Heterocyclic RIP1 kinase inhibitors

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 the earlier filing dates of U.S. Provisional Application No. 62 / 897,223, filed on September 6, 2019, U.S. Provisional Application No. 62 / 932,404, filed on November 7, 2019, U.S. Provisional Application No. 63 / 001,016, filed on March 27, 2020, U.S. Provisional Application No. 63 / 004,290, filed on April 2, 2020, U.S. Provisional Application No. 63 / 004,301, filed on April 2, 2020, and U.S. Provisional 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 ("RIP1") kinase, 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 necroptotic cell death. Summary of the invention

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

[0006]

[0007] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof. With respect to Formula I, Ring B is a heteroaryl group and may be a monocyclic heteroaryl group. In some embodiments, Ring B is a 5-membered or 6-membered heteroaryl group and may be a pyrazolyl group or a pyridinyl group.

[0008] Each R 1 is independently halogen 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(Rf )2; R 2 YesR a ; R 3 YesR a and may be H; if present, each R 4 Independently R e ; and L is a heteroatom or R a , the condition is R a Not H or D.

[0009] 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 group; for each occurrence, 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; for each occurrence, 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 Substitution, or C 5-10 Aromatic groups, which may be 1, 2 or 3 R e Replace; for each occurrence, R d Independently H; C 1-6 Alkyl groups, which may be 1, 2 or 3 R eSubstitution 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 forms a 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; for each occurrence, 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 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 forms a C 2-6 Alkenyl group, C 3-6 Cycloalkyl groups, which may be replaced by one or more R e Substitution, or C 3-10 Heterocyclic rings, which may be replaced by one or more R e or acyl substitution.

[0010] In addition, with respect to Formula I, X is CH2 or O; Z is heteroaryl; m is 1, 2, 3, or 4; and n is 0, 1, or 2. In some embodiments, m is 1, and / or n is 0 or n is 1.

[0011] In some embodiments, R 2 It is C 1-6 alkyl, and may be CH3 or CD3.

[0012] In certain embodiments, n is 0, while in other embodiments, n is 1. In such embodiments, R 4 Can be C 1-6 Alkyl groups, such as methyl.

[0013] In certain embodiments, L is a heteroatom, such as O, but in other instances, L is C 1-6 Alkyl, such as CH2.

[0014] In some embodiments, Z can be a 6-membered heteroaryl group, and can be pyridyl, pyrimidinyl, or pyridazinyl. In any embodiment, Z can be unsubstituted or Z can be substituted, such as by halogen, C 1-6 Alkyl, C 1-6 In some embodiments, Z is , p is 0, 1, 2, 3, or 4, and if present, each R 5 Independently R e . Each R 5 independently can be OH, halogen, C 1-6 Alkyl, or C 1-6 haloalkyl, such as OH, CF3, methyl or fluorine. and / or in some embodiments, p is 1, but in other embodiments, p is 0.

[0015] And in any embodiment, the -LZ moiety can be (6-fluoropyridin-2-yl)methyl, (6-methylpyridin-2-yl)methyl, (2-methylpyridin-5-yl)oxy, (2-fluoropyridin-5-yl)oxy, pyridin-2-ylmethyl, (6-trifluoromethylpyridin-2-yl)methyl, (6-hydroxypyridin-2-yl)methyl, pyridin-3-ylmethyl, pyridazin-3-ylmethyl, (2-methylpyridin-5-yl)methyl, (2-fluoropyridin-5-yl)methyl, (2-fluoropyridin-3-yl)methyl, (2,6-difluoropyridin-3-yl)methyl, pyrimidin-2-ylmethyl, or pyridin-4-ylmethyl.

[0016] In some embodiments, Ring B is pyrazolyl and in some embodiments, at a ring nitrogen atom on Ring B, -N(R 3 )C(O)-moiety is attached to ring B.

[0017] At least one R 1 can be a halogen, such as Br, and / or at least one R 1 Can be -linker-R 6 In some embodiments, at least one R 1 is an 8- to 12-membered spiroheterocyclic group, C 1-10 Alkyl or C 2-10 And in certain embodiments, at least one R 1 yes

[0018]

[0019] and can be

[0020] .

[0021] One of ordinary skill will appreciate that all stereoisomers of compounds are included in Formula 1, including but not limited to compounds having the formula

[0022]

[0023] Or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof. In a particular embodiment of a compound according to formula I, the compound may have the formula as indicated below, including any and all stereoisomers thereof:

[0024]

[0025] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof.

[0026] Also disclosed herein are embodiments of compositions comprising one or more of the disclosed compounds. The composition may further comprise an excipient, a therapeutic agent, or a combination thereof.

[0027] Also disclosed herein are embodiments of methods of using the disclosed compounds, or compositions thereof. In some embodiments, the method may include administering one or more of the disclosed compounds, or compositions 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 pharmaceutically acceptable salt thereof, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or 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.

[0028] Also disclosed herein are embodiments of methods comprising contacting a receptor-interacting protein-1 (RIP1) kinase with one or more disclosed compounds or pharmaceutical compositions thereof. The method can be an in vitro method or an in vivo method, such as when the RIP1 kinase is in a subject.

[0029] The foregoing and other objects and features of the present disclosure will become more apparent from the following detailed description.

[0030] Detailed description

[0031] I. Definition of Terms

[0032] 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 other elements.

[0033] 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.

[0034] 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.

[0035] 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.

[0036]

[0037] 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.

[0038] If the R group is depicted as "floating" on the ring system, such as in the following group R 1 :

[0039]

[0040] 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.

[0041] When the group R is depicted as being present on a ring system containing a saturated carbon, such as in the following formula:

[0042]

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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(R 80 )2, haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 ,-OSO2R 70 ,-OSO3 - M + ,-OSO3R 70 , -P(O)(O - )2(M + )2,-P(O)(O - )2M 2+ , -P(O)(OR 70 ) - M + , -P(O)(OR 70 )2,-C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 ,-C(O)N(R 80 )2,-C(NR 70 )(R 80 )2,-OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80)2, -NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R 60 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 the compound of the present invention in ionized form and the other typical counterion such as chloride, or both ionized compounds can serve as the counterions of such a divalent alkaline earth (metal) ion, or doubly ionized compounds can serve as the 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 -pyrrolidyl, 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.

[0047] 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 ) - M + , -P(O)(OR 70 )2,-C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )N(R 80 )2,-OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70, -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R 60 , R 70 , R 80 and M+ is as previously defined. In independent embodiments, the substituent is not -O - M + , -OR 70 , -SR 70 , or -S - M + .

[0048] 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(NR70 )R 70 , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R 60 , R 70 , R 80 and M + is as defined previously.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] "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.

[0053] "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).

[0054] "Lower aliphatic" refers to a group containing 1 to 10 carbon atoms (C 1-10 ), such as 1 to 6 carbon atoms (C1-6 ), 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 ).

[0055] "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.

[0056] "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.

[0057] "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).

[0058] "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 attached 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 attached 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 and , where Rg YesR 70 , -C(O)R 70 , -C(O)OR 60 or -C(O)N(R 80 )2.

[0059] "Amide" refers to the group -N(R)acyl, where R is hydrogen, heteroaliphatic or aliphatic, such as alkyl, especially C 1-6 alkyl.

[0060] "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. For example 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.

[0061] "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.

[0062] "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.

[0063] "Carboxyl" refers to -CO2H.

[0064] "Carboxamide" refers to a -C(O)amino group.

[0065] "Carboxyl ester" or "carboxy ester" refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including aryl and heteroaryl).

[0066] "Carboxylate" refers to -C(O)O- or a salt thereof.

[0067] "Cyano" refers to the radical -CN.

[0068] "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.

[0069] "Halo", "halide" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0070] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CH2F, -CHF2 and -CF3.

[0071] "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.

[0072] "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.

[0073] "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 nitrogen, 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 invention, the corresponding pyridyl-N-oxide is included unless explicitly excluded or excluded by the 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.

[0074] "Hydroxy" refers to the group -OH.

[0075] "Nitro" refers to the radical -NO2.

[0076] "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.

[0077] "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 the dialkyl ester of phosphonoalkyl, such as, for example, -CH2P(O)(O-tert-butyl)2.

[0078] "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.

[0079] "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.

[0080] 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.

[0081] "Pharmaceutically acceptable carrier" refers to an excipient that serves 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 the pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0082] 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.

[0083] "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, e.g., 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.

[0084] 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.

[0085] "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 conversion in vivo may occur, for example, by hydrolysis or enzymatic conversion. 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 invention 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 invention 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 invention 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.

[0086] "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.

[0087] "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).

[0088] "Sulfanyl" refers to the radical or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic, (including both -S-aryl and -S-heteroaryl).

[0089] "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).

[0090] "Sulfonyl" refers to the radical: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including both -SO2aryl and -SO2heteroaryl).

[0091] 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:

[0092] (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;

[0093] (ii) inhibiting the disease or condition, such as arresting or slowing its progression;

[0094] (iii) alleviate the disease or condition, such as causing a decrease in symptoms or regression of the disease or condition or its symptoms; or

[0095] (iv) stabilizing the disease or condition.

[0096] 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.

[0097] 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.

[0098] 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 invention.

[0099] 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.

[0100] II. RIP1-active compounds and pharmaceutical compositions comprising RIP1-active compounds

[0101] A. Compounds

[0102] 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.

[0103] In some embodiments, the compounds of the present disclosure have a structure according to Formula I

[0104]

[0105] Or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will understand that compounds within the scope of Formula I also include stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs thereof, unless otherwise specified. With respect to Formula I, Ring B is a heteroaryl, and may be a monocyclic heteroaryl. In some embodiments, Ring B is a 5- or 6-membered heteroaryl. In some embodiments, Ring B is a 5- or 6-membered heteroaryl, wherein the heteroaryl 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 containing oxygen or sulfur ring atoms, such as oxazole, thiazole or isoxazole. In certain embodiments, Ring B is a pyrazolyl, and in other particular embodiments, Ring B is a pyridyl.

[0106] Each R 1 is independently halogen 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. In some embodiments, R 1 is halogen, such as fluorine, chlorine, bromine, or iodine, typically bromine. In certain other embodiments, each R 1 is independently -linker-R 6 .

[0107] R 2 YesR a In some embodiments, R 2 Is H or C 1-10 Aliphatic, such as H or C 1-6 alkyl, and in certain embodiments, R 2 It is C 1-6 Alkyl, such as CH3 or CD3.

[0108] R 3 YesR a In some embodiments, R 3 Is H or C 1-10 Aliphatic, such as H or C 1-6 alkyl, and in certain embodiments, R 3 It's H.

[0109] If present, each R 4 Independently R e and can be a halogen such as F, Cl, Br, or I, or C 1-10 Aliphatic, such as C 1-6 Alkyl, for example, methyl.

[0110] L is a heteroatom or R a , the condition is R a is not H or D. In some embodiments, L is oxygen or C 1-10 Alkyl, such as C 1-6 Alkyl, more particularly methylene (-CH2-).

[0111] X is CH2 or O.

[0112] Z is a heteroaryl group, and may be a monocyclic heteroaryl group.

[0113] m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3, and can be 1 or 2, and in certain embodiments, m is 1.

[0114] n is 0, 1 or 2, and can be 0 or 1.

[0115] For every existence, R a are independently H or D, except where L is R a 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.

[0116] 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)NRd 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.

[0117] 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 Substitution, or C 5-10 Aromatic groups, which may be 1, 2 or 3 R e replace.

[0118] 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 forms a 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.

[0119] 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.

[0120] 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 forms a C 2-6 Alkenyl group, C 3-6 Cycloalkyl groups, which may be replaced by one or more R e Substitution, or C 3-10 Heterocyclic rings, which may be replaced by one or more R e or acyl substitution.

[0121] In some embodiments, n is 0. In other embodiments, n is 1, and in such embodiments, R 4 Can be C 1-6 Alkyl groups, such as methyl.

[0122] In certain embodiments of Formula I, Ring B is pyridyl or pyrazolyl; L is a heteroatom or C 1-10 alkyl; Z is heteroaryl; each R 1 is a heterocyclic group, or C 1-10 Aliphatic; R 2 Is H or C 1-6 Alkyl; R 3 Yes H, C 1-6 alkyl; m is 1; and n is 0.

[0123] In any embodiment, Z can be 5-membered or 6-membered heteroaryl, such as 5-membered or 6-membered nitrogen-containing heteroaryl, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, or triazolyl. In certain such embodiments, Z is 6-membered heteroaryl, such as 6-membered nitrogen-containing heteroaryl, and can be pyridyl, pyrimidinyl or pyridazinyl.

[0124] In any embodiment, Z may be unsubstituted, or Z may be substituted, as defined herein. In some embodiments, Z is halogen, C 1-6 Alkyl, C 1-6 In certain embodiments, Z is unsubstituted or substituted with OH, CH 3 , F, or CF 3 .

[0125] In any embodiment, ring B can be a 5-membered heteroaryl ring having at least 1 ring nitrogen atom, such as 1, 2 or 3, preferably 1 or 2, more preferably 2 ring nitrogen atoms, and the remaining ring atoms are carbon. In some embodiments, at the ring nitrogen atom on ring B, -N(R 3 )C(O)-moiety is attached to ring B.

[0126] In some embodiments, Ring B is pyrazolyl and at a ring nitrogen atom on Ring B, -N(R 3 )C(O)-moiety is attached to ring B.

[0127] In some embodiments, X is O. And in some other embodiments, X is CH2.

[0128] In any embodiment, each R 1 independently may be 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.

[0129] 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,

[0130] -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,

[0131] -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2CH2NHC(O)(NH)NH2, , -CH2CH2CH2CH2NH2, -CH2CO2H, or CH2CH2CO2H.

[0132] In addition, about R 1 , at least one R 1 It can be an 8- to 12-membered spiroheterocyclic group, C 1-10 Alkyl or C 2-10 Alkyne. C 1-10 Alkyl or C 2-10 The alkyne may be linear, branched, and / or cyclic, and have one or two substituents. One substituent may be OH. In some embodiments, one substituent is oxetanyl, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, amino, or phosphate, and / or in some embodiments, one substituent is -OC(O)-R 8 . C 1-10 Alkyl or C 2-10 Alkynes may include linear and / or branched moieties and cyclic moieties, for example , or In.

[0133] In some embodiments, Z is , where each R, if any, 5 Independently R e , and p is 0, 1, 2, 3, or 4, typically 0, 1 or 2, more typically 0 or 1, and in some embodiments, p is 0 and in other certain embodiments, p is 1. In any embodiment, each R 5 independently can be OH, halogen, C 1-6 Alkyl, or C 1-6Haloalkyl, such as OH, CF3, methyl or fluorine. In some embodiments, p is 1, but in other embodiments, p is 0. And in certain embodiments, the -LZ moiety is (6-fluoropyridin-2-yl)methyl, (6-methylpyridin-2-yl)methyl, (2-methylpyridin-5-yl)oxy, (2-fluoropyridin-5-yl)oxy, pyridin-2-ylmethyl, (6-trifluoromethylpyridin-2-yl)methyl, (6-hydroxypyridin-2-yl)methyl, pyridin-3-ylmethyl, pyridazine-3-ylmethyl, (2-methylpyridin-5-yl)methyl, (2-fluoropyridin-5-yl)methyl, (2-fluoropyridin-3-yl)methyl, (2,6-difluoropyridin-3-yl)methyl, pyrimidin-2-ylmethyl, or pyridin-4-ylmethyl.

[0134] In some embodiments of Formula I, the compound can have a structure according to Formula I-1 or I-2:

[0135]

[0136] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof.

[0137] In some embodiments, the compound may have a structure according to one or more of the following formulas:

[0138]

[0139] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof.

[0140] Regarding Formulas I-1 to I-13, Ring B, L, X, Z, R 1 , R 2 , R 3 , R 4 , m and n, if present, are as defined herein for Formula I.

[0141] In any of the above embodiments of Formula I and / or Formulas I-1 to I-13, R 1 Can be selected from any of the following:

[0142]

[0143]

[0144]

[0145] And in certain embodiments, in Formula I and / or Formulas I-1 to I-13, R 1 Can be selected from any of the following:

[0146]

[0147]

[0148]

[0149] or .

[0150] In particular embodiments of formula I and / or formula I-1 to I-13, R 1 yes

[0151] .

[0152] And in other particular embodiments of formula I and / or formula I-1 to I-13, R 1 yes ,

[0153] .

[0154] In other embodiments of Formula I and / or Formulas I-1 to I-13, R 1 is a halogen, such as Br.

[0155] Certain disclosed exemplary compounds within the scope of one or more of Formula I, and I-1 to I-13 include:

[0156]

[0157]

[0158]

[0159]

[0160]

[0161] Exemplary compounds within the scope of one or more of Formulas I and I-1 to I-13 include:

[0162] I-1: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0163] I-2: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide;

[0164] I-3: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)oxy)picolinamide;

[0165] I-4: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)oxy)picolinamide;

[0166] I-5: (S)-4-((6-fluoropyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide;

[0167] I-6: (S)-4-((6-fluoropyridin-3-yl)oxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide;

[0168] I-7: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide;

[0169] I-8: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-2-ylmethyl)-1H-pyrazole-1-carboxamide;

[0170] I-9: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide;

[0171] I-10: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-hydroxypyridin-2-yl)methyl)picolinamide;

[0172] I-11: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)picolinamide;

[0173] I-12: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)picolinamide;

[0174] I-13: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide;

[0175] I-14: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxamide;

[0176] I-15: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide;

[0177] I-16: (S)-4-((6-fluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0178] I-17: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxamide;

[0179] I-18: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-2-ylmethyl)-1H-pyrazole-1-carboxamide;

[0180] I-19: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide;

[0181] I-20: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide;

[0182] I-21: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide;

[0183] I-22: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxamide;

[0184] I-23: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide;

[0185] I-24: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-fluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide;

[0186] I-25: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxamide;

[0187] I-26: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide;

[0188] I-27: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide;

[0189] I-28: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxamide;

[0190] I-29: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxamide;

[0191] I-30: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyrimidin-2-ylmethyl)-1H-pyrazole-1-carboxamide;

[0192] I-31: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyrimidin-2-ylmethyl)-1H-pyrazole-1-carboxamide;

[0193] I-32: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0194] I-33: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0195] I-34: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0196] I-35: (S)-N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide;

[0197] I-36: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide;

[0198] I-37: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0199] I-38: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide;

[0200] I-39: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide;

[0201] I-40: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide;

[0202] I-41: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((1-hydroxycyclobutyl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide;

[0203] I-42: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((2-fluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide;

[0204] I-43: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0205] I-44: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0206] I-45: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0207] I-46: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0208] I-47: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0209] I-48: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0210] I-49: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((2,6-difluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide; or

[0211] I-50: (S)-4-((2,6-difluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide.

[0212] Additional exemplary compounds within the scope of one or more of Formulas I and I-1 to I-13 include:

[0213]

[0214]

[0215]

[0216]

[0217] .

[0218] Further exemplary compounds within the scope of one or more of Formulas I and I-1 to I-13 include:

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226] .

[0227] B. Combinations of Therapeutic Agents

[0228] 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 invention can be used in combination with other therapeutic agents useful for the disorder or condition being treated. These other therapeutic agents can be administered simultaneously, sequentially in any order, 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 of a combination comprising 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.

[0229] 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.

[0230] 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.

[0231] These and other useful anticancer compounds are described in the Merck Index, 13th Ed. (O'Neil MJ et al.) Merck Publishing Group (2001) and Goodman and Gilman, The Pharmacological Basis of Therapeutics, 12th Edition, Brunton LL, Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0232] Among the CTLA 4 antibodies that may be used in combination with the inhibitors disclosed herein is ipilimumab, which is sold as YERVOY® by Bristol-Myers Squibb.

[0233] 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).

[0234] 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).

[0235] 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.

[0236] Additional anti-proliferative compounds that can be used in combination with the compounds of the invention 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.

[0237] 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.

[0238] 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.

[0239] In other embodiments, the second therapeutic agent may be selected from any of the following:

[0240] pain medication--morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromorphamide, dipipanone;

[0241] 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), polypeptides (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;

[0242] Antibodies - anti-TNF-α antibodies, e.g., infliximab (RemicadeTM), adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g., rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1 antibodies, e.g., anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, e.g., nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP -224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab;

[0243] Anticoagulants - warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin;

[0244] 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;

[0245] Immunosuppressants - mercaptopurine, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus, inosine monophosphate dehydrogenase inhibitors (IMPDH) such as mycophenolate, mycophenolate mofetil, mofetil) and azathioprine, as well as 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 Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune; tacrolimus is currently available from Fujisawa under the trade name Prograf; cyclosporine is currently available from Novartis under the trade name Sandimmune and from Abbott under the trade name Gengraf; IMPDH inhibitors such as mycophenolate mofetil are currently available from Novartis under the trade name Sandimmune and from Abbott under the trade name Gengraf. mofetil) and mycophenolic acid are currently available from Roche under the trade name Cellcept and from Novartis under the trade name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the trade name Imuran; and antibodies are currently available from Ortho Biotech under the trade name Orthoclone, from Novartis under the trade name Simulect (basiliximab) and from Roche under the trade name Zenapax (daclizumab); and

[0246] Guanylate cyclase-C receptor agonists or intestinal secretagogues, such as linaclotide, which is sold under the name Linzess.

[0247] 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.

[0248] III. Methods of preparing compounds

[0249] 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.

[0250]

[0251] Solution 1

[0252] Referring to Scheme 1, a protected amine precursor 100 can be coupled with an R1 group 102, which includes an "R6-linker" group as shown in Scheme 1, using a metal-mediated cross-coupling reaction 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., XPhos Pd 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 the Sonogoshira reaction. Metal-mediated cross-coupling can 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 can 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.

[0253] A representative example of the method steps shown in Scheme 1 is provided below in Scheme 2.

[0254]

[0255] Solution 2

[0256] 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.

[0257]

[0258] Solution 3

[0259] With reference 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, one 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.

[0260] Alternatively, urea-linked compounds can be prepared from the cross-coupling product 104 as illustrated in Scheme 4.

[0261]

[0262] Solution 4

[0263] With respect to Scheme 4, the cross-coupling product 104 is deprotected to provide an amine, which is then treated with phosgene or a phosgene substitute such as diphosgene or triphosgene to form an isocyanate 1500. Typically, the phosgene or phosgene substitute treatment is in the presence of a suitable base, such as a trialkylamine, such as triethylamine or diisopropylethylamine, and in an aprotic solvent such as toluene, hexane, or a chlorinated solvent such as dichloromethane. The isocyanate 1500 is then treated with an azocyclic ring 1502 to form a urea-linked compound 1504. The reaction is typically carried out in a suitable solvent and in the presence of a suitable base such as a solvent and / or base for the phosgene or phosgene substitute treatment. In some embodiments, the isocyanate 1500 is not separated after formation, and the azocyclic ring 1502 is simply added to the reaction mixture.

[0264] 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.

[0265]

[0266] Solution 5

[0267] With reference to Scheme 5, nitrogen is bubbled through a stirred solution of halide (1 equivalent), compound 700, 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. 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 the halide 700 or 706 is consumed. The dark reaction solution was treated by one of the following methods: a) post-treatment with ice water / organic solvent dilution; b) concentration to dryness followed by post-treatment after dilution with ice water / organic solvent; or c) the crude residue was diluted with ice water, sonicated, and the slurry was warmed to room temperature. The resulting gray / dark solid was collected by filtration, suction dried, dissolved in THF (20 mL), filtered through a celite® / silica gel pad, and the pad was washed with THF. Subsequently, the crude material was purified by reverse phase column chromatography or by normal phase silica gel flash column chromatography to provide the corresponding alkynyl-substituted analog (yield: 25-69%), compound 704.

[0268] IV. Methods of Using the Compounds

[0269] A. Disease / Disorder

[0270] 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 in which inhibition of RIP1 or a channel involving RIP1 is therapeutically useful. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds can be used to treat autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancer, ischemic conditions, red blood cell deficiency, lung and brain damage (e.g., induced by ischemia-reperfusion or cisplatin and / or cerebrovascular accident), and bacterial and viral infections.

[0271] In some embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof, can be used to treat or prevent allergic diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmyopathy, or asthma.

[0272] The disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof, may also be used to treat immunoregulatory disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunoregulatory disorders that may be treated with the compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, organ or tissue transplantation, graft-versus-host disease caused by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammation, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, exogenous 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, Crohn's disease, 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, fibrosing 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 (including systemic scleroderma),Antiphospholipid syndrome, Wegener's granuloma, Sjögren's syndrome, obesity, eosinophilic fasciitis, lesions of the gums, periodontium, alveolar bone, cementum, glomerulonephritis, male pattern baldness or senile alopecia (by preventing hair loss or providing hair initiation and / or promoting hair production and hair growth), muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs during storage, transplantation or ischemic diseases, endocrine dysfunction Toxin 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 scarring, corneal alkali burns, dermatitis erythema multiforme, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, environmental Diseases caused by pollution, aging, carcinogenesis, metastasis 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 hepatic necrosis, necrosis caused by toxins, viral hepatitis, shock, or hypoxia, hepatitis B, non-A, non-B hepatitis, cirrhosis, alcoholic liver disease, including alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic fatty liver NASH, autoimmune hepatobiliary disease, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, "acute-on-chronic" liver failure, chronic kidney disease, renal impairment / injury (e.g., caused by nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs, acute kidney injury), increased effects of chemotherapy, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, Parkinson's disease, trauma, or chronic bacterial infection.

[0273] In certain embodiments, the compounds of the invention are useful for treating neurological pain, including neuropathic pain and inflammation-induced pain.

[0274] In certain embodiments, the compounds are useful for treating interleukin-1 converting enzyme-associated febrile syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO-deficient syndrome, HOIL-1 deficiency, linear ubiquitination chain assembly complex deficiency syndrome, lysosomal storage diseases (e.g., Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, rock algal storage diseases, 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, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage diseases, Tay-Sachs disease, and Wolman disease).

[0275] In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof, are useful for treating and / or preventing rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, particularly pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia d and periodic fever syndromes, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout flares, pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0276] 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.

[0277] Proliferative diseases that can be treated by the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof include benign or malignant tumors, solid tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, gastric tumors, 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 or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, tumors of the neck and head, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermal hyperplasia, leukemia ... Dermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphomas such as Hodgkin and non-Hodgkins lymphomas, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, hematopoietic neoplasms such as the lymphomas listed above, MyD88 driven disorders (such as ABC diffuse large B-cell lymphoma (DLBCL) and Waldenström's macroglobulinemia), Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, or chronic lymphocytic leukemia), smoldering or indolent multiple myeloma, or hematologic malignancies (including leukemias, 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, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds disclosed herein can be used to treat drug-resistant malignancies, such as those resistant to JAK inhibitors, ibrutinib-resistant malignancies, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenström's macroglobulinemia.

[0278] 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.

[0279] As another example, rheumatoid arthritis (RA) usually 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 achieving the alleviation or improvement of any symptom usually associated with RA, 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").

[0280] The American College of Rheumatology (ACR) has developed criteria for defining improvement and clinical remission 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).

[0281] 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.

[0282] In one embodiment, the compounds disclosed herein can be used to slow the onset of the consequences of aging. For example, the compounds of the invention reduce the increased chronic inflammation associated with advanced age ("inflammaging"). Numerous symptoms and conditions are associated with inflammatory aging, and such conditions that can be treated with the compounds of the invention include, by way of example, neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, hematopoietic neoplasms, and myeloproliferative disorders. Additional conditions that can be treated or ameliorated by the compounds of the invention include those described in the following references: 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 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 aging of reproductive organs, see Li et al. eLife 2017;6:e27692 and Chaudhary et al. Journal of Biomedical Science (2019) 26:11, therefore the compounds of the present invention may be used to treat symptoms associated with aging, such as decreased testosterone levels, decreased fertility and prostate hyperplasia.

[0283] Additional diseases or disorders that can be treated and / or prevented using the compounds and compositions of the present invention include amyotrophic lateral sclerosis (ALS), autoimmune syndromes, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or habitual asthma, delayed asthma and airway hyperresponsiveness, allergic rhinitis, spondyloarthritis, ankylosing spondylitis, autoimmune hepatitis, autoimmune hepatobiliary disease, cerebrovascular accident, allergic disease, chronic obstructive Lung disease, emphysema, Friedreich's ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (polyQ) disease, Fahr's disease, Menke's disease, Wilson's disease, prion disorders, destructive bone disorders such as bone resorption diseases, multiple myeloma-related bone disorders; benign tumors, proliferative disorders, inflammatory and hyperproliferative skin disorders, epidermal hyperproliferation, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, dermatitis multiforme erythema, linear IgA bullous dermatitis, cement dermatitis, gingivitis, periodontitis, lesions of the gums, alveolar bone, cementum, sepsis, pancreatitis, lichen planus, pemphigus, bullous Pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, obesity, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burns, Behcet's disease, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Vogt-Koyanagi-Harada syndrome, hematological disorders, hematological malignancies, lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, nipple carcinoma, seminoma, melanoma, ABC diffuse large B-cell lymphoma (DLBCL), Waldenström's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or indolent multiple myeloma, leukemia, acute myeloid leukemia (AML), 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, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma,Intravascular large B-cell lymphoma, IL-1 driven disorders, MyD88 driven disorders, resistant malignancies such as JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies such as ibrutinib-resistant hematologic malignancies, ibrutinib-resistant CLL and ibrutinib-resistant Waldenström's macroglobulinemia, acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovascularization, hemangiomas such as infantile hemangiomas; sepsis, septic shock , shigellosis; migraine, bronchitis, gastric ulcer, necrotizing enterocolitis, intestinal damage associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 converting enzyme-associated febrile syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO-deficient 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, S Hoff disease, Schindler disease, sialic acid storage diseases, Tay-Sachs disease, Wolman disease, Huntington's disease, Parkinson's disease, neurodegenerative diseases, Huntington's disease, Parkinson's disease, metastatic melanoma, neurodegeneration associated with HIV infection and CMV retinitis, such as associated neurocognitive disorders or dementia, fibrotic conditions such as nonalcoholic steatohepatitis, steatohepatitis) and cardiac conditions such as ischemia reperfusion; allergies, 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, inflammatory reactions induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, rubella arthritis, acute synovitis,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, fibrotic lung, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgia due to infection, keloid formation, scar tissue formation, 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 infarction, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, angiogenesis, cardiac and renal reperfusion injury, ischemia-reperfusion injury of organs during storage, transplantation or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthase (syndase)-2, pemphigus vulgaris, autoimmune / polymyositis, dermatomyositis, vitiligo vulgaris, photoallergic sensitivity, ischemia-reperfusion reperfusion injury, ischemia reperfusion injury due to 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, systemic onset juvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), kidney transplantation, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), ARDS caused by COVID-19, post-infectious autoimmune disease, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO-deficiency syndrome (F-κ-B essential regulator gene (also known as IKKγ or IKKG) deficiency syndrome), solid organ malignancies, lysosomal storage diseases, glaucoma, retinal degenerative diseases, retinal local ischemia / reperfusion injury, renal ischemia-reperfusion injury, cataract, siderosis, retinitis pigmentosa, retinal degeneration,Retinal detachment, age-related macular degeneration, vitreous scarring, anthrax toxin-induced septic shock, LPS-induced cell death, transmissible encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic scleroderma, yellow spots, diabetic retinopathy, central halo choroidal dystrophy, BEST disease, adult yolk disease, pattern dystrophy dystrophy, myopic degeneration, central serous retinopathy, Stargardt's disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, toxic retinitis and light-induced toxicity, yellow spot edema, central halo choroidal dystrophy, BEST disease, adult yolk disease, pattern dystrophy dystrophy), optic nerve injury, optic neuritis, optic neuropathy, 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, cerebral ischemia, 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, interstitial kidney inflammation, obstruction, polycystic kidney disease), focal glomerulosclerosis, immune complex nephropathy, diabetic nephropathy, Goodpasture's syndrome, hepatocellular carcinoma, pancreatic cancer, urinary system cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostatic hyperplasia, renal cancer, kidney cancer, liver cancer, adrenal cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, neuroendometrial cancer Secretory carcinoma, CNS cancer, brain tumors (e.g., brain cancer, 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, Wilms tumor, trophoblastic tumor, epithelial neoplasia, gastric cancer, ovarian cancer, colorectal 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, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, colon cancer, colorectal adenoma, hemangiopericytoma, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, vulvar cancer, adrenal cortical carcinoma, ACTH-producing tumors, 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, 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), acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, "acute on chronic" liver failure, chronic kidney disease, renal damage / injury, renal damage / injury caused by nephritis, renal damage / injury caused by kidney transplantation, renal damage / injury caused by surgery, nephrotoxic drugs Renal impairment / injury caused by administration, increased chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, hypotension, diseases caused by histamine or leukotriene-C4 release, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxic diseases caused by pulmonary oxygen or drugs, congenital hypophosphatasia, fibromatosis, fibrous dysplasia, bone turnover, osteolytic bone disease, treatment of trauma after bone surgery, treatment of prosthetic joint surgery, treatment of plastic bone surgery, treatment of dental surgery, bone chemotherapy or bone radiotherapy, bone cancer, fragile plaque (fragile plaque) plaque), obstruction, occlusive obstruction, stenosis, coronary artery obstruction, peripheral arterial obstruction, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, post-operative graft occlusion, Guillain-Barre syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease,Autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoito's thyroiditis, myasthenia gravis, cold and warm agglutinin disease, Evan's syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoiesis, and combinations thereof. ,

[0284] 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.

[0285] B. Preparation and Administration

[0286] The pharmaceutical composition comprising one or more active compounds of the present invention can be prepared by any suitable method, such as mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing. The pharmaceutical composition can be formulated using one or more physiologically acceptable excipients (e.g., diluents, carriers, or auxiliary agents), one or more adjuvants, or a combination thereof, to provide a pharmaceutically usable product.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0294] 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.

[0295] 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 that are constructed with water or other suitable vehicles before use. Such liquid preparations may be prepared in a conventional manner with pharmaceutically acceptable excipients, such as: suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol, cremophore™ or fractionated vegetable oils); and preservatives (e.g., methylparaben or propylparaben or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents and sweeteners as desired.

[0296] Preparations for oral administration may be suitably formulated to give controlled release of the active compound, as is well known.

[0297] For buccal administration, the pharmaceutical compositions may take the form of tablets or lozenges formulated in conventional manner.

[0298] 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.

[0299] 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.

[0300] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray device includes the following ingredients: active compound (0.5-20 mg / mL); benzalkonium chloride (0.1-0.2 mg / mL); polysorbate 80 (TWEEN® 80; 0.5-5 mg / mL); sodium carboxymethylcellulose or microcrystalline cellulose (1-15 mg / mL); phenylethyl alcohol (1-4 mg / mL); and dextrose (20-50 mg / mL). The pH of the final suspension may be adjusted to about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

[0301] 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 (TWEEN® 80), 50 mM citrate and / or 0.9% sodium chloride.

[0302] For ocular administration, the active compound (one or more) can be formulated into solutions, emulsions, suspensions, etc. suitable for administration to the eye. Various 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] C. Dosage

[0309] 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.

[0310] 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.

[0311] 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.

[0312] 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 dosage can be calculated to achieve such circulating blood or serum concentrations of the active compound. The dosage can be calculated to achieve such circulating blood or serum concentrations, taking into account the bioavailability of a particular compound. Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and references cited therein, provide additional guidance on effective dosages.

[0313] 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.

[0314] 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 mentioned 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, discussing 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.

[0315] In some embodiments, tests suitable for determining the activity of RIP1 can be used. Such test methods can be used to evaluate the efficacy of the compound embodiments disclosed herein and / or can be used to determine the quantity / dose of the compound embodiments that can provide the desired efficacy. In some embodiments, the test can be an ADP-Glo™ test, which evaluates the ability of the 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 (necroptosis) tests, can be performed to determine the safe and effective doses of the compounds that can be used for in vivo studies. Using these whole cell tests, the activity of the compounds on human and / or mouse RIP1 can be evaluated in an in vitro context, which then allows a person of ordinary skill in the art to determine a safe and effective dose for in vivo use. Another test that can be used to evaluate the activity of the compound embodiments described herein for the treatment of diseases or conditions involving RIP1 is an acute hypothermic mouse model, which evaluates the ability of the compound 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.

[0316] 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, administered 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.

[0317] 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.

[0318] The pharmaceutical composition comprising one or more of the disclosed compounds generally comprises greater than 0 up to 99% of the disclosed one or more compounds, and / or other therapeutic agents (by total weight %). More representatively, the pharmaceutical composition comprising one or more of the disclosed compounds comprises 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.

[0319] 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.

[0320] V. Examples

[0321] Example 1

[0322] 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.

[0323]

[0324] Scheme 6A

[0325]

[0326] Option 6B

[0327] 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 of C(C6H5)3), 4.37 (1H, d, J 2.5 Hz, oxobenzoxazapine H-6), 4.70 (1H, dd, J 10.1, 7.5 Hz, oxobenzoxazapine H-8, 1H of C(C6H5)3). 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).

[0328] Example 2

[0329]

[0330] 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 bromooxazapine (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); 1Hnmr (400 MHz, CDCl3) δ 7.40-7.38 (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, 2.0 Hz, oxobenzoxazapine H-8), 6.96 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 6.95 (1H, d, J 2.5 Hz, oxobenzoxazapine H-6), 4.48 (1H, dd, J 10.0, 7.5 Hz, oxobenzoxazapine H-2 of 1H), 4.37 (1H, dd, J 11.5, 10.0 Hz, oxobenzoxazapine H-2 of 1H), 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] + .

[0331]

[0332] Deprotection of trityl: To a solution of trityl protected amine (0.079 g, 0.153 g, 1.0 eq) 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 eq). 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] + .

[0333] Example 3

[0334] This example provides a method for preparing N-substituted-4-[(heteroaryl)methyl]-1H-pyrazole-1-carboxamides according to Scheme 7 via intermediate pyrazole-1-carbonyl chloride formation (Scheme 1).

[0335]

[0336] Solution 7

[0337] To a stirred heterogeneous mixture of compound 1400 (1 eq.) and triphosgene (1.5 eq.) / CH2Cl2 (15 mL / mmol) at 0°C under nitrogen was added i-Pr2NEt (5-9 eq.) over time (15 min / mmol). The red reaction solution was stirred at 0°C for 1 h, warmed to room temperature (2 h), analyzed by LC / MS for consumption of 4-[(heteroaryl)methyl]-1H-pyrazole, and concentrated to dryness to provide 1402. The red semi-solid concentrate was added to 1404 or the corresponding amine or its salt (1 eq.) and DMAP (0.1 eq.) and cooled in an ice bath under nitrogen. CH2Cl2 (15 mL / mmol) was added to a flask, stirred for 15 min, and the stirred red solution was treated with i-Pr2NEt (5-9 eq.) over time (15 min / mmol). The ice bath was removed after 1 hour and the reaction solution was warmed to room temperature. Upon analysis of the progress of the reaction, the reaction solution was concentrated to dryness, diluted with water and subjected to extractive workup with EtOAc or CH2Cl2. Silica gel flash column chromatography of the crude concentrate provided the desired N-substituted-4-[(heteroaryl)methyl]-1H-pyrazole-1-carboxamides 1406 (yields: 20-75%).

[0338] Example 4

[0339] This example provides a method for preparing N-substituted-4-[(heteroaryl)methyl]-1H-pyrazole-1-carboxamides via intermediate isocyanate formation according to Scheme 8 (Scheme 2).

[0340]

[0341] Solution 8

[0342] i-Pr2NEt (10-15 equiv) was added to a stirred heterogeneous mixture of compound 1420, or its corresponding amine or its salt (1 equiv), and triphosgene (2.3 equiv) / CH2Cl2 (15 mL / mmol) at 0°C over time (20 min / mmol) under nitrogen. The light yellow reaction solution was stirred at 0°C for 1 h, warmed to room temperature (2 hours), analyzed for corresponding amine consumption by LC / MS, and concentrated to dryness. 4-[(heteroaryl)methyl]-1H-pyrazole hydrochloride 1424 (0.9 equiv) and DMAP (0.1 equiv) were added to the red semi-solid concentrate containing compound 1422 and cooled in an ice bath under nitrogen. CH2Cl2 (15 mL / mmol) was added to the flask, stirred for 15 minutes, and the stirred red solution was treated with i-Pr2NEt (10-15 equiv) over time (15 min / mmol). In 4-nitropropene 1 ...

[0343] Example 5

[0344] This example provides a method for preparing an embodiment of the disclosed alkynyl substituted compounds according to Scheme 9 (Scheme 3).

[0345]

[0346] Solution 9

[0347] Nitrogen was bubbled through a stirred solution of halide 1440 (1 equivalent) and CuI (0.1-0.2 equivalent), Pd(PPh3)4 (0.05-0.1 equivalent) / dry DMF (3-4 mL / mmol) in a bottle for 3 minutes. Subsequently, NEt3 (10 equivalents) was added to the dark reaction solution, followed by the addition of the corresponding alkyne 1442 (1.5-3 equivalents). 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 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 1444 (yields: 25-69%).

[0348] Example 6

[0349] This example provides a method for preparing embodiments of the disclosed 4-[(heteroaryl)methyl]-1H-pyrazole compounds according to Scheme 10.

[0350]

[0351] Solution 10

[0352] A stirred mixture of 1-boc-pyrazole-4-boronic acid pinacol ester 1450 (1 mmol), (chloromethyl)heteroarene (1.3 mmol) 1452, XPhos-Pd-G2 (0.05 mmol) and K2CO3 (3-4 mmol) / 1,4-dioxane:H2O (9:1, 10 mL / mmol) was degassed by high vacuum and backflushed with argon in a balloon in three cycles over a period of 5-10 minutes and heated at 70-75°C for 2-6 hours. The reaction mixture was cooled and concentrated to dryness. The crude residue was diluted with EtOAc (or CH2Cl2), water and saturated aqueous Na2CO3 solution (6 mL / mmol). The organic layer was separated and the aqueous layer was extracted with EtOAc (or CH2Cl2). The combined organic layers were washed with aqueous NaCl solution, stirred over anhydrous Na2SO4, and filtered through celite(R). After the filtrate is concentrated, the crude product is purified by silica gel chromatography to obtain tert-butyl 4-[(heteroaryl) methyl]-1H-pyrazole-1-carboxylate (yield 49-85%) 1454. 4.0N HCl / 1,4-dioxane (5-7 equivalents) are added to a stirred solution of 4-[(heteroaryl) methyl]-1H-pyrazole (1 equivalent) / CH2Cl2 (3-6 mL / mmol) at room temperature. The reaction mixture is stirred until tert-butyl 4-[(heteroaryl) methyl]-1H-pyrazole-1-carboxylate is exhausted and concentrated to dryness. The rough solid is sonicated in EtOAc (6-7 mL / mmol), filtered, washed on funnel with EtOAc, and suction dried for a short time. Thus, the collected semi-dried solid was further dried under high vacuum and gave 4-[(heteroaryl)methyl]-1H-pyrazole hydrochloride 1456 (80-98%) and used in the next step without further purification (purity >95%).

[0353] tert-Butyl 4-(pyridin-2-ylmethyl)-1H-pyrazole-1-carboxylate

[0354]

[0355] 1 H NMR (400 MHz, chloroform-d ) δ 8.49 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H), 7.89(q, J = 0.9 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 7.7, 1.9 Hz,1H), 7.15 - 6.99 (m, 2H), 3.94 (d, J = 0.9 Hz, 2H), 1.57 (s, 9H). LCMS: purity 95%, MS (m / e) 260 (M+H) + .

[0356] 2-((1H-pyrazol-4-yl)methyl)pyridine dihydrochloride

[0357]

[0358] LC / MS: purity 96%, MS (m / e) 160 (M-2HCl+H) + .

[0359] tert-Butyl 4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxylate

[0360]

[0361] 1 H NMR (400 MHz, chloroform- d ) δ 7.92 (q, J = 0.9 Hz, 1H), 7.62 (d, J = 0.9Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.00 (ddd, J = 7.7, 1.1, 0.5 Hz, 1H), 6.96- 6.89 (m, 1H), 3.96 (app m, 2H), 2.54 (s, 3H), 1.63 (s, 9H). LCMS: purity 94%, MS (m / e) 274 (M+H) + .

[0362] 2-((1H-pyrazol-4-yl)methyl)-6-methylpyridine dihydrochloride

[0363]

[0364] 1 H NMR (400 MHz, DMSO- d 6) δ 8.34 (t, J = 7.9 Hz, 1H), 8.23 ​​- 7.81 (brs, 2H), 7.75 (s, 1H), 7.72 (dt, J = 7.9, 0.9 Hz, 1H), 7.66 (dt, J = 7.9, 0.9Hz, 1H), 4.32 (s, 2H), 2.77 (s, 3H). LCMS: purity 94%, MS (m / e) 174 (M-2HCl+H) + .

[0365] tert-Butyl 4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxylate

[0366]

[0367] 1 H NMR (400 MHz, chloroform- d ) δ 7.94 (s, 1H), 7.69 (q, J = 7.9 Hz, 1H),7.61 (s, 1H), 7.00 (dd, J = 7.4, 2.4 Hz, 1H), 6.77 (dd, J = 8.2, 2.8 Hz, 1H),3.92 (s, 2H), 1.62 (s, 9H). LCMS: purity 98%, MS (m / e) 278 (M+H) + .

[0368] 2-((1H-pyrazol-4-yl)methyl)-6-fluoropyridine hydrochloride

[0369]

[0370] 1 H NMR (400 MHz, DMSO- d 6) δ 10.24 (br s, 2H), 7.89 (td, J = 8.4, 7.4Hz, 1H), 7.76 (s, 2H), 7.20 (ddd, J= 7.4, 2.7, 0.7 Hz, 1H), 6.98 (ddd, J =8.2, 2.8, 0.7 Hz, 1H), 3.91 (s, 2H). LCMS: purity 98%, MS (m / e) 178 (M-HCl+H) + .

[0371] tert-Butyl 4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxylate

[0372]

[0373] LC / MS: purity 92%, MS (m / e) 261 (M+H) + .

[0374] 3-((1H-pyrazol-4-yl)methyl)pyridazine dihydrochloride

[0375]

[0376] LC / MS: purity 92%, MS (m / e) 161 (M-2HCl+H) + .

[0377] tert-Butyl 4-((6-(Trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazole-1-carboxylate

[0378]

[0379] 1 H NMR (400 MHz, chloroform- d ) δ 7.99 (d, J = 0.9 Hz, 1H), 7.78 (t, J = 7.5Hz, 1H), 7.66 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H),4.08 (s, 2H), 1.63 (s, 9H). LCMS: purity 96%, MS (m / e) 328 (M+H) + .

[0380] 2-((1H-pyrazol-4-yl)methyl)-6-(trifluoromethyl)pyridine

[0381]

[0382] 1 H NMR (400 MHz, DMSO- d 6) δ 12.11 (br , 2H), 8.00 (tt, J = 7.8, 0.9Hz, 1H), 7.83 (s, 2H), 7.72 (d, J = 8.0, 2.4 Hz, 1H), 7.58 (dd, J = 8.0, 2.4Hz, 1H), 4.06 (s, 2H). 19 F NMR (376 MHz, DMSO- d 6) δ -66.47. LCMS: purity 96%, MS (m / e) 228 (M+H) + .

[0383] tert-Butyl 4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxylate

[0384]

[0385] LC / MS: purity 95%, MS (m / e) 260 (M+H) + .

[0386] 2-((1H-pyrazol-4-yl)methyl)pyridine dihydrochloride

[0387]

[0388] 1 H NMR (400 MHz, DMSO- d 6) δ 10.5 (br s, 3H), 8.88 - 8.83 (m, 1H), 8.79(d, J = 5.2 Hz, 1H), 8.47 (ddd, J = 8.1, 2.0, 1.3 Hz, 1H), 8.00 (ddd, J =8.1, 5.7, 0.7 Hz, 1H), 7.74 (s, 2H), 4.06 (2H). LCMS: purity 95%, MS (m / e) 160 (M-2HCl+H) + .

[0389] tert-Butyl 4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxylate

[0390]

[0391] LC / MS: purity 97%, MS (m / e) 260 (M+H) + .

[0392] 4-((1H-pyrazol-4-yl)methyl)pyridine dihydrochloride

[0393]

[0394] 1 H NMR (400 MHz, methanol- d 4) δ 8.82 - 8.72 (m, 2H), 8.16 (s, 2H), 8.04 -7.98 (m, 2H), 4.36 (s, 2H). LCMS: purity 98%, MS (m / e) 160 (M-2HCl+H) + .

[0395] Example 7

[0396] Scheme 11 provides a method for preparing 4-((6-methylpyridin-3-yl)oxy)picolinic acid.

[0397]

[0398] Solution 11

[0399] With respect to Scheme 11, cesium carbonate (1.1 eq) was added to a solution of 4-fluoro-2-cyanopyridine 90 (1.0 eq) and 6-methylpyridin-3-ol 92 (1.05 eq) in dimethylformamide. The reaction was heated to 80°C for 8 hours and cooled. The reaction was poured into ice water and 4-((6-methylpyridin-3-yl)oxy)-2-cyanopyridine 94 was isolated.

[0400] A mixture of 4-((6-methylpyridin-3-yl)oxy)-2-cyanopyridine 94 / hydrochloric acid (6M) was heated to 100°C for 8 hours. The reaction was cooled to room temperature and 4-((6-methylpyridin-3-yl)oxy)picolinic acid 96 was isolated.

[0401] Example 8

[0402] 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-((6-methylpyridin-3-yl)oxy)picolinamide according to Scheme 12.

[0403]

[0404] Solution 12

[0405] Dimethylformamide (80 mL) is added to a mixture of bromooxobenzoxazapine 1100 (8.36 g, 16.3 mmol, 1.0 equivalent) and cuprous iodide (0.31 g, 1.6 mmol, 0.1 equivalent). Argon is introduced by bubbling for 5 minutes to degas the mixture. Triethylamine (11.4 mL, 81.6 mmol, 5.0 equivalent) is added, followed by hydroxyethynyloxetane 1102 (3.20 g, 32.7 mmol, 2.0 equivalent) and tetrakis(triphenylphosphine)palladium (0.94 g, 0.8 mmol, 0.05 equivalent). The resulting brown solution is heated to 80 ° C for 4 hours. The reaction is 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) produced compound 1104 (6.18 g, 72%) as a yellow solid. 1H 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, 10.0Hz, 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).

[0406] 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 of the 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 (5M, 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 afford (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 (400 MHz, D6-DMSO) δ 7.51 (1H, d, J 2.0 Hz, oxobenzoxazapine H-6), 7.29 (1H, dd, J 8.0,2.0 Hz, oxobenzoxazapine H-8), 7.14 (1H, d, J 8.0 Hz,oxobenoxazapine H-9), 4.74 (2H, d, J 7.0 Hz, 2H of oxetane H-2, 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), 4.01 (1H, dd, J 11.5, 10.0 Hz, 1H), 3.59 (1H, dd, J 11.5, 7.5Hz, oxobenzoxazapine H-3), 3.28 (3H, s, NCH3); 13C nmr (100 MHz, D6-DMSO) δ 173.7, 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]+.

[0407] A solution of aminooxobenzoxazapine 1106 (1.0 equiv) in dimethylformamide was degassed by bubbling nitrogen for 5 minutes. 4-((6-methylpyridin-3-yl)oxy)picolinic acid 96 (1.0 equiv) was added and the solution was cooled to 0°C, then diisopropylethylamine (2.5 equiv) was added. HATU (1.1 equiv) was added portionwise and the reaction was stirred at 0°C for 1 hour and at room temperature for 15 hours. The reaction was poured into ice water and the product was isolated.

[0408] Example 9

[0409] Exemplary compounds and characterization data are provided below.

[0410] (S)-3-Amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one

[0411]

[0412] 1 H nmr (400 MHz, CDCl3) δ 7.24 (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, oxobenzoxazapine H-2 of 1H), 4.12 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.72 (1H, dd, J 11.5, 7.5 Hz, 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).

[0413] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-1)

[0414]

[0415] Route 3. 1 H NMR (400 MHz, chloroform- d ) δ 7.99 - 7.93 (m, 2H), 7.68 (td, J =8.2, 7.3 Hz, 1H), 7.55 (d, J = 0.8 Hz, 1H), 7.32 - 7.23 (m, 2H), 7.11 (d, J =8.8 Hz, 1H), 7.02 - 6.95 (m, 1H), 6.76 (dd, J = 8.2, 2.8 Hz, 1H), 4.86 (dt, J = 11.3, 7.2 Hz, 1H), 4.68 (dd, J = 9.8, 7.3 Hz, 1H), 4.29 (dd, J = 11.3, 9.8Hz, 1H), 3.91 (s, 2H), 3.41 (s, 3H), 1.61 (s, 6H). 19 F NMR (376 MHz, chloroform- d ) δ-66.98 (d, J = 8.2 Hz). LC / MS: purity 98%, MS (m / e) 478 (M+H) + .

[0416] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-2)

[0417]

[0418] Route 3. 1 H NMR (400 MHz, chloroform-d ) δ 7.95 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 0.9 Hz, 1H), 7.54 (d, J = 0.8 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.30 -7.23 (m, 2H), 7.14 - 7.07 (m, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 7.7Hz, 1H), 5.28 (s, 1H), 4.86 (dt, J = 11.3, 7.3 Hz, 1H), 4.67 (dd, J = 9.8,7.3 Hz, 1H), 4.29 (dd, J = 11.3, 9.8 Hz, 1H), 3.93 (s, 2H), 3.40 (s, 3H),2.52 (s, 3H), 1.61 (s, 6H). LC / MS: purity 98%, MS (m / e) 474 (M+H) + .

[0419] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)oxy)picolinamide (I-3)

[0420]

[0421] 1H nmr (400 MHz, CDCl3) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.47 (1H, d, J 5.5 Hz, pyH-6), 8.33 (1H, d, J 2.5 Hz, Me-pyH-2), 7.58 (1H, d, J 2.5 Hz, pyH-3), 7.34-7.26 (3H, m, oxobenzoxazapine H-6, H-8, Me-pyH-4), 7.23 (1H, d, J 8.5 Hz, Me-pyH-5), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.70 (1H, d, J 10.7 Hz, Me-pyH-10), 6.85 (1H, d, J 20.9 Hz, Me-pyH-11), 6.54 (1H, d, J 10.7 Hz, Me-pyH-12), (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.93 (2H, d, J 5.0 Hz, 2H of oxetane H-2, H-4), 4.80 (2H, d, J 6.5 Hz, 2H of oxetane H-2, H-4), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H, t, J 10.5 Hz, 1H of oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 2.59 (3H, s, pyCH3); m / z : 501[M+H] + (Measured value [M+H] + , 501.1776, C 27 H 24 N4O6 theoretical value [M+H] + 501.1769).

[0422] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)oxy)picolinamide (I-4)

[0423]

[0424] 1H nmr (400 MHz, CDCl3) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.47 (1H, d, J 5.5 Hz, pyH-6), 8.33 (1H, d, J 2.5 Hz, Me-pyH-2), 7.58 (1H, d, J 2.5 Hz, pyH-3), 7.32 (1H, dd, J 8.5, 3.0 Hz, Me-pyH-4), 7.29-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.22 (1H, d, J 8.5 Hz, Me-pyH-5), 7.12 (1H, d, J 9.0 Hz, Me-pyH-6), 7. oxobenzoxazapine H-9), 6.97 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, oxobenzoxazapine H-2 of 1H), 4.30 (1H, dd, J 11.0, 9.5 Hz, oxobenzoxazapine H-2 of 1H), 3.43 (3H, s, NCH3), 2.59 (3H, s, pyCH3), 1.63(6H, s, C(C H 3)2OH); m / z : 487 [M+H] + , 469 [M+H-H2O] + (Measured value [M+H] + , 487.1991,C 27 H 26 N4O5 theoretical value [M+H] + 487.1976).

[0425] (S)-4-((6-fluoropyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide (I-5)

[0426]

[0427] 1 H nmr (400 MHz, CDCl3) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.50 (1H, d, J 5.5 Hz, pyH-6), 8.05 (1H, dd, J 2.5, 1.0 Hz, F-pyH-2), 7.58 (1H, d, J 2.5 Hz,pyH-3), 7.54 (1H, ddd, J 9.0, 6.0, 3.0 Hz, F-pyH-4), 7.33-7.30 (2H, m, oxobenzoxazapine H-6, H-8), 7.16 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.02 (1H, dd, J 9.0, 3.5 Hz, F-pyH-5),6.98 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.94-4.92 (2H, m, 2H of oxetane H-2, H-4), 4.79 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.71 (1H, dd, J 10.0,7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s,NCH3), 2.95 (1H, s, OH); 19 F nmr (380 MHz, CDCl3) δ -70.4; m / z : 505 [M+H] + (Measured value [M+H] + , 505.1516, C 26 H 21 FN4O6 theoretical value [M+H] + 505.1518).

[0428] (S)-4-((6-fluoropyridin-3-yl)oxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide (I-6)

[0429]

[0430] 1 H nmr (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.50 (1H, d, J 5.5 Hz, pyH-3), 8.05 (1H, dd, J 3.0, 1.0 Hz, F-pyH-2), 7.58 (1H, d, J 2.5 Hz,pyH-3), 7.53 (1H, ddd, J 9.0, 6.0, 3.0 Hz, F-pyH-4), 7.29-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.02 (1H, dd, J 9.0, 3.0 Hz, F-pyH-5),6.98 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J 10.0, 7.5 Hz, oxobenzoxazapine H-2 of 1H), 4.29 (1H, dd, J 11.5, 10.0 Hz, oxobenzoxazapine H-2 of 1H), 3.43 (3H, s, NCH3), 1.62 (6H, s,C(C H 3)2OH); 19 F nmr (380 MHz, CDCl3) δ -70.4; m / z : 491 [M+H] + , 473 [M+H-H2O] + (Measured value [M+H] + , 491.1722, C 26 H 23FN4O5 theoretical value [M+H] + 491.1725).

[0431] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide (I-7)

[0432]

[0433] 1 H nmr (400 MHz, CDCl3) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.51 (1H, dd, J 5.0, 1.0 Hz, pyH-6), 7.95 (1H, d, J 1.0 Hz, pyH-3), 7.70 (1H, m, F-pyH-4),7.36 (1H, dd, J 5.0, 2.0 Hz, pyH-5), 7.31-7.28 (2H, m, oxobenzoxazapine H-6, H-8), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.00 (1H, dd, J 7.5, 2.0 Hz, F-pyH-3 or H-5), 6.79 (1H, dd, J 8.0, 2.5 Hz, F-pyH-3 or H-5), 5.05 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, dd, J 6.5, 4.0 Hz, 2H of oxetane H-2, H-4), 4.79 (2H, ddd, J 7.0, 2.0, 1.0 Hz, 2H of oxetane H-2, H-4), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.11 (2H, s, pyCH2py), 3.41 (3H, s, NCH3); 19F nmr (380 MHz, CDCl3) δ -66.6 (d, J 8.0 Hz); m / z : 503 [M+H] + (Measured value [M+H] + , 503.1724, C 27 H 23 FN4O5 theoretical value [M+H] + 503.1725).

[0434] ( S )- N -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b [1,4]oxazepine-3-yl)-4-(pyridin-2-ylmethyl)-1 H -Pyrazole-1-carboxamide (I-8)

[0435]

[0436] Route 3. 1 H NMR (400 MHz, chloroform- d ) δ 8.54 (d, J = 4.9 Hz, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.96 (s, 1H), 7.60 (td, J = 7.7, 1.9 Hz, 1H), 7.55 (s, 1H), 7.27 (d, J = 9.5 Hz, 1H), 7.25 (s, 1H), 7.13 (dt, J = 9.0, 5.0 Hz, 3H), 4.87(dt, J = 11.2, 7.2 Hz, 1H), 4.68 (dd, J = 9.8, 7.3 Hz, 1H), 4.30 (dd, J =11.3, 9.8 Hz, 1H), 3.99 (s, 2H), 3.41 (s, 3H), 2.10 (s, 1H), 1.62 (s, 6H). LC / MS: purity 97%, MS (m / e) 460 (M+H) + .

[0437] ( S )- N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b [1,4]oxazepine-3-yl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1 H -Pyrazole-1-carboxamide (I-9)

[0438]

[0439] Route 3. 1 H NMR (400 MHz, dichloromethane- d 2) δ 8.00 (q, J = 0.8 Hz, 1H), 7.91(d, J = 7.1 Hz, 1H), 7.82 (td, J = 7.8, 0.7 Hz, 1H), 7.62 (d, J = 0.9 Hz,1H), 7.58 - 7.53 (m, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H),7.30 (dd, J = 8.2, 2.0 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 4.86 (dt, J = 11.2,7.2 Hz, 1H), 4.71 (dd, J = 9.8, 7.3 Hz, 1H), 4.31 (dd, J = 11.3, 9.8 Hz, 1H), 4.08 (s, 2H), 3.41 (s, 3H), 1.60 (s, 6H). 19 F NMR (376 MHz, dichloromethane- d 2) δ -68.40. LC / MS: purity 95%, MS (m / e) 528 (M+H) + .

[0440] ( S )- N -(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b[1,4]oxazepine-3-yl)-4-((6-hydroxypyridin-2-yl)methyl)picolinamide

[0441] (I-10)

[0442]

[0443] 1 H nmr (400 MHz, CD3OD) δ 8.54 (1H, d, J 5.0 Hz, pyH-3), 7.51 (1H, d,J 2.0 Hz, oxobenzoxazapine H-6), 7.49 (1H, dd, J 9.0,7.0 Hz, (OH)-pyH-4), 7.42 (1H, dd, J 5.0, 2.0 Hz, pyH-5), 7.37 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.93 (1H, br d, J 1.0 Hz, pyH-3), 7.20 (1H, d, J 8.5 Hz, pyH-9), oxobenzoxazapine H-9), 6.40 (1H, d, J 9.0 Hz, (OH)-pyH-3 or H-5), 6.20 (1H,d, J 7.0 Hz, (OH)-pyH-3 or H-5), 5.01 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.89-4.87 (2H, m, 2H of oxetane H-2, H-4), 4.71 (2H, d, J 6.5 Hz, 2H of oxetane H-2, H-4), 4.63 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.41 (1H, dd, J 11.5, 10..0Hz, 1H of oxobenzoxazapine H-2), 3.98 (2H, s, pyCH2(OH)-py), 3.41 (3H, s, NCH3); m / z : 501 [M+H] + (Measured value [M+H] + , 501.1776, C 27 H24 N4O6 theoretical value [M+H] + 501.1769).

[0444] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)picolinamide (I-11)

[0445]

[0446] 1 H nmr (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.49 (1H, d, J 5.0 Hz, pyH-6), 7.97 (1H, d, J 1.0 Hz, pyH-3), 7.48 (1H, t, J 8.0 Hz, Me-pyH-4), 7.33 (1H, dd, J 5.0, 1.5 Hz, pyH-5), 7.29-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.01 (1H, d, J 8.0 Hz, Me-pyH-3 or H-5), 6.88 (1H,d, J 8.0 Hz, Me-pyH-3 or H-5), 5.05 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.16 (2H, s, pyCH2py), 3.42 (3H, s,NCH3), 2.53 (3H, s, pyCH3), 1.62 (6H, s, C(CH3)2OH); m / z : 485 [M+H] + , 467 [M+H-H2O] + (Measured value [M+H]+ , 485.2182, C 28 H 28 N4O4 theoretical value [M+H] + 485.2183).

[0447] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)picolinamide (I-12)

[0448]

[0449] 1H nmr (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.49 (1H, d, J Hz, pyH-6), 7.96 (1H, br d, J 1.0 Hz, pyH-3), 7.49 (1H, t, J 7.5 Hz, MepyH-4), 7.33 (1H, dd, J 5.0, 2.0 Hz, pyH-5), 7.31-7.29 (2H, m, oxobenzoxazapine H-6, H-8), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.01 (1H, d, J 1.0 Hz, pyH-10), 7.5 Hz, MepyH-3 or H-5), 6.89 (1H, d, J 7.5 Hz, MepyH-3 or H-5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.94-4.92 (2H, m, 2H of oxetane H-2, H-4), 4.80 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.71 (1H, dd, J 9.5, 7.5 Hz, oxobenzoxazapine H-2), 4.31 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.16 (2H, s, pyCH2py), 3.42 (3H, s, NCH3), 2.53 (3H, s, pyCH3); m / z : 499 [M+H] + (Measured value [M+H] + , 499.1972,C 28 H 26 N4O5 theoretical value [M+H] + 499.1976).

[0450] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide (I-13)

[0451]

[0452] 1 H nmr (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.52 (1H, d, J 5.0 Hz, pyH-6), 7.96 (1H, d, J 1.0 Hz, pyH-3), 7.70 (1H, q, J 8.0 Hz, F-pyH-4), 7.36 (1H, dd, J 5.0, 3.0 Hz, pyH-5), 7.29-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.00 (1H, dd, J 7.5, 2.5 Hz, F-pyH-3 or H-5), 6.80 (1H, dd, J 8.0, 3.0 Hz, F-pyH-3 or H-5), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.13, 10 (2H, 2d AB system, J11.0 Hz, pyCH2py), 3.42 (3H, s, NCH3), 1.62 (6H, s, C(C H 3)2OH); m / z : 489 [M+H] + (Measured value [M+H] + , 489.1944, C 27 H 25 FN4O4 theoretical value [M+H] + 489.1933).

[0453] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxamide (I-14)

[0454]

[0455] Route 3. 1 H NMR (400 MHz, dichloromethane- d 2) δ 8.53 - 8.42 (app m, 2H), 7.95 -7.87 (m, 2H), 7.56 - 7.49 (m, 2H), 7.32 (d, J = 1.9 Hz, 1H), 7.31 - 7.22 (m,2H), 7.14 (d, J = 8.2 Hz, 1H), 4.86 (dt, J = 11.2, 7.2 Hz, 1H), 4.70 (dd, J =9.8, 7.3 Hz, 1H), 4.31 (dd, J = 11.2, 9.8 Hz, 1H), 3.84 (s, 2H), 3.40 (s,3H), 1.60 (s, 6H). LC / MS: purity 98%, MS (m / e) 442 (M-H2O+H) + .

[0456] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (I-15)

[0457]

[0458] 1 H NMR (400 MHz, dichloromethane- d 2) δ 8.34 (d, J = 2.4 Hz, 1H), 7.89 (d, J =7.1 Hz, 1H), 7.87 (q, J = 0.9 Hz, 1H), 7.50 (d, J= 0.9 Hz, 1H), 7.39 (dd, J = 8.0, 2.4 Hz, 1H), 7.33 (dd, J = 2.0, 0.4 Hz, 1H), 7.30 (dd, J = 8.2, 2.0Hz, 1H), 7.16 (dd, J = 8.2, 0.4 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 4.86 (dt, J = 11.2, 7.2 Hz, 1H), 4.70 (dd, J = 9.8, 7.3 Hz, 1H), 4.31 (dd, J = 11.2,9.8 Hz, 1H), 3.79 (s, 2H), 3.41 (s, 3H), 2.49 (s, 3H), 1.60 (s, 6H). LCMS: purity 97%, MS (m / e) 474 (M+H) + .

[0459] (S)-4-((6-fluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-16)

[0460]

[0461] 1 H NMR (400 MHz, chloroform- d ) δ 8.08 - 8.03 (m, 1H), 7.97 (d, J = 7.2 Hz,1H), 7.87 (q, J = 0.9 Hz, 1H), 7.60 - 7.50 (m, 1H), 7.45 (d, J = 0.9 Hz, 1H),7.31 - 7.24 (m, 2H), 7.12 (d, J = 8.7 Hz, 1H), 6.86 (ddd, J = 8.4, 3.0, 0.6Hz, 1H), 4.86 (dt, J= 11.3, 7.2 Hz, 1H), 4.68 (dd, J = 9.8, 7.3 Hz, 1H),4.30 (dd, J = 11.3, 9.8 Hz, 1H), 3.80 (s, 2H), 3.41 (s, 3H), 2.02 (s, 1H), 1.61 (s, 6H). 19 F NMR (376 MHz, chloroform- d ) δ -70.88 (d, J = 5.9 Hz). LCMS: purity 96%, MS (m / e) 478 (M+H) + .

[0462] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxamide (I-17)

[0463]

[0464] Route 3. 1 H NMR (400 MHz, dichloromethane- d 2) δ 9.07 (d, J = 4.8 Hz, 1H), 8.01(s, 1H), 7.91 (d, J = 7.1 Hz, 1H), 7.61 (s, 1H), 7.45 (dd, J = 8.9, 4.8 Hz,1H), 7.39 - 7.27 (m, 3H), 7.15 (d, J = 8.2 Hz, 1H), 4.86 (dt, J = 10.8, 7.1Hz, 1H), 4.70 (dd, J = 9.7, 7.3 Hz, 1H), 4.31 (t, J = 10.5 Hz, 1H), 4.22 (s,2H), 3.41 (s, 3H), 1.60 (s, 6H). LC / MS: purity 95%, MS (m / e) 443 (M-H2O+H) + .

[0465] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-2-ylmethyl)-1H-pyrazole-1-carboxamide (I-18)

[0466]

[0467] Route 2. 1 H NMR (400 MHz, chloroform- d ) δ 8.54 (dt, J = 4.6, 1.6 Hz, 1H),7.99 - 7.92 (m, 2H), 7.60 (td, J = 7.7, 1.9 Hz, 1H), 7.55 (d, J = 0.8 Hz,1H), 7.39 - 7.31 (m, 2H), 7.14 (t, J = 6.2 Hz, 2H), 7.07 (dd, J = 8.2, 0.6Hz, 1H), 4.89 (dt, J = 11.2, 7.3 Hz, 1H), 4.67 (dd, J = 9.8, 7.3 Hz, 1H),4.30 (dd, J = 11.3, 9.8 Hz, 1H), 3.99 (s, 2H), 3.41 (s, 3H). LC / MS: purity 98%, MS (m / e) 457 (M+H) + .

[0468] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-19)

[0469]

[0470] Route 2 1 H NMR (400 MHz, methanol- d 4) δ 8.33 (t, J = 8.0 Hz, 1H), 8.16 (q, J = 0.8 Hz, 1H), 7.72 (d, J= 8.6, 2.3 Hz, 1H), 7.69 (d, J = 0.8 Hz, 1H),7.63 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 8.6, 2.3Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 4.86 (dd, J = 7.9, 3.5 Hz, 1H), 4.58 (dd, J = 9.9, 7.5 Hz, 1H), 4.45 (ddd, J = 11.1, 9.9, 1.1 Hz, 1H), 4.26 (s, 2H),3.38 (s, 3H), 2.75 (s, 3H). LC / MS: purity 98%, MS (m / e) 471 (M+H) + .

[0471] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-20)

[0472]

[0473] Route 2 1 H NMR (400 MHz, chloroform- d ) δ 7.97 (d, J = 1.0 Hz, 1H), 7.94 (d, J = 7.3 Hz, 1H)., 7.68 (td, J = 8.2, 7.3 Hz, 1H), 7.55 (d, J = 0.8 Hz, 1H),7.38 - 7.30 (m, 2H), 7.06 (dd, J = 8.1, 0.6 Hz, 1H), 6.98 (dd, J = 7.4, 2.4Hz, 1H), 6.76 (dd, J = 8.2, 2.8 Hz, 1H), 4.87 (dt, J= 11.2, 7.3 Hz, 1H),4.66 (dd, J = 9.8, 7.4 Hz, 1H), 4.29 (dd, J = 11.3, 9.8 Hz, 1H), 3.91 (s, 2H), 3.40 (s, 3H). 19 F NMR (376 MHz, chloroform- d ) δ -66.96 (d, J = 8.0 Hz). LC / MS: purity 98%, MS (m / e) 475 (M+H) + .

[0474] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-21)

[0475]

[0476] Route 2 1 H NMR (400 MHz, dichloromethane- d 2) δ 8.00 (q, J = 0.9 Hz, 1H), 7.89(d, J = 7.1 Hz, 1H), 7.82 (td, J = 7.8, 0.7 Hz, 1H), 7.62 (d, J = 0.8 Hz,1H), 7.59 - 7.53 (m, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.11(d, J = 8.5 Hz, 1H), 4.88 (dt, J = 11.2, 7.3 Hz, 1H), 4.70 (dd, J = 9.8, 7.3Hz, 1H), 4.30 (dd, J = 11.3, 9.8 Hz, 1H), 4.08 (s, 2H), 3.41 (s, 3H). 19 F NMR (376 MHz, dichloromethane- d2) δ -68.40. LC / MS: purity 95%, MS (m / e) 525 (M+H) + .

[0477] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxamide (I-22)

[0478]

[0479] Route 2 1 H NMR (400 MHz, dichloromethane- d 2) δ 8.49 (d, J = 2.3 Hz, 1H), 8.47(dd, J = 4.9, 1.6 Hz, 1H), 7.93 - 7.84 (m, 2H), 7.58 - 7.53 (m, 1H), 7.52 (d, J = 0.9 Hz, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.5, 2.3 Hz, 1H),7.27 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 4.87 (dt, J =11.3, 7.3 Hz, 1H), 4.70 (dd, J = 9.8, 7.4 Hz, 1H), 4.30 (dd, J = 11.3, 9.8Hz, 1H), 3.86 (s, 2H), 3.41 (s, 3H). LC / MS: purity 98%, MS (m / e) 457 (M+H) + .

[0480] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (I-23)

[0481]

[0482] 1 H NMR (400 MHz, chloroform- d ) δ 8.35 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 7.2Hz, 1H), 7.85 (app q, J = 0.9 Hz, 1H), 7.45 (d, J = 0.9 Hz, 1H), 7.38 - 7.31(m, 3H), 7.07 (app dd, J = 7.9, 0.9 Hz, 2H), 4.87 (dt, J = 11.3, 7.3 Hz, 1H),4.66 (dd, J = 9.8, 7.4 Hz, 1H), 4.29 (dd, J = 11.3, 9.8 Hz, 1H), 3.76 (s,2H), 3.40 (s, 3H), 2.51 (s, 3H). LC / MS: purity 94%, MS (m / e) 472 (M+H) + .

[0483] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-fluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (I-24)

[0484]

[0485] 1 H NMR (400 MHz, chloroform- d ) δ 8.06 (ddd, J = 2.6, 1.2, 0.6 Hz, 1H), 7.95(d, J = 7.2 Hz, 1H), 7.87 (q, J = 0.9 Hz, 1H), 7.60 - 7.51 (m, 1H), 7.45 (d, J = 0.9 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.11 - 7.03 (m, 1H), 6.86 (ddd, J =8.3, 3.0, 0.7 Hz, 1H), 4.87 (dt,J = 11.3, 7.3 Hz, 1H), 4.67 (dd, J = 9.8,7.4 Hz, 1H), 4.29 (dd, J = 11.3, 9.8 Hz, 1H), 3.81 (s, 2H), 3.41 (s, 3H). 19 FNMR (376 MHz, chloroform- d ) δ -70.85 (d, J = 5.7 Hz). LCMS: purity 96%, MS (m / e) 475(M+H) + .

[0486] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxamide (I-25)

[0487]

[0488] Route 2 1 H NMR (400 MHz, dichloromethane- d 2) δ 9.06 (dd, J = 4.8, 1.7 Hz,1H), 8.02 (q, J = 0.9 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 0.9 Hz,1H), 7.48 - 7.31 (m, 4H), 7.11 (d, J = 8.6 Hz, 1H), 4.88 (dt, J = 11.2, 7.3Hz, 1H), 4.70 (dd, J = 9.8, 7.3 Hz, 1H), 4.30 (dd, J = 11.3, 9.8 Hz, 1H),4.22 (d, J = 0.8 Hz, 2H), 3.41 (s, 3H). LC / MS: purity 97%, MS (m / e) 458 (M+H) + .

[0489] (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide (I-26)

[0490]

[0491] 1 H nmr (400 MHz, CDCl3) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.52 (1H, dd, J 5.0, 0.5 Hz, pyH-6), 8.11 (1H, dt, J 5.0, 1.0 Hz, FpyH-4), 7.92 (1H, br s,pyH-3), 7.55 (1H, ddd, J 9.5, 7.5, 2.0 Hz, FpyH-6), 7.31-7.26 (3H, m, pyH-5, oxobenzoxazapine H-6, H-8), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.15-7.12 (1H, m, FpyH-5), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, dd, J 6.5, 4.0 Hz, oxetane H-2, 2H of H-4), 4.80-4.48 (2H, m, 2H of oxetane H-2, H-4), 4.71 (1H, dd, J 9.5, 7.5 Hz, oxobenzoxazapine H-2 1H), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.02 (2H, s, pyCH2Fpy), 3.41 (3H, s, NCH3); 19 F nmr (380 MHz, CDCl3) δ -71.1 (d, J 9.5 Hz); m / z : 503 [M+H] + (Measured value [M+H] + ,503.1746, C 27 H23 FN4O5 theoretical value [M+H] + 503.1725).

[0492] (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide (I-27)

[0493]

[0494] 1 H nmr (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.52 (1H, d, J 5.0 Hz, pyH-6), 8.11 (1H, br d, J 4.5 Hz, FpyH-6), 7.92 (1H, d, J 1.0 Hz,pyH-3), 7.54 (1H, ddd, J 9.5, 7.5, 2.0 Hz, FpyH-4), 7.28-7.25 (3H, m, pyH-5,oxobenzoxazapineH-6, H-8), 7.15-7.11 (2H, m, FpyH-5, oxobenzoxazapine H-9), 5.03 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.02 (2H, s, pyCH2Fpy),3.41 (3H, s, NCH3), 1.61 (6H, s, C(C H 3)2OH); 19 F nmr (380 MHz, CDCl3) δ -71.1(d, J 9.5 Hz); m / z : 489 [M+H] + , 471 [M+H-H2O] + (Measured value [M+H] +, 489.1938,C 27 H 25 FN4O4 theoretical value [M+H] + 489.1933).

[0495] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxamide (I-28)

[0496]

[0497] 1 H NMR (400 MHz, dichloromethane- d 2) δ 8.52 - 8.46 (m, 2H), 7.93 (q, J = 0.9Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.52 (d, J = 0.9 Hz, 1H), 7.43 (d, J = 2.3Hz, 1H), 7.39 (dd, J = 8.5, 2.3 Hz, 1H), 7.17 - 7.13 (m, 2H), 7.12 (d, J =8.5 Hz, 1H), 4.88 (dt, J = 11.1, 7.2 Hz, 1H), 4.70 (dd, J = 9.8, 7.4 Hz, 1H),4.31 (dd, J = 11.3, 9.8 Hz, 1H), 3.85 (s, 2H), 3.41 (s, 3H). LC / MS: purity 99%, MS (m / e) 457 (M+H) + .

[0498] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxamide (I-29)

[0499]

[0500] 1H NMR (400 MHz, dichloromethane- d 2) δ 8.53 (s, 2H), 7.96 - 7.90 (m, 2H), 7.51 (d, J = 0.8 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.28 (dd, J = 8.3, 1.9Hz, 1H), 7.18 - 7.11 (m, 3H), 4.87 (dt, J = 11.2, 7.2 Hz, 1H), 4.71 (dd, J =9.7, 7.3 Hz, 1H), 4.32 (dd, J = 11.3, 9.8 Hz, 1H), 3.84 (s, 2H), 3.40 (s,3H), 1.60 (s, 6H). LC / MS: purity 98%, MS (m / e) 460 (M+H) + .

[0501] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyrimidin-2-ylmethyl)-1H-pyrazole-1-carboxamide (I-30)

[0502]

[0503] 1 H NMR (400 MHz, dichloromethane- d 2) δ 8.65 (d, J = 4.9 Hz, 2H), 8.04 (app q, J = 0.9 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.5, 2.3 Hz, 1H), 7.15 (t, J = 4.9 Hz, 1H),7.09 (d, J = 8.5 Hz, 1H), 4.87 (dt, J= 11.2, 7.3 Hz, 1H), 4.68 (dd, J = 9.8,7.4 Hz, 1H), 4.30 (dd, J = 11.3, 9.8 Hz, 1H), 4.13 (s, 2H), 3.39 (s, 3H).LCMS: purity 96%, MS (m / e) 457 / 459 (M+H) + .

[0504] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyrimidin-2-ylmethyl)-1H-pyrazole-1-carboxamide (I-31)

[0505]

[0506] 1 H NMR (400 MHz, chloroform- d ) δ 8.66 (d, J = 4.9 Hz, 2H), 8.05 (app q, J =0.8 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.25 (dd, J = 4.8, 1.9 Hz, 2H), 7.14 (t, J = 4.9 Hz, 1H), 7.12 - 7.08 (m, 1H), 4.85 (dt, J = 11.3, 7.3 Hz, 1H), 4.66 (dd, J = 9.8, 7.3 Hz, 1H), 4.28 (dd, J = 11.3,9.8 Hz, 1H), 4.13 (s, 2H), 3.39 (s, 3H), 2.02 (s, 1H), 1.60 (s, 6H). LCMS: purity 99%, MS (m / e) 461 (M+H) + .

[0507] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-32)

[0508]

[0509] 1 H NMR (400 MHz, dichloromethane- d 2) δ 7.97 (app q, J = 0.9 Hz, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.72 (td, J = 8.3, 7.4 Hz, 1H), 7.59 (d, J = 0.8 Hz, 1H),7.38 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 8.2, 2.0 Hz, 1H), 7.18 (d, J = 8.2Hz, 1H), 7.05 (ddd, J = 7.4, 2.6, 0.7 Hz, 1H), 6.78 (app dd, J = 8.1, 2.9 Hz,1H), 4.93 - 4.82 (m, 3H), 4.76 - 4.67 (m, 3H), 4.32 (dd, J = 11.3, 9.8 Hz,1H), 3.93 (s, 2H), 3.41 (s, 3H), 2.71 (s, 1H). 19 F NMR (376 MHz, dichloromethane- d 2)δ -68.27 (d, J = 8.2 Hz). LCMS: purity 98%, MS (m / e) 492 (M+H) + .

[0510] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-33)

[0511]

[0512] 1 H NMR (400 MHz, dichloromethane- d 2) δ 7.97 (app q, J = 0.8 Hz, 1H), 7.89 (d, J = 7.1 Hz, 1H), 7.72 (td, J = 8.3, 7.4 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H),7.35 - 7.31 (m, 2H), 7.16 (dd, J = 8.2, 0.5 Hz, 1H), 7.05 (ddd, J = 7.4, 2.5,0.7 Hz, 1H), 6.82 - 6.73 (app m, 1H), 4.86 (dt, J = 11.3, 7.2 Hz, 1H), 4.70(dd, J = 9.8, 7.3 Hz, 1H), 4.31 (dd, J = 11.3, 9.8 Hz, 1H), 3.93 (s, 2H), 3.92 - 3.86 (m, 2H), 3.68 (ddd, J = 11.8, 9.0, 2.9 Hz, 2H), 3.41 (s, 3H), 2.22 (s, 1H), 2.04 - 1.98 (m, 2H), 1.84 (ddd, J = 13.0, 9.1, 4.0 Hz, 2H). 19 FNMR (376 MHz, dichloromethane-d2) δ -68.27 (d, J = 8.2 Hz). LCMS: purity 97%, MS (m / e) 520 (M+H) + .

[0513] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-34)

[0514]

[0515] 1 H NMR (400 MHz, dichloromethane-d2) δ 7.97 (q, J = 0.9 Hz, 1H), 7.89 (d, J = 7.1 Hz, 1H), 7.72 (td, J = 8.2, 7.4 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.33- 7.24 (m, 2H), 7.13 (dd, J = 8.2, 0.4 Hz, 1H), 7.05 (ddd, J = 7.4, 2.5, 0.7Hz, 1H), 6.78 (ddd, J = 8.2, 2.8, 0.7 Hz, 1H), 4.85 (dt, J = 11.2, 7.2 Hz,1H), 4.69 (dd, J = 9.8, 7.3 Hz, 1H), 4.29 (dd, J = 11.2, 9.8 Hz, 1H), 3.92(s, 2H), 3.92 - 3.88 (m, 2H), 3.50 (ddd, J = 11.7, 8.9, 2.9 Hz, 2H), 3.40 (s,3H), 2.84 (tt, J = 8.7, 4.1 Hz, 1H), 1.93 - 1.86 (m, 2H), 1.79 - 1.67 (m, 2H). 19 F NMR (376 MHz, dichloromethane-d2) δ -68.27 (d, J = 8.2 Hz). LCMS: purity 91%, MS (m / e) 504 (M+H) + .

[0516] (S)-N-(8-Bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-35)

[0517]

[0518] 1H NMR (400 MHz, dichloromethane-d2) δ 7.97 (app q, J = 0.8 Hz, 1H), 7.86(d, J = 7.5 Hz, 1H), 7.71 (td, J = 8.2, 7.4 Hz, 1H), 7.56 (d, J = 0.9 Hz,1H), 7.41 - 7.33 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.04 (ddd, J = 7.4, 2.5,0.7 Hz, 1H), 6.78 (ddd, J = 8.2, 2.8, 0.7 Hz, 1H), 4.40 (dt, J = 11.4, 7.4Hz, 1H), 3.92 (s, 2H), 3.39 (s, 3H), 2.91 - 2.76 (m, 1H), 2.78 - 2.52 (m,2H), 2.12 - 2.00 (m, 1H). 19 F NMR (376 MHz, dichloromethane-d2) δ -68.34 (d, J = 8.2Hz). LCMS: purity 94%, MS (m / e) 472 / 474 (M+H) + .

[0519] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide (I-36)

[0520]

[0521] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.97 (q, J = 0.9 Hz, 1H), 7.95 (s, 1H), 7.68 (td, J = 8.2, 7.4 Hz, 1H), 7.53 (d, J= 0.8 Hz, 1H), 7.30 - 7.25 (m,2H), 7.25 - 7.18 (m, 1H), 7.04 - 6.94 (m, 1H), 6.76 (ddd, J = 8.1, 2.8, 0.7Hz, 1H), 4.93 (dd, J = 6.6, 0.8 Hz, 2H), 4.79 (dd, J = 6.6, 0.9 Hz, 2H), 4.45(dt, J = 11.4, 7.4 Hz, 1H), 3.91 (s, 2H), 3.41 (s, 3H), 2.95 - 2.80 (m, 1H), 2.75 - 2.60 (m, 2H), 2.14 - 2.04 (m, 1H), 2.03 (s, 1H). 19 F NMR (376 MHz, chloroform-d) δ -67.08 (d, J = 8.2 Hz). LCMS: purity 97%, MS (m / e) 490 (M+H) + .

[0522] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-37)

[0523]

[0524] 1 H NMR (400 MHz, dichloromethane-d2) δ 7.98 (app q, J = 0.9 Hz, 1H), 7.89(d, J = 7.1 Hz, 1H), 7.72 (app td, J = 8.3, 7.4 Hz, 1H), 7.58 (d, J = 0.8 Hz,1H), 7.33 - 7.22 (m, 2H), 7.16 - 7.06 (m, 1H), 7.05 (ddd, J = 7.4, 2.5, 0.7Hz, 1H), 6.78 (ddd, J= 8.2, 2.8, 0.7 Hz, 1H), 4.84 (dt, J = 11.2, 7.2 Hz,1H), 4.69 (dd, J = 9.8, 7.3 Hz, 1H), 4.29 (dd, J = 11.3, 9.8 Hz, 1H), 3.93(s, 2H), 3.48 (d, J = 5.9 Hz, 2H), 3.40 (s, 3H), 1.83 (t, J = 6.8 Hz, 1H),1.29 (s, 6H). 19 F NMR (376 MHz, dichloromethane-d2) δ -68.27 (d, J = 8.2 Hz). LCMS: purity 98%, MS (m / e) 492 (M+H) + .

[0525] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide (I-38)

[0526]

[0527] 1 H NMR (400 MHz, dichloromethane-d2) δ 7.97 (t, J = 0.9 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.71 (td, J = 8.2, 7.4 Hz, 1H), 7.55 (d, J = 0.8 Hz, 1H), 7.28- 7.23 (m, 3H), 7.04 (ddd, J = 7.4, 2.5, 0.6 Hz, 1H), 6.77 (ddd, J = 8.2,2.9, 0.6 Hz, 1H), 4.39 (dt, J= 11.4, 7.4 Hz, 1H), 3.92 (s, 2H), 3.39 (s,3H), 2.96 - 2.81 (m, 1H), 2.75 - 2.60 (m, 2H), 2.12 - 1.98 (m, 1H), 1.59 (s,6H). 19 F NMR (376 MHz, dichloromethane-d2) δ -68.35 (d, J = 8.1 Hz). LCMS: purity 95%, MS (m / e) 476 (M+H) + .

[0528] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide (I-39)

[0529]

[0530] 1 H NMR (400 MHz, dichloromethane-d2) δ 7.97 (q, J = 0.9 Hz, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.71 (td, J = 8.2, 7.4 Hz, 1H), 7.55 (d, J = 0.8 Hz, 1H), 7.28- 7.18 (m, 3H), 7.04 (ddd, J = 7.4, 2.6, 0.7 Hz, 1H), 6.77 (ddd, J = 8.1,2.8, 0.7 Hz, 1H), 4.38 (dt, J = 11.5, 7.4 Hz, 1H), 3.92 (s, 2H), 3.48 (d, J =6.8 Hz, 2H), 3.39 (s, 3H), 2.95 - 2.81 (m, 1H), 2.73 - 2.58 (m, 2H), 2.09 -2.01 (m, 1H) (td, J = 11.5, 8.0 Hz, 1H), 1.82 (t, J= 6.9 Hz, 1H), 1.29 (s,6H). 19 F NMR (376 MHz, dichloromethane- d 2) δ -68.35 (d, J = 8.3 Hz). LCMS: purity 94%, MS (m / e) 490 (M+H) + .

[0531] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide (I-40)

[0532]

[0533] 1 H NMR (400 MHz, dichloromethane-d2) δ 7.97 (d, J = 1.0 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.56 (app m, 1H), 7.32 - 7.20 (m, 3H),7.04 (dd, J = 7.4, 2.5 Hz, 1H), 6.77 (dd, J = 8.2, 2.8 Hz, 1H), 4.39 (dt, J =11.5, 7.3 Hz, 1H), 3.92 (s, 2H), 3.90 - 3.86 (m, 1H), 3.68 (ddd, J = 11.8,9.1, 2.9 Hz, 2H), 3.39 (s, 3H), 2.94 - 2.84 (m, 1H), 2.72 - 2.61 (m, 3H), 2.13 - 1.95 (m, 3H), 1.90 - 1.82 (m, 2H). 19 F NMR (376 MHz, dichloromethane-d2) δ -68.30 (d, J = 8.5 Hz). LCMS: purity 97%, MS (m / e) 518 (M+H) + .

[0534] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((1-hydroxycyclobutyl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide (I-41)

[0535]

[0536] 1 H NMR (400 MHz, chloroform- d ) δ 7.97 (q, J = 0.9 Hz, 1H), 7.95 (s, 1H), 7.67 (td, J = 8.2, 7.4 Hz, 1H), 7.53 (d, J = 0.9 Hz, 1H), 7.27 (d, J = 6.9Hz, 2H), 7.22 - 7.15 (m, 1H), 6.98 (dd, J = 7.5, 2.4 Hz, 1H), 6.76 (dd, J =8.2, 2.9 Hz, 1H), 4.45 (dt, J = 11.0, 7.3 Hz, 1H), 3.91 (s, 2H), 3.41 (s,3H), 2.94 - 2.81 (m, 1H), 2.75 - 2.59 (m, 2H), 2.59 - 2.44 (m, 2H), 2.40 -2.24 (m, 2H), 2.23 (s, 1H), 2.11 - 2.03 (m, 1H) 1.94 - 1.81 (m, 2H). 19 F NMR (376 MHz, chloroform- d ) δ -67.09 (d, J = 8.1 Hz). LCMS: purity 96%, MS (m / e) 488 (M+H) + .

[0537] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((2-fluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (I-42)

[0538]

[0539] 1 H NMR (400 MHz, chloroform- d ) δ 8.09 (d, J = 5.0 Hz, 1H), 7.97 (d, J = 7.3Hz, 1H), 7.93 (s, 1H), 7.55 (ddd, J = 9.7, 7.4, 1.9 Hz, 1H), 7.51 (s, 1H),7.39 - 7.31 (m, 2H), 7.12 (ddd, J = 7.1, 4.9, 1.7 Hz, 1H), 4.88 (dt, J =11.3, 7.3 Hz, 1H), 4.67 (dd, J = 9.8, 7.4 Hz, 1H), 4.30 (dd, J = 11.3, 9.8Hz, 1H), 3.83 (s, 2H), 3.41 (s, 3H). 13 C NMR (101 MHz, chloroform- d ) δ 168.47,162.93, 149.10 (d, J = 14.4 Hz), 146.01 (d, J = 14.6 Hz), 143.07, 140.69 (d, J = 5.3 Hz), 137.52, 130.71, 127.14, 126.49, 124.57, 121.99 (d, J = 30.7 Hz),121.78 (d, J = 4.4 Hz), 121.30, 118.23, 77.27, 50.16, 35.65, 23.71. 19 F NMR (376 MHz, chloroform- d ) δ -71.94. LCMS: purity 96%, MS (m / z) 474 / 476 (M+H) + .

[0540] (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-43)

[0541]

[0542] 1 H NMR (400 MHz, chloroform- d ) δ 8.06 (d, J = 4.7 Hz, 1H), 7.97 (d, J = 7.2Hz, 1H), 7.91 (s, 1H), 7.52 (t, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.26 - 7.20(m, 2H), 7.12 - 7.05 (m, 2H), 4.84 (dt, J = 11.2, 7.2 Hz, 1H), 4.65 (dd, J =9.8, 7.3 Hz, 1H), 4.29 (dd, J = 11.3, 9.8 Hz, 1H), 3.79 (s, 2H), 3.37 (s, 3H), 1.58 (s, 6H). 13 C NMR (101 MHz, chloroform- d ) δ 168.40, 162.80, 160.42, 149.79,148.93, 145.81 (d, J = 14.4 Hz), 142.96, 140.69 (d, J = 5.0 Hz), 135.98,130.94, 127.09, 126.52, 123.06, 121.95 (d, J = 30.6 Hz), 121.72 (d, J = 4.2Hz), 121.16, 120.58, 94.89, 80.41, 77.11, 65.42, 50.03, 35.55, 31.42, 23.57. 19 F NMR (376 MHz, chloroform- d) δ -72.07. LCMS: purity 97%, MS (m / z) 478 (M+H) + .

[0543] (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-44)

[0544]

[0545] 1 H NMR (400 MHz, chloroform- d ) δ 8.05 (d, J = 4.8 Hz, 1H), 7.95 (d, J = 7.3Hz, 1H), 7.90 (d, J = 1.0 Hz, 1H), 7.52 (ddd, J = 9.5, 7.3, 2.0 Hz, 1H), 7.48(s, 1H), 7.29 - 7.23 (m, 2H), 7.14 - 7.05 (m, 2H), 6.19 (d, J = 16.0 Hz, 1H),5.77 (d, J = 16.0 Hz, 1H), 4.84 (dt, J = 11.3, 7.3 Hz, 1H), 4.64 (dd, J =9.8, 7.3 Hz, 1H), 4.29 (dd, J = 11.3, 9.8 Hz, 1H), 3.96 - 3.82 (m, 2H), 3.79 (s, 2H), 3.76 - 3.56 (m, 4H), 3.38 (s, 3H). 13 C NMR (101 MHz, chloroform- d ) δ168.47, 162.88, 160.50, 150.08 (d, J = 15.7 Hz), 149.03, 145.88 (d, J = 14.5Hz), 143.04, 140.74 (d, J= 5.4 Hz), 136.19, 131.13, 127.12, 126.65, 123.25,121.99 (d, J = 30.5 Hz), 121.76 (d, J = 4.4 Hz), 121.29, 120.24, 107.45,92.79, 92.55, 83.34, 82.77, 77.19, 69.29, 66.07, 64.87, 63.47, 50.10, 39.99,37.35, 35.62, 23.66. 19 F NMR (376 MHz, chloroform- d ) δ -72.03. LCMS: purity 95%, MS (m / z) 520 (M+H) + .

[0546] (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-45)

[0547]

[0548] 1 H NMR (400 MHz, chloroform- d ) δ 8.07 (s, 1H), 7.96 (d, J = 7.2 Hz, 1H),7.91 (s, 1H), 7.52 (t, J = 9.9 Hz, 1H), 7.49 (s, 1H), 7.28 - 7.21 (m, 2H), 7.13 - 7.05 (m, 2H), 4.85 (dt, J = 11.2, 7.3 Hz, 1H), 4.66 (dd, J = 9.8, 7.3Hz, 1H), 4.28 (dd, J = 11.3, 9.8 Hz, 1H), 3.92 (ddd, J = 11.6, 5.4, 3.7 Hz,2H), 3.80 (s, 2H), 3.52 (ddd, J= 11.7, 8.8, 2.9 Hz, 2H), 3.40 (s, 3H), 2.82(tt, J = 8.5, 4.1 Hz, 1H), 1.96 - 1.83 (m, 2H), 1.74 (dtd, J = 12.8, 8.8, 3.7 Hz, 2H). 13 C NMR (101 MHz, chloroform- d ) δ 168.37, 162.79, 160.41, 149.51, 145.82(d, J = 14.5 Hz), 142.87, 140.52 (d, J = 5.3 Hz), 135.94, 130.91, 126.99,126.40, 122.96, 122.05, 121.72 - 121.49 (m), 121.36, 121.11, 93.17, 79.97,77.13, 66.38, 50.03, 35.45, 32.13, 26.81, 23.55. 19 F NMR (376 MHz, chloroform- d ) δ -71.95. LCMS: purity 98%, MS (m / z) 504 (M+H) + .

[0549] (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-46)

[0550]

[0551] 1 H NMR (400 MHz, chloroform- d ) δ 8.10 - 8.03 (m, 1H), 7.96 (d, J = 7.2 Hz,1H), 7.91 (s, 1H), 7.52 (ddd, J = 9.6, 7.3, 1.9 Hz, 1H), 7.49 (s, 1H), 7.28 -7.18 (m, 2H), 7.12 - 7.06 (m, 2H), 4.84 (dt,J = 11.2, 7.3 Hz, 1H), 4.66 (dd, J = 9.7, 7.3 Hz, 1H), 4.28 (dd, J = 11.3, 9.8 Hz, 1H), 3.80 (s, 2H), 3.49 (s,2H), 3.40 (s, 3H), 1.29 (s, 6H). 13 C NMR (101 MHz, chloroform- d ) δ 168.50, 162.92,160.54, 149.64, 149.01, 145.95 (d, J = 14.5 Hz), 143.00, 140.65 (d, J = 5.3Hz), 136.07, 131.04, 127.12, 126.53, 123.09, 122.18, 121.83 - 121.65 (m),121.49, 121.24, 93.30, 80.10, 77.26, 66.51, 50.16, 35.58, 32.26, 26.94,23.68. 19 F NMR (376 MHz, chloroform- d ) δ -71.97. LCMS: purity 96%, MS (m / z) 492 (M+H) + .

[0552] (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-47)

[0553]

[0554] 1 H NMR (400 MHz, chloroform- d ) δ 8.10 - 8.03 (m, 1H), 7.98 (d, J= 7.2 Hz,1H), 7.92 (s, 1H), 7.58 - 7.51 (m, 1H), 7.50 (s, 1H), 7.43 (s, 1H), 7.29 -7.24 (m, 1H), 7.16 - 7.08 (m, 2H), 4.94 - 4.90 (m, 2H), 4.87 (dt, J = 11.3,7.3 Hz, 1H), 4.81 - 4.77 (m, 2H), 4.67 (dd, J = 9.7, 7.3 Hz, 1H), 4.32 (dd, J = 11.3, 9.8 Hz, 1H), 3.85 (s, 1H), 3.81 (s, 2H), 3.40 (s, 3H). 13 C NMR (101MHz, chloroform- d ) δ 168.37, 162.80, 160.42, 150.35, 148.95, 145.81 (d, J = 14.5Hz), 145.37 (d, J = 14.3 Hz), 142.96, 140.64 (d, J = 5.3 Hz), 136.17, 133.20,131.00, 127.03, 126.58, 123.28, 121.90 (d, J = 30.5 Hz), 121.67 (d, J = 4.4Hz), 121.57 (d, J = 4.4 Hz), 121.20, 119.58, 88.93, 84.60, 77.11, 67.38,50.02, 35.54, 23.58. 19 F NMR (376 MHz, chloroform- d ) δ -72.04. LCMS: purity 95%, MS (m / z) 492.6 (M+H) + .

[0555] (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-48)

[0556]

[0557] 1 H NMR (400 MHz, chloroform- d ) δ 8.07 (d, J = 5.0 Hz, 1H), 7.97 (d, J = 7.2Hz, 1H), 7.92 (s, 1H), 7.53 (ddd, J = 9.5, 7.3, 2.0 Hz, 1H), 7.50 (s, 1H), 7.30 - 7.26 (m, 2H), 7.13 - 7.08 (m, 2H), 4.86 (dt, J = 11.2, 7.2 Hz, 1H),4.67 (dd, J = 9.8, 7.3 Hz, 1H), 4.30 (dd, J = 11.3, 9.8 Hz, 1H), 3.81 (s,2H), 3.40 (s, 3H), 2.58 - 2.45 (m, 2H), 2.40 - 2.26 (m, 2H), 1.94 - 1.80 (m,2H). 13 C NMR (101 MHz, chloroform- d ) δ 168.37, 162.80, 160.42, 149.90, 148.91,145.83 (d, J = 14.6 Hz), 142.91, 140.58 (d, J = 5.3 Hz), 136.01, 130.98,127.02, 126.54, 123.07, 121.89 (d, J = 30.7 Hz), 121.63 (d, J = 4.4 Hz),121.14, 120.52, 93.47, 81.79, 77.12, 68.19, 50.03, 38.55, 35.50, 23.55,12.98. 19 F NMR (376 MHz, chloroform- d ) δ -71.98. LCMS: purity 98%, MS (m / z) 490.6 (M+H) + .

[0558] (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((2,6-difluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (I-49)

[0559]

[0560] 1 H NMR (400 MHz, DMSO- d 6) δ 8.54 - 8.47 (m, 1H), 8.09 (s, 1H), 8.02(dt, J = 9.9, 8.0 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.71 (s, 1H), 7.43 (dd, J = 8.6, 2.4 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 7.11 - 7.07 (m, 1H), 4.74 -4.61 (m, 2H), 4.48 - 4.35 (m, 1H), 3.82 (s, 2H), 3.27 (s, 3H). 13 C NMR (101MHz, DMSO- d 6) δ 168.76, 161.97 - 159.22 (m), 158.38 (d, J = 13.7 Hz), 149.36,149.18, 147.11 (dd, J = 7.8, 5.5 Hz), 143.27, 138.48, 130.33, 127.88, 126.75,124.93, 121.79, 119.49 (dd, J = 28.0, 5.5 Hz), 117.79, 107.19 (dd, J = 34.3,5.4 Hz), 76.09, 50.62, 35.27, 22.24. 19 F NMR (376 MHz, DMSO- d 6) δ -72.95 (ddd, J = 10.9, 7.9, 2.5 Hz), -73.77 (t, J= 11.0 Hz). LCMS: purity 97%, MS (m / z) 492 / 494 (M+H) + .

[0561] (S)-4-((2,6-difluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (I-50)

[0562]

[0563] 1 H NMR (400 MHz, chloroform- d ) δ 7.98 (d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.63 (dt, J = 9.5, 7.8 Hz, 1H), 7.48 (s, 1H), 7.28 - 7.22 (m, 2H), 7.14 -7.07 (m, 1H), 6.75 (dd, J = 8.0, 2.9 Hz, 1H), 4.85 (dt, J = 11.2, 7.2 Hz,1H), 4.67 (dd, J = 9.8, 7.3 Hz, 1H), 4.30 (dd, J = 11.3, 9.8 Hz, 1H), 3.79(s, 2H), 3.40 (s, 3H), 1.61 (s, 6H). 13 C NMR (101 MHz, chloroform- d ) δ 168.36,160.80 (dd, J = 122.8, 13.8 Hz), 158.35 (dd, J = 123.2, 14.0 Hz), 149.83,148.86, 144.76 (dd, J = 7.6, 5.3 Hz), 142.75, 135.97, 132.09 (d, J = 10.0Hz), 130.94, 128.51 (d, J= 12.1 Hz), 126.98, 126.51, 123.03, 121.04, 120.54,118.19 (dd, J = 28.4, 6.0 Hz), 106.23 (dd, J = 34.4, 5.7 Hz), 94.74, 80.48,77.09, 65.51, 50.04, 35.50, 31.39, 22.67. 19 F NMR (376 MHz, chloroform- d ) δ -71.01(t, J = 9.7 Hz), -71.98 (t, J = 10.5 Hz). ). LCMS: purity 97%, MS (m / z) 496 (M+H) + .

[0564] Example 10

[0565] In this example, compounds of the disclosure were evaluated using a biochemical assay using ADP-Glo™ technology.

[0566] ADP-Glo™ (Promega, Madison, WI, USA) reagent was thawed at ambient temperature. Kinase assay reagent was prepared by mixing kinase assay buffer with lyophilized kinase assay substrate.

[0567] 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.

[0568] 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).

[0569] 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.

[0570] 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.

[0571] Table 1

[0572] Compound <![CDATA[RIPK1 ADP-Glo Kinase (IC 50 )]]> I-1 0.0206 I-2 0.0422 I-3 0.0289 I-4 0.0553 I-5 0.0246 I-6 0.0409 I-7 0.0186 I-8 0.0264 I-9 0.0643 I-10 0.3035 I-11 0.1203 I-12 0.0252 I-13 0.0212 I-14 0.0176 I-15 0.0194 I-16 0.0379 I-17 0.111 I-18 0.0652 I-19 0.1045 I-20 0.0217 I-21 0.168 I-22 0.0083 I-23 0.0257 I-24 0.0403 I-25 0.83 I-26 0.0355 I-27 0.0193 I-28 0.1019 I-29 0.0694 I-30 0.4798 I-31 0.1057 I-32 0.0162 I-33 0.0171 I-34 0.0153 I-35 0.0194 I-36 0.0118 I-37 0.0162 I-38 0.0194 I-39 0.0283 I-40 0.0129 I-41 I-42 0.0182 I-43 0.0177 I-44 0.0629 I-45 0.045 I-46 0.0375 I-47 0.0175 I-48 0.6455 I-49 0.2067 I-50 0.1806

[0573] Embodiment 11

[0574] 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.

[0575] U937 and L929 cells were obtained from American Type Culture Collection (Manassa, VA, USA). At 37 ° C and 5% CO2, in complete RPMI 1640 culture medium (Sigma, ST Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis, MO, USA), both cells were maintained in the logarithmic growth phase. For necrosis assay, L929 cells were plated in 100 μL / well culture 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 test, U937 cells were plated in 50 μL / well culture medium containing 60uMzVAD-fmk (Lonza, Basel, Switzerland) at 50K cells / well. The culture medium was removed from the L929 cells of the 96-well plate and replaced with a new culture medium containing 40uM zVAD-fmk of 50 μL / well. Each compound of the present disclosure evaluated in this embodiment was serially diluted by 4 times dilution in DMSO from 2.5mM, and then diluted 1:125 in complete medium.Then the compound of 2x of 50 μ L / holes was added to the cells in the flat board.The cells were pre-incubated for 1 hour at 37 ° C and 5% CO2 together with the compound, and then the 11x TNFa (Peprotech, Rocky Hill, NJ, the U.S.) of 10 μ L / holes was added to obtain the final concentration 2ng / mL of TNFa.After TNFa stimulated 18 hours at 37 ° C and 5% CO2, WallacVictor2 photometer (PerkinElmer, Waltham, MA, the U.S.) and CellTiter-Glo® luminescent cell viability reagent were used to measure (Promega, Madison, WI, the U.S.) (add according to the manufacturer's instructions), and the relative amount of necrotic cells was determined by luminescence.The results from the present embodiment are summarized in Table 2. This example establishes that embodiments of the compounds described herein have unexpectedly potent activity against human and murine RIP1, which allows their evaluation in in vivo mouse models of disease. These results can be used to determine safe and effective doses for humans.

[0576] Table 2

[0577] Compound <![CDATA[L929-CTG-recovery, L929, TNFa+zVAD (IC 50 )]]> <![CDATA[U937 Zvad TNF CTG recovery, U937, TNFa+zVAD (IC 50 )]]> I-1 2.303 0.0114 I-2 1.801 0.0497 I-3 3.847 0.1523 I-4 7.062 0.3612 I-5 2.016 0.0349 I-6 3.425 0.0496 I-7 0.4492 0.0148 I-8 0.1072 0.009 I-8 2.334 0.0492 I-9 2.693 0.1631 I-10 ND* 2.831 I-11 7.431 0.1263 I-12 3.471 0.0734 I-13 1.312 0.042 I-14 1.174 0.0143 I-15 1.683 0.0275 I-16 2.39 0.0172 I-17 ND 0.7147 I-18 5013 0.2858 I-19 ND 0.2639 I-20 5004 0.0502 I-21 30.42 1.37 I-22 5004 0.0351 I-23 5000 0.0818 I-24 ND 0.0698 I-25 ND 4.119 I-26 0.4069 0.0053 I-27 0.6218 0.0097 I-28 5027 0.2353 I-29 1.724 0.0472 I-30 ND 7.21 I-31 ND 1.977 I-32 0.6825 0.0163 I-33 1.127 0.0116 I-34 0.0681 0.0013 I-35 6.859 0.07 I-36 0.037 0.0013 I-37 0.6966 0.004 I-38 0.0512 0.001 I-39 0.0385 0.0005 I-40 0.0694 0.0005 I-41 0.0131 0.0012 I-42 28.38 0.0586 I-43 2.519 0.0179 I-44 4.115 0.018 I-45 0.5123 0.0052 I-46 2.369 0.0097 I-47 2.895 0.0408 I-48 1.466 0.0249 I-49 ND 0.1696 I-50 17.65 0.0623

[0578] * 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.

[0579] Example 12

[0580] 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.

[0581] 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.

[0582] Certain embodiments of the present invention 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.

[0583] Embodiment 13

[0584] 2-((Trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol

[0585]

[0586] A two-necked flask containing a stirring bar was heated, cooled to room temperature under vacuum, and backfilled with argon through a balloon. Trimethylsilylacetylene (1.4 mL, 1.0 g, 10.2 mmol) followed by anhydrous THF was transferred to the flask and cooled to -78 °C. n-BuLi (1.6M in hexane, 7.0 mL, 11.2 mmol) was added dropwise to the above stirred solution over 15 minutes. After 30 minutes, spiro[3.3]heptanone (1.0 mL, 1.0 g, 9.09 mmol) was added to the reaction solution for 15 minutes, stirred at the same temperature for 1 hour, and stirred at °C for 1 hour. The reaction solution was slowly quenched with ice-cold aqueous NH4Cl solution (5 mL), concentrated to remove volatiles, and diluted with Et2O (30 mL) and H2O (10 mL). After separation of the organic layer, the aqueous layer was extracted with additional Et2O (2×20 mL). The combined organic layers were washed with brine (15 mL), stirred over anhydrous Na2SO4, polish filtered and concentrated. The crude concentrate was dried under high vacuum to provide 2-((trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol (1.71 g, 81%) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.54 - 2.43 (m, 2H), 2.26 - 2.19 (m, 2H), 2.12 (s, 1H), 2.12 - 2.07 (m,2H), 2.04 - 1.93 (m, 2H), 1.88 - 1.75 (m, 2H), 0.15 (s, 9H). (PMA, KMnO4 and ammonium molybdate stains were used to understand the progress of the reaction).

[0587] 2-Ethynylspiro[3.3]heptan-2-ol

[0588]

[0589] To a stirred solution of 2-((trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol (1.71 g, 8.2 mmol) in dry Et2O (30 mL) at 0°C under nitrogen was added solid n-Bu4NF.3H2O all at once. After 2 h, the clear light brown reaction solution was quenched slowly with saturated aqueous NH4Cl (10 mL) over 10 min, warmed to room temperature, diluted with H2O (6 mL) and Et2O (20 mL). After separation of the organic layer, the aqueous layer was extracted with additional Et2O (3 x 20 mL). After washing the combined organic layers sequentially with water (10 mL), aqueous NaHCO3 (10 mL) and brine, the organic layer was separated, stirred over anhydrous Na2SO4, polish filtered, and concentrated to afford ethynylspiro[3.3]heptan-2-ol (1.11 g, 99%) as a light brown liquid. The title compound thus obtained was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.58- 2.46 (m, 3H), 2.43 (br s, 1H), 2.30 - 2.21 (m, 2H), 2.16 - 2.06 (m, 2H), 2.09 - 1.95 (m, 2H), 1.89 - 1.76 (m, 2H). (PMA, KMnO4 and ammonium molybdate stains were used to understand the progress of the reaction).

[0590] 6-((Trimethylsilyl)ethynyl)-2-oxaspiro[3.3]heptan-6-ol

[0591]

[0592] Analogously to the preparation of 2-((trimethylsilyl)ethynyl)spiro[3.3]hept-2-ol, 6-((trimethylsilyl)ethynyl)-2-oxaspiro[3.3]hept-6-ol was obtained by reaction of lithium trimethylsilyl acetylide with 2-oxaspiro[3.3]hept-6-one as a crude light brown solid and used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.75 - 4.62 (m, 4H)), 2.77 - 2.60 (m, 2H), 2.47 - 2.36 (m, 2H), 2.23 (s, 1H), 0.14 (s, 9H).

[0593] 6-Ethynyl-2-oxaspiro[3.3]heptan-6-ol

[0594]

[0595] 6-Ethynyl-2-oxaspiro[3.3]heptan-6-ol was prepared in a manner similar to that of 2-ethynylspiro[3.3]heptan-2-ol and obtained as a light brown solid which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.74 (s, 2H), 4.66 (s, 2H), 2.76 - 2.67 (m,2H), 2.50 (s, 1H), 2.48 -2.39 (m, 2H), 2.24 (s, 1H).

[0596] 1-Methyl-4-(2-methylbut-3-yn-2-yl)piperazine

[0597]

[0598] 1-Methyl-4-(2-methylbut-3-yn-2-yl)piperazine was prepared by a modified procedure of Imada, Y.; Yurasa, M.; Nakamura, I.; Murahashi, S.-iJ Org. Chem. 1998, 63, 2342-2347.

[0599] To a stirred light green solution of CuCl (0.10 g, 10 mmol) in anhydrous THF were added 1-methylpiperazine (1.10 g, 1.22 mL, 11 mmol), NEt3 (1.11 g, 1.53 ml, 11 mmol) successively over a period of 20 min at room temperature under argon. After stirring the blue heterogeneous mixture for 10 minutes, (2-methylbut-3-yn-2-yl) acetate (1.27 g, 10 mmol) (Lepronier, A.; Achard, T.; Giordano, L.; Tenaglia, A.; Buono, G.; Clavier, H. Adv. Synth. Catal. 2016. 358 (4), 631-642. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi, M.; Rinaldi, S.; Sambri, L. Synlett 2003, 39-42.) in anhydrous THF (5 mL) was added slowly over 20 minutes and a gentle exotherm was observed. The reaction mixture was stirred for 30 minutes, heated at 58°C for 7 hours and cooled. The brown-red reaction mixture was diluted with Et2O (70 mL) and NaHCO3 aqueous solution (40 mL). After separation of the organic layer, the red heterogeneous aqueous layer was extracted with Et2O (3×75 mL). The combined light green organic layer was washed with NaHCO3 aqueous solution (40 mL) and then with NaCl aqueous solution, stirred over anhydrous Na2SO4, and filtered through celite®. The filtrate was concentrated and the title compound was obtained as a crude yellow solid (1.16 g). Further purification by silica gel chromatography (Combiflash® Teledyne RediSep® 12G gold column. A: CH2Cl2 BB: 20% MeOH / CH2Cl2 @15% B / A. Detection λ=220 and 230 nm) provided an off-white solid (0.54 g, yield 33%). 1H NMR (400 MHz, CHLOROFORM-d) δ 2.67 (br s, 4H), 2.46 (br s, 4H), 2.26(app s, 4H), 1.37 (s, 6H). 13C NMR (101 MHz, CHLOROFORM-d) δ 85.55, 71.50, 55.45,53.82, 46.64, 45.88, 27.71.

[0600] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are merely preferred examples of the invention and should not be viewed as limiting the scope of the invention. Instead, the scope of the invention is defined by the following claims. Therefore, we claim as our invention all that falls within the scope and spirit of these claims.

Claims

1. Compounds according to formula I or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Ring B is pyrazolyl, pyridinyl or pyrimidinyl; m is 1; n is 0; R 1 yes or R 2 It is CH3; R 3 It is H; L is CH2 or O; X is CH2 or O; and Z is pyridinyl, pyridazinyl or pyrimidinyl, wherein the pyridinyl, pyridazinyl or pyrimidinyl is optionally substituted with one or two F, CH3, CF3 or OH.

2. The compound of claim 1, wherein ring B is pyrazolyl or pyridinyl.

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

4. The compound of claim 1, wherein X is CH2.

5. The compound of claim 1, wherein L is O.

6. The compound of claim 1, wherein L is CH2.

7. The compound of claim 1, wherein Z is unsubstituted.

8. The compound of claim 1, wherein the -LZ moiety is (6-fluoropyridin-2-yl)methyl, (6-methylpyridin-2-yl)methyl, (2-methylpyridin-5-yl)oxy, (2-fluoropyridin-5-yl)oxy, pyridin-2-ylmethyl, (6-trifluoromethylpyridin-2-yl)methyl, (6-hydroxypyridin-2-yl)methyl, pyridin-3-ylmethyl, pyridazin-3-ylmethyl, (2-methylpyridin-5-yl)methyl, (2-fluoropyridin-5-yl)methyl, (2-fluoropyridin-3-yl)methyl, (2,6-difluoropyridin-3-yl)methyl, pyrimidin-2-ylmethyl, or pyridin-4-ylmethyl.

9. The compound of claim 1 or claim 2, wherein R 1 yes 10. The compound of claim 1, wherein R 1 yes 11. The compound of claim 1, wherein the compound is: I-1: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-2: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide; I-3: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)oxy)picolinamide; I-4: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)oxy)picolinamide; I-5: (S)-4-((6-fluoropyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide; I-6: (S)-4-((6-fluoropyridin-3-yl)oxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide; I-7: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide; I-8: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-2-ylmethyl)-1H-pyrazole-1-carboxamide; I-9: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide; I-10: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-hydroxypyridin-2-yl)methyl)picolinamide; I-11: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)picolinamide; I-12: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-2-yl)methyl)picolinamide; I-13: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide; I-14: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxamide; I-15: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-((6-methylpyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide; I-16: (S)-4-((6-fluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-17: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxamide; I-26: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide; I-27: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)picolinamide; I-29: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxamide; I-31: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(pyrimidin-2-ylmethyl)-1H-pyrazole-1-carboxamide; I-32: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-33: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-34: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-36: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-37: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-38: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-39: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-40: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-41: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((1-hydroxycyclobutyl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-43: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-44: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-45: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-46: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-47: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-48: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; or I-50: (S)-4-((2,6-difluoropyridin-3-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide.

12. A pharmaceutical composition comprising a compound according to claim 1 or claim 11.

13. The pharmaceutical composition according to claim 12, comprising an excipient, a therapeutic agent, or a combination thereof.

14. Use of a compound according to claim 1 or claim 11 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease in a subject, wherein the subject has, is suspected of having or develops a disease involving receptor-interacting protein-1 (RIP1) kinase.

15. Use of a compound according to claim 1 or claim 11 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of an inflammatory or immunoregulatory disorder.

16. Use of a compound according to claim 1 or claim 11 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of ageing disorders.

17. Use of a compound according to claim 1 or claim 11 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease or Alzheimer's disease.

18. Use of a compound according to claim 1 or claim 11 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating atopic dermatitis, rheumatoid arthritis, or ankylosing spondylitis.

19. Use of a compound according to claim 1 or claim 11 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of myelodysplastic syndrome.

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