered overlaps with the effective period of the second component but not with the third or fourth components, the effective period of the second component overlaps with the effective periods of the first and third components, and the effective period of the fourth component overlaps only with the effective period of the third component. In some embodiments, the effective periods of all compounds and / or therapeutic agents overlap with each other.

[0098] In some embodiments, the compound is administered with another therapeutic agent, such as an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof. The anti-inflammatory agent can be a steroid or a nonsteroidal anti-inflammatory agent. In certain embodiments, the nonsteroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immune inhibitor is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an antilymphocyte globulin, an antithymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0099] In some embodiments, the compounds may be used with anti-cancer or cytotoxic agents.Various classes of anti-cancer and anti-neoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, multiple 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, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimine, methylmelamine, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, by way of example and not limitation, the folic acid analog methotrexate; pyrimidine analogs fluorouracil, cytosine albinoside; purine analogs mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkyloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. Exemplary enzymes effective as antineoplastic agents include L-asparaginase. Exemplary coordination compounds include, by way of example and not limitation, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, by way of example and not limitation, the adrenal corticosteroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

[0100] These and other useful anti-cancer compounds are described in the Merck Index, 13th Ed. (O'Neil MJ et al., ed.) Merck Publishing Group (2001), and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Brunton LL ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0101] Among the CTLA4 antibodies that may be used in combination with the inhibitors of the present disclosure is ipilimumab, available commercially as YERVOY® by Bristol-Myers Squibb.

[0102] Other chemotherapeutic agents for combination include immuno-oncology agents such as checkpoint pathway inhibitors, e.g., 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).

[0103] Additional 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).

[0104] The compounds of the present disclosure may also be advantageously used in conjunction with CAR-T therapy. Examples of currently available CAR-T therapies are axicabtagenecilloreucel and tisagenlecleucel.

[0105] Additional anti-proliferative compounds useful in combination with the compounds of the invention include, by way of example and not limitation, antibodies against growth factor receptors (e.g., anti-Her2); cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.

[0106] Additional chemotherapeutic agents useful in combination with the present compounds include proteasome inhibitors, such as bortezomib, carfilzomib, and marizomib.

[0107] Examples of kinase inhibitors that are useful in combination with the compounds of the present disclosure, particularly in the treatment of malignant tumors, 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, and pazopanib; BCR-Abl inhibitors such as bosutinib, dasatinib, imatinib, and nilotinib; FLT-3 inhibitors such as gilteritinib and quizartinib; PI3-kinase inhibitors such as idelalisib, Syk inhibitors such as fostamatinib; and JAK inhibitors such as ruxolitinib and fedratinib.

[0108] In other embodiments, the second therapeutic agent may be selected from any of the following: Painkillers, including morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, and dipipanone; Aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, , ceftibuten, ceftizoxime, ceftriaxone, cefepime, and cefoviprole), glycopeptides (e.g., teicoplanin, vancomycin, and telavancitin), lincosamides (e.g., clindamycin and incomysin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spectinomycin), monobactams (e.g., aztreonam, onam), nitrofurans (e.g., furazolidone and nitrofurantoin), penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), penicillin combinations (e.g., amoxicillin / clavulanate, ampicillin / sulfactam, piperacillin / tazobactam, and ticarcillin / clavulanate), poly peptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide, sulfonamide chrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole,sulfanilimides, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole), tetracyclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoflurane, cyclosporine ... Antibiotics, including soniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin) and others such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinuplicin / dalfopristin, rifaximin, thiamphenicol, tigecycline, and timidazole; Anti-TNF-α antibodies, such as infliximab (Remicade™), adalimumab, golimumab, certolizumab; anti-B cell antibodies, such as rituximab; anti-IL-6 antibodies, such as tocilizumab; anti-IL-1 antibodies, such as anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, such as nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; antibodies including ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fretikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab; Anticoagulants, including warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin; steroids, e.g., budesonide, non-steroidal anti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors such as rofecoxib, celecoxib), anti-inflammatory agents including diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin; Agents designed to inhibit cellular immunity while leaving the recipient's humoral immune response intact, including corticosteroids such as mercaptopurine, dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisone; alkylating agents such as cyclophosphamide; calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus; inhibitors of inosine monophosphate dehydrogenase (IMPDH) such as mycophenolic acid, mycophenolate mofetil, and azathioprine; and various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T cell antibody (OKT3)); and immune suppressants including radiation. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trade name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name Purinethol; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune; tacrolimus is currently available from Fujisawa under the trade name Prograf; cyclosporine is currently available from Novartis under the trade name Sandimmune and from Abbott under the trade name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the trade name Cellcept and from Novartis under the trade name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the trade name Imuran; antibodies are currently available from Ortho It is available from Biotech under the trade name Orthoclone, from Novartis under the trade name Simulect (basiliximab), and from Roche under the trade name Zenapax (daclizumab). Guanylate cyclase-C receptor agonists or intestinal secretagogues, such as linaclotide, are sold under the name Linzess.

[0109] These various agents may be used according to standard or customary dosages as specified in the prescribing information accompanying the commercially available drug form (see also the formulation information in the 2006 Edition of The Physician's Desk Reference), the disclosures of which are incorporated herein by reference.

[0110] IV. Methods of Making Compounds The compounds can be prepared by any suitable method, as would be understood by those skilled in the art. One exemplary suitable method is provided below with reference to certain compounds in the Examples and may include the following first reaction step according to Scheme 1: [ka]

[0111] Referring to Scheme 1, a metal-mediated cross-coupling reaction can be used to prepare the cross-coupled product 104, which is shown in Scheme 1 as "R 6 -R containing a "linker" group 1The protected amine precursor 100 can be coupled with the group 102. In some embodiments, the metal-mediated cross-coupling reaction can be carried out using a transition metal catalyst, such as a palladium catalyst. Exemplary palladium catalysts include, but are not limited to, Pd(0) catalysts (e.g., Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, etc.) or Pd(II) catalysts (e.g., second or third generation XPhos Pd, PdCl2, Pd(OAc)2, etc.). In some embodiments, the palladium catalyst can be used in combination with another co-catalyst, such as CuI, to facilitate the cross-coupling reaction, such as in the Sonogoshira reaction. The metal-mediated cross-coupling can also include using a base, such as an amine base (e.g., Et3N), or an inorganic base (e.g., Cs2CO3, Na2CO3, K2CO3, etc.), and a solvent (e.g., dimethylformamide). Referring to Scheme 1, X is a group suitable for metal-mediated cross-coupling, such as a halogen or a triflate group, and PG is an amine protecting group, which may be selected from, but is not limited to, a 9-fluorenylmethoxycarbonyl ("Fmoc") group, a t-butyloxycarbonyl ("Boc") group, a trityl ("Tr") group, an allyloxycarbonyl ("Alloc") group, a benzyloxycarbonyl ("Cbz") group, and the like.

[0112] Synthesis of tert-butyl (S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 8 and tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 9 [ka] Intermediates 8 and 9 are referred to as intermediates II and I, respectively, in other schemes herein.

[0113] Synthesis of N-(tert-butoxycarbonyl)-O-(2-nitropyridin-3-yl)-L-serine (3) To a solution of (tert-butoxycarbonyl)-L-serine 2 (5.13 g, 25.0 mmol) in anhydrous DMF (100 mL) was added sodium hydride (2.0 g, 60% in oil, 50 mmol) at 0° C. The resulting solution was stirred at this temperature for 2 h, and then 3-fluoro-2-nitropyridine 1 (3.60 g, 25.3 mmol) was added. The resulting solution was warmed to ambient temperature over 8 h and slowly quenched with aqueous HCl (3N, 25 mL) until the pH of the solution was about 4. The reaction solution was extracted with ethyl acetate (3×120 mL) and the combined organic layers were washed with brine (40 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0 to 10% methanol in dichloromethane to give N-(tert-butoxycarbonyl)-O-(2-nitropyridin-3-yl)-L-serine 3 (5.35 g, 65%) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.18-8.08(m, 1H), 7.57(d, J=3.3Hz, 2H), 5.60(d, J=7.9Hz, 1H), 4.76(d, J=7.8 Hz, 1H), 4.64(dd, J=9.3, 2.9Hz, 1H), 4.46(dd, J=9.3, 3.1Hz, 1H), 1.46(s, 9H). MS (ESI, m / e) calculated value 327.1066, actual value 228.1 [M-Boc+H] + .

[0114] Synthesis of O-(2-aminopyridin-3-yl)-N-(tert-butoxycarbonyl)-L-serine (4) To a solution of N-(tert-butoxycarbonyl)-O-(2-nitropyridin-3-yl)-L-serine 3 (4.81 g, 14.72 mmol) in methanol (100 mL) was added 5% palladium on carbon (950 mg). The resulting solution was hydrogenated on a Parr-Shaker at 60 PSI for 16 h, filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure to give the crude product O-(2-aminopyridin-3-yl)-N-(tert-butoxycarbonyl)-L-serine 4 (4.40 g, >95% yield) as a pale yellow solid, which was used directly in the next step without purification. MS (ESI, m / e) calculated 297.1325, found 298.0 [M+H] + .

[0115] Synthesis of tert-butyl (S)-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (5) To a solution of crude O-(2-aminopyridin-3-yl)-N-(tert-butoxycarbonyl)-L-serine 4 (4.40 g, 14.72 mmol) in anhydrous DMF (300 mL) was added diisopropylethylamine (2.09 g, 2.80 mL, 16.19 mmol) followed by HATU (6.16 g, 16.19 mmol). The resulting solution was stirred at ambient temperature for 2 days, then water (200 mL) was added and the aqueous solution was extracted with ethyl acetate (4×200 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0 to 5% methanol in dichloromethane to afford tert-butyl (S)-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 5 (899 mg, 22% over two steps) as a white solid. 1H NMR (400MHz, CDCl3) δ 8.86(s, 1H), 8.16(dd, J=4.7, 1.5Hz, 1H), 7.42(dd, J=8.0, 1.5Hz, 1H), 7.08(dd, J=8.0, 4.7Hz, 1H), 5.64(s, 1H), 4.73-4.47(m, 2H), 4.17(dd, J=10.7, 9.4Hz, 1H), 1.46(s, 9H). MS (ESI, m / e) calculated value 279.1219, actual value 280.1 [M+H] + .

[0116] Synthesis of tert-butyl (S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (6) To a solution of tert-butyl (S)-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 5 (796 mg, 2.85 mmol) in anhydrous DMF (28 mL) was added anhydrous cesium carbonate (930 mg, 2.85 mmol) followed by methyl iodide (368 mg, 162 μL, 2.59 mmol). The resulting solution was stirred at ambient temperature for 2 days followed by the addition of water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were then washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue in DMF solution (approximately 12 mL). The crude product was purified by reverse HPLC using a gradient of 0-50% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 6 (434 mg, 57%) as a white solid. 1H NMR (400MHz, CDCl3) δ 8.28(dd, J=4.8, 1.6Hz, 1H), 7.47(dd, J=7.9, 1.6Hz, 1H), 7.14(dd, J=7.9, 4.7Hz, 1H), 5.59(d, J=5.2Hz, 1H), 4.73-4.53(m, 2H), 4.31-4.12(m, 1H), 3.51(s, 3H), 1.41(s, 9H). MS (ESI, m / e) calculated value 293.1376, actual value 194.1 [M-Boc+H] + .

[0117] Synthesis of (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine 6-oxide (7) To a solution of tert-butyl (S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 6 (429 mg, 1.46 mmol) in anhydrous dichloromethane (5 mL) was added mCPBA (730 mg, maximum purity 77%, 2.93 mmol). The resulting solution was stirred at ambient temperature for 20 h, diluted with dichloromethane (200 mL), washed with saturated aqueous sodium carbonate solution (20 mL) and saturated sodium thiosulfate solution (20 mL). The resulting organic layer was separated, washed with brine (2×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-5% methanol in dichloromethane to give (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine 6-oxide 7 (303 mg, 67%). MS (ESI, m / e) calculated 309.1325, found 310.0 [M+H]. + The starting material tert-butyl (S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 6 (139 mg, 32%) was partially recovered.

[0118] Synthesis of tert-butyl (S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (8) and tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (9) To a solution of (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine 6-oxide 7 (303 mg, 0.98 mmol) in anhydrous 1,2-dichloroethane (20 mL) was added 4 Å molecular sieves (303 mg) followed by n-tetrabutylammonium bromide (474 ​​mg, 1.47 mmol). The reaction solution was stirred at ambient temperature for 10 min, then 4-methylbenzenesulfonic anhydride (480 mg, 1.47 mmol) was added. The resulting reaction mixture was then stirred at ambient temperature for 17 h, heated at 65° C. for 8 h, cooled to ambient temperature, filtered through Celite, and washed with dichloromethane (ca. 100 mL). The filtrate was then washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-10% methanol in dichloromethane to give tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 9 (67 mg, 18%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 7.59(d, J=8.2Hz, 1H), 7.49(d, J=8.2Hz, 1H), 7.30(d, J=7.0Hz, 1H), 4.50-4.21(m, 3H), 3.27(s, 3H), 1.33(s, 9H). MS (ESI, m / e) calculated value 371.0481, actual value 372.0 [M+H] +Additional impure fractions were combined and further purified by reverse HPLC using a gradient of 35-80% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined and lyophilized to give the more polar isomer of tert-butyl (S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 8 (85 mg, 23%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.19(d, J=5.2Hz, 1H), 7.63(d, J=5.2Hz, 1H), 7.38-7.27(m, 1H), 4.51-4.32(m, 3H), 3.32(s, 3H), 1.35(s, 9H). MS (ESI, m / e) calculated value 371.0481, actual value 372.0 [M+H] + The starting material (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine 6-oxide 7 (61 mg, 20%) was also partially recovered.

[0119] Synthesis of (S)-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 14 [ka]

[0120] Synthesis of tert-butyl (S)-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 11 To a solution of (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine 6-oxide 7 (24.5 mg, 0.079 mmol) and 8-oxa-2-azaspiro[4.5]decane 10 (14.6 mg, 0.103 mmol) in anhydrous dichloroethane (1 mL) was added diisopropylethylamine (41 mg, 55 μL, 0.317 mmol) followed by PyBrOP (48 mg, 0.103 mmol). The resulting solution was stirred at ambient temperature for 19 h and then heated at 60 °C for 2 days. All solvents were removed under reduced pressure and the resulting residue was purified by reverse HPLC using a gradient of 0-80% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined and diluted with ethyl acetate, and the solution was washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (S)-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 11 (2.8 mg, 8%). MS (ESI, m / e) calculated 432.2373, found 433.2 [M+H]. + .

[0121] Synthesis of (S)-3-amino-5-methyl-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 12 Hydrogen chloride solution (0.5 mL, 4.0 M in dioxane, 2 mmol) was added to a vial containing tert-butyl (S)-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 11 (2.8 mg) and the resulting solution was stirred at ambient temperature for 16 h. The reaction mixture was then concentrated under reduced pressure to give the crude product (S)-3-amino-5-methyl-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 12 (2.4 mg, >95% yield), which was used directly in the next step. MS (ESI, m / e) calculated value 332.1848, found value 333.1 [M+H] + .

[0122] Synthesis of (S)-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 14 To a solution of (S)-3-amino-5-methyl-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 12 (2.4 mg, 6.48 μmol) and 4-phenoxypicolinic acid 13 (2.8 mg, 13 μmol) in anhydrous DMF (0.5 mL) was added diisopropylethylamine (4.2 mg, 5.6 μL, 32 μmol) followed by HATU (4.9 mg, 13 μmol). The resulting solution was stirred at ambient temperature for 16 h. The reaction was quenched by adding one drop of water and the resulting solution was directly purified by reverse HPLC using a gradient of 40-100% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined and diluted with ethyl acetate (60 mL). The solution was washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 14 (2.2 mg, 64%) as a white solid. MS (ESI, m / e) calculated 529.2325, found 530.2 [M+H] + .

[0123] Synthesis of (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2]-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 18 [ka]

[0124] Synthesis of tert-butyl (S)-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 16 To a solution of tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 9 (32 mg, 85 μmol), Pd2(dba)3 (7.8 mg, 8.5 μmol), Xantphos (4.9 mg, 8.5 μmol) and cesium carbonate (56 mg, 170 μmol) in anhydrous 1,4-dioxane solution (1 mL) was added 7-oxa-2-azaspiro[3.5]nonane (13 mg, 102 μmol). The reaction solution was purged with nitrogen for 1 min, sealed and heated at 90° C. for 16 h. The reaction solution was cooled to ambient temperature and diluted with ethyl acetate (50 mL). The resulting solution was washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse HPLC using a gradient of 30-80% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined, diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (S)-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 16 (35 mg, >95% yield) as a thin liquid. MS (ESI, m / e) calculated 418.2216, found 419.2 [M+H] + .

[0125] Synthesis of (S)-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 17 Hydrogen chloride solution (0.5 mL, 4 M in dioxane, 2 mmol) was added to a vial containing tert-butyl (S)-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 16 (35 mg, 0.085 mmol) and the reaction mixture was stirred at ambient temperature for 16 h. All solvent was removed under reduced pressure to give a 1:1 mixture of azetidine ring-opened by-product and the desired product (S)-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride salt 17, which was used directly in the next step without purification. MS (ESI, m / e) calculated 318.1692, found 319.1 [M+H] + .

[0126] Synthesis of (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 18 The crude product (S)-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 17 and 4-phenoxypicolinic acid 13 (27.5 mg, 0.128 mmol) were dissolved in anhydrous DMF (1 mL) and diisopropylethylamine (55 mg, 74 μL, 0.425 mmol) was added followed by HATU (48.5 mg, 0.128 mmol). The resulting solution was stirred at ambient temperature for 16 h. The reaction was quenched by adding 2 drops of water and the resulting solution was directly purified by reverse HPLC using a gradient of 40-80% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined and diluted with ethyl acetate (60 mL) and the resulting organic solution was washed with saturated aqueous sodium bicarbonate (5 mL), brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting product was dissolved in 80% acetonitrile in water and lyophilized to give (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 18 (5.7 mg, 13% over two steps). MS (ESI, m / e) calculated 515.2169, found 516.1 [M+H] + .

[0127] General procedure for the preparation of 9-substituted pyridooxazepine compounds [ka] Exemplary 9-substituted pyridooxazepine compounds were prepared according to the general procedure above. The multifunctional intermediate II can be coupled with various groups via metal-catalyzed (e.g., palladium-catalyzed) cross-coupling reactions, as known to those skilled in the art. In particular, alkynyl groups can be easily coupled to the pyridooxepine ring according to this general scheme by adapting the procedure shown below. As examples, compounds I-14, I-15 and I-16 were synthesized by this method.

[0128] Step 1: Synthesis of intermediate (III) To intermediate II (0.1 mmol, 1 equiv.), substituted ethyne (0.2-0.3 mmol, 2-3 equiv.), Pd(PPh3)4 (0.01 mmol, 0.1 equiv.) and CuI (0.01 mmol, 0.1 equiv.) in anhydrous DMF (1 mL) in a vial was added Et3N (0.4 mmol, 4 equiv.). The reaction solution was purged with nitrogen for 1 min, then sealed and heated at 70 °C for 14-24 h. The reaction solution was cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse HPLC (mobile phase A: water with 0.1% HCOOH, mobile phase B: acetonitrile with 0.1% HCOOH) to give intermediate III.

[0129] Step 2: Synthesis of intermediate (IV) Intermediate III (1 eq.) was dissolved in dichloromethane, then TFA (concentration: 10% in dichloromethane) or HCl (40 eq., 4N in dioxane) was added. The resulting solution was stirred at ambient temperature until all starting material disappeared (monitored by reverse HPLC). All solvents were removed under reduced pressure to give the crude product of intermediate IV, which was used directly in the next step.

[0130] Step 3: Synthesis of the final product (V) Intermediate IV (1 equiv.), the corresponding acid (1.2 equiv.), and diisopropylethylamine (5 equiv.) were dissolved in DMF (concentration 0.05M-0.1M) and then HATU (1.2 equiv.) was added. The resulting solution was stirred at ambient temperature for 14-24 h. Brine and ethyl acetate were added to the reaction solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse HPLC (mobile phase A: water with 0.1% HCOOH, mobile phase B: acetonitrile with 0.1% HCOOH) to give the final product (V).

[0131] Synthesis of (S)-N-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 21 [ka]

[0132] Synthesis of (S)-3-amino-9-bromo-5-methyl-2,3-dihydropyrid[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 20 Hydrogen chloride solution (1 mL, 4 M in dioxane, 4 mmol) was added to a vial containing tert-butyl (S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 8 (52 mg, 0.139 mmol). The resulting solution was stirred at ambient temperature for 19 h. All solvents were removed under reduced pressure to give (S)-3-amino-9-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride salt 20 (43 mg, 100%) as a white solid. MS (ESI, m / e) calculated 270.9956, found 272.0 [M+H] + .

[0133] (S)-N-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 21 To a solution of (S)-3-amino-9-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 20 (43 mg, 85.8 μmol) and 4-phenoxypicolinic acid 13 (45 mg, 0.209 mmol) in anhydrous DMF (1.4 mL) was added diisopropylethylamine (135.2 mg, 0.18 mL, 1.05 mmol) followed by HATU (79.5 mg, 0.209 mmol). The resulting solution was stirred at ambient temperature for 16 h. Water (0.1 mL) was then added and the solution was directly purified by reverse HPLC using a gradient of 37-90% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined and diluted with ethyl acetate (100 mL) and the resulting solution was washed with saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-N-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 21 (50 mg, 77%) as a white solid. MS (ESI, m / e) calculated 468.0433, found 469.0 [M+H] + .

[0134] Synthesis of (S)-N-(9-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 23 (I-15) [ka] To a solution of (S)-N-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 21 (25 mg, 53 μmol), 3-ethynyloxetan-3-ol 22 (15.7 mg, 0.160 mmol), CuI (1 mg, 5.3 μmol) and Pd(PPh3)4 (6.2 mg, 5.3 μmol) in anhydrous DMF (1 mL) was added triethylamine (32.4 mg, 45 μL, 0.320 mmol). The reaction solution was purged with nitrogen for 1 min, then sealed and heated at 70° C. for 16 h, cooled to ambient temperature and diluted with ethyl acetate (60 mL). The diluted reaction mixture was then washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC using a gradient of 27-67% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined and lyophilized to give (S)-N-(9-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 23 (8.5 mg, 33%) as a white solid. MS (ESI, m / e) calculated 486.1539, found 487.1 [M+H] + .

[0135] Synthesis of (S)-N-(9-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 25 (I-16) [ka] To a solution of (S)-N-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 21 (24 mg, 51 μmol), 4-ethynyltetrahydro-2H-pyran-4-ol 24 (19.4 mg, 0.153 mmol), CuI (1 mg, 5.1 μmol) and Pd(PPh3)4 (5.9 mg, 5.1 μmol) in anhydrous DMF (1 mL) was added triethylamine (31 mg, 43 μL, 0.307 mmol). The reaction mixture was then purged with nitrogen for 1 min, sealed and heated at 70° C. for 16 h, cooled to ambient temperature and diluted with ethyl acetate (60 mL). The reaction mixture was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by reverse HPLC using a gradient of 27-67% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined and lyophilized to give (S)-N-(9-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 25 (13.6 mg, 52%) as a white solid. MS (ESI, m / e) calculated 514.1852, found 515.1 [M+H] + .

[0136] Synthesis of (S)-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 29 (I-14) [ka]

[0137] Synthesis of tert-butyl (S)-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 27 To a solution of tert-butyl (S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 8 (32 mg, 0.086 mmol) and 2-methylbut-3-yn-2-ol 26 (22 mg, 0.257 mmol) in anhydrous DMF (1 mL) was added Pd(PPh3)4 (9.9 mg, 8.6 μmol), CuI (1.6 mg, 8.6 μmol) and triethylamine (52 mg, 72 μL, 0.515 mmol). The reaction mixture was then purged with nitrogen for 1 min, sealed, heated at 70 °C for 22 h, cooled to ambient temperature and diluted with ethyl acetate (80 mL). The resulting organic mixture was washed with water (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC using a gradient of 20-70% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (S)-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 27 (32 mg, >95% yield). MS (ESI, m / e) calculated 375.1794, found 320.0 [M- t Bu+H] + .

[0138] Synthesis of (S)-3-amino-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 28 To a solution of tert-butyl (S)-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 27 (32 mg, 0.086 mmol) in anhydrous 1,4-dioxane (2 mL) was added hydrogen chloride solution (0.2 mL, 4 M in dioxane, 0.8 mmol). The reaction mixture was stirred at ambient temperature for 15 h, then an additional amount of hydrogen chloride solution (0.6 mL, 4 M in dioxane, 2.4 mmol) was added and the reaction mixture was stirred for an additional 9 h. All solvents were removed under reduced pressure to give (S)-3-amino-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 28 (27 mg, 100%) as a pale yellow solid, which was used directly in the next step. MS (ESI, m / e) calculated 275.1270, found 276.1 [M+H] + .

[0139] Synthesis of (S)-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 29 To a solution of (S)-3-amino-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 28 (27 mg, 0.0858 mmol) and 4-phenoxypicolinic acid 13 (28 mg, 0.129 mmol) in anhydrous DMF (1.4 mL) was added diisopropylethylamine (55.5 mg, 74 μL, 0.429 mmol) followed by HATU (48.9 mg, 0.129 mmol). The resulting reaction mixture was stirred at ambient temperature for 14 h. One drop of water was added and the solution was directly purified by reverse HPLC using a gradient of 40-80% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined and lyophilized to give (S)-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 29 (22.1 mg, 55%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 8.96(d, J=7.1Hz, 1H), 8.46(dd, J=5.6, 0.5Hz, 1H), 8.23(d, J=5.0Hz, 1H), 7.62(d d, J=2.6, 0.5Hz, 1H), 7.48-7.38(m, 2H), 7.31-7.22(m, 1H), 7.19(d, J=5.0Hz, 1H) , 7.12-7.06(m, 2H), 6.97(dd, J=5.6, 2.5Hz, 1H), 5.03(dt, J=11.3, 7.2Hz, 1H), 4. 89(dd, J=9.6, 7.2Hz, 1H), 4.39(dd, J=11.3, 9.6Hz, 1H), 3.52(s, 3H), 1.63(s, 6H). MS (ESI, m / e) calculated value 472.1747, measured value 473.1 [M+H] + .

[0140] General procedure for the preparation of 7-substituted pyridooxazepine compounds VIII [ka] 7-Substituted pyridooxazepine compounds were prepared according to the general procedure of Method A above. The multifunctional intermediate I can be coupled with various groups via metal-catalyzed (e.g., palladium-catalyzed) cross-coupling reactions, as known to those skilled in the art. In particular, alkynyl groups can be easily coupled to the pyridooxepine ring according to this general scheme by adapting the procedure shown below. As examples, compounds prepared by Method A include I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-41, I-42, I-43, I-44, I-45, I-46, and I-47.

[0141] (S)-N-(7-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-32) [ka] This compound was obtained from the corresponding aldehyde obtained by oxidation of (S)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide. MS (ESI, m / z) calculated 506.1766, found [M+1] + 507.1. 1H NMR (400MHz, chloroform-d) δ(ppm) 8.93(d, J=7.0Hz, 1H), 8.45(d, J=5.6Hz, 1H), 7.61(d, J=2.5Hz, 1H), 7.49(d, J=8.1Hz, 1H), 7. 46-7.38(m, 2H), 7.36(d, J=8.1Hz, 1H), 7.28-7.23(m, 1H), 7.10-7.05(m, 2H), 6.96(dd, J=5.6, 2.5Hz, 1H), 5.25(dd, J=48.3, 10.7Hz, 1H), 5.02(dt, J=11.4, 6.9Hz, 1H), 4.79(ddd, J=9.7, 6.8 , 1.3Hz, 1H), 4.37(dd, J=11.4, 9.7Hz, 1H), 3.53(s, 3H), 1.62-1.59(m, 3H), 1.55-1.51(m, 3H).

[0142] N-((3S)-5-Methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-33) [ka] MS (ESI, m / z) calculated value 512.1308, observed value [M+1] + 513.0. 1 H NMR (400 MHz, chloroform-d) δ (ppm) 9.03-8.89 (m, 1H), 8.45 (dt, J = 5.7, 0.6 Hz, 1H), 7.61 (dt, J = 2.6, 0.7 Hz, 1H), 7.52-7.46 (m, 1H), 7.46-7.38 (m, 2H), 7.35 (dd, J = 8.1, 4.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.10- 7.04(m, 2H), 6.96(dd, J=5.6, 2.5Hz, 1H), 5.18-4.99(m, 1H), 4.94(t, J=6.3Hz, 1H), 4 .81(dt, J=9.7, 7.2Hz, 1H), 4.43-4.31(m, 1H), 3.54-3.46(m, 3H), 3.23-2.86(m, 1H).

[0143] (S)-5-(2-Fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-34) [ka] MS (ESI, m / z) calculated value 478.1765, observed value [M+1] + 479.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 12.18(s, 1H), 8.10(d, J=7.0Hz, 1H), 7.44(s, 1H), 7.27(d, J=8.1Hz, 1H), 7.26-7.18(m, 2H), 7.10-6.97(m, 2H), 5.01(dt , J=11.4, 7.0Hz, 1H), 4.75(dd, J=9.8, 7.0Hz, 1H), 4.32(dd, J=11.4, 9.8Hz, 1H), 4.20(s, 2H), 3.50(s, 3H), 1.64(s, 6H).

[0144] (S)-5-(4-Fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-35) [ka] MS (ESI, m / z) calculated value 478.1765, observed value [M+1] + 479.1.

[0145] (S)-5-Benzyl-N-(7-((3,3-difluoro-1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-36) [ka] MS (ESI, m / z) calculated value 508.1671, observed value [M+1] + 509.5. 1 H NMR (400MHz, chloroform-d) δ(ppm) 12.33(s, 1H), 8.11(d, J=7.0Hz, 1H), 7.42(d, J=8.1Hz, 1H), 7.31-7.17(m, 6H), 5.02(dt, J=11.3, 6.9Hz, 1H), 4.73(dd, J=9.8, 6.9Hz , 1H), 4.33(dd, J=11.4, 9.8Hz, 1H), 4.14(s, 2H), 3.51(s, 1H), 3.46(s, 3H), 3.27-3.11(m, 2H), 2.99(dtd, J=13.0, 11.7, 4.0Hz, 2H).

[0146] 5-Benzyl-N-((3S)-5-methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-37) [ka] MS (ESI, m / z) calculated value 500.1420, observed value [M+1] + 501.5. 1 H NMR (400MHz, chloroform-d) δ(ppm) 9.20(s, 0.5H), 8.11(dd, J=6.9, 3.2Hz, 1H), 7.47(dd, J=8.1, 1.2Hz, 1H), 7.36-7.29(m, 3H), 7.28(d, J=4.0Hz, 2H), 6.27(q, J=5. 7Hz, 0.5H), 5.13-4.89(m, 2H), 4.78(ddd, J=9.8, 6.8, 3.0Hz, 1H), 4.35(ddd, J=11.3, 9.9, 1.2Hz, 1H), 4.16(s, 2H), 3.48(m, 3H).

[0147] (S)-4-Fluoro-1-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide (I-38) [ka] MS (ESI, m / z) calculated value 495.1718, observed value [M+1] + 496.5. 1 H NMR (400MHz, chloroform-d) δ(ppm) 7.64(d, J=6.4Hz, 1H), 7.43(d, J=8.1Hz, 1H), 7.25-7.16(m, 4H), 7.07-6.98(m, 2H), 5.17(s, 2H), 5.00(dt , J=11.3, 6.7Hz, 1H), 4.82(dd, J=9.7, 6.9Hz, 1H), 4.28(dd, J=11.3, 9.7Hz, 1H), 3.49(s, 3H), 1.62(s, 6H).

[0148] (S)-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-(3-fluorophenoxy)picolinamide (I-39) [ka] This compound was obtained from the desilylation of (S)-4-(3-fluorophenoxy)-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide. MS (ESI, m / z) calculated 432.1234, found [M+1] + 433.1. 1H NMR (400MHz, chloroform-d) δ(ppm) 8.94(d, J=7.0Hz, 1H), 8.49(dd, J=5.6, 0.5Hz, 1H), 7.63(dd, J=2.5, 0.5Hz, 1H) , 7.49(d, J=8.1Hz, 1H), 7.42-7.32(m, 2H), 7.02-6.94(m, 2H), 6.88(ddt, J=8.1, 2.2, 0.8Hz, 1H), 6.82(dt, J=9.3, 2.3Hz, 1H), 5.03(dt, J=11.4, 6.9Hz, 1H), 4.79 (dd, J=9.7, 6.9Hz, 1H), 4.38(dd, J=11.4, 9.7Hz, 1H), 3.54(s, 3H), 3.17(s, 1H).

[0149] (S)-4-Fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(prop-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide (I-41) [ka] MS (ESI, m / z) calculated value 451.1456, found value [M+1] + 452.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 7.66(d, J=6.4Hz, 1H), 7.43(d, J=8.1Hz, 1H), 7.24(d, J=1.2Hz, 1H), 7.21(td, J=4.3, 1.4Hz, 3H), 7.09-6.97(m, 2H), 5.19( s, 2H), 5.01(dt, J=11.2, 6.7Hz, 1H), 4.83(dd, J=9.7, 7.0Hz, 1H), 4.29(dd, J=11.3, 9.7Hz, 1H), 3.51(s, 3H), 2.08(s, 3H).

[0150] (S)-4-Fluoro-1-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-4-oxo-7-(prop-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide (I-42) [ka] MS (ESI, m / z) calculated value 452.1408, observed value [M+1] + 453.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 7.85-7.75(m, 1H), 7.65(d, J=6.4Hz, 1H), 7.50(d, J=4.7Hz, 1H), 7.44(d, J=8.1Hz, 1H), 7.24(d, J=8.1Hz, 1H), 7.06-7.00(m, 1H), 6.94-6. 88(m, 1H), 5.28(s, 2H), 5.02(dt, J=11.2, 6.7Hz, 1H), 4.83(dd, J=9.7, 6.9Hz, 1H), 4.29(dd, J=11.2, 9.7Hz, 1H), 3.52(s, 3H), 2.09(s, 3H).

[0151] N-((3S)-5-Methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxy-3-methylbut-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-43) [ka] MS (ESI, m / z) calculated value 526.1464, observed value [M+1] + 527.3. 1H NMR (400MHz, chloroform-d) δ(ppm) 9.01(dd, J=23.0, 6.7Hz, 1H), 8.44(dt, J=5.6, 0.7Hz, 1H), 7.62(ddd, J=3.3, 2.5, 0.5Hz, 1H), 7. 47(d, J=8.1Hz, 1H), 7.45-7.38(m, 2H), 7.30-7.26(m, 1H), 7.25-7.21(m, 1H), 7.07(dq, J=7.3, 1 .0Hz, 2H), 6.94(ddd, J=5.6, 2.5, 1.5Hz, 1H), 5.19(ddt, J=51.2, 11.3, 6.7Hz, 1H), 4.85(ddd, J= 19.7, 9.7, 6.7Hz, 1H), 4.35(ddd, J=11.5, 9.7, 1.8Hz, 1H), 3.49-3.37(m, 3H), 1.80-1.72(m, 3H).

[0152] (S)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-44) [ka] MS (ESI, m / z) calculated value 470.1590, observed value [M+1] + 471.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.92(d, J=7.0Hz, 1H), 8.44(dd, J=5.6, 0.5Hz, 1H), 7.61(dd, J=2.5, 0.5Hz, 1H), 7.46(d, J=8 .1Hz, 1H), 7.44-7.37(m, 2H), 7.28(d, J=8.1Hz, 1H), 7.26-7.22(m, 1H), 7.09-7.04(m, 2H), 6. 95(dd, J=5.6, 2.6Hz, 1H), 5.01(dt, J=11.4, 7.0Hz, 1H), 4.86(dq, J=7.4, 5.6Hz, 4H), 4.78(d d, J=9.7, 6.9Hz, 1H), 4.34(dd, J=11.4, 9.7Hz, 1H), 4.11(tt, J=8.5, 7.4Hz, 1H), 3.52(s, 3H).

[0153] (S)-N-(7-(3,3-difluoro-3-(oxetan-3-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-45) [ka] MS (ESI, m / z) calculated value 520.1558, observed value [M+1] + 521.1. 1 H NMR (400 MHz, chloroform-d) δ (ppm) 8.92 (d, J = 6.9 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.46-7.37 (m, 3H), 7.29-7.23 (m, 1H), 7.11-7.04 (m, 2H), 6.96 (d d, J=5.6, 2.5Hz, 1H), 5.02(dt, J=11.4, 6.8Hz, 1H), 4.88-4.75(m, 5H), 4.39(d d, J=11.4, 9.8Hz, 1H), 3.73(dtdd, J=14.6, 12.5, 8.1, 6.5Hz, 1H), 3.54(s, 3H).

[0154] N-((3S)-7-(3-amino-4,4,4-trifluoro-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-46) [ka] MS (ESI, m / z) calculated value 525.1624, observed value [M+1] + 526.0. 1H NMR (400MHz, chloroform-d) δ(ppm) 8.91(d, J=7.0Hz, 1H), 8.44(d, J=5.6Hz, 1H), 7.61(d, J=2.4Hz, 1H), 7.50-7 .37(m, 3H), 7.31(d, J=8.2Hz, 1H), 7.27-7.21(m, 1H), 7.10-7.03(m, 2H), 6.9 5(dd, J=5.6, 2.5Hz, 1H), 5.00(dt, J=11.4, 6.9Hz, 1H), 4.78(dd, J=9.7, 6.8H z, 1H), 4.35(dd, J=11.4, 9.7Hz, 1H), 3.52(s, 3H), 1.92(s, 2H), 1.66(s, 3H).

[0155] (S)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-47) [ka] MS (ESI, m / z) calculated value 498.1903, observed value [M+1] + 499.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.92(d, J=7.0Hz, 1H), 8.44(dd, J=5.6, 0.5Hz, 1H), 7.61(dd, J=2.5, 0.5Hz, 1H), 7.47-7.37(m, 3H) , 7.29-7.22(m, 2H), 7.10-7.03(m, 2H), 6.95(dd, J=5.6, 2.5Hz, 1H), 5.01(dt, J=11.3, 6.9Hz, 1H), 4.78(dd, J=9.7, 6.9Hz, 1H), 4.33(dd, J=11.4, 9.7Hz, 1H), 3.96(ddd, J=11.7, 5.3, 3.8Hz, 2H), 3.5 9-3.49(m, 5H), 2.88(tt, J=8.7, 4.1Hz, 1H), 1.98-1.87(m, 2H), 1.81(ddt, J=13.7, 9.2, 4.4Hz, 2H).

[0156] Step 1: Synthesis of intermediate (VI) To intermediate I (0.1 mmol, 1 equiv.), substituted ethyne (0.2-0.3 mmol, 2-3 equiv.), Pd(PPh3)4 (0.01 mmol, 0.1 equiv.) and CuI (0.01 mmol, 0.1 equiv.) in anhydrous DMF (1 mL) in a vial was added Et3N (0.4 mmol, 4 equiv.). The reaction solution was purged with nitrogen for 1 min, then sealed and heated at 70 °C for 14-24 h. The reaction solution was cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse HPLC (mobile phase A: water with 0.1% HCOOH, mobile phase B: acetonitrile with 0.1% HCOOH) to give intermediate VI.

[0157] Step 2: Synthesis of intermediate (VII) Intermediate VI (1 eq.) was dissolved in dichloromethane, then TFA (concentration: 10% in dichloromethane) or HCl (40 eq., 4N in dioxane) was added. The resulting solution was stirred at ambient temperature until all starting material disappeared (monitored by reverse HPLC). All solvents were removed under reduced pressure to give the crude product of intermediate VII, which was used directly in the next step.

[0158] Step 3: Synthesis of the final product (VIII) Intermediate VII (1 eq.), the corresponding acid (1.2 eq.), and diisopropylethylamine (5 eq.) were dissolved in DMF (concentration 0.05M-0.1M) and then HATU (1.2 eq.) was added. The resulting solution was stirred at ambient temperature for 14-24 hours. Brine and ethyl acetate were added to the reaction solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse HPLC (mobile phase A: water with 0.1% HCOOH, mobile phase B: acetonitrile with 0.1% HCOOH) to give the final product (VIII).

[0159] Exemplary 7-substituted pyridooxazepine compounds were also prepared according to general procedure Method B shown below. [ka]

[0160] Step 1: Synthesis of intermediate IX Intermediate I was dissolved in 10% trifluoroacetic acid (0.1 M) in dichloromethane and stirred at room temperature for about 3 h. All solvents were removed under reduced pressure to give the crude trifluoroacetate salt of IX, which was used directly in the next step. MS (ESI, m / z) calculated 270.9956, found [M+1] + 271.9.

[0161] Step 2: Synthesis of intermediate X Intermediate IX (1 eq.), the corresponding acid (1.2 eq.), and diisopropylethylamine (5 eq.) were dissolved in DMF (concentration 0.05M-0.1M) and then HATU (1.2 eq.) was added. The resulting solution was stirred at ambient temperature for 14-24 hours. Brine and ethyl acetate were added to the reaction solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse HPLC (mobile phase A: water with 0.1% HCOOH, mobile phase B: acetonitrile with 0.1% HCOOH) to give intermediate (X).

[0162] Step 2: Synthesis of the final product VIII To intermediate X (0.1 mmol, 1 equiv.), substituted ethyne (0.2-0.3 mmol, 2-3 equiv.), Pd(PPh3)4 (0.01 mmol, 0.1 equiv.) and CuI (0.01 mmol, 0.1 equiv.) in anhydrous DMF (1 mL) in a vial was added Et3N (0.4 mmol, 4 equiv.). The reaction solution was purged with nitrogen for 1 min, then sealed and heated at 70 °C for 14-24 h. The reaction solution was cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse HPLC (mobile phase A: water with 0.1% HCOOH, mobile phase B: acetonitrile with 0.1% HCOOH) to give the final product VIII.

[0163] Compounds synthesized by Method B include compounds I-17, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, and I-40.

[0164] ((S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-17) [ka] MS (ESI, m / z) calculated value 486.1539, observed value [M+1] + 487.1.

[0165] (S)-4-(4-Fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide (I-19) [ka] MS (ESI, m / z) calculated value 504.1445, observed value [M+1] + 505.1.

[0166] (S)-N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2,b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-20) [ka] To a solution of ((S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (9.5 mg, 0.0195 mmol) in anhydrous dichloromethane (1 mL) was added Deoxo-Fluor (8.6 mg, 7.2 uL, 0.039 mmol) at -78 °C. The resulting solution was stirred at this temperature for 30 minutes, then additional Deoxo-Fluor (4.3 mg, 3.6 uL, 0.020 mmol) was added and stirred for an additional 15 minutes. Saturated sodium bicarbonate solution (0.1 mL) was added followed by dichloromethane (60 mL). The solution was diluted with water (15 mL), brazil, and ethyl acetate. The residue was purified by reverse HPLC (40-70% acetonitrile in water with 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate, washed with a small amount of saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give (S)-N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2,b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (2.5 mg, 26%) as a white solid. MS (ESI, m / z) calculated 488.1496, found [M+1] + 489.1. 1 H NMR (400 MHz, chloroform-d) δ (ppm) 8.98-8.87 (m, 1H), 8.48-8.37 (m, 1H), 7.64-7.52 (m, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.46-7.39 (m, 2H), 7.39-7.33 (m, 1H), 7.08 (dd, J = 2.0, 1.3 Hz, 1H), 7.07 (dd, J=2.1, 1.0Hz, 1H), 7.05-7.01(m, 1H), 6.96(dd, J=5.6, 2.6Hz, 1H), 5.12-4.86( m, 5H), 4.79 (dd, J=9.7, 6.8Hz, 1H), 4.38 (dd, J=11.4, 9.7Hz, 1H), 3.55 (m, 3H).

[0167] (S)-4-(3-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide (I-21) [ka] MS (ESI, m / z) calculated value 490.1652, observed value [M+1] + 491.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) δ 8.93(d, J=7.0Hz, 1H), 8.48(dd, J=5.6, 0.6Hz, 1H), 7.62(dd, J=2.5, 0.5Hz, 1 H), 7.38(td, J=8.3, 6.5Hz, 1H), 7.29(s, 1H), 7.01-6.92(m, 2H), 6.87(ddt, J= 8.2, 2.2, 0.8Hz, 1H), 6.81(dt, J=9.4, 2.4Hz, 1H), 5.02(dt, J=11.4, 7.0Hz, 1H) ), 4.83-4.71(m, 1H), 4.34(dd, J=11.4, 9.7Hz, 1H), 3.53(s, 3H), 1.64(s, 6H).

[0168] (S)-4-(3-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide (I-22) [ka] MS (ESI, m / z) calculated value 504.1445, observed value [M+1] + 505.1. 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.01-8.86 (m, 1H), 8.53-8.41 (m, 1H), 7.65-7.54 (m, 1H), 7.53-7.46 (m, 1H), 7.38 (td, J = 8.3, 6.5 Hz, 1H), 7.35-7.30 (m, 1H), 7.14-6.92 (m, 2H), 6.87 (ddt, J = 8.2, 2.3, 0.8 Hz, 1H), 6. 84-6.78(m, 1H), 5.06(dt, J=11.4, 6.9Hz, 1H), 4.97(td, J=6.2, 5.8, 0.9Hz, 2H), 4.86-4.76 (m, 3H), 4.71 (dt, J=6.9, 0.7Hz, 1H), 4.37 (dd, J=11.4, 9.7Hz, 1H), 3.54 (d, J=13.5Hz, 3H).

[0169] (S)-N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-(3-fluorophenoxy)picolinamide (I-23) [ka] To a solution of (S)-4-(3-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide (12.4 mg, 0.0246 mmol) in anhydrous dichloromethane (1 mL) was added Deoxo-Fluor (16.3 mg, 14 uL, 0.0737 mmol) at -78 °C. The resulting solution was stirred at this temperature for 30 minutes, then saturated sodium bicarbonate solution (0.2 mL) was added, followed by dichloromethane (80 mL). The solution was washed with water (15 mL), brine (15 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse HPLC (40-70% acetonitrile in water with 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate, washed with a small amount of saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give (S)-N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-(3-fluorophenoxy)picolinamide (4.7 mg, 38%) as a white solid. MS (ESI, m / z) calculated 506.1402, found [M+1] + 507.0. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.99-8.85(m, 1H), 8.53-8.41(m, 1H), 7.67-7.60(m, 1H), 7.52(d, J=8.1Hz, 1H), 7.44-7.34(m, 2H), 7.03-6.92(m, 2H), 6.92-6. 85(m, 1H), 6.85-6.79(m, 1H), 5.10-4.88(m, 5H), 4.81(dd, J=9.7, 6.8Hz, 1H), 4.39(dd, J=11.4, 9.7Hz, 1H), 3.65-3.40(m, 3H).

[0170] (S)-5-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-24) [ka] MS (ESI, m / z) calculated value 460.1859, observed value [M+1] + 461.1. 1 H NMR (400MHz, methanol-d4) δ(ppm) 7.61(d, J=8.2Hz, 1H), 7.36(d, J=8.1Hz, 1H), 7.35-7.15(m, 5H), 5.03(dd, J=11.5, 7.1Hz, 1H), 4 .67(dd, J=9.8, 7.1Hz, 1H), 4.51(dd, J=11.6, 9.8Hz, 1H), 4.17(s, 2H), 3.45(s, 3H), 1.58(s, 6H).

[0171] (S)-5-Benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-25) [ka] MS (ESI, m / z) calculated value 474.1652, found value [M+1] + 475.1. 1 H NMR (400MHz, methanol-d4) δ(ppm) 7.64(d, J=8.2Hz, 1H), 7.44(d, J=8.1Hz, 1H), 7.36-7.20(m, 5H), 5.04(dd, J=11.5, 7.0Hz, 1H), 4.89(d, J=0.9H) z, 2H), 4.73-4.69(m, 2H), 4.67(dd, J=7.2, 2.7Hz, 1H), 4.52(dd, J=11.6, 9.8Hz, 1H), 4.16(s, 2H), 3.46(s, 3H).

[0172] (S)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-26) [ka] MS (ESI, m / z) calculated value 484.1747, observed value [M+1] + 485.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.93(d, J=7.0Hz, 1H), 8.44(d, J=5.6Hz, 1H), 7.61(d, J=2.5Hz, 1H), 7.50-7.37(m, 3H), 7.30(d, J=8.1Hz, 1H), 7.27-7.23(m, 1H), 7.11-7.03(m, 2H), 6.95(dd, J=5.6, 2.5Hz, 1H ), 5.03(dt, J=11.4, 6.9Hz, 1H), 4.79(dd, J=9.7, 7.0Hz, 1H), 4.35(dd, J=11.4, 9.7Hz, 1 H), 3.52(s, 3H), 2.65-2.52(m, 2H), 2.44(s, 1H), 2.40-2.30(m, 2H), 1.96-1.85(m, 2H).

[0173] (S)-4-(4-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide (I-27) [ka] MS (ESI, m / z) calculated value 490.1652, observed value [M+1] + 491.1. 1H NMR (400MHz, chloroform-d) δ(ppm) 8.92(d, J=7.0Hz, 1H), 8.45(dd, J=5.6, 0.6Hz, 1H), 7.57(dd, J=2.6, 0.5H z, 1H), 7.45(d, J=8.1Hz, 1H), 7.28(d, J=8.1Hz, 1H), 7.14-7.08(m, 2H), 7. 08-7.02(m, 2H), 6.93(dd, J=5.6, 2.6Hz, 1H), 5.01(dt, J=11.3, 7.0Hz, 1H ), 4.82-4.72(m, 1H), 4.34(dd, J=11.4, 9.7Hz, 1H), 3.52(d, J=1.3Hz, 3H).

[0174] (S)-4-(2-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide (I-28) [ka] MS (ESI, m / z) calculated value 490.1652, observed value [M+1] + 491.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.95(d, J=7.0Hz, 1H), 8.48(dd, J=5.6, 0.5Hz, 1H), 7.59(dt, J=2.6, 0.6Hz, 1H), 7. 47(d, J=8.1Hz, 1H), 7.30-7.23(m, 4H), 7.23-7.21(m, 1H), 7.21-7.17(m, 2H), 6.98( ddd, J=5.6, 2.6, 0.5Hz, 1H), 5.03(dt, J=11.4, 6.9Hz, 1H), 4.79(dd, J=9.7, 6.9Hz, 1H), 4.35(dd, J=11.4, 9.7Hz, 1H), 4.13(q, J=7.1Hz, 1H), 3.53(s, 3H), 1.65(s, 6H).

[0175] (S)-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-fluoro-1-(4-fluorobenzyl)-1H-pyrazole-3-carboxamide (I-40) [ka] This compound was obtained from the desilylation of (S)-4-fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide. MS (ESI, m / z) calculated 437.1299, found [M+1] + 438.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 7.66(d, J=6.4Hz, 1H), 7.48(d, J=8.1Hz, 1H), 7.35(d, J=8.1Hz, 1H), 7.25-7.18(m, 3H), 7.11-7.01(m, 2H), 5.19(s, 2H) ), 5.03(dt, J=11.3, 6.7Hz, 1H), 4.84(dd, J=9.7, 6.8Hz, 1H), 4.32(dd, J=11.3, 9.7Hz, 1H), 3.53(s, 3H), 3.16(s, 1H).

[0176] A general synthesis of 7-ethynylpyridoazepine compounds XI. [ka] As one of ordinary skill in the art would readily appreciate, the synthesis of exemplified compound XI is applicable to compounds having a variety of R groups.

[0177] 6-Amino-5-bromopyridin-2-ol 6-Aminopyridin-2-ol (11 g, 0.1 mmol) was dissolved in acetic acid (220 mL) and then bromine (16 g, 5.12 mL, 0.1 mmol) was added at ambient temperature. The resulting solution was stirred at this temperature for 40 min. Water (200 mL) was added and the solution was filtered through Celite. The solution was extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with water (2×100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude 6-amino-5-bromopyridin-2-ol (8.3 g), which was used directly in the next step without further purification. MS (ESI, m / z) calculated 187.9585, found [M+1] + 188.9. 1 H NMR (400MHz, DMSO-d6) δ(ppm) 10.79(s, 1H), 7.38(d, J=8.8Hz, 1H), 5.93(s, 2H), 5.60(d, J=8.8Hz, 1H).

[0178] 3-Bromo-6-methoxypyridin-2-amine The crude 6-amino-5-bromopyridin-2-ol (8.3 g, 43.9 mmol) was dissolved in acetone (130 mL) and potassium hydroxide (7.4 g, 0.132 mol) was added followed by dimethyl sulfate (7.20 g, 5.4 mL, 57.1 mmol). The reaction solution was stirred at ambient temperature for 4 hours. All solvents were removed under reduced pressure. Brine (100 mL) was added to the residue and extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-30% ethyl acetate in hexanes to give 3-bromo-6-methoxypyridin-2-amine (4.09 g, 20% over two steps) as a white solid. MS (ESI, m / z) calculated 201.9742, found [M+1] + 202.9. 1 H NMR (400 MHz, chloroform-d) δ (ppm) 7.48 (d, J = 8.4 Hz, 1H), 6.02 (d, J = 8.3 Hz, 1H), 4.73 (s, 2H), 3.82 (s, 3H).

[0179] 6-Methoxy-3-vinylpyridin-2-amine Pd(PPh3)4 (1.17 g, 1.01 mmol) in anhydrous toluene (66 mL) was added to a solution of 3-bromo-6-methoxypyridin-2-amine (4.09 g, 20.3 mmol) and tributyl(vinyl)stannane (9.64 g, 30.4 mmol). The reaction solution was purged with nitrogen for 1 min, then sealed and heated at 110 °C for 16 h. The reaction solution was cooled to ambient temperature. Aqueous potassium fluoride (100 mL, 1 M) was added, followed by ethyl acetate (500 mL). The solution was filtered through Celite and washed with ethyl acetate. The organics were separated, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-10% ethyl acetate in hexanes to give 6-methoxy-3-vinylpyridin-2-amine (2.09 g, 69%) as a pale liquid. MS (ESI, m / z) calculated value 150.0793, observed value [M+1] + 150.9. 1 H NMR (400MHz, chloroform-d) δ(ppm) 7.46(dd, J=8.2, 0.6Hz, 1H), 6.57(ddt, J=17.4, 11.1, 0.6Hz, 1H), 6.14(dd, J=8.2, 0.6Hz, 1H), 5.49(dd, J=17.4, 1.2Hz, 1H), 5.21(dd, J=11.1, 1.2Hz, 1H), 4.45(s, 2H), 3.85(s, 3H).

[0180] tert-Butyl (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate To a solution of (S)-4-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (20 g, 59.3 mmol) in anhydrous benzene (600 mL) was added copper(II) acetate (2.7 g, 14.8 mmol). The resulting solution was stirred under nitrogen at ambient temperature for 2 h, then lead tetraacetate (55.3 g, 0.119 mol) was added. The resulting solution was refluxed under nitrogen for 14 h, then cooled to ambient temperature. The reaction solution was filtered through Celite and washed with ethyl acetate (1200 mL). The organic layer was washed with water (2×300 mL), brine (300 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-10% ethyl acetate in hexanes to give tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate (4.3 g, 25%) as a pale yellow liquid. MS (ESI, m / z) calculated 291.1471, found [M- t Bu+1] + 236.0. 1 H NMR (400 MHz, chloroform-d) δ (ppm) 7.44-7.27 (m, 5H), 5.90 (ddd, J = 16.3, 10.4, 5.3 Hz, 1H), 5.44 (d, J = 8.1 Hz, 1H), 5.34 (ddd, J = 17.2, 1.8, 0.7 Hz, 1H), 5.24 (ddd, J = 10.4, 1.8, 0.7 Hz, 1H), 5.12 (s, 2H), 4.86-4.74 (m, 1H), 1.46 (s, 9H).

[0181] (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoic acid To a solution of tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate (4.3 g, 14.8 mmol) in anhydrous dichloromethane (340 mL) was added trifluoroacetic acid (50.5 g, 34 mL, 0.443 mol) at 0° C. The resulting solution was stirred at ambient temperature for 16 h. All solvents were removed under reduced pressure to give (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoic acid (3.3 g, 95%) as a white solid. MS (ESI, m / z) calculated 235.0845, found [M-1] + 234.1. 1 H NMR (400MHz, DMSO-d6) δ(ppm) δ 12.80(s, 1H), 7.83(d, J=8.2Hz, 1H), 7.42-7.25(m, 5H), 5.91(ddd, J=16.8, 10.4, 6.1Hz, 1H), 5.33(d t, J=17.2, 1.5Hz, 1H), 5.21(dt, J=10.4, 1.4Hz, 1H), 5.05(s, 2H), 4.62(ddt, J=7.8, 6.1, 1.7Hz, 1H).

[0182] Benzyl (S)-(1-((6-methoxy-3-vinylpyridin-2-yl)amino)-1-oxobut-3-en-2-yl)carbamate To a solution of (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoic acid (1.75 g, 7.55 mmol) in anhydrous dichloromethane (35 mL) was added dropwise 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.01 g, 1 mL, 7.55 g) at 0° C. and stirred at this temperature for 30 min. Then 6-methoxy-3-vinylpyridin-2-amine (1.03 g, 6.87 mmol) in anhydrous dichloromethane (5 mL) was added dropwise followed by triethylamine (0.76 g, 1.05 mL, 7.55 mmol). The resulting solution was stirred at ambient temperature for another 2 h and dichloromethane (150 mL) was added. The solution was washed with a small amount of aqueous HCl (1N), aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-50% ethyl acetate in hexanes to give benzyl (S)-(1-((6-methoxy-3-vinylpyridin-2-yl)amino)-1-oxobut-3-en-2-yl)carbamate (568 mg, 23%) as a pale yellow liquid. MS (ESI, m / z) calculated 367.1532, found [M+1]. + 368.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 7.75(d, J=8.5Hz, 1H), 7.67(s, 1H), 7.43-7.27(m, 5H), 6.63(d, J=8.5Hz, 1H ), 6.54(dd, J=17.5, 11.1Hz, 1H), 6.02(ddd, J=16.9, 10.2, 6.3Hz, 1H), 5.79( s, 1H), 5.59(dd, J=17.4, 0.9Hz, 1H), 5.47(d, J=17.0Hz, 1H), 5..37(d, J=10 .1Hz, 1H), 5.30(d, J=11.0Hz, 1H), 5.14(d, J=1.3Hz, 2H), 3.98-3.72(s, 3H).

[0183] Benzyl (S)-(2-methoxy-8-oxo-8,9-dihydro-7H-pyrido[2,3-b]azepin-7-yl)carbamate To a suspension of benzyl (S)-(1-((6-methoxy-3-vinylpyridin-2-yl)amino)-1-oxobut-3-en-2-yl)carbamate (573 mg, 1.56 mmol) in anhydrous toluene (78 mL) was added Grubb's second generation catalyst (133 mg, 0.156 mmol). The reaction solution was purged with nitrogen for 1 min, then sealed and heated at 80 °C under nitrogen for 15 h. The reaction solution was cooled to ambient temperature. All solvents were removed under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-30% ethyl acetate in hexanes to give benzyl (S)-(2-methoxy-8-oxo-8,9-dihydro-7H-pyrido[2,3-b]azepin-7-yl)carbamate (343 mg, 65%) as a white solid. MS (ESI, m / z) calculated value 339.1219, observed value [M+1] + 340.0. 1 H NMR (400MHz, chloroform-d) δ(ppm) 7.97(s, 1H), 7.55(d, J=8.4Hz, 1H), 7.44-7.27(m, 5H), 6.63-6.53(m, 2H), 6.22(d, J=6. 2Hz, 1H), 5.67(dd, J=10.0, 4.4Hz, 1H), 5.14(s, 2H), 4.41(d, J=6.7Hz, 1H), 3.91(s, 3H).

[0184] tert-Butyl (S)-(2-methoxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate To a solution of benzyl (S)-(2-methoxy-8-oxo-8,9-dihydro-7H-pyrido[2,3-b]azepin-7-yl)carbamate (341 mg, 1 mmol) in MeOH was added 10% palladium on carbon (110 mg) and di-tert-butyl carbonate (537 mg, 2 mmol). The reaction was hydrogenated in a Parr-Shaker under 50 PSI hydrogen pressure for 15 hours. The reaction solution was filtered through Celite and washed with MeOH. All solvents were removed under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-40% ethyl acetate in hexanes to give tert-butyl (S)-(2-methoxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (151 mg, 49%) as a white solid. MS (ESI, m / z) calculated 307.1532, found [M+1-Boc] + 208.0. 1 H NMR (400 MHz, chloroform-d) δ (ppm) 7.82 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 8.2 Hz, 1H), 5.53 (d, J = 7.5 Hz, 1H), 4.29 (dt, J = 11.5, 7.2 Hz, 1H), 3.85 (s, 3H), 2.87-2.73 (m, 1H), 2.73-2.55 (m, 2H), 2.02-1.89 (m, 1H), 1.39 (s, 9H).

[0185] tert-Butyl (S)-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate To a solution of tert-butyl (S)-(2-methoxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (150 mg, 0.489 mmol) in anhydrous DMF (4 mL) was added methyl iodide (69.3 mg, 30.4 uL, 0.489 mmol) followed by cesium carbonate (159 mg, 0.489 mmol). The resulting solution was stirred at ambient temperature for 2 days. The reaction solution was diluted with ethyl acetate (150 mL), washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-30% ethyl acetate in hexanes to give tert-butyl (S)-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (147 mg, 94%) as a white solid. MS (ESI, m / z) calculated 321.1689, found [M+1-Boc]. + 222.0. 1 H NMR (400 MHz, chloroform-d) δ (ppm) 7.40 (d, J = 8.1 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 5.53 (d, J = 7.7 Hz, 1H), 4.26 (dt, J = 11.2, 7.4 Hz, 1H), 3.89 (s, 3H), 3.45 (s, 3H), 2.77-2.56 (m, 2H), 2.52 (dd, J = 12.3, 6.4 Hz, 1H), 2.02-1.84 (m, 1H), 1.40 (s, 9H).

[0186] (S)-7-Amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one To a solution of tert-butyl (S)-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (35 mg, 0.11 mmol) in anhydrous dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL). The resulting solution was stirred at ambient temperature for 3 h. Anhydrous 1,2-dichloroethane (1 mL) was then added. All solvents were removed under reduced pressure to give the crude trifluoroacetate salt of (S)-7-amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one. The resulting residue was used directly in the next step. MS (ESI, m / z) calculated 221.1164, found [M+1] + 222.1.

[0187] (S)-N-(2-Methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide To a solution of the crude trifluoroacetate salts of (S)-7-amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one (0.11 mmol) and 4-phenoxypicolinic acid (28 mg, 0.13 mmol) in anhydrous DMF (1 mL) was added diisopropylethylamine (56 mg, 75 uL, 0.43 mmol) followed by HATU (49.4 mg, 0.13 mmol). The resulting solution was stirred at ambient temperature for 19 hours. The reaction was quenched by the addition of one drop of water. The solution was directly purified by reverse phase HPLC (30-70% acetonitrile in water with 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give (S)-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (43 mg, 95%) as a white solid. MS (ESI, m / z) calculated 418.1641, found [M+1] + 419.1. 1H NMR (400MHz, chloroform-d) δ(ppm) 8.90(d, J=7.6Hz, 1H), 8.43(dd, J=5.6, 0.5Hz, 1H), 7.62(dd, J=2.5, 0.5Hz, 1H), 7 .46(d, J=8.2Hz, 1H), 7.44-7.37(m, 2H), 7.26-7.20(m, 1H), 7.10-7.04(m, 2H), 6. 93(dd, J=5.6, 2.6Hz, 1H), 6.57(d, J=8.2Hz, 1H), 4.66(dt, J=11.4, 7.5Hz, 1H), 3. 90(s, 3H), 3.48(s, 3H), 2.83-2.69(m, 2H), 2.64-2.52(m, 1H), 2.15-2.02(m, 1H).

[0188] (S)-N-(2-hydroxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide To a solution of (S)-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (29 mg, 0.069 mmol) in anhydrous acetonitrile (1 mL) was added phosphorus tribromide (56 mg, 20 uL, 0.21 mmol). The resulting solution was heated at 80 °C for 3 h. The reaction solution was cooled to ambient temperature and the reaction was quenched by careful addition of methanol. All solvents were removed under reduced pressure. The crude solid was dissolved in DMSO and purified by reverse HPLC (20-56% acetonitrile in water with 0.1% formic acid). The desired fractions were combined and lyophilized to give (S)-N-(2-hydroxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (24 mg, 87%) as a white solid. MS (ESI, m / z) calculated 404.1485, found [M+1] + 405.1.

[0189] (S)-9-Methyl-8-oxo-7-(4-phenoxypicolinamido)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl trifluoromethanesulfonate To a solution of (S)-N-(2-hydroxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (24.2 mg, 0.06 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (25.6 mg, 0.072 mmol) in anhydrous DMF (1 mL) was added anhydrous potassium carbonate (17.4 mg, 0.126 mmol). The resulting solution was stirred at ambient temperature for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-50% ethyl acetate in hexanes to give (S)-9-methyl-8-oxo-7-(4-phenoxypicolinamido)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl trifluoromethanesulfonate (30 mg, 92%) as a white solid. MS (ESI, m / z) calculated 536.0977, found [M+1]. + 537.0.

[0190] General procedure for preparing 7-ethynylpyridoazepine compounds XI (S)-9-Methyl-8-oxo-7-(4-phenoxypicolinamido)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl trifluoromethanesulfonate (0.03 mmol, 1 equiv.), substituted ethyne (0.06-0.09 mmol, 2-3 equiv.), Pd(PPh3)4 (0.01 mmol, 0.1 equiv.) and CuI (0.01 mmol, 0.1 equiv.), Et3N (0.4 mmol, 4 equiv.) in anhydrous DMF (0.5 mL) in a vial were added. The reaction solution was purged with nitrogen for 1 min, then sealed and heated at 70 °C for 14-24 h. The reaction solution was cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse HPLC (mobile phase A: water with 0.1% HCOOH, mobile phase B: acetonitrile with 0.1% HCOOH) to give intermediate final product XI. Compounds I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59 and I-60 are exemplary compounds synthesized by this general method. The picolinamide ring (the "B" ring according to the formula shown herein) can be replaced with other heteroaryl groups in the above general synthesis of XI, as would be readily understood by one of skill in the art. For example, the picolinamide moiety can be replaced by another 5- or 6-membered heteroaryl ring as described herein. As an example of such a substitution, compound I-54 contains a triazole at the "B" ring position. The above general synthesis was adapted according to the following examples.

[0191] Synthesis of (S)-5-benzyl-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide (I-54) [ka]

[0192] Step 1 (S)-5-benzyl-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide To a solution of the crude trifluoroacetate salts of (S)-7-amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one (0.0523 mmol) and 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (10.6 mg, 0.0523 mmol) in anhydrous DMF (0.5 mL) was added diisopropylethylamine (27 mg, 37 uL, 0.209 mmol) followed by HATU (21.9 mg, 0.0575 mmol). The resulting solution was stirred at ambient temperature for 19 hours. The reaction was quenched by the addition of one drop of water. The solution was directly purified by reverse phase HPLC (15-52% acetonitrile in water with 0.1% formic acid). The desired fractions were combined and lyophilized to give (S)-5-benzyl-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide (21 mg, 97%) as a white solid. MS (ESI, m / z) calculated 406.1753, found [M+1] + 407.1.

[0193] Step 2 (S)-5-benzyl-N-(2-hydroxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide To a solution of (S)-5-benzyl-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide (21 mg, 0.051 mmol) in anhydrous acetonitrile (1 mL) was added phosphorus tribromide (41 mg, 14 uL, 0.15 mmol). The resulting mixture was heated at 80 °C for 3 h. The reaction solution was cooled to ambient temperature and the reaction was quenched by careful addition of methanol. All solvents were removed under reduced pressure. The crude solid was dissolved in DMSO and purified by reverse HPLC (10-40% acetonitrile in water with 0.1% formic acid). The desired fractions were combined and lyophilized to give (S)-5-benzyl-N-(2-hydroxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide (18 mg, 91%) as a white solid. MS (ESI, m / z) calculated 392.1597, found [M+1] + 393.1.

[0194] Step 3 (S)-7-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl trifluoromethanesulfonate To a solution of (S)-5-benzyl-N-(2-hydroxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide (18 mg, 0.046 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (19.7 mg, 0.055 mmol) in anhydrous DMF (1 mL) was added anhydrous potassium carbonate (15.2 mg, 0.11 mmol). The resulting solution was stirred at ambient temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-50% acetone in hexanes to give (S)-7-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl trifluoromethanesulfonate (22 mg, 92%) as a white solid. MS (ESI, m / z) calculated 524.1090, found [M+1] + 525.0.

[0195] Step 4 (S)-5-benzyl-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide To (S)-7-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl trifluoromethanesulfonate (22 mg, 0.0422 mmol), 2-methylbut-3-yn-2-ol (11.6 mg, 0.0138 mmol), Pd(PPh3)4 (5.3 mg, 0.0046 mmol), and CuI (0.9 mg, 0.0046 mmol) in anhydrous DMF (1 mL) in a vial was added Et3N (18.6 mg, 26 uL, 0.184 mmol). The reaction solution was purged with nitrogen for 1 min, then sealed and heated at 70 °C for 14 h. The reaction solution was cooled to ambient temperature, diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse HPLC (15-47% acetonitrile in water with 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate, washed with a small amount of saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give (S)-5-benzyl-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide (4.0 mg, 21%) as a white solid. MS (ESI, m / z) calculated 458.2066, found [M+1] + 459.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.12(d, J=7.2Hz, 1H), 7.53(d, J=7.7Hz, 1H), 7.35-7.25(m, 5H), 7.23(d, J=7.7Hz, 1H), 4.57(dt, J=12.1, 6.9Hz, 1 H), 4.14(s, 2H), 3.50(s, 3H), 2.90-2.73(m, 2H), 2.71-2.57(m, 1H), 2.20(s, 1H), 2.13-2.03(m, 1H), 1.63(s, 6H).

[0196] (S)-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (I-52) [ka] MS (ESI, m / z) calculated value 470.1954, observed value [M+1] + 471.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.93(d, J=7.3Hz, 1H), 8.43(dd, J=5.6, 0.5Hz, 1H), 7.62(dd, J=2.6, 0.5Hz, 1H) , 7.55(d, J=7.7Hz, 1H), 7.45-7.36(m, 2H), 7.26-7.21(m, 2H), 7.11-7.03(m, 2H) ), 6.93(dd, J=5.6, 2.6Hz, 1H), 4.59(dt, J=11.1, 7.2Hz, 1H), 3.52(s, 3H), 2.93 -2.73(m, 2H), 2.73-2.58(m, 1H), 2.14(s, 1H), 2.13-1.99(m, 1H), 1.65(s, 6H).

[0197] (S)-N-(2-((3-hydroxyoxetan-3-yl)ethynyl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (I-53) [ka] MS (ESI, m / z) calculated value 484.1747, observed value [M+1] + 485.1. 1H NMR (400MHz, chloroform-d) δ(ppm) 8.94(d, J=7.3Hz, 1H), 8.44(dd, J=5.6, 0.6Hz, 1H), 7.62(dd, J=2.6, 0.5Hz, 1H), 7.59(d, J=7.7H z, 1H), 7.45-7.37(m, 2H), 7.30(d, J=7.6Hz, 1H), 7.26-7.20(m, 1H), 7.11-7.04(m, 2H), 6.93(dd , J=5.6, 2.5Hz, 1H), 4.98(dd, J=6.6, 1.0Hz, 2H), 4.80(dt, J=6.8, 0.7Hz, 2H), 4.61(dt, J=11.1, 7.3Hz, 1H), 3.52(s, 3H), 2.89(s, 1H), 2.88-2.75(m, 2H), 2.75-2.62(m, 1H), 2.18-2.04(m, 1H).

[0198] N-((7S)-9-Methyl-8-oxo-2-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (I-55) [ka] MS (ESI, m / z) calculated value 510.1515, observed value [M+1] + 511.0. 1 H NMR (400MHz, chloroform-d) δ(ppm) 9.01(dd, J=20.7, 7.2Hz, 1H), 8.42(dd, J=5.6, 1.2Hz, 1H), 7.63-7.53(m, 2H), 7.45-7. 35(m, 2H), 7.31-7.25(m, 1H), 7.24-7.18(m, 1H), 7.09-7.00(m, 2H), 6.92(dd, J=5.6, 2 .5Hz, 1H), 4.91(d, J=6.4Hz, 1H), 4.80-4.52(m, 1H), 3.97-3.77(m, 0.5H), 3.66-3.52( m, 0.5H), 3.52-3.34(m, 3H), 2.97-2.76(m, 2H), 2.76-2.59(m, 1H), 2.19-2.00(m, 1H).

[0199] N-((7S)-9-Methyl-8-oxo-2-(4,4,4-trifluoro-3-hydroxy-3-methylbut-1-yn-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (I-56) [ka] MS (ESI, m / z) calculated value 524.1671, observed value [M+1] + 525.2. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.97(dd, J=12.6, 7.2Hz, 1H), 8.43(d, J=5.6Hz, 1H), 7.64-7.54(m, 2H), 7 .46-7.35(m, 2H), 7.32-7.18(m, 2H), 7.10-7.01(m, 2H), 6.96-6.87(m, 1H) , 4.64(ddt, J=20.4, 11.3, 7.1Hz, 1H), 3.55-3.39(m, 3.5H), 3.23(s, 0.5 H), 2.93-2.76(m, 2H), 2.75-2.63(m, 1H), 2.19-1.98(m, 1H), 1.74(s, 3H).

[0200] (S)-N-(2-((3,3-difluoro-1-hydroxycyclobutyl)ethynyl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (I-57) [ka] MS (ESI, m / z) calculated value 518.1766, observed value [M+1] + 519.1. 1H NMR (400MHz, chloroform-d) δ(ppm) 8.95(d, J=7.3Hz, 1H), 8.43(dd, J=5.6, 0.6Hz, 1H), 7.62(dd, J=2.6, 0.5Hz, 1H), 7.58(d, J= 7.7Hz, 1H), 7.45-7.37(m, 2H), 7.27(d, J=5.2Hz, 1H), 7.26-7.21(m, 1H), 7.10-7.04(m, 2H), 6.93(dd, J=5.6, 2.5Hz, 1H), 4.61(dt, J=11.1, 7.1Hz, 1H), 3.52(s, 3H), 3.29-3.14(m, 2H), 3 .07-2.92(m, 2H), 2.84(dtd, J=15.2, 7.5, 5.6Hz, 2H), 2.75-2.59(m, 1H), 2.19-2.03(m, 1H).

[0201] (S)-N-(9-methyl-2-(oxetan-3-ylethynyl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (I-58) [ka] MS (ESI, m / z) calculated value 468.1798, observed value [M+1] + 469.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.94(d, J=7.3Hz, 1H), 8.43(dd, J=5.6, 0.5Hz, 1H), 7.62(dd, J=2.5, 0.5Hz, 1H), 7.5 6(d, J=7.7Hz, 1H), 7.45-7.35(m, 2H), 7.27-7.22(m, 3H), 7.10-7.04(m, 2H), 6.93(dd , J=5.6, 2.6Hz, 1H), 4.92-4.79(m, 4H), 4.60(dt, J=11.2, 7.3Hz, 1H), 4.12(tt, J=8. 5, 7.4Hz, 1H), 3.52(s, 3H), 2.94-2.73(m, 2H), 2.73-2.61(m, 1H), 2.19-2.03(m, 1H).

[0202] (S)-N-(2-(3,3-difluoro-3-(oxetan-3-yl)prop-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (I-59) [ka] MS (ESI, m / z) calculated value 518.1766, observed value [M+1] + 519.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.93(d, J=7.3Hz, 1H), 8.44(d, J=5.6Hz, 1H), 7.65-7.59(m, 2H), 7.45-7.3 5(m, 3H), 7.26-7.20(m, 1H), 7.10-7.04(m, 2H), 6.94(dd, J=5.6, 2.5Hz, 1H) , 4.90-4.74(m, 4H), 4.59(dt, J=11.3, 7.2Hz, 1H), 3.83-3.62(m, 1H), 3.53( s, 3H), 2.96-2.76(m, 2H), 2.72(dd, J=11.9, 6.2Hz, 1H), 2.20-2.06(m, 1H).

[0203] N-((7S)-2-(3-amino-4,4,4-trifluoro-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (I-60) [ka] MS (ESI, m / z) calculated value 523.1831, observed value [M+1] + 524.1. 1H NMR (400MHz, chloroform-d) δ(ppm) 8.93(d, J=7.3Hz, 1H), 8.43(dd, J=5.6, 0.6Hz, 1H), 7.62(dd, J=2.6, 0.5Hz, 1H), 7. 57(d, J=7.7Hz, 1H), 7.44-7.37(m, 2H), 7.30-7.21(m, 2H), 7.09-7.04(m, 2H), 6.93 (dd, J=5.6, 2.5Hz, 1H), 4.58(dt, J=11.1, 7.2Hz, 1H), 3.52(s, 3H), 2.93-2.75(m, 2 H), 2.75-2.63(m, 1H), 2.17-2.02(m, 1H), 2.02-1.81(m, 2H), 1.67(d, J=0.9Hz, 3H).

[0204] (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (I-1) [ka] 1 H NMR (400MHz, CD2Cl2) δ 8.30(dd, J=4.7, 1.6Hz, 1H), 8.06(d, J=7.0Hz, 1H), 7.53(dd, J=8.0, 1.6Hz, 1H), 7.32-7.21(m, 5H), 7.18(dd, J=8.0, 4.7Hz, 1H ), 4.99(dt, J=11.3, 7.0Hz, 1H), 4.76(dd, J=9.8, 7.1Hz, 1H), 4.32(dd, J=11.3, 9.8Hz, 1H), 4.17(d, J=2.1Hz, 2H), 3.49(s, 3H). HRMS (TOFMS ES+) accurate mass C 19 H 18 N6O3378.1440, measured value 379.1566.

[0205] (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide (I-2) [ka] MS (ESI, m / e) calculated value 379.1281, found value 380.0 [M+H] + .

[0206] (S)-5-Benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (I-3) [ka] MS (ESI, m / e) calculated value 460.1859, found value 443.1 [M-H2O+H] + .

[0207] (S)-5-Benzyl-N-(5-methyl-8-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide (I-5) [ka] MS (ESI, m / e) calculated value 502.1965, found value 503.1 [M+H] + .

[0208] Synthesis of (S)-3-amino-8-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride (I-6) [ka] The 8-bromo compound shown in the above scheme as structure 4 is compound I-6 of the present disclosure. In addition to exhibiting RIP1K inhibitory activity, compound I-6 is useful as an intermediate for synthesizing 8-substituted pyridoxazepines. For example, compound I-6 can be cross-coupled, for example under palladium catalyzed conditions, with an amino moiety and an unsaturated group, as known to those skilled in the art.

[0209] Hydrogen chloride solution (1 mL, 4 M in dioxane, 4 mmol) was added to a vial containing tert-butyl (S)-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 1 (prepared as described in WO2020 / 239074, 52 mg, 0.139 mmol). The resulting solution was stirred at ambient temperature for 19 h. All solvent was removed under reduced pressure to give (S)-3-amino-8-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 2 (43 mg, 100%) as a white solid. MS (ESI, m / e) calculated 270.9956, found 272.0 [M+H] + .

[0210] Synthesis of (S)-N-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (4) To a solution of (S)-3-amino-8-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride 2 (43 mg, 86 μmol) and 4-phenoxypicolinic acid 3 (45 mg, 0.21 mmol) in anhydrous DMF (1.4 mL) was added diisopropylethylamine (135 mg, 0.18 mL, 1.1 mmol) followed by HATU (80 mg, 0.21 mmol). The resulting solution was stirred at ambient temperature for 16 h. Water (0.1 mL) was then added and the solution was directly purified by reverse HPLC using a gradient of 37-90% acetonitrile in water buffered with 0.1% formic acid. The desired fractions were combined and diluted with ethyl acetate (100 mL) and the resulting solution was washed with saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-N-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide 4 (50 mg, 77%) as a white solid. MS (ESI, m / e) calculated 468.0433, found 468.9 [M+H]. + .

[0211] (S)-N-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-6) [ka] MS (ESI, m / e) calculated value 468.0433, found value 468.9 [M+H] + (I-6)

[0212] (S)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b]][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-7) [ka] MS (ESI, m / e) calculated value 472.1747, found value 473.1 [M+H] + .

[0213] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-18) [ka] MS (ESI, m / z) calculated value 472.1747, observed value [M+1] + 473.1. 1 H NMR (400MHz, methanol-d4) δ(ppm) 8.52(dd, J=5.7, 0.5Hz, 1H), 7.61(d, J=8.1Hz, 1H), 7.52-7.44(m, 3H), 7.36(d, J=8.2Hz, 1H), 7.34-7.27(m, 1H), 7.17-7.12(m, 2H), 7.09( dd.

[0214] (S)-N-(7-((3,3-difluoro-1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-30) [ka] MS (ESI, m / z) calculated value 520.1558, observed value [M+1] + 521.1. 1H NMR (400MHz, chloroform-d) δ(ppm) 8.97(d, J=6.9Hz, 1H), 8.45(d, J=5.6Hz, 1H), 7.61(d, J=2.5Hz, 1H), 7.48(d, J=8.1Hz, 1H) , 7.46-7.39(m, 2H), 7.29(d, J=8.1Hz, 1H), 7.24(t, J=1.2Hz, 1H), 7.11-7.04(m, 2H), 6.96 (dd, J=5.6, 2.5Hz, 1H), 5.09(dt, J=11.4, 6.8Hz, 1H), 4.81(dd, J=9.7, 6.8Hz, 1H), 4.36(d d, J=11.4, 9.7Hz, 1H), 3.50(s, 3H), 3.22(tdd, J=11.9, 9.3, 3.7Hz, 2H), 3.08-2.86(m, 3H).

[0215] (S)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-31) [ka] MS (ESI, m / z) calculated value 486.1903, observed value [M+1] + 487.1. 1 H NMR (400MHz, chloroform-d) δ(ppm) 8.92(d, J=7.0Hz, 1H), 8.44(d, J=5.6Hz, 1H), 7.61(d, J=2.5Hz, 1H), 7.47-7. 37(m, 3H), 7.28(d, J=1.1Hz, 1H), 7.25(d, J=5.9Hz, 1H), 7.10-7.04(m, 2H), 6. 96(dd, J=5.6, 2.5Hz, 1H), 5.00(dt, J=11.4, 7.0Hz, 1H), 4.78(dd, J=9.7, 7.0 Hz, 1H), 4.34(dd, J=11.4, 9.7Hz, 1H), 3.54(s, 2H), 3.53(s, 3H), 1.34(s, 6H).

[0216] (S)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-31) [ka] 1 H NMR (400MHz, CD2Cl2) δ 8.74(d, J=7.2Hz, 1H), 8.47(dd, J=5.6, 0.5Hz, 1H), 7.56(dd, J=2.6, 0.5Hz, 1 H), 7.49-7.40(m, 2H), 7.31-7.25(m, 3H), 7.14-7.08(m, 3H), 6.98(dd, J=5.6 , 2.6Hz, 1H), 4.97(dt, J=11.2, 7.3Hz, 1H), 4.69(dd, J=9.7, 7.3Hz, 1H), 4.25 (dd, J=11.3, 9.7Hz, 1H), 3.48(s, 2H), 3.40(s, 3H), 1.87(s, 1H), 1.29(s, 6H). HRMS (TOFMS ES+) accurate mass C 28 H 27 N3O5485.1951, actual value 486.2024.

[0217] (S)-N-(8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-8) [ka] 1H NMR (400MHz, CDCl3) δ 8.91(d, J=7.0Hz, 1H), 8.44(d, J=5.6Hz, 1H), 8.30(d, J=1.9Hz, 1H), 7.62(d, J=2.5Hz, 1 H), 7.51(d, J=2.0Hz, 1H), 7.41(td, J=8.9, 7.2Hz, 2H), 7.27-7.24(m, 1H), 7.12-7.03(m , 2H), 6.95(dd, J=5.6, 2.5Hz, 1H), 5.00(dt, J=11.4, 7.0Hz, 1H), 4.76(dd, J=9.7, 7.0Hz , 1H), 4.34(dd, J=11.4, 9.7Hz, 1H), 3.54(s, 2H), 3.51(s, 3H), 1.91(s, 1H), 1.33(s, 6H). HRMS (TOFMS ES+) accurate mass C 27 H 26 N4O5486.1903, actual value 487.1988.

[0218] (S)-N-(5-methyl-4-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-9) [ka] HRMS (TOFMS ES+) accurate mass C 28 H 21 N5O4491.1594, actual value 492.1680.

[0219] Kinase Inhibition In this example, the disclosed compounds were evaluated using a biochemical assay that uses ADP-Glo™ technology.

[0220] ADP-Glo™ (Promega, Madison, WI, USA) reagent was thawed at ambient temperature. Kinase detection reagent was prepared by mixing kinase detection buffer with lyophilized kinase detection substrate.

[0221] A 500 ml stock volume of 5x reaction kinase buffer was made by mixing 1000 μl 1 M MgCl2, 500 μl 1 M Tris-HCL (pH 7.4), 0.5 mg / ml (25 mg) BSA, and 3475 μl distilled H2 O. A 3 ml working stock volume of 2x reaction kinase buffer was made containing final concentrations of 100 μM DTT and 4 mM MnCl2.

[0222] RIPK1 enzyme (Rigel Pharmaceuticals, South San Francisco, CA, USA) components were thawed on ice. RIPK1 was diluted in 1x kinase reaction buffer (diluted from 2x buffer) to 31 ng / well. A working stock ATP assay solution of 166 μM was prepared in 1x kinase reaction buffer (diluted from 2x buffer).

[0223] Compounds were serially diluted in DMSO starting at 250uM in 4-fold dilutions, then diluted 1:5 in 2x reaction buffer in a 96-well plate. 1.0ul of diluted compound was added to a duplicate 384-well plate. 2ul of diluted active RIPK1 was added to the 384-well plate (not to column 1) and 2x rxn buffer was added to column 1. 150nM AKT (Anaspec, Fremont, CA, USA) was combined with an equal volume of ATP working stock and added 2ul / well to the 384-well plate. The final reaction volume was 5.0ul.

[0224] The plate was quickly centrifuged and the reaction was incubated at 30° C. for 30 minutes. 5 μl of ADP-Glo™ was added to terminate the reaction. The plate was quickly centrifuged and the reaction was incubated at room temperature for 40 minutes. Kinase detection reagent was then added and incubated at room temperature for 30 minutes. Relative light units (RLU) of the kinase reaction were determined by luminescence (Luminescence 0.1s) using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, MA, USA). ICs obtained from this example 50 The values ​​are provided in Table 1. [Table 2-1] [Table 2-2] [Table 2-3]

[0225] Whole Cell Assay Data In this example, U937 and L929 cells were exposed to compounds of the present disclosure and a cell necroptosis assay was performed to evaluate the activity of the compounds against human RIP1 and mouse RIP1.

[0226] U937 and L929 cells were obtained from the American Type Culture Collection (Manassa, VA, USA). Both cells were maintained in logarithmic growth phase in complete RPMI 1640 medium (Sigma, ST Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis, MO, USA) at 37 °C with 5% CO2. For necroptosis assays, L929 cells in 100 μL / well medium were seeded at 10K cells / well in Costar 96-well black clear-bottom plates (Fisher Scientific, Hampton, NH, USA) for 18 h, and on the day of the assay, U937 cells were seeded at 50K cells / well in 50 μL / well medium containing 60 uM zVAD-fmk (Lonza, Basel, Switzerland). The L929 cell medium was removed from the 96-well plate and replaced with 50 μL / well of fresh medium containing 40 uM zVAD-fmk. Each compound of the present disclosure evaluated in this example was serially diluted in DMSO starting at 2.5 mM in 4-fold dilutions and then diluted 1:125 in complete medium. 50 μL / well of 2× compound was then added to the cells in the plate. Cells were pre-incubated with compound for 1 hour at 37° C. with 5% CO2, after which 10 μL / well of 11× TNFa (Peprotech, Rocky Hill, NJ, USA) was added to bring the final concentration of TNFa to 2 ng / mL. The relative amount of necroptotic cells was determined by luminescence using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, MA, USA) and CellTiter-Glo® Luminescent Cell Viability Reagent Assay (Promega, Madison, WI, USA) added according to the manufacturer's instructions at 37°C, 5% CO2, 18 hours after TNFa stimulation. The results of this example are summarized in Table 2. This example establishes that embodiments of the compounds described herein have unexpectedly potent activity against human RIP1 and mouse RIP1, allowing their evaluation in an in vivo mouse model of disease. These results are useful for determining safe and effective dosing in humans. [Table 3-1] [Table 3-2]

[0227] Acute in vivo assays In this example, an acute hypothermia mouse model assay was used to evaluate the ability of compounds disclosed herein to inhibit TNF-alpha induced hypothermia.

[0228] Female C57BL / 6 mice are randomly divided into groups and weighed on day 1. On the day of the study (day 0), mice are gavaged with vehicle or test article. 15 minutes after oral administration of the test agent, each mouse is administered an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor alpha (TNF-a, 25.0 μg) and zVAD-FMK (200 μg). Body temperature is measured at time 0 (before IP injection) and every hour via a rectal probe temperature measurement device. Three hours after IP injection of TNF-a and zVAD / FMK, mice are euthanized by CO2 asphyxiation and blood is collected via cardiac puncture. Serum and plasma are collected for determination of cytokine and compound levels, respectively. A separate group of mice (satellite mice) is included to determine compound levels in plasma upon administration of TNFa / zVAD-FMK. Compounds of the present disclosure inhibited TNF-alpha-induced hypothermia.

[0229] Brain penetration Certain embodiments of the invention provide a compound, a plurality of compounds, or compositions thereof, for crossing the blood-brain barrier. Disclosed compound and composition embodiments exhibit sufficient brain penetration as a potential therapy in neurological disorders. Brain penetration can be assessed by evaluating the brain / plasma ratio (B / P) measured through in vivo pharmacokinetic studies in rodents and determining the rodent brain free fraction in vitro. As an example, compound I-44 exhibited a B / P ratio of 1.6 and compound I-58 exhibited a B / P ratio of 0.44. Other examples exhibited higher distribution ratios. Without being bound by theory, it is believed that compounds with higher brain / plasma distribution ratios may be more pharmacologically active against neurological disorders. Other methods for assessing brain penetration are known to those of skill in the art. See, for example, Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008. 1I-MDR1 permeability. In this method, passive membrane permeability (Papp) and P-gp (P-glycoprotein) substrate efflux potential are determined using the MDCKII-MDR1 cell line as an in vitro model of effective permeability of compounds through the BBB. Compounds with an MDCKII-MDR1 efflux ratio of 2.5 or less may exhibit the ability to cross the blood-brain barrier.

[0230] Brain free fraction is a predictive marker for evaluating potential therapeutic potential in the CNS. See Read KD; Braggio S. Assessing brain free fraction in early drug discovery. Expert. Opin. Drug. Metab. Toxicol. 2010, 6, 337-344.

[0231] Thus, brain-free fractions of representative compounds are provided in Table 3. [Table 4]

[0232] Determination of the ineffective fraction is known to enable one of skill in the art to determine the ineffective fraction for additional compounds disclosed herein. See Srinivas, Nithya et al. "Clinical Pharmacokinetics and Pharmacodynamics of Drugs in the Central Nervous System." Clinical pharmacokinetics vol. 57, 9 (2018): 1059-1074. doi: 10.1007 / s40262-018-0632-y. The ineffective fractions reported in Table 3 indicate that the exemplary compounds exhibit the characteristics of CNS active compounds.

[0233] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are merely preferred examples of the invention and should not be construed as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

1. A compound according to formula I, 【Chemistry 1】 wherein Ring B is a 5- or 6-membered heteroaryl; X is CH ２ or O, L is a heteroatom or R ａ where R ａ is not hydrogen, Z is C １－１０ Aliphatic (C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－６ cycloalkyl, each of which optionally has one or more R ５ aryl or heteroaryl substituted with a group; R １ is, independently for each occurrence, -NR ｄ R ｄ In the formula, two R ｄ The groups, together with the nitrogen to which they are attached, are ３－１０ Heterocyclic group, -C≡CH, or -linker-R ６ group, said linker being a divalent C １－１０ Aliphatic moiety (C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ alkynyl, etc.) or C １－１０ is an alicyclic moiety, R ６ But, R ｂ , -C(R ｆ ) ３ , or -C(R ｆ ) = C(R ｆ ) ２ each linker optionally containing one or more halo, R ａ , or C substituted with ５－１０ Aromatic or C ３－６ is heterocyclic, R ２ and R ３ But independently, R ａ and R ４ and R ５ is expressed independently for each occurrence as R ｅ and R ａ independently for each occurrence: hydrogen, C １－１０ aliphatic, C １－１０ Haloaliphatic, C ５－１０ Aromatic or C ３－６ is heterocyclic, R ｂ independently for each occurrence, -OH, -SH, -OR ｃ , -SR ｃ , -NR ｅ R ｅ , -Si(R ａ ) ３ , -C(O)OH, -C(O)OR ｃ or -C(O)NR ｅ R ｅ and R ｃ independently for each occurrence, (1, 2, or 3 R ｅ Optionally substituted with １－１０ alkyl, (1, 2 or 3 R ｅ Optionally substituted with ２－１０ alkenyl, (1, 2 or 3 R ｅ Optionally substituted with ２－１０ alkynyl, (1, 2 or 3 R ｅ Optionally substituted with ３－６ cycloalkyl, or (1, 2, or 3 R ｅ Optionally substituted with ５－１０ It is aromatic, R ｄ 1, 2, or 3 R ａ , R ｂ and / or R ｅ C optionally substituted with a group １－９ It is aliphatic, R ｅ independently at each occurrence, oxo (=O), -OR ａ , N(R ａ ) ２ , Haro, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Heteroalkyl, C ３－６ cycloalkyl or two R ｅ The two R ｅ C having a nitrogen atom to which a group is bonded ３－１０ providing a heterocyclic group, m is 1 to 4; A compound wherein n is 0, 1, or 2.

2. 13. A method of inhibiting RIP kinase, comprising contacting said kinase with a compound of claim 1.

3. The compound of claim 1 , wherein Ring B is a 5- or 6-membered heteroaryl.

4. The compound of claim 1 , wherein Ring B is a 5-membered heteroaryl.

5. The compound of claim 4, wherein Ring B is a triazole, diazole, oxazole or oxadiazole.

6. Ring B is pyrazolyl, -N(R ３ 2. The compound of claim 1, wherein the C(O)- moiety is attached to Ring B at a ring nitrogen atom on Ring B.

7. The compound of claim 1 , wherein Ring B is a 6-membered heteroaryl.

8. The compound of claim 7, wherein Ring B is pyridinyl.

9. R ２ But, C １－６ The compound of claim 1 , wherein the aryl group is an alkyl group.

10. R ２ The compound of claim 1 , wherein is methyl.

11. R ２ But, CD ３ 11. The compound of claim 10,

12. R ３ The compound of claim 1 , wherein

13. The compound of claim 1 , wherein n is 0.

14. The compound of claim 1 , wherein n is 1.

15. At least one R ４ But, C １－６ The compound of claim 1 , wherein the aryl group is an alkyl group.

16. At least one R ４ The compound of claim 1 , wherein is fluoro.

17. R ４ But, C １－６ 15. The compound of claim 14, which is alkyl or fluoro.

18. The compound of claim 1 , wherein X is O.

19. X is -CH ２ The compound according to claim 1, wherein

20. The compound of claim 1 , wherein L is a heteroatom.

21. The compound of claim 13 , wherein L is O.

22. L is C １－６ The compound of claim 1 , wherein the aryl group is an alkyl group.

23. Formula II 【Chemistry 2】 2. The compound of claim 1 having the formula:

24. Formula IIA 【Chemistry 3】 2. The compound of claim 1 having the formula:

25. having the formula IIB, IIC, IID or IIE, 【Chemistry 4-1】 【Chemistry 4-2】 2. The compound of claim 1, wherein each W is independently N or O.

26. Formulas IIF, IIG, IIH 【Chemistry 5】 2. The compound of claim 1 having the formula:

27. Formula IIK 【Chemistry 6】 2. The compound of claim 1 having the formula:

28. The compound of claim 1 , wherein m is 1.

29. At least one R １ The compound of claim 1 , wherein is a halogen.

30. At least one R １ -Linker-R ６ 2. The compound of claim 1,

31. At least one R １ 8-12 membered spiroheterocyclyl, C １－１０ Alkyl, or C ２－１０ 30. The compound of claim 29 which is an alkyne.

32. At least one R １ but the following: 【Chemistry 7-1】 【Chemistry 7-2】 【Chemistry 7-3】 2. The compound of claim 1 , selected from:

33. At least one R １ but, 【Chemistry 8】 2. The compound of claim 1,

34. At least one R １ but, 【Chemistry 9】 2. The compound of claim 1 , selected from:

35. At least one R １ but, 【Chemistry 10】 2. The compound of claim 1 , selected from:

36. The following formula: 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 2. The compound of claim 1 having the formula:

37. The following formula: 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 2. The compound of claim 1 having the formula:

38. 41. A method for treating a disease in a subject, comprising administering to the subject (i) a therapeutically effective amount of a compound according to any one of claims 1 to 38, or (ii) a pharmaceutical composition of said compound, wherein said subject has or is suspected of having or developing said disease, and wherein said disease is a disease involving receptor interacting protein-1 (RIP1) kinase.

39. 39. The method of claim 38, wherein the disease is an inflammatory or immunoregulatory disorder.

40. 39. The method of claim 38, wherein the disease is a disorder of aging.

41. The disease is amyotrophic lateral sclerosis (ALS), autoimmune syndromes, rheumatoid arthritis, type I diabetes, inflammatory bowel disease including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hypersensitivity, allergic rhinitis, spondyloarthritis, ankylosing spondylitis, autoimmune hepatitis, autoimmune hepatobiliary disease, cerebrovascular accident, allergic disease, chronic obstructive pulmonary disease, emphysema, Friedreich's ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (polyQ) disease, Fahr's disease, Menkes disease, Wilson's disease, prion disorder, bone resorption disease, destructive bone disorders such as myeloma, osteoporosis ... multiforme), linear IgA bullous dermatosis, cementodermatitis, gingivitis, periodontitis, gingival, alveolar bone, dental cemental lesions, sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lipopathy, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burns, Behçet's disease, uveitis associated with Behçet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigoid, Mooren's ulcer, scleral inflammatory bowel disease, Falk-Koyanagi-Harada disease, hematological disorders, hematological malignancies, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, anaplastic carcinoma, papillary carcinoma, seminoma, melanoma, ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or asymptomatic multiple myeloma, leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, chronic myelogenous leukemia (CML), primary effusion lymphoma,Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, disorders caused by IL-1, disorders caused by MyD88, drug-resistant malignancies such as JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies, e.g. ibrutinib-resistant hematological malignancies, ibrutinib-resistant CLL, and ibru-resistant Waldenstrom's macroglobulinemia. angiogenic disorders including solid tumors, ocular angiogenesis, hemangiomas such as infantile hemangiomas; sepsis, septic shock, shigellosis; migraine, bronchitis, gastric ulcers, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, associated fever syndromes associated with interleukin-1 converting enzyme, periodic syndromes associated with tumor necrosis factor receptor, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex complex) deficiency syndrome, lysosomal storage disease, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Ni fibrotic conditions such as CMV retinitis, non-alcoholic steatohepatitis, and cardiac conditions such as ischemia-reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,Autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, rubella arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterized by massive neutrophil infiltration; ankylosing spondylitis, gouty arthritis, psoriatic arthritis, and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgia due to infection, keloid formation, scar tissue formation, fever, influenza, chronic myelogenous Leukemia; angiogenesis disorders including solid tumors; acute hepatitis infections (including Hepatitis A, Hepatitis B, and Hepatitis C), AIDS, ARC or malignant tumors, viral diseases including herpes; stroke, myocardial infarction, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardial ischemia, ischemia in heart attacks, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, ischemia-reperfusion injury of organs occurring during storage, transplantation, or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, prostaglandin endoperoxides Synthase 2 associated conditions, pemphigus vulgaris, autoimmune / polymyositis, dermatomyositis, vitiligo vulgaris, photoallergic sensitivity, ischemia-reperfusion injury, cardiac ischemia-reperfusion injury resulting from myocardial infarction, multiple system atrophy, Parkinson's plus syndrome, frontotemporal dementia, intracranial hemorrhage, cerebral hemorrhage, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, demyelinating diseases, systemic juvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, antiphospholipid syndrome ( APS), primary sclerosing cholangitis (PSC), kidney transplant, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), ARDS resulting from COVID-19, post-infectious autoimmune diseases, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accidents (CVA), chronic obstructive pulmonary disease (COPD), NEMO deficiency syndrome (F-kappa-B essential modulator gene (also known as IKK gamma or IKKG) deficiency syndrome), solid organ malignancies, lysosomal storage diseases, glaucoma,Retinal degenerative diseases, retinal ischemia / reperfusion injury, renal ischemia-reperfusion injury, cataract, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scar, anthrax lethal toxin-induced septic shock, LPS-induced cell death, infectious encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic scleroderma, macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, adult vitelliform nematode vitelliform disease, pattern dystrophies, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, toxic retinitis and light-induced toxicity, macular edema, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophies, optic nerve injury, optic neuritis, optic neuropathy, retinal central membranous artery occlusion, ischemic optic neuropathy (e.g., arterial or non-arterial anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, dominant optic neuropathy, Beer's syndrome, Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paraplegia, subarachnoid hemorrhage, perinatal brain injury injury, subclinical brain injury, spinal cord injury, anoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia, and hypoxic hypoxia, peritoneal damage caused by peritoneal dialysis fluid (PDF) and PD-related side effects, glomerular disease, tubulointerstitial disease, interstitial nephritis, obstruction, polycystic kidney disease), focal glomerulosclerosis, immune complex nephropathy, diabetic nephropathy, Goodpasture's syndrome, hepatocellular carcinoma, pancreatic cancer, urinary cancer, bladder cancer, colorectal cancer, cancer, colon cancer, breast cancer, prostate cancer, prostatic hyperplasia, renal cancer, kidney carcinoma, liver carcinoma, adrenal carcinoma, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, stomach cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., brain carcinoma, glioma, anaplastic oligodendroglioma, adult glioblastoma, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion,Malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic neoplasm, epithelial neoplasm, gastric carcinoma, ovarian carcinoma, rectal carcinoma, prostate carcinoma, pancreatic carcinoma, lung carcinoma, vaginal carcinoma, cervical carcinoma, testicular carcinoma, genitourinary carcinoma, esophageal carcinoma, laryngeal carcinoma, skin carcinoma, bone carcinoma, thyroid carcinoma, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, colon carcinoma, colorectal adenoma, vascular pericyte Cysts, mucinous carcinomas, round cell carcinomas, squamous cell carcinomas, esophageal squamous cell carcinomas, oral carcinomas, vulvar cancer, adrenal cortex cancer, ACTH-producing tumors, and leukemia, respiratory infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS virus, adenovirus, and reovirus), herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, Bacillus cereus, Vibrio parahaemolyticus, Enterohemorhagic Escherichia coli, Staphylococcus aureus, MRS Bacterial infections such as Salmonella, Botulinus, Candida, Paget's disease, achondroplasia, osteoporosis, hyperparathyroidism, osteogenesis imperfecta, partial liver resection, acute liver necrosis, necrosis caused by toxins, necrosis caused by viral hepatitis, necrosis caused by shock, necrosis caused by anoxia, viral hepatitis type B, non-A / non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NAL) ASH), acetaminophen toxicity, hepatotoxicity, liver failure, fulminant hepatic failure, delayed hepatic failure, acute exacerbation of chronic liver failure, chronic kidney disease, kidney damage / injury, kidney damage / injury caused by nephritis, kidney damage / injury caused by kidney transplantation, kidney damage / injury caused by surgery, kidney damage / injury caused by administration of nephrotoxic drugs, enhancement of chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, altitude sickness,Diseases caused by histamine or leukotriene-C4 release, muscular dystrophies, pyoderma and Sézary syndrome, Addison's disease, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary oxygen or drug-induced, toxicosis, congenital hypophosphatasia, fibromatous lesions, fibrous dysplasia, bone metabolism, osteolytic bone disease, treatment of post-traumatic bone surgery, treatment after joint replacement surgery, treatment after orthopedic bone surgery, treatment after dental surgery, bone chemotherapy or bone radiotherapy, bone cancer, atherosclerotic lesions (fragile plaque), disorders, occlusive disorders, stenosis, coronary artery disorders, peripheral artery disorders, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, occlusion after graft surgery, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis 39. The method of claim 38, wherein the autoimmune idiopathic thrombocytopenic purpura (ITP), membranous nephritis, autoimmune thyroiditis, Hashimoito thyroiditis, myasthenia gravis, cold and warm agglutinin disease, Evan's syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, or a combination thereof.

42. 38. The method of claim 37, wherein the disease is atopic dermatitis, rheumatoid arthritis, or ankylosing spondylitis.

43. 38. The method of claim 37, wherein the disease is a myelodysplastic syndrome.

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