Rip1k inhibitors

Abstract

To provide compounds and methods of making and using the compounds, e.g., for inhibiting receptor-interacting protein-1 kinase ("RIP1") and for treating diseases and / or conditions related to RIP1.SOLUTION: Disclosed herein are: kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds; and pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions and / or combinations may be used to treat or prevent a kinase-associated disease or condition, particularly a RIP1-associated disease or condition.SELECTED DRAWING: None

Description

[Technical field]

[0001] 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]

[0002] 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

[0003] A compound according to the formula: [ka] During the ceremony, X is CH2, O, S, S(O), S(O)2, and NR a is selected from R a However, for each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 acyl, Y 1 , Y 2 , and Y 3 But N, N(R a ), O, C(R b ) 1-2 and C=O; R b But hydrogen, C 1-6 alkyl, and halo; Z is C(R c ) or NR c and Rc one or more R optionally interrupted by one or two heteroatoms selected from O, N, and S; 1 C optionally substituted with a group 1-4 It is an unsaturated carbon chain, R z is N, CH, or C(R 1 ) and ZR c and together with the carbon to which they are attached, m R 1 forming a 5- or 6-membered heteroaryl or 6-membered aryl ring optionally substituted with a group; R 1 But halogen, linker-R 6 group, wherein the linker is a bond, a (C-C) alkanyl, a (C-C) alkenyl, or a (C-C) alkynyl, and one or more R b and optionally substituted by R 6 But R e , -C(R f )3, or -C(R f )=C(R f )2, R 2 But R a and Ring B is a 5- to 10-membered heteroaryl; R 3 For each occurrence, R b and OR a are independently selected from L is O, NR a or alkylene, W is p R 4 is a 5-10 membered aryl or heteroaryl optionally substituted by R 4 For each occurrence, R b and OR a is selected from R d However, for each occurrence, hydrogen, C 1-6 Alkyl, aralkyl, C 5-10 aryl or heteroaryl, or two R dtogether with the nitrogen to which they are both attached, form one or more R e C optionally replaced by 3-10 Forming a heterocyclic group, R e But for each occurrence, independently, halo, -OR d , -SR d , -S(O)2R d , -NR d R d , -Si(R a )3, -C(O)OH, -C(O)OR a or -C(O)NR d R d and R f But for each occurrence, R a , R b , or R e or two R f Each of the groups, together with the carbon atom to which it is attached, can be one or more R e C optionally substituted with 3-6 Cycloalkyl group or C 3-10 providing a heterocyclic group, m is 1, 2, 3, or 4; n is 0, 1, or 2; Disclosed herein are compounds wherein p is 0, 1, 2, 3, 4, or 5.

[0004] In addition, methods and intermediates for making the compounds are disclosed, along with pharmaceutical formulations and methods for using the compounds and formulations. 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

[0005] 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.

[0006] 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.

[0007] 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.

[0008] As used herein, for example, "substituted aryl C 1-8 The term "substituted" in the term "alkyl" refers to all subsequent modifiers, and the substitution is 1-8 The alkyl group, "C 1-8It may occur in the "alkyl" portion, the "aryl" portion, or both portions.

[0009] "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.

[0010] A "substituent" or "substituent group" to replace one or more hydrogen atoms on a saturated carbon atom of a specified group or moiety. As used herein, for example, "substituted aryl C 1-8 The term "substituted" in the term "alkyl" refers to all subsequent modifiers, and the substitution is 1-8 The alkyl group, "C 1-8 It may occur in the "alkyl" portion, the "aryl" portion, or both portions.

[0011] "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.

[0012] A "substituent" or "substituent group" to replace one or more hydrogen atoms on a saturated carbon atom of a specified group or moiety described herein is 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, where 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 is, independently at each occurrence, hydrogen or R 60 And each R 80 But for each occurrence, R 70 or two R 80 Groups, together with the nitrogen atom to which they are attached, form a 3-7 membered heteroalicyclic ring, optionally containing 1-4 identical or different additional heteroatoms selected from O, N, and S, where N is H or a C1-C3 alkyl substituted or other R 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 compounds of the present disclosure, 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.

[0013] 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 + , -SO3R70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 -2 (M + )2, -PO3 -2 M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )N(R 80 )2, -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )N(R 80 )2, and R 60 , R 70 , R 80 , and M + is as defined above. In an independent embodiment, the substituent is -O- M + , -OR 70 , -SR 70 , or -S - M + isn't it.

[0014] 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 , -NR70 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.

[0015] In one embodiment, a substituted group has at least one substituent selected from those listed above up to the maximum number of substituents possible for a particular moiety, for example, 1 to 5 substituents, 1 substituent, 2 substituents, 3 substituents, 4 substituents, or 5 substituents.

[0016] 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.

[0017] 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.

[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), cyclic versions thereof, such as alicyclic groups or moieties, including cycloalkyl, cycloalkenyl, or cycloalkynyl, including linear and branched chain arrangements, as well as all stereoisomers and positional isomers. 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 3-6Cycloalkyl 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 (-CH2-CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), t-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), and neopentyl (-CH2C(CH3)3).

[0023] "Alkylene" refers to a divalent alkyl group or alkyl chain. As with the alkyl groups described above, such alkylene groups are optionally substituted with one or more of the substituents described above. By way of example, such alkylene groups include, but are not limited to, -CH2, -CH(Me), -C(Me)2, -CF2-, -CH(F), -CH2CH2-, and the like. As disclosed herein, such alkylene moieties are useful as linking groups.

[0024] Similarly, the terms "alkenylene" and "alkynylene" refer to a divalent aliphatic chain containing at least one alkene or at least one alkyne, respectively. Such alkenylene and alkynylene groups may be optionally substituted with one or more of the substituents described above.

[0025] "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.

[0026] 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.

[0027] "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 it 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 can be substituted or unsubstituted.

[0028] "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.

[0029] "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.

[0030] "Carboxyl" refers to -CO2H.

[0031] "Carboxamide" refers to --C(O)amino.

[0032] 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).

[0033] "Carboxylate" is -C(O)O - Or its salt.

[0034] "Cyano" refers to the group --CN.

[0035] "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.

[0036] "Halo," "halide," or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0037] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CH2F, -CHF2, and -CF3.

[0038] "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.

[0039] "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 or moiety can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, a heteroaryl group or moiety can be substituted or unsubstituted.

[0040] "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, in compounds having a pyridinyl ring, the corresponding pyridinyl-N-oxide is included as another compound of the disclosure 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.

[0041] "Hydroxyl" refers to the group --OH.

[0042] "Nitro" refers to the group --NO.sub.2.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] "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.

[0049] 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.

[0050] "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.

[0051] 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.

[0052] "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 present disclosure 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), etc. 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 present disclosure 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 present disclosure 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.

[0053] "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.

[0054] "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).

[0055] "Sulfanyl" refers to the groups or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic (including both -S-aryl and -S-heteroaryl).

[0056] "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).

[0057] "Sulfonyl" refers to the groups: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including both -SO2aryl and -SO2heteroaryl).

[0058] 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, preventing 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.

[0059] 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.

[0060] 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.

[0061] Those skilled in the art will understand that certain 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. Mixtures of different isomeric forms, including mixtures of enantiomers and / or stereoisomers, can be separated to provide each separate enantiomer and / or stereoisomer using techniques known to those of skill in the art who have the benefit of the present disclosure, particularly those that provide methods such as chiral HPLC for separating such mixtures. Alternatively, compounds can be synthesized in enantiopure or enantiopure form, as known to those of skill in the art of organic synthesis. In the case of limited rotation, for example around an amide bond or between two directly bonded rings such as pyridinyl rings, biphenyl groups, etc., atropisomers are also possible and are also specifically included in the disclosed compounds.

[0062] In any embodiment, any or all hydrogens present in the compound, or in a particular group or moiety within the compound, can be replaced with deuterium or tritium. Thus, the recitation of alkyl includes deuterated alkyl, where the group is enriched with deuterium relative to its natural abundance, or where from one to a maximum number of hydrogens present can be replaced with 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.

[0063] 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 are capable of selectively inhibiting RIP1 over other kinases, including over RIP2, RIP3, or both.

[0064] In some embodiments, the compounds of the present disclosure have a structure according to formula I, [ka] During the ceremony, X is a bond, CH2, O, S, S(O), S(O)2, and NR a is selected from R a For each occurrence, hydrogen and C 1-6 alkyl, Y 1 , Y 2 , and Y 3 But N, N(R a ), O, C(R b ) 1-2 and C=O; R b But hydrogen, C 1-6 alkyl, and halo; Z is C(R c ) or NR c and R c one or more R optionally interrupted by one or two heteroatoms selected from O, N, and S; 1 C optionally substituted with a group 1-4 It is an unsaturated carbon chain, R z is N, CH, or C(R 1 ) and ZR c and together with the carbon to which they are attached, m R 1 forming a 5- or 6-membered heteroaryl or 6-membered aryl ring optionally substituted with a group; R 1 But halogen, linker-R 6 group, wherein the linker is a bond, a (C-C) alkanyl, a (C-C) alkenyl, or a (C-C) alkynyl, and one or more R b and optionally substituted by R 6 But R e , -C(R f )3, or -C(R f )=C(R f )2, R 2 But R a and Ring B is a 5- to 10-membered heteroaryl; R 3 For each occurrence, R b and OR a are independently selected from L is O, NR a or alkylene, W is p R 4 is a 5-10 membered aryl or heteroaryl optionally substituted by R 4 For each occurrence, R b and OR a is selected from R d However, for each occurrence, hydrogen, C 1-6 Alkyl, aralkyl, C5-10 aryl or heteroaryl, or two R d together with the nitrogen to which they are both attached, form one or more R e C optionally replaced by 3-10 Forming a heterocyclic group, R e But for each occurrence, independently, halo, -OR d , -SR d , -S(O)2R d , -NR d R d , -Si(R a )3, -C(O)OH, -C(O)OR a or -C(O)NR d R d and R f But for each occurrence, R a , R b , or R e or two R f Each of the groups, together with the carbon atom to which it is attached, can be one or more R e C optionally substituted with 3-6 Cycloalkyl group or C 3-10 providing a heterocyclic group, m is 1, 2, 3, or 4; n is 0, 1, or 2; wherein p is 0, 1, 2, 3, 4, or 5.

[0065] Those skilled in the art will understand that compounds within the scope of formula I also include their stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs unless otherwise specified. With reference to formula 1, exemplary compounds are isolated as racemic mixtures, while other compounds are synthesized and / or isolated as single enantiomers. In particular, the carbons marked with * in formula I may be in the R or S configuration.

[0066] Certain embodiments of formula I have the structures IA, IB, IC, or ID. [ka]

[0067] With reference to Formulas I, IA, IB, IC, and ID, R z is ZR c and together with the carbon to which they are attached, m R 1 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 c is optionally interrupted by 1 or 2 heteroatoms selected from O, N, and S; C 1-4 It is an unsaturated carbon chain. Thus, with continued reference to Formulas I, IA, IB, and IC, certain embodiments of the disclosed compounds have Formulas II, III, or IV. [ka]

[0068] With reference to formulas I, IA, IB, IC, ID, II, III, and IV, m is 0, 1, 2, 3, or 4, such as 1, 2, 3, or 4, and in certain cases, m is 1 or 2, such as 1. In other embodiments, m is 0 or 1. In particular embodiments of formulas I, IA, IB, IC, ID, II, III, and IV, wherein B is [ka] and m is 0, 1, 2, 3, or 4, for example, 0 or 1.

[0069] Referring to Formula IV, Z 1 is selected from C and N; Z 2 , Z 3 , and Z 4 is O, S, S(O)2, CH, N, N(R a ), and CR 1With continued reference to Formula IV, m is 0, 1, 2, or 3, and in certain embodiments of Formula IV, m is 0 or 1. In one embodiment of Formula IV, Z 2 and Z 4 At least one of the groups is CH or CR. 1 and has the formula IVA, [ka] In one embodiment of Formulas IV and IVA, Z 1 is N and Z 3 CH or CR 1 Such compounds have the formula IVB [ka]

[0070] In embodiments of the disclosed RIP1K inhibitor compounds, including those of formulas I, IA, IB, IC, ID, II and III, IV, IVA, and IVB, and those of formulas V, VA, VB, VC, VD, and VI below, R 1 In each case, the linker R 6 In such embodiments, the linker -R 6 The linker moiety is a C1, C2, C3, or C4 aliphatic group, such as a C2 alkylene, alkenylene, or alkynylene group, or a C1, C2, C3, or C4 haloaliphatic group, such as a C2 haloalkylene or haloalkenylene group. 1 The linker group in a where R a But, C 1- C4 alkylene, for example -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-, or the linker group is 2- C alkenylene, for example, -CH=CH-, -CH=CHCH2-, -CH2CH=CH-, or -CH2CH=CHCH2-, or the linker group is 2-C alkynylene, for example, -C≡C-, -C≡CCH2-, -CH2C≡C-, or -CHC≡C-CH2-. Such groups may optionally be joined by, for example, one or more R b wherein R b But, C 1-6 In some embodiments, the linker group is selected from alkyl and halo. 2- C4 haloalkenylene, for example, -CF=CH-, -CCl=CH-, -CH=CCl-, -CH=CF-, -CCl=CCl-, -CF=CF-, or -CCl=CF-, -CF=CCl-. In some embodiments, the linker group is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, -CCl=CH-, -CH=CCl-, or -C≡C-.

[0071] In some embodiments, R 1 R 6 The group is C(R f )3 and one R f But R e and R e But -OR a (e.g., hydroxyl or OMe), and R f are independent of each other, R a and R a But, C 1-4 aliphatic, preferably R f are mutually, R a and R a But for each occurrence, C 1-4 In certain embodiments, R a But methyl or CD 3 R f are mutually exclusive, R a In further embodiments, R 6 is -C(R f ) 3, wherein each R f But R a where R a is methyl or H, or f But R a where R ais methyl or R b where R b But -C(O)OR c In some additional embodiments, one R f is R e and -OR a (e.g., hydroxyl or OMe), and the other two R f The groups, taken together with the carbon atoms to which they are attached, provide alicyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or heterocyclic groups (e.g., epoxide, oxetane, tetrahydrofuran, tetrahydropyran, piperidinyl, piperazinyl, hexahydrofuro[3,2-b]furan), etc. In some such embodiments, the alicyclic and / or heterocyclic groups can be substituted, and in some particular embodiments, substituted with one or more hydroxyl groups or benzyl-carbonyl groups.

[0072] Some compound embodiments may include an alkyne. 2-4 In certain embodiments, R 1 -Linker-R 6 group, and the linker is R a where R a is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, -C≡C-, or -CH2C≡C-, and R 6 But R b where R b is -C(O)OEt or -C(O)NR d R d or -NR d R d where each R d However, each occurrence is independent of hydrogen, C 5-10 Heteroaryl, C 3-6 Cycloalkyl or both R d The groups, together with the nitrogen atom to which they are attached, form R dHeterocyclic groups are provided that may further include one or more additional heteroatoms apart from the nitrogen atom to which the group is attached. In some embodiments, one R d is hydrogen, and the other R d is one or more R, such as one of the following: e may be substituted with C 5-10 Heteroaryl: [ka] It is.

[0073] In certain embodiments of formulas I, IA, IB, IC, ID, II and III, IV, IVA, and IVB, at least one R 1 The part is [ka] [ka] It is.

[0074] In other embodiments, R 1 -NR d R d and the like, wherein two R d The group, together with the nitrogen to which it is attached, is C 3-10 In some embodiments, two R d The group, together with the nitrogen to which it is attached, is C 3-10 When heterocyclic groups are provided, in certain embodiments, C 3-10 A heterocyclic group can be formed by one or more R e group and / or both R d In addition to the nitrogen to which the group is attached, there is one or more additional heteroatoms. 3-10 The heterocyclic groups, taken together, are C 3-10 Two R's providing a heterocyclic group e is substituted with a C 3-10 Heterocyclic rings are R bWith the group, a spirocyclic group or a bicyclic group may be provided. Certain disclosed spirocyclic groups include at least two rings, each ring having a different number of atoms in the ring. In some embodiments, the spirocyclic group includes at least two rings, the first ring and the second ring of the spirocyclic group having a different number of carbon atoms, a different number of heteroatoms, or both. In still further embodiments, each ring of the spirocyclic group includes a heteroatom in the ring, each ring of the spirocyclic group may have different heteroatoms in the ring or the same heteroatom in the ring, for example, at least one oxygen atom and at least one nitrogen atom. In some embodiments, the spirocyclic group includes a first ring including a nitrogen atom and a second ring including an oxygen atom. The spirocyclic group includes a first ring coupled to a ring A phenyl group, the first ring having 3-7 atoms and the second ring having 3-7 atoms. Typically, the spirocyclic group contains more than 7 total atoms in the spirocyclic ring system, and some embodiments have spirocyclic groups containing a total of 9 atoms in the spirocyclic ring system. e C formed by the group 3-10 Heterocyclic and R b The two R's d C formed by the group 3-10 The heterocyclic group may provide a bicyclic group, for example a bicyclic group containing two or more heteroatoms within the bicyclic group, for example nitrogen and / or oxygen. The bicyclic group may be attached to the Ring A phenyl group through a nitrogen atom of the bicyclic group. In some embodiments, the bicyclic group may be a fused bicyclic group or a bridged bicyclic group.

[0075] In any or all of formulas I, IA, IB, IC, ID, II and III, IV, IVA, and IVB, and formulas V, VA, VB, VC, VD, and VI below, R 1 teeth, [ka] is selected from.

[0076] With respect to formulas I, IA, IB, IC, II, III, IV, IVA, and IVB, Y 1 , Y 2 , and Y 3is N, N(R a ), O, C(R b ) 1-2 and C=O. In one embodiment of the above formula, the disclosed compounds have the formula V: [ka] In the formula, Y 2 and Y 3 The bond between Y and Y is single or double, such as in formulas VA, VB, VC, or VD illustrated below. With continued reference to formula V, in certain embodiments, Y 2 and Y 3 In another embodiment of Formula V, Y 2 and Y 3 For example, Y 2 is CH2 and Y 3 is CHCl or Y 2 is CHCl, and Y 3 When is CH2, it is independently selected from the group consisting of CH2 and CHCl. [ka]

[0077] In another embodiment of formulas I, IA, IB, II, III, IV, IVA, and IVB, the compounds of the disclosure have formula VI. [ka]

[0078] Regarding the above formula, R 2 may be any suitable substituent, for example, R a Moieties such as hydrogen, C 1-6 Alkyl or C 1-6 R may be acyl, for example hydrogen or methyl. 2 When is methyl, the methyl moiety may be -CD3-, ie, the methyl group may be enriched with deuterium relative to its natural abundance.

[0079] With respect to formulas IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI, ring B is heteroaryl, e.g., a 5-10 membered heteroaryl group, e.g., a 5- or 6-membered heteroaryl. In some embodiments, ring B is a 5- or 6-membered heteroaryl, where the heteroaryl has one or two rings, or three nitrogen atoms, and the remaining ring atoms are carbon, e.g., pyrrole, diazole, or triazole. In other embodiments, ring B is oxazole, thiazole, or isoxazole. In certain embodiments, ring B is pyrazolyl, and in other certain embodiments, ring B is pyridinyl or pyrimidinyl. In certain embodiments, ring B is a bicyclic ring system in which at least one ring is aromatic. Examples of such bicyclic ring systems of B include, but are not limited to, dihydropyrrolotriazole, triazolopyridine, imidazolopyridine, tetrahydrotriazolopyrazine, tetrahydropyrazolopyridine, and the like. In certain embodiments, the group B has the formula: [ka]

[0080] In certain embodiments of formulas IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI where ring B is a 5-membered heteroaryl group, ring B is a group of formula [ka] where at least one W is nitrogen and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In some embodiments, the 5-membered heteroaryl group is a diazole, triazole, oxadiazole, or oxazole. Exemplary triazoles include any of the following: [ka]

[0081] Exemplary diazoles are selected from any of the following: [ka]

[0082] Exemplary oxazoles are selected from any of the following: [ka]

[0083] Exemplary oxadiazoles are selected from any of the following: [ka]

[0084] As described above with reference to I, IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI, the "B" ring is optionally selected from the group consisting of R b and OR a and so on, where each occurrence is replaced by R b But, C 1-6 It is selected from alkyl, for example methyl, and halo, for example fluoro or chloro.

[0085] With continued reference to Formulas I, IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI, L is O, N(R a ), -NR a The linker moiety may be one or more of -O-, -N(R a )- or -NR a By way of example, such a linker moiety may be -(CH2) m -R e , -(CHR a ) m -R e , -O-(CH2) m -R e, -C(O)NH-(CH2) m -R e , -C(O)NH-(CHR a ) m -R e , -O-(CH2) m -C(O)NH-(CH2) m -R e For example, -CH2, -CH(Me), -C(Me)2, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-. -CF2-, -CH(F), and one or more R b Optionally substituted cycloalkanyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0086] In formulas IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI, the W moiety is p R 4 is a 5-10 membered aryl or heteroaryl optionally substituted by a group, R 4 For each occurrence, R b and OR a In certain embodiments of the disclosed compounds, W is selected from: [ka] is selected from.

[0087] Certain disclosed exemplary compounds within the scope of one or more of formulas I, IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI are listed in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

[0088] Those skilled in the art will understand that certain compounds disclosed herein 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. Mixtures of different isomeric forms, including mixtures of enantiomers and / or stereoisomers, can be separated to provide each separate stereoisomer by techniques known to those skilled in the art and exemplified in the present disclosure. In cases of restricted rotation, for example around an amide bond or between two directly bonded rings such as a pyridinyl ring, a biphenyl group, etc., atropisomers are possible, which are simply interconverted forms of the compounds of the present disclosure.

[0089] B. Pharmaceutical Compositions In some embodiments, one or more of the compounds may be included in a pharmaceutical composition or medicament, and in some embodiments, the compounds may be in the form of a parent compound, or a pharma- ceutically acceptable salt, co-crystal, 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.

[0090] 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.

[0091] III. METHODS FOR 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.

[0092] 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.

[0093] The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof may also be useful in treating immune regulating disorders associated with bone marrow or organ transplant rejection or graft versus host disease. Examples of inflammatory and immune regulating disorders that may be treated with the compounds (or pharmaceutical compositions or combinations thereof) include 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, autoimmune syndromes including glomerulonephritis, rheumatic fever. and post-infectious autoimmune diseases including post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, hidradenitis suppurativa, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behçet's disease, keratitis, herpetic keratitis, keratoconus, dysplasia, psoriasis ... Trophia 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 enteropathy, 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 anemia), hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell aplasia, 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 sclerosis), antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, adiposity, eosinophilic fasciitis, lesions of the gums, 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 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 toxicosis, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scar, 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, Behçet'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 B, non-A / non-B hepatitis, liver cirrhosis, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic liver disease, These include, but are not limited to, alcoholic liver disease, including nonalcoholic steatohepatitis (NASH), autoimmune hepatobiliary disease, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed onset liver failure, acute exacerbation of chronic liver failure, chronic kidney disease, kidney damage / injury (e.g., caused by nephritis, kidney transplant, surgery, administration of nephrotoxic drugs, acute kidney injury), enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, or chronic bacterial infection.

[0094] In certain embodiments, the compounds are useful for treating neuropathic pain, including inflammation-induced pain.

[0095] 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).

[0096] 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 syndrome, and periodic fever syndromes, such as cryopyrin-associated periodic syndrome, familial Mediterranean fever (FMF) syndrome, Schnitzler syndrome, and TNF receptor-associated periodic fever syndrome (TRAPS), systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout flare, pseudogout, Saffo syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptor antagonists),

[0097] The disclosed RIP1K inhibitors are particularly useful for treating neurological disorders, including neurodegenerative disorders, as described above. By way of example, the compounds of the present invention can be used to treat Alzheimer's disease, ALS, Huntington's disease, and Parkinson's disease.

[0098] 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; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, particularly colon carcinoma or colorectal adenoma, tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, epithelial neoplasms, adenomas, adenocarcinomas, keratoacanthoma, leukemia, and leukemia. Breast cancer, 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 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 JAK inhibitors or BTK inhibitors, e.g., ibrutinib-resistant malignancies, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenstrom's macroglobulinemia.

[0099] Although CMML has certain clinical and pathological features of both myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDS), it is separated by the World Health Organization (WHO) into 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, the diagnosis of CMML currently requires a minimum 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 for which the WHO diagnostic criteria (i.e., 1×10 9 and identifying a subject with persistent peripheral blood monocytosis of ≥ 100 / 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.

[0100] 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.

[0101] 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").

[0102] 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).

[0103] 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.

[0104] Additional diseases or disorders that may be treated and / or prevented using the compounds and compositions of the invention include axial spondyloarthritis, e.g., spondyloarthritis including ankylosing spondylitis, SoJIA, autoimmune hepatitis, autoimmune hepatitis-related diseases, autoimmune ITP, cerebrovascular accidents, myocardial infarction, allergic diseases, chronic obstructive pulmonary disease, cardiac infarction, HIV-associated dementia, glaucoma, Friedreich's ataxia, Lewy body disease, spinal cord injury, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, prion disorders; bone-destroying disorders, e.g., bone resorption disorders, bone disorders associated with multiple myeloma; proliferative disorders, e.g., acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders, e.g., solid tumors, ocular neovascularization, and breast cancer. angiogenic disorders including infantile hemangiomas; infectious diseases such as sepsis, septic shock, and shigellosis; neurodegenerative diseases such as metastatic melanoma, HIV infection and CMV retinitis, fibrotic conditions such as non-alcoholic steatohepatitis, and cardiac conditions such as ischemia-reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft versus host. Diseases, inflammatory responses induced by endotoxins, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, rubella arthritis, acute synovitis, pancreatic beta cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, allograft rejection, fever and muscle pain due to infection, keloid formation, scar tissue formation, ulcerative colitis, heartburn, influenza, chronic myeloid leukemia; angiogenic disorders including solid tumors; acute hepatitis infection (including hepatitis A, B, and C), AIDS, ARC or malignant tumors, viral diseases including herpes; stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthase 2, pemphigus vulgaris,Ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury resulting from stroke, 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, spondyloarthritis, systemic juvenile idiopathic arthritis (SoJIA), systemic lupus erythematosus (SLE), Sjögren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), kidney transplant, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA), pulmonary sarcoidosis, interleukin-1 converting enzyme (also known as caspase-1) Fever syndromes associated with ICE, chronic obstructive pulmonary disease (COPD), periodontal disease, NEMO deficiency syndrome (F-kappa-B essential modulator gene (also known as IKK gamma or IKKG) deficiency syndrome), hematologic and solid organ malignancies, lysosomal storage disorders, glaucoma, spondyloarthritis, retinal degenerative diseases, retinal ischemia / reperfusion injury, renal ischemia / reperfusion injury, anthrax toxin-induced septic shock, LPS-induced cell death, infectious encephalopathy, encephalitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic lupus erythematosus, macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease vitelliform disease), pattern dystrophies, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity, macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophies, optic nerve injury, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, ischemic optic neuropathy (e.g., arterial or non-arterial anterior ischemic optic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber's optic neuropathy), nutritional, toxic and hereditary optic neuropathy, dominant optic atrophy, Beer's syndrome,Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paraplegia, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, anoxic-ischemic brain injury, 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, obstruction, polycystic kidney disease), focal glomerulosclerosis, immune complex nephropathy, hepatocellular carcinoma, pancreatic cancer, urinary tract cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, renal cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult human glioblastoma, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic neoplasm, hemangiopericytoma, mucinous carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral carcinoma, vulvar carcinoma; cancer of the adrenal cortex, ACTH-producing tumors, lymphoma, and leukemia; respiratory tract infections caused by viruses, e.g., influenza virus, rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, adenovirus, reovirus, etc.), herpes zoster caused by herpes viruses, diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infections, e.g., Bacillus cereus, Vibrio parahaemolyticus, Enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRS A, Salmonella, Botulinus, Candida, Paget's disease, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, congenital hypophosphatasia, fibromatous lesions, fibrous dysplasia, bone metabolism, osteolytic bone disease, periodontal disease, post-operative treatment of traumatic bone, post-operative treatment of prosthetic joints, post-operative treatment of orthopedic bone, post-operative treatment of therapeutic dental surgery, bone chemotherapy treatment or bone radiotherapy treatment, bone cancer, vulnerable plaque, disorders, occlusive disorders, stenosis, coronary artery disorders, peripheral artery disorders, arterial occlusion, aneurysm formation, aneurysm formation after trauma, restenosis, graft occlusion after surgery, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis,These include autoimmune thyroiditis, cold and warm agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), and pemphigus vulgaris.

[0105] B. Therapeutic Combinations Those skilled in the art will understand that the above conditions for treatment with the RIP1K inhibitors of the present disclosure may benefit from treatment with one or more additional therapeutic agents in combination with the RIP1K inhibitor. Indeed, the RIP1K inhibitor compounds described herein may be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to or in combination with other established therapies. The compound or compounds, or a composition containing the compound (or compounds), may be administered once or 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 comprising 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 independently overlap with each other. 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.

[0106] 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.

[0107] The compounds described herein may be administered in combination with other anti-inflammatory or immunomodulatory agents for any of the above indications, including oral or topical corticosteroids, anti-TNF agents, 5-aminosalicylic acid and mesalamine modifiers, hydroxychloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors; anti-inflammatory biologics, including anti-IL6 biologics, anti-IL1 agents, anti-IL17 biologics, anti-CD22, anti-integrins, anti-IFNα, anti-CD20, or anti-CD4 biologics; and other cytokine inhibitors or biologics against T cell or B cell receptors or interleukins.

[0108] Particularly in the treatment of rheumatoid arthritis, the subject RIP1K inhibitors are useful in combination with ibuprofen, naproxen, prednisone, methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, abatacept, adalimumab, anakinra, baracitinib, certolizumab, etanercept, fostamatinib, golimumab, infliximab, rituximab, tocilizumab, and tofacitinib.

[0109] 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.

[0110] In one aspect, the compounds are useful for blocking cytokine responses. Overproduction of proinflammatory cytokines can cause a "cytokine storm" during which inflammation spreads throughout the body via the circulation. These cytokines include interferons, interleukins, chemokines, colony stimulating factors, and tumor necrosis factors, and are produced in immune responses. Overproduction of these cytokines can result in a condition called cytokine response syndrome or CRS. The compounds can be used to inhibit the production of cytokines, thus ameliorating their destructive effects in CRS. CRS can occur during treatment with therapies in which cells express recombinant receptors, such as chimeric antigen receptors (CARs), and / or other transgenic receptors, such as T cell receptors (TCRs). Thus, the compounds are useful in combination with CAR-T therapies. Exemplary CAR-T therapies for use in combination with the compounds include activated T cells, antibodies, including those that activate T cells, YESCARTA, and KYMRIAH is a commercially available example. CRS can also occur in response to severe bacterial and viral infections. Specifically, the result of CRS in response to COVID-19 is acute lung injury, which can lead to severe lung damage resulting in a condition known as acute respiratory distress syndrome. In one embodiment, the compounds of the present invention are used in patients with or suspected of having COVID-19 to inhibit CRS. In this context, the compounds can be used in combination with antiviral agents such as remdesivir. Similarly, the compounds can be used in combination with antibiotics to regulate CRS associated with bacterial infection.

[0111] 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.

[0112] 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.

[0113] 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).

[0114] 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).

[0115] 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.

[0116] 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.

[0117] Additional chemotherapeutic agents useful in combination with the present compounds include proteasome inhibitors, such as bortezomib, carfilzomib, and marizomib.

[0118] 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.

[0119] In other embodiments, the second therapeutic agent may be selected from any of the following: Analgesics-morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone; Antibiotics - aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, cef tazidime, 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., azoxymethylene ... threonam), 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), Polypeptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., 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, ethionamivir sulphate, tetracyclines ... amide, isoniazid, 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; Antibodies - anti-TNF-α antibodies, e.g., infliximab (Remicade™), adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g., rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1 antibodies, e.g., anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, e.g., nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fretikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab; Anticoagulants--warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin; Anti-inflammatory agents - steroids such as budesonide, non-steroidal anti-inflammatory agents such as aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin; Immunosuppressants - 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 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.

[0120] 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. EXAMPLES

[0121] IV. METHODS FOR MAKING COMPOUNDS The disclosed compounds can be prepared by any suitable method as would be understood by one of skill in the art. An overview of the assembly of the tricyclic core portion of the compounds is provided in Scheme 1 below. [ka]

[0122] Scheme 2 provides an overview of another method for synthesizing the RIP1K inhibitor compounds disclosed herein. Scheme 2: General method for forming tricyclic rings [ka]

[0123] Scheme 3 provides an overview of methods for functionalizing the tricyclic intermediates described herein. Such methods include those comprising the R 1 Moiety, B ring, and R 3 , L and W groups. [ka]

[0124] One exemplary suitable method is provided below with reference to specific compounds in the Examples and described in Scheme 4. This Example provides a general method for linking a tricyclic core molecule (prepared as described in Scheme 1) to the B ring described in Formula I. Scheme 4: General method for amide formation [ka] Referring to Scheme 4, a stirred mixture of amine / amine hydrochloride (1 equiv.), aryl / heteroaryl acid / salt (1.2 equiv.), and HATU (1.3-1.4 equiv.) in dry DMF (0.3-0.8 mL / 0.1 mmol) was degassed under vacuum and back-filled with argon. After three degassing cycles, i-Pr2NEt (4-7 equiv.) was added to the above stirred mixture at 0.05° C. for 1 hour. 0 C or at room temperature and stirred until the amine was consumed. The reaction solution was worked up in one of the following ways: a) dilution with ice water followed by a standard extractive workup using either EtOAc or CH2Cl2, b) concentration of the reaction solution to dryness followed by a standard workup, or c) dilution of the crude concentrate with ice water, sonication, and allowing the slurry to warm to room temperature and filtering to give a crude grey / dark solid after drying by suction. Purification of the crude material from either of the workup methods by normal phase silica gel or reverse phase chromatography provided the respective amide compounds. (Yields: 31-82%).

[0125] With reference to Schemes 1, 2, 3, and 4, the variables X, Y 1 , Y 2 , Y 3 and Z are as previously described herein, and P is a protecting group known to those of skill in the art and further exemplified herein. R is R as described herein. 1 The moiety or precursor thereof may be one or more of any suitable substituents known to those of skill in the art.

[0126] Scheme 5 describes a method for halogenating certain intermediate compounds to produce the RIP1K inhibitors described herein. Scheme 5: General method for the chlorination of the imidazole ring of the 5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepine core. [ka]

[0127] Referring to Scheme 5, a mixture of 5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepine core (0.1 mmol), N-chlorosuccinimide (0.11 mmol), and dry acetonitrile (1 mL / 0.1 mmol) was added to 50 mL of 10 ... 0 The mixture was stirred at RT overnight, diluted with water and filtered. The solid on the funnel upon drying was dissolved in CH2Cl2 and loaded onto a silica gel column. Flash silica gel column chromatography purification provided the dichloro-substituted compound (fast elution) and the monochloro-substituted compound (slow elution), respectively.

[0128] The following compounds were synthesized using methods disclosed herein and known to those skilled in the art of organic synthesis and medicinal chemistry.

[0129] I-1(±)-5-Benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 7.94(d,J=9.0 Hz,1H),7.45-7.17(m,9H),7.11(d,J=1.4 Hz,1H),6.70(s,1H),5.32-5.21(m,1H),4.11(s,2H),2.76-2.66(m,2H),2.58-2.48(m,1H),2.22(td,J=11.7,7.6 Hz,1H).LCMS: Purity 95%, MS(m / e)385(M+H) + .

[0130] I-2(±)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-4-phenylpyrimidine-2-carboxamide [ka] 1H NMR(400 MHz,chloroform-d)δ 9.44(d,J=7.5 Hz,1H),8.93(d,J=5.3 Hz,1H),8.25-8.16(m,2H),7.81(d,J=5.3 Hz,1H),7.62-7.50(m,3H),7.44-7.29(m,4H),7.23(d,J=1.4 Hz,1H),7.18(d,J=1.4 Hz,1H),5.22(dt,J=10.2,7.7 Hz,1H),3.19-3.05(m,1H),2.74(ddd,J=14.0,6.7,2.0 Hz,1H),2.64(td,J=13.1,7.4 Hz,1H),2.27-2.14(m,1H).LCMS: Purity 99%, MS(m / e)382(M+H) + .

[0131] I-6(±)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-5-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.69(d,J=7.5 Hz,1H),7.84(s,1H),7.44-7.30(m,6H),7.28-7.19(m,2H),7.17(d,J=1.4 Hz,1H),6.15(app q,J=17.7 Hz,2H),5.10(dt,J=10.4,7.6 Hz,1H),3.02(tt,J=12.6,7.2 Hz,1H),2.82-2.58(m,2H),2.28-2.16(m,1H).LCMS: Purity 98%, MS(m / e)454(M+H) + .

[0132] I-7(±)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.44(d,J=7.7 Hz,1H),7.95(s,1H),7.46-7.27(m,7H),7.20(d,J=1.4 Hz,1H),7.15(d,J=1.4 Hz,1H),5.71(s,2H),5.15(dt,J=10.5,7.7 Hz,1H),3.10-2.95(m,1H),2.73-2.56(m,2H),2.17(app td,J=11.1,7.2 Hz,1H).LCMS: Purity 98%, MS(m / e)454(M+H) + .

[0133] I-9(±)-5-Benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)isoxazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.10(d,J=7.4 Hz,1H),7.41-7.25(m,8H),7.25-7.21(m,2H),7.19(d,J=1.4 Hz,1H),7.13(d,J=1.4 Hz,1H),6.33(t,J=0.8 Hz,1H),5.06(dt,J=10.3,7.6 Hz,1H),4.11(s,2H),2.97(tdd,J=12.7,7.8,6.8 Hz,1H),2.70(ddd,J=14.0,6.8,1.8 Hz,1H),2.60(td,J=13.2,7.5 Hz,1H),2.19-2.09(m,1H).LCMS: Purity 98%, MS(m / e)385(M+H) + .

[0134] I-14(±)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide [ka] LCMS: 98% purity, MS(m / e)403(M+H)+ .

[0135] I-19(±)-5-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.03(br s,1H),7.44-7.29(m,6H),7.19-7.10(m,2H),6.91(s,1H),5.14(dt,J=10.7,8.0 Hz,1H),4.48(s,2H),2.87-2.71(m,2H),2.57(app td,J=13.2,7.3 Hz,1H),2.32-2.22(m,1H).LCMS: 98% purity, MS(m / e)454(M+H) + .

[0136] I-27(±)-1-(2,6-dichlorobenzyl)-N-(6,7-dihydrobenzo[b]pyrrolo[1,2-d][1,4]oxazepin-7-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 7.93(d,J=0.6 Hz,1H),7.43-7.16(m,8H),7.00(t,J=2.3 Hz,1H),6.28(d,J=2.3 Hz,2H),5.66(s,2H),5.62(ddd,J=9.1,6.7,6.0 Hz,1H),4.68(dd,J=10.8,6.0 Hz,1H),4.35(dd,J=10.8,6.8 Hz,1H).LCMS: 99% purity, MS(m / e)455(M+H) + .

[0137] I-29 (±)-1-(2,6-dichlorobenzyl)-N-(4,5-dihydroimidazo[1,2-d]pyrrolo[2,1-b][1,3,4]thiadiazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.38(d,J=7.9 Hz,1H),7.96(s,1H),7.43(d,J=1.2 Hz,1H),7.41(s,1H),7.33(dd,J=8.9,7.1 Hz,1H),7.27(d,J=1.5 Hz,1H),7.16(d,J=1.5 Hz,1H),7.11(dd,J=3.2,1.7 Hz,1H),6.52(dd,J=4.0,1.7 Hz,1H),6.31(dd,J=4.0,3.2 Hz,1H),5.71(s,2H),5.22(ddd,J=10.2,7.9,6.7 Hz,1H),3.97(dd,J=11.4,6.7 Hz,1H),2.76(dd,J=11.4,10.2 Hz,1H).LCMS: Purity 99%,MS(m / e)461(M+H) + .

[0138] I-34(±)-5-Benzyl-N-(6,7-dihydrobenzo[b]pyrrolo[1,2-d][1,4]oxazepin-7-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 11.86(s,1H),7.47-7.35(m,2H),7.34-7.18(m,8H),7.02(t,J=2.3 Hz,1H),6.33-6.26(app m,2H),5.58(dt,J=8.9,6.4 Hz,1H),4.65(dd,J=10.9,6.0 Hz,1H),4.36(dd,J=10.9,6.9 Hz,1H),4.14(s,2H).LCMS: Purity 96%, MS(m / e)386(M+H) + .

[0139] I-35(±)-1-(2,6-dichlorobenzyl)-N-(2-methyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.41(d,J=7.5 Hz,1H),7.96(d,J=0.7 Hz,1H),7.47-7.20(m,7H),6.90(q,J=1.0 Hz,1H),5.71(app s,2H),5.09(dt,J=10.4,7.6 Hz,1H),3.03(tt,J=12.6,7.3 Hz,1H),2.72-2.54(m,2H),2.30(d,J=1.0 Hz,3H),2.18-2.05(m,1H).LCMS: Purity 95%, MS(m / e)468(M+H) + .

[0140] I-36(±)-1-(2,6-dichlorobenzyl)-N-(1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 8.53(s,1H),7.58(dd,J=8.0,1.4 Hz,1H),7.53-7.34(m,7H),5.79(s,2H),4.89(dd,J=10.3,8.0 Hz,1H),2.89-2.68(m,2H),2.66-2.51(m,1H),2.37-2.25(m,1H).Purity 95%, MS(m / e)471(M+H) + .

[0141] I-37(±)-N-(6,7-dihydrobenzo[b]pyrrolo[1,2-d][1,4]oxazepin-7-yl)-5-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 13.40(br s,1H),7.50(d,J=9.0 Hz,1H),7.44-7.36(m,1H),7.30-7.17(m,3H),7.17(dd,J=8.6,5.4 Hz,2H),7.02(dd,J=2.9,1.7 Hz,1H),6.91(t,J=8.6 Hz,2H),6.32-6.23(m,2H),5.55(dt,J=9.0,6.4 Hz,1H),4.63(dd,J=10.9,6.0 Hz,1H),4.36(dd,J=10.9,6.8 Hz,1H),4.12(s,2H). 19 F NMR (376 MHz, chloroform-d) δ-115.74. Purity 98%, MS (m / e) 404 (M+H) + .

[0142] I-38(±)-N-(6,7-dihydrobenzo[b]pyrrolo[1,2-d][1,4]oxazepin-7-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.06(d,J=0.9 Hz,1H),7.45-7.32(m,3H),7.37-7.29(m,1H),7.28-7.19(m,3H),7.23-7.06(m,2H),7.01(t,J=2.3 Hz,1H),6.29(app d,J=2.4 Hz,2H),5.63(ddd,J=9.1,6.9,6.0 Hz,1H),5.41(app d,J=1.2 Hz,2H),4.68(dd,J=10.8,6.0 Hz,1H),4.35(dd,J=10.8,6.9 Hz,1H).19 F NMR (376 MHz, chloroform-d) δ-118.06--118.09 (m). Purity 97%, MS (m / e) 404 (M+H) + .

[0143] I-39(±)-5-Benzyl-N-(9-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 8.10-8.06(m,2H),7.47(d,J=1.6 Hz,1H),7.44-7.36(m,3H),7.33-7.19(m,5H),7.03(d,J=1.5 Hz,1H),6.85-6.80(m,2H),5.03(dd,J=10.6,7.5 Hz,1H),4.14(s,2H),3.62(app q,J=17.3 Hz,2H),3.41(app t,J=5.2 Hz,4H),2.82-2.74(m,1H),2.74-2.62(m,1H),2.59(app t,J=5.2 Hz,4H),2.56-2.47(m,1H),2.37-2.32 9(m,1H).Purity 96%, MS(m / e)560(M+H) + .

[0144] I-40 (±)-5-Benzyl-N-(1-methyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1H NMR(400 MHz, methanol-d4)δ 7.50-7.43(m,2H),7.43-7.35(m,2H),7.33-7.17(m,5H),6.77(q,J=1.0 Hz,1H),4.88(dd,J=11.2,7.5 Hz,1H),4.14(s,2H),2.73(dd,J=13.4,6.2 Hz,1H),2.63-2.53(m,1H),2.43-2.34(m,1H),2.27-2.19(m,1H),2.22(d,J=1.1 Hz,3H).Purity 95%, MS(m / e)399(M+H) + .

[0145] I-44(±)-1-(2,6-dichlorobenzyl)-N-(1-methyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.49-8.42(app m,1H),7.91(s,1H),7.44-7.26(m,6H),7.24-7.17(m,1H),6.85(t,J=1.1 Hz,1H),5.69(s,2H),5.06-4.95(m,1H),3.01-2.87(m,1H),2.67-2.57(m,1H),2.48-2.44(m,1H),2.23(d,J=1.1 Hz,3H),2.10-1.97(m,1H).Purity 92%, MS(m / e)468(M+H) + .

[0146] I-45(±)-5-Benzyl-N-(4,5-dihydroimidazo[1,2-d]pyrrolo[2,1-b][1,3,4]thiadiazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1H NMR(400 MHz,chloroform-d)δ 9.09(s,1H),7.35-7.20(m,6H),7.18(d,J=1.6 Hz,1H),7.15(dd,J=3.3,1.7 Hz,1H),6.63(s,1H),6.50(dd,J=4.0,1.7 Hz,1H),6.31(dd,J=4.0,3.2 Hz,1H),5.29(q,J=9.1 Hz,1H),4.18(s,2H),3.74(dd,J=11.3,6.7 Hz,1H),2.80(t,J=11.2 Hz,1H).Purity 96%, MS(m / e)392(M+H) + .

[0147] I-47 (±)-1-(2,6-dichlorobenzyl)-N-(9-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.44(d,J=7.7 Hz,1H),8.28-8.21(m,2H),7.93(d,J=0.6 Hz,1H),7.41(dd,J=8.0,0.9 Hz,2H),7.36-7.24(m,4H),7.19(d,J=1.4 Hz,1H),7.12(d,J=1.4 Hz,1H),6.67-6.60(m,2H),5.70(s,2H),5.15(dt,J=10.5,7.8 Hz,1H),3.63-3.50(m,2H),3.39-3.31(m,4H),3.07-2.92(m,1H),2.68(dd,J=13.9,6.4 Hz,1H),2.62-2.52(m,5H),2.12-2.08(m,1H).Purity 97%, MS(m / e)629(M+H) + .

[0148] R955314(±)-5-Benzyl-N-(1-oxo-5,6-dihydro-1H,4H-benzo[f][1,2,4]oxadiazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 7.58(dd,J=7.9,1.4 Hz,1H),7.50-7.36(m,3H),7.36-7.16(m,5H),4.94(dd,J=10.4,8.3 Hz,1H),4.15(s,2H),2.91-2.84(m,2H),2.60-2.50(m,1H),2.48-2.32(m,1H).Purity 93%, MS(m / e)403(M+H) + .

[0149] I-51(±)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-4-phenoxypicolinamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 9.21(d,J=7.7 Hz,1H),8.46(dd,J=5.6,0.6 Hz,1H),7.65(d,J=2.6 Hz,1H),7.43-7.26(m,5H),7.25-7.19(m,2H),7.18(d,J=1.4 Hz,1H),7.15(d,J=1.4 Hz,1H),7.08-7.03(m,2H),6.93(dd,J=5.6,2.5 Hz,1H),5.07(dt,J=10.5,7.7 Hz,1H),3.01-2.92(m,1H),2.72-2.56(m,2H),2.19-2.11(m,1H).Purity 94%, MS(m / e)397(M+H) + .

[0150] I-52(±)-N-(1-oxo-5,6-dihydro-1H,4H-benzo[f][1,2,4]oxadiazolo[4,3-a]azepin-4-yl)-4-phenoxypicolinamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.53(d,J=8.8 Hz,1H),8.38(d,J=5.6 Hz,1H),7.62(d,J=2.5 Hz,1H),7.58(dd,J=7.9,1.3 Hz,1H),7.48-7.30(m,5H),7.24(app dt,J=14.9,1.2 Hz,1H),7.10-7.01(m,2H),6.95(dd,J=5.6,2.5 Hz,1H),5.10(dt,J=9.8,8.3 Hz,1H),2.91-2.80(m,2H),2.80-2.56(m,1H),2.33-2.12(m,1H).Purity 95%, MS(m / e)415(M+H) + .

[0151] I-54(±)-N-(6,7-dihydrobenzo[b]pyrrolo[1,2-d][1,4]oxazepin-7-yl)-4-phenoxypicolinamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.38-8.29(m,2H),7.66-7.61(m,1H),7.46-7.36(m,3H),7.29-7.18(m,4H),7.10-7.02(m,2H),7.00(t,J=2.3 Hz,1H),6.93(dd,J=5.6,2.5 Hz,1H),6.32-6.25(m,2H),5.54(ddd,J=9.2,7.3,6.1 Hz,1H),4.67(dd,J=10.7,6.1 Hz,1H),4.35(dd,J=10.7,7.3 Hz,1H).Purity 99%, MS(m / e)398(M+H) + .

[0152] I-55(±)-5-Benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 7.49(d,J=1.4 Hz,1H),7.43-7.36(m,3H),7.34-7.19(m,5H),7.03(d,J=1.5 Hz,1H),5.02(dd,J=10.7,7.5 Hz,1H),4.15(s,2H),2.84-2.76(m,1H),2.73-2.61(m,1H),2.52-2.48(m,1H),2.38-2.34(m,1H),1.55(s,6H).Purity 96%, MS(m / e)467(M+H) + .

[0153] I-56(±)-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-4-phenoxypicolinamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 8.49(dd,J=5.6,0.5 Hz,1H),7.51-7.37(m,7H),7.29(ddt,J=7.9,7.0,1.1 Hz,1H),7.18-7.09(m,2H),7.13-7.02(m,2H),5.02(dd,J=10.3,7.3 Hz,1H),2.84-2.66(m,2H),2.60-2.48(m,1H),2.39-2.26(m,1H),1.55(s,6H).Purity 97%, MS(m / e)479(M+H) + .

[0154] I-57(±)-5-Benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 8.84(s,1H),7.70-7.38(m,4H),7.38-7.08(m,5H),5.13(dd,J=10.6,7.9 Hz,1H),4.16(s,2H),2.90-2.81(m,1H),2.77-2.63(m,1H),2.64-2.52(m,1H),2.48-2.37(m,1H).Purity 90%, MS(m / e)386(M+H) + .

[0155] I-58(±)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.52 (s, 1H), 7.58-7.43 (m, 6H), 7.47-7.35 (m, 1H), 5.78 (s, 2H), 5.13 (dd, J = 10.5, 7.9 Hz, 1H), 2.85 (ddd, J = 13.6, 5.9, 2.2 Hz, 1H), 2.77-2.63 (m, 1H), 2.64-2.52 (m, 1H), 2.49-2.36 (m, 1H). Purity 91%, MS (m / e) 455 (M+H). + .

[0156] I-59(±)-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-4-phenoxypicolinamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 8.84(s,1H),8.50(d,J=5.6 Hz,1H),7.58-7.41(m,7H),7.33-7.24(m,1H),7.18-7.10(m,2H),7.07(dd,J=5.6,2.6 Hz,1H),5.13(dd,J=10.3,7.9 Hz,1H),2.86(ddd,J=13.5,6.2,2.3 Hz,1H),2.82-2.68(m,1H),2.68-2.55(m,1H),2.49-2.36(m,1H).Purity 90%, MS(m / e)398(M+H) + .

[0157] I-60 (±)-1-(2,6-dichlorobenzyl)-N-(2-methyl-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 7.96(s,1H),7.76(d,J=8.4 Hz,1H),7.60(dt,J=7.9,1.0 Hz,1H),7.45-7.25(m,6H),5.70(s,2H),5.08(dt,J=10.2,8.1 Hz,1H),3.52(s,3H),2.90-2.75(m,1H),2.74-2.71(m,2H),2.12-2.00(m,1H).Purity 96%, MS(m / e)485(M+H) + .

[0158] I-61(±)-N-(9-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.41(d,J=7.8 Hz,1H),7.92(d,J=0.6 Hz,1H),7.41(dd,J=8.0,0.9 Hz,2H),7.31(dd,J=8.9,7.1 Hz,1H),7.22-7.14(m,2H),7.11(d,J=1.4 Hz,1H),6.85(dd,J=8.4,2.5 Hz,1H),6.80(d,J=2.6 Hz,1H),5.70(s,2H),5.14(dt,J=10.4,7.7 Hz,1H),3.72-3.65(m,4H),3.19(dd,J=7.0,4.6 Hz,4H),3.02-2.87(m,1H),2.63-2.54(m,1H),2.48(td,J=13.3,7.4 Hz,1H),2.12-2.00(m,1H),1.74-1.66(m,4H),1.59-1.51(m,4H).Purity 99%, MS(m / e)607(M+H) + .

[0159] I-62(±)-N-(9-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-4-phenoxypicolinamide [ka] 1H NMR(400 MHz,chloroform-d)δ 9.19(d,J=7.8 Hz,1H),8.46(dd,J=5.6,0.6 Hz,1H),7.68-7.63(m,1H),7.44-7.35(m,2H),7.24-7.18(m,2H),7.15(dd,J=15.9,1.4 Hz,2H),7.09-7.04(m,2H),6.93(dd,J=5.6,2.6 Hz,1H),6.86(dd,J=8.4,2.5 Hz,1H),6.81(d,J=2.5 Hz,1H),5.09(dt,J=10.5,7.8 Hz,1H),3.72-3.65(m,4H),3.23-3.14(m,4H),2.97-2.79(m,1H),2.64-2.41(m,2H) ,2.16-2.04(m,1H),1.74-1.67(m,4H),1.57-1.53(m,4H).Purity 99%, MS(m / e)550(M+H) + .

[0160] I-63(±)-1-Benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.40(s,1H),8.37(d,J=8.1 Hz,1H),8.01(s,1H),7.46-7.31(m,7H),7.31-7.25(m,2H),5.38(s,2H),5.30(dt,J=10.4,8.1 Hz,1H),3.10-2.93(m,1H),2.83-2.67(m,1H),2.67-2.47(m,1H),2.25-2.11(m,1H).Purity 98%, MS(m / e)386(M+H) + .

[0161] I-64(±)-N-(9-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR (400 MHz, chloroform-d) δ 8.02 (d, J = 8.8 Hz, 1H), 7.33-7.26 (m, 1H), 7.30-7.23 (m, 2H), 7.26-7.18 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.4 Hz,1H),6.90-6.80(m,2H),6.76(s,1H),5.31-5.17(m,1H),4.10(s,2H),3.73-3.66(m,5H),3.24-3.17 (m,5H),2.74-2.55(m,2H),2.50-2.37(m,1H),2.21-2.09(m,1H),1.74-1.69(m,4H),1.56-1.52(m,4H). 1 H NMR(400 MHz, methanol-d4)δ 7.41(d,J=1.5 Hz,1H),7.36-7.20(m,6H),7.05-6.95(m,3H),5.05(dd,J=10.4,7.1 Hz,1H),4.16(s,2H),3.73-3.66(m,4H),3.28-3.20(m,4H),2.73-2.56(m,2H),2.49-2.36 (m,1H),2.32-2.24(m,1H),1.76-1.68(m,4H),1.60-1.53(m,4H).Purity 99%, MS(m / e)538(M+H) + .

[0162] I-65(±)-5-Benzyl-N-(1-oxo-9-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-5,6-dihydro-1H,4H-benzo[f][1,2,4]oxadiazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 11.13(br s,1H),7.61(d,J=8.9 Hz,1H),7.38-7.24(m,5H),7.15(d,J=8.5 Hz,1H),7.06(d,J=2.5 Hz,1H),6.87(dd,J=8.5,2.6 Hz,1H),5.13(q,J=9.0 Hz,1H),4.16(s,2H),3.72-3.65(m,4H),3.20(app dd,J=7.3,4.6 Hz,4H),2.76-2.59(m,3H),2.20-2.09(m,1H),1.72-1.65(m,4H),1.57-1.52(m,4H).Purity 94%, MS(m / e)556(M+H) + .

[0163] I-66(±)-5-Benzyl-N-(4,5-dihydroimidazo[1,2-a]quinolin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 7.77(d,J=1.6 Hz,1H),7.58-7.54(m,1H),7.42-7.35(m,2H),7.33-7.17(m,6H),7.10(d,J=1.6 Hz,1H),5.54(dd,J=9.2,6.1 Hz,1H),4.12(s,2H),3.35-2.87(app m,2H).Purity 95%,MS(m / e)371(M+H) + .

[0164] I-67(±)-N-(4,5-dihydroimidazo[1,2-a]quinolin-4-yl)-4-phenoxypicolinamide [ka] 1H NMR(400 MHz, methanol-d4)δ 8.43(d,J=5.6 Hz,1H),7.77(d,J=1.6 Hz,1H),7.59(d,J=2.5 Hz,1H),7.58-7.54(m,1H),7.51-7.44(m,2H),7.43-7.35(m,2H),7.34-7.27(m,1H),7.23(td,J=7.5,1.2 Hz,1H),7.17-7.13(m,2H),7.09(d,J=1.5 Hz,1H),7.05(dd,J=5.6,2.6 Hz,1H),5.48(dd,J=9.2,6.1 Hz,1H),3.38-3.24(app m,2H).Purity 96%, MS(m / e)383(M+H) + .

[0165] I-68(±)-5-Benzyl-N-(9-(3-hydroxy-3-methylbutyl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 7.97(d,J=8.5 Hz,1H),7.31-7.27(m,1H),7.26(d,J=0.9 Hz,1H),7.25-7.19(m,4H),7.17-7.14(m,2H),7.11(d,J=1.4 Hz,1H),6.72(s,1H),5.28-5.20(app m,1H),4.10(s,2H),2.80-2.62(m,5H),2.54-2.45(m,1H),2.22-2.18(m,1H),1.86-1.77(m,2H),1.31(s,6H).Purity 93%, MS(m / e)471(M+H) + .

[0166] I-72 (±)-5-Benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 8.86(s,1H),7.63(d,J=1.2 Hz,1H),7.49(s,2H),7.36-7.20(m,5H),5.15(dd,J=10.5,7.9 Hz,1H),4.17(s,2H),2.92-2.82(m,1H),2.78-2.64(m,1H),2.64-2.52(m,1H),2.50-2.38(m,1H),1.56(s,6H).Purity 98%, MS(m / e)468(M+H) + .

[0167] I-77(±)-N-(9-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1-benzyl-1H-pyrazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.11(d,J=7.9 Hz,1H),7.41-7.28(m,4H),7.24(d,J=2.0 Hz,1H),7.26-7.17(m,3H),7.15(d,J=1.4 Hz,1H),6.88(dd,J=8.4,2.5 Hz,1H),6.83(d,J=2.5 Hz,1H),6.77(d,J=2.3 Hz,1H),5.32(app q,J=17.3 Hz,2H),5.17(dt,J=10.5,7.8 Hz,1H),3.74-3.66(m,4H),3.24-3.17(m,4H),2.96-2.82(m,1H),2.65-2.56(m,1H),2.43-2.45(app m,1H),2.21-2.09(m,1H),1.75-1.68(m,4H),1.60-1.53(m,4H).Purity 95%, MS(m / e)537(M+H) + .

[0168] I-82(S)-5-Benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 7.50(d,J=1.3 Hz,1H),7.45-7.40(m,3H),7.35-7.21(m,5H),7.05(d,J=1.5 Hz,1H),5.04(dd,J=10.7,7.5 Hz,1H),4.16(s,2H),2.85-2.75(m,1H),2.74-2.65(m,1H),2.58-2.48(m,1H),2.40-2.30(m,1H),1.56(s,6H).Purity 97%, MS(m / e)467(M+H) + .

[0169] I-83(S)-N-(9-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 7.41(d,J=1.4 Hz,1H),7.36-7.18(m,6H),7.03(d,J=1.4 Hz,1H),7.02-6.97(m,2H),5.12-5.01(app m,1H),4.16(s,2H),3.75-3.64(m,4H),3.27-3.20(m,4H),2.75-2.55(m,2H),2.55-2.36( m,1H),2.36-2.17(m,1H),1.79-1.65(m,4H),1.65-1.49(m,4H).Purity 95%, MS(m / e)538(M+H) + .

[0170] I-84(±)-N-(9-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 7.39(d,J=1.4 Hz,1H),7.35-7.18(m,6H),7.02(d,J=1.4 Hz,1H),6.53(d,J=2.3 Hz,1H),6.49(dd,J=8.2,2.4 Hz,1H),5.05(dd,J=10.5,7.0 Hz,1H),4.16(s,2H),3.75-3.57(m,8H),2.72-2.53(m,2H),2.52-2.33(m,1H),2.34-2.17(m,1H),1.90-1.76(m,4H).Purity 97%, MS(m / e)510(M+H) + .

[0171] I-85(±)-N-(9-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1-benzyl-1H-pyrazole-3-carboxamide [ka] H NMR(400 MHz, methanol-d4)δ 7.70(d,J=2.4 Hz,1H),7.47(d,J=1.6 Hz,1H),7.39-7.21(m,6H),7.12(d,J=1.5 Hz,1H),6.75(d,J=2.4 Hz,1H),6.55(d,J=2.3 Hz,1H),6.51(dd,J=8.2,2.4 Hz,1H),5.40(s,2H),5.09(dd,J=10.3,7.1 Hz,1H),3.74-3.61(m,8H),2.72-2.55(m,2H),2.50-2.38(m,1H),2.38-2.22(m,1H),1.87-1.78(m,4H).Purity 96%, MS(m / e)509(M+H)+ .

[0172] I-86 (S)-N-(9-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 7.38(d,J=1.5 Hz,1H),7.35-7.20(m,6H),7.02(d,J=1.5 Hz,1H),6.52(d,J=2.3 Hz,1H),6.49(dd,J=8.2,2.4 Hz,1H),5.05(dd,J=10.5,7.0 Hz,1H),4.16(s,2H),3.73-3.61(m,8H),2.71-2.53(m,2H),2.52-2.34(m,1H),2.33-2.15(m,1H),1.84(app t,J=5.3 Hz,4H).Purity 96%, MS(m / e)510(M+H) + .

[0173] R955395(R)-N-(9-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide [ka] 1H NMR(400 MHz, methanol-d4)δ 7.50(d,J=1.5 Hz,1H),7.36-7.19(m,5H),7.14(d,J=8.7 Hz,1H),7.07(d,J=1.5 Hz,1H),6.60(d,J=2.7 Hz,1H),6.48(dd,J=8.7,2.7 Hz,1H),5.48(dd,J=9.5,7.0 Hz,1H),4.60(dd,J=10.6,7.0 Hz,1H),4.38(dd,J=10.5,9.5 Hz,1H),4.16(s,2H),3.73-3.64(m,8H),1.88-1.80(m,4H).Purity 98%, MS(m / e)512(M+H) + .

[0174] I-88(R)-N-(9-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-4-phenoxypicolinamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 9.18(d,J=7.6 Hz,1H),8.48(d,J=5.6 Hz,1H),7.66(d,J=2.5 Hz,1H),7.48-7.36(m,2H),7.30-7.22(m,2H),7.19(d,J=1.4 Hz,1H),7.17-7.12(m,1H),7.12-7.04(m,2H),6.96(dd,J=5.6,2.5 Hz,1H),6.38(app dd,J=6.7,2.7 Hz,2H),5.43(dt,J=9.8,7.2 Hz,1H),4.84(dd,J=10.1,7.0 Hz,1H),4.25(t,J=10.0 Hz,1H),3.72-3.63(m,8H),1.34-1.20(m,4H).Purity 97%, MS(m / e)524(M+H) + .

[0175] I-89(R)-5-Benzyl-N-(9-(pyridin-2-ylethynyl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 8.72(dd,J=2.1,0.9 Hz,1H),8.53(dd,J=5.0,1.6 Hz,1H),7.99(dt,J=7.9,1.9 Hz,1H),7.88(d,J=1.9 Hz,1H),7.65(d,J=1.6 Hz,1H),7.57(dd,J=8.3,2.0 Hz,1H),7.47(ddd,J=7.9,5.0,0.9 Hz,1H),7.37-7.19(m,6H),7.13(d,J=1.5 Hz,1H),5.60(dd,J=8.8,6.1 Hz,1H),4.70(dd,J=11.0,6.1 Hz,1H),4.54(dd,J=11.0,8.9 Hz,1H),4.16(s,2H).Purity 96%, MS(m / e)488(M+H) + .

[0176] I-90 (±)-5-Benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR (400 MHz, methanol-d4) δ 7.67(s,1H), 7.58(s,1H), 7.40(d,J=8.5 Hz,1H), 7.33-7.21(m,6H), 7.11(s,1H), 5.61-5.51(app m,1H), 4.67(app t,J=8.3 Hz,1H), 4.50(app t,J=10.0 Hz,1H), 4.15(s,2H), 1.56(s,6H). Purity 92%, MS(m / e) 469(M+H). + .

[0177] I-93(±)-4-(4-Fluorobenzyl)-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-pyrazole-1-carboxamide [ka] 1 H NMR(400 MHz, dichloromethane-d2)δ 8.31(d,J=7.2 Hz,1H),7.89(q,J=0.9 Hz,1H),7.49(d,J=0.9 Hz,1H),7.41-7.33(m,3H),7.25(d,J=1.5 Hz,1H),7.22-7.15(m,2H),7.13(d,J=1.4 Hz,1H),7.03-6.94(m,2H),4.87(dt,J=10.5,7.5 Hz,1H),3.81(s,2H),3.04-2.85(m,1H),2.81-2.67(m,1H),2.62-2.54(m,1H),2.25-2.13(m,1H),2.08(s,1H),1.59(s,6H). 19 F NMR (376 MHz, dichloromethane-d2) δ-117.81--117.88 (ddd, J = 14.2, 8.9, 5.4 Hz). Purity 92%, MS (m / e) 484 (M+H) + .

[0178] Chromatographic separation of enantiomers: The compounds disclosed herein may be synthesized in racemic or enantiomerically enriched form as taught herein to those skilled in the art of organic synthesis. Racemic mixtures of the compounds disclosed herein may be separated into their constituent enantiomers using the following chiral chromatographic procedures and adaptations thereof known to those skilled in the art.

[0179] I-4(S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide and I-5(R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] Chiral separation of (±)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide was performed on a Thar SFC instrument equipped with a Chiracel AD-H, 10 micron, 10×250 mm column. The mobile phase was 18% methanol (0.1% DEA) and 82% CO2 with a total flow rate of 12 mL / min. The total elution time for the enantiomeric separation was 14.3 min. A total of 61 50 μL injections were made with a sample concentration of 11 mg / mL (in methanol) using a cycle time of 4.8 min and injection stacking at 0.3 min intervals. Samples were collected by monitoring UV adsorption at 214 nm. Peak-1 (fast eluting peak) corresponds to (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide, and peak-2 (slow eluting peak) corresponds to (R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide. The solid obtained after concentrating the mixed fractions of each enantiomer was dissolved in 5% MeOH / EtOAc and passed through EtOAc-conditioned silica gel. The concentrate of the filtrate was dissolved in acetonitrile / water and lyophilized. Enantiomeric enrichment was measured by analytical method on the same instrument using Chiralcel-IA-H, 5 micron, 4.6x250mm with 20% methanol (0.1% DEA) 80% CO2 as mobile phase eluted at 3.0mL / min flow rate by injection of 15μL with concentration of 1mg / mL at detector UV wavelength of 214nm. I-4(S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide (white solid). 98.5%ee. 1H NMR(400 MHz,chloroform-d)δ 8.60(d,J=9.0 Hz,1H),7.46-7.39(m,1H),7.36-7.34(m,3H),7.28(d,J=6.9 Hz,1H),7.29-7.17(m,4H),7.10(d,J=1.4 Hz,1H),6.59(s,1H),5.30(q,J=9.5 Hz,1H),4.16(app q,J=16.1 Hz,2H),2.84-2.65(m,2H),2.57-2.49(m,1H),2.28(td,J=11.4,10.9,7.0 Hz,1H).LCMS: Purity 99%, MS(m / e)385(M+H) + I-5(R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide (white solid). 98.8% ee. 1 H NMR(400 MHz,chloroform-d)δ 8.59(d,J=9.0 Hz,1H),7.44-7.39(m,1H),7.36-7.33(m,3H),7.30-7.21(m,5H),7.10(d,J=1.4 Hz,1H),6.61(s,1H),5.36-5.15(m,1H),4.16(app q,J=16.0 Hz,2H),2.88-2.63(m,2H),2.57-2.48(m,1H),2.27(td,J=11.4,11.0,7.0 Hz,1H).LCMS: Purity 99%, MS(m / e)385(M+H) + .

[0180] I-12(R)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide and I-13(S)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] Chiral separation of (±)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide was performed on a Thar SFC instrument equipped with a Chiralcel OJ-H, 10 micron, 10×250 mm column. The mobile phase was 27% isopropyl alcohol (0.1% DEA) and 73% CO2 with a total flow rate of 10.0 mL / min. The total elution time for the enantiomeric separation was 12 min. A total of 61 injections of 40 μL were performed with a sample concentration of 25 mg / mL (in methanol) using a cycle time of 5 min and injection stacking at 0.25 min intervals. Samples were collected by monitoring UV adsorption at 214 nm. Peak-1 (fast eluting peak) corresponds to (R)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide, and peak-2 (slow eluting peak) corresponds to (S)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide. The solid obtained after concentrating the mixed fractions of each enantiomer was dissolved in EtOAc and passed through EtOAc-conditioned silica gel. The concentrate of the filtrate was dissolved in acetonitrile / water and subjected to a freeze-drying process. Enantiomeric enrichment was measured by analytical method on the same instrument using Chiralcel-OJ-H, 5 micron, 4.6x250mm with 27% isopropyl alcohol (0.1% DEA) 73% CO2 as mobile phase eluted at a flow rate of 3.0mL / min by injection of 10μL with a concentration of 1mg / mL at detector UV wavelength of 214nm. I-12: (R)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide (white solid). 98.9%ee. 1H NMR(400 MHz,chloroform-d)δ 8.45(d,J=7.6 Hz,1H),7.95(s,1H),7.46-7.26(m,7H),7.20(s,1H),7.14(s,1H),5.71(s,2H),5.14(q,J=8.3 Hz,1H),3.11-2.96(m,1H),2.70(dd,J=13.7,6.5 Hz,1H),2.60(td,J=13.2,7.4 Hz,1H),2.18-2.10(m,1H).LCMS: 99% purity, MS(m / e)454(M+H) + I-13: (S)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide (white solid). 99.6% ee. 1 H NMR(400 MHz,chloroform-d)δ 8.47(d,J=7.7 Hz,1H),7.94(s,1H),7.46-7.37(m,2H),7.41-7.27(m,5H),7.19(d,J=1.4 Hz,1H),7.14(d,J=1.4 Hz,1H),5.71(s,2H),5.15(dt,J=10.5,7.7 Hz,1H),3.10-2.95(m,1H),2.75-2.53(m,2H),2.21-2.11(m,1H).LCMS: 99% purity, MS(m / e)454(M+H) + .

[0181] I-91 (S)-5-benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide and I-92 (R)-5-benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] The run was performed on a Thar SFC instrument equipped with a Chiralcel OJ-H, 10 micron, 10x250mm column. The mobile phase was 18% methanol (0.1% DEA) 82% CO2 with a total flow rate of 10.0mL / min. The total elution time for the enantiomer separation is 11.3 minutes. A total of 40 50μL injections were made with a sample concentration of 17mg / mL (in methanol) using a cycle time of 2.9 minutes and injection stacking at 0.3 minutes intervals. Samples were collected by monitoring UV adsorption at 214nm. Peak-1 (fast eluting peak) corresponds to (S)-5-benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide, and peak-2 (slow eluting peak) corresponds to (R)-5-benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide. The solid obtained after concentrating the mixed fractions of each enantiomer was dissolved in a minimum amount of acetonitrile and diluted with water. The precipitated suspension was filtered by suction and the collected solid was dried to provide the respective compound. Enantiomeric enrichment was measured by analytical method on the same instrument using Chiralcel-OJ-H, 5 micron, 4.6x250mm with 18% methanol (0.1% DEA) 82% CO2 as mobile phase eluted at a flow rate of 3.0mL / min by injection of 10μL with a concentration of 1mg / mL at detector UV wavelength of 214nm. I-91: (S)-5-benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide (white solid). 99.7%ee. 1H NMR(400 MHz, methanol-d4)δ 7.67(d,J=1.9 Hz,1H),7.58(d,J=1.5 Hz,1H),7.39(dd,J=8.3,1.9 Hz,1H),7.36-7.18(m,6H),7.10(d,J=1.5 Hz,1H),5.56(dd,J=9.0,6.2 Hz,1H),4.67(dd,J=11.0,6.2 Hz,1H),4.49(dd,J=10.9,9.0 Hz,1H),4.15(s,2H),1.56(s,6H).Purity 99%, MS(m / e)469(M+H) + I-92: (R)-5-benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide (white solid). 99.7% ee. 1 H NMR(400 MHz, methanol-d4)δ 7.67(d,J=1.9 Hz,1H),7.58(d,J=1.6 Hz,1H),7.40(dd,J=8.3,1.9 Hz,1H),7.33-7.20(m,6H),7.11(d,J=1.5 Hz,1H),5.56(dd,J=9.0,6.2 Hz,1H),4.67(dd,J=11.0,6.2 Hz,1H),4.50(dd,J=10.9,9.0 Hz,1H),4.15(s,2H),1.56(s,6H).Purity 95%, MS(m / e)469(M+H) + .

[0182] I-60: (±)-1-(2,6-dichlorobenzyl)-N-(2-methyl-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] Iodomethane (2.6 μL, 6 mg, 0.042 mmol) was added all at once to a stirred heterogeneous suspension of (±)-5-benzyl-N-(1-oxo-5,6-dihydro-1H,4H-benzo[f][1,2,4]oxadiazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide (15 mg, 0.032 mmol) and Cs2CO3 (11 mg, 0.033 mmol) in dry DMF (0.2 mL) at room temperature under nitrogen. The reaction mixture was stirred for 1 day, diluted with water (1 mL) and filtered. The solid thus collected by suction drying was dissolved in CHCl, loaded onto a silica gel column, and purified by flash chromatography [Combiflash® Teledyne RediSep® 50% EtOAc / Hexane conditioned silica gel column (4G Gold) and eluted with 50-100% EtOAc / Hexane solvent] to give (±)-1-(2,6-dichlorobenzyl)-N-(2-methyl-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide (11 mg) as a white solid. 1 H NMR(400 MHz,chloroform-d)δ 7.96(s,1H),7.76(d,J=8.4 Hz,1H),7.60(dt,J=7.9,1.0 Hz,1H),7.45-7.25(m,6H),5.70(s,2H),5.08(dt,J=10.2,8.1 Hz,1H),3.52(s,3H),2.90-2.75(m,1H),2.74-2.71(m,2H),2.12-2.00(m,1H).Purity 96%, MS(m / e)485(M+H) + .

[0183] I-70 (±)-5-Benzyl-N-(1,2-dichloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)isoxazole-3-carboxamide [ka] 1H NMR(400 MHz,chloroform-d)δ 7.83(d,J=7.8 Hz,1H),7.49-7.20(m,9H),6.32(d,J=0.9 Hz,1H),4.99(dt,J=10.7,7.7 Hz,1H),4.11(s,2H),2.94-2.79(m,1H),2.76-2.66(m,1H),2.61-2.52(m,1H),2.17-2.04(m,1H).Purity 97%, MS(m / e)454(M+H) + .

[0184] I-71(±)-5-Benzyl-N-(1-chloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)isoxazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.02(d,J=7.6 Hz,1H),7.47-7.19(m,9H),7.04(s,1H),6.33(s,1H),4.95(dt,J=10.6,7.7 Hz,1H),4.11(s,2H),2.96-2.81(m,1H),2.74-2.64(m,1H),2.59-2.50(m,1H),2.15-2.02(m,1H).Purity 93%, MS(m / e)420(M+H) + .

[0185] I-73(±)-N-(1,2-dichloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide [ka] 1H NMR(400 MHz,chloroform-d)δ 8.17(d,J=8.0 Hz,1H),7.96(s,1H),7.48-7.37(m,6H),7.41-7.29(m,1H),5.72(s,2H),5.07(dt,J=10.6,7.8 Hz,1H),3.00-2.85(m,1H),2.75-2.65(m,1H),2.63-2.49(m,1H),2.16-2.05(m,1H).Purity 95%, MS(m / e)523(M+H) + .

[0186] I-74(±)-N-(1-chloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,chloroform-d)δ 8.36(d,J=7.8 Hz,1H),7.94(s,1H),7.46-7.33(m,6H),7.32(dd,J=8.9,7.1 Hz,1H),7.05(s,1H),5.71(s,2H),5.03(dt,J=10.5,7.8 Hz,1H),3.01-2.87(m,1H),2.73-2.63(m,1H),2.58-2.50(app m,1H),2.14-2.02(m,1H).Purity 90%, MS(m / e)489(M+H) + .

[0187] I-80 (±)-5-Benzyl-N-(1,2-dichloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1H NMR(400 MHz, methanol-d4)δ 7.56-7.43(m,4H),7.36-7.20(m,5H),4.95-4.86(app m,1H),4.18(s,2H),2.87-2.78(m,1H),2.70-2.49(m,2H),2.37-2.30(m,1H).Purity 94%, MS(m / e)454(M+H) + .

[0188] I-81 (±)-5-Benzyl-N-(1-chloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz, methanol-d4)δ 7.58-7.41(m,4H),7.38-7.18(m,5H),7.03(s,1H),4.89(app dd,J=11.2,7.7 Hz,1H),4.17(s,2H),2.81(dd,J=13.4,6.2 Hz,1H),2.63(tt,J=13.0,6.8 Hz,1H),2.48(td,J=13.0,7.2 Hz,1H),2.31(td,J=11.7,7.0 Hz,1H).Purity 93%, MS(m / e)420(M+H) + .

[0189] I-75 1-Benzyl-5-hydroxy-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazepin-4-yl)-1H-pyrazole-3-carboxamide [ka] 1 H NMR(400 MHz,CD3OD)δ 7.71(d,J=8.0 Hz,1H),7.52-7.15(m,9H),5.46(dd,J=9.5,7.9 Hz,1H),5.18(s,2H),4.65-4.48(m,2H). 13C NMR (100 MHz, CD3OD) δ 164.6, 158.5, 158.1, 154.9, 150.9, 144.4, 138.2, 131.1, 129.6, 129.6, 128.7, 128.5, 127.3, 127.1, 125.0, 124.2, 75.6, 51.6, 45.8. MS (ESI, m / e) calculated 419.1230; found 420 [M+H] + .

[0190] I-76 (R)-1-Benzyl-5-hydroxy-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazepin-4-yl)-1H-pyrazole-3-carboxamide [ka] 1 H NMR(400 MHz,CD3OD)δ 8.31(d,J=8.5 Hz,1H),7.41-7.13(m,8H),5.91(dd,J=6.4,4.3 Hz,1H),5.14(s,2H),4.56-4.39(m,2H),1.57(s,6H). 13 C NMR (100 MHz, CD3OD) δ 164.3, 155.2, 155.1, 151.3, 144.7, 138.2, 129.6, 128.9, 128.6, 128.5, 127.7, 126.5, 126.3, 123.7, 97.8, 80.7, 72.1, 65.8, 51.5, 47.1, 31.5. MS (ESI, m / e) calculated 485.1812; found 486 [M+H] + I-3(R)-5-benzyl-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1H NMR(400 MHz,DMSO-d6)δ 8.31(dd,J=8.2,1.6 Hz,1H),7.56-7.15(m,8H),5.91(td,J=7.2,3.9 Hz,1H),4.50(dd,J=12.3,4.0 Hz,1H),4.39(dd,J=12.3,6.8 Hz,1H),4.12(s,2H).MS(ESI,m / e) Calculated value 388.1396;Actual value 389.0[M+H] + I-8(R)-5-benzyl-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazepin-4-yl)isoxazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.61(d,J=8.1 Hz,1H),8.33(dd,J=8.2,1.6 Hz,1H),7.57-7.18(m,8H),6.61(d,J=0.8 Hz,1H),5.91(ddd,J=8.2,5.7,3.7 Hz,1H),4.58-4.36(m,2H),4.23(s,2H).MS(ESI,m / e) Calculated value 388.1284;Actual value 389.0[M+H] + .

[0191] I-10 (R)-1-(2,6-dichlorobenzyl)-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-5-carboxamide [ka] MS (ESI, m / e) calculated: 456.0617; found: 457.0 [M+H] + ,455.0[MH] - .

[0192] I-11(R)-1-(2,6-dichlorobenzyl)-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.35(d,J=8.3 Hz,1H),8.84(s,1H),8.31(dd,J=8.2,1.6 Hz,1H),7.62-7.26(m,5H),5.87(ddd,J=8.4,6.8,4.0 Hz,1H),5.71(s,2H),4.58-4.30(m,2H).MS(ESI,m / e) Calculated value 456.0617;Actual value 457.0[M+H] + ,455.0[MH] - .

[0193] I-20(R)-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazepin-4-yl)-1-(2,6-dimethylbenzyl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.33(d,J=8.3 Hz,1H),8.66(s,1H),8.31(dd,J=8.3,1.5 Hz,1H),7.47(ddd,J=8.1,7.4,1.7 Hz,1H),7.38(ddd,J=8.2,7.3,1.5 Hz,1H),7.31(dd,J=8.1,1.5 Hz,1H),7.17(dd,J=8.3,6.7 Hz,1H),7.08(d,J=7.5 Hz,2H),5.87(ddd,J=8.3,6.9,4.1 Hz,1H),5.48(s,2H),4.49(dd,J=12.3,4.1 Hz, 1H), 4.37(dd, J=12.3, 6.9 Hz, 1H), 2.35(s, 6H). MS(ESI, m / e) calculated 416.1709; found 417.1[M+H] + ,415.1[MH] - .

[0194] I-21(R)-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazepin-4-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.37(d,J=8.3 Hz,1H),8.83(s,1H),8.31(dd,J=8.2,1.6 Hz,1H),7.51-7.29(m,5H),7.29-7.18(m,2H),5.90(ddd,J=8.4,6.7,4.0 Hz,1H),5.56(s,2H),4.50(dd,J=12.3,4.0 Hz,1H),4.38(dd,J=12.3,6.7 Hz,1H).MS(ESI,m / e) Calculated value 406.1302;Actual value 407.0[M+H] + ,405.0[MH] - .

[0195] I-41 5-benzyl-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.23(br s,1H),7.73(dd,J=7.9,1.7 Hz,1H),7.49(td,J=7.7,1.8 Hz,1H),7.43(td,J=7.7,1.6 Hz,1H),7.38(dd,J=7.9,1.6 Hz,1H),7.33(t,J=7.4 Hz,2H),7.26(dt,J=8.1,1.8 Hz,3H),5.46-5.33(m,1H),4.83-4.71(m,1H),4.54(dd,J=10.5,8.0 Hz,1H),4.13(s,2H).MS(ESI,m / e) Calculated value 404.1233; Measured value 405.0 [M+H] + ,403.0[MH]- .

[0196] I-42 1-(2,6-Dichlorobenzyl)-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.25(d,J=8.5 Hz,1H),8.88(s,1H),7.73(dd,J=7.9,1.7 Hz,1H),7.58(d,J=1.1 Hz,1H),7.56(s,1H),7.51-7.45(m,2H),7.42(td,J=7.7,1.6 Hz,1H),7.37(dd,J=7.9,1.6 Hz,1H),5.71(s,2H),5.38(dt,J=9.7,8.1 Hz,1H),4.74(t,J=10.2 Hz,1H),4.53(dd,J=10.6,7.9 Hz,1H).MS(ESI,m / e)calculated value 472.0454; Measured value 473.0 [M+H] + ,471.0[MH] - .

[0197] I-43 5-Benzyl-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazepin-4-yl)isoxazole-3-carboxamide [ka] 1H NMR(400 MHz,DMSO-d6)δ 9.52(d,J=8.2 Hz,1H),7.72(dd,J=7.8,1.7 Hz,1H),7.49(td,J=7.7,1.8 Hz,1H),7.43(td,J=7.7,1.6 Hz,1H),7.40-7.35(m,2H),7.34(t,J=1.4 Hz,1H),7.32-7.25(m,3H),6.59(d,J=0.8 Hz,1H),5.41(dt,J=9.5,8.1 Hz,1H),4.66(dd,J=10.7,9.6 Hz,1H),4.59(dd,J=10.7,8.0 Hz,1H),4.23(s,2H).MS(ESI,m / e) Calculated value 404.1121; Actual value 405.0[M+H] + ,403.0[MH] - .

[0198] I-49 5-(2,4-difluorobenzyl-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 7.74(dd,J=7.8,1.8 Hz,1H),7.63(dd,J=7.9,1.7 Hz,1H),7.52-7.46(m,1H),7.45-7.42(m,2H),7.38(dd,J=7.7,1.5 Hz,2H),7.33(dd,J=7.9,1.6 Hz,1H),5.45-5.35(m,1H),4.75(t,J=10.2 Hz,1H),4.58-4.51(m,1H),4.25-4.16(m,2H).MS(ESI,m / e) Calculated value 440.1045;Actual value 441.2[M+H] + .

[0199] I-50 5-(4-Fluorobenzyl-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.18(br s,1H),7.74(dd,J=7.9,1.7 Hz,1H),7.50(dd,J=7.7,1.8 Hz,1H),7.46(dd,J=10.1,1.8 Hz,1H),7.42(dd,J=7.6,1.6 Hz,1H),7.38(dd,J=7.9,1.6 Hz,1H),7.31(ddd,J=8.5,5.7,2.7 Hz,2H),7.20-7.10(m,2H),5.41(dt,J=9.8,8.1 Hz,1H),4.76(t,J=10.2 Hz,1H),4.54(dd,J=10.6,7.8 Hz,1H),4.14(s,2H).MS(ESI,m / e) Calculated value 422.1139;Actual value 423.2[M+H] + .

[0200] I-53 N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazepin-4-yl)-4-phenoxypicolinamide [ka] 1H NMR(400 MHz,DMSO-d6)δ 9.52(d,J=8.5 Hz,1H),8.59(d,J=5.6 Hz,1H),7.74(dd,J=7.9,1.7 Hz,1H),7.55-7.50(m,2H),7.48(dd,J=7.7,1.8 Hz,1H),7.42(td,J=7.7,1.6 Hz,1H),7.39-7.31(m,3H),7.26-7.21(m,3H),5.42(dt,J=9.7,8.1 Hz,1H),4.81(dd,J=10.7,9.7 Hz,1H),4.55(dd,J=10.6,7.8 Hz,1H).MS(ESI,m / e)calculated value 416.1121; Measured value 417.3 [M+H] + .

[0201] I-69(R)-5-Benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.30(s,1H),8.29(d,J=8.5 Hz,1H),7.37(dd,J=8.6,1.9 Hz,1H),7.34-7.27(m,2H),7.24(d,J=7.4 Hz,3H),5.90(ddd,J=8.3,6.3,3.7 Hz,1H),4.49(dd,J=12.4,3.7 Hz,1H),4.40(dd,J=12.4,6.4 Hz,1H),4.11(s,2H),1.47(s,6H).MS(ESI,m / e) Calculated value 470.1815;Actual value 471.1[M+H] + ,469.1[MH] - .

[0202] I-79 (R)-2-benzyl-3-chloro-5-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazepin-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one [ka] 1 H NMR(400 MHz,DMSO-d6)δ 8.32(dd,J=8.2,1.6 Hz,1H),7.53-7.47(m,1H),7.44-7.29(m,5H),7.27-7.23(m,2H),6.07(dd,J=5.4,4.0 Hz,1H),5.52(s,2H),4.74(dd,J=12.7,5.5 Hz,1H),4.62(dd,J=12.6,4.0 Hz,1H),4.58-4.26(m,2H).MS(ESI,m / e) Calculated value 433.1054;Actual value 434.0[M+H] + .

[0203] tert-Butyl (R)-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazepin-4-yl)carbamate (intermediate) [ka] MS (ESI, m / e) calculated: 319.1103; found: 342.1 [M+Na] + ,264.1[M-56+H] + .

[0204] I-22(R)-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazepin-4-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide [ka] 1H NMR(400 MHz,DMSO-d6)δ 9.52(d,J=8.2 Hz,1H),8.81(s,1H),8.00(dd,J=8.1,1.3 Hz,1H),7.82(dd,J=7.7,1.5 Hz,1H),7.71(ddd,J=8.0,7.5,1.5 Hz,1H),7.58(td,J=7.6,1.4 Hz,1H),7.45-7.30(m,2H),7.27-7.14(m,2H),5.75(ddd,J=11.0,8.3,7.4 Hz,1H),5.47(s,2H),3.69(dd,J=13.4,7.4 Hz, 1H), 3.30-3.16 (m, 1H). MS (ESI, m / e) calculated 422.1074; found 423.2 [M+H] + .

[0205] I-23(R)-5-Benzyl-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazepin-4-yl)isoxazole-3-carboxamide [ka] 1 H NMR(400 MHz,CDCl3)δ 8.00(d,J=8.1 Hz,1H),7.88(dd,J=8.0,1.4 Hz,1H),7.80(dd,J=7.7,1.5 Hz,1H),7.62(td,J=7.7,1.5 Hz,1H),7.51(td,J=7.7,1.4 Hz,1H),7.37-7.27(m,3H),7.25-7.21(m,2H),5.66(ddd,J=10.0,8.0,6.7 Hz,1H),4.11(s,2H),3.93(dd,J=12.6,6.7 Hz,1H),3.27(dd,J=12.6,10.0 Hz, 1H). MS (ESI, m / e) calculated 404.1055; found 405.2 [M+H] + , 427.2[M+Na] + .

[0206] I-24(R)-5-Benzyl-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,CD3OD)δ 7.98(dd,J=8.1,1.4 Hz,1H),7.84(dd,J=7.7,1.4 Hz,1H),7.74-7.64(m,1H),7.56(td,J=7.6,1.4 Hz,1H),7.35-7.18(m,5H),5.72(dd,J=10.5,7.1 Hz,1H),4.15(s,2H),3.77(dd,J=13.3,7.1 Hz,1H),3.38(dd,J=13.3,10.5 Hz,1H).MS(ESI,m / e) Calculated value 404.1168;Actual value 405.2[M+H] + .

[0207] I-25(R)-5-Benzyl-N-(6,6-dioxide-4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazepin-4-yl)isoxazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.80(d,J=6.9 Hz,1H),8.22-8.07(m,3H),7.95(ddd,J=7.8,6.7,2.0 Hz,1H),7.40-7.24(m,5H),6.54(s,1H),5.93(td,J=8.7,6.9 Hz,1H),4.54(dd,J=13.9,8.3 Hz,1H),4.38(dd,J=13.9,9.2 Hz,1H),4.23(s,2H).MS(ESI,m / e) Calculated value 436.0954;Actual value 437.2[M+H] + .

[0208] I-26 5-Benzyl-N-((4R)-6-oxido-4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazepin-4-yl)isoxazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.83(d,J=7.8 Hz,1H),8.05(dd,J=7.8,1.3 Hz,1H),8.02-7.92(m,2H),7.83(td,J=7.6,1.2 Hz,1H),7.42-7.23(m,5H),6.57(d,J=0.8 Hz,1H),5.81(dt,J=9.8,8.0 Hz,1H),4.23(s,2H),4.19(dd,J=13.9,8.0 Hz,1H),3.88(dd,J=13.9,9.9 Hz,1H).MS(ESI,m / e) Calculated value 420.1005; Actual value 421.0[M+H] + , 443.0[M+Na] + .

[0209] I-28 5-Benzyl-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]thiazepin-4-yl)isoxazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.63(d,J=7.7 Hz,1H),7.82(dd,J=7.7,1.4 Hz,1H),7.76(dd,J=8.0,1.5 Hz,1H),7.70(td,J=7.7,1.5 Hz,1H),7.55(td,J=7.5,1.6 Hz,1H),7.39-7.25(m,5H),6.54(d,J=0.8 Hz,1H),5.05(dt,J=10.1,7.7 Hz,1H),4.22(s,2H),3.74(dd,J=12.1,7.7 Hz,1H),3.44(dd,J=12.1,10.1 Hz, 1H).MS(ESI, m / e) calculated 420.0892; found 421.2 [M+H] + .

[0210] I-30(R)-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazepin-4-yl)-5-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,CD3OD)δ 7.98(dd,J=8.0,1.4 Hz,1H),7.84(dd,J=7.7,1.5 Hz,1H),7.69(td,J=7.8,1.5 Hz,1H),7.57(td,J=7.6,1.4 Hz,1H),7.38-7.22(m,2H),7.04(t,J=8.8 Hz,2H),5.72(dd,J=10.5,7.1 Hz,1H),4.15(s,2H),3.77(dd,J=13.3,7.1 Hz,1H),3.38(dd,J=13.3,10.5,1H).MS(ESI,m / e) Calculated value 422.1074;Actual value 421.3[MH] - .

[0211] I-31 5-(4-Fluorobenzyl)-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]thiazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,CD3OD)δ 7.83(dd,J=7.7,1.4 Hz,1H),7.71(dd,J=8.0,1.5 Hz,1H),7.69-7.63(m,1H),7.51(td,J=7.5,1.6 Hz,1H),7.33-7.27(m,2H),7.10-7.01(m,2H),5.15(dd,J=10.3,7.6 Hz,1H),4.15(s,2H),3.78(dd,J=12.1,7.6 Hz,1H),3.35(dd,J=12.1,10.3 Hz,1H).MS(ESI,m / e) Calculated value 438.0910; Actual value 439.2[M+H] + .

[0212] I-32 1-(4-Fluorobenzyl)-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]thiazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400 MHz,DMSO-d6)δ 9.36(d,J=8.2 Hz,1H),8.83(s,1H),7.82(dd,J=7.7,1.4 Hz,1H),7.76(dd,J=8.0,1.5 Hz,1H),7.73-7.67(m,1H),7.55(td,J=7.5,1.6 Hz,1H),7.41-7.35(m,2H),7.25-7.18(m,2H),5.48(s,2H),5.04(dt,J=10.2,7.9 Hz,1H),3.70(dd,J=12.0,7.8 Hz,1H),3.57(dd,J=12.0,10.3 Hz, 1H).MS(ESI, m / e) calculated 438.0910; found 439.2 [M+H] + .

[0213] I-33 5-Benzyl-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]thiazepin-4-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1H NMR(400 MHz,CD3OD)δ 7.83(dd,J=7.7,1.5 Hz,1H),7.71(dd,J=8.0,1.6 Hz,1H),7.65(td,J=7.7,1.5 Hz,1H),7.51(td,J=7.5,1.6 Hz,1H),7.35-7.22(m,5H),5.15(dd,J=10.3,7.6 Hz,1H),4.17(s,2H),3.78(dd,J=12.1,7.5 Hz,1H),3.35(dd,J=12.1,10.3 Hz,1H).MS(ESI,m / e) Calculated value 420.1005;Actual value 421.2[M+H] + .

[0214] I-46 5-Benzyl-N-((4R)-1-oxo-4,5-dihydro-1H-[1,2,4]oxadiazolo[4,3-d]pyrido[2,3-b][1,4]oxazepin-4-yl)isoxazole-3-carboxamide [ka] MS (ESI, m / e) calculated: 405.1073; found: 406.1 [M+H] + .

[0215] The compounds disclosed herein may be identified and evaluated using the following assays.

[0216] Identification of biological activity In this example, the disclosed compounds were evaluated using a biochemical assay that uses ADP-Glo™ technology.

[0217] 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.

[0218] 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.

[0219] 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).

[0220] 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. 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 50The values ​​are provided in Table 2. The data in Table 2 establish that compounds of the invention inhibit RIP1K. [Table 2-1] [Table 2-2] [Table 2-3]

[0221] Whole cell assay In this example, U937 and L929 cells were exposed to compounds of the disclosure and cell necroptosis assays were performed to evaluate the activity of the compounds in functional human RIP1 and mouse RIP1 assays.

[0222] 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 3. 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] [Table 3-3] [Table 3-4]

[0223] In vivo activity 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.

[0224] 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. The activity in this example demonstrates that embodiments of compounds of the disclosure inhibit TNF-alpha signaling in vivo and therefore can be used to treat diseases in which TNF-alpha is implicated.

[0225] 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. The following formula: 【Chemistry 1】 [In the formula, X is CH ２ ,O,S,S(O),S(O) ２ , and N.R. ａ is selected from R ａ For each occurrence, hydrogen, C １－６ Alkyl, and C １－６ acyl, Y １ , Y ２ , and Y ３ is N, N(R ａ ), O, C(R ｂ ) １－２ and C=O; R ｂ is selected from hydrogen, C1-6 alkyl, and halo; Z is C(R ｃ ) or NR ｃ and R ｃ is one or more R optionally interrupted by one or two heteroatoms selected from O, N, and S; １ C optionally substituted with a group １－４ It is an unsaturated carbon chain, R ｚ is N, CH, or C(R １ ) and ZR ｃ and together with the carbon to which they are attached, m R １ forming a 5- or 6-membered heteroaryl or 6-membered aryl ring substituted with a group, R １ is the linker R ６ a group, wherein the linker is a bond, a (C1-C4) alkanyl, a (C1-C4) alkenyl, or a (C1-C4) alkynyl, and one or more R ｂ and R is optionally substituted by ６ is R ｅ , -C(R ｆ ) ３ , or -C(R ｆ ) = C(R ｆ ) ２ and R ２ is R ａ and Ring B is a 5-10 membered heteroaryl; R ３ For each occurrence, R ｂ and OR ａ are independently selected from L is O, NR ａ or alkylene, W is p R ４ is a 5-10 membered aryl or heteroaryl optionally substituted by R ４ For each occurrence, R ｂ and OR ａ is selected from R ｄ For each occurrence, hydrogen, C １－６ Alkyl, aralkyl, C ５－１０ aryl or heteroaryl, or two R ｄ together with the nitrogen to which they are both attached, represent one or more R ｅ C optionally substituted by ３－１０ forming a heterocyclic group, R ｅ independently for each occurrence: halo, -OR ｄ , -SR ｄ , -S(O) ２ R ｄ , -NR ｄ R ｄ , -Si(R ａ ) ３ , -C(O)OH, -C(O)OR ａ or -C(O)NR ｄ R ｄ and R ｆ is independently expressed for each occurrence as R ａ , R ｂ , or R ｅ or two R ｆ Groups, together with the carbon atoms attached thereto, each represent one or more R ｅ C optionally substituted with ３－６ Cycloalkyl group or C ３－１０ providing a heterocyclic group, m is 1, 2, 3, or 4; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5. A compound represented by the formula:

2. The following formula: 【Chemistry 2】 2. The compound of claim 1 having the formula:

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

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

5. The following formula: 【Chemistry 5】 [In the formula, Z １ is selected from C and N; Z ２ , Z ３ , and Z ４ is O, S, S(O) ２ , CH, N, N(R ａ ), and C.R. １ are independently selected from 2. The compound of claim 1 having the formula:

6. The following formula: 【Chemistry 6】 [In the formula, Z １ is C or N, Z ３ is O, S, N, or N(R ａ ) 2. The compound of claim 1 having the formula:

7. The following formula: 【Chemistry 7】 [In the formula, X is CH ２ ,O,S,S(O),S(O) ２ , and N.R. ａ is selected from R ａ For each occurrence, hydrogen, C １－６ Alkyl, and C １－６ acyl, Y １ , Y ２ , and Y ３ is N, N(R ａ ), O, C(R ｂ ) １－２ and C=O; R ｂ is hydrogen, C １－６ alkyl, and halo; Z is C(R ｃ ) or NR ｃ and R ｃ is one or more R optionally interrupted by one or two heteroatoms selected from O, N, and S; １ C optionally substituted with a group １－４ It is an unsaturated carbon chain, R ｚ is N, CH, or C(R １ ) and ZR ｃ and together with the carbon to which they are attached, m R １ forming a 5- or 6-membered heteroaryl or 6-membered aryl ring optionally substituted with a group; R １ is a halo or linker -R ６ a group, wherein the linker is a bond, a (C1-C4) alkanyl, a (C1-C4) alkenyl, or a (C1-C4) alkynyl, and one or more R ｂ and R is optionally substituted by ６ is R ｅ , -C(R ｆ ) ３ , or -C(R ｆ ) = C(R ｆ ) ２ and R ２ is R ａ and Ring B is a 5-10 membered heteroaryl; R ３ For each occurrence, R ｂ and OR ａ are independently selected from L is O, NR ａ or alkylene, W is p R ４ is a 5-10 membered aryl or heteroaryl optionally substituted by R ４ For each occurrence, R ｂ and OR ａ is selected from R ｄ For each occurrence, hydrogen, C １－６ Alkyl, aralkyl, C ５－１０ aryl or heteroaryl, or two R ｄ together with the nitrogen to which they are both attached, represent one or more R ｅ C optionally substituted by ３－１０ forming a heterocyclic group, R ｅ independently for each occurrence: halo, -OR ｄ , -SR ｄ , -S(O) ２ R ｄ , -NR ｄ R ｄ , -Si(R ａ ) ３ , -C(O)OH, -C(O)OR ａ or -C(O)NR ｄ R ｄ and R ｆ is independently expressed for each occurrence as R ａ , R ｂ , or R ｅ or two R ｆ Groups, together with the carbon atoms attached thereto, each represent one or more R ｅ C optionally substituted with ３－６ Cycloalkyl group or C ３－１０ providing a heterocyclic group, m is 1, 2, 3, or 4; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5. A compound represented by the formula:

8. The following formula: 【Chemistry 8】 [In the formula, X is CH ２ ,O,S,S(O),S(O) ２ , and N.R. ａ is selected from R ａ For each occurrence, hydrogen, C １－６ Alkyl, and C １－６ acyl, Y １ , Y ２ , and Y ３ is N, N(R ａ ), O, C(R ｂ ) １－２ and C=O; R ｂ is hydrogen, C １－６ alkyl, and halo; Z is C(R ｃ ) or NR ｃ and R ｃ is one or more R optionally interrupted by one or two heteroatoms selected from O, N, and S; １ C optionally substituted with a group １－４ It is an unsaturated carbon chain, R ｚ is N, CH, or C(R １ ) and ZR ｃ and together with the carbon to which they are attached, m R １ forming a 5- or 6-membered heteroaryl or 6-membered aryl ring optionally substituted with a group; R １ is a halo or linker -R ６ a group, wherein the linker is a bond, a (C1-C4) alkanyl, a (C1-C4) alkenyl, or a (C1-C4) alkynyl, and one or more R ｂ and R is optionally substituted by ６ is R ｅ , -C(R ｆ ) ３ , or -C(R ｆ ) = C(R ｆ ) ２ and R ２ is R ａ and Ring B is a 5-10 membered heteroaryl; R ３ For each occurrence, R ｂ and OR ａ are independently selected from L is O, NR ａ or alkylene, W is p R ４ is a 5-10 membered aryl or heteroaryl optionally substituted by R ４ For each occurrence, R ｂ and OR ａ is selected from R ｄ For each occurrence, hydrogen, C １－６ Alkyl, aralkyl, C ５－１０ aryl or heteroaryl, or two R ｄ together with the nitrogen to which they are both attached, represent one or more R ｅ C optionally substituted by ３－１０ Forming a heterocyclic group, R ｅ independently for each occurrence: halo, -OR ｄ , -SR ｄ , -S(O) ２ R ｄ , -NR ｄ R ｄ , -Si(R ａ ) ３ , -C(O)OH, -C(O)OR ａ or -C(O)NR ｄ R ｄ and R ｆ is independently expressed for each occurrence as R ａ , R ｂ , or R ｅ or two R ｆ Groups, together with the carbon atoms attached thereto, each represent one or more R ｅ C optionally substituted with ３－６ Cycloalkyl group or C ３－１０ providing a heterocyclic group, m is 1, 2, 3, or 4; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5. A compound represented by the formula:

9. The compound according to any one of claims 1 to 8, wherein X is O.

10. Y １ The compound according to any one of claims 1 to 8, wherein is N.

11. Y １ , Y ２ , and Y ３ The compound according to any one of claims 1 to 8, wherein each is N.

12. Y ２ The compound according to any one of claims 1 to 8, wherein is O.

13. Y ３ The compound according to any one of claims 1 to 8, wherein is C=O.

14. Y １ , Y ２ , and Y ３ are respectively C(R ｂ ) １－２ The compound according to any one of claims 1 to 8,

15. Y １ , Y ２ , and Y ３ At least one R ｂ The compound of claim 14 , wherein is halo.

16. The compound according to any one of claims 1 to 8, wherein m is zero.

17. At least one R １ But, linker-R ６ group, and said R ６ The compound according to any one of claims 1 to 8, wherein the group is selected from the group consisting of:

18. At least one R １ but, 【Chemistry 9】 【Chemistry 10】 The compound according to any one of claims 1 to 8,

19. At least one R １ but, 【Chemistry 11】 The compound according to any one of claims 1 to 8,

20. W, 【Chemistry 12】 The compound according to any one of claims 1 to 8,

21. The compound of any one of claims 1 to 8, wherein W is pyridyl.

22. The B ring is represented by the following formula: 【Chemistry 13】 The compound according to any one of claims 1 to 6, having the formula:

23. The compound according to any one of claims 1 to 8, wherein the compound is present in a salt form.

24. 13. A method for treating a condition associated with RIP1K in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 6.

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