Rip1k inhibitors

Abstract

Disclosed herein are kinase inhibiting compounds, such as receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, and pharmaceutical compositions and combinations comprising such inhibiting compounds. The disclosed compounds, pharmaceutical compositions, and / or combinations can be used to treat or prevent a kinase-related disease or disorder, particularly a RIP1-related disease or disorder.

Description

[0001] This disclosure relates to compounds and methods of preparing and using said compounds, such as for inhibiting receptor-interacting protein-1 kinase (“RIP1”) and for treating diseases and / or conditions associated with RIP1.

[0002] Receptor-interacting protein-1 kinase (referred to as "RIP1" in this paper) belongs to the tyrosine kinase-like family and is a serine / threonine protein kinase involved in innate immune signaling. RIP1 plays a central role in regulating cell signaling, and its role in programmed cell death has been associated with a variety of inflammatory diseases, such as inflammatory bowel disease, psoriasis, and other diseases and / or conditions associated with inflammation and / or necrotic cell death.

[0003] This article discloses compounds according to the following formula.

[0004]

[0005] in

[0006] X is selected from CH2, O, S, S(O), S(O)2 and NR. a ;

[0007] R a Each time it appears, it is selected from hydrogen, C 1-6 Alkyl and C 1-6 Acyl group;

[0008] Y 1 Y 2 and Y 3 Independently selected from N, N(R) a ), O, C(R) b ) 1-2 And C=O;

[0009] R b Selected from hydrogen, C 1-6 Alkyl and halogen;

[0010] Z is C(R) c ) or NR c ;

[0011] R c It is optionally controlled by one or more R 1 C with substituent group 1-4 An unsaturated carbon chain, which optionally contains one or two heteroatoms selected from O, N and S;

[0012] R z Is it N, CH or C(R) 1 And with ZR c And together with the carbon they bind, they form optionally m R1 A 5- or 6-membered heteroaryl or 6-membered aryl ring substituted with a functional group;

[0013] R 1 It is a halogen, linker group -R 6 Groups, wherein the linking group is a bond, optionally bounded by one or more R groups. b Substituted (C1-C4)alkyl, (C1-C4)alkenyl, or (C1-C4)ynyl, and R 6 It is R e -C(R) f )3 or -C(R f )=C(R f )2;

[0014] R 2 It is R a ;

[0015] Ring B is a 5-10 member heteroaryl group;

[0016] R 3 Each time it appears, it is independently selected from R. b and OR a ;

[0017] L is O, NR a or alkylene;

[0018] W is arbitrarily assigned to p R. 4 Substituted 5-10 aryl or heteroaryl groups;

[0019] R 4 Selected from R each time it appears b and OR a ;

[0020] R d Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, Aryl, C 5-10 aryl or heteroaryl, or two R d Together with the nitrogen attached to both of them, they form a mixture optionally bound by one or more R e Replacement C 3-10 Heterocyclic groups;

[0021] R e Each time it appears, it is independently halogen, -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 Rd ;

[0022] R f It is R independently each time it appears. a R b Or R e , or two R f The groups, together with the carbon atoms they are bonded to, form C. 3-6 cycloalkyl or C 3-10 Heterocyclic groups, each optionally bound by one or more R e replace;

[0023] m is 1, 2, 3, or 4;

[0024] n is 0, 1, or 2; and

[0025] p is 0, 1, 2, 3, 4 or 5.

[0026] Furthermore, methods for preparing the compounds and intermediates, as well as pharmaceutical formulations and methods for using said compounds and formulations, are disclosed. The foregoing and other objects, features, and advantages of the present invention will become more apparent from the following detailed description.

[0027] I. Terminology Overview

[0028] The following explanations of terms and methods are provided to better describe this disclosure and to guide those skilled in the art in practicing it. The singular forms “a,” “an,” and “described” mean one or more than one, unless the context clearly indicates otherwise. The term “or” means a single element among the alternative elements, or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, “comprising” means “including.” Thus, “comprising A or B” means “including A, B, or A and B,” without excluding additional elements. All references (including patents and patent applications cited herein) are incorporated by reference.

[0029] Unless otherwise stated, all figures representing component amounts, molecular weights, percentages, temperatures, times, etc., as used in this specification or claims should be understood to be modified by the term "about". Therefore, unless otherwise implicitly or explicitly stated, the numerical parameters presented are approximate values ​​that may depend on the desired performance sought and / or the detection limits under standard test conditions / methods. When embodiments are directly and explicitly distinguished from the prior art discussed, the figures for the embodiments are not approximate values ​​unless the word "about" is explicitly stated.

[0030] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. While similar or equivalent methods and materials to those described herein may be used in the practice or experimentation of this disclosure, suitable methods and materials are described below. The materials, methods, and embodiments described are merely exemplary and are not intended to be limiting.

[0031] As used herein, the term "substituted" refers to all subsequent modifying parts of a term, such as in the term "substituted aryl C". 1-8 In alkyl groups, substitution can occur at the aryl C. 1-8 alkyl "C" 1-8 On the "alkyl" part, the "aryl" part, or both parts.

[0032] When used to modify a specified group or portion, "substituted" means that at least one, and possibly two or more, hydrogen atoms of the specified group or portion are independently substituted by the same or different substituents as defined below. In a particular embodiment, a group, portion, or substituent may be substituted or unsubstituted unless explicitly defined as "unsubstituted" or "substituted". Thus, any of the groups specified herein may be unsubstituted or substituted unless the context otherwise indicates or the specific structural formula excludes substitution. In a particular embodiment, a substituent may or may not be explicitly defined as substituted, but is still considered to be optionally substituted. For example, an "aliphatic" or "cyclic" portion may be unsubstituted or substituted, but an "unsubstituted aliphatic" or "unsubstituted cyclic" portion is unsubstituted.

[0033] A "substituent" or "substituted group" is used to replace one or more hydrogen atoms on a saturated carbon atom in a specified group or portion. As used herein, the term "substituted" refers to all subsequent modifications in the term, such as in the term "substituted aryl C". 1-8 In alkyl groups, substitution can occur at the aryl C. 1-8 alkyl "C" 1-8 On the "alkyl" part, the "aryl" part, or both parts.

[0034] When used to modify a specified group or portion, "substituted" means that at least one, and possibly two or more, hydrogen atoms of the specified group or portion are independently substituted by the same or different substituents as defined below. In a particular embodiment, a group, portion, or substituent may be substituted or unsubstituted unless explicitly defined as "unsubstituted" or "substituted". Thus, any of the groups specified herein may be unsubstituted or substituted unless the context otherwise indicates or the specific structural formula excludes substitution. In a particular embodiment, a substituent may or may not be explicitly defined as substituted, but is still considered to be optionally substituted. For example, an "aliphatic" or "cyclic" portion may be unsubstituted or substituted, but an "unsubstituted aliphatic" or "unsubstituted cyclic" portion is unsubstituted.

[0035] Unless otherwise specified, the “substituent” or “substituted group” described herein for replacing one or more hydrogen atoms on a saturated carbon atom in a specified group or portion may be -R 60 Halogen, =O, -OR 70 -SR 70 -N(R) 80 2. Halogenated alkyl, perhalogenated alkyl, -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)R70 -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 It is C 1-10 Aliphatic groups, heteroaliphatic groups, or alicyclic groups are usually C 1-6 Aliphatic groups, more commonly C 1-6 Alkyl, wherein R 60 Optionally, it can be replaced; each R 70 Each time it appears, it is independently either hydrogen or R. 60 ; Each R 80 It is R independently each time it appears. 70 Alternatively, both R 80 The groups, together with the nitrogen atoms to which they are bonded, form 3- to 7-membered heterocyclic groups, which optionally include 1-4 identical or different additional heteroatoms selected from O, N, and S, wherein N optionally has R 70 Substitution, such as H or C1-C3 alkyl substitution; and each M + It is a counterion with a net single positive charge. Each M + Independently, each occurrence is, for example, alkali metal ions, such as K+. + Na + Li + Ammonium ions, such as + N(R 60 4; protonated amino acid ions, such as lysine or arginine ions; or alkaline earth metal ions, such as [Ca] 2+ ]05、[Mg 2+ ]05 or [Ba 2+]05 (The subscript "0.5" means, for example, that one of the counterions of such a divalent alkaline earth metal ion can be the ionized form of the compound of this disclosure and other typical counterions (such as chloride ions), or two ionized compounds can act as counterions of such a divalent alkaline earth metal ion, or a double-ionized compound can act as a counterion of such a divalent alkaline earth metal ion). As a specific example, -N(R 80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidine-3-yl, N-pyrrolidine, N-piperazinyl, 4N-methyl-piperazin-1-yl, N-morpholinyl, etc. Any two hydrogen atoms on a single carbon can also be represented by, for example, =O, =NR 70 =N-OR 70 =N2 or =S can be substituted.

[0036] Unless otherwise specified, the substituent group used to replace the hydrogen atom on the unsaturated carbon atom in a group containing unsaturated carbon is -R. 60 halogen, -O - M + -OR 70 -SR 70 -S - M + -N(R) 80 2. Fully halogenated alkyl groups, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 -SO3 - M + -SO3R 70 -OSO2R 70 -OSO3 - M + -OSO3R 70 -PO3 -2 (M + )2、-PO3 - 2 M 2+ -P(O)(OR) 70 )O - M + -P(O)(OR) 70 )2、-C(O)R 70 -C(S)R 70 -C(NR) 70 )R 70 -CO2 - M + -CO2R 70 -C(S)OR 70 -C(O)NR 80 R 80-C(NR) 70 )N(R 80 )2、-OC(O)R 70 -OC(S)R 70 -OCO2 - M + -OCO2R 70 -OC(S)OR 70 -NR 70 C(O)R 70 -NR 70 C(S)R 70 -NR 70 CO2 - M + -NR 70 CO2R 70 -NR 70 C(S)OR 70 -NR 70 C(O)N(R 80 )2、-NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )N(R 80 )2, where R 60 R 70 R 80 and M + As defined above. In a standalone implementation, the substituent is not -O. - M + -OR 70 -SR 70 or -S - M + .

[0037] Unless otherwise specified, the substituent group used to replace the hydrogen atom on the nitrogen atom in a group containing such a nitrogen atom is -R. 60 -O - M + -OR 70 -SR 70 -S - M + -N(R) 80 2. Fully halogenated alkyl groups, -CN, -NO, -NO2, -S(O)2R 70 -SO3 - M + -SO3R 70 -OS(O)2R 70 -OSO3 - M+ -OSO3R 70 -PO3 2- (M + )2、-PO3 2- M 2+ -P(O)(OR) 70 )O - M + -P(O)(OR) 70 (OR) 70 -C(O)R 70 -C(S)R 70 -C(NR) 70 )R 70 -CO2R 70 -C(S)OR 70 -C(O)NR 80 R 80 -C(NR) 70 )NR 80 R 80 -OC(O)R 70 -OC(S)R 70 -OCO2R 70 -OC(S)OR 70 -NR 70 C(O)R 70 -NR 70 C(S)R 70 -NR 70 CO2R 70 -NR 70 C(S)OR 70 -NR 70 C(O)N(R 80 )2、-NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )N(R 80 )2, where R 60 R 70 R 80 and M + As defined above.

[0038] In one embodiment, the substituted group has at least one substituent selected from those mentioned above, up to the possible number of substituents for a particular portion, such as one to five substituents, one substituent, two substituents, three substituents, four substituents, or five substituents.

[0039] Furthermore, in embodiments where a group or portion is substituted by a substituted substituent, the nesting of such substituted substituents is limited to three, thereby preventing polymer formation. Therefore, in a group or portion containing a first group (where the first group is a substituent on a second group, and the second group itself is a substituent on a third group, which is connected to the parent structure), the first (outermost) group can be substituted only by unsubstituted substituents. For example, in a group containing -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can be substituted only by its own unsubstituted substituent.

[0040] Those skilled in the art will understand that any group or portion defined herein may be connected to any other part of the disclosed structure (such as a parent structure or core structure), such as by taking into account valence rules, comparison with example types, and / or functionality, unless the context explicitly states or implies the connectivity of the group or portion to other parts of the structure.

[0041] "Aliphatic group" refers to a group or part that is substantially based on hydrocarbons. Aliphatic groups or parts can be acyclic, including alkyl, alkenyl, or ynyl groups (and alkylene, alkenyl, or ynylene groups), cyclic in form such as alicyclic groups or parts, including cycloalkyl, cycloalkenyl, or cycloynyl groups, and further include straight-chain and branched arrangements, as well as all stereo and positional isomers. Unless explicitly stated otherwise, aliphatic groups contain 1 to 25 carbon atoms (C1 to C2). 1-25 For example, for acyclic aliphatic groups or portions, 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), 1 to 6 (C 1-6 ), or 1 to 4 carbon atoms (C 1-4 ), or for alicyclic groups or portions, 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), 3 to 6 (C 3-6 ), or 3 to 4 (C 3-4 ( ) carbon atoms. Aliphatic groups can be substituted or unsubstituted unless explicitly stated as "unsubstituted aliphatic group" or "substituted aliphatic group". Aliphatic groups can be substituted by one or more substituents (up to two substituents for each methylene carbon in the aliphatic chain, or up to one substituent for each carbon of the -C=C- double bond in the aliphatic chain, or up to one substituent for the carbon of the terminal methine).

[0042] "Lower aliphatic groups" refer to groups containing 1 to 10 carbon atoms (C 1-10 Aliphatic groups, such as 1 to 6 (C 1-6 ), or 1 to 4 (C 1-4) carbon atoms; or for lower alicyclic groups, 3 to 10 (C 3-10 ), such as 3 to 6 (C 3-6 ) carbon atoms.

[0043] "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl. In some instances, R is C 1-6 Alkyl or C 3-6 Cycloalkyl. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In substituted alkoxy groups, R is a substituted alkyl group or a substituted cycloalkyl group, examples of which in the compounds disclosed herein include haloalkoxy groups, such as -OCF2H.

[0044] "Alkoxyalkyl" refers to the group -alkyl-OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl; -CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl.

[0045] "alkyl" refers to a saturated aliphatic hydrocarbon group having 1 to at least 25 carbon atoms (C60-C65). 1-25 More typically, 1 to 10 carbon atoms (C) 1-10 ), such as 1 to 6 carbon atoms (C 1-6 The alkyl moiety can be substituted or unsubstituted. As examples, this term includes straight-chain and branched hydrocarbon groups such as methyl (CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), and neopentyl (-CH2C(CH3)3).

[0046] "alkylene" refers to a divalent alkyl group or alkyl chain. Like the alkyl groups described above, such alkylene groups may optionally be substituted with one or more substituents as described above. Examples of such alkylene groups include, but are not limited to, -CH2, -CH(Me), -C(Me)2, -CF2-, -CH(F), -CH2CH2-, etc. As disclosed herein, such alkylene moiety may be used as a linking group.

[0047] Similarly, the terms "alkenyl" and "ynyne" refer to a divalent aliphatic chain containing at least one olefin or at least one alkyne, respectively. Such alkenyl and ynyne groups can be substituted by one or more of the aforementioned substituents.

[0048] "Amino" refers to the group -NH2, -NHR, or -NRR, where each R is independently selected from H, an aliphatic group, a heteroaliphatic group, an aromatic group (including aryl and heteroaryl), or a heterocyclic group, or two R groups together with the nitrogen they are attached to form a heterocycle. Examples of such heterocycles include those where two R groups together with the nitrogen they are attached to form -(CH2). 2-5 Those with rings, wherein the ring is optionally surrounded by one or two heteroatomic groups (such as -O- or -N(R)). g Insertion, such as in a group In, R g It is R 70 -C(O)R 70 -C(O)OR 60 or -C(O)N(R) 80 )2.

[0049] "Amide" refers to the group -N(R) acyl, where R is hydrogen, a heteroaliphatic group, or an aliphatic group, such as an alkyl group, especially C. 1-6 alkyl.

[0050] Unless otherwise specified, "aromatic group" refers to a cyclic conjugated group or portion having 5 to 15 ring atoms, having a monocyclic ring (e.g., phenyl, pyridyl, or pyrazolyl) or multiple fused rings, wherein at least one ring in the fused rings is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridyl), that is, at least one ring and optionally multiple fused rings have a continuous delocalized π-electron system. Typically, the number of out-of-plane π electrons corresponds to Hückel's rule (4n+2). The connection point with the parent structure is usually through the aromatic portion of the fused ring system. For example, However, in some instances, context or explicit disclosure may indicate that the connection point is through the non-aromatic portion of the fused ring system. For example, Aromatic groups or portions may contain only carbon atoms in the ring, such as in aryl groups or portions, or they may contain one or more cyclic carbon atoms and one or more cyclic heteroatoms (e.g., S, O, N, P, or Si) containing lone pairs of electrons, such as in heteroaryl groups or portions. Unless otherwise stated, aromatic groups may be substituted or unsubstituted.

[0051] Unless otherwise specified, "aryl" refers to an aromatic carbocyclic group with 6 to 15 carbon atoms, having a monocyclic (e.g., phenyl) or multiple fused rings, at least one of which is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxane, etc.). 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 specified, aryl groups can be substituted or unsubstituted.

[0052] "Aromatic aliphatic group" refers to an aryl group that is attached to the parent compound via an aliphatic moiety. Aromatic aliphatic groups include aralkyl or arylalkyl groups, such as benzyl and phenylethyl.

[0053] The "carboxyl group" refers to -CO2H.

[0054] "Carboxamide" refers to -C(O) amino.

[0055] "Carboxy ester" refers to the group -C(O)OR, where R is an aliphatic group, a heteroaliphatic group, or an aromatic group (including aryl and heteroaryl).

[0056] "Carboxylate" refers to -C(O)O - Or its salt.

[0057] "Cyano" refers to the group -CN.

[0058] "Alicyclic group" refers to a cyclic alicyclic group having a monocyclic (e.g., cyclohexyl) or polycyclic structure, such as in fused, bridged, or spirocyclic systems, where the ring or at least one ring in the system is alicyclic. Typically, the connection point to the parent structure is through the alicyclic portion of the polycyclic system. Alicyclic groups include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloynyl groups. Alicyclic groups may contain 3 to 25 carbon atoms; for example, 3 to 15, 3 to 10, or 3 to 6 carbon atoms. Unless otherwise stated, alicyclic groups may be substituted or unsubstituted. Exemplary alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0059] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0060] "Halogenated alkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary halogenated alkyl moieties include -CH2F, -CHF2, and -CF3.

[0061] A "heteroaliphatic group" refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, that is, at least one carbon atom from an aliphatic compound or group containing at least two carbon atoms has been replaced by an atom having at least one lone pair of electrons (typically nitrogen, oxygen, phosphorus, silicon, or sulfur). Heteroaliphatic compounds or groups can be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic, such as heterocyclic groups.

[0062] "Heteroaryl" refers to an aromatic group or portion that, unless otherwise specified, has 5 to 15 ring atoms, wherein the ring atoms comprise at least one carbon atom and at least one heteroatom, such as N, S, O, P, or Si. The heteroaryl group or portion may comprise a monocyclic ring (e.g., pyridinyl, pyrimidinyl, or pyrazolyl) or multiple fused rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). The heteroaryl group or portion may be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, the heteroaryl group or portion may be substituted or unsubstituted.

[0063] "Heterocyclic group" and "heterocycle" refer to aromatic and non-aromatic ring systems, and more specifically to a stable three- to fifteen-membered ring moiety containing at least one carbon atom, and usually multiple carbon atoms and at least one (such as 1 to 5) heteroatoms. The heteroatoms can be nitrogen, phosphorus, oxygen, silicon, or sulfur atoms. The heterocyclic group moiety can be a monocyclic moiety or can contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such polycyclic moiety can include fused or bridged ring systems as well as spirocyclic systems; and any nitrogen, phosphorus, carbon, silicon, or sulfur atom in the heterocyclic group moiety can optionally be oxidized to various oxidation states. For convenience, nitrogen, particularly but not exclusively, defined as those cyclic aromatic nitrogens, is intended to include its corresponding N-oxide form, although not explicitly defined in certain instances. Thus, for compounds having, for example, a pyridyl ring, the corresponding pyridyl-N-oxide is included as another compound of this disclosure unless explicitly excluded or excluded by the context. Furthermore, the cyclic nitrogen atom may optionally be quaternized. The heterocycle includes a heteroaryl moiety and a heterocyclic or heterocyclic group moiety, which is a partially or completely saturated heterocyclic ring. Examples of heterocyclic groups include, but are not limited to, azirrobutyl, oxacyclobutyl, acridine, benzo[-m-dioxacyclopentenyl], benzo[-dioxacyclohexyl], benzofuranyl, carbazoyl, borazinyl, dioxacyclopentenyl, indazinyl, naphridinyl, perhydroazirrobutylheptatrienyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purine, quinazolinyl, and quinoxalyl. Phinyl, quinolinyl, isoquinolinyl, tetrazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, 2-oxozadicyclic heptadienyl, azaheptadienyl, pyrroleyl, 4-piperidinoneyl, pyrrolealkyl, pyrazolyl, pyrazolalkyl, imidazolyl, imidazolinyl, imidazoalkyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl Pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolylalkyl, triazolyl, isoxazolyl, isoxazolylalkyl, morpholinyl, thiazolyl, thiazolyl, thiazolylalkyl, isothiazolyl, quininecycloyl, isothiazolyl, indolyl, isotindolyl, indololinyl, isotindololinyl, octahydroindolyl, octahydroisoindolyl, quinolinyl, isoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furanyl, diazabicycloheptane, diazapane, diazacycloheptane, tetrahydrofuranyl, tetrahydropyranyl, thiophene, benzothiaphenyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxaphosphazenecyclopentyl, and oxadiazolyl.

[0064] "Hydroxy group" refers to the -OH group.

[0065] "Nitro" refers to the group -NO2.

[0066] "Phosphate ester group" refers to the group -OP(O)(OR')2, where each -OR' is independently -OH; -O-aliphatic group, such as -O-alkyl or -O-cycloalkyl; -O-aromatic group, including -O-aryl and -O-heteroaryl; -O-aralkyl; or -OR' is -O - M + M + It is a counterion with a single positive charge. Each M + It can be an alkali metal ion, such as K. + Na + Li + Ammonium ions, such as +N(R”)4, where R” is H, an aliphatic group, a heteroaliphatic group, or an aromatic group (including aryl and heteroaryl); or alkaline earth metal ions, such as [Ca 2+ ] 0.5 、[Mg 2+ ] 0.5 or[Ba 2+ 0.5. Phosphonoyl alkyl refers to the group -alkyl-phosphate ester, such as, for example, -CH2OP(O)(OH)2 or its salt, such as -CH2OP(O)(O - Na + )2, and (((dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ester of phosphonoyl alkyl, such as, for example, -CH2OP(O)(O-tert-butyl)2.

[0067] "Phosphate group" refers to the group -P(O)(OR')2, where each -OR' is independently -OH; -O-aliphatic group such as -O-alkyl or -O-cycloalkyl; -O-aromatic group, including -O-aryl and -O-heteroaryl; or -O-aralkyl; or -OR' is -OM. + And M + It is a counterion with a single positive charge. Each M + It is a positively charged counterion, and can be, for example, an alkali metal ion, such as K+. + Na + Li + Ammonium ions, such as +N(R”)4, where R” is H, an aliphatic group, a heteroaliphatic group, or an aromatic group (including aryl and heteroaryl); or alkaline earth metal ions, such as [Ca 2+ ] 0.5 、[Mg 2+ ] 0.5 or[Ba 2+ ] 0.5Phosphonylalkyl refers to the group -alkyl-phosphonate, such as, for example, -CH2P(O)(OH)2, or -CH2P(O)(O - Na + )2, and ((dialkoxyphosphoryl)alkyl) refers to a dialkyl ester of phosphonoalkyl, such as, for example, -CH2P(O)(O-tert-butyl)2.

[0068] The term "patient" or "object" can generally refer to any living organism, but more commonly to mammals and other animals, especially humans. Therefore, the disclosed methods can be applied to both human therapeutics and veterinary applications.

[0069] "Pharmaceutically acceptable excipients" refers to substances other than the active ingredient that are included in a composition containing the active ingredient. As used herein, excipients may be incorporated into or physically mixed with particles of a pharmaceutical composition. For example, excipients may be used to dilute the active ingredient and / or modify the properties of the pharmaceutical composition. Excipients may include, but are not limited to, anti-adhesives, binders, coatings, enteric coatings, disintegrants, flavorings, sweeteners, colorants, lubricants, flow aids, adsorbents, preservatives, carriers, or mediators. Excipients may be starch and modified starch, cellulose and cellulose derivatives, sugars and their derivatives (such as disaccharides, polysaccharides, and sugar alcohols), proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids, or preservatives. Exemplary 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), tocopherol polyethylene glycol 1000 succinate (also known as vitamin ETPGS or TPGS), carboxymethyl cellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silicon dioxide, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

[0070] An adjuvant is a component that enhances the effect of other agents (usually the active ingredient). Adjuvants are often pharmacological and / or immunological agents. Adjuvants can enhance the effect of the active ingredient by increasing the immune response. Adjuvants can also act as stabilizers in formulations. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, bactericidal agents, squalene, detergents, cytokines, paraffin oils, and combination adjuvants, such as Freund's complete adjuvant or Freund's incomplete adjuvant.

[0071] "Pharmaceutically acceptable carrier" refers to an excipient that serves as a carrier or medium, such as a suspending agent, a dissolving agent, or a nebulizing agent. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21st edition (2005) (incorporated herein by reference) describes exemplary compositions and formulations suitable for drug delivery in one or more therapeutic compositions and additional pharmaceutical agents.

[0072] Generally, the nature of the carrier will depend on the specific mode of administration employed. For example, parenteral preparations typically contain injectable fluids, including pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, dextran aqueous solutions, glycerol, etc., as a medium. In some instances, a pharmaceutically acceptable carrier may be sterile to suit its administration to the recipient (e.g., via parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical composition to be administered may contain trace amounts of non-toxic excipients, such as wetting agents or emulsifiers, preservatives, and pH buffers, such as sodium acetate or sorbitol monolaurate.

[0073] "Pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts derived from various organic and inorganic counterions as known to those skilled in the art, and includes, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and salts of organic or inorganic acids, such as hydrochlorides, hydrobromic acids, tartrates, methanesulfonates, acetates, maleates, oxalates, etc., when the molecule contains a basic functional group. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological effectiveness of the free base upon formation via acid-coupled compounds. Specifically, the disclosed compounds form salts with various pharmaceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, hydroxyethanesulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, etc. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, 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, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, for example, SMBerge et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference). In certain disclosed embodiments, the compound may be a formate, trifluoroacetate, hydrochloride, or sodium salt.

[0074] The term "effective amount" for a compound or pharmaceutical composition refers to an amount sufficient to achieve a specific desired outcome, such as inhibition of a protein or enzyme. In a particular embodiment, an "effective amount" is an amount sufficient to achieve the following outcomes: inhibition of RIP1; inducing a desired biological or medical response in a tissue, system, subject, or patient; treatment of a specified disorder or disease; improvement or eradication of one or more of its symptoms; and / or prevention of the occurrence of the disease or disorder. As will be understood by those skilled in the art, the amount of compound constituting an "effective amount" can vary depending on the compound, the desired outcome, the disease state and its severity, the body size, age, and sex of the patient to be treated, etc.

[0075] "Prodrug" refers to a compound that is converted in vivo to produce a biologically active compound or a compound that is more biologically active than the parent compound. In vivo conversion can occur, for example, through hydrolysis or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, esters and amides of compounds having an active form with a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds disclosed herein include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (e.g., C14-C ... 1-6 Alkyl esters). Other prodrug moieties include phosphate esters, such as -CH2-OP(O)(OR′)2 or salts thereof, where R′ is H or C. 1-6 Alkyl groups. Acceptable esters also include cycloalkyl esters and arylalkyl esters, such as, but not limited to, benzyl esters. Examples of pharmaceutically acceptable amides of the compounds of this disclosure include, but are not limited to, primary amides, and secondary and tertiary alkylamides (e.g., having about one to about six carbons). Amides and esters of the disclosed exemplary embodiments of the compounds according to this disclosure can be prepared according to conventional methods. A full discussion of prodrugs is provided in the following literature: T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” ACSSymposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0076] A "solvent" is a complex formed by the combination of solvent molecules and solute molecules or ions. The solvent can be an organic solvent, an inorganic solvent, or a mixture of both. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, propanol; amides such as N,N-dialiphatic amides such as N,N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides such as dimethyl sulfoxide; water; and combinations thereof. The compounds described herein can exist in both unsolvated and solvated forms when combined with pharmaceutically acceptable or unacceptable solvents (such as water, ethanol, etc.). The solvated forms of the compounds disclosed herein are within the scope of the embodiments disclosed herein.

[0077] "Sulfanamide" refers to a group or part of -SO2amino or -N(R)sulfonyl group, where R is H, an aliphatic group, a heteroaliphatic group or an aromatic group (including aryl and heteroaryl).

[0078] "Thio group" refers to a group or -SH, -S-aliphatic group, -S-heteroaliphatic group, -S-aromatic group (including -S-aryl and -S-heteroaryl).

[0079] "Sulfinyl group" refers to a group or part of -S(O)H, -S(O) aliphatic group, -S(O) heteroaliphatic group or -S(O) aromatic group (including -S(O) aryl and -S(O) heteroaryl).

[0080] "Sulfonyl" refers to the following groups: -SO2H, -SO2 aliphatic group, -SO2 heteroaliphatic group, and -SO2 aromatic group (including -SO2 aryl and -SO2 heteroaryl).

[0081] As used in this article, “treatment” refers to treating a patient or subject (particularly a person with a target disease or condition) of a target disease or condition, and includes, for example, but not limited to:

[0082] (i) To prevent the disease or condition from occurring in a patient or subject, especially when such a patient or subject is susceptible to the condition but has not yet been diagnosed with the condition;

[0083] (ii) To suppress the disease or condition, for example, to stop or slow its development;

[0084] (iii) Alleviating the disease or condition, for example, causing a reduction in symptoms or the disappearance of the disease or condition or its symptoms; or

[0085] (iv) To stabilize the disease or condition.

[0086] The terms “disease” and “symptom” used in this article may be used interchangeably or may be different, because a particular disease or symptom may not have a known causative agent (so the cause has not yet been determined) and is therefore not yet considered a disease, but only an undesirable symptom or syndrome in which a more or less specific set of symptoms is identified by a clinician.

[0087] The above definitions and the following general formulas are not intended to include unacceptable substitutions (e.g., methyl groups substituted with five fluorine groups). Such unacceptable substitutions will be readily identifiable by those skilled in the art.

[0088] Those skilled in the art will understand that specific compounds may exhibit tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, some disclosed compounds may include one or more chiral centers and / or double bonds, and thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, some disclosed compounds may exist in several tautomeric forms, including enol forms, ketone forms, and mixtures thereof. Since the various compound names, formulas, and compound diagrams in the specification and claims may only represent 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 isomeric forms. Using techniques known to those skilled in the art, and particularly with the aid of this disclosure (which provides methods for separating such mixtures, such as chiral HPLC), mixtures of different isomeric forms (including mixtures of enantiomers and / or stereoisomers) can be separated to provide each individual enantiomer and / or stereoisomer. Alternatively, as known to those skilled in the art of organic synthesis, compounds can be synthesized in enantiomerically pure or enantiomerically enriched forms. Transisomers are also possible, and are explicitly included in the compounds of this disclosure, in cases of restricted rotation (e.g., around an amide bond or between two directly linked rings, such as a pyridyl ring, biphenyl, etc.).

[0089] In any embodiment, any or all hydrogens present in the compound or in a particular group or portion thereof may be replaced by deuterium or tritium. Thus, the description of alkyl groups includes deuterated alkyl groups, wherein the group is rich in deuterium relative to its natural abundance, or one to the maximum number of hydrogens present may be replaced by deuterium. For example, ethyl refers to C2H5 or C2H5, wherein 1 to 5 hydrogens are replaced by deuterium, for example in C2D. x H 5-x middle.

[0090] II. RIP1-active compounds and pharmaceutical compositions containing RIP1-active compounds

[0091] A. Compound

[0092] This document discloses compounds that can be used to inhibit RIP1 and / or for treating diseases and / or conditions related to RIP1, and pharmaceutical compositions comprising such compounds. In some embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds are capable of selectively inhibiting RIP1 relative to other kinases, including relative to RIP2, RIP3, or both.

[0093] In some embodiments, the compounds of this disclosure have a structure according to Formula I.

[0094]

[0095] in

[0096] X is selected from bonds, CH2, O, S, S(O), S(O)2, and NR. a ;

[0097] R a Each time it appears, it is selected from hydrogen and C. 1-6 alkyl;

[0098] Y 1 Y 2 and Y 3 Independently selected from N, N(R) a ), O, C(R) b ) 1-2 And C=O;

[0099] R b Selected from hydrogen, C 1-6 Alkyl and halogen;

[0100] Z is C(R) c ) or NR c ;

[0101] R c It is optionally controlled by one or more R 1 C with substituent group 1-4 An unsaturated carbon chain, which optionally contains one or two heteroatoms selected from O, N and S;

[0102] R z Is it N, CH or C(R) 1 And with ZR c And together with the carbon they bind, they form optionally m R 1 A 5- or 6-membered heteroaryl or 6-membered aryl ring substituted with a functional group;

[0103] R 1 It is a halogen, linker group -R 6 Groups, wherein the linking group is a bond, optionally bounded by one or more R groups. b Substituted (C1-C4)alkyl, (C1-C4)alkenyl or (C1-C4)ynyl and R 6 It is R e -C(R) f )3 or -C(R f )=C(R f )2;

[0104] R 2 It is R a ;

[0105] Ring B is a 5-10 member heteroaryl group;

[0106] R 3 Each time it appears, it is independently selected from R. b and OR a ;

[0107] L is O, NR a or alkylene;

[0108] W is arbitrarily assigned to p R. 4 Substituted 5-10 aryl or heteroaryl groups;

[0109] R 4 Selected from R each time it appears b and OR a ;

[0110] R d Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, Aryl, C 5-10 aryl or heteroaryl, or two R d Together with the nitrogen attached to both of them, they form a mixture optionally bound by one or more R e Replacement C 3-10 Heterocyclic groups;

[0111] R e Each time it appears, it is independently halogen, -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 ;

[0112] Rf It is R independently each time it appears. a R b Or R e , or two R f The groups, together with the carbon atoms they are bonded to, form C. 3-6 cycloalkyl or C 3-10 Heterocyclic groups, each optionally bound by one or more R e replace;

[0113] m is 1, 2, 3, or 4;

[0114] n is 0, 1, or 2; and

[0115] p is 0, 1, 2, 3, 4 or 5.

[0116] 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 indicated. Referring to Formula 1, exemplary compounds are isolated into racemic mixtures, and other compounds are synthesized and / or isolated into single enantiomers. In particular, carbons marked with * in Formula I may be in the R or S configuration.

[0117] Some embodiments of Formula I have structures IA, IB, IC, or ID.

[0118]

[0119] Reference formulas I, IA, IB, IC, and ID, R z With ZR c And together with the carbon they bind, they form optionally m R 1 A 5- or 6-membered heteroaryl or 6-membered aryl ring with substituted groups, where m is 1, 2, 3, or 4. R c C is a carbon matrix that optionally contains one or two heteroatoms selected from O, N, and S. 1-4 Unsaturated carbon chains. Therefore, continuing with reference to Formulas I, IA, IB and IC, certain embodiments of the disclosed compounds have Formulas II, III or IV.

[0120]

[0121] Referring 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 some cases, m is 1 or 2, such as 1. In other embodiments, m is 0 or 1. Specifically, in embodiments of Formulas I, IA, IB, IC, ID, II, III, and IV, where B is...

[0122] m is 0, 1, 2, 3, or 4, such as 0 or 1.

[0123] Reference IV, Z 1 Selected from C and N; and Z 2 Z 3 and Z 4 Independently selected from O, S, S(O)2, CH, N, N(R) a ) and CR 1 Continuing with Formula IV, m is 0, 1, 2, or 3, and in some embodiments of Formula IV, m is 0 or 1. In one embodiment of Formula IV, Z 2 and Z 4 At least one of them is CH or CR 1 And has the formula IVA

[0124] In one implementation of formulas IV and IVA, Z 1 It is N and Z 3 Is it CH or CR? 1 Such compounds have the formula IVB.

[0125]

[0126] In the disclosed embodiments of RIP1K inhibitor compounds (including those of formulas I, IA, IB, IC, ID, II and III, IV, IVA and IVB), and in formulas V, VA, VB, VC, VD and VI described below, R 1 In each case, it can be a linker base -R 6 In such an implementation, the connection base -R 6 The linker is a C1, C2, C3, or C4 aliphatic group, such as a C2 alkylene, alkenylene, or ynylene group, or a C1, C2, C3, or C4 haloaliphatic group, such as a C2 haloalkylene or haloalkenylene group. In some embodiments, R 1 The linker is R a , where R a It is a C1-C4 alkylene group, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-; or the linking group is a C2-C4 alkenyl group, such as -CH=CH-, -CH=CHCH2-, -CH2CH=CH-, or -CH2CH=CHCH2-; or the linking group is a C2-C4 alkyne group, such as -C≡C-, -C≡CCH2-, -CH2C≡C-, or -CHC≡C-CH2-. Such groups are optionally substituted, such as by one or more R b Replace, where R b Selected from C1-6 Alkyl and halogen. In some embodiments, the linking group is a C2-C4 haloalkenyl group, such as -CF=CH-, -CCl=CH-, -CH=CCl-, -CH=CF-, -CCl=CCl-, -CF=CF-, or -CCl=CF-, -CF=CCl-. In some embodiments, the linking group is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, -CCl=CH-, -CH=CCl-, or -C≡C-.

[0127] In some implementations, R 1 R 6 The group is C(R) f )3, one of which is R f It is R e , where R e Yes - OR a (e.g., hydroxyl or OMe) and each other R f R is independent a , where R a It is C 1-4 Aliphatic groups and preferably each other R f It is R a , where R a It is C independently each time it appears. 1-4 Alkyl group. In a particular embodiment, each other R f It is R a , where R a It is methyl or CD3. In another embodiment, R 6 It is -C(R) f )3, where each R f It is R a , where R a It is methyl or H, or each of the R's f It is R a , where R a It is methyl; or R b , where R b It is -C(O)OR c In some other implementations, an R f It is R e Yes - OR a (e.g., hydroxyl or OMe), and the other two R fThe groups are attached to the carbon atoms to form alicyclic groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or heterocyclic groups (e.g., epoxides, oxetanes, tetrahydrofuran, tetrahydropyran, piperidinyl, piperazine, hexahydrofuran[3,2-b]furan), etc. In some such embodiments, the alicyclic groups and / or heterocyclic groups may be substituted, and in some specific embodiments, they may be substituted by one or more hydroxyl or benzyl-carbonyl groups.

[0128] Some compound implementation schemes have C 2-4 The linking group of the group may contain an alkyne. In a particular embodiment, R 1 Is - Connector-R 6 Group and the linking group is R a , where R a It is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, or -C≡C-, or -CH2C≡C-, and R 6 It is R b , where R b Is it -C(O)OEt or -C(O)NR? d R d or -NR d R d , where each R d Each time it appears, it is independently hydrogen and C. 5-10 heteroaryl, C 3-6 cycloalkyl, or two R d The groups are attached to the nitrogen atoms to form heterocyclic groups, which may further contain one or more atoms other than R. d Other heteroatoms besides the nitrogen atom bonded to the group. In some embodiments, an R d It is hydrogen and another R d It is C 5-10 heteroaryl, the C 5-10 Heteroaryl groups can be denoted by one or more R groups. e Replace, such as one of the following:

[0129]

[0130] In specific embodiments of formulas I, IA, IB, IC, ID, II and III, IV, IVA and IVB, at least one R 1 Part of it is

[0131]

[0132]

[0133] In other implementations, R 1 It is a heterocyclic group, such as -NR d R d Two of the R d The groups together with the nitrogen they are bonded to form C 3-10 Heterocyclic groups. In some implementations, when two R groups... d The groups together with the nitrogen they are bonded to form C 3-10 When the heterocyclic group is used, the C 3-10 Heterocyclic groups are substituted by one or more R e Group substitution, and / or having one or more R groups in some embodiments in addition to the two R groups. d Other heteroatoms besides nitrogen are bonded to the group. In some embodiments, the C 3-10 Heterocyclic groups are divided by two R e Group substitution, the two R e Groups link together to form C 3-10 Heterocyclic group, and the C 3-10 Heterocyclic groups and R b Groups together can form spirocyclic or bicyclic groups. Some disclosed spirocyclic groups comprise at least two rings, each ring having a different number of atoms. In some embodiments, the spirocyclic group comprises at least two rings, wherein the first and second rings of the spirocyclic group have different numbers of carbon atoms, different numbers of heteroatoms, or both. In still other embodiments, each ring of the spirocyclic group contains a heteroatom in the ring, and each ring of the spirocyclic group may have different heteroatoms in the ring or have the same heteroatoms in the ring, such as at least one oxygen atom and at least one nitrogen atom. In some embodiments, the spirocyclic group comprises a first ring containing a nitrogen atom and a second ring containing an oxygen atom. The spirocyclic group comprises a first ring coupled to ring A phenyl, wherein the first ring has 3-7 atoms and the second ring has 3-7 atoms. Typically, the spirocyclic group comprises more than 7 atoms in total in the spirocyclic system, and some embodiments have spirocyclic groups comprising 9 atoms in total in the spirocyclic system. e C formed by group 3-10 Heterocyclic groups and those derived from R b Two R d C formed by group 3-10 Heterocyclic groups can form bicyclic groups, such as bicyclic groups containing two or more heteroatoms (such as nitrogen and / or oxygen). The bicyclic group can be linked to a cyclic A phenyl group via the nitrogen atom of the bicyclic group. In some embodiments, the bicyclic group can be a fused bicyclic group or a bridged bicyclic group.

[0134] In any or all of formulas I, IA, IB, IC, ID, II and III, IV, IVA and IVB, and in formulas V, VA, VB, VC, VD and VI described below, R 1 Selected from

[0135]

[0136] Regarding formulas I, IA, IB, IC, II, III, IV, IVA, and IVB, Y 1 Y 2 and Y 3 Independently selected from N, N(R) a ), O, C(R) b ) 1-2 and C=O. In one embodiment of the above formula, the disclosed compound has formula V.

[0137]

[0138] Where Y 2 and Y 3 The bond between them is a single or double bond, such as in formulas VA, VB, VC, or VD shown below. Continuing with formula V, in some embodiments, Y 2 and Y 3 Each is CH2. In other embodiments of formula V, Y 2 and Y 3 Independently selected from CH2 and CHCl, such as when Y 2 It is CH2 and Y 3 When it is CHCl, or when Y 2 It is CHCl and Y 3 When it is CH2.

[0139]

[0140] In another embodiment of formulas I, IA, IB, II, III, IV, IVA, and IVB, the disclosed compound has formula VI.

[0141]

[0142] Referring to the above formula, R 2 It can be any suitable substituent, such as R a Parts, such as hydrogen, C 1-6 Alkyl or C 1-6 Acyl groups, such as hydrogen or methyl. When R 2 When it is methyl, the methyl moiety can be -CD3-, that is, the methyl group can be rich in deuterium relative to the natural abundance of deuterium.

[0143] Regarding formulas IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI, ring B is a heteroaryl group, such as a 5- to 10-membered heteroaryl group, for example, a 5- or 6-membered heteroaryl group. In some embodiments, ring B is a 5- or 6-membered heteroaryl group, wherein the heteroaryl group has one or two rings or three nitrogen atoms, and the remaining ring atoms are carbon, such as pyrrole, diazole, or triazole. In other embodiments, ring B is an oxazole, thiazole, or isoxazole. In some embodiments, ring B is a pyrazolyl group, and in other specific embodiments, ring B is a pyridinyl or pyrimidinyl group. In some embodiments, ring B is a bicyclic ring system, wherein at least one ring is aromatic. Examples of such bicyclic ring systems of B include, but are not limited to, dihydropyrrolotriazole, triazolopyridine, imidazopyridine, tetrahydrotriazolopyrazine, tetrahydropyrazolopyridine, etc. In some embodiments, group B has the formula...

[0144]

[0145] In specific embodiments of formulas IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI, ring B is a 5-membered heteroaryl group, and ring B may have the following properties: The structure wherein at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In some embodiments, the 5-membered heteroaryl group is a diazole, triazole, oxadiazole, or oxazole. Exemplary triazoles include any of the following:

[0146]

[0147] The exemplary diazole is selected from any of the following:

[0148]

[0149] Exemplary oxazoles are selected from any of the following:

[0150]

[0151] The exemplary oxadiazole is selected from any of the following:

[0152]

[0153] As described above with references to I, IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI, the "B" ring may be optionally replaced, such as by R. b and OR a Replacement, where R occurs each time. b Selected from C 1-6 Alkyl groups (such as methyl groups) and halogens (such as fluorine or chlorine).

[0154] Continuing with reference to equations I, IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI, L is the connecting base part such as O, N(R) a -NR a - alkylene, cycloalkyl, or combinations thereof. The alkylene moiety may optionally contain one or more -O-, -N(R) groups. a - or -NR a As an example, such linker bases include, but are not limited to, -(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 Such as -CH2, -CH(Me), -C(Me)2, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CF2-, -CH(F); and optionally by one or more R b Substituted cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0155] In equations IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI, the W portion is optionally divided by p R. 4 5-10 membered aryl or heteroaryl groups substituted with functional groups, wherein:

[0156] R 4 Selected from R each time it appears b and OR a In some embodiments of the disclosed compound, W is selected from...

[0157]

[0158] Table 1 lists certain disclosed exemplary compounds within the range of one or more of formulas I, IA, IB, II, III, IV, IVA, IVB, V, VA, VB, VC, VD, and VI.

[0159] Table 1

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175] Those skilled in the art will understand that some of the compounds disclosed herein may exhibit tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, some disclosed compounds may include one or more chiral centers and / or double bonds, and thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, some disclosed compounds may exist in several tautomer forms, including enol forms, ketone forms, and mixtures thereof. Since the various compound names, formulas, and compound diagrams in the specification and claims may only represent one of the possible tautomerisms, conformational isomers, optical isomers, or geometric isomers, those skilled in the art will understand that the disclosed compounds encompass any tautomerisms, conformational isomers, optical isomers, and / or geometric isomers of the compounds described herein, as well as mixtures of these various isomers. Mixtures of different isomeric forms, including mixtures of enantiomers and / or stereoisomers, can be separated to provide each individual stereoisomer technique known to those skilled in the art, as well as those described in this disclosure. Restricted rotational isomers are possible and are simple tautomers of the compounds of this disclosure, in cases of restricted rotation (e.g., around an amide bond or between two directly linked rings, such as a pyridyl ring, biphenyl, etc.).

[0176] B. Pharmaceutical Composition

[0177] In some embodiments, one or more compounds may be included in a pharmaceutical composition or a drug, and in some embodiments, the one or more compounds may be in the form of a parent compound or a pharmaceutically acceptable salt, cocrystal, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug. The pharmaceutical composition typically includes at least one additional component besides the disclosed one or more compounds, such as a pharmaceutically acceptable excipient, adjuvant, additional therapeutic agent (described below), or any combination thereof.

[0178] Pharmaceutically acceptable excipients can be included in pharmaceutical compositions for a variety of purposes, such as diluting the pharmaceutical composition for delivery to a subject, facilitating the processing of the formulation, providing the formulation with favorable material properties, promoting dispersion from a delivery device, stabilizing the formulation (e.g., an antioxidant or buffer), and providing the formulation with a pleasant or palatable taste or consistency. Pharmaceutically acceptable excipients may include pharmaceutically acceptable carriers. Exemplary excipients include, but are not limited to: monosaccharides, disaccharides, and polysaccharides; sugar alcohols and other polyols, such as lactose, glucose, raffinose, mesotriose, 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-adhesion agents, such as magnesium stearate; binders, such as sugars (including disaccharides, such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coating agents (such as cellulose ethers, including hydroxypropyl methylcellulose, shellac, corn gluten, and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, croscarmellose sodium, and starch glycolate sodium); and fillers. Agents (such as dicalcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavorings and sweeteners (such as mint, cherry, star anise, peach, apricot, or licorice, raspberry, and vanilla); lubricants (such as minerals, such as talc or silica, fats, such as vegetable stearin, magnesium stearate, or stearic acid); preservatives (such as antioxidants, such as vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids, such as cysteine ​​and methionine, citric acid and sodium citrate, parabens, such as methylparaben and propylparaben); colorants; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0179] III. Methods using compounds

[0180] A. Illness / Disorder

[0181] The disclosed compounds, combinations thereof, and / or pharmaceutical compositions can be used to inhibit RIP1 kinase by contacting RIP1 kinase in vivo or in vitro with one or more compounds of this disclosure, or a composition comprising one or more compounds of this disclosure. The disclosed compounds, or compositions comprising one or more disclosed compounds, can also be used to improve, treat, or prevent a variety of diseases and / or disorders. In certain embodiments, the disclosed compounds, combinations thereof, or pharmaceutical compositions thereof can be used to treat conditions in which inhibition of RIP1 or a pathway containing RIP1 is therapeutically useful. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In some embodiments, the disclosed compounds can be used to treat autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancer, ischemic diseases, erythrocyte apoptosis, lung and brain injuries (e.g., induced by ischemia-reperfusion or cisplatin and / or cerebrovascular accidents), and bacterial and viral infections.

[0182] In some embodiments, the disclosed compounds, combinations of the 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.

[0183] The disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof may also be used to treat immunomodulatory disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunomodulatory disorders that can be treated with said compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, organ or tissue transplantation, graft-versus-host disease resulting from transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, suppurative dermatitis, etc. Hidradenitis suppurativa, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Bechtel's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoma, ocular pemphigoid, Moren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, hay fever, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-stage asthma, and airway hyperresponsiveness. Adverse reactions, bronchitis, gastric ulcers, vascular injury caused by ischemic diseases and thrombosis, ischemic bowel disease, ischemia-reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, intestinal injury associated with heat burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, pulmonary hemorrhage-nephritis syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Grievance-Bartholin's syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Bartholin's disease, pure red cell aplasia, aplastic anemia, aplastic anemia, aplastic syndrome Anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoiesis, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy or myocardial infarction, scleroderma (including systemic scleroderma), antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, obesity, eosinophilic fasciitis, lesions of the gingiva, periodontal tissues, alveolar bone, and cementum, glomerulonephritis.Male pattern baldness or age-related alopecia (by preventing hair loss or providing hair germination and / or promoting hair production and growth), muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemia-reperfusion injury of organs following preservation, transplantation or ischemic disease, endotoxic shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, toxicosis caused by pulmonary oxygen or drugs, lung cancer, emphysema, cataracts, falconetitis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, corneal alkali burns, erythema multiforme dermatitis, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenic effects, cancer metastasis and barotrauma, caused by histamine or leukotriene-C4 release. Diseases including Bechtel's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock, or hypoxia, hepatitis B, non-A / non-B hepatitis, cirrhosis, alcoholic liver disease, including alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), autoimmune hepatobiliary diseases, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant hepatic failure, delayed hepatic failure, "chronic plus acute" liver failure, chronic kidney disease, kidney damage / injury (caused by, for example, nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs, acute kidney injury), increased chemotherapy efficacy, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, Parkinson's disease, trauma, or chronic bacterial infection.

[0184] In some embodiments, the compounds of the present invention can be used to treat neuropathic pain, including neuropathic pain and inflammation-induced pain.

[0185] In some embodiments, the compound can be used to treat interleukin-1 converting enzyme-related febrile syndrome, tumor necrosis factor receptor-related periodic syndrome, NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases (e.g., Gaucher disease, GM2 ganglioside storage disease, α-mannoside storage disease, aspartate glucosamineuria, cholesterol ester storage disease, chronic hexosaminease A deficiency, cystinosis, Danon's disease, Fabry disease, Fabry disease, fucose Glycosyl storage disease, galactosylsialic acid storage disease, GM1 ganglioside storage disease, mucolipid storage disease, infantile free sialic acid storage disease, adolescent hexosamine A deficiency, Krabby disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharide storage disorder, multiple sulfatase deficiencies, Niemann-Pick disease, neuronal ceramide lipofuscin deposition disease, Pompe disease, osteogenesis imperfecta condensans, Sandhof disease, Schindler disease, sialic acid storage disease, Tay-Sach disease, and Wollman disease.

[0186] In some embodiments, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof may be used to treat and / or prevent rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis (especially pustular psoriasis), type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D syndrome and periodic fever syndromes, such as cold pyridine-associated periodic syndromes, familial Mediterranean fever (FMF) syndrome, Schnitzler syndrome, and TNF-receptor-associated periodic fever syndromes (TRAPS), systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, acute gout attacks, pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, and DIRA (deficiency of Il-1 receptor antagonists).

[0187] Disclosed RIP1K inhibitors are particularly useful for the treatment of neurological disorders (including neurodegenerative disorders, as described above). As examples, the compounds of this invention can be used to treat Alzheimer's disease, ALS, Huntington's disease, and Parkinson's disease.

[0188] Proliferative diseases that can be treated by the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof include benign or malignant tumors, solid tumors, cancers of the brain, kidneys, liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland, sarcomas, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancers, especially colon cancer or colorectal cancer. Intestinal adenoma, neck and head tumors, epidermal hyperplasia, psoriasis, benign prostatic hyperplasia, tumor formation, epithelial tumor formation, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, MyD88 driven disorders (such as ABC diffuse large B-cell lymphoma (DLBCL), Walden...) Stromb's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), condensing or painless multiple myeloma, or hematologic malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, ABCDLBCL, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B... - Cytoprolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic / myeloproliferative neoplasms (MDS / MPN) such as chronic myelomonocytic leukemia (CMML, including CMML-0, CMML-1, and CMML-2), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma. Specifically, the compounds disclosed herein can be used to treat drug-resistant malignancies, such as those resistant to JAK inhibitors or BTK inhibitors, malignancies such as those resistant to ibrutinib, including hematologic malignancies such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenström's macroglobulinemia.

[0189] Although CMML shares some clinical and pathological features with both myeloid neoplasms (MPNs) and myelodysplastic syndromes (MDS), it remains a separate category within the MDS / MPN overlap group classified by the World Health Organization (WHO) (Arber et al., “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia,” Blood, Vol. 127, No. 20, pp. 2391-2405, May 19, 2016). According to the WHO, a diagnosis of CMML now requires the presence of ≥1×10-1 9 Persistent peripheral blood monocytosis of ≥10% of white blood cell (WBC) differential count. Furthermore, CMML can only be diagnosed by definition after excluding rearrangements in the PDGFRA, PDGFRB, or FGFR1 genes, and the PCM1-JAK2 fusion gene was added as an exclusion criterion in the 2016 update. In some implementations, a method for treating CMML includes identifying individuals with WHO diagnostic criteria (i.e., ≥1 × 10⁹ / L). 9 Subjects with persistent peripheral blood monocytosis (≥10% of white blood cell differential count) and excluding rearrangements in the PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 genes, and treated by administration of the RIP1 inhibitor disclosed herein, combinations of such compounds, and / or combinations thereof.

[0190] Examples of allergic disorders that can 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, idiopathic asthma, true asthma, endogenous asthma caused by pathophysiological disorders, idiopathic asthma of unknown or unexplained cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, and exogenous asthma caused by environmental factors). Cold air-induced asthma, occupational asthma, infectious asthma caused by or related to bacterial, fungal, protozoan, or viral infections, early-stage asthma, wheezing infant syndrome, bronchiolitis, cough variant asthma or drug-induced asthma, allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, purulent or nonpurulent sinusitis, acute or chronic sinusitis, as well as ethmoid sinusitis, frontal sinusitis, maxillary sinusitis, or sphenoid sinusitis.

[0191] As another example, rheumatoid arthritis (RA) typically causes swelling, pain, loss of mobility, and tenderness in target joints throughout the body. RA is characterized by a chronically inflammatory synovium densely packed with lymphocytes. The synovium, normally a single cell layer thick, becomes densely cellular and presents a form similar to lymphoid tissue, including dendritic cells, T cells, B cells and NK cells, macrophages, and clusters of plasma cells. This process, along with numerous immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, ultimately leads to the disruption of joint integrity, resulting in deformities, 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, improve, or prevent any, several, or all of these symptoms of RA. Therefore, in the context of RA, when a reduction or improvement of any symptom commonly associated with RA is achieved, the compound is considered to provide a therapeutic benefit, regardless of whether the treatment results in concomitant treatment of fundamental RA and / or a reduction in the amount of circulating rheumatoid factor (“RF”).

[0192] The American College of Rheumatology (ACR) has developed criteria for defining improvement and clinical remission in rheumatoid arthritis (RA). One such criterion, ACR20 (the ACR standard for 20% clinical improvement), requires a 20% improvement in the number of tender and swollen joints, and a 20% improvement in three of the following five parameters: overall patient assessment, overall physician assessment, patient pain assessment, degree of disability, and level of acute-phase reactants. These criteria were expanded to 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include the Paulu criteria and radiographic progress (e.g., Sharp score).

[0193] In some implementations, treatment benefits are achieved in patients with RA when they exhibit ACR20. In specific implementations, ACR improvement of ACRC50 or even ACR70 can be achieved.

[0194] Other diseases or disorders that can be treated and / or prevented using the compounds and compositions of the present invention include spondyloarthritis, including axial spondylitis, such as ankylosing spondylitis, SoJIA, autoimmune hepatitis, autoimmune hepatobiliary diseases, autoimmune ITP, cerebrovascular accident, myocardial infarction, allergic diseases, chronic obstructive pulmonary disease, myocardial infarction, HIV-related dementia, glaucoma, Friedreich ataxia, Lewy body disease, spinal cord injury, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, prion disorders, destructive bone disorders such as bone resorption diseases, multiple myeloma-related bone disorders; proliferative disorders such as acute myeloid leukemia, chronic myeloid leukemia; angiogenesis disorders such as angiogenesis disorders including solid tumors, ocular neovascularization, and infantile hemangiomas; infectious diseases such as sepsis, septic shock, and Shigella infection; neurodegenerative diseases such as metastatic melanoma, HIV infection and CMV retinitis, fibrotic conditions such as non-alcoholic steatohepatitis and cardiological conditions such as ischemia-reperfusion; allergic reactions, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythematosis, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle atrophy, cachexia, Lightolt syndrome, rubella arthritis, acute synovitis, pancreatic β-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritis conditions, cerebral malaria, chronic pneumonia, silicosis, pulmonary sarcoidosis, allogeneic graft rejection, fever and myalgia caused by infection, keloid formation. Angiogenesis disorders include: scar tissue formation, ulcerative colitis, febrile diseases, influenza, chronic myeloid leukemia; angiogenesis disorders including solid tumors; viral diseases, including acute hepatitis infections (including hepatitis A, hepatitis B, and hepatitis C), AIDS, ARC, or malignant tumors, herpes; stroke, myocardial ischemia, local ischemia in stroke-cardiac attacks, organ hypoxia, angiogenesis, cardiac and renal reperfusion injury, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia, and / or toxic shock syndrome. Symptoms related to prostaglandin intraperoxidase synthase-2, pemphigus vulgaris, ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury caused by stroke, myocardial ischemia-reperfusion injury caused by 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, cortical-basal degeneration, demyelinating diseases.Vertebral arthritis, systemic paroxysmal juvenile idiopathic arthritis (SoJIA), systemic lupus erythematosus (SLE), Sjögren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), kidney transplantation, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA), pulmonary sarcoidosis, interleukin-1 converting enzyme (ICE, also known as aspartate-specific cysteine ​​protease-1)-associated febrile syndrome, chronic obstructive pulmonary disease (COPD), periodontitis, NEMO-deficiency syndrome (F-κ-B essential regulatory gene (also known as IKKγ or IKKG) deficiency syndrome), hematologic and solid organ malignancies, lysozyme Storage diseases, glaucoma, spondyloarthritis, retinal degenerative diseases, retinal ischemia / reperfusion injury, renal ischemia / reperfusion injury, anthrax-induced septic shock, LPS-induced cell death, infectious encephalopathy, encephalitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, segmental ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic lupus erythematosus, macular edema, diabetic retinopathy, central reticular choroidal dystrophy, Best's disease, adult yolk sac disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt's disease, cone-rod dystrophy, North Carolina Malnutrition, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis and photoinduced toxicity, macular edema, diabetic retinopathy, central retinal dystrophy, Best's disease, adult yolk sac disease, pattern dystrophy, optic nerve injury, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, ischemic optic neuropathy (e.g., arteritis- or non-arteritis-related anterior and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber's optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, significant optic atrophy, Beh R-syndrome (Cjuglandular disease), progressive supranuclear palsy, hereditary spastic hemiparesis, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, hypoxic-ischemic brain injury, focal cerebral ischemia, global cerebral ischemia and hypoxic-ischemic stroke, peritoneal injury caused by peritoneal dialysis fluid (PDF) and PD-related side effects, glomerular diseases, tubulointerstitial diseases, 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, kidney cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, neuroendocrine cancer, central nervous system cancer.Brain tumors (e.g., glioma, anaplastic oligodendroglioma, glioblastoma multiforme in adults, and anaplastic astrocytoma in adults), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, ascites, malignant pleural effusion, mesothelioma, nephroblastoma, trophoblastic tumor, hemangiopericytoma, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, vulvar cancer, adrenocortical cancer, ACTH-producing tumors, lymphoma and leukemia, respiratory infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, adenovirus, reovirus, etc.), herpes zoster caused by herpesvirus, diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infectious diseases such as Bacillus cereus, Vibrio parahaemolyticus, and enterohemorrhagic Escherichia coli. Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Salmonella, Botulinum toxin, Candida, Paget's disease, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, congenital hypophospholipid syndrome, fibromatosis, fibrous dysplasia, bone turnover, osteolytic bone disease, periodontal disease, post-traumatic bone surgery, post-articular joint surgery, post-plastic surgery, post-dental surgery, bone chemotherapy. Or bone radiation therapy, bone cancer, fragile plaques, obstructive lesions, stenosis, coronary artery obstruction, peripheral artery obstruction, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, post-operative graft occlusion, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, cold and warm agglutinin disorders, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), and pemphigus vulgaris.

[0195] B. Combination of therapeutic agents

[0196] Those skilled in the art will understand that conditions treated with the RIP1K inhibitors disclosed herein may benefit from treatment in combination with one or more other therapeutic agents. In fact, the RIP1K inhibitor compounds described herein can be used alone, in combination with each other, in separate pharmaceutical compositions, in a single pharmaceutical composition, or as an adjunct to or in combination with other established therapies. The one or more compounds or compositions comprising the one or more compounds can be administered once or multiple times. In some embodiments, the compounds of the present invention can be used in combination with other therapeutic agents useful for the disorder or condition being treated. These other therapeutic agents can be administered simultaneously, sequentially in any order, or via the same or different routes of administration as the compounds disclosed herein. For sequential administration, the one or more compounds and the one or more therapeutic agents can be administered such that the effective time period of at least one compound and therapeutic agent overlaps with the effective time period of at least one other compound and / or therapeutic agent. In an exemplary embodiment comprising a combination of four components, the effective time period of the administered first component may overlap with the effective time periods of the second, third, and fourth components, but the effective time periods of the second, third, and fourth components may independently overlap or not overlap with each other. In another exemplary embodiment comprising a combination of four components, the effective time period of the first component overlaps with the effective time period of the second component, but not with the effective time period of the third or fourth component; the effective time period of the second component overlaps with the effective time periods of the first and third components; and the effective time period of the fourth component overlaps only with the effective time period of the third component. In some embodiments, the effective time periods of all compounds and / or therapeutic agents overlap with each other.

[0197] In some embodiments, the compound is administered together with another therapeutic agent (such as analgesics, antibiotics, anticoagulants, antibodies, anti-inflammatory agents, immunosuppressants, guanylate cyclase-C agonists, incretins, antiviral agents, anticancer agents, antifungals, or combinations thereof). The anti-inflammatory agent may be a steroid or a non-steroidal anti-inflammatory agent. In some embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylate, cyclooxygenase inhibitors, diclofenac, etodoxacin, famotidine, fenprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, meloxicam, naproxen, naproxen, oxaprazin, piroxicam, disalicylate, sulindac, tometidine, or combinations thereof. In some embodiments, the immunosuppressant is a mercaptopurine, a corticosteroid, an alkylating agent, a troponin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an anti-lymphocyte globulin, an anti-thymocyte globulin, an anti-T-cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0198] The compounds described herein can be used 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 mesalazine products, hydroxychloroquine, thiopurine, methotrexate, cyclophosphamide, cyclosporine, troponin 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-integrin agents, anti-IFNa, anti-CD20 or CD4 biologics) and other cytokine inhibitors or biologics targeting T-cell or B-cell receptors or interleukins.

[0199] Especially in the treatment of rheumatoid arthritis, the RIP1K inhibitor of the present invention can be used in combination with ibuprofen, naproxen, prednisone, methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, abatasex, adalimumab, anaproximil, baricitinib, sertocilizumab, etanercept, fotatinib, golimumab, infliximab, rituximab, tocilizumab, and tofacitinib.

[0200] In some embodiments, the compounds of the present invention can be used in conjunction with anticancer agents or cytotoxic agents. Various anticancer and antitumor compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkaloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents, such as DNMT inhibitors, such as azacitidine and decitabine. Exemplary alkylating agents include, but are not limited to, nitrogen mustard, 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; the pyrimidine analog fluorouracil and cytarabine; and the purine analog mercaptopurine, thioguanine, and azathiopurine. Exemplary vinca alkaloids include, by way of example and not limitation, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. Exemplary enzymes effective as antitumor 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 corticosteroids prednisone and dexamethasone; aromatase inhibitors ammoniaglutide, formetanercept, and anastrozole; progesterone compounds hydroxyprogesterone caproate and medroxyprogesterone; and the anti-estrogenic compound tamoxifen.

[0201] In one aspect, the compounds of the present invention can be used to block cytokine responses. Excessive production of pro-inflammatory cytokines can lead to a “cytokine storm,” during which inflammation spreads throughout the body via circulation. These cytokines include interferons, interleukins, chemokines, colony-stimulating factors, and tumor necrosis factors, which are produced during immune responses. Excessive production of these cytokines can lead to a condition known as cytokine response syndrome or CRS. The compounds of the present invention can be used to inhibit the production of cytokines, thereby improving their destructive effects in CRS. CRS can occur during therapeutic treatment where the cells express recombinant receptors such as chimeric antigen receptors (CARs) and / or other transgenic receptors such as T-cell receptors (TCRs). Therefore, the compounds of the present invention can be used in combination with CAR-T therapy. Exemplary CAR-T therapies used in combination with the compounds of the present invention include activated T cells; antibodies, including antibodies that activate T cells; YESCARTA and KYMRIAH are commercially available examples. CRS can also occur in response to severe bacterial and viral infections. Specifically, the response of CRS to COVID-19 results in acute lung injury, which can lead to severe lung damage and a condition known as acute respiratory distress syndrome. In one aspect, 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 of the present invention can be used in combination with antiviral agents such as remdesivir. Similarly, the compounds of the present invention can be used in combination with antibiotics to modulate CRS associated with bacterial infection.

[0202] These and other useful anticancer compounds are described in Merck Index, 13th edition (edited by O'Neil MJ et al.) Merck Publishing Group (2001) and Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition, edited by Brunton LL, Chapters 60-63, McGraw Hill (2011), both of which are incorporated herein by reference.

[0203] Among CTLA 4 antibodies, ipilimumab, developed by Bristol-Myers Squibb, can be combined with the inhibitors disclosed in this paper. sell.

[0204] Other chemotherapeutic agents that can be used in combination include immuno-oncology agents, such as checkpoint pathway inhibitors, for example, PD-1 inhibitors such as nivolumab and pembrolizumab (1ambrolizumab), and PD-L1 inhibitors such as pembrolizumab, MEDI-4736, and MPDL3280A / RG7446. Additional checkpoint inhibitors that can be used in combination with the compounds disclosed herein include anti-LAG-3 agents such as BMS-986016 (MDX-1408).

[0205] Other chemotherapeutic agents that can be used in combination with the inhibitors disclosed herein include anti-SLAMF7 agents, such as the humanized monoclonal antibody erlotuzumab (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 urilumab (BMS-663513).

[0206] The compounds disclosed herein can also be advantageously used in conjunction with CAR-T therapy. Examples of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

[0207] Additional antiproliferative compounds that can be used in combination with the compounds of the present invention include, by way of example and not limitation, antibodies against growth factor receptors (e.g., anti-Her2); and cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.

[0208] Other chemotherapeutic agents that can be used in combination with the compounds of the present invention include proteasome inhibitors, such as bortezomib, carfilzomib, marizomib, etc.

[0209] Examples of kinase inhibitors that can be used in combination with the compounds disclosed herein, particularly in the treatment of malignancies, include: Btk inhibitors, such as ibrutinib; CDK inhibitors, such as palbociclib; EGFR inhibitors, such as afatinib, erlotinib, gefitinib, lapatinib, osimertinib, and vandetanib; Mek inhibitors, such as trametinib; Raf inhibitors, such as dabrafenib, sorafenib, and vemurafenib; VEGFR inhibitors, such as axitinib, lenvatinib, nintedanib, and pazopanib; BCR-Abl inhibitors, such as bosutinib, dasatinib, imatinib, and nilotinib; FLT-3 inhibitors, such as gipretinib and quezatinib; PI3-kinase inhibitors, such as ederaris; Syk inhibitors, such as fantatinib; and JAK inhibitors, such as ruxotinib and fentatinib.

[0210] In other embodiments, the second therapeutic agent may be selected from any of the following:

[0211] Analgesics - Morphine, Fentanyl, Hydromorphone, Oxycodone, Codeine, Acetaminophen, Hydrocodone, Buprenorphine, Tramadol, Venlafaxine, Flupirtine, Pethidine, Pentazocine, Dextromethorphan, Dipiperazine;

[0212] Antibiotics – aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromomycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cefotaxime, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, ceftoranol, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefbufen, cefazolin, ceftriaxone, cefepime, and cefbiprole), glycopeptides (e.g., teicoplanin). Laning, vancomycin, and terabycin; lincosamides (e.g., clindamycin and incomysin); lipopeptides (e.g., daptomycin); macrolides (azithromycin, clarithromycin, erythromycin, roxithromycin, acetomycin, telithromycin, and spectinomycin); monocyclic β-lactams (e.g., aztreonam); nitrofurans (e.g., furazolidone and nitrofurantoin); penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temoxicillin, and ticarcillin). Penicillin combinations (e.g., amoxicillin / clavulanate, ampicillin / sulbactam, piperacillin / tazobactam, and ticarcillin / clavulanate), peptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, gapfloxacin, sparfloxacin, and temafloxacin), and sulfonamides (e.g., sulfamidone, sulfamethoxazole, sulfacetyl, sulfadiazine, silver sulfadiazine, sulfamethoxazole, sulfanilimide, sulfasalazine, etc.). Pyridine, sulfamethoxazole, trimethoprim and trimethoprim-sulfamethoxazole), tetracyclines (e.g., demecycline, doxycycline, minocycline, oxytetracycline and tetracycline), anti-mycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine and streptomycin), and others such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, acanthoxycycline, quinupristin / dalfopristin, rifaximin, thiamphenicol, tigecycline and tinidazole;

[0213] Antibody-anti-TNF-α antibody, for example, infliximab (Remicade) TMAdalimumab, golimumab, sertozumab; anti-B cell antibodies, such as rituximab; anti-IL-6 antibodies, such as tocilizumab; anti-IL-1 antibodies, such as anaspirin; anti-PD-1 and / or anti-PD-L1 antibodies, such as nivolumab, pembrolizumab, pildizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; isibetatumab, brodatumab, ofamumab, sirukumab, crixacillin, clazazumab, fezanumab, flekumab, malfralimumab, ozoglumbab, sarilumab, secukinumab, tolizumab, zamumab;

[0214] Anticoagulant - Warfarin (Cormidin) TM ), acetocoumarin, phenylpropargyl, atromentin, phenylindidine, heparin, fondaparin, edaparin, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, simegaran, batroxobin, hementin;

[0215] Anti-inflammatory agents - steroids, such as budesonide; non-steroidal anti-inflammatory agents, such as aminosalicylates (e.g., sulfasalazine, mesalazine, oxalazine, and balsalazine); cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib and celecoxib); diclofenac, etodoxacin, famotidine, fenprofen, flurbiprofen, ketoprofen, ketoroxyprofen, ibuprofen, indomethacin, meclofenamic acid, meloxicam, naproxen, naproxen, oxaprozin, piroxicam, disalicylate, sulindac, tometidine;

[0216] Immunosuppressants such as mercaptopurines, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus, inosine monophosphate dehydrogenase inhibitors (IMPDH) such as mycophenolate mofetil, mycophenolate mofetil, and azathioprine, and agents designed to suppress cellular immunity while maintaining the integrity of the recipient's humoral immune response, including various antibodies (e.g., anti-lymphocyte globulin (ALG), anti-thymocyte globulin (ATG), monoclonal anti-T-cell antibody (OKT3)) and irradiation. Azathioprine is currently available under the trademark name Azasan from Salix Pharmaceuticals, Inc.; mercaptopurine is currently available under the trademark name Purinethol from Gate Pharmaceuticals, Inc.; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available under the trademark name Rapamune from Wyeth-Ayerst; tacrolimus is currently available under the trademark name Prograf from Fujisawa; cyclosporine is currently available under the trademark name Sandimmune from Novartis and under the trademark name Gengraf from Abbott; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available under the trademark name Cellcept from Roche and under the trademark name Myfortic from Novartis; azathioprine is currently available under the trademark name Imuran from Glaxo Smith Kline; and antibodies are currently available under the trademark name Orthoc1one from Ortho Biotech obtained it from Novartis under the trademark name Simulect (bariliximab) and from Roche under the trademark name Zenapax (daktarizumab); and

[0217] Guanylate cyclase-C receptor agonists or incretins, such as linaclotide, are marketed under the name Linzess.

[0218] These different medications may be used in their standard or usual dosages, as indicated in the prescribing information in the commercially available form of the accompanying medication (see also the prescribing information in the 2006 edition of The Physician's Desk Reference), the disclosure of which is incorporated herein by reference.

[0219] III. Methods for preparing compounds

[0220] The disclosed compounds can be prepared by any suitable method as understood by those skilled in the art. An assembly overview of the tricyclic core portion of the compounds of the present invention is provided in the following embodiment 1.

[0221] Option 1: Construction of a Three-Ring Core

[0222]

[0223] Scheme 2 provides another overview of the methods for synthesizing the RIP1K inhibitory compounds disclosed herein.

[0224] Option 2: General method for forming three rings

[0225]

[0226] Scheme 3 provides an overview of methods for functionalizing the tricyclic intermediates described in this paper. Such methods can be used to introduce the R described in this paper. 1 Partial, B ring and R 3 L and W groups.

[0227] Option 3: An overview of methods for functionalizing the three-ring core

[0228]

[0229] The specific compounds in the following reference examples provide an exemplary suitable method, as shown in Scheme 4. This embodiment provides a general method for attaching a tricyclic core molecule (prepared as shown in Scheme 1) to the B ring shown in Formula I.

[0230] Option 4: General methods for amide formation

[0231]

[0232] According to Scheme 4, the stirred mixture of amine / amine hydrochloride (1 equivalent), aryl / heteroaryl acid / salt (1.2 equivalent), and HATU (1.3-1.4 equivalent) in dry DMF (0.3-0.8 mL / 0.1 mmol) is degassed under vacuum and backfilled with argon. After three degassed cycles, i-Pr2NEt (4-7 equivalent) is added to the stirred mixture at 0 °C or room temperature and stirred until the amine is exhausted. The reaction solution is treated by one of the following methods: (a) after dilution with ice water, common extraction post-treatment with EtOAc or CH2Cl2; (b) after concentrating the reaction solution to dryness, common post-treatment; or (c) dilution of the crude concentrate with ice water, sonication, warming the slurry to room temperature, and filtration to obtain a crude gray / dark solid after suction drying. Purification of the crude substance by any treatment method by normal-phase silica gel chromatography or reversed-phase chromatography yields various amide compounds (yields: 31-82%).

[0233] Refer to schemes 1, 2, 3, and 4, with variables X and Y. 1 Y 2 Y 3 And Z as described above; P is a protecting group known to those skilled in the art and further illustrated herein. R is one or more of any suitable substituents known to those skilled in the art, such as R described herein. 1 Part of or its precursor.

[0234] Scheme 5 describes a method for halogenating certain intermediate compounds to produce the RIP1K inhibitor described herein.

[0235] Scheme 5: A general method for chlorinating the imidazole ring of a 5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatriene core.

[0236]

[0237] According to Scheme 5, a mixture of 0.1 mmol of a 5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatriene core, 0.1 mmol of N-chlorosuccinimide, and 1 mL / 0.1 mmol of dried acetonitrile was stirred overnight at 50 °C, diluted with water, and filtered. The dried solid on the funnel was dissolved in CH2Cl2 and loaded onto a silica gel column. Rapid silica gel column chromatography was used to purify the dichloro-substituted compounds (rapid elution) and the monochloro-substituted compounds (slow elution), respectively.

[0238] The following compounds were synthesized using the methods disclosed herein and those known to those skilled in the art of organic synthesis and medicinal chemistry.

[0239] I-1(±)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0240]

[0241] 1 ¹H 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: 95% purity, MS (m / e) 385 (M+H). + .

[0242] I-2(±)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-4-phenylpyrimidin-2-carboxamide

[0243]

[0244] 1 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) 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: 99% purity, MS(m / e) 382 (M+H) + .

[0245] I-6(±)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-5-carboxamide

[0246]

[0247] 1 ¹H 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: 98% purity, MS (m / e) 454 (M+H). + .

[0248] I-7(±)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0249]

[0250] 1 ¹H 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: 98% purity, MS (m / e) 454 (M+H). + .

[0251] I-9(±)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)isoxazol-3-carboxamide

[0252]

[0253] 1¹H 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 (d t (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) + .

[0254] I-14(±)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide

[0255]

[0256] LCMS: Purity 98%, MS (m / e) 403 (M+H) + .

[0257] I-19(±)-5-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0258]

[0259] 1 ¹H 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). + .

[0260] I-27(±)-1-(2,6-dichlorobenzyl)-N-(6,7-dihydrobenzo[b]pyrrolo[1,2-d][1,4]oxazapyridine-7-yl)-1H-1,2,4-triazol-3-carboxamide

[0261]

[0262] 1 ¹H 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). + .

[0263] I-29(±)-1-(2,6-dichlorobenzyl)-N-(4,5-dihydroimidazo[1,2-d]pyrrolo[2,1-b][1,3,4]thiadiazacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0264]

[0265] 1 ¹H NMR (400MHz, chloroform-d) δ 8.38 (d, J = 7.9Hz, 1H), 7.96 (s, 1H), 7.43 (d, J = 1.2Hz, 1H), 7.41 (s, 1H), 7.33 (dd, J = 8.9, 7.1Hz, 1H), 7.27 (d, J = 1.5Hz, 1H), 7.16 (d, J = 1.5Hz, 1H), 7.11 (dd, J = 3. 2, 1.7Hz, 1H), 6.52 (dd, J=4.0, 1.7Hz, 1H), 6.31 (dd, J=4.0, 3.2Hz, 1H), 5.71 (s, 2H), 5.22 ( ddd, J=10.2, 7.9, 6.7Hz, 1H), 3.97 (dd, J=11.4, 6.7Hz, 1H), 2.76 (dd, J=11.4, 10.2Hz, 1H). LCMS: Purity 99%, MS (m / e) 461 (M+H) + .

[0266] I-34(±)-5-benzyl-N-(6,7-dihydrobenzo[b]pyrrolo[1,2-d][1,4]oxazapyridine-7-yl)-1H-1,2,4-triazol-3-carboxamide

[0267]

[0268] 1 ¹H 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: 96% purity, MS (m / e) 386 (M+H). + .

[0269] I-35(±)-1-(2,6-dichlorobenzyl)-N-(2-methyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0270]

[0271] 1 ¹H 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: 95% purity, MS (m / e) 468 (M+H). + .

[0272] I-36(±)-1-(2,6-dichlorobenzyl)-N-(1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0273]

[0274] 1 ¹H 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) + .

[0275] I-37(±)-N-(6,7-dihydrobenzo[b]pyrrolo[1,2-d][1,4]oxazapyridine-7-yl)-5-(4-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide

[0276]

[0277] 1 H NMR(400MHz, chloroform-d)δ13.40(br s, 1H), 7.50 (d, J=9.0Hz, 1H), 7.44-7.36 (m, 1H), 7.30-7.17 (m, 3H), 7.17 (dd, J=8.6, 5.4Hz, 2H), 7.02 (dd, J=2.9, 1.7Hz, 1H), 6.91 (t, J=8.6Hz, 2H), 6.32-6.23 (m, 2H), 5.55 (dt, J=9.0, 6.4Hz, 1H), 4.63 (dd, J=10.9, 6.0Hz, 1H), 4.36 (dd, J=10.9, 6.8Hz, 1H), 4.12 (s, 2H). 19 F NMR (376 MHz, chloroform-d) δ -115.74. Purity 98%, MS (m / e) 404 (M+H) + .

[0278] I-38(±)-N-(6,7-dihydrobenzo[b]pyrrolo[1,2-d][1,4]oxazapyridine-7-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide

[0279]

[0280] 1H NMR (400MHz, chloroform-d) δ8.06 (d, J=0.9Hz, 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=2.3Hz, 1H), 6.29 (app d, J=2.4Hz, 2H), 5.63 (ddd, J=9.1, 6.9, 6.0Hz, 1H), 5.41 (app d, J=1.2Hz, 2H), 4.68 (dd, J=10.8, 6.0Hz, 1H), 4.35 (dd, J=10.8, 6.9Hz, 1H). 19 FNMR (376 MHz, chloroform-d) δ -118.06–118.09 (m). Purity 97%, MS (m / e) 404 (M+H) + .

[0281] I-39(±)-5-benzyl-N-(9-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0282]

[0283] 1 ¹H 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 (obvious 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), 2.37-2.329 (m, 1H). Purity 96%, MS (m / e) 560 (M+H) + .

[0284] I-40(±)-5-benzyl-N-(1-methyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0285]

[0286] 1 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) + .

[0287] I-44(±)-1-(2,6-dichlorobenzyl)-N-(1-methyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0288]

[0289] 1 ¹H 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) + .

[0290] I-45(±)-5-benzyl-N-(4,5-dihydroimidazo[1,2-d]pyrrolo[2,1-b][1,3,4]thiadiazacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0291]

[0292] 1¹H 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). + .

[0293] 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]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0294]

[0295] 1 H NMR (400MHz, chloroform-d) δ8.44 (d, J=7.7Hz, 1H), 8.28-8.21 (m, 2H), 7.93 (d, J=0.6Hz, 1H), 7.41 ( dd, J=8.0, 0.9Hz, 2H), 7.36-7.24 (m, 4H), 7.19 (d, J=1.4Hz, 1H), 7.12 (d, J=1.4Hz, 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) + .

[0296] R955314(±)-5-benzyl-N-(1-oxo-5,6-dihydro-1H,4H-benzo[f][1,2,4]oxadiazolo[4,3-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0297]

[0298] 1¹H 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) + .

[0299] I-51(±)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-4-phenoxypyridineamide

[0300]

[0301] 1 ¹H 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 0.15 (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) + .

[0302] I-52(±)-N-(1-oxo-5,6-dihydro-1H,4H-benzo[f][1,2,4]oxadiazolo[4,3-a]azacycloheptatrien-4-yl)-4-phenoxypyridineamide

[0303]

[0304] 1H NMR (400MHz, chloroform-d) δ8.53 (d, J=8.8Hz, 1H), 8.38 (d, J=5.6Hz, 1H), 7.62 (d, J=2.5Hz, 1H), 7.58 (dd, J=7.9, 1.3Hz, 1H), 7.48-7.30 (m, 5H), 7.24 (app dt, J=14.9, 1.2Hz, 1H), 7.10-7.01 (m, 2H), 6.95 (dd, J=5.6, 2.5Hz, 1H), 5.10 (d t, J=9.8, 8.3Hz, 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) + .

[0305] I-54(±)-N-(6,7-dihydrobenzo[b]pyrrolo[1,2-d][1,4]oxazapyridine-7-yl)-4-phenoxypyridineamide

[0306]

[0307] 1 ¹H NMR (400MHz, 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). + .

[0308] I-55(±)-5-benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0309]

[0310] 1¹H 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) + .

[0311] I-56(±)-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-4-phenoxypyridineamide

[0312]

[0313] 1 ¹H 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) + .

[0314] I-57(±)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0315]

[0316] 1¹H 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) + .

[0317] I-58(±)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0318]

[0319] 1 ¹H 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) + .

[0320] I-59(±)-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptatrien-4-yl)-4-phenoxypyridineamide

[0321]

[0322] 1¹H 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) + .

[0323] 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]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0324]

[0325] 1 ¹H 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). + .

[0326] I-61(±)-N-(9-(3-oxa-9-azaspiro[5.5]undecane-9-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1-(2,6-dichlorobenzyl)-1H-1,2,4-triazol-3-carboxamide

[0327]

[0328] 1H NMR (400MHz, chloroform-d) δ8.41 (d, J=7.8Hz, 1H), 7.92 (d, J=0.6Hz, 1H), 7.41 (dd, J=8.0, 0.9Hz, 2H), 7.31 (dd, J=8 .9, 7.1Hz, 1H), 7.22-7.14 (m, 2H), 7.11 (d, J=1.4Hz, 1H), 6.85 (dd, J=8.4, 2.5Hz, 1H), 6.80 (d, J=2.6Hz, 1H), 5.70 (s, 2H), 5.14 (dt, J=10.4, 7.7Hz, 1H), 3.72-3.65 (m, 4H), 3.19 (dd, J=7.0, 4.6Hz, 4H), 3.02-2.87 (m, 1H ), 2.63-2.54 (m, 1H), 2.48 (td, J=13.3, 7.4Hz, 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) + .

[0329] I-62(±)-N-(9-(3-oxa-9-azaspiro[5.5]undecane-9-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-4-phenoxypyridine amide

[0330]

[0331] 1 H NMR (400MHz, chloroform-d) δ9.19 (d, J=7.8Hz, 1H), 8.46 (dd, J=5.6, 0.6Hz, 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, 1.4Hz, 2H), 7.09-7.04 (m, 2H), 6.93 (dd, J=5.6, 2.6Hz, 1H), 6.8 6 (dd, J=8.4, 2.5Hz, 1H), 6.81 (d, J=2.5Hz, 1H), 5.09 (dt, J=10.5, 7.8Hz, 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) + .

[0332] I-63(±)-1-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0333]

[0334] 1 ¹H 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). + .

[0335] I-64(±)-N-(9-(3-oxa-9-azaspiro[5.5]undecane-9-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-5-benzyl-1H-1,2,4-triazol-3-carboxamide

[0336]

[0337] 1 ¹H 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), 2.74-2.5 5(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). 1¹H 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) + .

[0338] I-65(±)-5-benzyl-N-(1-oxo-9-(3-oxa-9-azaspiro[5.5]undecane-9-yl)-5,6-dihydro-1H,4H-benzo[f][1,2,4]oxadiazolo[4,3-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0339]

[0340] 1 H NMR(400MHz, chloroform-d)δ11.13(br s, 1H), 7.61 (d, J = 8.9Hz, 1H), 7.38-7.24 (m, 5H), 7.15 (d, J = 8.5Hz, 1H), 7.06 (d, J = 2.5Hz, 1H) , 6.87 (dd, J=8.5, 2.6Hz, 1H), 5.13 (q, J=9.0Hz, 1H), 4.16 (s, 2H), 3.72-3.65 (m, 4H), 3.20 (app dd, J=7.3, 4.6Hz, 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) + .

[0341] I-66(±)-5-benzyl-N-(4,5-dihydroimidazo[1,2-a]quinoline-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0342]

[0343] 1¹H 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) + .

[0344] I-67(±)-N-(4,5-dihydroimidazo[1,2-a]quinolin-4-yl)-4-phenoxypyridineamide

[0345]

[0346] 1 H NMR (400MHz, methanol-d4) δ8.43 (d, J=5.6Hz, 1H), 7.77 (d, J=1.6Hz, 1H), 7.59 (d, J =2.5Hz, 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, 1.2Hz, 1H), 7.17-7.13 (m, 2H), 7.09 (d, J = 1.5Hz, 1H), 7.05 (dd, J=5.6, 2.6Hz, 1H), 5.48 (dd, J=9.2, 6.1Hz, 1H), 3.38-3.24 (app m, 2H). Purity 96%, MS (m / e) 383 (M+H) + .

[0347] I-68(±)-5-benzyl-N-(9-(3-hydroxy-3-methylbutyl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0348]

[0349] 1H NMR (400MHz, chloroform-d) δ7.97 (d, J=8.5Hz, 1H), 7.31-7.27 (m, 1H), 7.26 (d, J=0.9Hz, 1H), 7. 25-7.19(m, 4H), 7.17-7.14(m, 2H), 7.11(d, J=1.4Hz, 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) + .

[0350] 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]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0351]

[0352] 1 ¹H 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) + .

[0353] I-77(±)-N-(9-(3-oxa-9-azaspiro[5.5]undecane-9-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1-benzyl-1H-pyrazole-3-carboxamide

[0354]

[0355] 1H NMR (400MHz, chloroform-d) δ8.11 (d, J=7.9Hz, 1H), 7.41-7.28 (m, 4H), 7.24 (d, J=2.0Hz, 1H), 7.26-7.17 (m, 3H), 7 .15 (d, J=1.4Hz, 1H), 6.88 (dd, J=8.4, 2.5Hz, 1H), 6.83 (d, J=2.5Hz, 1H), 6.77 (d, J=2.3Hz, 1H), 5.32 (app q, J=17.3Hz, 2H), 5.17 (dt, J=10.5, 7.8Hz, 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) + .

[0356] 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]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0357]

[0358] 1 ¹H 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) + .

[0359] I-83(S)-N-(9-(3-oxa-9-azaspiro[5.5]undecane-9-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-5-benzyl-1H-1,2,4-triazol-3-carboxamide

[0360]

[0361] 1 ¹H 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) + .

[0362] I-84(±)-N-(9-(7-oxa-2-azaspiro[3.5]non-2-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-5-benzyl-1H-1,2,4-triazol-3-carboxamide

[0363]

[0364] 1 ¹H 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) + .

[0365] I-85(±)-N-(9-(7-oxa-2-azaspiro[3.5]non-2-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1-benzyl-1H-pyrazole-3-carboxamide

[0366]

[0367] H NMR (400MHz, methanol-d4) δ7.70 (d, J=2.4Hz, 1H), 7.47 (d, J=1.6Hz, 1H), 7.39-7.21 (m , 6H), 7.12 (d, J=1.5Hz, 1H), 6.75 (d, J=2.4Hz, 1H), 6.55 (d, J=2.3Hz, 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) + .

[0368] I-86(S)-N-(9-(7-oxa-2-azaspiro[3.5]non-2-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-5-benzyl-1H-1,2,4-triazol-3-carboxamide

[0369]

[0370] 1 ¹H 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) + .

[0371] R955395(R)-N-(9-(7-oxa-2-azaspiro[3.5]non-2-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxaazacycloheptatrien-4-yl)-5-benzyl-1H-1,2,4-triazol-3-carboxamide

[0372]

[0373] 1H NMR (400MHz, methanol-d4) δ7.50 (d, J=1.5Hz, 1H), 7.36-7.19 (m, 5H), 7.14 (d, J= 8.7Hz, 1H), 7.07 (d, J=1.5Hz, 1H), 6.60 (d, J=2.7Hz, 1H), 6.48 (dd, J=8.7, 2 .7Hz, 1H), 5.48 (dd, J=9.5, 7.0Hz, 1H), 4.60 (dd, J=10.6, 7.0Hz, 1H), 4.38( dd, J=10.5, 9.5Hz, 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) + .

[0374] I-88(R)-N-(9-(7-oxa-2-azaspiro[3.5]non-2-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxaazacycloheptatrien-4-yl)-4-phenoxypyridine amide

[0375]

[0376] 1 H NMR (400MHz, chloroform-d) δ9.18 (d, J=7.6Hz, 1H), 8.48 (d, J=5.6Hz, 1H), 7.66 (d, J=2.5Hz, 1H), 7.48-7.36 (m, 2H), 7.30 -7.22 (m, 2H), 7.19 (d, J=1.4Hz, 1H), 7.17-7.12 (m, 1H), 7.12-7.04 (m, 2H), 6.96 (dd, J=5.6, 2.5Hz, 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) + .

[0377] I-89(R)-5-benzyl-N-(9-(pyridin-2-ylethynyl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0378]

[0379] 1 H NMR (400MHz, methanol-d4) δ8.72 (dd, J=2.1, 0.9Hz, 1H), 8.53 (dd, J=5.0, 1.6Hz, 1H), 7.99 (dt, J =7.9, 1.9Hz, 1H), 7.88 (d, J = 1.9Hz, 1H), 7.65 (d, J = 1.6Hz, 1H), 7.57 (dd, J = 8.3, 2.0Hz, 1H ), 7.47 (ddd, J=7.9, 5.0, 0.9Hz, 1H), 7.37-7.19 (m, 6H), 7.13 (d, J=1.5Hz, 1H), 5.60 (dd, J =8.8, 6.1Hz, 1H), 4.70 (dd, J=11.0, 6.1Hz, 1H), 4.54 (dd, J=11.0, 8.9Hz, 1H), 4.16 (s, 2H). Purity 96%, MS (m / e) 488 (M+H) + .

[0380] I-90(±)-5-benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0381]

[0382] 1 ¹H 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) + .

[0383] 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]azacycloheptatrien-4-yl)-1H-pyrazole-1-carboxamide

[0384]

[0385] 1¹H 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, 7.5Hz, 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) + .

[0386] Chromatographic separation of enantiomers:

[0387] As taught herein to those skilled in the art of organic synthesis, the compounds disclosed herein can be synthesized in racemic or enantiomerically enriched forms. Racemic mixtures of the compounds disclosed herein can be separated into their component enantiomers using the following chiral chromatographic procedures and modifications known to those skilled in the art.

[0388] I-4(S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide and 1-5(R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0389]

[0390] Chiral separation of (±)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide was performed on a Thar SFC instrument equipped with a Chiracel AD-H, 10 μm, 10 x 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 enantiomer separation was 14.3 min. A total of 61 50 μL injections were performed at a sample concentration of 11 mg / mL (in methanol) using an injection stack with a cycle time of 4.8 min and an interval of 0.3 min. Samples were collected by monitoring UV adsorption at 214 nm. Peak 1 (rapid elution peak) corresponds to (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide, while peak 2 (slow elution peak) corresponds to (R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide. The solids obtained after concentrating the mixed fractions of each enantiomer were dissolved in 5% MeOH / EtOAc and passed through EtOAc-conditioned silica gel. The concentrate of the filtrate was dissolved in acetonitrile / water and lyophilized. Enantiomer enrichment was measured using an analytical method on the same instrument, with a Chiralcel-IA-H, 5 μm, 4.6 x 250 mm lens, using 20% ​​methanol (0.1% DEA) and 80% CO2 as the mobile phase, eluted at a flow rate of 3.0 mL / min, and injected with 15 μL of a solution containing 1 mg / mL at a UV detector of 214 nm. I-4(S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide (white solid). 98.5% ee. 1 H NMR (400MHz, chloroform-d) δ8.60 (d, J=9.0Hz, 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=1.4Hz, 1H), 6.59 (s, 1H), 5.30 (q, J=9.5Hz, 1H), 4.16 (app q, J=16.1Hz, 2H), 2.84-2.65 (m, 2H), 2.57-2.49 (m, 1H), 2.28 (td, J=11.4, 10.9, 7.0Hz, 1H). LCMS: Purity 99%, MS (m / e) 385 (M+H)+ 1-5(R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide (white solid). 98.8% ee. 1 ¹H 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: 99% purity, MS (m / e) 385 (M+H). + .

[0391] I-12(R)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide and 1-13(S)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0392]

[0393] Chiral separation of enantiomers was performed on a Thar SFC instrument equipped with a Chiralcel OJ-H, 10 μm, 10 x 250 mm column. The mobile phase was 27% isopropanol (0.1% DEA) and 73% CO2, with a total flow rate of 10.0 mL / min. The total elution time for enantiomer separation was 12 min. A total of 61 40 μL injections were performed using an injection stack with a cycle time of 5 min and an interval of 0.25 min, at a sample concentration of 25 mg / mL (in methanol). Samples were collected by monitoring UV adsorption at 214 nm. Peak 1 (rapid elution peak) corresponds to (R)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide, while peak 2 (slow elution peak) corresponds to (S)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide. The solids obtained after concentrating the mixed fractions of each enantiomer were dissolved in EtOAc and passed through EtOAc-conditioned silica gel. The concentrate of the filtrate was dissolved in acetonitrile / water and then lyophilized. Enantiomer enrichment was measured using an analytical method on the same instrument, with a Chiralcel-OJ-H, 5 μm, 4.6 x 250 mm lens, using 27% isopropanol (0.1% DEA) and 73% CO2 as the mobile phase, eluted at a flow rate of 3.0 mL / min, and injected with 10 μL of a solution containing 1 mg / mL at a UV detector of 214 nm. I-12: (R)-1-(2,6-dichlorobenzyl)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide (white solid). 98.9% ee. 1 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]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide (white solid). 99.6% ee. 1 ¹H 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). + .

[0394] 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]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide and 1-92(R)-5-benzyl-N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0395]

[0396] Chiral separation was performed on a Thar SFC instrument equipped with a Chiralcel OJ-H, 10 μm, 10 x 250 mm column. The mobile phase was 18% methanol (0.1% DEA) + 82% CO2, with a total flow rate of 10.0 mL / min. The total elution time for enantiomer separation was 11.3 min. Forty 50 μL injections were performed using an injection stack with a cycle time of 2.9 min and an interval of 0.3 min, at a sample concentration of 17 mg / mL (in methanol). Samples were collected by monitoring UV adsorption at 214 nm. Peak 1 (rapid elution 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]oxazacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide, while peak 2 (slow elution 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]oxazacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide. The solids obtained after concentrating the mixed fractions of each enantiomer were dissolved in a minimum amount of acetonitrile and diluted with water. The precipitous suspension was filtered, and the collected solids were dried to provide the compounds. Enantiomer enrichment was determined by analytical methods on the same instrument, using a Chiralcel-OJ-H, 5 μm, 4.6 x 250 mm, with 18% methanol (0.1% DEA) and 82% CO2 as the mobile phase, eluting at a flow rate of 3.0 mL / min, and injected with 10 μL of a solution at a concentration of 1 mg / mL at a detector of 214 nm in the UV. 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]oxazacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide (white solid). 99.7% ee. 1 H NMR (400MHz, methanol-d4) δ7.67 (d, J=1.9Hz, 1H), 7.58 (d, J=1.5Hz, 1H), 7.39 (dd, J=8.3, 1.9Hz, 1H), 7.36-7.18 (m, 6H), 7.10 (d, J= 1.5Hz, 1H), 5.56 (dd, J=9.0, 6.2Hz, 1H), 4.67 (dd, J=11.0, 6.2Hz, 1H), 4.49 (dd, J=10.9, 9.0Hz, 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]oxazacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide (white solid). 99.7% ee. 1 H NMR (400MHz, methanol-d4) δ7.67 (d, J=1.9Hz, 1H), 7.58 (d, J=1.6Hz, 1H), 7.40 (dd, J=8.3, 1.9Hz, 1H), 7.33-7.20 (m, 6H), 7.11 (d, J= 1.5Hz, 1H), 5.56 (dd, J=9.0, 6.2Hz, 1H), 4.67 (dd, J=11.0, 6.2Hz, 1H), 4.50 (dd, J=10.9, 9.0Hz, 1H), 4.15 (s, 2H), 1.56 (s, 6H). Purity 95%, MS (m / e) 469 (M+H) + .

[0397] 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]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0398]

[0399] Iodomethane (2.6 μL, 6 mg, 0.042 mmol) was added in a single addition 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]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide (15 mg, 0.032 mmol) and Cs₂CO₃ (11 mg, 0.033 mmol) in anhydrous DMF (0.2 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 day, diluted with water (1 mL), and filtered. The solid thus collected was dried by suction drying, dissolved in CH₂Cl₂, loaded onto a silica gel column, and subjected to rapid chromatography. Teledyne Purified by silica gel column conditioning with 50% EtOAc / hexane (4G Gold) and eluting 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]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide (11 mg) as a white solid. 1 ¹H 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). + .

[0400] I-70(±)-5-Benzyl-N-(1,2-Dichloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)isoxazole-3-carboxamide

[0401]

[0402] 1 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) + .

[0403] I-71(±)-5-Benzyl-N-(1-Chloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)isoxazole-3-carboxamide

[0404]

[0405] 1¹H 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) + .

[0406] I-73(±)-N-(1,2-dichloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1-(2,6-dichlorobenzyl)-1H-1,2,4-triazol-3-carboxamide

[0407]

[0408] 1 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) + .

[0409] I-74(±)-N-(1-chloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1-(2,6-dichlorobenzyl)-1H-1,2,4-triazol-3-carboxamide

[0410]

[0411] 1¹H 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) + .

[0412] I-80(±)-5-benzyl-N-(1,2-dichloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0413]

[0414] 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.56–7.43 (m, 4H), 7.36–7.20 (m, 5H), 4.95–4.86 (appm, 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) + .

[0415] I-81(±)-5-benzyl-N-(1-chloro-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azacycloheptatrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0416]

[0417] 1 ¹H 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) + .

[0418] 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]oxazapyridine-4-yl)-1H-pyrazole-3-carboxamide

[0419]

[0420] 1 H NMR (400MHz, CD3OD) δ7.71 (d, J=8.0Hz, 1H), 7.52-7.15 (m, 9H), 5.46 (dd, J=9.5, 7.9Hz, 1H), 5.18 (s, 2H), 4.65-4.48 (m, 2H). 13 C NMR (100MHz, 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; measured 420 [M+H] + .

[0421] 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]oxazapyridine-4-yl)-1H-pyrazole-3-carboxamide

[0422]

[0423] 1 H NMR (400MHz, CD3OD) δ 8.31 (d, J=8.5Hz, 1H), 7.41-7.13 (m, 8H), 5.91 (dd, J=6.4, 4.3Hz, 1H), 5.14 (s, 2H), 4.56-4.39 (m, 2H), 1.57 (s, 6H). 13 C NMR (100MHz, 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; measured 486 [M+H]+ I-3(R)-5-benzyl-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0424]

[0425] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.31 (dd, J = 8.2, 1.6Hz, 1H), 7.56–7.15 (m, 8H), 5.91 (td, J = 7.2, 3.9Hz, 1H), 4.50 (dd, J = 12.3, 4.0Hz, 1H), 4.39 (dd, J = 12.3, 6.8Hz, 1H), 4.12 (s, 2H). MS (ESI, m / e) calculated 388.1396; measured 389.0 [M+H] + I-8(R)-5-benzyl-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazapyridine-4-yl)isoxazo-3-carboxamide

[0426]

[0427] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.61 (d, J = 8.1Hz, 1H), 8.33 (dd, J = 8.2, 1.6Hz, 1H), 7.57–7.18 (m, 8H), 6.61 (d, J = 0.8Hz, 1H), 5.91 (ddd, J = 8.2, 5.7, 3.7Hz, 1H), 4.58–4.36 (m, 2H), 4.23 (s, 2H). MS (ESI, m / e) calculated 388.1284; measured 389.0 [M+H] + .

[0428] I-10(R)-1-(2,6-dichlorobenzyl)-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazapyridine-4-yl)-1H-1,2,4-triazol-5-carboxamide

[0429]

[0430] MS(ESI, m / e) calculated value: 456.0617; measured value: 457.0 [M+H] + 455.0 [MH] - .

[0431] I-11(R)-1-(2,6-dichlorobenzyl)-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0432]

[0433] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.35 (d, J = 8.3Hz, 1H), 8.84 (s, 1H), 8.31 (dd, J = 8.2, 1.6Hz, 1H), 7.62–7.26 (m, 5H), 5.87 (ddd, J = 8.4, 6.8, 4.0Hz, 1H), 5.71 (s, 2H), 4.58–4.30 (m, 2H). MS (ESI, m / e) calculated 456.0617; measured 457.0 [M+H] + 455.0 [MH] - .

[0434] I-20(R)-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazapyridine-4-yl)-1-(2,6-dimethylbenzyl)-1H-1,2,4-triazol-3-carboxamide

[0435]

[0436] 1 H NMR (400MHz, DMSO-d6) δ9.33 (d, J=8.3Hz, 1H), 8.66 (s, 1H), 8.31 (dd, J=8.3, 1.5Hz, 1H), 7 .47 (ddd, J=8.1, 7.4, 1.7Hz, 1H), 7.38 (ddd, J=8.2, 7.3, 1.5Hz, 1H), 7.31 (dd, J=8.1, 1.5H z, 1H), 7.17 (dd, J = 8.3, 6.7Hz, 1H), 7.08 (d, J = 7.5Hz, 2H), 5.87 (ddd, J = 8.3, 6.9, 4.1Hz, 1H), 5.48 (s, 2H), 4.49 (dd, J = 12.3, 4.1Hz, 1H), 4.37 (dd, J = 12.3, 6.9Hz, 1H), 2.35 (s, 6H). MS (ESI, m / e) calculated value 416.1709; measured value 417.1 [M+H] + 415.1 [MH] - .

[0437] I-21(R)-N-(4,5-dihydrobenzo[b]tetrazo[1,5-d][1,4]oxazapyridine-4-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide

[0438]

[0439] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.37 (d, J = 8.3Hz, 1H), 8.83 (s, 1H), 8.31 (dd, J = 8.2, 1.6Hz, 1H), 7.51–7.29 (m, 5H), 7.29–7.18 (m, 2H), 5.90 (ddd, J = 8.4, 6.7, 4.0Hz, 1H), 5.56 (s, 2H), 4.50 (dd, J = 12.3, 4.0Hz, 1H), 4.38 (dd, J = 12.3, 6.7Hz, 1H). MS (ESI, m / e) calculated 406.1302; measured 407.0 [M+H] + 405.0 [MH] - .

[0440] I-41 5-Benzyl-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0441]

[0442] 1 H NMR(400MHz, DMSO-d6)δ9.23(br s, 1H), 7.73 (dd, J=7.9, 1.7Hz, 1H), 7.49 (td, J=7.7, 1.8Hz, 1H), 7.43 (td, J=7.7, 1.6Hz, 1H), 7.38 (dd, J=7.9, 1.6Hz, 1H), 7.33 (t, J=7.4Hz, 2H), 7.26 (dt, J=8.1, 1.8Hz, 3H), 5.46-5.33 (m, 1H), 4.83-4.71 (m, 1H), 4.54 (dd, J=10.5, 8.0Hz, 1H), 4.13 (s, 2H). MS(ESI, m / e) calculated value: 404.1233; measured value: 405.0 [M+H] + 403.0 [MH] - .

[0443] 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]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0444]

[0445] 1 H NMR (400MHz, DMSO-d6) δ9.25 (d, J=8.5Hz, 1H), 8.88 (s, 1H), 7.73 (dd, J=7.9, 1.7Hz, 1H), 7.58 (d, J=1.1Hz, 1H), 7.56 (s, 1H), 7.51-7.45 (m, 2H), 7.42 (td, J=7.7, 1.6Hz, 1H), 7.37 (dd, J=7.9, 1.6Hz, 1H), 5.71 (s, 2H), 5.38 (dt , J=9.7, 8.1Hz, 1H), 4.74 (t, J=10.2Hz, 1H), 4.53 (dd, J=10.6, 7.9Hz, 1H). MS(ESI, m / e) calculated value: 472.0454; measured value: 473.0 [M+H] + 471.0 [MH] - .

[0446] I-435-Benzyl-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazapyridine-4-yl)isoxazol-3-carboxamide

[0447]

[0448] 1 H NMR (400MHz, DMSO-d6) δ9.52 (d, J=8.2Hz, 1H), 7.72 (dd, J=7.8, 1.7Hz, 1H), 7.4 9 (td, J=7.7, 1.8Hz, 1H), 7.43 (td, J=7.7, 1.6Hz, 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; measured value 405.0 [M+H]+ 403.0 [MH] - .

[0449] 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]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0450]

[0451] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.74 (dd, J = 7.8, 1.8Hz, 1H), 7.63 (dd, J = 7.9, 1.7Hz, 1H), 7.52–7.46 (m, 1H), 7.45–7.42 (m, 2H), 7.38 (dd, J = 7.7, 1.5Hz, 2H), 7.33 (dd, J = 7.9, 1.6Hz, 1H), 5.45–5.35 (m, 1H), 4.75 (t, J = 10.2Hz, 1H), 4.58–4.51 (m, 1H), 4.25–4.16 (m, 2H). MS (ESI, m / e) calculated 440.1045; measured 441.2 [M+H] + .

[0452] I-50 5-(4-fluorobenzyl)-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0453]

[0454] 1H NMR(400MHz, DMSO-d6)δ9.18(br s, 1H), 7.74 (dd, J=7.9, 1.7Hz, 1H), 7.50 (dd, J=7.7, 1.8Hz, 1H), 7.46 (dd, J =10.1, 1.8Hz, 1H), 7.42 (dd, J = 7.6, 1.6Hz, 1H), 7.38 (dd, J = 7.9, 1.6Hz, 1H) , 7.31 (ddd, J=8.5, 5.7, 2.7Hz, 2H), 7.20-7.10 (m, 2H), 5.41 (dt, J=9.8, 8.1 Hz, 1H), 4.76 (t, J=10.2Hz, 1H), 4.54 (dd, J=10.6, 7.8Hz, 1H), 4.14 (s, 2H). MS(ESI, m / e) calculated value: 422.1139; measured value: 423.2 [M+H] + .

[0455] I-53N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]oxazapyridine-4-yl)-4-phenoxypyridineamide

[0456]

[0457] 1 H NMR (400MHz, DMSO-d6) δ9.52 (d, J=8.5Hz, 1H), 8.59 (d, J=5.6Hz, 1H), 7.74 (dd, J=7.9, 1.7Hz, 1H), 7.55-7.50 (m, 2H), 7.48 (dd, J=7.7, 1.8Hz, 1H), 7.42 (td, J=7.7, 1.6Hz, 1H), 7.39-7.31 (m, 3H), 7.26-7.21 (m, 3H), 5.42 (dt, J=9 .7, 8.1Hz, 1H), 4.81 (dd, J=10.7, 9.7Hz, 1H), 4.55 (dd, J=10.6, 7.8Hz, 1H). MS(ESI, m / e) calculated value: 416.1121; measured value: 417.3 [M+H] + .

[0458] 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]oxazapyridine-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0459]

[0460] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.30 (s, 1H), 8.29 (d, J = 8.5Hz, 1H), 7.37 (dd, J = 8.6, 1.9Hz, 1H), 7.34–7.27 (m, 2H), 7.24 (d, J = 7.4Hz, 3H), 5.90 (ddd, J = 8.3, 6.3, 3.7Hz, 1H), 4.49 (dd, J = 12.4, 3.7Hz, 1H), 4.40 (dd, J = 12.4, 6.4Hz, 1H), 4.11 (s, 2H), 1.47 (s, 6H). MS (ESI, m / e) calculated 470.1815; measured 471.1 [M+H] + 469.1 [MH] - .

[0461] I-79(R)-2-Benzyl-3-chloro-5-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]oxazapyridine-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one

[0462]

[0463] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.32 (dd, J = 8.2, 1.6Hz, 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, 4.0Hz, 1H), 5.52 (s, 2H), 4.74 (dd, J = 12.7, 5.5Hz, 1H), 4.62 (dd, J = 12.6, 4.0Hz, 1H), 4.58–4.26 (m, 2H). MS (ESI, m / e) calculated 433.1054; measured 434.0 [M+H] + .

[0464] (R)-(4,5-dihydrobenzo[b]tetrazo[1,5-d][1,4]thiazazonyl-heptane-4-yl)tert-butyl carbamate (intermediate)

[0465]

[0466] MS(ESI, m / e) calculated value: 319.1103; measured value: 342.1 [M+Na] + 264.1 [M-56+H] + .

[0467] I-22(R)-N-(4,5-dihydrobenzo[b]tetrazo[1,5-d][1,4]thiazazonium-heptanetrien-4-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide

[0468]

[0469] 1 H NMR (400MHz, DMSO-d6) δ9.52 (d, J=8.2Hz, 1H), 8.81 (s, 1H), 8.00 (dd, J=8.1, 1. 3Hz, 1H), 7.82 (dd, J=7.7, 1.5Hz, 1H), 7.71 (ddd, J=8.0, 7.5, 1.5Hz, 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 value 422.1074; measured value 423.2 [M+H] + .

[0470] I-23(R)-5-benzyl-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazazonium-4-yl)isoxazo-3-carboxamide

[0471]

[0472] 1 H NMR (400MHz, CDCl3) δ8.00 (d, J=8.1Hz, 1H), 7.88 (dd, J=8.0, 1.4Hz, 1H), 7.80 (dd, J=7.7, 1.5Hz, 1H), 7.62 (td, J=7.7, 1.5Hz, 1H), 7.51 (td, J=7.7, 1.4Hz , 1H), 7.37-7.27(m, 3H), 7.25-7.21(m, 2H), 5.66(ddd, J=10.0, 8.0, 6.7Hz, 1 H), 4.11 (s, 2H), 3.93 (dd, J=12.6, 6.7Hz, 1H), 3.27 (dd, J=12.6, 10.0Hz, 1H). MS(ESI, m / e) calculated value: 404.1055; measured value: 405.2 [M+H] + 427.2 [M+Na] + .

[0473] I-24(R)-5-benzyl-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazazonium-heptanetrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0474]

[0475] 1 ¹H NMR (400MHz, CD₃OD) δ 7.98 (dd, J = 8.1, 1.4Hz, 1H), 7.84 (dd, J = 7.7, 1.4Hz, 1H), 7.74–7.64 (m, 1H), 7.56 (td, J = 7.6, 1.4Hz, 1H), 7.35–7.18 (m, 5H), 5.72 (dd, J = 10.5, 7.1Hz, 1H), 4.15 (s, 2H), 3.77 (dd, J = 13.3, 7.1Hz, 1H), 3.38 (dd, J = 13.3, 10.5Hz, 1H). MS (ESI, m / e) calculated 404.1168; measured 405.2 [M+H] + .

[0476] I-25(R)-5-benzyl-N-(6,6-dioxo-4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazazonium-4-yl)isoxazo-3-carboxamide

[0477]

[0478] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.80 (d, J = 6.9Hz, 1H), 8.22–8.07 (m, 3H), 7.95 (ddd, J = 7.8, 6.7, 2.0Hz, 1H), 7.40–7.24 (m, 5H), 6.54 (s, 1H), 5.93 (td, J = 8.7, 6.9Hz, 1H), 4.54 (dd, J = 13.9, 8.3Hz, 1H), 4.38 (dd, J = 13.9, 9.2Hz, 1H), 4.23 (s, 2H). MS (ESI, m / e) calculated 436.0954; measured 437.2 [M+H] + .

[0479] I-26 5-Benzyl-N-((4R)-6-oxo-4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazazonium-4-yl)isoxazo-3-carboxamide

[0480]

[0481] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.83 (d, J = 7.8Hz, 1H), 8.05 (dd, J = 7.8, 1.3Hz, 1H), 8.02–7.92 (m, 2H), 7.83 (td, J = 7.6, 1.2Hz, 1H), 7.42–7.23 (m, 5H), 6.57 (d, J = 0.8Hz, 1H), 5.81 (dt, J = 9.8, 8.0Hz, 1H), 4.23 (s, 2H), 4.19 (dd, J = 13.9, 8.0Hz, 1H), 3.88 (dd, J = 13.9, 9.9Hz, 1H). MS (ESI, m / e) calculated 420.1005; measured 421.0 [M+H] + 443.0 [M+Na] + .

[0482] I-28 5-Benzyl-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d]1,4]thiazazonium-4-yl)isoxazol-3-carboxamide

[0483]

[0484] 1 H NMR (400MHz, DMSO-d6) δ9.63 (d, J=7.7Hz, 1H), 7.82 (dd, J=7.7, 1.4Hz, 1H), 7 .76 (dd, J=8.0, 1.5Hz, 1H), 7.70 (td, J=7.7, 1.5Hz, 1H), 7.55 (td, J=7.5, 1.6 Hz, 1H), 7.39-7.25 (m, 5H), 6.54 (d, J=0.8Hz, 1H), 5.05 (dt, J=10.1, 7.7Hz, 1 H), 4.22 (s, 2H), 3.74 (dd, J=12.1, 7.7Hz, 1H), 3.44 (dd, J=12.1, 10.1Hz, 1H). MS(ESI, m / e) calculated value: 420.0892; measured value: 421.2 [M+H] + .

[0485] I-30(R)-N-(4,5-dihydrobenzo[b]tetrazolo[1,5-d][1,4]thiazazonium-heptanetrien-4-yl)-5-(4-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide

[0486]

[0487] 1H NMR (400MHz, CD3OD) δ7.98 (dd, J=8.0, 1.4Hz, 1H), 7.84 (dd, J=7.7, 1.5Hz, 1H), 7.69 (td, J=7.8, 1.5Hz, 1H), 7.57 (td, J=7.6, 1.4Hz, 1H), 7.3 8-7.22 (m, 2H), 7.04 (t, J=8.8Hz, 2H), 5.72 (dd, J=10.5, 7.1Hz, 1H), 4.15 (s, 2H), 3.77 (dd, J=13.3, 7.1Hz, 1H), 3.38 (dd, J=13.3, 10.5, 1H). MS (ESI, m / e) calculated value: 422.1074; measured value: 421.3 [MH] - .

[0488] I-31 5-(4-fluorobenzyl)-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]thiazazonium-heptadiene-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0489]

[0490] 1 ¹H NMR (400MHz, CD₃OD) δ 7.83 (dd, J = 7.7, 1.4Hz, 1H), 7.71 (dd, J = 8.0, 1.5Hz, 1H), 7.69–7.63 (m, 1H), 7.51 (td, J = 7.5, 1.6Hz, 1H), 7.33–7.27 (m, 2H), 7.10–7.01 (m, 2H), 5.15 (dd, J = 10.3, 7.6Hz, 1H), 4.15 (s, 2H), 3.78 (dd, J = 12.1, 7.6Hz, 1H), 3.35 (dd, J = 12.1, 10.3Hz, 1H). MS (ESI, m / e) calculated 438.0910; measured 439.2 [M+H]. + .

[0491] I-32 1-(4-fluorobenzyl)-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]thiazazonium-heptadiene-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0492]

[0493] 1H NMR (400MHz, DMSO-d6) δ9.36 (d, J=8.2Hz, 1H), 8.83 (s, 1H), 7.82 (dd, J=7.7, 1.4Hz, 1H), 7.76 (dd, J=8.0, 1.5Hz, 1H), 7.73-7.67 (m, 1H), 7.55 (td, J=7.5, 1.6Hz, 1H), 7.41-7.35(m, 2H), 7.25-7.18(m, 2H), 5.48(s, 2H), 5.04(dt, J=1 0.2, 7.9Hz, 1H), 3.70 (dd, J=12.0, 7.8Hz, 1H), 3.57 (dd, J=12.0, 10.3Hz, 1H). MS(ESI, m / e) calculated value: 438.0910; measured value: 439.2 [M+H] + .

[0494] I-33 5-Benzyl-N-((4R)-1-oxo-4,5-dihydro-1H-benzo[b][1,2,4]oxadiazolo[4,3-d][1,4]thiazazonium-heptanetrien-4-yl)-1H-1,2,4-triazol-3-carboxamide

[0495]

[0496] 1 ¹H NMR (400MHz, CD₃OD) δ 7.83 (dd, J = 7.7, 1.5Hz, 1H), 7.71 (dd, J = 8.0, 1.6Hz, 1H), 7.65 (td, J = 7.7, 1.5Hz, 1H), 7.51 (td, J = 7.5, 1.6Hz, 1H), 7.35–7.22 (m, 5H), 5.15 (dd, J = 10.3, 7.6Hz, 1H), 4.17 (s, 2H), 3.78 (dd, J = 12.1, 7.5Hz, 1H), 3.35 (dd, J = 12.1, 10.3Hz, 1H). MS (ESI, m / e) calculated 420.1005; measured 421.2 [M+H] + .

[0497] 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]oxazapyridine-4-yl)isoxazol-3-carboxamide

[0498]

[0499] MS(ESI, m / e) calculated value: 405.1073; measured value: 406.1 [M+H] +.

[0500] The compounds disclosed herein can be identified and evaluated using the following assays.

[0501] Identification of biological activity

[0502] In this embodiment, ADP-Glo ​​is used. TM The compounds disclosed herein were evaluated using biochemical assays.

[0503] ADP-Glo TM (Promega, Madison, WI, USA) The reagent was thawed at ambient temperature. The kinase detection reagent was prepared by mixing the kinase detection buffer with the lyophilized kinase detection substrate.

[0504] Prepare a 500 mL stock volume of 5X reaction kinase buffer by mixing 1000 μL of 1M MgCl2, 500 μL of 1M Tris-HCl pH 7.4, 0.5 mg / mL (25 mg) BSA, and 3475 μL of distilled H2O. Prepare a 3 mL working stock volume of 2X reaction kinase buffer containing a final concentration of 100 μL M DTT and 4 mM MnCl2.

[0505] Thaw the RIPK1 enzyme components (Rigel Pharmaceuticals, South San Francisco, CA, USA) on ice. Prepare diluted RIPK1 to 31 ng / well in 1X kinase reaction buffer (diluted from 2X buffer). Prepare a 166 μM working stock solution for ATP assay in 1X kinase reaction buffer (diluted from 2X buffer).

[0506] In 96-well plates, the compound was serially diluted 4-fold from 250 μM in DMSO, followed by a 1:5 dilution in 2X reaction buffer. 1.0 μL of the diluted compound was added in duplicate to 384-well plates. 2 μL of the diluted active RIPK1 was added to each well (excluding column 1), and 2X reaction buffer was added to column 1. 150 nM AKT (Anaspec, Fremont, CA, USA) was combined with an equal volume of ATP working stock solution, and 2 μL / well was added to each well of the 384-well plate. The final reaction volume was 5.0 μL.

[0507] Centrifuge the plate rapidly and incubate the reaction at 30°C for 30 minutes. Add 5 μl of ADP-Glo TMTerminate the reaction. Centrifuge the plate rapidly and incubate the reaction at room temperature for 40 minutes. Then add the kinase assay reagent and incubate at room temperature for 30 minutes. The relative light units (RLU) of the kinase response were determined by luminescence (0.1 s) using a Wallac Victor2 spectrophotometer (PerkinElmer, Waltham, MA, USA). Table 2 provides the ICs obtained from this example. 50 Values. The data in Table 2 confirm that the compounds of the present invention inhibit RIP1K.

[0508]

[0509]

[0510]

[0511]

[0512] Whole cell assay

[0513] In this embodiment, U937 and L929 cells were exposed to the compounds of this disclosure, and programmed cell necrosis assays were performed to evaluate the activity of the compounds in functional human RIP1 and mouse RIP1 assays.

[0514] U937 and L929 cells were obtained from the American Type Culture Collection (Manassa, VA, USA). Both cell types were maintained in logarithmic growth phase at 37°C and 5% CO2 in complete RPMI 1640 medium (Sigma, ST Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis, MO, USA). For programmed necrosis assays, L929 cells were seeded at 10,000 cells / well in 100 μL / well of Costar 96-well black clear-bottom plates (Fisher Scientific, Hampton, NH, USA) for 18 h; on the day of the assay, U937 cells were seeded at 50,000 cells / well in 50 μL / well of medium containing 60 μM zVAD-fmk (Lonza, Basel, Switzerland). The culture medium was removed from L929 cells in 96-well plates and replaced with 50 μL / well of fresh medium containing 40 μM zVAD-fmk. Each compound of the present disclosure evaluated in this example was serially diluted 4-fold from 2.5 mM in DMSO, followed by a 1:125 dilution in complete medium. 50 μL / well of the 2x compound was then added to the cells in the plates. Cells were pre-incubated with the compound at 37°C and 5% CO2 for 1 h, followed by the addition of 10 μL / well of 11x TNFa (Peprotech, Rocky Hill, NJ, USA) to obtain a final TNFa concentration of 2 ng / mL. After TNFa stimulation at 37°C and 5% CO2 for 18 h, the cells were analyzed using a Wallac Victor2 spectrophotometer (PerkinElmer, Waltham, MA, USA) and a CellTiter. A luminescent cell viability assay (Promega, Madison, WI, USA) (added according to the manufacturer's instructions) was used to determine the relative amount of programmed necrosis cells by luminescence. Results from this embodiment are summarized in Table 3. This embodiment determined that the embodiments of the compounds described herein possess unexpectedly potent activity against human and mouse RIP1, which allows for their evaluation in in vivo mouse models of the disease. These results can be used to determine a safe and effective dose for humans.

[0515]

[0516]

[0517]

[0518]

[0519] in vivo activity

[0520] In this embodiment, an acute hypothermic mouse model was used to evaluate the ability of the compounds disclosed herein to inhibit TNF-α-induced hypothermia.

[0521] Female C57BL / 6 mice were randomly assigned to groups and weighed on day -1. On the study day (day 0), mice were administered the mediator or test substance via oral feeding. Fifteen minutes after oral administration of the test substance, each mouse was given an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor α (TNF-α, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured at hour 0 (before intraperitoneal injection) and hourly via a rectal probe thermometer. Three (3) hours after intraperitoneal injection of TNF-α and zVAD / FMK, mice were euthanized by CO2 asphyxiation and blood was collected via cardiac puncture. Serum and plasma were harvested to determine cytokine and compound levels, respectively. A separate group of mice (satellite mice) was included to determine the compound levels in plasma at the time of administration of TNF-α / zVAD-FMK. The activity demonstrated in this embodiment confirms that the embodiments of the compounds disclosed herein inhibit TNF-α signaling in vivo and can therefore be used to treat diseases in which TNF-α is involved.

[0522] Considering the many possible embodiments to which the principles of the disclosed invention can be applied, it should be recognized that the explained embodiments are merely preferred examples of the invention and should not be considered as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. Therefore, we declare all content falling within the scope and spirit of these claims as our invention.

Claims

1. A compound, wherein the compound is 2. Use of the compound according to claim 1 in the preparation of a medicament for treating a disease, wherein the disease is amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, or Alzheimer's disease.

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