RIP1 inhibitory compounds and methods of making and using the same

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of earlier filing dates of U.S. Provisional Patent Application No. 62 / 897,223 filed on September 6, 2019, U.S. Provisional Patent Application No. 62 / 932,404 filed on November 7, 2019, U.S. Provisional Patent Application No. 63 / 001,016 filed on March 27, 2020, U.S. Provisional Patent Application No. 63 / 004,290 filed on April 2, 2020, and U.S. Provisional Patent Application No. 63 / 004,319 filed on April 2, 2020. Technical Field

[0003] The present disclosure relates to compounds and methods of making and using the compounds, such as for inhibiting receptor-interacting protein-1 kinase ("RIP1"), and for treating diseases and / or conditions associated with RIP1. Background Art

[0004] Receptor-interacting protein-1 kinase (herein referred to as "RIP1") belongs to the tyrosine kinase-like family and is a serine / threonine protein kinase involved in innate immune signaling. RIP1 plays a key role in regulating cell signaling, and its role in programmed cell death is associated with various inflammatory diseases, such as inflammatory bowel disease, psoriasis, and other diseases and / or conditions associated with inflammatory and / or necrotic cell death. Summary of the invention

[0005] The disclosed compounds according to the present disclosure have the formula I

[0006]

[0007] Wherein X is C or N;

[0008] Y is selected from O, S and CH2;

[0009] Depend on The ring system represented is optionally substituted on ring A, ring B, or both by one or more R 4 a group-substituted bicyclic heteroaryl;

[0010] L is a divalent moiety selected from R a , heteroatom; C 1-4 Alkyl, or C 3-6 Cycloalkyl;

[0011] Z is for C 1-10 Aliphatic, Z is C 1-10 aliphatic, including cycloaliphatic, heteroaromatic or aromatic;

[0012] Each R 1 are independently halogen, -C≡CH, or -linker-R 6 group, wherein the linker is a bond or R a , the condition is R a Not H or D, and R 6 is a heterocyclic group, R b , -C(R f )3, or -C(R f )=C(R f )2;

[0013] R 2 YesR a ;

[0014] Each R 4 are independently oxo, C 3-6 Heterocyclic group or R e ;

[0015] For every existence, R a are independently H or D, except where L is R a In addition to the implementation plan, C 1-10 Aliphatic group, C 1-10 Halogenated aliphatic group, C 5-10 Aromatic group, C 3-6 Heterocyclic group, or C 3-10 spiroheterocyclic groups;

[0016] For every existence, R b are independently -OH, -SH, -OR c , -SR c , -NR d R d , -Si(R a )3, -C(O)OH, -C(O)OR c , -C(O)NR d R d , -OC(O)NR d R d , -OC(O)C 1-10 Alkyl, substituted with: one or two NR d R d , carboxyl, or a combination thereof, and optionally further substituted with: an aromatic moiety, -SH, -O-acyl, or -C(O)NH2;

[0017] For every existence, R c Independently C 1-10 Alkyl groups, which may be 1, 2 or 3 R e Replacement, C 2-10Alkenyl, which may be 1, 2 or 3 R e Replacement, C 2-10 Alkynyl, which may be replaced by 1, 2 or 3 R e Replacement, C 3-6 Cycloalkyl, which may be replaced by 1, 2 or 3 R e Replacement, or C 5-10 Aromatic, which may be 1, 2 or 3 R e replace;

[0018] For every existence, R d Independently H; C 1-6 Alkyl groups, which may be 1, 2 or 3 R e Substitution or C 3-9 Heterocyclic group; C 3-6 Cycloalkyl, which may be replaced by 1, 2 or 3 R e Replace; C 3-6 Heterocyclic ring, which may be replaced by 1, 2 or 3 R e Replace; C 5-10 Aryl, which may be replaced by 1, 2 or 3 R b Replace; C 5-10 Heteroaryl, which may be replaced by 1, 2 or 3 R e Replace; or two R d The group together with the nitrogen to which it is bonded provides C 3-9 Heterocyclic rings, which may be replaced by one or more R e Replace), or C 5-10 Heteroaryl, which may be replaced by one or more R e replace;

[0019] For every existence, R e are independently halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a ;and

[0020] For every existence, R f are independently -alkyl-phosphates, R a , R b , or R e , or two R f The group together with the carbon atom to which it is bonded provides C 2-6 Alkenyl group, C 3-6 Cycloalkyl groups, which may be replaced by one or more R e Replacement, or C 3-10 Heterocyclic rings, which may be replaced by one or more R eor acyl substitution;

[0021] m is 1, 2, 3, or 4; and

[0022] n is 0, 1 or 2.

[0023] The disclosed embodiments also include pharmaceutical compositions containing the disclosed compounds. Such compositions may further comprise excipients, additional therapeutic agents, or combinations thereof.

[0024] A method may include administering to a subject one or more compounds disclosed, or a composition comprising one or more compounds disclosed. A particular embodiment involves contacting a receptor-interacting protein-1 (RIP1) kinase with one or more compounds disclosed, or a composition comprising one or more compounds disclosed. The method may be an in vitro method or an in vivo method, such as when the RIP1 kinase is in a subject.

[0025] In some embodiments, the method may include administering one or more of the disclosed compounds, or a composition thereof, to a subject. The method may be a method for treating a disease in a subject and / or may include administering to the subject (i) a therapeutically effective amount of a disclosed compound or a stereoisomer thereof, an N-oxide, a tautomer, or a prodrug; or (ii) a therapeutically effective amount of a pharmaceutical composition of the compound. In some embodiments, the subject may have, or may be suspected of having or developing a disease, such as a disease involving receptor-interacting protein-1 (RIP1) kinase. Examples of diseases that can be treated according to this method embodiment include diseases or disorders associated with inflammation, necrosis, or both. In certain embodiments, the disease to be treated with the compounds of the present invention is an inflammatory or immunomodulatory disorder, including autoimmune and proliferative disorders. Exemplary diseases are disclosed herein.

[0026] The foregoing and other objects and features of the present disclosure will become more apparent from the following detailed description.

[0027] Detailed description

[0028] I. Definition of Terms

[0029] The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art to practice the present disclosure. The singular forms "a / an" and "the" refer to one / a or more than one / a, unless the context clearly indicates otherwise. The term "or" refers to a single element of the stated alternative element or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, "comprises" means "includes". Therefore, "comprising A or B" means "comprising A, B, or A and B," without excluding additional elements. All references, including patents and patent applications cited herein, are incorporated by reference.

[0030] Unless otherwise stated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, etc., as used in the specification or claims will be understood to be modified by the term "about". Therefore, unless otherwise indicated, implicitly or explicitly, the numerical parameters displayed are approximate values ​​that may depend on the desired properties sought and / or the detection limits under standard test conditions / methods. When directly and clearly distinguishing between an embodiment and the prior art being discussed, the numbers of the embodiments are not approximate values ​​unless the word "about" is explicitly stated.

[0031] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. Although methods and materials similar to or equivalent to those described herein may be employed in the implementation or testing of the present disclosure, suitable methods and materials are described below. Materials, methods, and embodiments are illustrative only and are not intended to be limiting.

[0032] When depicting or describing chemical structures, unless otherwise explicitly stated, it is assumed that all carbons include hydrogen so that each carbon meets the valence of four. For example, in the structure on the left hand side of the schematic diagram below, nine hydrogen atoms are implied. The nine hydrogen atoms are depicted in the right hand structure.

[0033]

[0034] Sometimes specific atoms in a structure are described in literal formulae as having hydrogen or a hydrogen atom, such as -CH2CH2-. One of ordinary skill in the art will appreciate that the above descriptive techniques are common in the chemical arts to provide brevity and simplicity in the description of organic structures.

[0035] If the R group is depicted as "floating" on the ring system, such as in the following group R 1 :

[0036]

[0037] Then, unless otherwise defined, a substituent R (e.g., R 1 ) may be present on any atom of a fused bicyclic ring system, excluding those carrying The atoms of the bonds with the symbols can form a stable structure.

[0038] When the group R is depicted as being present on a ring system containing a saturated carbon, such as in the following formula:

[0039]

[0040] Wherein, in this example, y can be greater than 1, assuming that each replaces the currently depicted, implicit or clearly defined hydrogen on the ring; then, unless otherwise defined, two R can be located on the same carbon. A simple example is when R is a methyl group. The depicted structure can be present in the form of paired dimethyl on the carbon ("annular" carbon) of the depicted ring. In another example, two R on the same carbon, including the same carbon, can be included in the ring, thereby producing a spirocyclic ring ("spirocyclyl" group) structure.

[0041] As used herein, the term "substituted" refers to all subsequent modifications in the term, for example, in the term "substituted aryl C 1-8 In the case of an alkyl group, substitution can occur on the aromatic C 1-8 The alkyl group "C 1-8 on the "alkyl" portion, the "aryl" portion, or both.

[0042] When used to modify a specific group or part, "substituted" means that at least one, possibly two or more hydrogen atoms of a specific group or part are independently replaced with the same or different substituent groups defined below. In a particular embodiment, a group, part or substituent can be substituted or unsubstituted, unless explicitly defined as "unsubstituted" or "substituted". Therefore, any group specified herein can be unsubstituted or substituted, unless the context otherwise indicates or a particular 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" part can be unsubstituted or substituted, but an "unsubstituted aliphatic" or "unsubstituted cyclic" is not substituted.

[0043] Unless otherwise specified, a "substituent" or "substituent group" used to replace one or more hydrogen atoms on a saturated carbon atom in a particular group or moiety may be -R 60 , halogen, =O, -OR 70 , -SR 70 , -N(R80 )2, haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 ,-OSO2R 70 , -OSO3 - M + ,-OSO3R 70 , -P(O)(O - )2(M + )2,-P(O)(O - )2M 2+ , -P(O)(OR 70 ) - M + , -P(O)(OR 70 )2,-C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 ,-C(O)N(R 80 )2,-C(NR 70 )(R 80 )2,-OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R60 It is C 1-10 Aliphatic, heteroaliphatic, or cycloaliphatic, typically C 1-6 Aliphatic, more typically C 1-6 Alkyl, where R 60 may be optionally substituted; for each occurrence, each R 70 are independently hydrogen or R 60 ; For each existence, each R 80 Independently R 70 Or alternatively, two R 80 The groups, taken together with the nitrogen atom to which they are bound, form a 3- to 7-membered heterocyclic aliphatic, which optionally includes 1-4 identical or different additional heteroatoms selected from O, N and S, wherein N optionally has R 70 substituted, such as H or C1-C3 alkyl; and each M + is a counterion with a net single positive charge. For each occurrence, each M + independently are, 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 ions, or arginine ions; or alkaline earth metal ions, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 (The subscript "0.5" means, for example, that one of the counterions of such a divalent alkaline earth (metal) ion can be a compound of the present disclosure in ionized form and the other typical counterion such as chloride, or both ionized compounds can serve as counterions of such a divalent alkaline earth (metal) ion, or doubly ionized compounds can serve as counterions of such a divalent alkaline earth (metal) ion). As a specific example, -N(R 80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, N-morpholinyl, etc. Any two hydrogen atoms on a single carbon can also be replaced by, for example, =O, =NR 70 , =N-OR 70 , =N2 or =S.

[0044] Unless otherwise specified, the substituent group used to replace the hydrogen atom on the unsaturated carbon atom in the group containing unsaturated carbon is, -R 60 , halogen, -O - M+ , -OR 70 , -SR 70 , -S - M + , -N(R 80 )2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 -2 (M + )2, -PO3 -2 M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )N(R 80 )2, -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 , -C(O)N(R 80 )2, -NR 70 , -C(NR70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R 60 , R 70 , R 80 and M+ is as previously defined. In independent embodiments, the substituent is not -O - M + , -OR 70 , -SR 70 , or -S - M + .

[0045] Unless otherwise specified, the substituent groups used to replace hydrogen atoms on nitrogen atoms in groups containing such nitrogen atoms are, -R 60 , -O - M + , -OR 70 , -SR 70 , -S - M + , -N(R 80 )2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R 70 , -SO3 - M + , -SO3R 70 , -OS(O)2R 70 ,-OSO3 - M + ,-OSO3R 70 ,-PO3 2- (M + )2, -PO3 2- M 2+ , -P(O)(OR 70 ) - 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)R70 , -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 + is as defined previously.

[0046] In one embodiment, a substituted group has at least one substituent, up to the number of substituents possible for the particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

[0047] In addition, in the embodiment where the group or part is substituted by a substituted substituent, the nesting of such a substituted substituent is limited to three, thereby preventing the formation of a polymer. Therefore, in a group or part comprising a first group (the first group is a substituent on a second group, the second group itself is a substituent on a third group, and the third group is connected to a parent structure), the first (outermost) group can be replaced only by an unsubstituted substituent. For example, in a group comprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can be replaced only by a substituent that is itself unsubstituted.

[0048] Any group or moiety defined herein may be linked to any other part of the disclosed structure, such as a parent or core structure, as understood by one of ordinary skill in the art, such as by considering valence rules, comparison with exemplary substances, and / or considering functionality, unless the connectivity of the group or moiety to the rest of the structure is explicitly stated or is implied by the context.

[0049] "Acyl" refers to the radical -C(O)R, where R is H, aliphatic, heteroaliphatic, or aromatic (including aryl and heteroaryl). Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C1-C6alkyl, -C(O)C1-C6haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include, -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0050] "Aliphatic" refers to a radical or moiety that is substantially hydrocarbon-based. Aliphatic radicals or moieties may be non-cyclic, including alkyl, alkenyl, or alkynyl radicals (as well as alkylene, alkenylene, alkynylene radicals), cyclic versions thereof, such as cycloaliphatic radicals or moieties (including cycloalkyl, cycloalkenyl, or cycloalkynyl, and further including straight and branched chain arrangements, as well as all stereo and positional isomers. Unless expressly stated otherwise, aliphatic radicals contain 1 to 25 carbon atoms (C 1-25 ); for example, for a non-cyclic aliphatic group or moiety, 1 to 15 carbon atoms (C 1-15 ), 1 to 10 carbon atoms (C 1-10 ), 1 to 6 carbon atoms (C 1-6 ), or 1 to 4 carbon atoms (C 1-4 ), or for a cycloaliphatic radical or moiety, 3 to 15 carbon atoms (C 3-15 ), 3 to 10 carbon atoms (C 3-10 ), 3 to 6 carbon atoms (C 3-6 ), or 3 to 4 carbon atoms (C 3-4 ). Aliphatic groups may be substituted or unsubstituted unless specifically referred to as "unsubstituted aliphatic" or "substituted aliphatic". Aliphatic groups may be substituted with one or more substituents (up to two substituents for each methylene carbon in the aliphatic chain, or up to one substituent for each carbon of a -C=C- double bond in the aliphatic chain, or up to one substituent for a terminal methine carbon).

[0051] "Lower aliphatic" refers to a group containing 1 to 10 carbon atoms (C 1-10 ), such as 1 to 6 carbon atoms (C 1-6 ), or 1 to 4 carbon atoms (C 1-4 ) aliphatic groups; or for lower cycloaliphatic groups, 3 to 10 carbon atoms (C 3-10 ), such as 3 to 6 carbon atoms (C 3-6 ).

[0052] "Alkoxy" refers to a group -OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group. In certain instances, R is C 1-6 Alkyl or C 3-6 Cycloalkyl groups. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In substituted alkoxy groups, R is a substituted alkyl or a substituted cycloalkyl, examples of which in the presently disclosed compounds include haloalkoxy groups, such as -OCF2H.

[0053] "Alkoxyalkyl" refers to the group -alkyl-OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group; -CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl group.

[0054] "Alkyl" refers to a group having 1 to at least 25 carbon atoms (C 1-25 ), more typically 1 to 10 carbon atoms (C 1-10 ), such as 1 to 6 carbon atoms (C 1-6 ) saturated aliphatic hydrocarbon groups. The alkyl moiety may be substituted or unsubstituted. The term includes, for example, linear 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).

[0055] "Amino" refers to the radical -NH2, -NHR, or -NHR, wherein each R is independently selected from H, aliphatic, heteroaliphatic, aromatic, including both aryl and heteroaryl, or heterocycloaliphatic, or two R groups taken together with the nitrogen to which they are bound form a heterocyclic ring. Examples of such heterocyclic rings include those wherein the two R groups taken together with the nitrogen to which they are bound form a heterocyclic ring optionally substituted by one or two heteroatom groups such as -O- or -N(R g )Interrupted-(CH2) 2-5 - those of rings, such as radicals Where R g YesR 70 , -C(O)R 70 , -C(O)OR 60 or -C(O)N(R 80 )2.

[0056] "Amide" refers to the group -N(R)acyl, where R is hydrogen, heteroaliphatic or aliphatic, such as alkyl, especially C 1-6 alkyl.

[0057] "Aromatic" means, unless otherwise specified, a cyclic conjugated group or moiety of 5 to 15 ring atoms having a single ring (e.g., phenyl, pyridyl, or pyrazolyl) or multiple fused rings, at least one of which is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl), i.e., at least one ring, and optionally multiple fused rings, having a continuous delocalized π electron system. Typically, the number of out-of-plane π electrons corresponds to Hückel's rule (4n+2). The point of attachment to the parent structure is typically through the aromatic portion of the fused ring system. For example, However, in some instances, the context or explicit disclosure may indicate that the point of attachment is through the non-aromatic portion of the fused ring system. An aromatic group or moiety may include only carbon atoms in the ring, as in an aryl group or moiety, or it may include one or more ring carbon atoms and one or more ring heteroatoms containing a lone pair of electrons (e.g., S, O, N, P, or Si), as in a heteroaryl group or moiety. Unless otherwise stated, an aromatic group may be substituted or unsubstituted.

[0058] "Aryl" means, unless otherwise specified, an aromatic carbocyclic group of 6-15 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, etc.). If any aromatic ring portion contains heteroatoms, the group is a heteroaryl group, not an aryl group. An aryl group can be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise stated, an aryl group can be substituted or unsubstituted.

[0059] "Araliphatic" refers to an aryl group attached to the parent moiety through an aliphatic moiety. Araliphatic includes aralkyl or arylalkyl groups such as benzyl and phenethyl.

[0060] "Carboxyl" refers to -CO2H.

[0061] "Carboxamide" refers to a -C(O)amino group.

[0062] "Carboxyl ester" or "carboxy ester" refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including aryl and heteroaryl).

[0063] "Carboxylate" refers to -C(O)O- or a salt thereof.

[0064] "Cyano" refers to the radical -CN.

[0065] "Cycloaliphatic" refers to a cyclic aliphatic group having a single ring (e.g., cyclohexyl), or multiple rings, such as in a fused, bridged, or spiro ring system, wherein at least one of the rings or multiple rings in the system is aliphatic. Typically, the point of attachment to the parent structure is through the aliphatic portion of the polycyclic system. Cycloaliphatics include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. Cycloaliphatic 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, cycloaliphatic groups may be substituted or unsubstituted. Exemplary cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0066] "Halo", "halide" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0067] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CH2F, -CHF2 and -CF3.

[0068] "Heteroaliphatic" refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., an aliphatic compound or group containing at least two carbon atoms in which at least one carbon atom has been replaced by an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon or sulfur). The heteroaliphatic compound or group may be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic, such as a heterocycloaliphatic group.

[0069] "Heteroaryl" refers to an aromatic group or moiety, unless otherwise specified, having 5-15 ring atoms, including at least one carbon atom and at least one heteroatom, such as N, S, O, P, or Si. Heteroaryl groups or moieties can include a single ring (e.g., pyridyl, pyrimidinyl, or pyrazolyl) or multiple fused rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). Heteroaryl groups or moieties can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, heteroaryl groups or moieties can be substituted or unsubstituted.

[0070] "Heterocyclyl", "heterocyclic" and "heterocycle" refer to aromatic and non-aromatic ring systems, and more specifically to stable 3 to 15 membered ring moieties containing at least one carbon atom and typically multiple carbon atoms and at least one (e.g., 1 to 5 heteroatoms). The heteroatom may be a nitrogen, phosphorus, oxygen, silicon or sulfur atom. The heterocyclyl moiety may be a monocyclic moiety, or may include multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the multiple rings contains a heteroatom. Such polycyclic moieties may include fused or bridged ring systems as well as spiro ring systems; and any nitrogen, phosphorus, carbon, silicon or sulfur atom in the heterocyclyl moiety may be optionally oxidized to various oxidation states. For convenience, nitrogen, particularly, but not exclusively, those defined as cyclic aromatic nitrogens, are meant to include their corresponding N-oxide forms, although not explicitly defined as such in a particular instance. Thus, for example, for a compound having a pyridyl ring, as another compound of the present disclosure, the corresponding pyridyl-N-oxide is included unless explicitly excluded or excluded by context. In addition, the cyclic nitrogen atom may be optionally quaternized. The heterocycle includes a heteroaryl moiety and a heteroalicyclic or heterocycloaliphatic moiety, which is a partially or completely saturated heterocyclic ring. Examples of heterocyclic radicals include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolyl, indolizinyl, naphthyridinyl, perhydroazacycloheptatrienyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolyl, isoquinolyl, tetrazolyl, tetrahydroisoquinoline pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolidinyl, oxazolidinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxadiazolyl,

[00136] The invention also includes but is not limited to oxadiazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolyl, octahydroindolyl, octahydroisoindolyl, quinolinyl, isoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furanyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholyl, and oxadiazolyl.

[0071] "Hydroxy" refers to the group -OH.

[0072] "Nitro" refers to the radical -NO2.

[0073] "Phosphate" refers to the group -OP(O)(OR')2, wherein each -OR' is independently -OH; -O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; -O-aralkyl; or -OR' is -O - M + , where M + is a counter ion with a single positive charge. + Can be an alkali ion such as K + , Na + , Li + ; ammonium ions, such as + N(R")4, wherein R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth ion such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 Phosphonyloxyalkyl refers to the group -alkyl-phosphate, such as, for example, -CH2OP(O)(OH)2, or a salt thereof, such as -CH2OP(O)(O-Na+)2, and (((dialkoxyphosphoryl)oxy)alkyl) refers to the dialkyl ester of the phosphonyloxyalkyl group, such as, for example, -CH2OP(O)(O-tert-butyl)2.

[0074] "Phosphonate" refers to the group -P(O)(OR')2, wherein each -OR' is independently -OH; -O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; or -O-aralkyl; or -OR' is -O - M + , and M + is a counter ion with a single positive charge. + is a positively charged counterion and may be, for example, an alkali metal ion such as K + , Na + , Li + ; ammonium ions, such as + N(R")4, wherein R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth metal ion, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba2+ ] 0.5 Phosphonoalkyl 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 a phosphonoalkyl group, such as, for example, -CH2P(O)(O-tert-butyl)2.

[0075] "Patient" or "subject" may generally refer to any organism, but more typically refers to mammals and other animals, especially humans. The disclosed methods are therefore applicable to both human treatment and veterinary applications.

[0076] "Pharmaceutically acceptable excipient" refers to a substance other than the active ingredient that is included in a composition containing an active ingredient. As used herein, an excipient may be incorporated into the particles of the pharmaceutical composition, or it may be physically mixed with the particles of the pharmaceutical composition. An excipient may be used, for example, to dilute the active agent and / or to change the properties of the pharmaceutical composition. An excipient may include, but is not limited to, an anti-adhesive, a binder, a coating, an enteric coating, a disintegrant, a flavoring agent, a sweetener, a colorant, a lubricant, a glidant, an adsorbent, a preservative, a carrier or a vehicle. An excipient may be starch and modified starches, 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, hydroxypropylcellulose, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silicon dioxide, talc, magnesium carbonate, sodium starch glycolate, tartrate, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite or lanolin.

[0077] An "adjuvant" is a component that modifies the effect of other agents (typically active ingredients). Adjuvants are typically pharmacological and / or immunological agents. Adjuvants can modify the effect of active ingredients by increasing the immune response. Adjuvants can also act as stabilizers for formulations. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, inactivated bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants, such as Freund's complete adjuvant or Freund's incomplete adjuvant.

[0078] "Pharmaceutically acceptable carrier" refers to an excipient that acts as a carrier or vehicle, such as a suspending aid, a solubilizing aid, or an aerosolizing aid. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21st edition (2005), incorporated herein by reference, describes exemplary compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0079] Typically, the nature of the carrier will depend on the specific mode of administration adopted. For example, parenteral preparations typically include injectable fluids, which include pharmaceutically and physiologically acceptable fluids, such as water, saline, balanced salt solutions, dextrose aqueous solutions, glycerol, etc., as vehicles. In some instances, pharmaceutically acceptable carriers can be sterile to be suitable for administering to a subject (e.g., by parenteral, intramuscular or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical composition to be administered may contain a small amount of non-toxic auxiliary substances, such as wetting agents or emulsifiers, preservatives and pH buffers, such as sodium acetate or sorbitan monolaurate.

[0080] "Pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of compounds derived from various organic and inorganic counterions as would be known to one of ordinary skill in the art, and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, and the like. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed with acids while retaining the biological effectiveness of the free bases. In particular, the disclosed compounds form salts with various pharmaceutically acceptable acids, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, carotene 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, 1-hydroxy-2-naphthoic acid (xinafoic acid), and the like. "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, and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference.) In particularly disclosed embodiments, the compound can be a formate salt, a trifluoroacetate salt, a hydrochloride salt, or a sodium salt.

[0081] An "effective amount" with respect to a compound or pharmaceutical composition refers to an amount of the compound or pharmaceutical composition sufficient to obtain a specific desired result, such as inhibition of a protein or enzyme. In particular embodiments, an "effective amount" is an amount sufficient to inhibit RIP1; to induce a desired biological or medical response in a tissue, system, subject or patient; to treat a specific disorder or disease; to ameliorate or eradicate one or more of its symptoms; and / or to prevent the occurrence of a disease or disorder. The amount of a compound that constitutes an "effective amount" may vary depending on the compound, the desired result, the disease state and its severity, the size, age and sex of the patient to be treated, etc., as will be understood by those of ordinary skill in the art.

[0082] "Prodrug" refers to a compound that is transformed in vivo to produce a biologically active compound, or a compound that is more biologically active than the parent compound. The in vivo transformation can occur, for example, by hydrolysis or enzymatic transformation. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of compounds having an active form with a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the present disclosure include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (e.g., C 1-6 Other prodrug moieties include phosphate esters, such as -CH2-OP(O)(OR')2 or salts thereof, wherein R' is H or C 1-6 Alkyl. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of the present disclosure include, but are not limited to, primary amides and secondary alkyl amides and tertiary alkyl amides (e.g., having about 1 to about 6 carbon atoms). Amides and esters of the disclosed exemplary embodiments of the compounds of the present disclosure can be prepared according to conventional methods. An in-depth discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14 of the ACSSymposium Series, 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.

[0083] "Solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of a solute. The solvent may be an organic solvent, an inorganic solvent, or a mixture of the two. 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 may exist in unsolvated and solvated forms when combined with a solvent, pharmaceutically acceptable or not, such as water, ethanol, and the like. The solvated forms of the compounds disclosed herein are within the scope of the embodiments disclosed herein.

[0084] "Sulfonamide" refers to the group or moiety -SO2amino, or -N(R)sulfonyl, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0085] "Sulfanyl" refers to the radical or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic, (including both -S-aryl and -S-heteroaryl).

[0086] "Sulfinyl" refers to the group or moiety -S(O)H, -S(O)aliphatic, -S(O)heteroaliphatic, or -S(O)aromatic (including both -S(O)aryl and -S(O)heteroaryl).

[0087] "Sulfonyl" refers to the radical: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including both -SO2aryl and -SO2heteroaryl).

[0088] As used herein, "treat" or "treatment" refers to treating a disease or condition of interest in a patient or subject, particularly a human having the disease or condition of interest, and includes, for example, and without limitation:

[0089] (i) preventing the occurrence of the disease or condition in a patient or subject, in particular, when the patient or subject is susceptible to the condition but has not yet been diagnosed as having it;

[0090] (ii) inhibiting the disease or condition, such as arresting or slowing its progression;

[0091] (iii) alleviate the disease or condition, such as causing a decrease in symptoms or regression of the disease or condition or its symptoms; or

[0092] (iv) stabilizing the disease or condition.

[0093] As used herein, the terms "disease" and "condition" may be used interchangeably, or may be distinct, wherein a particular disease or condition may not have a known etiology (such that a cause has not been determined), and therefore it is not yet considered a disease but merely as an undesirable condition or syndrome in which a more or less specific set of symptoms has been recognized by a clinician.

[0094] The above definitions and the following formulae are not intended to include impermissible substitution patterns (eg, a methyl group substituted with 5 fluoro groups). One of ordinary skill in the art will readily recognize such impermissible substitution patterns.

[0095] It will be understood by those skilled in the art that compounds may exhibit tautomerism, structural isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may include one or more chiral centers and / or double bonds and may therefore exist in the form of stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, certain disclosed compounds may exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Since the various compound names, chemical formulas, and compound diagrams in the specification and claims may represent only one of the possible tautomeric, structural, optical, or geometric isomeric forms, it will be understood by those skilled in the art that the disclosed compounds include any tautomeric, structural, optical, and / or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. Mixtures of different isomeric forms, including mixtures of enantiomers and / or stereoisomers, can be separated using techniques known to those of ordinary skill in the art, particularly with the benefit of this disclosure, to provide each individual enantiomer and / or stereoisomer. In cases of limited rotation, for example around an amide bond or between two directly connected rings such as a pyridine ring, biphenyl, etc., atropisomers are also possible and are also explicitly included in the compounds of the present disclosure.

[0096] In any embodiment, any or all hydrogens present in the compound, or in a specific group or moiety within the compound, may be replaced by deuterium or tritium. Thus, the recitation of alkyl includes deuterated alkyls in which one to the maximum number of hydrogens present may be replaced by deuterium. For example, ethyl may be C2H5 or C2H5 in which 1 to 5 hydrogens are replaced by deuterium, such as in C2D x H 5-x middle.

[0097] II. RIP1-active compounds and pharmaceutical compositions comprising RIP1-active compounds

[0098] A. Compounds

[0099] Disclosed herein are compounds and pharmaceutical compositions comprising such compounds that can be used to inhibit RIP1 and / or to treat diseases and / or conditions associated with RIP1. In some embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds can selectively inhibit RIP1 relative to RIP2, RIP3, or both RIP2 and RIP3.

[0100] In certain embodiments, the compound has Formula I

[0101]

[0102] Wherein X is C or N;

[0103] Y is selected from O, S and CH2;

[0104] Depend on The ring system represented is optionally substituted on ring A, ring B, or both by one or more R 4 a group-substituted bicyclic heteroaryl;

[0105] L is a heteroatom; -CH2-, -CH2CH2-, or C 3-6 Cycloalkyl;

[0106] Z is for C 1-10 Aliphatic, Z is C 1-10 aliphatic, including cycloaliphatic, heteroaromatic or aromatic;

[0107] Each R 1 are independently halogen, -C≡CH, or -linker-R 6 group, wherein the linker is a bond or R a , the condition is R a Not H or D, and R 6 is a heterocyclic group, R b , -C(R f )3, or -C(R f )=C(R f )2;

[0108] R 2 YesR a ;

[0109] Each R 4 are independently oxo, C 3-6 Heterocyclic group or R e ;

[0110] For every existence, R a are independently H or D, except where L is R a In addition to the implementation plan, C 1-10 Aliphatic group, C1-10 Halogenated aliphatic group, C 5-10 Aromatic group, C 3-6 Heterocyclic group, or C 3-10 spiroheterocyclic groups;

[0111] For every existence, R b are independently -OH, -SH, -OR c , -SR c , -NR d R d , -Si(R a )3, -C(O)OH, -C(O)OR c , -C(O)NR d R d , -OC(O)NR d R d , -OC(O)C 1-10 Alkyl, substituted with: one or two NR d R d , carboxyl, or a combination thereof, and optionally further substituted with: an aromatic moiety, -SH, -O-acyl, or -C(O)NH2;

[0112] For every existence, R c Independently C 1-10 Alkyl groups, which may be 1, 2 or 3 R e Replacement, C 2-10 Alkenyl, which may be 1, 2 or 3 R e Replacement, C 2-10 Alkynyl, which may be replaced by 1, 2 or 3 R e Replacement, C 3-6 Cycloalkyl, which may be replaced by 1, 2 or 3 R e Replacement, or C 5-10 Aromatic, which may be 1, 2 or 3 R e replace;

[0113] For every existence, R d Independently H; C 1-6 Alkyl groups, which may be 1, 2 or 3 R e Substitution or C 3-9 Heterocyclic group; C 3-6 Cycloalkyl, which may be replaced by 1, 2 or 3 R e Replace; C 3-6 Heterocyclic ring, which may be replaced by 1, 2 or 3 R e Replace; C 5-10 Aryl, which may be replaced by 1, 2 or 3 R b Replace; C 5-10 Heteroaryl, which may be replaced by 1, 2 or 3 R eReplace; or two R d The group together with the nitrogen to which it is bonded provides C 3-9 Heterocyclic rings, which may be replaced by one or more R e Replace), or C 5-10 Heteroaryl, which may be replaced by one or more R e replace;

[0114] For every existence, R e are independently halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a ;and

[0115] For every existence, R f are independently -alkyl-phosphates, R a , R b , or R e , or two R f The group together with the carbon atom to which it is bonded provides C 2-6 Alkenyl group, C 3-6 Cycloalkyl groups, which may be replaced by one or more R e Replacement, or C 3-10 Heterocyclic rings, which may be replaced by one or more R e or acyl substitution;

[0116] m is 1, 2, 3, or 4; and

[0117] n is 0, 1 or 2.

[0118] In some embodiments, in Formula I, X represents CH, and such compounds can be represented by Formula IA:

[0119]

[0120] In alternative compounds according to formula I, X is N. Examples of such compounds may be represented by formula IB:

[0121] The compound of claim 1, which is according to the formula:

[0122]

[0123] In one embodiment of Formula I, IA, IB and IC, Ring B is a 5- or 6-membered heteroaryl group, wherein the heteroaryl group has one or two ring nitrogen atoms and the remaining ring atoms are carbon.

[0124] In certain embodiments of Formula I, IA, IB and IC, The ring systems represented are represented by the following illustrative formulae 1(a)-1(e):

[0125] 1(a) wherein p is 0 or 1; and Ring A, Ring B, or both are optionally replaced by one or more R 4 replace;

[0126] 1(b) wherein p is 0 or 1; and Ring B is optionally replaced by one or more R 4 replace;

[0127] 1(c) Where p is 0 or 1;

[0128] 1(d) or

[0129] 1(e)

[0130] With respect to Formula I, IA, IB, IC and ID, and in each combination of Formula I, IA, IB, IC and ID with the ring systems exemplified in Formulae 1(a)-1(e), Z is C 1-10 The Z of aliphatic is C 1-10 Aliphatic, including cycloaliphatic, heteroaromatic or aromatic. More particularly in such compounds, Z, when cycloaliphatic, can be cyclopentyl, cyclohexyl, etc. In the case when Z is heteroaromatic, Z can be a 6-membered heteroaryl, such as pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl, or a 5-membered heteroaryl, such as a nitrogen-containing 5-membered heteroaryl, for example, a diazole, triazole, tetrazole, oxazole, isoxazole or thiazole moiety. Each Z moiety can be substituted, such as by one or more halogen, alkyl, C 3-6 The Z moiety may be unsubstituted or substituted once up to the number of potential substitution sites available for substitution. For example, when Z is phenyl, it may be represented by the formula Represented by, where each R 5 Independently R e , and q is 0, 1, 2, 3, 4, or 5. Similarly, when Z is pyridyl, it may be optionally substituted by 1, 2, or 3 R 5 In an example of such an embodiment, each R 5 independently may be halogen or C 1-6 In some embodiments, q is 1 or 2, but in other embodiments, q is 0.

[0131] In some embodiments of Formula I, IA and IC, the compounds of the present disclosure have a structure according to Formula ID

[0132] or a pharmaceutically acceptable salt thereof. One of ordinary skill in the art will understand that compounds within the scope of Formula ID also include stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs thereof, unless otherwise specified. With respect to Formula ID, Ring B is a heteroaryl group, such as a 5-membered or 6-membered heteroaryl group, wherein R 3 Together with the -NC(O) moiety to which it is bonded and the two ring atoms from ring B, it forms a 5- or 6-membered heterocyclic group fused to ring B. In forming such a ring, R 3 Can be selected from C 1-10 An aliphatic group, optionally substituted with one or more R 4 In one embodiment, wherein R 3 Together with the -NC(O) moiety to which it is bonded and the two ring atoms from ring B, it forms a 5- or 6-membered heterocyclic group, R 3 It is C 1-3 An aliphatic group, which is composed of one or more R 4 In a particular example, R 3 is -CH2- or -(CH2)2-, wherein one or more hydrogen atoms are replaced by one or more R 4 In one embodiment, such compounds may have Formula 1(b). In some embodiments, Ring B is a 5-membered or 6-membered heteroaryl group, wherein the heteroaryl group has one or two ring nitrogen atoms and the remaining ring atoms are carbon, i.e., Ring B is not a triazole, a triazine, or a heteroaryl group containing oxygen or sulfur ring atoms, such as oxazole, thiazole or isoxazole. In certain embodiments, Ring B is pyrazolyl, and in other particular embodiments, Ring B is pyridinyl.

[0133] Each R 1 independently may be halogen, -C≡CH, or -linker-R 6 group, wherein the linker is a bond or R a , the condition is R a Not H or D, and R 6 is a heterocyclic group, R b , -C(R f )3, or -C(R f )=C(R f )2.

[0134] R 2 YesR a .

[0135] If present, each R 4 Independently Re .

[0136] L is a heteroatom or R a , the condition is R a Not H or D.

[0137] Z is for C 1-10 Aliphatic or aromatic.

[0138] m is 1, 2, 3, or 4, and n is 0, 1, or 2.

[0139] For every existence, R a are independently H or D, except where L is R a In addition to the implementation plan, C 1-10 Aliphatic group, C 1-10 Halogenated aliphatic group, C 5-10 Aromatic group, C 3-6 Heterocyclic group, or C 3-10 Spiro heterocyclic group.

[0140] For every existence, R b are independently -OH, -SH, -OR c , -SR c , -NR d R d , -Si(R a )3, -C(O)OH, -C(O)OR c , -C(O)NR d R d , -OC(O)NR d R d , -OC(O)C 1-10 Alkyl, substituted with: one or two NR d R d , carboxyl, or a combination thereof, and is optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH2.

[0141] For every existence, R c Independently C 1-10 Alkyl groups, which may be 1, 2 or 3 R e Replacement, C 2-10 Alkenyl, which may be 1, 2 or 3 R e Replacement, C 2-10 Alkynyl, which may be replaced by 1, 2 or 3 R e Replacement, C 3-6 Cycloalkyl, which may be replaced by 1, 2 or 3 R e Replacement, or C 5-10 Aromatic groups, which may be 1, 2 or 3 R e replace.

[0142] For every existence, R d Independently H; C 1-6 Alkyl groups, which may be 1, 2 or 3 R e Substitution or C 3-9 Heterocyclic group; C 3-6 Cycloalkyl, which may be replaced by 1, 2 or 3 R e Replace; C 3-6 Heterocyclic ring, which may be replaced by 1, 2 or 3 R e Replace; C 5-10 Aryl, which may be replaced by 1, 2 or 3 R b Replace; C 5-10 Heteroaryl, which may be replaced by 1, 2 or 3 R e Replace; or two R d The group together with the nitrogen to which it is bonded provides C 3-9 Heterocyclic rings, which may be replaced by one or more R e Replacement, or C 5-10 Heteroaryl, which may be replaced by one or more R e replace.

[0143] For every existence, R e are independently halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a .

[0144] And for every existence, R f are independently -alkyl-phosphates, R a , R b , or R e , or two R f The group together with the carbon atom to which it is bonded provides C 2-6 Alkenyl group, C 3-6 Cycloalkyl groups, which may be replaced by one or more R e Replacement, or C 3-10 Heterocyclic rings, which may be replaced by one or more R e or acyl substitution.

[0145] In certain embodiments of Formula ID, Ring B is pyridyl or pyrazolyl; L is a heteroatom or C 1-10 Aliphatic; Z is C 1-10 aliphatic or aromatic; each R 1 is a heterocyclic group, or C 1-10 Aliphatic; R 2 Is H or C1-10 Aliphatic; R 3 The -NC(O) moiety to which it is bonded and the two ring atoms from ring B together form a 5- or 6-membered heterocyclyl fused to ring B - the heterocyclyl thus formed, in certain embodiments, is unsubstituted, and in other embodiments, is substituted with groups such as oxo, alkyl and halogen; each R 4 are independently halogen or C 1-10 aliphatic; m is 1, 2, 3, or 4; and n is 0, 1 or 2.

[0146] In some embodiments of Formula I, IA, IB, IC, ID and in each combination of Formula I, IA, IB, IC and ID with the ring systems illustrated in Formulae 1(a)-1(e), each R 1 is independently a heterocyclic group, an unsubstituted C 1-10 Aliphatic, or C 1-10 aliphatic, which is substituted by one or two radicals selected from -OH, halogen, carboxyl, carboxyl ester, heterocyclic, amino, alkoxy, phosphate, cycloalkyl, alkenyl, -OC(O)NH(C 1-4 Alkyl)-amino, -OC(O)R 8 , or -OC(O)(CHR 9 )2CO2H is substituted by a substituent. -OC(O)-R 8 Some of them are derived from amino acids, where -OC(O)-R 8 The -OC(O)- portion corresponds to the acid portion on the amino acid and R 8 Includes -N(R 10 )2 or a nitrogen-containing non-aromatic heterocyclic group, wherein R 10 is H or a carboxyl ester. And each R 9 is independently H or -O-acyl.

[0147] About -OC(O)-R 8 Part, the nitrogen-containing non-aromatic heterocyclic group can be a 5- or 6-membered unsaturated nitrogen-containing heterocyclic group, for example, pyrrolidinyl. The amino acid can be any amino acid, such as a naturally occurring amino acid, and can be an amino acid selected from glycine, valine, alanine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine, glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine, or proline. One of ordinary skill in the art will understand that in the case where an amino acid includes one or more chiral centers, all enantiomers, diastereomers and / or mixtures thereof are taken into account. For example, the amino acid can be an L-amino acid, a D-amino acid or a mixture thereof. In some embodiments, the amino acid is an L-amino acid. And in certain embodiments,

[0148] -OC(O)-R 8 Yes -OC(O)CH(NH2)R 11 , or -OC(O)-(CH2) 1-2 C(NH2)CO2H, where R 11 is an amino acid side chain, and / or may be H, -CH3, isopropyl, -CH2CH(CH3)2, -CH(CH3)Et, -CH2CH2SCH3, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2CH2NHC(O)(NH)NH2, -CH2CH2CH2CH2NH2, -CH2CO2H, or CH2CH2CO2H.

[0149] In addition, about R 1 , at least one R 1 It may be an 8- to 12-membered spiro heterocyclic group or a C 1-10 Alkyne. C 1-10 The alkyne may have one or two substituents. One substituent may be OH. In some embodiments, one substituent is oxetanyl, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or phosphate, and / or in some embodiments, one substituent is -OC(O)-R 8 .

[0150] In some embodiments, m is 1, 2, or 3, and can be 1 or 2, and in certain embodiments, m is 1.

[0151] R 2 Can be H or C 1-6 Alkyl groups, such as methyl.

[0152] R 3 Can be C 1-6 Alkyl, and R 3 , together with the -NC(O)- moiety to which it is bonded and the two ring atoms from ring B, form a 5- or 6-membered heterocyclic group fused to ring B.

[0153] Each R 4 independently may be a halogen, such as F, Br, Cl or I, or C 1-10 Aliphatic, such as C 1-6 In some embodiments, each R 4 is independently chloro, fluoro or methyl.

[0154] In certain embodiments n is 0, and in other particular embodiments n is 1.

[0155] In addition, with respect to Formula I, L is a heteroatom or R a , the condition is R a Not H or D. L can be oxygen or C 1-10 Alkyl, such as C 1-6 alkyl, more particularly methylene (-CH2-). Z is C 1-10 aliphatic or aromatic, such as aryl or heteroaryl. In some embodiments, Z is C 3-6 Cycloalkyl, such as cyclobutyl or cyclopentyl, or C 1-6 In other embodiments, Z is heteroaryl, such as pyridinyl, or Z is Each R 5 Independently R e , and q is 0, 1, 2, 3, 4, or 5. In such embodiments, each R 5 independently may be halogen or C 1-6 Alkyl, such as methyl or fluoro. In some embodiments, q is 1 or 2, but in other embodiments, q is 0. And in certain embodiments, such as in Formulas I, IA, IB, IC and ID, the -LZ moiety is phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 2-fluorophenoxy, 2,4-difluorophenoxy, 2,6-difluorophenoxy, 4-fluorobenzyl, 2,6-dimethylphenoxy, cyclobutyloxy, cyclopentyloxy, methoxy, 4-methylphenoxy, benzyl, (6-methylpyridin-2-yl)methyl or (6-fluoropyridin-2-yl)methyl.

[0156] In some embodiments of Formula I, IA, IB, IC and ID, the compound may have a structure according to Formula I-1 or I-2:

[0157]

[0158] In some embodiments, the compound may have a structure according to one or more of the following formulas:

[0159]

[0160]

[0161]

[0162] Regarding Formulas I-1 to I-20, Ring B, L, Z, R 1 , R 2 , R 3 , R 4, m and n, if present, are as defined herein for Formula I. 3 The ring formed together with the NC(O) moiety and the two ring atoms from ring B forms a heterocyclic ring fused to ring B. Examples of compounds according to formulae I-1 to I-20 have a structure according to one of the following formulae:

[0163]

[0164]

[0165] And with respect to Formulas I-21 to I-32, L, Z, R 1 , R 2 , R 4 , and n, are as defined herein for Formula I.

[0166] In any of the above embodiments involving Formula I, IA, IB, IC and ID and / or Formulas I-1 to I-32, R 1 Can be selected from any of the following:

[0167]

[0168]

[0169]

[0170] And in certain embodiments, in Formula I and / or Formulas I-1 to I-32, R 1 Can be selected from any of the following:

[0171]

[0172]

[0173] In other embodiments of Formula I, the disclosed compounds have Formula ID

[0174]

[0175] Ring B is a 5-membered or 6-membered heteroaryl group, wherein R 3 The -NC(O) moiety to which it is bonded and the two ring atoms from ring B together form a 5- or 6-membered heterocyclic group fused to ring B;

[0176] L is a heteroatom or R a , the condition is R a Not H or D;

[0177] Z is for C 1-10 Aliphatic (such as C 1-10 Alkyl, C 2-10Alkenyl, C 2-10 Alkynyl, or C 3-6 cycloalkyl); or R 1 is a halogen, -C≡CH, or a linker-R 6 group, wherein the linker is R a , the condition is R a Not H or D, and R 6 YesR b , -C(R f )3, or -C(R f )=C(R f )2;

[0178] R 2 and R 3 Independently R a ;

[0179] R 4 and R 5 Independently R e ;

[0180] For every existence, R a are independently H or D (except where L is R a Implementation plan), C 1-10 Aliphatic (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 Cycloalkyl), C 1-10 Halogenated aliphatic, C 5-10 Aromatic, or C 3-6 heterocyclic;

[0181] For every existence, R b are independently -OH, -SH, -OR c , -SR c , -NR d R d , -Si(R a )3, -C(O)OH, -C(O)OR c , or -C(O)NR d R d ;

[0182] For every existence, R c Independently C 1-10 Alkyl (which may be 1, 2 or 3 R e Replace), C 2-10 Alkenyl (which may be replaced by 1, 2 or 3 R e Replace), C 2-10 Alkynyl (which may be replaced by 1, 2 or 3 Re Replace), C 3-6 Cycloalkyl (which may be 1, 2 or 3 R e Replace), or C 5-10 Aromatic (which may be 1, 2 or 3 R e replace);

[0183] For every existence, R d Independently H; C 1-6 Alkyl (which may be 1, 2 or 3 R e Replacement); C 3-6 Cycloalkyl (which may be 1, 2 or 3 R e Replacement); C 3-6 Heterocyclic (which may be 1, 2 or 3 R e Replacement); C 5-10 Aryl (which may be replaced by 1, 2 or 3 R b Replacement); C 5-10 Heteroaryl (which may be replaced by 1, 2 or 3 R e Replaced); or two R d The group together with the nitrogen to which it is bonded provides C 3-9 Heterocyclic ring (which may be replaced by one or more R e Replace), or C 5-10 Heteroaryl (which may be replaced by one or more R e replace);

[0184] For every existence, R e are independently halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a ;and

[0185] For every existence, R f Independently R a , R b , or R e , or two R f The group together with the carbon atom to which it is bonded provides C 3-6 Cycloalkyl groups (which may be replaced by one or more R e Replace), or C 3-10 Heterocyclic ring (which may be replaced by one or more R e substituted); m is 1 to 4, such as 1, 2, 3, or 4, and for particular embodiments, is 1 or 2;

[0186] n is 0, 1 or 2; and

[0187] q is 0, 1, 2, 3, 4, or 5.

[0188] In some embodiments, the compounds of the present disclosure may have a structure satisfying Formula IA

[0189] Or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will understand that the disclosed formulae include, within their scope, all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs of compounds that otherwise have the structural features required by such formulae.

[0190] About Formula IA:

[0191] Ring B is a 5-membered or 6-membered heteroaryl group, wherein R 3 The -NC(O) moiety to which it is bonded and the two ring atoms from ring B together form a 5- or 6-membered heterocyclic group fused to ring B;

[0192] L is a heteroatom or R a , the condition is R a Not H or D;

[0193] R 1 is a halogen, -C≡CH, or a linker-R 6 group, wherein the linker is R a , the condition is R a Not H or D, and R 6 YesR b , -C(R f )3, or -C(R f )=C(R f )2;

[0194] R 2 and R 3 Independently R a ;

[0195] R 4 and R 5 Independently R e ;

[0196] For every existence, R a are independently H or D (except where L is R a Implementation plan), C 1-10 Aliphatic (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 Cycloalkyl), C 1-10 Halogenated aliphatic, C 5-10 Aromatic, or C 3-6heterocyclic;

[0197] For every existence, R b are independently -OH, -SH, -OR c , -SR c , -NR d R d , -Si(R a )3, -C(O)OH, -C(O)OR c , or -C(O)NR d R d ;

[0198] For every existence, R c Independently C 1-10 Alkyl (which may be 1, 2 or 3 R e Replace), C 2-10 Alkenyl (which may be replaced by 1, 2 or 3 R e Replace), C 2-10 Alkynyl (which may be replaced by 1, 2 or 3 R e Replace), C 3-6 Cycloalkyl (which may be 1, 2 or 3 R e Replace), or C 5-10 Aromatic (which may be 1, 2 or 3 R e replace);

[0199] For every existence, R d Independently H; C 1-6 Alkyl (which may be 1, 2 or 3 R e Replacement); C 3-6 Cycloalkyl (which may be 1, 2 or 3 R e Replacement); C 3-6 Heterocyclic (which may be 1, 2 or 3 R e Replacement); C 5-10 Aryl (which may be replaced by 1, 2 or 3 R b Replacement); C 5-10 Heteroaryl (which may be replaced by 1, 2 or 3 R e Replaced); or two R d The group together with the nitrogen to which it is bonded provides C 3-9 Heterocyclic ring (which may be replaced by one or more R e Replace), or C 5-10 Heteroaryl (which may be replaced by one or more R e replace);

[0200] For every existence, R e are independently halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a ;and

[0201] For every existence, R f Independently R a , R b , or R e or two R f The group together with the carbon atom to which it is bonded provides C 3-6 Cycloalkyl groups (and in some embodiments, C 3-6 A cycloalkyl group is a e substituted), or C 3-10 Heterocyclic (and in some embodiments, C 3-10 A heterocyclic group is a e replaced);

[0202] m is 1 to 4, such as 1, 2, 3, or 4, and for particular embodiments, 1 or 2;

[0203] n is 0, 1 or 2; and

[0204] q is 0, 1, 2, 3, 4, or 5.

[0205] In particular embodiments of Formula I or IA, the 5-membered heteroaryl group of Ring B may have a structure satisfying the following formula Wherein at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In some embodiments, the 5-membered heteroaryl group is diazole, triazole, oxadiazole, or oxazole. Exemplary triazoles include any of the following:

[0206]

[0207] Exemplary oxadiazoles are selected from any of the following:

[0208]

[0209] Exemplary oxazoles are selected from any one of the following:

[0210]

[0211] Exemplary oxadiazoles are selected from any one of the following:

[0212]

[0213] In particular embodiments of Formula I, IA, IB, IC, ID or IE, L is oxygen or R a , where Ra is C1-C4 alkyl, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, L is -CH2- or oxygen.

[0214] R 1 A linker group, wherein R 1 is the linker-R 6 , is a C1, C2, C3, or C4 aliphatic group, such as a C2 alkyl, alkenyl group, or alkynyl group, or a C1, C2, C3, or C4 halogenated aliphatic group, such as a C2 halogenated alkyl group, or a halogenated alkenyl group. In some embodiments, R 1 The linker group is R a , where R a is a C1-C4 alkyl group, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-; or the linking group is C 2- C4 alkenyl, such as -CH=CH-, -CH=CHCH2-, -CH2CH=CH-, or -CH2CH=CHCH2-; or the linker group is C 2- C4 alkynyl, such as -C≡C-, -C≡CCH2-, -CH2C≡C-, or -CHC≡C-CH2-. In some embodiments, the linker group is C 2- C4 haloalkenyl, such as -CF=CH-, -CCl=CH-, -CH=CCl-, -CH=CF-, -CCl=CCl-, -CF=CF-, or -CCl=CF-, -CF=CCl-. In some embodiments, the linker group is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, -CCl=CH-, -CH=CCl-, or -C≡C-.

[0215] R 1 R 6 The group is C(R f )3, in some embodiments, one of the R f YesR e , where R e Yes-OR a (e.g., hydroxyl or OMe) and each other R f Independently R a , where R a It is C 1-4 aliphatic and preferably each other R f YesR a , where for every existence, R a Independently C1-4 In a particular embodiment, each of the other R f YesR a , where R a is methyl or CD3. In yet other embodiments, R 6 Yes-C(R f )3, where each R f YesR a , where R a is methyl or H or each of R f YesR a , where R a is methyl or R b , where R b Yes - C(O)OR c In some other embodiments, an R f YesR e Yes-OR a (e.g., hydroxyl or OMe) and the other two R f The groups, together with the carbon atoms to which they are bonded, are linked together to provide a cycloaliphatic (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane) or heterocyclic groups (e.g., epoxide, oxetane, tetrahydrofuran, tetrahydropyran, or hexahydrofuro[3,2-b]furan). In some such embodiments, the cycloaliphatic and / or heterocyclic groups may be substituted, for some particular embodiments, with one or more hydroxyl groups or benzyl-carbonyl groups.

[0216] Some compound embodiments have C 2-4 In a particular embodiment, R 1 Yes-Linker-R 6 group and the linker is R a , where R a is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, or -C≡C-, or -CH2C≡C-, and R 6 YesR b , where R b Is -C(O)OEt or -C(O)NR d R d or -NR d R d , where for each existence, each R d are independently hydrogen, C 5-10 Heteroaryl, C 3-6 Cycloalkyl, or both R dThe groups are linked together with the nitrogen atom to which they are bonded to provide a heterocyclic group which may further include one or more additional groups in addition to R d In some embodiments, one R d is hydrogen and the other R d It is C 5-10 Heteroaryl, which may be replaced by one or more R e Replace with one of the following:

[0217]

[0218] R 6 It can also be R b , where R b is a heterocyclic group, such as pyridyl, which may be substituted or unsubstituted. In yet another embodiment, R 6 It can be R b , where R b Is -OH or -OR c (where R c It is C 1-6 Alkyl and in some embodiments C 1-6 Alkyl is C 5-10 Heteroaryl, such as pyridyl substituted; or wherein R c It is C 5-10 heteroaryl, such as quinolyl), or R b Can be -NR d R d , where for every existence, R d Independently H, C 5-10 Heteroaryl (and in some embodiments, C 5-10 A heteroaryl group is a e or two R d The group together with the nitrogen to which it is bonded provides C 3-9 Heterocyclic (and in some embodiments, C 3-9 A heterocyclic ring is a ring consisting of one or more R e group substituted) or C 5-10 Heteroaryl (and in some embodiments, C 5-10 Heteroaryl is a e In the case of R e In the substitution embodiment, for each occurrence of R e Independently C 5-10 Heteroaryl, or -OR a , where R a It is C 1-10 alkyl.

[0219] Some compounds include a linker (which is a C1 group) and R 6 Group (which is R b ), where R b Yes - NR d R d One of the R d is H and the other R d is pyridyl, or two R d The group together with the nitrogen to which it is bonded provides C 5-10 heteroaryl; or R b Yes OR c , where R c is a C substituted with a pyridyl group 1-4 In some embodiments, R b yes

[0220]

[0221] In some embodiments, R 1 Can be selected from any of the following:

[0222]

[0223] In some embodiments, R 2 and R 3 Each of which is independently R a , where in each existence, R a are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In a particular embodiment, R 2 and R 3 Each of which is independently R a For each occurrence, it is independently hydrogen, methyl, or ethyl. In an exemplary embodiment, R 2 It's methyl.

[0224] In some embodiments, or, each R 4 Independently and / or each R 5 Independently R e , where R e is alkyl, alkenyl, alkynyl, chlorine, bromine, iodine, or fluorine. In a particular embodiment, each R 4 and / or each R 5 Independently R e , where R e is lower aliphatic (eg, methyl), fluorine, or chlorine.

[0225] In some embodiments of Formulas I, IA, IB, IC, ID, and IE, m is 1; n is 0 or 1; p is 0 or 1; and q is 0, 1, or 2. In particular embodiments, m is 1, n is 0, p is 0 or 1, and q is 0, 1, or 2.

[0226] The compound of Formula I or IA may also have a structure satisfying any one or more of Formulae II and IIA-IIF.

[0227]

[0228] With respect to Formula II and IIA-IIE, R 1 and R 5 Each of R is as described above for Formula I and / or IA. In particular embodiments, 0, 1, or 2 R 5 The group exists. 5 It can be R e , where R e is fluorine or chlorine. In other particular embodiments, R 5 With respect to Formulae IIA-IIE, each W is independently nitrogen or oxygen, and particularly nitrogen.

[0229] Certain disclosed embodiments have the formula IIF.

[0230]

[0231] About Formula IIF, R 1 , R 2 and R 3 As mentioned above. 10 is an alkyl group, a cyclic alkyl group or an aryl group. More particularly, R 10 is a lower alkyl group, such as C 1-10 Alkyl, more particularly C 1-5 Alkyl, including methyl, ethyl, propyl, butyl and pentyl. Cyclic alkyl is typically selected from cyclobutyl, cyclopentyl, or cyclohexyl, in particular cyclobutyl or cyclopentyl. In some embodiments, the compounds according to the present disclosure have formula IIG.

[0232]

[0233] For many of the disclosed embodiments, R 10 is phenyl. Accordingly, certain disclosed embodiments of the present disclosure have the formula IIH.

[0234]

[0235] Regarding formula IIG and IIH, R 1 and R 5Each of R is as described above for Formula I and / or IA. 5 YesR e In particular embodiments, 0, 1, or 2 R 5 In certain embodiments, R 5 is absent or is a halogen, such as fluorine or chlorine, especially fluorine, or C 1-6 Alkyl groups, such as methyl.

[0236] In some embodiments, the compounds of Formula I, IA, IC, ID and IE may also have a structure satisfying any one or more of Formulas III-VI:

[0237]

[0238] With respect to Formulae III-VI, each R 5 independently may be as described above and in some particular embodiments be lower aliphatic (e.g., methyl) or halogen, such as chloro or fluoro. In addition, Ring B is as described above and in some embodiments is selected from

[0239] As exemplified in Formula III-VI, R 6 is as described above, and in some embodiments of Formulas I, IA, IB, IC, ID and IE is selected from one of the following:

[0240]

[0241]

[0242]

[0243] Certain disclosed exemplary compounds within one or more of Formulas I, I-1 to I-35, IA, II, IIA-IIJ, and III-VI include:

[0244]

[0245]

[0246]

[0247] Exemplary compounds within the scope of one or more of Formulas I, IA, IB, IC, ID, IE, I-1 to I-32, IA, II, IIA-IIH, and III-VI include:

[0248] I-1: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0249] I-2: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0250] I-3: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((1-hydroxycyclopentyl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0251] I-4: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-4-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0252] I-5: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-3-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0253] I-6: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0254] I-7: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-(tert-butoxy)prop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0255] I-8: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0256] I-9: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0257] I-10: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0258] I-11: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0259] I-12: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0260] I-13: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0261] I-14: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0262] I-15: (S)-6-((3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-8-yl)ethynyl)-2-cyanopyridine;

[0263] I-16: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazacycloheptatrien-4(5H)-one;

[0264] I-17: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazacycloheptan-4(5H)-one;

[0265] I-18: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0266] I-19: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0267] I-20: (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyrrolidin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0268] I-21: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0269] I-22: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; or

[0270] I-23: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one.

[0271]

[0272]

[0273]

[0274]

[0275] In some embodiments, one or more of the compounds may be included in a pharmaceutical composition or medicine, and in some embodiments, the one or more compounds may be in the form of a parent compound or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof. The pharmaceutical composition typically includes at least one additional component in addition to the disclosed one or more compounds, such as a pharmaceutically acceptable excipient, adjuvant, additional therapeutic agent (described in the following section) or any combination thereof.

[0276] Pharmaceutically acceptable excipients may be included in pharmaceutical compositions for a variety of purposes, such as to dilute the pharmaceutical composition for delivery to a subject, to facilitate processing of the formulation, to provide favorable material properties to the formulation, to facilitate dispersion from a delivery device, to stabilize the formulation (e.g., antioxidants or buffers), to provide a pleasant or palatable taste or consistency to the formulation, etc. The pharmaceutically acceptable excipient(s) may include a pharmaceutically acceptable carrier(s). Exemplary excipients include, but are not limited to: monosaccharides, disaccharides and polysaccharides, sugar alcohols and other polyols, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch or combinations thereof; surfactants, such as sorbitol, diphosphatidyl choline and lecithin; fillers; buffers, such as phosphate and citrate buffers; anti-adhesive 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 polyvinyl pyrrolidone, polyalkylene glycols); coating agents (such as cellulose ethers, including hydroxypropyl methylcellulose, shellac, corn protein zein) and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, cross-linked carboxymethylcellulose sodium and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable oils and fats, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate and magnesium stearate); flavoring and sweetening agents (such as mint, cherry, star anise, peach, apricot or licorice, raspberry and vanilla); lubricants (such as minerals, such as talc or silicon dioxide, 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); coloring agents; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0277] B. Combinations of Therapeutic Agents

[0278] The compounds described herein can be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to or in combination with other established therapies. The one or more compounds or compositions comprising the compound(s) can be administered once or in multiple administrations. In certain embodiments, the compounds of the present disclosure 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, by the same administration route as the compounds disclosed herein or by a different route. For sequential administration, the compound(s) and the therapeutic agent(s) can be administered so 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 first component administered can overlap with the effective time period of the second, third, and fourth components, but the effective time periods of the second, third, and fourth components independently may or may not overlap with each other. In another exemplary embodiment of a combination comprising four components, the effective time period of the administered 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 period 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.

[0279] In some embodiments, the compound is administered with another therapeutic agent (such as an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof). The anti-inflammatory agent can be a steroid or a non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylate, a cyclooxygenase inhibitor, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is a mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an antilymphocyte globulin, an antithymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0280] In some embodiments, the compounds of the invention can be used together with anticancer or cytotoxic agents. Various types of 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, without limitation, mechlorothamine, cyclophosphamide, ifosfamide, phenylalanine mustard, chlorambucil, ethyleneimine, methylmelamine, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, for example and without limitation, the folic acid analog methotrexate; the pyrimidine analogs fluorouracil, cytosine arabinoside; the purine analogs mercaptopurine, thioguanine and thioazapurine. Exemplary vinca alkaloids include, for example and without limitation, vinblastine, vincristine, paclitaxel and colchicine. Exemplary antibiotics include, for example and without limitation, actinomycin D, daunorubicin and bleomycin. Exemplary enzymes effective as antitumor agents include L-asparaginase. Exemplary coordination compounds include, for example and without limitation, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, by way of example and without limitation, the adrenocortical steroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

[0281] These and other useful anticancer compounds are described in the Merck Index, 13th Edition (O'Neil M.J. et al.) Merck Publishing Group (2001) and Goodman and Gilman, The Pharmacological Basis of Therapeutics, 12th Edition, Brunton LL, Chapters 60-63, McG Raw Hill, (2011), both of which are incorporated herein by reference.

[0282] Among the CTLA4 antibodies that can be used in combination with the inhibitors disclosed herein is ipilimumab, which is marketed by Bristol-Myers Squibb as Sale.

[0283] Other chemotherapeutic agents for combination include immunooncology agents, such as checkpoint pathway inhibitors, for example, PD-1 inhibitors, such as nivolumab and lambrolizumab, and PD-L1 inhibitors, such as pembrolizumab, MEDI-4736 and MPDL3280A / RG7446. Additional checkpoint inhibitors for combination with the compounds disclosed herein include anti-LAG-3 agents, such as BMS-986016 (MDX-1408).

[0284] Other chemotherapeutic agents for use in combination with the inhibitors disclosed herein include anti-SLAMF7 agents, such as the humanized monoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such as the anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137 agents, such as the fully human monoclonal antibody urelumab (BMS-663513), anti-CD123 agents, such as tagraxofusp-erzs sold under the trade name Elzonris.

[0285] The compounds disclosed herein may also be advantageously used with CAR-T therapies. Examples of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

[0286] The combination of the compounds of the present invention with other therapies is particularly useful in treating hyperproliferative disorders. The compounds of the present invention can be used to treat disorders such as cancer, leukemia and lymphoma in combination with the standard of care. As an example, myelodysplastic syndrome (MDS) can be treated with the compounds disclosed herein together with the standard of care. Therapeutic agents used in combination with the compounds of the present invention include hypomethylating agents such as azacitidine and decitabine, and other chemotherapeutic agents such as cytarabine, daunorubicin and idarubicin. Immunomodulatory therapies, such as lenalidomide and CAR-T therapy, can also be used in combination with the compounds of the present invention for the treatment of MDS.

[0287] Additional anti-proliferative compounds that can be used in combination with the compounds of the present disclosure include, for example and without limitation, antibodies directed against growth factor receptors (eg, anti-Her2); and cytokines such as interferon-α and -γ, interleukin-2, and GM-CSF.

[0288] Additional chemotherapeutic agents that may be used in combination with the compounds of the invention include proteasome inhibitors such as bortezomib, carfilzomib, marizomib, and the like.

[0289] 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 vandetinib; Mek inhibitors such as trametinib; Raf inhibitors such as dabrafenib, sorafenib and vemurafenib; VEGFR inhibitors such as axitinib, tadalafil ... axitinib, lenvatinib, nintedanib, pazopanib; BCR-Abl inhibitors such as bosutinib, dasatinib, imatinib, and nilotinib; FLT-3 inhibitors such as gilteritinib and quizartinib, PI3-kinase inhibitors such as idelalisib, Syk inhibitors such as fostamatinib; and JAK inhibitors such as ruxolitinib and fedratinib.

[0290] In other embodiments, the second therapeutic agent may be selected from any of the following:

[0291] pain medication--morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromorphamide, dipipanone;

[0292] Antibiotics - aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cefalotin, cephalexin, cefaclor, cefmandole, cefoxitin, cefprozil, cephalosporins) cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, ncomycin, and telavancin), lincosamides (e.g., clindamycin and incomysin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin), ), and spectinomycin), monobactams (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, temocillin, 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), acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine), sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole), tetracyclines (e.g., demeclocycline, doxetine, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid,pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin), and others, such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinuprisin / dalfopristin, rifaximin, thiamphenicol, tigecycline, and timidazole;

[0293] Antibodies - anti-TNF-α antibodies, e.g., infliximab (ramicadeTM), adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g., rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1 antibodies, e.g., anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, e.g., nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AM P-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toraizumab, zanolimumab;

[0294] Anticoagulants - warfarin TM), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin;

[0295] Anti-inflammatory agents - steroids, e.g., budesonide, nonsteroidal anti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin; immunosuppressants - mercaptopurine, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone and prednisolone, alkylating agents such as cyclophosphamide In some embodiments, the present invention relates to cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus and tacrolimus, inosine monophosphate dehydrogenase inhibitors (IMPDH) such as mycophenolate, mycophenolate mofetil and azathioprine, and agents designed to suppress cellular immunity while preserving the integrity of the recipient's humoral immunological response, including various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibody (OKT3)) and irradiation.Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trade name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name Purinethol; prednisone and prednisolone are currently available from Roxane Pharmaceuticals, Inc. Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (Rapamycin) is currently available from Wyeth-Ayerst under the brand name rapamune; tacrolimus is currently available from Fujisawa under the brand name Prograf; cyclosporine is currently available from Novartis under the brand name Sandimmune and from Abbott under the brand name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the brand name Cellcept and from Novartis under the brand name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the brand name Imuran; and antibodies are currently available from Ortho Biotech under the trade name Orthoclone, available from Novartis under the trade name Simulect (basiliximab) and from Roche under the trade name Zenapax (daclizumab); and.

[0296] Guanylate cyclase-C receptor agonists or intestinal secretagogues, such as linaclotide, which is sold under the name Linzess.

[0297] These various agents can be used according to their standard or conventional dosages as indicated in the prescribing information accompanying commercially available forms of the drugs (see also, prescribing information in the 2006 edition of The Physician's Desk Reference), the disclosure of which is incorporated herein by reference.

[0298] III. Methods of preparing compounds

[0299] The disclosed embodiments of the compounds of the present invention may be prepared by any suitable method as would be appreciated by one of ordinary skill in the art. An exemplary suitable method is provided below with reference to specific compounds in the Examples, and may include the following first reaction step according to Scheme 1.

[0300]

[0301] Solution 1

[0302] Referring to Scheme 1, a metal-mediated cross-coupling reaction can be used to couple the protected amine precursor 100 with R 1 The group 102 is coupled, the latter comprising "R 6 -linker" group to provide a cross-coupled product 104. In some embodiments, a metal-mediated cross-coupling reaction can be performed using a transition metal catalyst, such as a palladium catalyst. Exemplary palladium catalysts include, but are not limited to, Pd(0) catalysts (e.g., Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, etc.) or Pd(II) catalysts (e.g., XPhosPd 2nd or 3rd generation, PdCl2, Pd(OAc)2, etc.). In some embodiments, the palladium catalyst can be used in combination with another co-catalyst (such as CuI) to promote the cross-coupling reaction, such as in Sonogoshira reaction. The metal-mediated cross-coupling may also include the use of a base, such as an amine base (e.g., Et3N) or an inorganic base (e.g., Cs2CO3, Na2CO3, K2CO3, etc.) and a solvent (e.g., dimethylformamide). Referring to Scheme 1, X is a suitable group for metal-mediated cross-coupling, such as a halogen or triflate group, and PG is an amine protecting group, which may be selected from, but is not limited to, a 9-fluorenylmethoxycarbonyl ("Fmoc") group, a tert-butyloxycarbonyl ("Boc") group, a trityl ("Tr") group, an allyloxycarbonyl ("Alloc") group, a benzyloxycarbonyl ("Cbz") group, and the like.

[0303] Representative examples of the process steps shown in Scheme 1 are provided below in Schemes 2A-2F. Methods analogous to those illustrated in Scheme 2A can be used to prepare compounds I-14 to I-17 and I-35 by replacing the propargylic alcohol in Scheme 2A with the corresponding alkynyl group to produce each of compounds I-14 to I-17 and I-35; further modifications that can be used to arrive at the final structures of compounds I-14 to I-17 are discussed below.

[0304]

[0305] Once the cross-coupled product 104 is produced, it can be subjected to an optional linker group reduction step, wherein a linker group containing one or more unsaturated sites can be reduced to a saturated linker group and / or a linker group having less unsaturation. If a linker reducing group is used, it can be followed by a deprotection step and then an amide formation step, as shown in Scheme 3. Alternatively, if a linker group reduction step is not used, the cross-coupled product 104 can be deprotected and converted to an amide compound 302.

[0306]

[0307] Solution 3

[0308] Referring to Scheme 3, an optional linker reduction step may be performed. For example, if the linker contains an unsaturated site (e.g., a double bond or a triple bond), the unsaturated site may be reduced so that it becomes fully saturated (e.g., such as reducing a double bond and / or a triple bond to a single bond), or it has less unsaturation (e.g., such as reducing a triple bond to a double bond). One of ordinary skill in the art, with the benefit of this disclosure, will recognize suitable reagents for performing such an optional linker reduction step; however, an exemplary set of conditions includes exposing the cross-coupled product 104 to H2 in the presence of Pd / C. Since these steps are optional, they need not be performed in all embodiments. Instead, in some embodiments, the cross-coupled product 104 may be deprotected to provide an amine, which is then converted to an amide compound 302 by reacting the amine with a suitable acid coupling partner 300, as shown in Scheme 3. In some embodiments, the method may further include performing one or more additional modifications to the amide compound 302 to provide an amide compound 500, such as modifying R 6 Groups to form different R 6 Group, as shown in Scheme 4.

[0309]

[0310] Solution 4

[0311] Refer to Scheme 5, you can perform R 6 For example, if R 6 If it is an ester group, it can be converted to a carboxylic acid or a primary alcohol. One of ordinary skill in the art, with the benefit of this disclosure, will recognize suitable reagents for carrying out such an optional modification step; however, an exemplary set of conditions includes converting R 6 Exposure of the ester group to LiOH provides the corresponding acid.

[0312] Many exemplary disclosed compounds are alkynyl substituted analogs. These compounds can be prepared using metal-mediated coupling strategies as discussed above with reference to Scheme 1. Scheme 5 illustrates a more detailed general method for preparing alkynyl substituted analogs according to the present disclosure.

[0313]

[0314] Solution 5

[0315] With reference to Scheme 5, nitrogen is bubbled through a stirred solution of aryl / heteroaryl halide (1 equivalent), compound 700 or 706, CuI (0.1-0.2 equivalent) and Pd(PPh3)4 (0.05-0.1 equivalent) / dry DMF (3-4 mL / mmol) in a vial for 3 minutes. Subsequently, NEt3 (10 equivalents) is added to the dark reaction solution, followed by the corresponding alkyne (1.5-3 equivalents), compound 702 or 708. Nitrogen is bubbled through the reaction mixture for 2 minutes, and the vial is capped. The reaction mixture is stirred at an effective reaction temperature (such as 70-90° C.) for an effective reaction period, such as 3-6 hours. Alternatively, the reaction mixture can be heated in a microwave reactor (30-45 minutes) until aryl / heteroaryl halide 700 or 706 is consumed. The dark reaction solution was worked up by one of the following methods: a) work-up with dilution with ice water / organic solvent; b) concentration to dryness followed by work-up after dilution with ice water / organic solvent; or c) dilution of the crude residue with ice water, sonication, and warming the slurry to room temperature. The resulting grey / dark solid was collected by filtration, suction dried, dissolved in THF (20 mL), and purified by / silica gel pad, and the pad was washed with THF. The crude material was then purified by reverse phase column chromatography or by normal phase silica gel flash column chromatography to provide the corresponding alkynyl substituted analogs (yield: 25-69%), compound 704 or 710.

[0316] IV. Methods of Using the Compounds

[0317] A. Disease / Disorder

[0318] The disclosed compounds, and combinations and / or pharmaceutical compositions thereof, can be used to inhibit RIP1 kinase by contacting the kinase with one or more compounds of the disclosure, or compositions comprising one or more compounds of the disclosure, in vivo or in vitro. One or more 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 particular embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be used to treat conditions where inhibition of RIP1 or a channel involving RIP1 is therapeutically useful. In some embodiments, the compound directly inhibits RIP1 kinase activity. Examples of diseases that can be treated according to this method embodiment include diseases or disorders associated with inflammation, necroptosis, or both. In certain embodiments, the disease to be treated with the compounds of the present invention is an inflammatory or immunoregulatory disorder, including autoimmune and proliferative disorders.

[0319] In one embodiment, the disease to be treated with one or more compounds according to the invention, or a composition containing one or more compounds according to the invention, is selected from the group consisting of amyotrophic lateral sclerosis (ALS), rheumatoid arthritis, type I diabetes, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, bullous pemphigoid, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, asthma, spondyloarthritis, SoJIA, or Still's disease, autoimmune hepatitis, autoimmune hepatobiliary disease, autoimmune ITP, cerebrovascular accident, myocardial infarction, allergic diseases, chronic obstructive pulmonary disease, myocardial infarction, HIV-related dementia, glaucoma, Friedreich's 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 hyperproliferative skin diseases and hematological disorders such as lymphomas, for example, Hodgkin lymphoma and non-Hodgkin lymphoma, ABC diffuse large B-cell lymphoma (DLBCL), Macroglobulinemia, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia, smoldering or indolent multiple myeloma, or hematologic malignancies, leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, drug-resistant malignancies such as JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies such as ibrutinib-resistant hematologic malignancies, ibrutinib-resistant CLL, and ibrutinib-resistant macroglobulinemia, acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovascularization, hemangiomas such as infantile hemangiomas; infectious diseases such as sepsis, septic shock, and shigellosis; neurodegenerative diseases such as metastatic melanoma, neurodegeneration associated with HIV infection and CMV retinitis, such as associated neurocognitive disorders or dementia, fibrotic conditions such as nonalcoholic steatohepatitis and cardiac conditions such as ischemia reperfusion. reperfusion); allergic, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, systemic lupus erythematosis, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, rubella arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis, psoriatic arthritis, and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, allograft rejection , fever and myalgia due to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, chronic myeloid leukemia; angiogenic disorders including solid tumors; viral diseases including acute hepatitis infection (including hepatitis A, B and C), AIDS, ARC or malignancy, herpes; stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, angiogenesis, cardiac and renal reperfusion injury, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions related to prostaglandin endoperoxidase synthase (syndase)-2, pemphigus vulgaris, ischemia reperfusion (ischemia reperfusion) reperfusion injury, including cerebral ischemia reperfusion injury caused by stroke, cardiac ischemia reperfusion injury caused by myocardial infarction, multiple system atrophy, Parkinson-Chiari syndrome, frontotemporal dementia, intracranial hemorrhage, cerebral hemorrhage, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, demyelinating disease, spondylarthritis, systemic onset juvenile idiopathic arthritis (SoJIA), systemic lupus erythematosus (SLE),Sjogren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), renal transplantation, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), ARDS caused by COVID-19, cerebrovascular accident (CVA), pulmonary sarcoidosis, interleukin-1 converting enzyme (ICE, also known as caspase-1)-associated febrile syndrome, chronic obstructive pulmonary disease (COPD), periodontitis , NEMO-deficient syndrome (F-κ-B essential regulator (also known as IKKγ or IKKG) deficiency syndrome), hematologic and solid organ malignancies, lysosomal storage diseases, glaucoma, spondyloarthritis, retinal degenerative diseases, retinal ischemia / reperfusion injury, renal ischemia / reperfusion injury, anthrax lethal toxin-induced septic shock, LPS-induced cell death, infectious encephalopathy, encephalitis, autoimmune uveoretinitis (autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic lupus erythematosus, yellow spots, diabetic retinopathy, central halo choroidal dystrophy, BEST disease, yolk disease in adults, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt's disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity, yellow spots, diabetic retinopathy, central halo choroidal dystrophy, BEST disease, yolk disease in adults, pattern dystrophy dystrophy), optic nerve injury, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, ischemic optic neuropathy (e.g., arteritic or nonarteritic anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber's optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, significant optic atrophy, Behr's syndrome, Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paresis, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, hypoxic-ischemic brain injury, focal cerebral ischemia, global cerebral ischemia, and anoxic hypoxia, peritoneal injury caused by peritoneal dialysis fluid (PDF) and PD-related side effects, glomerular disease, tubulointerstitial disease, obstruction, polycystic kidney disease),Focal glomerulosclerosis, immune complex nephropathy, hepatocellular carcinoma, pancreatic cancer, urinary tract cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, glioblastoma multiforme in adults, and anaplastic astrocytoma in adults), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wi LMS tumors, trophoblastic tumors, hemangiopericytoma, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, vulvar cancer, adrenocortical carcinoma, ACTH-producing tumors, lymphoma, and leukemia, respiratory infectious viruses, such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS virus, adenovirus, reovirus, etc.), herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infectious diseases, such as Bacillus cereus, Vibrio parahaemolyticus, enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRS A, Salmonella, Clostridium botulinum, Candida species, Paget's disease, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, congenital hypophosphatasia, fibromatosis, fibrous dysplasia, bone turnover, osteolytic bone disease, periodontal disease, post-traumatic bone surgery, post-prosthetic joint surgery, post-orthopedic bone surgery, post-dental surgery, chemotherapy or radiotherapy of bone, bone cancer, fragile plaque ( fragileplaque), disorders, occlusive disorders, stenosis, coronary artery disorders, peripheral arterial disorders, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, post-surgical graft occlusion, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, cold and warm agglutinin diseases, Evan's syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), and pemphigus vulgaris.

[0320] In another embodiment, the disease to be treated with one or more compounds according to the invention, or a composition containing one or more compounds according to the invention, is selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, Crohn's disease, ulcerative colitis, biliary cirrhosis, uveitis, multiple sclerosis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmomyopathy (Graves' ophthalmomyopathy), myasthenia gravis, ... ophthalmyopathy, asthma, bone marrow rejection, organ transplant rejection, graft-versus-host disease, inflammatory and immunoregulatory disorders, organ or tissue transplantation, graft-versus-host disease due to transplantation, autoimmune syndrome, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes mellitus, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, postinfectious autoimmune disease, rheumatic fever, postinfectious glomerulonephritis, inflammation Sexual and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, localized alopecia, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoma, ocular pemphigus, Moren's ulcer, scleritis, Graves' ophthalmomyopathy (Gravesoptha lmopathy), Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or habitual asthma, delayed asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular damage caused by ischemic disease and thrombosis, ischemic bowel disease, ischemia-reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, intestinal damage associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, ulcerative colitis, Migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, aplastic 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, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, non-inflammatory cardiomyopathy or myocardial infarction, scleroderma, systemic sclerosis, antiphospholipid syndrome, Wegener's granuloma, syndrome, obesity, eosinophilic fasciitis, lesions of the gums, periodontal tissues, alveolar bone, cementum, glomerulonephritis, male pattern baldness, senile alopecia (by preventing hair loss or providing hair initiation and / or promoting hair production and hair growth), muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemia-reperfusion injury of organs during storage, transplantation or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, toxic diseases caused by pulmonary oxygen or drugs, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scar scar formation, corneal alkali burns, dermatitis erythema multiforme, linear IgA bullous dermatitis, cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of cancer and hypotension, diseases caused by the release of histamine or leukotriene-C4, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis caused by toxins, necrosis caused by viral hepatitis, necrosis caused by shock, necrosis caused by hypoxia, hepatitis B, non-A, non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), autoimmune Hepatobiliary disease, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant hepatic failure, delayed hepatic failure, "acute-on-chronic" liver failure, chronic kidney disease, renal damage / injury, renal damage / injury caused by nephritis, renal damage / injury caused by renal transplantation, renal damage / injury caused by surgery, renal damage / injury caused by administration of nephrotoxic drugs, renal damage / injury caused by acute kidney injury, increased chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, Parkinson's disease, trauma, or chronic bacterial infection, interleukin-1 converting enzyme-associated febrile syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO-deficiency syndrome , HOIL-1 deficiency, linear ubiquitination chain assembly complex deficiency syndrome, lysosomal storage disease, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease,Neuronal ceroid lipofuscinosis, Pompe disease, pycnodystrophy, Sandhoff disease, Schindler disease, sialic acid storage diseases, Tay-Sachs disease, Wolman disease, Huntington's disease, Parkinson's disease, benign and malignant tumors, solid tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, stomach tumors / cancers, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, meat Neoplasms, Glioblastoma, Neuroblastoma, Multiple Myeloma, Gastrointestinal Cancer, Colon Cancer, Colorectal Adenoma, Neoplasms of the Neck and / or Head, Epidermal Hyperplasia, Psoriasis, Prostatic Hyperplasia, Neoplasia, Epithelial Neoplasia, Adenoma, Adenocarcinoma, Keratoacanthoma, Epidermoid Carcinoma, Large Cell Carcinoma, Non-Small Cell Lung Cancer, Lymphoma, Hodgkins Lymphoma, Non-Hodgkins Lymphoma, Breast Cancer, Follicular Carcinoma, Undifferentiated Carcinoma, Papillary Carcinoma, Seminoma, Melanoma, IL-1 Driven Disorders, MyD88 Driven Disorders, ABC Diffuse Large B-cell Lymphoma (DLBCL), macroglobulinemia, primary cutaneous T-cell lymphoma, chronic lymphocytic leukemia, smoldering multiple myeloma, indolent multiple myeloma, hematological malignancies, leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, drug-resistant malignancies, JAK inhibitor-resistant malignancies, ibrutinib-resistant malignancies, ibrutinib-resistant hematologic malignancies, ibrutinib-resistant CLL, or ibrutinib-resistant Macroglobulinemia.

[0321] In one embodiment, the compounds disclosed herein can be used to slow the occurrence of the consequences of aging. For example, the compounds of the present invention reduce the increased chronic inflammation associated with advanced age ("inflammatory aging (inflammaging)"). Countless symptoms and conditions are associated with inflammatory aging, and as examples, such conditions that can be treated with the compounds of the present invention include neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, hematopoietic neoplasms, and myeloproliferative disorders. Additional conditions that can be treated or improved by the compounds of the present invention include those described in the following documents: Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014; 69 Suppl 1: S4-S9. In another aspect, the compounds of the present invention can be used to reduce the effects of aging on the reproductive system. For example, necroptosis induced by RIP1 signaling has been implicated in the aging of reproductive organs, see Li et al. eLife 2017; 6: e27692 and Chaudhary et al. Journal of Biomedical Science (2019) 26: 11, so the compounds of the present invention can be used to treat symptoms associated with aging, such as decreased testosterone levels, decreased fertility and prostate hyperplasia.

[0322] For a particular embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject having or potentially developing atopic dermatitis. In another particular embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject having or potentially developing rheumatoid arthritis. In another particular embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject having or potentially developing ankylosing spondylitis. In another particular embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject having or potentially developing myelodysplastic syndrome, such as a subject having myelofibrosis or polycythemia vera.

[0323] 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, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disturbances, essential asthma of unknown or unexplained cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, extrinsic asthma caused by environmental factors, cold air-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoan or viral infection, incipient asthma, wheezy infant syndrome, 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, and ethmoid, frontal, palatine, or sphenoid sinusitis.

[0324] Rheumatoid arthritis is another example of an obstacle that can be treated with the compounds of the present invention. Rheumatoid arthritis (RA) generally causes swelling, pain, loss of mobility and tenderness of target joints throughout the body. RA is characterized by a chronic inflammatory synovium of dense lymphocytes. The synovium, which is usually one cell layer thick, becomes densely packed with cells and presents a form similar to lymphoid tissue, including dendritic cells, T cells, B cells and NK cells, macrophages and plasma cell clusters. This process and a large number of immunopathological mechanisms including the formation of antigen-immunoglobulin complexes ultimately lead to the destruction of the integrity of the joint, resulting in deformity at or near the joint, permanent loss of function and / or bone erosion. The disclosed compound, the combination of the disclosed compound, or its pharmaceutical composition can be used to treat, improve or prevent any one, several or all of these symptoms of RA. Therefore, in the context of RA, when the reduction or improvement of any symptom usually associated with RA is achieved, it is believed that the compound provides a therapeutic benefit, regardless of whether the treatment results in a concomitant treatment of essential RA and / or a reduction in the amount of circulating rheumatoid factor ("RF").

[0325] The American College of Rheumatology (ACR) has developed criteria for defining improvement and clinical relief of RA. Once such a parameter, ACR20 (ACR criteria for 20% clinical improvement) requires a 20% improvement in tender and swollen joint counts, and a 20% improvement in 3 of the following 5 parameters: patient global assessment, physician global assessment, patient pain assessment, disability level, and acute phase reactant levels. These criteria have been extended to 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include Paulu's criteria and radiographic progression (e.g., Sharp score).

[0326] In certain embodiments, a therapeutic benefit is achieved in patients suffering from RA when the patient exhibits an ACR of 20. In specific embodiments, an ACR improvement of ACR 50 or even ACR 70 may be achieved.

[0327] B. Preparation and Administration

[0328] Pharmaceutical compositions comprising one or more active compounds of the present disclosure can be prepared by any suitable method, such as mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing processes. The pharmaceutical compositions can be formulated using one or more physiologically acceptable excipients (e.g., diluents, carriers, or auxiliary agents), one or more adjuvants, or combinations thereof, to provide pharmaceutically usable products.

[0329] The active compound (one or more) itself, or in the form of its pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug, can be formulated into a pharmaceutical composition. Typically, such salts are more soluble in aqueous solution than the corresponding free acids and bases, but salts with lower solubility than the corresponding free acids and bases can also be formed.

[0330] The pharmaceutical compositions of the present invention may be in a form suitable for nearly any mode of administration including, for example, topical, ocular, oral, buccal, systemic, nasal, injectable (e.g., intravenous or intraperitoneal), transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0331] For topical administration, the active compound(s), pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes or prodrugs may be formulated into solutions, gels, ointments, creams, suspensions, etc. as is well known in the art.

[0332] Systemic formulations include those designed for administration by injection (eg, subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

[0333] Useful injectable formulations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The pharmaceutical composition may also contain a formulation agent, such as a suspending agent, a stabilizer and / or a dispersant. The formulation for injection may be in unit dosage form, for example, in an ampoule or in a multidose container, and may contain an added preservative.

[0334] Alternatively, the injectable preparation may be provided in powder form to be reconstituted prior to use with a suitable vehicle, including, but not limited to, sterile, pyrogen-free water, buffer, dextrose solution, etc. For this purpose, the active compound(s) may be dried by any technique known in the art, such as lyophilization, and reconstituted prior to use.

[0335] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0336] For oral administration, the pharmaceutical composition can be in the form of, for example, lozenges, tablets or capsules, which are prepared by conventional means with pharmaceutically acceptable excipients, such as: binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silicon dioxide); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated with, for example, sugar, film or enteric coatings by methods well known in the art.

[0337] Liquid preparations for oral administration may be in the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as dry products to be reconstituted with water or other suitable vehicles before use. Such liquid preparations may be prepared in a conventional manner using pharmaceutically acceptable excipients, such as: suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol, cremophore TM or fractionated vegetable oils); and preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents and sweeteners as required.

[0338] Preparations for oral administration may be suitably formulated to give controlled release of the active compound, as is well known.

[0339] For buccal administration, the pharmaceutical compositions may take the form of tablets or lozenges formulated in conventional manner.

[0340] For rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas), suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0341] For nasal administration or administration by inhalation or insufflation, the active compound(s), pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug may be conveniently delivered as an aerosol spray from a pressurized pack or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges (e.g., those comprising gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0342] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray device comprises the following ingredients: active compound (0.520 mg / mL); benzalkonium chloride (0.10.2 mg / mL); polysorbate 80 ( 80; 0.55 mg / mL); sodium carboxymethylcellulose or microcrystalline cellulose (115 mg / mL); phenylethanol (14 mg / mL); and dextrose (2050 mg / mL). The pH of the final suspension can be adjusted to about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

[0343] Another specific example of an aqueous suspension suitable for administration of a compound via inhalation contains 20 mg / mL of a disclosed compound(s), 1% (v / v) polysorbate 80 ( 80), 50 mM citrate and / or 0.9% sodium chloride.

[0344] For ocular administration, the active compound(s) may be formulated into solutions, emulsions, suspensions, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in the following U.S. Patents: Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851, which are incorporated herein by reference.

[0345] For the delivery of extension, active compound (one or more) can be formulated into the long-acting (depot) preparation for giving by implantation or intramuscular injection. Active component can be formulated together with suitable polymer or hydrophobic material (for example, in the form of emulsion in acceptable oil) or ion exchange resin, or be formulated into the form of slightly soluble derivative, for example, the form of slightly soluble salt. Alternatively, a transdermal delivery system can be used, which is prepared as an adhesive disc or patch for slowly releasing active compound (one or more) with percutaneous absorption. For this purpose, penetration enhancer can be used to promote the transdermal penetration of active compound (one or more). For example, suitable transdermal patches are described in U.S. Patent Nos. 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which are incorporated herein by reference.

[0346] Alternatively, other drug delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver the active compound(s). Certain organic solvents such as dimethyl sulfoxide (DMSO) may also be employed, although usually at the expense of greater toxicity.

[0347] If desired, the pharmaceutical composition may be presented in a package or dispenser device which may contain one or more unit dosage forms containing the active compound(s). The package may comprise, for example, metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for administration.

[0348] There are several schemes for transporting molecules across the blood-brain barrier. These include, but are not limited to physical methods, lipid-based methods, and receptor- and channel-based methods. Physical methods for transporting compounds across the blood-brain barrier include, but are not limited to completely bypassing the blood-brain barrier and / or creating openings in the blood-brain barrier. Bypass methods include, but are not limited to direct injection (e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial infusion / convection-enhanced delivery (Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implanting delivery devices in the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003). Openings in the blood-brain barrier include, but are not limited to, ultrasound, osmotic pressure (e.g., by administration of hypertonic mannitol), and by permeabilization with, for example, bradykinin or the permeabilizing agent A-7 (see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416). The compound may also be encapsulated in liposomes coupled to an antibody binding fragment that binds to receptors on the vascular endothelium of the blood-brain barrier.

[0349] For certain embodiments, the compound can be continuously administered by infusion into a fluid reservoir of the CNS or by rapid bolus injection. The compound can be administered using an indwelling catheter and a continuous administration method (such as a pump) or by implanting a sustained release vehicle. For example, the compound can be injected by long-term implantation of a cannula or long-term infusion with the help of an osmotic mini pump. A subcutaneous pump can deliver the compound to the ventricles of the brain.

[0350] C. Dosage

[0351] The disclosed compounds, pharmaceutical compositions, or combinations of disclosed compounds will generally be used in an amount effective to achieve the desired result, for example, an amount effective to inhibit RIP1 kinase and / or to treat, prevent or improve a particular condition. The disclosed compound(s), or pharmaceutical compositions thereof, may be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a preventive benefit. The therapeutic benefit refers to the eradication or improvement of the underlying disorder being treated, and / or the eradication or improvement of one or more symptoms associated with the underlying disorder, so that although the patient may still be afflicted with the underlying disorder, the patient reports an improvement in feeling or condition. For example, administering a compound to a patient suffering from allergy provides a therapeutic benefit not only when the underlying allergic response is eradicated or improved, but also when the patient reports a decrease in the severity or duration of symptoms associated with the allergy after exposure to the allergen. As another example, the therapeutic benefit in terms of asthma includes an improvement in breathing after the onset of an asthma attack or a decrease in the frequency or severity of asthma attacks. Whether or not an improvement is achieved, the therapeutic benefit also includes stopping or slowing the progression of the disease.

[0352] As known to those of ordinary skill in the art, the preferred dosage of the disclosed compounds may depend on a variety of factors, including the age, weight, general health, and severity of the condition of the patient or subject being treated. When administered by inhalation, the dosage may also need to be adjusted to accommodate the sex of the individual and / or the lung capacity of the individual. The dosage may also be adjusted to accommodate individuals with more than one condition or those with additional conditions that affect lung capacity and normal breathing ability (e.g., emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and respiratory tract infections). The dosage and frequency of administration of the disclosed compound (one or more) or its pharmaceutical composition will also depend on whether the disclosed compound (one or more) is formulated for the treatment of acute attacks of the condition or for the preventive treatment of the disorder. One of ordinary skill in the art will be able to determine the optimal dosage for a particular individual.

[0353] For prophylactic administration, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof, can be administered to a patient or subject at risk of developing one of the previously described conditions. For example, if it is not known whether the patient or subject is allergic to a particular drug, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered prior to administration of the drug to avoid or ameliorate an allergic response to the drug. Alternatively, prophylactic administration can be used to avoid or ameliorate the onset of symptoms in a patient diagnosed with an underlying disorder. For example, the disclosed compound(s), or pharmaceutical compositions thereof, can be administered to an allergic victim prior to an anticipated exposure to an allergen. The disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can also be administered prophylactically to healthy individuals who are repeatedly exposed to agents known to be one of the above-mentioned ailments to prevent the onset of the disorder. For example, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered to healthy individuals who are repeatedly exposed to allergens known to induce allergies (such as latex) in an attempt to prevent the individual from developing allergies. Alternatively, a disclosed compound, a combination of disclosed compounds, or a pharmaceutical composition thereof can be administered to a patient suffering from asthma prior to engaging in an activity that provokes an asthma attack to reduce the severity of the asthma attack or to avoid the asthma attack altogether.

[0354] Effective doses can be estimated initially from in vitro assays. For example, an initial dose for a subject can be formulated to achieve an IC value equal to or greater than that of a particular compound as measured in an in vitro assay. 50 or EC 50 The circulating blood or serum concentration of the active compound is calculated to achieve such a circulating blood or serum concentration. The dose can be calculated to achieve such a circulating blood or serum concentration, taking into account the bioavailability of a particular compound. Fingl & Woodbury, "General Principles," in Goodman and Gilman's Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and references cited therein, provide additional guidance on effective doses.

[0355] In some embodiments, the disclosed compounds have an EC50 of greater than 0 to 20 μM, such as greater than 0 to 10 μM, greater than 0 to 5 μM, greater than 0 to 1 μM, greater than 0 to 0.5 μM, greater than 0 to 0.1 μM, or greater than 0 to 0.05 μM.

[0356] Initial doses can also be estimated from in vivo data such as animal models. Animal models that can be used to test the efficacy of compounds for treating or preventing the various diseases described above are well known in the art. Suitable animal models for hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50 (21 Suppl): 6-9, discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol. 107 (6): 1025-1033. Suitable animal models for allergic rhinitis are described in Szelenyi et al., (2000), Arzneimittelforschung 50 (11): 1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy 24 (3): 238-244 and Sugimoto et al., (2000), Immunopharmacology 48 (1): 1-7. One of ordinary skill in the art can adapt such information to determine appropriate dosages for human administration.

[0357] In some embodiments, an assay suitable for determining RIP1 activity may be used. Such assays may be used to evaluate the efficacy of the compound embodiments disclosed herein and / or may be used to determine the amount / dose of the compound embodiments that may provide the desired efficacy. In some embodiments, the assay may be ADP-Glo TM Tests that evaluate the ability of compound embodiments to inhibit RIP1. In other embodiments, whole cell tests using mouse and / or human cells, such as U937 and / or L929 cell necrosis tests, can be performed to determine safe and effective doses of compounds that can be used for in vivo studies in humans. Using these whole cell tests, the activity of compounds against human and / or mouse RIP1 can be evaluated in an in vitro context, which then allows one of ordinary skill in the art to determine safe and effective doses for in vivo use. Another test that can be used to evaluate the activity of compound embodiments described herein for treating diseases or conditions involving RIP1 is an acute hypothermic mouse model that evaluates the ability of compounds to inhibit TNF-α-induced hypothermia. Each of these tests, and the various results from using these tests, are described in detail in the Examples section of the present disclosure.

[0358] The dosage amount of the disclosed compound will typically be in the range of from greater than 0 mg / kg / day (such as 0.0001 mg / kg / day or 0.001 mg / kg / day or 0.01 mg / kg / day) up to at least about 100 mg / kg / day. More representatively, the dosage (or effective amount) can be about 0.0025 mg / kg to about 1 mg / kg, such as 0.01 mg / kg to about 0.5 mg / kg or about 0.05 mg / kg to about 0.15 mg / kg, given at least once a day. The total daily dose is typically about 0.1 mg / kg / day to about 5 mg / kg / day or to about 20 mg / kg / day, such as 0.5 mg / kg / day to about 10 mg / kg / day or about 0.7 mg / kg / day to about 2.5 mg / kg / day. The dosage can be higher or lower, depending on, among other factors, the activity of the disclosed compound, its bioavailability, mode of administration, and various factors discussed above.

[0359] The dose amount and dose interval can be adjusted for the individual to provide a plasma level of the disclosed compound sufficient to maintain a therapeutic or preventive effect. For example, the compound can be administered once a day, multiple times a day, once a week, multiple times a week (e.g., every other day), once a month, multiple times a month, or once a year, depending on the mode of administration, the specific indication being treated, and the judgment of the prescribing physician, among other factors. One of ordinary skill in the art will be able to optimize the effective topical dose without undue experimentation.

[0360] Pharmaceutical compositions comprising one or more of the disclosed compounds typically contain greater than 0 up to 99% of the disclosed one or more compounds, and / or other therapeutic agents (by total weight %). More typically, pharmaceutical compositions comprising one or more of the disclosed compounds contain about 1 to about 20 total weight % of the disclosed compounds and other therapeutic agents, and about 80 to about 99 weight % of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition may further comprise an adjuvant.

[0361] Preferably, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof, will provide therapeutic or preventive benefits without causing substantial toxicity. The toxicity of the disclosed compounds can be determined using standard pharmaceutical procedures. The dose ratio between toxicity and therapeutic (or preventive) effects is the therapeutic index. Disclosed compounds that exhibit high therapeutic indices are preferred.

[0362] V. Examples

[0363] Example 1

[0364] Compounds of the present disclosure can be prepared using appropriate starting compounds as illustrated in the above schemes, such as Compound 200 or Compound 206. A representative method for preparing Compound 200 is illustrated in Scheme 6A, and a representative method for preparing Compound 206 is illustrated in Scheme 6B.

[0365]

[0366] Spectral characteristics of 3-(S)-N-trityl-amino-7-bromo-5-methyl-4-oxobenzoxazapine (200): 1 H nmr (400 MHz, CDCl3) δ 7.41-7.38 (6H, m, 6H of C(C6H5)3), 7.25-7.15 (10H, m, oxobenzoxazapine H-8, 9H of C(C6H5)3), 7.00 (1H, d, J 2.5 Hz, oxobenzoxazapine H-6), 6.91 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 4.50 (1H, dd, J 10.0, 7.5 Hz, oxobenzoxazapine H-2 1H), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.53 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 3.30 (1H, br s, NH), 2.87 (3H, s, NCH3).

[0367] Provided below are characterizing data and specific methods for preparing representative compounds disclosed herein.

[0368] Example 2

[0369]

[0370] Synthesis of (S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one: A mixture of bromooxazepine (0.210 g, 0.410 mmol, 1.0 equiv), potassium carbonate (0.566 g, 4.101 mmol, 10.0 equiv) and copper (I) iodide (0.008 g, 0.041 mmol, 0.1 equiv) in dimethylformamide (3.0 mL) was degassed by bubbling argon therein for 5 min. 2-Methyl-2-hydroxybut-3-yne (0.052 g, 0.060 mL, 0.615 mmol, 1.5 equiv) and tetrakis(triphenylphosphine)palladium (0.024 g, 0.021 mmol, 0.05 equiv) were added, the reaction was sealed, and then heated to 120 °C in a microwave for 1 hour. The reaction was partitioned between EtOAc (80 mL) and water (80 mL). The organics were washed with brine (80 mL), water (80 mL) and brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (10→80% EtOAc-hexanes) produced starting material (0.091 g) and the title compound as a colorless oil (0.079 g); 1 Hnmr (400MHz,CDCl3)δ7.40-7.38(6H,m,6H of C(C6H5)3),7.24-7.7.14(9H,m,9H of C(C6H5)3),7.13(1H,dd,J 8.0,2.0Hz,oxobenzoxazapine H-8),6.96(1H,d,J 8.0Hz,oxobenzoxazapine H-9),6.95(1H,d,J 2.5Hz,oxobenzoxazapine H-6),4.48(1H,dd,J 10.0,7.5Hz,1H of oxobenzoxazapine H-2),4.37(1H,dd,J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.55 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 2.78 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2); m / z: 555 [M+K] + ,243[C(C6H5)3] + .

[0371]

[0372] Deprotection of trityl group: To a solution of trityl protected amine (0.079 g, 0.153 g, 1.0 equiv) in dioxane (2.0 mL) was added hydrogen chloride solution (0.15 mL of a 4 M solution in dioxane, 0.614 mmol, 4.0 equiv). The reaction was stirred at room temperature for 6 hours and then concentrated to dryness to give a white solid which was used without purification; m / z: 275 [M+H] + .

[0373] Example 3

[0374]

[0375] Synthesis of ethyl (S,E)-3-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)acrylate: A suspension of tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (0.500 g, 1.35 mmol, 1.0 equiv) in dimethylformamide (8 mL) was degassed by bubbling argon through it for 5 min. Ethyl acrylate (0.270 g, 0.29 mL, 2.70 mmol, 2.0 equiv) and triethylamine (0.272 g, 0.37 mL, 2.0 equiv) were added, followed by tetrakis(triphenylphosphine) (0.156 g, 0.14 mmol, 0.1 equiv). The reaction was sealed and heated to 100 °C for 1 hour and at 120 °C for 1 hour in a microwave. The reaction was partitioned between EtOAc (100 mL) and water (100 mL). The organics were washed with brine (70 mL), water (100 mL) and brine (70 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (10→40% EtOAc-hexanes) produced the title compound (0.250 g, %) as a yellow foam; 1Hnmr (400MHz,CDCl3)δ7.62(1H,d,J16.0Hz,ArCH=CHCO),7.35(1H,dd,J8.0,2.0Hz,oxybenzoxazepine H-8),7.33(1H,d,J2.0Hz,oxybenzoxazepine H-6),7.14(1H,d,J8.0Hz,oxybenzoxazepine H-9),6.37(1H,d,J16.0Hz,ArCH=CHCO),5.49(1H,d,J7.0Hz,NH),4.65(1H,dt,J11.0,7.0Hz,oxybenzoxazepine H-3),4.57(1H,dd,J 9.5, 7.0 Hz, 1H of oxybenzoxaazepine H-2), 4.27 (2H, q, J 7.0 Hz, OCH2CH3), 4.19 (1H, dd, J 11.0, 9.5 Hz, 1H of oxybenzoxaazepine H-2), 3.41 (3H, s, NCH3), 1.39 (9H, s, C(CH3)3), 1.34 (3H, t, J 7.0 Hz, OCH2CH3); m / z: 291 [M+H-CO2-C4H8] + .

[0376]

[0377] Synthesis of ethyl (S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)propanoate: To a solution of α,β-unsaturated ester (0.25 g, 0.64 mmol, 1.0 equiv) in ethyl acetate (20 mL) was added palladium on carbon (0.23 g). The reaction was purged with hydrogen and stirred under a hydrogen atmosphere for 14 hours. The reaction was purged with nitrogen and passed through Filter and elute with ethyl acetate (2×20 mL). Concentrate the filtrate under reduced pressure; 1H nmr (400 MHz, CDCl3) δ7.04-6.82 (3H, m, oxybenzoxaazepine H-6, H-8, H-9), 5.50 (1H, d, J 7.5 Hz, NH), 4.61 (1H, dt, J 11.0, 7.5 Hz, oxybenzoxaazepine H-3), 4.52 (1H, dd, J 9.5, 7.5 Hz, 1H of oxybenzoxaazepine H-2), 4.14-4.07 (1H, m, 1H of oxybenzoxaazepine H-2), 4.12 (2H, q, J 7.0 Hz, OCH2CH3), 3.36 (3H, s, NCH3), 2.91 (2H, t, J 7.5Hz, 2H of ArCH2CH2CO), 2.59(2H,t,J 7.5Hz, 2H of ArCH2CH2CO), 1.37(9H,s,C(CH3)3), 1.23(3H,t,J 7.0Hz,OCH2CH3); m / z: 337[M+H-C4H8] + ,293[M+H-CO2-C4H8] + . The crude material was dissolved in dichloromethane (10 mL). Hydrogen chloride (0.80 mL of a 4M solution in dioxane, 3.21 mmol, 5.0 equiv) was added. The reaction was stirred at room temperature for 14 hours, then additional hydrogen chloride solution (0.8 mL, 5.0 equiv) was added. After stirring for an additional 2 hours, the reaction was concentrated under reduced pressure and dried under vacuum to give a brown solid. The crude material was used without further purification; m / z: 293 [M+H] + .

[0378] Example 4

[0379]

[0380] Synthesis of (S,E)-3-(5-methyl-4-oxo-3-(tritylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)acrylamide: To a mixture of bromooxobenzoxazapine (0.300 g, 0.586 mmol, 1.0 eq) and acrylamide (0.062 g, 0.879 mmol, 1.5 eq) was added dimethylformamide (5 mL) and the mixture was degassed by bubbling argon therein for five minutes. Triethylamine (0.178 g, 0.24 mL, 1.758 mmol, 3.0 eq) was added followed by X-PhosPd G2 (0.046 g, 0.059 mmol, 0.1 eq) and the reaction was sealed and heated to 120 °C in a microwave for 1 hour. The reaction was partitioned between EtOAc (100 mL) and NaHCO3 (100 mL). The organics were washed with brine (80 mL), water (100 mL) and brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH-CH2Cl2) produced the title compound as a light yellow solid (0.267 g, 91%); 1 H nmr (400 MHz, CDCl3) δ 7.55 (1H, d, J 15.5 Hz, ArCH=CHCO), 7.39-7.36 (7H, m, 6H of C(C6H5)3, oxobenzoxazapine H-8), 7.25-7.13 (9H, m, 9H of C(C6H5)3), 7.01 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 6.97 (1H, d, J 2.0 Hz, oxobenzoxazapine H-6), 6.39 (1H, d, J 15.5 Hz, ArCH=CHCO), 5.95 (2H, br s, NH2), 4.51 (1H, dd, J 9.5,7.0Hz,1H of oxobenzoxazapine H-2), 4.39 (1H,dd,J 11.5,9.5Hz,1H of oxobenzoxazapine H-2), 3.54 (1H,dt,J 11.5,7.5Hz,oxobenzoxazapine H-3), 3.31 (1H,d,J 8.5Hz,NH), 2.94 (3H,s,NCH3); m / z: 526 [M+Na] + ,243[C(C6H5)3] + .

[0381]

[0382] Synthesis of (S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)propanamide: A solution of α,β-unsaturated carboxamide (0.267 g, 0.532 mmol, 1.0 equiv) / ethyl acetate-methanol (5:2, 7 mL) was purged with nitrogen and palladium / carbon (0.100 g) was added. The reaction was purged with hydrogen and stirred under a hydrogen atmosphere for 2 hours. The reaction was purged with nitrogen and filtered through celite, eluting with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in dioxane (5 mL) and hydrogen chloride (0.66 mL of a 4 M solution in dioxane, 2.659 mmol, 5.0 equiv) was added. The reaction was stirred at room temperature for 6 hours to form a white solid. The reaction was concentrated to dryness and used without purification; m / z: 265 [M+H] + .

[0383] Example 5

[0384]

[0385] Formation of (S)-7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8h)-yl)methyl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one: Dioxane (4 mL) and water (2 mL) were added to bromobenz A mixture of oxazapine) (0.270 g, 0.527 mmol, 1.0 equiv), 7-((trifluoro-λ4-boryl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, potassium salt (0.180 g, 0.738 mmol, 1.4 equiv) and cesium carbonate (0.515 g, 1.581 mmol, 3.0 equiv). The reaction was degassed by bubbling argon through it for ten minutes. X-PhosPd G2 (0.021 g, 0.026 mmol, 0.05 equiv) was added and the reaction was sealed and heated to 140 °C in a microwave for 45 minutes. The reaction was partitioned between EtOAc (80 mL) and NaHCO3 (80 mL). The organics were washed with brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH [2M NH3]-CH2Cl2) produced the title compound as a yellow oil (0.255 g, %); 1H nmr (400 MHz, CDCl3) δ 7.88 (1H, s, triazole H-3), 7.38-7.35 (6H, m, 6H of C(C6H5)3), 7.21-7.11 (9H, m, 9H of C(C6H5)3), 7.02 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapine H-8), 6.97 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 6.87 (1H, d, J 2.0 Hz, oxobenzoxazapine H-6), 4.50 (1H, dd, J 10.0,7.5Hz,1H of oxobenzoxazapine H-2),4.36(1H,dd,J 11.5,10.0Hz,1H of oxobenzoxazapine H-2),4.16(2H,t,J 5.5Hz,2H of NCH2CH2N),3.82(2H,s,ArCH2N or NCH2CN),3.69(2H,s,ArCH2N or NCH2CN),3.51(1H,dd,J 11.5,7.5Hz,oxobenzoxazapine H-3),2.91(2H,t,J 5.5Hz, 2H of ArCH2CH2N), 2.88(3H,s,NCH3); m / z:593[M+Na] + ,243[C(C6H5)3] + .

[0386]

[0387] Trityl deprotection: To a solution of trityl protected amine (0.255 g, 0.447 mmol, 1.0 equiv) in dioxazne (4.0 mL) was added hydrogen chloride (0.56 mL of a 4 M solution in dioxane, 2.237 mmol, 5.0 equiv). A white precipitate formed. The reaction was stirred at room temperature for 14 hours. The reaction was concentrated to dryness and used without purification; m / z: 329 [M+H] + .

[0388]

[0389] (S)-7-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one

[0390] 1 H nmr (400 MHz, CDCl3) δ 7.40-7.38 (6H, m, 3x 2H of C6H5), 7.24-7.20 (6H, m, 3x 2H of C6H5), 7.18-7.12 (4H, m, 3x 1H of C6H5, 1H of oxbenzoxazapine H-6, H-8, H-9), 6.97-6.95 (2H, m, 2H of oxobenzoxazapine H-6, H-8, H-9), 4.48 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.37 (1H, dd, J 11.5,9.5Hz,1H of oxobenzoxazapine H-2), 3.55(1H,dt,J 11.5,7.5Hz, oxobenzoxazapine H-3), 3.28(1H,d,J 8.5Hz,NH), 2.88(3H,s,NCH3), 1.63(6H,s,C(CH3)2OH); m / z:561[M-H+HCO2H] - .

[0391]

[0392] (S)-3-Amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one

[0393] 1H nmr (400 MHz, CDCl3) δ7.24 (1H, d, J 2.0 Hz, oxobenzoxazapine H-6), 7.22 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 4.41 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.12 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.72 (1H, dd, J 11.5,7.5Hz,oxobenzoxazapine H-3); m / z:275[M+H] + (Measured value [M+H] + ,275.1390,C 15 H 18 N2O3 theoretical value [M+H] + 275.1404).

[0394] Example 6

[0395] This example relates to a method for preparing (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide according to Scheme 7.

[0396]

[0397] Dimethylformamide (80 mL) was added to a mixture of bromooxobenzoxazapine 1100 (8.36 g, 16.3 mmol, 1.0 equiv) and cuprous iodide (0.31 g, 1.6 mmol, 0.1 equiv). Argon was introduced by bubbling for 5 minutes to degas the mixture. Triethylamine (11.4 mL, 81.6 mmol, 5.0 equiv) was added, followed by hydroxyethynyloxetane 1102 (3.20 g, 32.7 mmol, 2.0 equiv) and tetrakis(triphenylphosphine)palladium (0.94 g, 0.8 mmol, 0.05 equiv). The resulting brown solution was heated to 80 °C for 4 hours. The reaction was cooled and distributed between EtOAc (200 mL) and water (200 mL). The organics were washed with brine (150 mL), water (200 mL) and brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure.MPLC (10→70% EtoAc-hexanes) yielded compound 1104 (6.18 g, 72%) as a yellow solid. 1 H nmr (400 MHz, CD3Cl) δ7.41-7.39 (6H, m, 6H of C(C6H5)3), 7.25-7.15 (10H, m, 9H of C(C6H5)3, oxobenzoxazapine H-8), 7.00-6.98 (2H, m, oxobenzoxazapine H-6, H-9), 4.94 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.80 (2H, d, J 7.5 Hz, 2H of oxetane H-2, H-4), 4.50 (1H, dd, J 10.0, 7.0 Hz, 1H of oxobenzoxazapine H-2), 4.39 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.59-3.52 (1H, m, oxobenzoxazapine H-3), 3.29 (1H, d, J 9.0 Hz, NH), 2.89 (3H, s, NCH3).

[0398] Formic acid (50 mL) was added to trityl protected amine 1104 (7.49 g, 14.1 mmol, 1 eq) and the mixture was stirred at room temperature for 4 hours. Water (50 mL) was added and the reaction was stirred at room temperature for 15 hours. The reaction was concentrated to remove some formic acid and then diluted with water (100 mL). The organics were extracted with EtOAc (50 mL) and set aside. The aqueous phase was neutralized by adding NaOH (5 M, portionwise to about 40 mL). The organics were extracted with EtOAc (4×150 mL). The combined neutralized organics were dried (Na2SO4) and concentrated under reduced pressure to give (S)-3-amino-7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one 1106 (3.78 g, 93%) as a yellow solid which was used without further purification. 1H nmr (400MHz, D6-DMSO) δ7.51 (1H, d, J 2.0Hz, oxobenzoxazapine H-6), 7.29 (1H, dd, J 8.0, 2.0Hz, oxobenzoxazapine H-8), 7.14 (1H, d, J 8.0Hz, oxobenoxazapine H-9), 4.74 (2H, d, J 7.0Hz, oxetane H-2, 2H of H-4), 4.58 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.25 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.01 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.59 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 3.28 (3H, s, NCH3); 13C nmr(100MHz,D6-DMSO)δ173.7,150.7,137.7,130.2,126.2,126.6,123.3,119.1,90.9,84.5,83.7,80.3,66.3,51.1,35.1; m / z:289[M+H] + .

[0399] A solution of aminooxobenzoxazapine 1106 (3.78 g, 13.13 mmol, 1.0 eq) in dimethylformamide (70 mL) was degassed by bubbling nitrogen for 5 minutes. 4-Phenoxypyridine-2-carboxylic acid hydrochloride 1108 (3.30 g, 13.13 mmol, 1.0 eq) was added and the solution was cooled to 0°C, then diisopropylethylamine (5.7 mL, 32.81 mmol, 2.5 eq) was added. HATU (5.49 g, 14.44 mmol, 1.1 eq) was added in portions, the reaction was stirred at 0°C for 1 hour and at room temperature for 15 hours. The reaction was poured into ice water (500 mL) to form a precipitate, which was separated by filtration after stirring for 15 minutes. The filtrate was extracted with EtOAc (150 mL). The organic extract was washed with brine (100 mL), water (150 mL) and brine (100 mL), combined with the isolated precipitate, dried (Na2SO4) and concentrated under reduced pressure. MPLC (30→70% EtOAc-hexanes) yielded (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide I-110 (5.20 g, 82%) as a white foam.IR (thin film) v 3357, 2941, 2875, 1662, 1582, 1501, 1488, 1469, 1388, 1360, 1291, 1214, 1192, 1020, 979, 838, 730 cm-1; 1H nmr (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5 Hz, pyH-6), 7.61 (1H, d, J 2.5Hz,pyH-3), 7.44-7.40 (2H,m,2H of C6H5), 7.32-7.29 (2H,m,2H of C6H5 or oxobenzoxazapine H-6,H-8), 7.27-7.23 (1H,m,1H of C6H5 or oxobenzoxazapine H-6,H-8), 7.15 (1H,d,J9.0 Hz, oxobenzoxazapine H-9), 7.08-7.06 (2H, m, 2H of C6H5 or oxobenzoxazapine H-6, H-8), 6.50 (1H, dd, J 5.5, 2.5Hz, pyH-5), 5.04 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapine H-3), 4.93 (2H, dd, J 4.0, 0.5Hz, oxetane H-2, H-4), 4.79 (2H, dt, J 6.5, 1.0Hz, oxetane H-2, H-4), 4.71 (1H, dd, J 9.5,7.5Hz,1H of oxobenzoxazapine H-2),4.32(1H,dd,J11.0,9.5Hz,1H of oxobenzoxazapine H-2),3.42(3H,s,NCH3);13C nmr (100 MHz, CDCl3) δ 168.9, 166.1, 163.7, 153.7, 151.2, 150.5, 150.1, 136.4, 130.9, 130.3, 126.5, 125.7, 123.3, 120.7, 119.3, 114.5, 110.7, 88.6, 84.8, 84.5, 77.2, 67.4, 49.3, 35.4; m / z: 486 [M+H]+ (found [M+H]+, 486.1651, C. 27 H 23 N3O6 theoretical value [M+H]+ 486.1660).

[0400] Synthesis of tert-butyl 3-ethynyl-3-hydroxyazetidine-1-carboxylate

[0401]

[0402] Solution 8

[0403] A solution of (trimethylsilyl) acetylene 1302 (0.71 g, 1.00 mL, 6.28 mmol, 1.1 equivalents) / tetrahydrofuran (30 mL) was cooled to -78 ° C and butyl lithium (2.51 mL of a 2.5 M solution in hexane, 6.28 mmol, 1.1 equivalents) was added dropwise. The reaction was stirred at -78 ° C for 1 hour, and then Boc-azetidinone 1300 (0.98 g, 5.71 mmol, 1.0 equivalents) was added. The reaction was stirred between -78 ° C and room temperature for 20 hours, and then quenched by adding NH4Cl (20 mL). The reaction was distributed between EtOAc (100 mL) and NH4Cl-water (1: 1, 100 mL). The organic matter was washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure.

[0404] The residue containing 1304 was dissolved in tetrahydrofuran (30 mL) and cooled to 0 ° C, then tetrabutylammonium fluoride trihydrate (1.80 g, 5.71 mmol, 1.0 equiv) was added. The reaction was stirred at 0 ° C for 3 hours, then NH4Cl (20 mL) was added. The reaction was distributed between EtOAc (100 mL) and NH4Cl-water (1: 1, 100 mL). The organic matter was washed with NH4Cl (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to produce 1306 as a light yellow oil. 1 H nmr (400 MHz, CDCl3) δ 4.20 (2H, dd, J 9.0, 1.0 Hz, 2H of azetidine H-2, H-4), 4.02 (2H, dd, J 9.0, 1.0 Hz, 2H of azetidine H-2, H-4), 2.68 (1H, s, CCH), 1.44 (9H, s, C(CH3)3).

[0405] Example 7

[0406] This example provides methods for preparing embodiments of the disclosed alkynyl substituted compounds according to Scheme 8 below.

[0407]

[0408] Nitrogen was bubbled through a stirred solution of aryl / heteroaryl halide 1 (1 eq.) and CuI (0.1-0.2 eq.), Pd(PPh3)4 (0.05-0.1 eq.) / dry DMF (3-4 mL / mmol) in a bottle for 3 minutes. Subsequently, NEt3 (10 eq.) was added to the dark reaction solution, followed by the corresponding alkyne (1.5-3 eq.). Nitrogen was bubbled through the reaction mixture for 2 minutes, the bottle was capped, and the reaction mixture was stirred at 70-75 ° C for 5-6 hours. After the reaction progress was analyzed by LC / MS analysis, the dark reaction solution was concentrated to dryness. The crude residue was diluted with ice water, sonicated, and the slurry was warmed to room temperature. The obtained gray / dark solid was collected by filtration, suction dried, dissolved in THF (20 mL), filtered through a celite (R) / silica gel pad, and the pad was washed with THF. After concentration of the filtrate, the crude material was purified by flash chromatography to afford alkynyl substituted analogs 2 (yields: 25-69%).

[0409] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepine-4(5H)-one (I-23).

[0410]

[0411] 1 H NMR (400MHz, CDCl3) δ7.34-7.25(m,7H),7.09(d,J=8.2Hz,1H),5.89(dd,J=11 .7,8.0Hz,1H),5.39(s,2H),4.63(dd,J=11.8,9.9Hz,1H),4.40(dd,J=10.0,8. 0Hz,1H),4.23(dt,J=12.0,5.2Hz,1H),3.60-3.43(m,1H),3.37(s,3H),3.04(d dd,J=15.5,10.4,5.1Hz,1H),2.66(ddd,J=15.6,5.4,4.4Hz,1H),1.63(s,6H). 13C NMR (100 MHz, CDCl3) δ 169.43, 160.87, 149.99, 142.32, 136.85, 135.21, 130.66, 128.89, 128.35, 127.87, 126.64, 122.87, 120.70, 118.18, 94.60, 80.97, 74.87, 65.78, 53.99, 51.26, 45.48, 35.72, 31.59, 31.58, 19.91. MS (ESI, m / e) calcd 518.1721; found 519.1 [M+H] + .

[0412] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-1)

[0413]

[0414] 1 H NMR(400MHz, DMSO-d6)δ7.47(d,J=8.3Hz,1H),7.38-7.29(m,4H),7.23(d,J=1.9Hz,1H),7.21-7.17( m,2H),5.53(dd,J=11.9,7.9Hz,1H),5.43(s,2H),4.84(dd,J=12.0,10.1Hz,1H),4.38(dd,J=10.1,7 .8Hz,1H),4.00(dt,J=12.4,6.2Hz,1H),3.63(ddd,J=12.9,8.4,4.9Hz,1H),3.29(s,3H),2.85-2.74(m,1H),2.68(ddd,J=11.9,8.4,5.6Hz,1H),1.47(s,6H).MS(ESI,m / e)calcd.518.1721; found.519.1[M+H] + .

[0415] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-2)

[0416]

[0417] 1 H NMR(400MHz,DMSO-d6)δ7.45(d,J=8.3Hz,1H),7.38-7.26(m,4H),7.22-7.16(m,3H),5.52 (dd,J=11.9,7.8Hz,1H),5.43(s,2H),4.83(dd,J=12.0,10.1Hz,1H),4.37(dd,J=10.0,7.9 Hz, 1H), 4.00 (dt, J = 12.2, 5.7 Hz, 1H), 3.62 (ddd, J = 12.8, 8.4, 4.8 Hz, 1H), 3.28 (s, 3H), 2.83-2.74 (m, 1H), 2.73-2.65 (m, 1H), 1.29 (s, 9H). MS (ESI, m / e) calculated value 516.1928; found value 517.1 [M+H] + .

[0418] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (R938188)

[0419]

[0420] 1 H NMR(400MHz, DMSO-d6)δ7.47(d,J=8.4Hz,1H),7.38-7.27(m,4H),7.23(d,J=1.9Hz,1H),7.21-7.17 (m,2H),5.53(dd,J=11.9,7.9Hz,1H),5.43(s,2H),4.89-4.77(m,1H),4.37(dd,J=10.1,7.8Hz,1H) ,4.00(dt,J=12.4,6.1Hz,1H),3.63(ddd,J=12.8,8.4,4.8Hz,1H),3.29(s,3H),2.86-2.74(m,1H),2.74-2.62(m,1H),1.97-1.81(m,5H),1.81-1.61(m,2H).MS(ESI,m / e)calcd.544.1877; found.545.1[M+H] + .

[0421] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-4-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-4)

[0422]

[0423] 1 H NMR (400MHz, DMSO-d6) δ8.68-8.61(m,2H),7.67-7.48(m,5H),7.33(dt,J=14.2,7.0Hz,3 H),7.23-7.16(m,2H),5.56(dd,J=11.9,7.8Hz,1H),5.43(s,2H),4.98-4.79(m,1H),4.41 (dd, J = 10.0, 7.8 Hz, 1H), 4.08-3.96 (m, 1H), 3.64 (ddd, J = 12.7, 8.3, 4.7 Hz, 1H), 2.81 (ddd, J = 14.2, 8.4, 5.1 Hz, 1H), 2.75-2.66 (m, 1H). MS (ESI, m / e) calculated value 537.1568; found value 538.0 [M+H] + .

[0424] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-3-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-5)

[0425]

[0426] 1HNMR (400MHz, DMSO-d6) δ8.77(d,J=2.1Hz,1H),8.61(dd,J=4.9,1.6Hz,1H),8.00(dt,J=7.9,2.0Hz,1H),7. 63-7.43(m,4H),7.40-7.26(m,3H),7.23-7.13(m,2H),5.56(dd,J=11.9,7.8Hz,1H),5.43(s,2H),4.93-4.8 3 (m, 1H), 4.41 (dd, J = 10.1, 7.8 Hz, 1H), 4.01 (dt, J = 12.4, 6.1 Hz, 1H), 3.64 (ddd, J = 12.8, 8.4, 4.7 Hz, 1H), 3.32 (s, 3H), 2.81 (ddd, J = 13.9, 8.5, 5.1 Hz, 1H), 2.73-2.63 (m, 1H). MS (ESI, m / e) calculated value 537.1568; found value 538.1 [M+H] + .

[0427] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-6)

[0428]

[0429] 1HNMR (400MHz, DMSO-d6) δ8.63(d,J=4.6Hz,1H),7.87(td,J=7.7,1.8Hz,1H),7.67(d,J=7.8Hz,1H),7.57(d,J=1.5Hz,2H),7.4 9(s,1H),7.44(dd,J=7.7,4.8Hz,1H),7.39-7.26(m,3H),7.22-7.16(m,2H),5.56(dd,J=11.9,7.8Hz,1H),5.43(s,2H),4.89(d d, J = 12.0, 10.1 Hz, 1H), 4.42 (dd, J = 10.1, 7.8 Hz, 1H), 4.01 (ddd, J = 12.3, 7.3, 5.2 Hz, 1H), 3.65 (ddd, J = 12.8, 8.4, 4.9 Hz, 1H), 3.32 (s, 3H), 2.81 (ddd, J = 14.0, 8.4, 5.1 Hz, 1H), 2.69 (ddd, J = 15.4, 7.0, 4.8 Hz, 1H). MS (ESI, m / e) calculated value 537.1568; found value 538.2 [M+H] + .

[0430] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-(tert-butoxy)prop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-7)

[0431]

[0432] 1 H NMR (400MHz, DMSO-d6) δ7.49 (d, J=8.3Hz, 1H), 7.41-7.26 (m, 5H), 7.21-7.17 (m, 2H), 5.52 (dd, J= 11.9,7.8Hz,1H),5.43(s,2H),4.91-4.79(m,1H),4.37(dd,J=10.0,7.8Hz,1H),4.30(s,2H),4.00 (dt, J = 12.4, 6.0 Hz, 1H), 3.63 (ddd, J = 12.9, 8.4, 4.8 Hz, 1H), 3.29 (s, 3H), 2.80 (ddd, J = 14.0, 8.4, 5.1 Hz, 1H), 2.68 (dt, J = 15.8, 6.4 Hz, 1H), 1.20 (s, 9H). MS (ESI, m / e) calculated value 546.2034; found value 547.2 [M+H] + .

[0433] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-8)

[0434]

[0435] 1 H NMR(400MHz, DMSO-d6)δ7.52(d,J=8.3Hz,1H),7.42(dd,J=8.3,1.9Hz,1H),7.39-7.26(m,4H),7.23-7.14(m,2H),5 .53(dd,J=11.9,7.8Hz,1H),5.43(s,2H),4.86(dd,J=11.9,10.1Hz,1H),4.76(d,J=6.3Hz,2H),4.60(d,J=6.4Hz,2H ), 4.38 (dd, J = 10.0, 7.8 Hz, 1H), 4.01 (ddd, J = 12.4, 7.0, 5.0 Hz, 1H), 3.63 (ddd, J = 12.9, 8.3, 4.8 Hz, 1H), 3.30 (s, 3H), 2.80 (ddd, J = 15.4, 8.4, 5.1 Hz, 1H), 2.68 (ddd, J = 15.7, 7.0, 4.8 Hz, 1H). MS (ESI, m / e) calculated value 532.1513; found value 533.0 [M+H] + .

[0436] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-9)

[0437]

[0438] 1H NMR(400MHz, DMSO-d6)δ7.50(d,J=8.3Hz,1H),7.41(dd,J=8.5,1.9Hz,1H),7.38-7.27(m,4H),7.19(d, J=7.4Hz,2H),5.53(dd,J=11.9,7.8Hz,1H),5.43(s,2H),4.90-4.77(m,1H),4.38(dd,J=10.1,7.8Hz,1 H), 4.34 (s, 2H), 4.00 (dt, J = 12.3, 6.1 Hz, 1H), 3.63 (ddd, J = 12.8, 8.5, 4.8 Hz, 1H), 3.34 (s, 3H), 3.29 (s, 3H), 2.80 (ddd, J = 14.0, 8.4, 5.1 Hz, 1H), 2.74-2.66 (m, 1H). MS (ESI, m / e) calculated value 504.1564; found value 505.0 [M+H] + .

[0439] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-10)

[0440]

[0441] 1 H NMR (400MHz, DMSO-d6) δ7.49 (d, J=8.3Hz, 1H), 7.42-7.26 (m, 5H), 7.21-7.17 (m, 2H), 5.53 (dd, J= 11.9,7.8Hz,1H),5.43(s,2H),4.89-4.80(m,1H),4.38(dd,J=10.0,7.8Hz,1H),4.00(dt,J=12.3, 6.1 Hz, 1H), 3.63 (ddd, J = 12.9, 8.4, 4.8 Hz, 1H), 3.32 (s, 3H), 3.29 (s, 3H), 2.80 (ddd, J = 13.8, 8.5, 5.1 Hz, 1H), 2.75-2.62 (m, 1H), 1.48 (d, J = 0.8 Hz, 6H). MS (ESI, m / e) calculated value 532.1877; found value 533.1 [M+H] + .

[0442] (S)-3-(2-Benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-11)

[0443]

[0444] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 8.3 Hz, 1H), 7.39-7.28 (m, 4H), 7.25 (d, J = 1.9 Hz, 1H), 7.24-7.21 (m, 2H), 5.50 (s, 2H), 5.05 (dd, J = 12.2, 7.5 Hz, 1H), 4.93 (dd, J = 12.2, 9.8 Hz, 1H), 4.84 (d, J = 15.8 Hz, 1H), 4.53-4.43 (m, 2H), 3.28 (s, 3H), 1.47 (s, 6H). MS (ESI, m / e) calcd. 504.1564; found 527.0 [M+Na] + .

[0445] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-12)

[0446]

[0447] 1H NMR(400MHz, DMSO-d6)δ7.45(d,J=8.3Hz,1H),7.40-7.25(m,4H),7.22(d,J=1.9Hz,1H),7.21-7. 17(m,2H),5.52(dd,J=11.9,7.9Hz,1H),5.43(s,2H),4.83(dd,J=11.9,10.1Hz,1H),4.36(dd,J= 10.0,7.8Hz,1H),4.06-3.95(m,1H),3.62(ddd,J=12.8,8.5,4.8Hz,1H),3.35(s,2H),3.28(s,3H),2.86-2.74(m,1H),2.73-2.62(m,1H),1.20(s,6H).MS(ESI,m / e)calcd.532.1877; found.533.1[M+H] + .

[0448] (S)-3-(2-Benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-13)

[0449]

[0450] 1 HNMR (400MHz, DMSO-d6) δ8.96 (d, J=2.0Hz, 1H), 8.29 (dd, J=8.2, 2.1Hz, 1H), 8.00 (dd, J= 8.2,0.9Hz,1H),7.67-7.58(m,2H),7.56(d,J=1.7Hz,1H),7.41-7.29(m,3H),7.27-7.20( m, 2H), 5.51 (s, 2H), 5.10 (dd, J = 12.1, 7.5 Hz, 1H), 4.98 (dd, J = 12.2, 9.8 Hz, 1H), 4.84 (d, J = 15.8 Hz, 1H), 4.57-4.45 (m, 2H), 3.32 (s, 3H). MS (ESI, m / e) calculated value 591.1285; found value 592.1 [M+H] + .

[0451] (S)-3-(2-Benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-14)

[0452]

[0453] 1 H NMR (400MHz, DMSO-d6) δ8.63 (ddd, J=4.9, 1.8, 0.9Hz, 1H), 7.88 (td, J=7.7, 1.8Hz, 1H), 7.67 (dt, J=7 .8,1.1Hz,1H),7.64-7.56(m,2H),7.51(d,J=1.7Hz,1H),7.44(ddd,J=7.7,4.9,1.2Hz,1H),7.41-7. 27 (m, 3H), 7.27-7.19 (m, 2H), 5.51 (s, 2H), 5.10 (dd, J = 12.2, 7.5 Hz, 1H), 4.98 (dd, J = 12.2, 9.8 Hz, 1H), 4.84 (d, J = 15.8 Hz, 1H), 4.57-4.45 (m, 2H), 3.32 (s, 3H). MS (ESI, m / e) calculated value 523.1411; found value 524.0 [M+H] + .

[0454] (S)-6-((3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-8-yl)ethynyl)-2-cyanopyridine (I-15)

[0455]

[0456] 1HNMR (400MHz, DMSO-d6) δ8.13(d,J=7.8Hz,1H),8.07(dd,J=7.8,1.2Hz,1H),7.99(dd,J=7.9,1.2Hz,1H),7.61(dd,J=2.6,1. 2Hz,2H),7.55(dd,J=1.7,0.6Hz,1H),7.38-7.27(m,3H),7.22-7.16(m,2H),5.56(dd,J=11.9,7.8Hz,1H),5.43(s,2H),4.90 (dd, J = 12.0, 10.1 Hz, 1H), 4.42 (dd, J = 10.1, 7.8 Hz, 1H), 4.01 (dt, J = 12.3, 6.3 Hz, 1H), 3.65 (ddd, J = 12.8, 8.4, 4.9 Hz, 1H), 3.33 (s, 3H), 2.81 (ddd, J = 13.7, 8.3, 5.1 Hz, 1H), 2.69 (ddd, J = 15.3, 6.8, 4.7 Hz, 1H). MS (ESI, m / e) calculated value 562.1520; found value 563.1 [M+H] + .

[0457] (S)-3-(2-Benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazazepine-4(5H)-one (I-16)

[0458]

[0459] 1 HNMR (400 MHz, CD2Cl2) δ7.41-7.22 (m, 5H), 7.09-6.97 (m, 1H), 6.30 (d, J = 7.2 Hz, 2H), 5.42 (s, 2H), 5.13 (dd, J = 15.2, 0.6 Hz, 1H), 4.65 (dd, J = 12.1, 9.7 Hz, 1H), 4.34 (dd, J = 9.7, 7.9 Hz, 1H), 4.21 (d, J = 15.3 Hz, 1H), 3.67 (d, J = 0.8 Hz, 4H), 3.66-3.62 (m, 5H), 3.32 (s, 3H), 1.92-1.77 (m, 4H). MS (ESI, m / e) calculated value 547.1986; found value 548.1 [M+H] + .

[0460] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazazepine-4(5H)-one (I-17)

[0461]

[0462] MS (ESI, m / e) calculated value 561.2143; found value 562.2 [M+H] + .

[0463] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-18)

[0464]

[0465] MS (ESI, m / e) calculated value 537.1568.

[0466] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-19)

[0467]

[0468] MS (ESI, m / e) calculated value: 490.1408.

[0469] (3S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyrrolidin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-20)

[0470]

[0471] MS (ESI, m / e) calculated value 529.1881.

[0472] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-21)

[0473]

[0474] MS (ESI, m / e) calcd. 551.1724.

[0475] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-22)

[0476]

[0477] 1 HNMR (400MHz, DMSO-d6) δ8.19(td,J=7.9,0.8Hz,1H),7.98(d,J=8.0Hz,1H),7.95(dd,J=7.9,0.9Hz,1H),7.64(dd,J=8.3, 1.9Hz,1H),7.60(d,J=8.3Hz,1H),7.57(d,J=1.8Hz,1H),7.39-7.27(m,3H),7.23-7.16(m,2H),5.56(dd,J=11.9,7.9Hz,1H ),5.43(s,2H),4.98-4.82(m,1H),4.42(dd,J=10.1,7.8Hz,1H),4.01(p,J=6.1Hz,1H),3.65(ddd,J=12.8,8.4,4.8Hz,1H),3.33(s,3H),2.81(ddd,J=13.9,8.3,5.0Hz,1H),2.69(dt,J=15.4,5.2Hz,1H).MS(ESI,m / e)calcd:605.1442; found:606.1[M+H] + .

[0478] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (I-23)

[0479]

[0480] 1 HNMR(400MHz, CDCl3)δ7.34-7.23(m,7H),7.09(d,J=8.2Hz,1H),5.89(dd,J=11 .7,8.0Hz,1H),5.39(s,2H),4.63(dd,J=11.8,10.0Hz,1H),4.40(dd,J=10.0,8 .0Hz,1H),4.23(dt,J=12.0,5.2Hz,1H),3.59-3.45(m,1H),3.37(s,3H),3.04( ddd,J=15.5,10.4,5.1Hz,1H),2.66(ddd,J=15.6,5.4,4.4Hz,1H),1.63(s,6H). 13 C NMR (100 MHz, CDCl3) δ 169.4, 160.9, 150.0, 142.3, 136.9, 135.2, 130.7, 128.9, 128.4, 127.9, 126.6, 122.9, 120.7, 118.2, 94.6, 81.0, 74.9, 65.8, 54.0, 51.3, 45.5, 35.7, 31.6, 31.6, 19.9. MS (ESI, m / e) calcd. 518.1721; found 519.1 [M+H] + .

[0481] Example 8

[0482] This example provides general methods for preparing compounds described herein.Exemplary compounds were prepared according to Scheme 9.

[0483]

[0484] Referring to Scheme 9, as known to those of ordinary skill in the art, isomers and analogs of intermediate 6-bromo substituted compounds 9-E can be prepared, for example, starting from analogs such as 7-bromo compounds. Examples prepared according to the general method of Scheme 9 include I-11, I-13, I-14 and I-16.

[0485]

[0486] Additional examples, including I-1 to I-10, I-12, I-15, and I-17 to I-23, were prepared according to the general method of Scheme 10. As in Scheme 9, the position of the R1 substituent can be changed by changing the starting material 9-A, such as replacing the illustrated 6-bromo compound 9-A with, for example, the corresponding 7-bromo isomer. The detailed process according to Scheme 10 and the methods disclosed herein is:

[0487] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepine-4(5H)-one (I-23)

[0488]

[0489] To a solution of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-7-bromo-2,3-dihydropyrido[3,2-b][1,4]oxazepine-4(5H)-one 1 (460 mg, 0.9 mmol) and 2-methylbut-3-yn-2-ol (0.2 mL, 174 mg, 2.1 mmol) in anhydrous DMF (5 mL) was added Pd(PPh3)4 (55 mg, 48 umol), CuI (17 mg, 89 umol) and N,N-diisopropylethylamine (0.78 mL, 580 mg, 4.55 mmol). The sealed reaction vessel was then evacuated, filled with argon (3x) and heated at 80°C for 3 h. The reaction mixture was then cooled to ambient temperature, concentrated under reduced pressure and purified by column chromatography eluting with 0→100% ethyl acetate hexanes. The desired fractions were combined and lyophilized to give (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6h-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepine-4(5H)-one as an off-white solid (380 mg, 82% yield).

[0490] Example 9

[0491] In this example, ADP-Glo ​​was used. TM Techniques for evaluating compounds of the present disclosure using biochemical assays.

[0492] ADP-Glo TM(Promega, Madison, WI, USA) reagents were thawed at ambient temperature. The kinase assay reagents were prepared by mixing the kinase assay buffer with the lyophilized kinase assay substrate.

[0493] Prepare a 500 mL stock volume of 5X reaction kinase buffer by mixing 1000 μL 1 M MgCl 2, 500 μL 1 M Tris-HCL pH 7.4, 0.5 mg / mL (25 mg) of BSA and 3475 μL distilled H 2 O. Prepare a 3 mL 2X working stock volume of reaction kinase buffer containing a final concentration of 100 μM DTT and 4 mM MnCl 2.

[0494] Thaw the components of RIPK1 enzyme (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 166 μM working stock ATP assay solution in 1X kinase reaction buffer (diluted from 2X buffer).

[0495] In a 96-well plate, compounds were serially diluted in DMSO from 250uM in 4-fold dilutions and then diluted 1:5 in 2X reaction buffer. 1.0uL of diluted compound was added to a 384-well plate in duplicate. 2μL of diluted active RIPK1 was added to a 384-well plate (not added to column 1), and 2X reaction buffer was added to column 1. 150nM AKT (Anaspec, Fremont, CA, USA) was combined with ATP working stock solution in equal volumes and 2uL / well was added to a 384-well plate. The final reaction volume was 5.0μL.

[0496] The plate was centrifuged quickly and the reaction was incubated at 30°C for 30 minutes. 5 μL ADP-GloTM was added to terminate the reaction. The plate was centrifuged quickly and the reaction was incubated at room temperature for 40 minutes. The kinase detection reagent was then added and incubated at room temperature for 30 minutes. The relative light units (RLU) of the kinase reaction were determined by luminescence (luminescence 0.1 s) using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA). Table 1 provides the IC values ​​obtained from this example. 50 value.

[0497]

[0498] Example 10

[0499] In this example, U937 and L929 cells were exposed to compounds of the disclosure and cell necrosis assays were performed to evaluate the activity of the compounds against human and murine RIP1.

[0500] U937 and L929 cells were obtained from American Type Culture Collection (Manassa, VA, USA). Both cells were maintained in logarithmic growth phase in complete RPMI 1640 medium (Sigma, ST Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis, MO, USA) at 37°C and 5% CO2. For necrosis assay, L929 cells were plated in 100 μL / well medium at 10K cells / well in Costar 96-well black transparent bottom plates (Fisher Scientific, Hampton, NH, USA) for 18h; on the day of the assay, U937 cells were plated in 50 μL / well medium containing 60uM zVAD-fmk (Lonza, Basel, Switzerland) at 50K cells / well. Medium was removed from L929 cells in 96-well plates and replaced with 50 μL / well new medium containing 40uM zVAD-fmk. Each compound of the present disclosure evaluated in this example was serially diluted 4-fold from 2.5 mM in DMSO and then diluted 1:125 in complete medium. 50 μL / well of 2x compound was then added to the cells in the plate. The cells were pre-incubated with the compound for 1 hour at 37°C and 5% CO2, and then 10 μL / well of 11x TNFa (Peprotech, Rocky Hill, NJ, USA) was added to give a final concentration of TNFa of 2 ng / mL. After TNFa stimulation for 18 hours at 37°C and 5% CO2, the cells were measured using a Wallac Victor2 photometer (PerkinElmer, Waltham, MA, USA) and The relative amount of necrotic cells was determined by luminescence using a luminescent cell viability reagent assay (Promega, Madison, WI, USA) (added according to the manufacturer's instructions). The results from this example are summarized in Table 2. This example establishes that embodiments of the compounds described herein have unexpectedly potent activity against human RIP1 and mouse RIP1, which allows them to be evaluated in an in vivo mouse model of the disease. These results can be used to determine safe and effective doses for humans.

[0501]

[0502]

[0503] *ND indicates that no activity was detected, or that the inhibition curve showed artifacts. This value does not necessarily indicate an inactive compound, but indicates that the experiment did not produce data for some reason. For example, insoluble compounds or other experimental artifacts can produce an "ND" value.

[0504] Embodiment 11

[0505] In this example, an acute hypothermia mouse model assay was used to evaluate the ability of compounds disclosed herein to inhibit TNF-α-induced hypothermia.

[0506] Female C57BL / 6 mice were randomized and weighed on day -1. On the day of the study (day 0), mice were given vehicle or test article by oral gavage. Fifteen minutes after oral administration of the test agent, each mouse was given an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor alpha (TNF-a, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured at hour 0 (before IP injection) and every hour via a rectal probe temperature measurement device. Three (3) hours after IP injection of TNF-a and zVAD / FMK, mice were euthanized by CO2 asphyxiation and blood was collected via cardiac puncture. Serum and plasma were harvested for determination of cytokine and compound levels, respectively. A separate group of mice (satellite mice) was included for determination of compound levels in plasma at the time of administration of TNFa / zVAD-FMK.

[0507] (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4H-1,2,4-triazole-3-carboxamide (WO 2014 / 125444), having the structure shown below, was used as a comparative compound and examined using a similar protocol as described in WO 2014 / 125444. According to WO 2014 / 125444, the comparative compound exhibited 93% inhibition at a dose of 30 mg / kg. In comparison, the compounds of the present disclosure achieved greater inhibition at lower doses using a similar test protocol as described above.

[0508]

[0509] Comparison Compounds

[0510] Certain embodiments of the present disclosure provide compounds (one or more) or compositions thereof that cross the blood-brain barrier. The disclosed compound and composition embodiments exhibit sufficient brain permeability as potential therapeutic agents for neurological diseases. Brain permeability can be assessed by evaluating the free brain / plasma ratio (Bu / Pu), as measured in in vivo pharmacokinetic studies in rodents. Other methods for assessing brain permeability are known to those of ordinary skill in the art. See, for example, Liu, X. et al., J. Pharmacol. Exp. Therap., 325: 349-56, 2008.

[0511] In view of the many possible embodiments to which the principles of the present disclosure may be applied, it should be recognized that the illustrated embodiments are merely preferred examples and should not be viewed as limiting. Instead, the scope of the present disclosure is defined by the following claims. We therefore claim as our invention all that falls within the scope and spirit of these claims.

Claims

1. Compounds having formula I Where X is C; Y is O; Depend on The ring system represented is L is -CH2-; Z is phenyl; m is 1; R 1 yes n is 1; R 2 is CH3; and R 4 It's chlorine.

2. The compound of claim 1, which is according to the formula:

3. A compound according to any one of claims 1 or 2, wherein the compound is selected from I-1: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-2: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-3: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((1-hydroxycyclopentyl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-4: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-4-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-5: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-3-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-6: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-7: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-(tert-butoxy)prop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-8: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-9: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-10: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-11: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-12: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-13: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-14: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-15: (S)-6-((3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-8-yl)ethynyl)-2-cyanopyridine; I-16: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazacycloheptatrien-4(5H)-one; I-17: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazacycloheptan-4(5H)-one; I-18: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-19: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-20: (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyrrolidin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-21: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-22: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; and I-23: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one.

4. A compound selected from: I-1: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-2: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-3: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((1-hydroxycyclopentyl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-4: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-4-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-5: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-3-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-6: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-7: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-(tert-butoxy)prop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-8: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-9: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-10: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-11: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-12: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-13: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-14: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-15: (S)-6-((3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-8-yl)ethynyl)-2-cyanopyridine; I-16: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazacycloheptatrien-4(5H)-one; I-17: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazacycloheptan-4(5H)-one; I-18: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-19: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-20: (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyrrolidin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-21: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-22: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; and I-23: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one.

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

6. A compound according to claim 5, which is:

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, and further comprising one or more pharmaceutically acceptable excipients or therapeutic agents.

8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease in a subject, wherein the subject has, or is suspected of having or developing a disease involving receptor-interacting protein-1 (RIP1) kinase.

9. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for treating a disease involving inflammation, necrosis, or both.

10. The use according to claim 9, wherein the disease is myelodysplastic syndrome.

11. The use according to claim 9, wherein the disease is atopic dermatitis, rheumatoid arthritis, or ankylosing spondylitis.

12. Use according to claim 9, wherein the disease is an inflammatory or immunoregulatory disorder.

13. Use according to claim 12, wherein the disease is an aging disorder.

14. Use according to claim 9, wherein the disease is amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease or Alzheimer's disease.

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