Heterocyclic RIP1 Kinase Inhibitors

Abstract

Disclosed herein are kinase inhibitor compounds, such as receptor interacting protein-1 (RIP1) kinase inhibitor compounds of formula (I), as well as pharmaceutical compositions and combinations comprising such inhibitor compounds. The disclosed compounds, pharmaceutical compositions, and / or combinations may be used to treat or prevent diseases or conditions associated with kinases, particularly diseases or conditions associated with RIP1. JPEG2024509466000271.jpg33169

Description

[Technical Field]

[0001] The present disclosure relates to compounds and methods of making and using the compounds, such as for inhibiting receptor-interacting protein-1 ("RIP1") kinase and for treating diseases and / or conditions associated with RIP1. [Background technology]

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

[0003] The compounds disclosed herein have formula I [ka] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof. With respect to Formula I, Ring B is heteroaryl and may be a monocyclic heteroaryl. In some embodiments, Ring B is a 5- or 6-membered heteroaryl and may be pyrazolyl or pyridinyl.

[0004] Each R 1 are independently a halogen or a linker-R 6 group, and the linker is a bond or R a where R a is neither H nor D, but R 6 is heterocyclyl, R b , -C(R f )3, or -C(R f )=C(R f )2 and R 2 But Ra and R 3 is R a and when present, each R 4 is independently R e and L is a heteroatom or R a where R a is neither H nor D.

[0005] R a are each independently a H or D, C, except for embodiments in which 1-10 aliphatic, C 1-10 Haloaliphatic, C 5-10 aromatic, C 3-6 Heterocycle, or C 3-10 spiro heterocycle, R b are each independently -OH, -SH, or -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 , 1 or 2 NR d R d , carboxyl, or combinations thereof, optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH 1-10 alkyl, and R c are each independently one, two, or three R e C can be substituted with 1-10 Alkyl, 1, 2, or 3 R e C can be substituted with 2-10 Alkenyl, 1, 2, or 3 R e C can be substituted with 2-10 Alkynyl, 1, 2, or 3 R e C can be substituted with 3-6 cycloalkyl, or one, two, or three R e C can be substituted with 5-10 Aromatic, Rd are each independently H; one, two or three R e or C 3-9 C optionally substituted with heterocyclyl 1-6 alkyl; 1, 2 or 3 R e C optionally substituted with 3-6 cycloalkyl; one, two or three R e C optionally substituted with 3-6 Heterocycle; 1, 2 or 3 R b C optionally substituted with 5-10 aryl; one, two or three R e C optionally substituted with 5-10 Heteroaryl or two R d The group, together with the nitrogen attached to it, can be one or more R e C optionally substituted with 3-9 heterocycle, or one or more R e C optionally substituted with 5-10 forming a heteroaryl, R e are each independently a 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 R f is independently, at each occurrence, -alkyl-phosphate; R a , R b or R e or two R's f The group, together with the carbon atom attached to it, is C 2-6 Alkenyl group, C 3-6 Cycloalkyl groups (one or more R e or C 3-10 Heterocycle (which is one or more R e or acyl-substituted).

[0006] Also with respect to Formula I, X is CH 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.

[0007] In some embodiments, R 2 is C 1-6 It is alkyl and can be CH3 or CD3.

[0008] In certain embodiments, n is 0, while in other embodiments, n is 1. In such embodiments, R 4 is C such as methyl 1-6 It can be alkyl.

[0009] In certain embodiments, L is a heteroatom such as O, while in other examples, L is a C, such as CH. 1-6 It is alkyl.

[0010] In some embodiments, Z can be a 6-membered heteroaryl, and can be pyridinyl, pyrimidinyl, or pyridazinyl. In any embodiment, Z can be unsubstituted or can be halogen, C 1-6 Alkyl, C 1-6 In some embodiments, Z can be substituted with haloalkyl, OH, or the like. [ka] and p is 0, 1, 2, 3, or 4; and, if present, each R 5 are independently e Each R 5 are independently OH, halogen, C, such as OH, CF, methyl, or fluoro. 1-6 Alkyl, or C 1-6 and / or in some embodiments, p is 1, while in other embodiments, p is 0.

[0011] In some embodiments, Z is a 5-membered heteroaryl, such as thiazolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, etc. Similar to the 6-membered heteroaryl Z moieties, the 5-membered heteroaryl Z moieties can also include halogen, C 1-6 Alkyl, C 1-6 It may be substituted with groups such as haloalkyl or OH.

[0012] In certain embodiments, the Z moiety is [ka] are selected from halogen, C 1-6 Alkyl, C 1-6 Optionally substituted with 1, 2 or 3 groups selected from haloalkyl or OH.

[0013] Also, 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.

[0014] In some embodiments, Ring B is pyrazolyl, and in some embodiments, —N(R 3 The C(O)- moiety is attached to Ring B at a ring nitrogen atom on Ring B.

[0015] At least one R 1 may be a halogen, such as Br, and / or at least one R 1 -linker-R 6 In some embodiments, at least one R1 is an 8- to 12-membered spiroheterocyclyl, C 1-10 Alkyl, or C 2-10 In certain embodiments, at least one R 1 teeth, [ka] It could be.

[0016] Those skilled in the art will recognize compounds having, but not limited to, the formula: [ka] It will be understood that all stereoisomeric forms of the compound, including pharmaceutically acceptable salts, N-oxides, solvates, tautomers, or stereoisomers thereof, are included in Formula 1. In certain embodiments of compounds according to Formula I, the compound is represented by the following, including any and all stereoisomers thereof: [ka] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof.

[0017] Also disclosed herein are embodiments of compositions comprising one or more of the disclosed compounds. The compositions may further comprise an excipient, a therapeutic agent, or a combination thereof.

[0018] Method embodiments using the disclosed compounds or compositions thereof are also disclosed herein. In some embodiments, the method can include administering one or more of the disclosed compounds or compositions thereof to a subject. The method can be for treating a disease in a subject and / or can include administering to the subject (i) a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof; or (ii) a therapeutically effective amount of a pharmaceutical composition of the compound. In some embodiments, the subject can have, or 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 the method embodiments include diseases or disorders associated with inflammation, necroptosis, or both. In certain embodiments, the disease treated with the compounds is an inflammatory or immunoregulatory disorder, including autoimmune and proliferative disorders. Exemplary diseases are disclosed herein.

[0019] Also disclosed herein are method embodiments that include contacting receptor-interacting protein-1 (RIP1) kinase with one or more of the disclosed compounds, pharmaceutical compositions thereof. The method can be an in vitro method, or an in vivo method, such as when the RIP1 kinase is present in a subject.

[0020] The foregoing and other objects and features of the present disclosure will become more apparent from the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0021] I. Terminology Overview The following explanations of terms and methods are provided to better describe the present disclosure and to guide those skilled in the art in practicing the disclosure. The singular forms "a," "an," and "the" refer to one or more, unless the context clearly dictates otherwise. The term "or" refers to any single element of the stated alternative elements or a combination of two or more elements, unless the context clearly dictates otherwise. As used herein, "comprises" means "includes." Thus, "comprising A or B" means "including A, B, or A and B," without excluding any additional elements.

[0022] Unless otherwise indicated, all numbers expressing amounts of ingredients, molecular weights, percentages, temperatures, times, and the like used in the specification or claims should be understood as being modified by the term "about." Accordingly, unless otherwise indicated, either implicitly or explicitly, the numerical parameters recited are approximations that may depend on the desired properties sought and / or the limits of detection under standard testing conditions / methods. Where the word "about" is explicitly recited to directly and explicitly distinguish the embodiments from the prior art discussed, the numerical values ​​of the embodiments are not approximations.

[0023] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0024] When chemical structures are shown or described, unless expressly stated otherwise, all carbons are assumed to contain hydrogen, so that each carbon corresponds to a valence of 4. For example, in the structure on the left of the schematic below, there are 9 implied hydrogen atoms. The 9 hydrogen atoms are shown in the structure on the right. [ka]

[0025] In some cases, certain atoms within a structure are described in textual form as having a hydrogen or hydrogen atom, e.g., -CHCH-. It will be appreciated by those skilled in the art that the foregoing descriptive technique is common in the chemical arts to provide brevity and simplicity in describing organic structures.

[0026] For example, [ka] R in 1 In the above, when an R group is shown "floating" on a ring group, unless otherwise defined, the substituent R (e.g., R 1 ) as long as a stable structure is formed, [ka] It may be present on any atom of the fused bicyclic ring system except the atom bearing the bond to the symbol.

[0027] The group R is present in a ring system containing saturated carbons, for example, of the formula: [ka] In a case where a ring is shown as: y = 1, it is assumed that in this example, y can be two or more, each replacing a currently shown, implied, or explicitly defined hydrogen on the ring; then, unless otherwise defined, two R's can be on the same carbon. A simple example is when R is a methyl group. The shown structure can exist as a pair of dimethyls on the shown ring carbons ("annular" carbons). In another example, two R's on the same carbon containing the same carbon can be included in the ring, thus creating a spirocyclic ring ("spirocyclyl" group) structure.

[0028] As used herein, for example, "substituted aryl C 1-8 The term "substituted" in the term "alkyl" refers to all subsequent modifiers, and substitution is1-8 The alkyl group, "C 1-8 It may occur in the "alkyl" portion, the "aryl" portion, or both portions.

[0029] "Substituted," when used to modify a specified group or moiety, means that at least one, and possibly more than one, hydrogen atom of the specified group or moiety is independently replaced with the same or different substituent(s), as defined below. In certain embodiments, a group, moiety, or substituent may be substituted or unsubstituted, unless expressly defined as either "unsubstituted" or "substituted." Thus, any of the groups identified herein may be unsubstituted or substituted, unless the context indicates otherwise or a particular structural formula precludes substitution. In certain embodiments, a substituent may or may not be expressly defined as substituted, but is still intended to be optionally substituted. For example, an "aliphatic" or "cyclic" moiety can be unsubstituted or substituted, but an "unsubstituted aliphatic" or "unsubstituted cyclic" is not substituted.

[0030] A "substituent" or "substituent group" to replace one or more hydrogen atoms on a saturated carbon atom of a specified group or moiety is defined as -R, unless otherwise indicated. 60 , halo, =O, -OR 70 , -SR 70 , -N(R 80 )2, haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -P(O)(O - )2(M + )2, -P(O)(O - )2M 2+ , -P(O)(OR 70 )O - M +, -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)N(R 80 )2, -C(NR 70 )(R 80 )2, -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )N(R 80 )2(wherein, R 60 is C 1-10 Aliphatic, heteroaliphatic or alicyclic, typically C 1-6 Aliphatic, more typically C 1-6 R may be alkyl; 60 may be optionally substituted, and each R 70 are each independently hydrogen or R 60 and each R 80 are each independently R 70 or two R 80The groups, together with the nitrogen atom to which they are attached, optionally contain 1 to 4 of the same or different additional heteroatoms selected from O, N and S, of which N is H or an R group such as a C1-C3 alkyl substituted group. 70 each M + forms a 3- to 7-membered heteroalicyclic ring, which is a counterion with a net single positive charge. + are each independently, for example, K + , Na + , Li + Alkali metal ions such as; + N(R 60 ) 4; protonated amino acid ions, such as lysine or arginine; [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 to such divalent alkaline earth ions is the ionized form of a compound of the invention and the other can be a typical counterion such as chloride, or that a two-ionized compound can serve as the counterion to such divalent alkaline earth ions, or that a doubly-ionized compound can serve as the counterion to such divalent alkaline earth ions.) Specific examples include -N(R 80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, N-methyl-piperazin-1-yl, N-morpholinyl, etc. Any two hydrogen atoms on a single carbon can also be, for example, =O, =NR 70 , =N-OR 70 , =N2, or =S.

[0031] Substituents for replacing a hydrogen atom on an unsaturated carbon atom of a group containing an unsaturated carbon are -R unless otherwise specified. 60 , halo, -O - M + , -OR 70 , -SR 70 , -S- M + ,-N(R 80 )2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 -2 (M + )2, -PO3 -2 M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )N(R 80 )2, -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 and -NR 70 C(NR70 )N(R 80 )2, where R 60 , R 70 , R 80 and M + is as defined above. In an independent embodiment, the substituent is -O - M + , -OR 70 , -SR 70 , or -S - M + isn't it.

[0032] The substituent for replacing a hydrogen atom on a nitrogen atom in such a nitrogen-containing group is, unless otherwise specified, -R 60 , -O - M + , -OR 70 , -SR 70 , -S - M + , -N(R 80 )2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R 70 , -SO3 - M + , -SO3R 70 , -OS(O)2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 2- (M + )2, -PO3 2- M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R70 , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )N(R 80 )2, where R 60 , R 70 , R 80 and M + is as defined above.

[0033] In one embodiment, a substituted group has at least one substituent, such as one substituent, two substituents, three substituents, or four substituents, up to the maximum number of substituents possible for a particular moiety.

[0034] Additionally, in embodiments in which groups or moieties are substituted with substituted substituents, the nesting of such substituted substituents is limited to three, thereby preventing the formation of polymers. Thus, in a group or moiety containing a first group that is a substituent of a second group attached to a parent structure, which is itself a substituent of a third group, the first (outermost) group can only be substituted with unsubstituted substituents. For example, in a group containing -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with substituents that are themselves unsubstituted.

[0035] Any group or moiety defined herein may be attached to any other portion of the disclosed structures, such as a parent or core structure, as would be understood by one of ordinary skill in the art, such as by considering valence rules and / or considering functionality, relative to exemplary species, unless the connectivity of the group or moiety to other portions of the structure is explicitly stated or implied by context.

[0036] "Acyl" refers to the group -C(O)R, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl). Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)Ci-C6 alkyl, -C(O)Ci-C6 haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0037] "Aliphatic" refers to a substantially hydrocarbon-based group or moiety. Aliphatic groups or moieties can be acyclic, including alkyl, alkenyl, or alkynyl groups (as well as alkylene, alkenylene, or alkynylene groups), or cyclic versions thereof, such as alicyclic groups or moieties, including cycloalkyl, cycloalkenyl, or cycloalkynyl, further including straight-chain and branched-chain configurations, and all stereoisomers and positional isomers as well. Unless otherwise specified, aliphatic groups are groups containing 1 to 25 carbon atoms (C 1-25 ), for example, 1 to 15 (C 1-15 ), 1~10 pieces (C 1-10 ), 1~6 pieces (C 1-6 ), or 1 to 4 carbon atoms (C 1-4 ), or 3 to 15 (C 3-15 ), 3~10 pieces (C 3-10 ), 3~6 pieces (C 3-6 ), or 3 to 4 (C 3-4) carbon atoms. An aliphatic group can be substituted or unsubstituted, unless expressly referred to as "unsubstituted aliphatic" or "substituted aliphatic." An aliphatic group can be substituted with one or more substituents (up to two substituents for each methylene carbon of the aliphatic chain, or up to one substituent for each carbon of the -C=C- double bond of the aliphatic chain, or up to one substituent for the carbon of the terminal methine group).

[0038] "Lower aliphatic" refers to a group of 1 to 10 carbon atoms (C 1-10 ), e.g., 1 to 6 carbon atoms (C 1-6 ) or 1 to 4 carbon atoms (C 1-4 or for lower alicyclic groups, 3 to 10 carbon atoms (C 3-10 ), for example, 3 to 6 carbon atoms (C 3-6 ) refers to an aliphatic group containing

[0039] "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl group. In certain instances, R is C 1-6 Alkyl group or C 3-6 is a cycloalkyl group. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In substituted alkoxy, R is a substituted alkyl or substituted cycloalkyl, examples of which in compounds of the present disclosure include haloalkoxy groups such as -OCF2H.

[0040] "Alkoxyalkyl" refers to the group -alkyl-OR where R is a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl group, where -CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl group.

[0041] "Alkyl" is a group consisting of 1 to at least 25 (C 1-25 ) carbon atoms, more typically 1 to 6 (C 1-6 ) carbon atoms, such as 1 to 10 (C 1-10(-CHCHCHCHCH)), n-butyl (-CHCHCHCHCH), isobutyl (-CHCH(CH)), sec-butyl (-CH(CH)(CHCHCH), t-butyl (-C(CH)), n-pentyl (-CHCHCHCHCHCHCH), and neopentyl (-CHC(CH)).

[0042] "Amino" refers to the groups -NH, -NHR, or -NRR, where each R is independently selected from H, aliphatic, heteroaliphatic, aromatic, including both aryl and heteroaryl, or heteroalicyclic, or two R groups taken together with the nitrogen to which they are attached form a heterocyclic ring. Examples of such heterocyclic rings include those where two R groups taken together with the nitrogen to which they are attached form one or two heteroatom groups, such as the group [ka] -O- or -N(R g ) optionally interrupted by -(CH2) 2-5 - forms a ring, R g R 70 , -C(O)R 70 , -C(O)OR 60 or -C(O)N(R 80 )2.

[0043] "Amido" refers to a group in which R is hydrogen, heteroaliphatic, or alkyl, particularly C 1-6 It refers to the group -N(R) acyl, which is an aliphatic group such as alkyl.

[0044] "Aromatic," unless otherwise indicated, refers to a cyclic conjugated group or moiety of 5 to 15 ring atoms having a single ring (e.g., phenyl, pyridinyl, or pyrazolyl) or multiple fused rings (e.g., naphthyl, indolyl, or pyrazolopyridinyl) in which at least one ring is aromatic, i.e., at least one ring, and optionally multiple fused rings, have a contiguous 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, [ka] However, in certain instances, the context or explicit disclosure may dictate that the point of attachment is through the non-aromatic portion of the fused ring system. For example: [ka] An aromatic group or moiety can contain only carbon atoms in the ring, such as an aryl group or moiety, or it can contain one or more ring carbon atoms and one or more ring heteroatoms (e.g., S, O, N, P, or Si) containing lone pairs of electrons, such as a heteroaryl group or moiety. Unless otherwise stated, an aromatic group can be substituted or unsubstituted.

[0045] "Aryl" refers to an aromatic carbocyclic group of 6 to 15 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, etc.), unless otherwise indicated. If any aromatic ring moiety contains a heteroatom, the group is heteroaryl and not aryl. Aryl groups can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, aryl groups can be substituted or unsubstituted.

[0046] "Aroaliphatic" refers to an aryl group attached to the parent through an aliphatic moiety. Araliphatic groups include aralkyl or arylalkyl groups such as benzyl and phenylethyl.

[0047] "Carboxyl" refers to -CO2H.

[0048] "Carboxamido" refers to --C(O)amino.

[0049] "Carboxyl ester" or "carboxy ester" refers to the group --C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0050] "Carboxylate" is -C(O)O - Or its salt.

[0051] "Cyano" refers to the group --CN.

[0052] "Alicyclic" refers to a cyclic aliphatic group having a single ring (e.g., cyclohexyl) or multiple rings, such as in a fused, bridged, or spirocyclic system, where the ring or at least one of the rings in the system is aliphatic. Typically, the point of attachment to the parent structure is through the aliphatic portion of the multiple ring system. Alicyclics include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. Alicyclic groups can contain 3 to 25 carbon atoms, e.g., 3 to 15, 3 to 10, or 3 to 6 carbon atoms. Unless otherwise stated, alicyclic groups can be substituted or unsubstituted. Exemplary alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0053] "Halo," "halide," or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0054] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CHF, -CHF, and -CF.

[0055] "Heteroaliphatic" refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., at least one carbon atom from an aliphatic compound or group containing at least two carbon atoms has been replaced with an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroaliphatic compounds or groups, such as heteroalicyclic groups, can be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic.

[0056] "Heteroaryl" refers to an aromatic group or moiety having 5 to 15 ring atoms, including at least one carbon atom and at least one heteroatom such as N, S, O, P, or Si, unless otherwise specified. A heteroaryl group or moiety can contain a single ring (e.g., pyridinyl, pyrimidinyl, or pyrazolyl) or multiple condensed rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). A heteroaryl group or moiety can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, a heteroaryl group or moiety can be substituted or unsubstituted.

[0057] "Heterocyclyl," "heterocyclo," and "heterocycle" refer to both aromatic and non-aromatic ring systems, and more specifically to stable 3- to 15-membered ring moieties containing at least one carbon atom, typically multiple carbon atoms, and at least one heteroatom, such as 1 to 5. The heteroatom can be a nitrogen, phosphorus, oxygen, silicon, or sulfur atom. A heterocyclyl moiety can be a monocyclic moiety or can contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such polycyclic moieties can include fused or bridged ring systems, as well as spirocyclic systems, and any nitrogen, phosphorus, carbon, silicon, or sulfur atom of the heterocyclyl moiety can be optionally oxidized to various oxidation states. For convenience, nitrogens, specifically, but not limited to, those defined as cyclic aromatic nitrogens, are meant to include their corresponding N-oxide forms, even if not expressly defined as such in specific instances. Thus, for example, for a compound having a pyridinyl ring, the corresponding pyridinyl-N-oxide is included as another compound of the invention unless expressly excluded or excluded by context. In addition, the ring nitrogen atom may optionally be quaternized. Heterocycles include heteroaryl moieties and heteroalicyclyl or heteroalicyclic moieties, which are partially or fully saturated heterocyclyl rings.Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, naphthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, iso-, benzophenone ... Quinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl nyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazebicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphosphoranyl, and oxadiazolyl.

[0058] "Hydroxyl" refers to the group --OH.

[0059] "Nitro" refers to the group -NO2.

[0060] "Phosphate" refers to the group -OP(O)(OR')2, where each -OR' is independently -OH; -O-aliphatic, e.g., -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 counterion with a single positive charge. + is K + , Na + , Li + Alkaline ions such as; + N(R"), where R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth ion, e.g., [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The phosphonooxyalkyl is, for example, —CH2OP(O)(O - Na + (((dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ester of a phosphonooxyalkyl group such as, for example, —CH2OP(O)(O-tert-butyl)2.

[0061] "Phosphonate" refers to the group -P(O)(OR')2, where each -OR' is independently -OH; -O-aliphatic, e.g., -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 counterion with a single positive charge. + is a positively charged counterion, e.g., K + , Na + , Li + Alkali metal ions such as +ammonium ions, such as N(R")4 (where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or alkaline earth metal ions, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The phosphonoalkyl can be, for example, —CH2P(O)(OH)2, or —CH2P(O)(O - Na + ((dialkoxyphosphoryl)alkyl) refers to a dialkyl ester of a phosphonoalkyl group such as, for example, —CH 2 P(O)(O-tert-butyl) 2 .

[0062] "Patient" or "subject" may generally refer to any living organism, but more typically refers to mammals and other animals, particularly humans. Thus, the disclosed methods are applicable to both human therapy and veterinary applications.

[0063] A "pharmaceutically acceptable excipient" refers to a substance, other than the active ingredient, contained in a composition containing the active ingredient. As used herein, an excipient may be incorporated within or physically mixed with particles of a pharmaceutical composition. An excipient may be used, for example, to dilute the active agent and / or modify the properties of a pharmaceutical composition. Excipients may include, but are not limited to, anti-adherents, binders, coatings, enteric coatings, disintegrants, flavors, sweeteners, colorants, lubricants, glidants, adsorbents, preservatives, carriers, or vehicles. An excipient may be starch and modified starches, cellulose and cellulose derivatives, sugars and sugar derivatives such as disaccharides, polysaccharides, and sugar alcohols, proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids, or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, hydroxypropyl cellulose, 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, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

[0064] An "adjuvant" is a component that modifies the effect of another agent, typically an active ingredient. Adjuvants are often pharmacological and / or immunological agents. Adjuvants can modify the effect of an active ingredient by increasing the immune response. Adjuvants can also act as stabilizers for the formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants such as Freund's complete or incomplete adjuvant.

[0065] "Pharmaceutically acceptable carrier" refers to an excipient that is a carrier or vehicle, such as a suspending aid, solubilizing aid, or aerosolizing aid. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21st Edition (2005), incorporated herein by reference, describes exemplary compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0066] Generally, the nature of the carrier will depend on the particular mode of administration used. For example, parenteral formulations usually comprise an injectable fluid containing pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solution, aqueous dextrose, glycerol, or the like as a vehicle. In some instances, the pharmaceutically acceptable carrier can be sterilized so as to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the administered pharmaceutical composition may contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, for example, sodium acetate or sorbitan monolaurate.

[0067] "Pharmaceutically acceptable salts," as would be known to one of ordinary skill in the art, refer to pharmaceutically acceptable salts of compounds derived from a variety of organic and inorganic counterions, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, where the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed with acid partners while retaining the biological effectiveness of the free base. In particular, the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and xinafoic acid. "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, and aluminum salts. 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, and polyamine resins.Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference.) In particularly disclosed embodiments, the compound may be a formate, trifluoroactate, hydrochloride, or sodium salt.

[0068] An "effective amount" of a compound or pharmaceutical composition refers to the amount of the compound or pharmaceutical composition sufficient to achieve a particular desired result, such as inhibiting a protein or enzyme. In certain embodiments, an "effective amount" is an amount sufficient to inhibit RIP1, elicit a desired biological or medical response in a tissue, system, subject, or patient, treat a particular disorder or disease, ameliorate or eradicate one or more of its symptoms, and / or prevent the onset of the disease or disorder. The amount of compound that constitutes an "effective amount" can vary depending on the compound, the desired result, the condition and its severity, the size, age, and sex of the patient being treated, etc., as will be understood by one of ordinary skill in the art.

[0069] "Prodrug" refers to a compound that is biologically active or that is converted in vivo to yield a compound that is more biologically active than the parent compound. In vivo conversion 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 the compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the invention include, but are not limited to, aliphatic esters, particularly alkyl esters (e.g., C 1-6 Other prodrug moieties include phosphate ester groups and carboxylic acid esters, such as alkyl esters (e.g., alkyl esters). Other prodrug moieties include those where R' is H or C 1-6Examples of alkyl phosphate esters include, but are not limited to, phosphate esters or salts thereof, such as -CH2-OP(O)(OR')2, where -CH2-OP(O)(OR')2 is an alkyl group. Acceptable esters also include, but are not limited to, cycloalkyl esters and arylalkyl esters, such as benzyl. Examples of pharmaceutically acceptable amides of the compounds of the present invention include, but are not limited to, primary amides and secondary and tertiary alkyl amides (e.g., having about 1 to about 6 carbons). Amides and esters of the disclosed exemplary embodiments of the compounds according to the present invention can be prepared according to conventional methods. A detailed discussion of prodrugs is provided in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, and in 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.

[0070] "Solvate" refers to a complex formed by the combination of solvent molecules with solute molecules or ions. The solvent can be an organic solvent, an inorganic solvent, or a mixture of both. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, and propanol; amides, such as N,N-dialiphatic amides, such as N,N-dimethylformamide; tetrahydrofuran alkyl sulfoxides, such as dimethyl sulfoxide; water; and combinations thereof. The compounds described herein can exist in unsolvated and solvated forms when combined with pharmaceutically acceptable or non-acceptable solvents, such as water, ethanol, and the like. Solvated forms of the compounds of the present disclosure are within the scope of the embodiments disclosed herein.

[0071] "Sulfonamido" refers to the group or moiety -SO2 amino, or -N(R)sulfonyl, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0072] "Sulfanyl" refers to the group or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic (including both -S-aryl and -S-heteroaryl).

[0073] "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).

[0074] "Sulfonyl" refers to the groups: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including both -SO2aryl and -SO2heteroaryl).

[0075] As used herein, "treating" or "treatment" relates to the treatment of a disease or condition of interest in a patient or subject, particularly a human having the disease or condition of interest, including, by way of example and not limitation, the following: (i) specifically, preventing a disease or condition from occurring in a patient or subject, where such patient or subject is susceptible to the condition but has not yet been diagnosed as having the disease or condition; (ii) inhibiting the disease or condition, e.g., preventing or delaying its onset; (iii) alleviating the disease or condition, e.g., reducing the symptoms thereof or causing regression of the disease or condition or its symptoms; or (iv) stabilizing the disease or condition;

[0076] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular disease or condition may not have a known causative agent (and thus the etiology has not yet been determined) and therefore is not yet recognized as a disease, but is recognized only as an undesirable state or syndrome in which a more or less specific set of symptoms has been identified by clinicians.

[0077] The above definitions and the general formula below are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups), which would be readily recognized by one of ordinary skill in the art.

[0078] Those of skill in the art will understand that compounds may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may contain one or more chiral centers and / or double bonds and, as a result, may exist as double bond isomers (i.e., geometric isomers), stereoisomers such as 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. Because the various compound names, formulas, and compound diagrams in the specification and claims may represent only one of the possible tautomeric, conformational, optical, or geometric isomeric forms, those of skill in the art will understand that the disclosed compounds encompass any tautomeric, conformational, optical, and / or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. Techniques known to those skilled in the art, particularly those having the benefit of this disclosure, can be used to separate mixtures of different isomeric forms, including mixtures of enantiomers and / or stereoisomers, to provide each individual enantiomer and / or stereoisomer. In cases of restricted rotation, for example, about an amide bond or between two directly bonded rings such as a pyridinyl ring, a biphenyl group, etc., atropisomers are also possible and are also specifically included in the compounds of the invention.

[0079] In any embodiment, any or all hydrogens present in a compound, or in a particular group or moiety within a compound, can be replaced with deuterium or tritium. Thus, the recitation of alkyl includes deuterated alkyls where from one to up to a maximum number of hydrogens present can be replaced with deuterium. For example, C2D x H 5-x When one to five hydrogens in, etc. are replaced with deuterium, ethyl refers to both C2H5 or C2H5.

[0080] II. RIP1-ACTIVE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING RIP1-ACTIVE COMPOUNDS A. Compound Disclosed herein are compounds and pharmaceutical compositions comprising such compounds that are useful for inhibiting RIP1 and / or treating diseases and / or conditions associated with RIP1. In some embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds are capable of selectively inhibiting RIP1 over RIP2, RIP3, or both RIP2 and RIP3.

[0081] In some embodiments, compounds of the present disclosure have Formula I [ka] or a pharmaceutically acceptable salt thereof. One 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 indicated. With respect to Formula I, Ring B is 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 in which the heteroaryl has one or two ring nitrogen atoms and the remaining ring atoms are carbon, i.e., Ring B is not a triazole, triazine, or heteroaryl containing an oxygen or sulfur ring atom, such as an oxazole, thiazole, or isoxazole. In certain embodiments, Ring B is pyrazolyl, and in other certain embodiments, Ring B is pyridinyl.

[0082] Each R 1 are independently a halogen or a linker-R 6 group, and the linker is a bond or R a where R a But it's not H or D, it's R 6 is heterocyclyl, R b , -C(R f )3, or -C(R f )=C(R f )2. In some embodiments, R 1 is a halogen such as fluoro, chloro, bromo, or iodo, typically bromo. In certain other embodiments, each R 1 independently, -linker-R 6 is.

[0083] R 2 is R a In some embodiments, R 2 is H or C 1-10 Aliphatic, e.g., H or C 1-6 alkyl, and in certain embodiments, R 2 is C 1-6 Alkyl, for example CH3 or CD3.

[0084] R 3 is R a In some embodiments, R 3 is H or C 1-6 H or C, such as alkyl 1-10 aliphatic, and in certain embodiments, R 3 is H.

[0085] If present, each R 4 are independently e and a halogen such as F, Cl, Br, or I, or C 1-6 Alkyl, e.g., methyl, C 1-10 It may be aliphatic.

[0086] L is a heteroatom or R a where R a is not H or D. In some embodiments, L is oxygen or C 1-6 C such as alkyl 1-10 Alkyl, more specifically methylene (-CH2-).

[0087] X is CH2 or O.

[0088] Z is heteroaryl and can be a monocyclic heteroaryl.

[0089] m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3, and can be 1 or 2;

[0090] n is 0, 1, or 2, and can be 0 or 1.

[0091] R a L is R a each independently H or D; C 1-10 Aliphatic;C 1-10 Haloaliphatic;C 5-10 Aromatic;C 3-6 Heterocycle; or C 3-10 It is a spiro heterocycle.

[0092] R b each independently represents -OH, -SH, or -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 , 1 or 2 NR d R d , carboxyl, or combinations thereof, optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH 1-10 It is alkyl.

[0093] R c are each independently 1, 2, or 3 R e C can be substituted with 1-10 alkyl; 1, 2, or 3 R e C can be substituted with 2-10 Alkenyl; 1, 2, or 3 R e C can be substituted with 2-10 Alkynyl; 1, 2, or 3 R e C can be substituted with 3-6 cycloalkyl; or one, two, or three R e C can be substituted with 5-10 It is aromatic.

[0094] R d are each independently H; one, two or three R e or C 3-9 C optionally substituted with heterocyclyl 1-6 alkyl; 1, 2 or 3 R e C optionally substituted with 3-6 cycloalkyl; one, two or three R e C optionally substituted with 3-6 Heterocycle; 1, 2 or 3 R b C optionally substituted with5-10 aryl; one, two or three R e C optionally substituted with 5-10 Heteroaryl or two R d The group, together with the nitrogen to which it is attached, may be one or more R e C optionally substituted with 3-9 heterocycle, or one or more R e C optionally substituted with 5-10 Forming a heteroaryl.

[0095] R e are each independently a 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 is.

[0096] Furthermore, R f are each independently an alkyl phosphate, R a , R b , or R e or two R f The group, together with the carbon atom to which it is attached, forms a C 2-6 alkenyl group, one or more R e C can be substituted with 3-6 Cycloalkyl group or one or more R e or C which can be substituted with acyl 3-10 Forms a heterocycle.

[0097] In some embodiments, n is 0. In other embodiments, n is 1, and in such embodiments, R 4 is C such as methyl 1-6 It can be alkyl.

[0098] In certain embodiments of formula I, ring B is pyridinyl or pyrazolyl and L is a heteroatom or C 1-10alkyl, Z is heteroaryl, and each R 1 is heterocyclyl or C 1-10 It is aliphatic and R 2 But H or C 1-6 alkyl, and R 3 But H or C 1-6 alkyl, m is 1, and n is 0.

[0099] In any embodiment, Z can be a 5- or 6-membered nitrogen-containing heteroaryl, such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, or triazolyl. In certain such embodiments, Z is a 6-membered heteroaryl, such as a 6-membered nitrogen-containing heteroaryl, which can be pyridinyl, pyrimidinyl, or pyridazinyl.

[0100] In any embodiment, Z can be unsubstituted or Z can be substituted as defined herein. In some embodiments, Z can be selected from halogen, C 1-6 Alkyl, C 1-6 In certain embodiments, Z is unsubstituted or substituted with OH, CH3, F, or CF3.

[0101] In some embodiments, ring B can be a 5-membered heteroaryl ring having at least one ring nitrogen atom, such as 1, 2, or 3, preferably 1 or 2, more preferably 2, ring nitrogen atoms, with the remaining ring atoms being carbon. In some embodiments, -N(R 3 The C(O)- moiety is attached to Ring B at a ring nitrogen atom on Ring B.

[0102] In some embodiments, Ring B is pyrazolyl, and is —N(R 3 The C(O)- moiety is attached to Ring B at a ring nitrogen atom on Ring B.

[0103] In some embodiments, X is O. In some other embodiments, X is CH.

[0104] In any embodiment, each R 1 are independently heterocyclyl, unsubstituted C 1-10 Aliphatic or -OH, halogen, carboxyl, carboxyl ester, heterocyclyl, amino, alkoxy, phosphate, cycloalkyl, alkenyl, -OC(O)NH(C 1-4 alkyl)-amino, -OC(O)R 8 C substituted with one or two substituents selected from 1-10 Aliphatic; or -OC(O)(CHR 9 )2CO2H. -OC(O)-R 8 The moiety is derived from an amino acid and is -OC(O)-R 8 The -OC(O)- portion of R corresponds to the acid moiety on the amino acid. 8 But -N(R 10 )2 or nitrogen-containing non-aromatic heterocyclyl, R 10 is H or a carboxyl ester. 9 is independently H or —O-acyl.

[0105] -OC(O)-R 8 With respect to the moiety, the nitrogen-containing non-aromatic heterocyclyl may be a 5- or 6-membered unsaturated nitrogen-containing heterocyclyl, such as pyrrolidinyl. The amino acid may be any amino acid, such as a naturally occurring 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. Those skilled in the art will understand that when an amino acid contains one or more chiral centers, all enantiomers, diastereomers, and / or mixtures thereof are contemplated. For example, the amino acid may be an L-amino acid, a D-amino acid, or a mixture thereof. In some embodiments, the amino acid is an L-amino acid. Also, in certain embodiments, -OC(O)-R 8 is -OC(O)CH(NH2)R 11, [ka] or -OC(O)-(CH2) 1-2 C(NH2)CO2H, where R 11 is an amino acid side chain, and / or H, -CH3, isopropyl, -CH2CH(CH3)2, -CH(CH3)Et, -CH2CH2SCH3, [ka] -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2CH2NHC(O)(NH)NH2, [ka] It can be -CH2CH2CH2CH2NH2, -CH2CO2H, or CH2CH2CO2H.

[0106] Also, R 1 With respect to at least one R 1 is an 8- to 12-membered spiroheterocyclyl, C 1-10 Alkyl, or C 2-10 It can be an alkyne. 1-10 Alkyl or C 2-10 The alkyne can be linear, branched, and / or cyclic and can have one or two substituents. One substituent can 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 are, for example, [ka] As such, it may contain linear and / or branched segments and cyclic segments.

[0107] In some embodiments, Z is [ka] and if present, each R 5 are independently e and p is 0, 1, 2, 3, or 4, typically 0, 1, or 2, more typically 0 or 1; in some embodiments, p is 0, and in certain other embodiments, p is 1. In any embodiment, each R 5 are independently OH, halogen, C 1-6 Alkyl, or C 1-6 It can be haloalkyl, such as OH, CF, methyl, or fluoro. In some embodiments, p is 1, while in other embodiments, p is 0. Also, 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, 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.

[0108] In some embodiments of Formula I, the compound has Formula I-1 or I-2 [ka] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof.

[0109] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof.

[0110] Regarding formulas I-1 to I-13, rings B, L, X, Z, R 1 , R 2 , R 3 , R 4 , m, and n, if present, are as defined herein for formula I.

[0111] In certain embodiments of the disclosed formulas, Z is a 5-membered heteroaryl, for example, Z is thiazole, pyrazole, oxazole, or furan, each of which may be selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 With respect to Formulae I-1 to I-13, Z is optionally substituted by haloalkyl, or OH. [ka] In certain embodiments of each of Formulas I-1 to I-13, [ka] is selected from the group consisting of:

[0112] In any of the above embodiments relating to Formula I and / or Formulas I-1 through I-13, R 1 may be selected from any of the following: [ka] [ka] [ka]

[0113] Certain embodiments of Formula I and / or Formulas I-1 through I-13 also include R 1may be selected from any of the following: [ka] [ka]

[0114] In certain embodiments of Formula I and / or Formulas I-1 through I-13, R 1 teeth, [ka] is.

[0115] Also in other specific embodiments of Formula I and / or Formulas I-1 to I-13, R 1 teeth, [ka] is.

[0116] In other embodiments of Formula I and / or Formulas I-1 to I-13, R 1 is a halogen such as Br.

[0117] Certain disclosed exemplary compounds within the scope of one or more of Formulas I, and I-1 through I-13, include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0118] Exemplary compounds within the scope of one or more of Formulas I, and I-1 through I-13, include the following: 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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-3-yl)-4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxamide; I-18: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-ylmethyl)-1H-pyrazole-1-carboxamide; I-19: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide; I-20: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide; I-21: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide; I-22: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxamide; I-23: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide; I-24: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide; I-25: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-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]oxazepin-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]oxazepin-3-yl)picolinamide; I-28: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxamide; 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]oxazepin-3-yl)-4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxamide; I-30: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyrimidin-2-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-35: (S)—N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-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]azepin-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]oxazepin-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]azepin-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]azepin-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]azepin-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]azepin-3-yl)-1H-pyrazole-1-carboxamide; I-42: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-fluoropyridin-3-yl)methyl)-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-49: (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2,6-difluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide; 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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; I-51: (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]oxazepin-3-yl)picolinamide; I-52: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-53: (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]oxazepin-3-yl)picolinamide; I-54: (S)-4-((2-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]oxazepin-3-yl)picolinamide I-55: (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-56: (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-57: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide I-58: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide I-59: (S)-4-((5-fluoropyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-60: (S)-4-((5-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]oxazepin-3-yl)picolinamide I-61: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-ylmethyl)picolinamide I-62: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-ylmethyl)picolinamide I-63: (S)—N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide I-64: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-ylmethyl)picolinamide I-65: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide I-66: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide I-67: (S)-4-((5-fluoropyridin-3-yl)oxy)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-68: (S)-4-((3,5-dimethylisoxazol-4-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-69: (S)-4-((3,5-dimethylisoxazol-4-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-70: (S)-4-((1H-pyrazol-1-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-71: (S)-4-((1H-pyrazol-1-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-72: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)methyl)picolinamide I-73: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)methyl)picolinamide I-74: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylpyridin-3-yl)oxy)picolinamide I-75: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylpyridin-3-yl)oxy)picolinamide I-76: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(thiazol-4-ylmethyl)picolinamide I-77: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(thiazol-4-ylmethyl)picolinamide I-78: (S)-4-((2,6-dimethylpyridin-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]oxazepin-3-yl)picolinamide I-79: (S)-4-((2,6-dimethylpyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-80: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide I-81: (S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide I-82: (S)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylpyridin-3-yl)oxy)picolinamide I-83: ​​(S)-4-((2-fluoropyridin-3-yl)oxy)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-84: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-85: (S)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide I-86: (S)-4-hydroxy-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-87: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide I-88: (S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide I-89: (S)-4-hydroxy-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-90: (S)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide I-91: (S)-4-((2-cyanopyridin-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]oxazepin-3-yl)picolinamide I-92: (S)-4-((2-cyanopyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-93: (S)-4-((6-cyanopyridin-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]oxazepin-3-yl)picolinamide I-94: (S)-4-((6-cyanopyridin-2-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-95: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-fluoropyridin-3-yl)oxy)picolinamide I-96: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide I-97: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)picolinamide I-98: (S)-4-((2-ethylthiazol-4-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-99: (S)-4-((2-ethylthiazol-4-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-100: (S)-4-((5-fluoropyridin-3-yl)oxy)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-101: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((5-fluoropyridin-3-yl)oxy)picolinamide I-102: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide I-103: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-104: (S)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-105: (±)-4-((6-fluoropyridin-2-yl)methyl)-N-((3S)-5-methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide I-106: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-107: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-7-(3-methyl-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide I-108: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide I-109: (S)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-110: (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-2-yl)oxy)-1H-pyrazole-1-carboxamide I-111: (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide I-112: (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide I-113: (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]azepin-3-yl)-1H-pyrazole-1-carboxamide I-114: (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]azepin-3-yl)-1H-pyrazole-1-carboxamide I-115: (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]azepin-3-yl)-1H-pyrazole-1-carboxamide I-116: (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]azepin-3-yl)-1H-pyrazole-1-carboxamide I-117: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((1-hydroxycyclobutyl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide I-118: (S)-N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-119: (S)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-120: (S)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-121: (S)-N-(6-fluoro-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-122: (S)-N-(6-fluoro-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-123: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)thiazol-4-yl)methyl)picolinamide I-124: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)thiazol-4-yl)methyl)picolinamide I-125: (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-126: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide I-127: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide I-128: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-yloxy)picolinamide I-129: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-yloxy)picolinamide I-130: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)oxy)picolinamide I-131: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)oxy)picolinamide I-132: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide I-133: (S)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide I-134: (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-135: (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-136: (S)-4-((1-methyl-1H-pyrazol-4-yl)oxy)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-137: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(oxazol-4-ylmethyl)picolinamide I-138: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(oxazol-4-ylmethyl)picolinamide I-139: tert-butyl (S)-4-((3-(4-((2-fluoropyridin-3-yl)oxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)piperidine-1-carboxylate I-140: (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-7-((1-methylpiperidin-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-141: (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-4-oxo-7-(piperidin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide.

[0119] Additional exemplary compounds within the scope of one or more of Formulas I, and I-1 through I-13, include the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0120] Further exemplary compounds within the scope of one or more of Formulas I, and I-1 through I-13, include the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0121] B. Therapeutic Combinations The compounds described herein may be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to or in combination with other established therapies. The compound or compounds, or compositions containing the compound (or compounds), may be administered once or multiple times. In some embodiments, the compounds of the present invention may be used in combination with other therapeutic agents useful for the disorder or condition being treated. These other therapeutic agents may be administered simultaneously, sequentially in any order, by the same route of administration as the compounds of the present disclosure or by different routes. In sequential administration, the compounds and therapeutic agents may be administered such that the effective period of at least one compound and therapeutic agent overlaps with the effective period of at least one other compound and / or therapeutic agent. In an exemplary embodiment of a combination containing four components, the effective period of the first component administered may overlap with the effective periods of the second, third, and fourth components, but the effective periods of the second, third, and fourth components may or may not independently overlap with each other. In another exemplary embodiment of a combination comprising four components, the effective period of the first component administered overlaps with the effective period of the second component but not with the effective period of the third or fourth component; the effective period of the second component overlaps with the effective period of the first component and the third component; and the effective period of the fourth component overlaps only with the effective period of the third component. In some embodiments, the effective periods of all compounds and / or therapeutic agents overlap with each other.

[0122] In some embodiments, the compound is administered with another therapeutic agent, such as an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof. The anti-inflammatory agent can be a steroid or a nonsteroidal anti-inflammatory agent. In certain embodiments, the nonsteroidal anti-inflammatory agent is selected from an aminosalicylates, a cyclooxygenase inhibitor, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an antilymphocyte globulin, an antithymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0123] In some embodiments, the compounds may be used in combination with anticancer or cytotoxic agents. Various classes of anticancer and anti-neoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, multiple hormones and hormone antagonists, and hypomethylating agents, e.g., DNMT inhibitors such as azacitidine and decitabine. Exemplary alkylating agents include, but are not limited to, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimine, methylmelamine, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, by way of example and not limitation, the folic acid analog methotrexate; pyrimidine analogs fluorouracil and cytosine arabinoside; and purine analogs mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkyloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. Exemplary enzymes effective as anti-neoplastic agents include L-asparaginase. Exemplary coordination compounds include, by way of example and not limitation, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, by way of example and not limitation, the corticosteroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

[0124] These and other useful anti-cancer compounds are described in The Merck Index, 13th Ed. (O'Neil MJ et al., ed.) Merck Publishing Group (2001) and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Brunton LL ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0125] Among the CTLA4 antibodies that may be used in combination with the inhibitors of the present disclosure is ipilimumab, available commercially as YERVOY® by Bristol-Myers Squibb.

[0126] Other chemotherapeutic agents for combination include immuno-oncology agents such as checkpoint pathway inhibitors, e.g., PD-1 inhibitors such as nivolumab and lambrolizumab, and PD-L1 inhibitors such as pembrolizumab, MEDI-4736, and MPDL3280A / RG7446. Additional checkpoint inhibitors for combination with the compounds disclosed herein include anti-LAG-3 agents such as BMS-986016 (MDX-1408).

[0127] Additional chemotherapeutic agents for combination with the inhibitors of the present disclosure include anti-SLAMF7 agents such as the humanized monoclonal antibody elotuzumab (BMS-901608), anti-KIR agents such as the anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137 agents such as the fully human monoclonal antibody urelumab (BMS-663513).

[0128] The compounds of the present disclosure may also be advantageously used in conjunction with CAR-T therapy. Examples of currently available CAR-T therapies are axicabtagenecilloreucel and tisagenlecleucel.

[0129] Additional anti-proliferative compounds useful in combination with the compounds of the present invention include, by way of example and not limitation, antibodies against growth factor receptors (e.g., anti-Her2); and cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.

[0130] Additional chemotherapeutic agents useful in combination with the present compounds include proteasome inhibitors such as bortezomib, carfilzomib, and marizomib.

[0131] Examples of kinase inhibitors that are useful in combination with the compounds of the present disclosure, 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, 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.

[0132] In other embodiments, the second therapeutic agent may be selected from any of the following: Analgesics - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone; Antibiotics—aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, cef antibacterial agents (e.g., ceftizime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, and telavancitin), lincosamides (e.g., clindamycin and incomysin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spectinomycin), monobactams (e.g., azoxymimidine, azoxym ... threonam), nitrofurans (e.g., furazolidone and nitrofurantoin), penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), penicillin combinations (e.g., amoxicillin / clavulanate, ampicillin / sulfactam, piperacillin / tazobactam, and ticarcillin / clavulanate), Polypeptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide, sulfonamide chrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole,sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole), tetracyclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamine, amide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin), and others such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinuplicin / dalfopristin, rifaximin, thiamphenicol, tigecycline, and timidazole; Antibodies—anti-TNF-α antibodies, such as infliximab (Remicade™), adalimumab, golimumab, certolizumab; anti-B cell antibodies, such as rituximab; anti-IL-6 antibodies, such as tocilizumab; anti-IL-1 antibodies, such as anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, such as nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakimab, fezakinumab, fretikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab; Anticoagulants—warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin; Anti-inflammatory agents - steroids such as budesonide, non-steroidal anti-inflammatory agents such as aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin; Immunosuppressants - drugs designed to inhibit cellular immunity while leaving the recipient's humoral immune response intact, including corticosteroids such as mercaptopurine, dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisone; alkylating agents such as cyclophosphamide; calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus; inhibitors of inosine monophosphate dehydrogenase (IMPDH) such as mycophenolic acid, mycophenolate mofetil, and azathioprine; and various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T cell antibody (OKT3)), as well as radiation. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trade name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name Purinethol; prednisone and prednisolone are available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune; tacrolimus is currently available from Fujisawa under the trade name Prograf; cyclosporine is currently available from Novartis under the trade name Sandimmune and from Abbott under the trade name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the trade name Cellcept and from Novartis under the trade name Myfortic; azathioprine is currently available from GlaxoSmithKline; is available from 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 Guanylate cyclase-C receptor agonists or intestinal secretagogues, such as linaclotide, are sold under the name Linzess.

[0133] These various agents may be used according to standard or conventional dosages as specified in the prescribing information accompanying the commercially available drug form (see also the compounding information in the 2006 Edition of The Physician's Desk Reference), the disclosures of which are incorporated herein by reference.

[0134] III. Methods of Making Compounds The disclosed embodiments of the present compounds can be prepared by any suitable method, as will be understood by those skilled in the art. One 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:

[0135] [ka] Referring to Scheme 1, a metal-mediated cross-coupling reaction can be used to prepare the cross-coupling product 104, which is shown in Scheme 1 as "R 6 - R containing a "linker" group 1The protected amine precursor 100 can be coupled with group 102. In some embodiments, the metal-mediated cross-coupling reaction can be carried out using a transition metal catalyst, such as a palladium catalyst. Exemplary palladium catalysts include, but are not limited to, Pd(0) catalysts (e.g., Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, etc.) or Pd(II) catalysts (e.g., second- or third-generation XPhos Pd, PdCl2, Pd(OAc)2, etc.). In some embodiments, a palladium catalyst can be used in combination with another co-catalyst, such as CuI, to facilitate the cross-coupling reaction, such as in a Sonogoshira reaction. The metal-mediated cross-coupling can also include using a base, such as an amine base (e.g., Et3N), or an inorganic base (e.g., Cs2CO3, Na2CO3, K2CO3, etc.), and a solvent (e.g., dimethylformamide). Referring to Scheme 1, X is a group suitable for metal-mediated cross-coupling, such as a halogen or a triflate group, and PG is an amine protecting group that may be selected from, but is not limited to, a 9-fluorenylmethoxycarbonyl ("Fmoc") group, a t-butyloxycarbonyl ("Boc") group, a trityl ("Tr") group, an allyloxycarbonyl ("Alloc") group, a benzyloxycarbonyl ("Cbz") group, and the like.

[0136] Representative examples of the process steps shown in Scheme 1 are provided in Scheme 2 below. [ka]

[0137] Once cross-coupling product 104 is produced, it may be subjected to an optional linker group reduction step, which can reduce linker groups containing one or more unsaturated sites to saturated linker groups and / or linker groups with a lower degree of unsaturation. If a linker reducing group is used, this may be followed by a deprotection step, as shown in Scheme 3, followed by an amide formation step. Alternatively, if a linker group reduction step is not used, cross-coupling product 104 may be deprotected and converted to amide compound 302.

[0138] [ka] Referring to Scheme 3, an optional linker reduction step can be performed. For example, if the linker contains an unsaturated site (e.g., a double or triple bond), the unsaturated site can be reduced to full saturation (e.g., reducing a double and / or triple bond to a single bond) or to a lesser degree of unsaturation (e.g., reducing a triple bond to a double bond). Suitable reagents for performing such an optional linker reduction step will be recognized by those of skill in the art with the benefit of this disclosure. However, one exemplary set of conditions involves exposing the cross-coupling product 104 to H2 in the presence of Pd on carbon. Because these steps are optional, they need not be performed in all embodiments. Alternatively, in some embodiments, the cross-coupling product 104 can be deprotected to provide an amine, which can then be converted to amide compound 302 by reacting with a suitable acid coupling partner 300, as shown in Scheme 3.

[0139] Alternatively, as shown in Scheme 4, urea-linked compounds can be prepared from the cross-coupling product 104. [ka]

[0140] With reference to Scheme 4, cross-coupling product 104 is deprotected to provide an amine and then treated with phosgene or a phosgene substitute, such as diphosgene or triphosgene, to form isocyanate 1500. Typically, the phosgene or phosgene substitute treatment is carried out in an aprotic solvent, such as toluene, hexane, or a chlorinated solvent, such as dichloromethane, in the presence of a suitable base, such as a trialkylamine, e.g., triethylamine or diisopropylethylamine. Isocyanate 1500 is then treated with nitrogen heterocycle 1502 to form urea-linked compound 1504. The reaction is typically carried out in a suitable solvent, such as the solvent and / or base used in the phosgene or phosgene substitute treatment, and in the presence of a suitable base. In some embodiments, isocyanate 1500 is not isolated after formation, and nitrogen heterocycle 1502 is simply added to the reaction mixture.

[0141] Some exemplary disclosed compounds are alkynyl-substituted analogs. These compounds can be made using a metal-mediated coupling strategy, as discussed above with reference to Scheme 1. Scheme 5 shows a more detailed general method for making alkynyl-substituted analogs according to the present disclosure.

[0142] [ka] Referring to Scheme 5, nitrogen was bubbled through a stirred solution of the halide (1 equiv.), compound 700, CuI (0.1–0.2 equiv.), and Pd(PPh3)4 (0.05–0.1 equiv.) in dry DMF (3–4 mL / mmol) in a vial for 3 minutes. Subsequently, NEt3 (10 equiv.) was added to the dark reaction solution, followed by the corresponding alkyne (1.5–3 equiv.), compound 702, in rapid succession. Nitrogen was bubbled through the reaction mixture for 2 minutes, and the vial was capped. The reaction mixture was stirred at a suitable reaction temperature, such as 70–90 °C, for a suitable 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 worked up by one of the following methods: a) ice-water / organic solvent dilution workup; b) concentration to dryness followed by ice-water / organic solvent dilution workup; or c) dilution of the crude residue with ice-water, sonication, and warming of the slurry to room temperature. The resulting gray / dark solid was collected by filtration, suction dried, dissolved in THF (20 mL), and filtered through a Celite® / silica gel pad, rinsing the pad with THF. The crude material was then purified by reverse-phase or normal-phase silica gel flash column chromatography to afford the corresponding alkynyl-substituted analogs, compound 704, in 25-69% yields.

[0143] IV. Methods of Using the Compounds A. Disease / Disorder The disclosed compounds, as well as combinations and / or pharmaceutical compositions thereof, can be used to inhibit RIP1 kinase by contacting the kinase either in vivo or ex vivo with a disclosed compound or compounds, or a composition comprising a disclosed compound or compounds. The disclosed compound or compounds, or a composition comprising a disclosed compound or compounds, can also be used to ameliorate, treat, or prevent a variety of diseases and / or disorders. In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be useful for treating conditions in which inhibition of RIP1 or a pathway involving RIP1 is therapeutically beneficial. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds are useful for treating autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancer, ischemic conditions, red blood cell deficiencies, lung and brain injuries (e.g., induced by ischemia-reperfusion, cisplatin, and / or cerebrovascular accidents), and bacterial and viral infections.

[0144] 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.

[0145] The disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof may also be useful for treating immunoregulatory disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunoregulatory disorders that can be treated with the compounds (or pharmaceutical compositions or combinations thereof) include organ or tissue transplantation, transplant-induced graft-versus-host disease, 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, autoimmune syndromes including glomerulonephritis, rheumatoid arthritis, and the like. Post-infectious autoimmune diseases including typhoid fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, dystrophy epithelial cornea, corneal leukemia, ocular pemphigus, Mooren's ulcer, scleritis, malignant exophthalmos, Falk-Koyanagi-Harada disease, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular damage caused by ischemic disease and thrombosis, ischemic bowel disease, ischemic reperfusion injury, inflammatory bowel disease Disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuropathy, polyneuropathy, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, hypoplastic anemiaanemia), idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, albinism, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy or cardiomyopathic infection, scleroderma (including systemic sclerosis), antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, adiposity, eosinophilic fasciitis, gums, teeth Lesions of periodontal tissue, alveolar bone, dental cementum, glomerulonephritis, male pattern baldness or alopecia due to prevention of hair loss or provision of hair growth and / or promotion of hair growth and hair growth, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, ischemia-reperfusion injury of organs occurring during preservation, transplantation, or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary toxicosis caused by oxygen or drugs, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment Sepsis, age-related macular degeneration, vitreous scarring, corneal alkali burns, erythematous polymorphic dermatitis, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, carcinoma metastasis and altitude sickness, diseases caused by histamine or leukotriene-C4 release, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock or anoxia, type B viral hepatitis, non-A / non-B hepatitis, liver cirrhosis These include, but are not limited to, alcoholic liver disease, including alcoholic cirrhosis, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH), autoimmune hepatobiliary disease, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, acute exacerbation of chronic liver failure, chronic kidney disease, kidney damage / injury (e.g., caused by nephritis, kidney transplant, surgery, administration of nephrotoxic drugs, acute kidney injury), enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, or chronic bacterial infection.

[0146] In certain embodiments, the compounds are useful for treating neuropathic pain, including inflammation-induced pain.

[0147] In certain embodiments, the compound is useful for treating interleukin-1 converting enzyme-associated related fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases (e.g., Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Fa It is useful in the treatment of diseases such as Barr disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, polysulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pyknodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease.

[0148] In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof are useful for the treatment and / or prevention of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, particularly pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout flare, pseudogout, Saffo's syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0149] The use of the present compounds in combination with other therapies is particularly useful for treating hyperproliferative disorders.The present compounds can be used in combination with standard therapy to treat disorders such as cancer, leukemia, and lymphoma.For example, myelodysplastic syndrome (MDS) can be treated with the compounds disclosed herein in conjunction with standard therapy.Therapeutic agents for use in combination with the present compounds 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 present compounds to treat MDS.

[0150] Proliferative diseases that may be treated by the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof include benign and malignant tumors, solid tumors, carcinomas of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, urogenital tract, esophagus, larynx, skin, bone, or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, particularly colon carcinoma or colorectal adenoma, tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, epithelial neoplasms, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma , non-small cell lung carcinoma, lymphomas such as Hodgkin's and non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-mediated disorders, hematopoietic neoplasms such as the lymphomas mentioned above, MyD88-mediated disorders (ABC diffuse large B-cell lymphoma (DLBCL) and Waldenstrom's macroglobulinemia), Hodgkin's lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), smoldering or asymptomatic multiple myeloma, or hematologic malignancies (leukemia, acute myeloid leukemia (AML), DLBCL, ABC and other malignancies, including DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma. Specifically, the compounds of the present disclosure are useful for treating drug-resistant malignancies, such as those resistant to the JAK inhibitor ibrutinib, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenstrom's macroglobulinemia.

[0151] Examples of allergic disorders that may be treated using the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by a pathophysiological disorder, essential asthma of unknown or undetermined cause, emphysema-like asthma, exercise-induced asthma, emotion-induced asthma, asthma caused by environmental factors, and the like). These include extrinsic asthma caused by or associated with bacterial, fungal, protozoan, or viral infections, cold-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoan, or viral infections, incipient asthma, wheezing infant syndrome, bronchitis, cough-variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis.

[0152] As another example, rheumatoid arthritis (RA) typically causes generalized swelling, pain, loss of motion, and tenderness in target joints. RA is characterized by a chronically inflamed synovium densely packed with lymphocytes. The synovium, typically one cell layer thick, appears to be cellularly dense and similar in morphology to lymphoid tissue, containing clusters of dendritic cells, T, B, and NK cells, macrophages, and plasma cells. This process, as well as numerous immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, ultimately leads to the destruction of joint integrity, resulting in deformity, permanent loss of function, and / or bone erosion at or near the joint. The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof, can be used to treat, ameliorate, or prevent any one, some, or all of these symptoms of RA. Thus, in the context of RA, a compound is considered to provide a therapeutic benefit if it achieves a reduction or amelioration of any of the symptoms commonly associated with RA, regardless of whether the treatment results in a treatment associated with the underlying RA and / or a reduction in the amount of circulating rheumatoid factor ("RF").

[0153] The American College of Rheumatology (ACR) has developed criteria to define improvement and clinical remission in RA. One such parameter, ACR20 (ACR criteria for 20% clinical improvement), requires a 20% improvement in tender and swollen joint counts, as well as a 20% improvement in three of the following five parameters: patient's global assessment, physician's global assessment, patient's pain assessment, degree of disability, and acute phase reactant levels. These criteria are expanded for ACR50 and ACR70, which are 50% and 70% improvements, respectively. Other criteria include Paulu's criteria and radiographic progression (e.g., Sharp score).

[0154] In some embodiments, therapeutic benefit in a patient with RA is achieved when the patient exhibits an ACR20. In certain embodiments, an ACR improvement of ACR50 or even ACR70 can be achieved.

[0155] In one embodiment, the compounds of the present disclosure can be used to delay the onset of the consequences of aging. For example, the compounds reduce the increased chronic inflammation ("inflammaging") associated with aging. Numerous symptoms and conditions are associated with inflammation, and examples of such conditions that can be treated with the compounds include 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 include those described by 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 can be used to reduce the effects of aging on the reproductive system. For example, necroptosis induced by RIP1 signaling has been implicated in reproductive aging according to Li et al. eLife 2017;6:e27692 and Chaudhary et al. Journal of Biomedical Science (2019) 26:11, and therefore the compounds can be used to treat age-related conditions such as declining testosterone levels, decreased fertility, and prostate hyperplasia.

[0156] Further diseases or disorders that can be treated and / or prevented using the compounds and compositions of the invention include amyotrophic lateral sclerosis (ALS), autoimmune syndromes, rheumatoid arthritis, type 1 diabetes, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, reversible obstructive airways disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hyperresponsiveness, allergic rhinitis, spondyloarthritis, ankylosing spondylitis, autoimmune hepatitis, autoimmune hepatobiliary diseases. Destructive bone disorders such as cerebrovascular disease, allergic diseases, chronic obstructive pulmonary disease, emphysema, Friedreich's ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (polyQ) disease, Fahr's disease, Menke's disease, Wilson's disease, prion disorders, bone resorption disorders, and multiple myeloma-associated 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 polymorpha, erythematous dermatitis, linear IgA bullous dermatitis, cemental dermatitis, gingivitis, periodontitis, inflammation, gingival lesions, alveolar bone, alveolar ridge stroma, sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, hemangioma, vasculitis, erythema, cutaneous eosinophilia, steatosis, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, verrucous conjunctivitis, alkali burns, Behçet's disease, uveitis associated with Behçet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukemia, ocular pemphigus, Mooren's ulcer, scleritis, Vogt-Koyanagi-Harada syndrome, hematological disorders, hematological malignancies, lymphoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom'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, Kitt-Barr lymphoma / leukemia, acute lymphocytic leukemia, B-cell lymphocytic 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, drug-resistant malignancies, e.g., JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies, e.g., ibrutinib-resistant hematologic malignancies, ibrutinib-resistant CLL, and ibrutinib-resistant Waldenstrom's macroglobulinemia, acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders, e.g., solid tumors, ocular angiogenesis, hemangiomas, including angiogenic disorders, e.g., infantile hemangiomas; sepsis, septic shock , dysentery; migraine, bronchitis, gastric ulcer, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 converting enzyme-associated fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease Disease, Farber disease, Fucosidosis, Galactosialidosis, GM1 gangliosidosis, Mucolipidosis, Childhood free sialic acid storage disease, Juvenile hexosaminidase A deficiency, Krabbe disease, Lysosomal acid lipase deficiency, Dystrophic leukodystrophy, Mucopolysaccharidosis disorders, Multiple sulfatase deficiency, Niemann-Pick disease, Neuronal ceroid lipofuscinosis, Pompe disease, Pycnodyssotosis, Sandhoff disease, Schindler disease, Sialic acid storage disease, Tay-Sachs disease, Wolman disease, Huntington's disease, Parkinson's disease, Neurodegenerative disorders, Huntington's disease , Parkinson's disease, metastatic melanoma, neurodegeneration associated with HIV infection and CMV retinitis, e.g. associated neurocognitive disorders or dementia, fibrotic conditions such as non-alcoholic steatohepatitis and cardiac conditions such as ischemia-reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Illness syndrome, rubella arthritis, acute synovitis,Pancreatic beta-cell diseases; 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, fibroid 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; acute hepatitis infection (including hepatitis A, B, and C), AIDS, ARC, or malignant tumors, viral diseases including herpes; stroke, myocardial infarction, arteriosclerosis, atherosclerosis, Atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardial ischemia, ischemia in stroke and heart attack, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, ischemia-reperfusion injury of organs occurring during storage, transplantation or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions related to prostaglandin-endoperoxidase-2, pemphigus vulgaris, autoimmune / polymyositis, dermatomyositis, vitiligo, photoallergic sensitivity, ischemia-reperfusion injury, cardiac ischemia-reperfusion injury due to myocardial infarction, multiple system atrophy, Parkinson's disease syndrome, frontotemporal dementia, intracranial hemorrhage, cerebral hemorrhage, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, demyelinating diseases, systemic juvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), kidney transplant, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), COVID-1 ARDS due to 9, post-infectious autoimmune diseases, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO deficiency syndrome (F-kappa-B essential regulator gene (also known as IKK gamma or IKKG) deficiency syndrome), solid organ malignancies, lysosomal storage diseases, glaucoma, retinal degenerative diseases, retinal ischemia / reperfusion injury, renal reperfusion injury, cataracts, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, anthrax lethal toxin-induced septic shock, LPS-induced cell death,Infectious encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic sclerosis, macular edema, diabetic retinopathy, central circular choroidal dystrophy, BEST disease, adult vitreous disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, toxic retinitis and light-induced toxicity, macula Edema, central circular choroidal dystrophy, BEST disease, adult vitreous disease, pattern dystrophy, optic nerve injury, optic neuritis, optic neuropathy, central retinal artery occlusion, ischemic optic neuropathies (e.g., arteritic or non-arteritic 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, toxic, and hereditary optic neuropathies, dominant optic atrophy, Beer's syndrome, Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paresis, subarachnoid hemorrhage, perinatal Brain injury, subclinical brain injury, spinal cord injury, anoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia and hypoxia, peritoneal damage caused by peritoneal dialysis fluid (PDF) and PD-related side effects, glomerular disease, tubulointerstitial disease, interstitial nephritis, obstruction, polycystic kidney disease), focal glomeruli, immune complex nephropathy, diabetic nephropathy, Goodcure syndrome, pancreatic cancer, urinary tract 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, head and neck cancer Neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., brain carcinoma, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, ascites, malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic neoplasm, epithelial neoplasm, gastric cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, 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 carcinoma, vulvar cancer, carcinoma of the adrenal cortex, ACTH-producing tumors and leukemia, respiratory infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, adenovirus, reovirus, etc., shingles caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infectious diseases such as Bacillus cereus, Vibrio parahemolyticus, Enterohemorrhagic Escherichia coli, Streptococcus areus, aureus, MRSA, Salmonella, Botulinum, Candida, Paget's disease, achondroplasia, xerostomy, hyperparathyroidism, osteogenesis imperfecta, partial hepatectomy, acute liver necrosis, toxic necrosis, viral hepatitis necrosis, shock necrosis, anoxic necrosis, B viral hepatitis, 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, kidney damage / injury, nephritic kidney damage / injury, kidney transplant Disorders / injuries, renal injury / injury due to surgery, renal injury / injury due to nephrotoxic drug administration, enhancement of chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, chronic bacterial infection, diseases due to environmental pollution, hypobaropathy, diseases caused by histamine or leukotriene-C4 release, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal insufficiency, intoxication caused by pulmonary oxygen or drugs, congenital hypophosphatasia, fibrous lesions, fibroelastosis, bone turnover, osteolytic bone diseases, treatment of bone surgery after trauma, treatment of joint surgery after prosthetics, treatment of bone surgery after plastic surgery, treatment after dental surgeryBone chemotherapy or bone radiotherapy, bone cancer, vulnerable plaque, disorders, occlusive disorders, coronary artery disorders, peripheral arterial disorders, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, postoperative graft occlusion, Guillain-Barre syndrome, Meniere's disease, polyneuropathy, polyneuropathy, mononeuropathy, radiculopathy, hyperthyroidism, Graves' disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoto's thyroiditis, myasthenia gravis, cold and warm agglutinin disease, Evans syndrome, hemolytic urine, These include toxic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, aerythroblastosis, and combinations thereof.

[0157] In a specific embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject who has or potentially has atopic dermatitis. In another specific embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject who has or potentially has rheumatoid arthritis. In another specific embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject who has or potentially has ankylosing spondylitis. In another specific embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject who has or potentially has myelodysplastic syndrome.

[0158] B. Formulation and Administration Pharmaceutical compositions containing one or more active compounds of the invention may be manufactured by any suitable method, such as mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. One or more physiologically acceptable excipients (e.g., diluents, carriers, or auxiliary agents), one or more adjuvants, or a combination thereof, may be used to formulate the pharmaceutical composition to provide a pharmaceutically usable preparation.

[0159] The active compounds may be formulated in pharmaceutical compositions per se or in the form of their pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, although salts having lower solubility than the corresponding free acids and bases can also be formed.

[0160] Pharmaceutical compositions of the invention can be in a form suitable for virtually any mode of administration, including, for example, topical, ophthalmic, oral, buccal, systemic, nasal, by injection such as iv or ip, transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0161] For topical administration, the active compounds, pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs may be formulated as solutions, gels, ointments, creams, suspensions, etc., as known in the art.

[0162] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral, or pulmonary administration.

[0163] Useful injectable preparations include sterile suspensions, solutions, or emulsions of active compounds in aqueous or oily vehicles. Pharmaceutical compositions may also contain compounding agents such as suspending agents, stabilizers, and / or dispersing agents. Injectable preparations may be presented in unit dosage form, for example, in ampoules or multi-dose containers, and may contain added preservatives.

[0164] Alternatively, injectable formulations may be provided in powder form for reconstitution with a suitable vehicle including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, etc. before use. To this end, the active compound may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

[0165] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0166] For oral administration, the pharmaceutical compositions can take the form of lozenges, tablets, or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate). Tablets can be coated, for example, with sugars, films, or enteric coatings by methods well known in the art.

[0167] Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups, or suspensions, or may be presented as dry products to be reconstituted with water or other suitable vehicles before use. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable excipients such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophore™, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents, and sweeteners, as needed.

[0168] Preparations for oral administration can, as is well known, be suitably formulated to give controlled release of the active compound.

[0169] For buccal administration, the pharmaceutical compositions may take the form of tablets or lozenges formulated in conventional manner.

[0170] For rectal and vaginal routes of administration, the active compounds may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0171] For nasal administration or administration by inhalation or insufflation, the active compound, pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug can be conveniently delivered in the form of an aerosol spray from a pressurized pack or a nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbon, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges (e.g., capsules and cartridges composed of gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0172] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray device contains the following components: 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); phenylethanol (1-4 mg / mL); and dextrose (20-50 mg / mL). The pH of the final suspension can be adjusted to a range of about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

[0173] Another specific example of an aqueous suspension suitable for administering a compound via inhalation contains 20 mg / mL of a disclosed compound, 1% (v / v) polysorbate 80 (TWEEN® 80), 50 mM citrate, and / or 0.9% sodium chloride.

[0174] For ophthalmic administration, active compound can be formulated as a solution, emulsion, suspension, etc. suitable for administration to the eye.Various vehicles suitable for administering compound to the eye are known in the art.Specific non-limiting examples are described in U.S. Patent 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.

[0175] For long-term delivery, the active compound can be formulated as a depot preparation for administration by implantation or intramuscular injection.The active ingredient can be formulated with a suitable polymer or hydrophobic material (for example, as an emulsion in an acceptable oil), or an ion exchange resin, or can be formulated as a sparingly soluble derivative, for example, as a sparingly soluble salt.Alternatively, a transdermal delivery system can be used, which is manufactured as an adhesive disk or patch that slowly releases the active compound for percutaneous absorption.For this purpose, a penetration enhancer can be used to promote percutaneous penetration of the active compound. Suitable transdermal patches are described, for example, 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.

[0176] Alternatively, other pharmaceutical delivery systems may be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compounds. Certain organic solvents, such as dimethyl sulfoxide (DMSO), may also be used, although usually at the expense of higher toxicity.

[0177] The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0178] There are several approaches to transport 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, bypassing the blood-brain barrier completely and / or creating an opening in the blood-brain barrier. Circumvention methods include, but are not limited to, direct injection (e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial injection / convection-enhanced delivery (Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implanting a delivery device into the brain (e.g., see Gill et al., Nature Med. 9:589-595, 2003). Opening of the blood-brain barrier includes, but is not limited to, ultrasound, administration of hypertonic mannitol, and osmotic pressure, e.g., by permeabilization with bradykinin or permeabilizing agent A-7 (see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416). Compounds can also be encapsulated in liposomes that bind to antibody-binding fragments that bind to receptors on the vascular endothelium of the blood-brain barrier.

[0179] In certain embodiments, the compound may be administered continuously by infusion into a fluid reservoir of the CNS or by bolus injection. The compound may be administered using a continuous administration means such as an indwelling catheter and a pump, or Administration can be by implantation of a sustained-release vehicle. For example, the compound can be injected chronically through an implanted cannula or infused chronically with the aid of an osmotic minipump. A subcutaneous pump can deliver the compound to the cerebral ventricles.

[0180] C. Dosage The disclosed compounds, pharmaceutical compositions, or combinations of disclosed compounds will generally be used in an effective amount to achieve the intended result, e.g., an effective amount to inhibit RIP1 kinase and / or an effective amount to treat, prevent, or ameliorate a particular condition. The disclosed compounds or their pharmaceutical compositions can be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder during treatment and / or the eradication or amelioration of one or more symptoms associated with the underlying disorder, such that the patient reports a sensory or physical improvement, even though the patient may still be suffering from the underlying disorder. For example, administration of a compound to a patient suffering from allergies provides therapeutic benefit not only when the underlying allergic reaction is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of allergy-related symptoms after exposure to an allergen. As another example, therapeutic benefit in the context of asthma includes improved breathing after the onset of an asthma attack or a reduction in the frequency or severity of asthma episodes. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.

[0181] As known by those skilled in the art, the preferred dosage of the disclosed compounds may depend on various factors, including the age, weight, general health, and severity of the condition of the patient or subject being treated. The dosage may also need to be adjusted to the individual's gender and / or lung capacity when administered by inhalation. The dosage may also be adjusted for individuals suffering from more than one condition, or for individuals with additional conditions that affect lung capacity and normal breathing ability, such as emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and respiratory infections. The dosage and frequency of administration of the disclosed compounds or pharmaceutical compositions thereof will also depend on whether the disclosed compounds are formulated for the treatment of an acute episode of a condition or for the prophylactic treatment of a disorder. Those skilled in the art will be able to determine the optimal dose for a particular individual.

[0182] In prophylactic administration, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered to patients or subjects at risk of developing one of the aforementioned conditions. For example, if it is unknown whether a patient or subject is allergic to a particular drug, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered before the drug is administered to avoid or ameliorate an allergic reaction to the drug. Alternatively, prophylactic administration can be used to avoid or ameliorate the onset of symptoms in patients diagnosed with an underlying disorder. For example, the disclosed compounds or pharmaceutical compositions thereof can be administered to allergy sufferers before 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 a known agent for one of the above-mentioned diseases 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 an allergen known to induce allergies, such as latex, to prevent the individual from developing the allergy. 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 participating in activities that induce asthma attacks in order to reduce the severity of or completely avoid asthma episodes.

[0183] An effective dosage can be estimated initially from in vitro assays. For example, an initial dosage for use in a subject may be determined to be IC 50 or EC 50The active compound may be formulated to achieve a circulating blood concentration or serum concentration of the above specific compound. Taking into account the bioavailability of the specific compound, the dosage to achieve such a circulating blood concentration or serum concentration can be calculated. Fingl & Woodbury, "General Principles," in: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and the references cited therein, provide additional guidance regarding effective dosages.

[0184] In some embodiments, disclosed compounds have an EC50 activity of 0-20 μM, such as 0-10 μM, 0-5 μM, 0-1 μM, 0-0.5 μM, 0-0.1 μM, or 0-0.05 μM. 50 It has.

[0185] The initial dosage can also be estimated from in vivo data, such as animal models. Animal models useful for testing the effectiveness of compounds for treating or preventing the various diseases mentioned above are well known in the art. Suitable animal models of hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50(21Suppl):6-9, discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol. 107(6):1025-1033. Suitable animal models of 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. Those skilled in the art can adapt such information to determine appropriate dosages for administration to humans.

[0186] In some embodiments, suitable assays for determining RIP1 activity may be used. Such assay methods may be used to evaluate the efficacy of compound embodiments disclosed herein and / or to determine amounts / dosages of compound embodiments that can provide the desired efficacy. In some embodiments, the assay may be an ADP-Glo™ assay, which evaluates the ability of compound embodiments to inhibit RIP1. In other embodiments, whole cell assays using mouse and / or human cells, such as U937 and / or L929 cell necroptosis assays, may be performed to determine safe and effective doses of compounds that can be used in human in vivo studies. These whole cell assays may be used to evaluate the activity of compounds against human and / or mouse RIP1 in an in vitro setting, thereby enabling one of skill in the art to determine safe and effective dosages for in vivo use. Yet another assay that can be used to evaluate the activity of compound embodiments described herein for treating diseases or conditions involving RIP1 is an acute hypothermia mouse model, which evaluates the ability of compounds to inhibit TNF-alpha-induced hypothermia. Each of these assays, and various results from the use of these assays, are described in detail in the Examples section of this disclosure.

[0187] Dosages of the disclosed compounds will typically be in the range of 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 typically, dosages (or effective amounts) can range from about 0.0025 mg / kg to about 1 mg / kg per at least one daily administration, such as 0.01 mg / kg to about 0.5 mg / kg, or about 0.05 mg / kg to about 0.15 mg / kg. Total daily dosages will typically range from about 0.1 mg / kg to about 5 mg / kg, or to about 20 mg / kg per day, such as 0.5 mg / kg to about 10 mg / kg per day, or about 0.7 mg / kg to about 2.5 mg / kg per day. Dosages may be higher or lower depending on, among other factors, the activity of the disclosed compound, its bioavailability, the mode of administration, and the various factors discussed above.

[0188] Dosage amount and dosing interval can be tailored to the individual to provide plasma levels of the disclosed compounds sufficient to maintain therapeutic or prophylactic effect. For example, the compounds can be administered once daily, multiple times daily, once weekly, multiple times weekly (e.g., every other day), once monthly, multiple times monthly, or once yearly, depending on, among other things, the mode of administration, the particular indication being treated, and the judgment of the prescribing physician. Those skilled in the art will be able to optimize effective local dosages without undue experimentation.

[0189] Pharmaceutical compositions comprising one or more of the disclosed compounds typically contain from greater than 0 up to 99% total weight percent of the disclosed compound(s) and / or other therapeutic agent(s). More typically, pharmaceutical compositions comprising one or more of the disclosed compounds contain from about 1 to about 20 total weight percent of the disclosed compound(s) and other therapeutic agent(s), and from about 80 to about 99 weight percent of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition may further comprise an adjuvant.

[0190] Preferably, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof will provide therapeutic or prophylactic benefit without causing substantial toxicity. The toxicity of the disclosed compounds can be determined using standard pharmaceutical procedures. The dose ratio between toxic effects and therapeutic (or prophylactic) effect is the therapeutic index. Disclosed compounds that exhibit high therapeutic indices are preferred. [Example]

[0191] V. Working Examples Example 1 Compounds of the present disclosure can be made using suitable starting compounds, such as compound 200 or compound 206 shown in the schemes above. A representative method for making compound 200 is shown in Scheme 6A, and a representative method for making compound 206 is shown in Scheme 6B. [ka] [ka]

[0192] 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, 9H of oxobenzoxazapine H-8, 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, 1H of oxobenzoxazapine H-2), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.53 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 3.30 (1H,br s,NH), 2.87 (3H,s,NCH3).

[0193] Example 2 [ka] Synthesis of (S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazapin-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 through it for 5 minutes. 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, and the reaction was sealed and then heated to 120 °C in a microwave for 1 h. 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 (NaSO), and concentrated under reduced pressure. MPLC (10→80% EtOAc-hexanes) afforded the starting material (0.091 g) and the title compound (0.079 g) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.40-7.38 (6H, m, 6H of C(C6H5)3), 7.24-7.14 (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, 1H of oxobenzoxazapine H-2), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.55 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 2.78 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2); m / z: 555 [M+K] +,243[C(C6H5)3] + .

[0194] [ka] Deprotection of the trityl group: To a solution of the trityl-protected amine (0.079 g, 0.153 g, 1.0 equiv.) in dioxane (2.0 mL) was added a solution of hydrogen chloride (0.15 mL of a 4 M solution in dioxane, 0.614 mmol, 4.0 equiv.). The reaction was stirred at room temperature for 6 hours and then concentrated to dryness to give a white solid that was used without purification; m / z: 275 [M+H] + .

[0195] Example 3 This example provides a method for making N-substituted-4-[(heteroaryl)methyl]-1H-pyrazole-1-carboxamides via the intermediate pyrazole-1-carbonyl chloride formation according to Scheme 7 (Route 1).

[0196] [ka] To a stirred heterogeneous mixture of compound 1400 (1 equiv.) and triphosgene (1.5 equiv.) in CHCl (15 mL / mmol) under nitrogen at 0 °C, i-PrNEt (5–9 equiv.) was added gradually (15 min / mmol). The red reaction solution was stirred at 0 °C for 1 h, warmed to room temperature (2 h), analyzed for 4-[(heteroaryl)methyl]-1H-pyrazole consumption by LC / MS, and concentrated to dryness to give 1402. The red semi-solid concentrate was added to 1404 or the corresponding amine or its salt (1 equiv.) and DMAP (0.1 equiv.) and cooled in an ice bath under nitrogen. CHCl (15 mL / mmol) was added to the flask, stirred for 15 min, and the stirred red solution was treated gradually (15 min / mmol) with i-PrNEt (5–9 equiv.). After 1 h, the ice bath was removed and the reaction solution was allowed to warm to room temperature. To analyze the reaction progress, the reaction solution was concentrated to dryness, diluted with water, and subjected to extractive workup with either EtOAc or CHCl. ​​Silica gel flash column chromatography purification of the crude concentrate afforded the required N-substituted-4-[(heteroaryl)methyl]-1H-pyrazole-1-carboxamides 1406 (yields: 20–75%).

[0197] Example 4 This example provides a method for making N-substituted-4-[(heteroaryl)methyl]-1H-pyrazole-1-carboxamides through the formation of an intermediate isocyanate according to Scheme 8 (Route 2). [ka]

[0198] To a stirred heterogeneous mixture of compound 1420, or its corresponding amine or its salt (1 equiv.), and triphosgene (2.3 equiv.) in CHCl (15 mL / mmol) under nitrogen at 0 °C, i-PrNEt (10–15 equiv.) was added gradually (20 min / mmol). The pale yellow reaction solution was stirred at 0 °C for 1 h, warmed to room temperature (2 h), 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. CHCl (15 mL / mmol) was added to the flask, stirred for 15 min, and the stirred red solution was treated gradually (15 min / mmol) with i-PrNEt (10–15 equiv.). After 1 h, the ice bath was removed and the reaction solution was allowed to warm to room temperature (6–8 h). To analyze progress, the reaction solution was concentrated to dryness, diluted with water, and subjected to extractive workup using either EtOAc or CHCl. ​​Silica gel flash column chromatography purification of the resulting crude material afforded the required N-substituted-4-[(heteroaryl)methyl]-1H-pyrazole-1-carboxamides 1426 (yields: 19–73%).

[0199] Example 5 This example provides a method for making embodiments of the disclosed alkynyl-substituted compounds according to Scheme 9 (Route 3). [ka]

[0200] Nitrogen was bubbled through a stirred solution of halide 1440 (1 equiv.), CuI (0.1–0.2 equiv.), and Pd(PPh3)4 (0.05–0.1 equiv.) in dry DMF (3–4 mL / mmol) in a vial for 3 min. Subsequently, NEt3 (10 equiv.) was added, followed by the corresponding alkyne 1442 (1.5–3 equiv.) in rapid succession to the dark reaction solution. Nitrogen was bubbled through the reaction mixture for 2 min, the vial was capped, and the reaction mixture was stirred at 70–75 °C for 5–6 h. After analyzing the reaction progress 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 allowed to warm to room temperature. The resulting gray / dark solid was collected by filtration, suction dried, dissolved in THF (20 mL), and filtered through a Celite® / silica gel pad, rinsing the pad with THF. After concentration of the filtrate, the crude material was purified by flash chromatography to give alkynyl-substituted analogs 1444 (yield: 25-69%).

[0201] Example 6 This example provides a method for making embodiments of the disclosed 4-[(heteroaryl)methyl]-1H-pyrazole compounds according to Scheme 10. [ka]

[0202] 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) in 1,4-dioxane was added. H2O (9:1, 10 mL / mmole) was degassed by high vacuum, back-purged with argon in a balloon for three cycles over 5-10 min, and heated at 70-75 °C for 2-6 h. The reaction mixture was cooled and concentrated to dryness. The crude residue was diluted with EtOAc (or CHCl2), water, and saturated aqueous Na2CO3 (6 mL / mmole). The organic layer was separated, and the aqueous layer was extracted with EtOAc (or CHCl2). The combined organic layers were washed with aqueous NaCl, stirred with anhydrous Na2SO4, and filtered through Celite®. After concentration of the filtrate, the crude material was purified by silica gel chromatography to give tert-butyl 4-[(heteroaryl)methyl]-1H-pyrazole-1-carboxylate 1454 (49–85% yield). To a stirred solution of 4-[(heteroaryl)methyl]-1H-pyrazole (1 equiv.) in CHCl (3–6 mL / mmol) was added 4.0 N HCl in 1,4-dioxane (5–7 equiv.) at room temperature. The reaction mixture was stirred until tert-butyl 4-[(heteroaryl)methyl]-1H-pyrazole-1-carboxylate was consumed and then concentrated to dryness. The crude solid was sonicated in EtOAc (6–7 mL / mmol), filtered, washed on the funnel with EtOAc, and briefly vacuum dried. Therefore, the collected semi-dry solid was further dried under high vacuum to give 4-[(heteroaryl)methyl]-1H-pyrazole hydrochloride salt 1456 (80–98%), which was used in the next step without further purification (purity >95%).

[0203] tert-Butyl 4-(pyridin-2-ylmethyl)-1H-pyrazole-1-carboxylate [ka] 1H NMR(400MHz,chloroform-d)δ 8.49(ddd,J=4.9,1.9,1.0Hz,1H),7.89(q,J=0.9Hz,1H),7.57(d,J=2.0Hz,1H),7 .54(dd,J=7.7,1.9Hz,1H),7.15-6.99(m,2H),3.94(d,J=0.9Hz,2H),1.57(s,9H). LCMS: Purity 95%, MS(m / e)260(M+H) +

[0204] 2-((1H-pyrazol-4-yl)methyl)pyridine dihydrochloride [ka] LC / MS: Purity 96%, MS (m / e) 160 (M-2HCl+H) + .

[0205] tert-Butyl 4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxylate [ka] 1 H NMR(400MHz,chloroform-d)δ 7.92(q,J=0.9Hz,1H),7.62(d,J=0.9Hz,1H),7.49(t,J=7.7Hz,1H),7.00(ddd,J=7.7,1.1,0.5Hz,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) + .

[0206] 2-((1H-pyrazol-4-yl)methyl)-6-methylpyridine dihydrochloride [ka] 1H NMR(400MHz,DMSO-d6)δ 8.34(t,J=7.9Hz,1H),8.23-7.81(br s,2H),7.75(s,1H),7.72(dt,J=7.9,0.9Hz,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) + .

[0207] tert-Butyl 4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxylate [ka] 1 H NMR(400MHz,chloroform-d)δ 7.94(s,1H),7.69(q,J=7.9Hz,1H),7.61(s,1H),7.00(dd,J=7.4,2.4Hz,1H),6.77(dd,J=8.2,2.8Hz,1H),3.92(s,2H),1.62(s,9H). LCMS: Purity 98%, MS(m / e)278(M+H) + .

[0208] 2-((1H-pyrazol-4-yl)methyl)-6-fluoropyridine hydrochloride [ka] 1 H NMR(400MHz,DMSO-d6)δ 10.24(br s,2H),7.89(td,J=8.4,7.4Hz,1H),7.76(s,2H),7.20(ddd,J=7.4,2.7,0.7Hz,1H),6.98(ddd,J=8.2,2.8,0.7Hz,1H),3.91(s,2H). LCMS: Purity 98%, MS (m / e) 178 (M-HCl+H) + .

[0209] tert-Butyl 4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxylate [ka] LC / MS: Purity 92%, MS(m / e)261(M+H) + .

[0210] 3-((1H-pyrazol-4-yl)methyl)pyridazine dihydrochloride [ka] LC / MS: Purity 92%, MS(m / e)161(M-2HCl+H) + .

[0211] tert-Butyl 4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazole-1-carboxylate [ka] 1 H NMR(400MHz,chloroform-d)δ 7.99(d,J=0.9Hz,1H),7.78(t,J=7.5Hz,1H),7.66(s,1H),7.54(d,J=7.8Hz,1H),7.32(d,J=7.9Hz,1H),4.08(s,2H),1.63(s,9H). LCMS: Purity 96%, MS(m / e)328(M+H) + .

[0212] 2-((1H-pyrazol-4-yl)methyl)-6-(trifluoromethyl)pyridine [ka] 1 H NMR(400MHz,DMSO-d6)δ 12.11(br,2H),8.00(tt,J=7.8,0.9Hz,1H),7.83(s,2H),7.72(d,J=8.0,2.4Hz,1H),7.58(dd,J=8.0,2.4Hz,1H),4.06(s,2H). 19 F NMR(376MHz,DMSO-d6)δ-66.47. LCMS: Purity 96%, MS(m / e)228(M+H) + .

[0213] tert-Butyl 4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxylate [ka] LC / MS: Purity 95%, MS(m / e)260(M+H) + .

[0214] 2-((1H-pyrazol-4-yl)methyl)pyridine dihydrochloride [ka] 1 H NMR(400MHz,DMSO-d6)δ 10.5(br s,3H),8.88-8.83(m,1H),8.79(d,J=5.2Hz,1H),8.47(ddd,J=8.1,2.0,1.3Hz,1H),8.00(ddd,J=8.1,5.7,0.7Hz,1H),7.74(s,2H),4.06(2H). LCMS: Purity 95%, MS (m / e) 160 (M-2HCl+H) + .

[0215] tert-Butyl 4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxylate [ka] LC / MS: Purity 97%, MS(m / e)260(M+H) + .

[0216] 4-((1H-pyrazol-4-yl)methyl)pyridine dihydrochloride [ka] 1 H NMR(400MHz,Methanol-d4)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) + .

[0217] Example 7 Scheme 11 provides a method for making 4-((6-methylpyridin-3-yl)oxy)picolinic acid. [ka]

[0218] Referring to Scheme 11, to a solution of 4-fluoropicolinonitrile 90 (1.0 equiv.) and 6-methylpyridin-3-ol 92 (1.05 equiv.) in dimethylformamide is added cesium carbonate (1.1 equiv.). The reaction is heated to 80° C. for 8 hours and cooled. The reaction is poured into ice water, and 4-((6-methylpyridin-3-yl)oxy)picolinonitrile 94 is isolated.

[0219] A mixture of 4-((6-methylpyridin-3-yl)oxy)picolinonitrile 94 in hydrochloric acid (6 M) is heated to 100° C. for 8 h. The reaction is cooled to room temperature and 4-((6-methylpyridin-3-yl)oxy)picolinic acid 96 is isolated.

[0220] Example 8 This example relates to a method for making (S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)oxy)picolinamide according to Scheme 12. [ka]

[0221] To a mixture of bromooxobenzoxazapine 1100 (8.36 g, 16.3 mmol, 1.0 equiv.) and copper iodide (0.31 g, 1.6 mmol, 0.1 equiv.) was added dimethylformamide (80 mL). The mixture was degassed by bubbling argon through it for 5 minutes. Triethylamine (11.4 mL, 81.6 mmol, 5.0 equiv.) was added, followed by hydroxyethynyloxetane 1102 (3.20 g, 32.7 mmol, 2.0 equiv.) and tetrakis(triphenylphosphine)palladium (0.94 g, 0.8 mmol, 0.05 equiv.). The resulting brown solution was heated to 80 °C for 4 h. The reaction was cooled and partitioned between EtOAc (200 mL) and water (200 mL). The organics were washed with brine (150 mL), water (200 mL), and brine (150 mL), dried (NaSO), and concentrated under reduced pressure. MPLC (10-70% EtOAc-hexanes) afforded compound 1104 as a yellow solid (6.18 g, 72%). 1H NMR (400 MHz, CD3Cl) δ 7.41-7.39 (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, H-4 of oxetane H-2), 4.80 (2H, d, J 7.5 Hz, 2H, H-4 of oxetane H-2), 4.50 (1H, dd, J 10.0, 7.0 Hz, 1H of oxobenzoxazapine H-2), 4.39 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.59-3.52 (1H, m, oxobenzoxazapine H-3), 3.29 (1H, d, J 9.0 Hz, NH), 2.89 (3H, s, NCH3).

[0222] Formic acid (50 mL) was added to the trityl-protected amine 1104 (7.49 g, 14.1 mmol, 1 equiv.) and the mixture was stirred at room temperature for 4 h. Water (50 mL) was added and the reaction was stirred at room temperature for 15 h. 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 (5 M, portionwise to approximately 40 mL). The organics were extracted with EtOAc (4 × 150 mL). The combined neutralized organics were dried (NaSO) and concentrated under reduced pressure to afford (S)-3-amino-7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b]][1,4]oxazepin-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, oxobenzoxazapine H-9), 4.74 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.58 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.25 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.01 (1H, dd, J 11.5, 10.0 Hz, oxobenzoxazapine H-2 (1H), 3.59 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 3.28 (3H, s, NCH); 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]+.

[0223] A solution of aminooxobenzoxazapine 1106 (1.0 equiv.) in dimethylformamide is degassed by bubbling nitrogen through for 5 minutes. 4-((6-methylpyridin-3-yl)oxy)picolinic acid 96 (1.0 equiv.) is added, the solution is cooled to 0°C, and then diisopropylethylamine (2.5 equiv.) is added. HATU (1.1 equiv.) is added portionwise, and the reaction is stirred at 0°C for 1 hour and at room temperature for 15 hours. The reaction is poured into ice water, and the product is isolated.

[0224] Example 9 This example describes the synthesis of (S)-3-amino-8-bromo-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one and provides characterization data for each intermediate. [ka]

[0225] E / Z-7-Bromo-5-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime [ka] 1 H NMR(400MHz,chloroform-d)δ 7.94-7.83(m,2H),7.16(dd,J=8.6,1.9Hz,1H),2.78(dd,J=7.1,6.2Hz,2H),2.73-2.66(m,3H),1.85(ddd,J=12.7,7.0,6.3Hz,2H). 19 F NMR (376 MHz, chloroform-d) δ -116.28. LCMS: Purity 98%, MS (m / z) 256 / 258 (M−H) - .

[0226] 8-Bromo-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one [ka] 1H NMR(400MHz,DMSO-d6)δ 9.76(s,1H),7.27(dd,J=8.9,1.9Hz,1H),6.99(s,1H),2.65(td,J=7.2,1.5Hz,2H),2.20(t,J=7.2Hz,2H),2.13-2.01(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-116.08. LCMS: Purity 95%, MS(m / z)258 / 260(M+H) + .

[0227] 8-Bromo-6-fluoro-3-iodo-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one [ka] The crude filtrate was used without further purification. LCMS: Purity 70%, MS (m / z) 383.8 / 385.8 (M+H) + .

[0228] (±)-3-Azido-8-bromo-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one [ka] 1 H NMR(400MHz,DMSO-d6)δ 10.27(s,1H),7.32(dd,J=8.9,1.9Hz,1H),7.01(s,1H),4.05(dd,J=11.4,7.7Hz,1H),2.97-2.88(m,1H),2.45-2.27(m,2H),2.14-2.00(m,1H). 19 F NMR (376MHz, DMSO-d6) δ-115.69. LCMS: Purity 97%, MS (m / z) 270.8 / 272.8 (M-N2) + .

[0229] (±)-3-Amino-8-bromo-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one [ka] 1 H NMR(400MHz,DMSO-d6)δ 7.28(dd,J=8.8,1.9Hz,1H),7.00-6.97(m,1H),3.21(dd,J=11.4,7.5Hz,1H),2.91-2.82(m,1H),2.37-2.15(m,2H),1.83-1.72(m,1H). 19 F NMR(376MHz,DMSO-d6)δ-116.16. LCMS: Purity 94%, MS(m / z)272.8 / 274.8(M+H) + .

[0230] (S)-3-Amino-8-bromo-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one [ka] 1 H NMR(400MHz,DMSO-d6)δ 9.92(s,1H),7.27(dd,J=8.8,1.9Hz,1H),6.97(s,1H),3.15(dd,J=11.4,7.5H z,1H),2.92-2.80(m,1H),2.38-2.12(m,2H),1.81-1.68(m,1H),1.62(s,2H). 19 F NMR(376MHz,DMSO-d6)δ-116.24. LCMS: Purity 97%, MS(m / z)272.8 / 274.8(M+H) + .

[0231] Example 10 This example describes the synthesis of (S)-3-amino-8-bromo-6-fluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one and provides characterization data for intermediates.

[0232] [ka] tert-Butyl (S)-(8-bromo-6-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate [ka] 1 H NMR(400MHz,DMSO-d6)δ 9.95(s,1H),7.31(dd,J=8.7,1.9Hz,1H),7.07(d,J=8.3Hz,1H),7.03(s,1H),3.85(dt,J=11.8 ,8.2Hz,1H),2.91(dd,J=14.0,6.4Hz,1H),2.39-2.25(m,1H),2.23-1.99(m,2H),1.31(s,9H). 19 F NMR(376MHz,DMSO-d6)δ-115.83. LCMS: Purity 96%, MS (m / z) 272.9 / 274.9 (M-Boc+H) + .

[0233] tert-Butyl (S)-(8-bromo-6-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate [ka] The crude filtrate was used without further purification. LCMS: Purity 89%, MS (m / z) 286.9 / 288.9 (M-Boc+H) + .

[0234] (S)-3-Amino-8-bromo-6-fluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one [ka] 1 H NMR(400MHz,DMSO-d6)δ 7.58-7.36(m,2H),3.43-3.23(m,3H),3.25-3.04(m,1H),2.99-2.75(m,1H),2.63-2.43(m,1H),2.42-1.98(m,1H),1.88-1.53(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-115.92. LCMS: Purity 98%, MS(m / z)286.8 / 288.8(M+H)+ .

[0235] (S)-N-(8-bromo-6-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide [ka] 1 H NMR(400MHz,chloroform-d)δ 7.98(d,J=0.9Hz,1H),7.92(d,J=7.6Hz,1H),7.68(q,J=7.3Hz,1H),7.53(d,J=0. 8Hz,1H),7.20-7.14(m,2H),6.99(ddd,J=7.4,2.4,0.7Hz,1H),6.76(ddd,J=8.2,2 .8,0.7Hz,1H),4.46(dt,J=11.2,7.8Hz,1H),3.92(s,2H),3.39(s,3H),3.14-3.03 (m,1H),2.73-2.58(m,1H),2.47(tdd,J=13.5,7.7,2.4Hz,1H),2.13-2.02(m,1H). 19 F NMR (376 MHz, chloroform-d) δ -67.05, -114.73. LCMS: Purity 93%, MS (m / z) 511.9 / 513.9 (M+Na) + .

[0236] Example 11 Exemplary compounds and characterization data are provided below.

[0237] (S)-3-Amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one [ka] 1H 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, 1H of oxobenzoxazapine H-2), 4.12 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.72 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3); m / z: 275 [M+H] + (Measured value [M+H] + ,275.1390,C 15 H 18 N2O3 is [M+H] + 275.1404).

[0238] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-1) [ka] Route 3. 1 H NMR(400MHz,chloroform-d)δ 7.99-7.93(m,2H),7.68(td,J=8.2,7.3Hz,1H),7.55(d,J=0.8Hz,1H),7 .32-7.23(m,2H),7.11(d,J=8.8Hz,1H),7.02-6.95(m,1H),6.76(dd,J= 8.2,2.8Hz,1H),4.86(dt,J=11.3,7.2Hz,1H),4.68(dd,J=9.8,7.3Hz,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 (376MHz, chloroform-d) δ-66.98 (d,J=8.2Hz). LC / MS: Purity 98%, MS(m / e)478(M+H)+ .

[0239] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-2) [ka] Route 3. 1 H NMR(400MHz,chloroform-d)δ 7.95(d,J=7.2Hz,1H),7.92(d,J=0.9Hz,1H),7.54(d,J=0.8Hz,1H),7.46(t,J=7. 7Hz,1H),7.30-7.23(m,2H),7.14-7.07(m,1H),6.98(d,J=7.7Hz,1H),6.89(d,J=7 .7Hz,1H),5.28(s,1H),4.86(dt,J=11.3,7.3Hz,1H),4.67(dd,J=9.8,7.3Hz,1H), 4.29(dd,J=11.3,9.8Hz,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) + .

[0240] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)oxy)picolinamide (I-3) [ka] 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, 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, H-4 of oxetane H-2), 4.80 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 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 is [M+H] + 501.1769).

[0241] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)oxy)picolinamide (I-4) [ka] 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, oxobenzoxazapine H-9), 6.97 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.02 (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), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 2.59 (3H, s, pyrCH3), 1.63 (6H, s, C(CH3)2OH); m / z: 487 [M+H] + ,469[M+H-H2O] + (Measured value [M+H] + ,487.1991,C 27 H 26 N4O5 is [M+H] + 487.1976 required).

[0242] (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]oxazepin-3-yl)picolinamide (I-5) [ka] 1H 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, H-4 of oxetane H-2), 4.79 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.71 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 2.95 (1H, s, OH); 19 F NMR(380MHz,CDCl3)δ-70.4;m / z:505[M+H] + (Measured value [M+H] + ,505.1516,C 26 H 21 FN4O6 is [M+H] + 505.1518).

[0243] (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]oxazepin-3-yl)picolinamide (I-6) [ka] 1H 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, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2OH); 19 F NMR(380MHz,CDCl3)δ-70.4;m / z:491[M+H] + ,473[M+H-H2O] + (Measured value [M+H] + ,491.1722,C 26 H 23 FN4O5 is [M+H] + (Requires 491.1725).

[0244] (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]oxazepin-3-yl)picolinamide (I-7) [ka] 1H NMR (400 MHz, CDCl3) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.51 (1H, dd, J 5.0, 1.0 Hz, pyrH-6), 7.95 (1H, d, J 1.0 Hz, pyrH-3), 7.70 (1H, m, F-pyH-4), 7.36 (1H, dd, J 5.0, 2.0 Hz, pyrH-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, H-4 of oxetane H-2), 4.79 (2H, ddd, J 7.0, 2.0, 1.0 Hz, 2H, H-4 of oxetane H-2), 4.71 (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); 19 F NMR(380MHz,CDCl3)δ-66.6(d,J 8.0Hz);m / z:503[M+H] + (Measured value [M+H] + ,503.1724,C 27 H 23 FN4O5 is [M+H] + 503.1725).

[0245] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-ylmethyl)-1H-pyrazole-1-carboxamide (I-8) [ka] Route 3. 1H NMR (400 MHz, chloroform-d) δ 8.54(d,J=4.9Hz,1H),7.97(d,J=7.0Hz,1H),7.96(s,1H),7.60(td,J=7.7,1 .9Hz,1H),7.55(s,1H),7.27(d,J=9.5Hz,1H),7.25(s,1H),7.13(dt,J=9.0, 5.0Hz,3H),4.87(dt,J=11.2,7.2Hz,1H),4.68(dd,J=9.8,7.3Hz,1H),4.30( dd,J=11.3,9.8Hz,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) + .

[0246] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-9) [ka] Route 3. 1 H NMR(400MHz, methylene chloride-d2)δ 8.00(q,J=0.8Hz,1H),7.91(d,J=7.1Hz,1H),7.82(td,J=7.8,0.7Hz,1H),7.62(d,J= 0.9Hz,1H),7.58-7.53(m,1H),7.37(d,J=7.9Hz,1H),7.33(d,J=1.9Hz,1H),7.30(dd ,J=8.2,2.0Hz,1H),7.16(d,J=8.3Hz,1H),4.86(dt,J=11.2,7.2Hz,1H),4.71(dd,J= 9.8,7.3Hz,1H),4.31(dd,J=11.3,9.8Hz,1H),4.08(s,2H),3.41(s,3H),1.60(s,6H). 19 F NMR (376 MHz, methylene chloride-d2) δ -68.40. LC / MS: Purity 95%, MS (m / e) 528 (M+H) + .

[0247] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-hydroxypyridin-2-yl)methyl)picolinamide [ka] 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, 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, H-4 of oxetane H-2), 4.71 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.63 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.41 (1H, dd, J 11.5, 10.0 Hz, 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 H 24 N4O6 is [M+H] + 501.1769).

[0248] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)picolinamide [ka] 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 is [M+H] + (Requires 485.2183).

[0249] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)picolinamide [ka] 1 H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.49 (1H, d, J Hz, pyrH-6), 7.96 (1H, br d, J 1.0 Hz, pyrH-3), 7.49 (1H, t, J 7.5 Hz, MepyH-4), 7.33 (1H, dd, J 5.0, 2.0 Hz, pyrH-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 7.5 Hz, MepyH-3 or H-5), 6.89 (1H, d, J 7.5 Hz, Mepy H-3 or H-5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.94-4.92 (2H, m, 2H, H-4 of oxetane H-2), 4.80 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of 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 is [M+H] + 499.1976 required).

[0250] (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]oxazepin-3-yl)picolinamide (I-13) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.52 (1H, d, J 5.0 Hz, pyrH-6), 7.96 (1H, d, J 1.0 Hz, pyrH-3), 7.70 (1H, q, J 8.0 Hz, F-pyH-4), 7.36 (1H, dd, J 5.0, 3.0 Hz, pyrH-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, J 11.0 Hz, pyCH2py), 3.42 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2OH); m / z: 489 [M+H] + (Measured value [M+H] + ,489.1944,C 27 H 25 FN4O4 is [M+H] + 489.1933 required).

[0251] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxamide (I-14) [ka] Route 3. 1H NMR(400MHz, methylene chloride-d2)δ 8.53-8.42(app m,2H),7.95-7.87(m,2H),7.56-7.49(m,2H),7.32(d,J=1.9Hz,1H),7.31-7.22(m,2H),7.14(d,J=8.2Hz,1H),4.86(dt ,J=11.2,7.2Hz,1H),4.70(dd,J=9.8,7.3Hz,1H),4.31(dd,J=11.2,9.8Hz,1H),3.84(s,2H),3.40(s,3H),1.60(s,6H). LC / MS: Purity 98%, MS(m / e)442(M-H2O+H) + .

[0252] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (I-15) [ka] 1 H NMR(400MHz, methylene chloride-d2)δ 8.34(d,J=2.4Hz,1H),7.89(d,J=7.1Hz,1H),7.87(q,J=0.9Hz,1H),7.50(d,J=0.9Hz,1H),7 .39(dd,J=8.0,2.4Hz,1H),7.33(dd,J=2.0,0.4Hz,1H),7.30(dd,J=8.2,2.0Hz,1H),7.16(d d,J=8.2,0.4Hz,1H),7.09(d,J=7.9Hz,1H),4.86(dt,J=11.2,7.2Hz,1H),4.70(dd,J=9.8,7 .3Hz,1H),4.31(dd,J=11.2,9.8Hz,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) + .

[0253] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-16) [ka] 1 H NMR(400MHz,chloroform-d)δ 8.08-8.03(m,1H),7.97(d,J=7.2Hz,1H),7.87(q,J=0.9Hz,1H),7.60-7.50(m,1 H),7.45(d,J=0.9Hz,1H),7.31-7.24(m,2H),7.12(d,J=8.7Hz,1H),6.86(ddd,J= 8.4,3.0,0.6Hz,1H),4.86(dt,J=11.3,7.2Hz,1H),4.68(dd,J=9.8,7.3Hz,1H),4 .30(dd,J=11.3,9.8Hz,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). + .

[0254] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxamide (I-17) [ka] Route 3. 1H NMR (400 MHz, methylene chloride-d) 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, 7.1 Hz, 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) + .

[0255] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-ylmethyl)-1H-pyrazole-1-carboxamide (I-18) [ka] Route 2. 1 H NMR(400MHz,chloroform-d)δ 8.54(dt,J=4.6,1.6Hz,1H),7.99-7.92(m,2H),7.60(td,J=7.7,1.9Hz,1H),7.55(d,J=0.8Hz,1H),7.39-7.31(m,2H),7.14(t,J=6.2Hz,2H),7 .07(dd,J=8.2,0.6Hz,1H),4.89(dt,J=11.2,7.3Hz,1H),4.67(dd,J=9.8,7.3Hz,1H),4.30(dd,J=11.3,9.8Hz,1H),3.99(s,2H),3.41(s,3H). LC / MS: Purity 98%, MS(m / e)457(M+H) + .

[0256] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-19) [ka] Route 2. 1 H NMR (400 MHz, Methanol-d4) δ 8.33(t,J=8.0Hz,1H),8.16(q,J=0.8Hz,1H),7.72(d,J=8.6,2.3Hz,1H),7.69(d, J=0.8Hz,1H),7.63(d,J=8.0Hz,1H),7.61(d,J=2.3Hz,1H),7.42(dd,J=8.6,2.3H z,1H),7.14(d,J=8.6Hz,1H),4.86(dd,J=7.9,3.5Hz,1H),4.58(dd,J=9.9,7.5Hz ,1H),4.45(ddd,J=11.1,9.9,1.1Hz,1H),4.26(s,2H),3.38(s,3H),2.75(s,3H). LC / MS: Purity 98%, MS(m / e)471(M+H) + .

[0257] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-20) [ka] 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=8.2,7.3Hz,1H),7.55(d,J=0.8Hz,1H),7.38-7.30(m,2H),7.06(dd,J=8.1,0.6Hz,1H),6.98(dd,J=7.4,2.4Hz,1H),6.76(d d,J=8.2,2.8Hz,1H),4.87(dt,J=11.2,7.3Hz,1H),4.66(dd,J=9.8,7.4Hz,1H),4.29(dd,J=11.3,9.8Hz,1H),3.91(s,2H),3.40(s,3H). 19F NMR (376 MHz, chloroform-d) δ -66.96 (d, J = 8.0 Hz). LC / MS: Purity 98%, MS (m / e) 475 (M+H) + .

[0258] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-21) [ka] Route 2. 1 H NMR(400MHz, methylene chloride-d2)δ 8.00(q,J=0.9Hz,1H),7.89(d,J=7.1Hz,1H),7.82(td,J=7.8,0.7Hz,1H) ,7.62(d,J=0.8Hz,1H),7.59-7.53(m,1H),7.42(d,J=2.3Hz,1H),7.42-7. 34(m,2H),7.11(d,J=8.5Hz,1H),4.88(dt,J=11.2,7.3Hz,1H),4.70(dd,J =9.8,7.3Hz,1H),4.30(dd,J=11.3,9.8Hz,1H),4.08(s,2H),3.41(s,3H). 19 F NMR (376 MHz, methylene chloride-d2) δ -68.40. LC / MS: Purity 95%, MS (m / e) 525 (M+H) + .

[0259] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxamide (I-22) [ka] Route 2. 1H NMR (400 MHz, methylene chloride-d2) 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), 7.2 7(ddd,J=7.9,4.9,0.9Hz,1H),7.11(d,J=8.5Hz,1H),4.87(dt,J=11.3,7.3Hz,1H), 4.70(dd,J=9.8,7.4Hz,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) + .

[0260] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (I-23) [ka] 1 H NMR(400MHz,chloroform-d)δ 8.35(d,J=2.1Hz,1H),7.94(d,J=7.2Hz,1H),7.85(app q,J=0.9Hz,1H),7.45(d,J=0.9Hz,1H),7.38-7.31(m,3H),7.07(app dd,J=7.9,0.9Hz,2H),4.87(dt,J=11.3,7.3Hz,1H),4.66(dd,J=9.8,7.4Hz ,1H),4.29(dd,J=11.3,9.8Hz,1H),3.76(s,2H),3.40(s,3H),2.51(s,3H). LC / MS: Purity 94%, MS(m / e)472(M+H) + .

[0261] (S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (I-24) [ka] 1 H NMR (400 MHz, chloroform-d) δ 8.06(ddd,J=2.6,1.2,0.6Hz,1H),7.95(d,J=7.2Hz,1H),7.87(q,J=0.9Hz,1 H),7.60-7.51(m,1H),7.45(d,J=0.9Hz,1H),7.38-7.31(m,2H),7.11-7.03(m ,1H),6.86(ddd,J=8.3,3.0,0.7Hz,1H),4.87(dt,J=11.3,7.3Hz,1H),4.67(d d,J=9.8,7.4Hz,1H),4.29(dd,J=11.3,9.8Hz,1H),3.81(s,2H),3.41(s,3H). 19 F NMR (376MHz, chloroform-d) δ-70.85 (d,J=5.7Hz). LCMS: Purity 96%, MS(m / e)475(M+H) + .

[0262] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxamide (I-25) [ka] Route 2. 1H NMR(400MHz, methylene chloride-d2)δ 9.06(dd,J=4.8,1.7Hz,1H),8.02(q,J=0.9Hz,1H),7.89(d,J=7.2Hz,1H),7.61(d,J=0.9Hz,1H),7.48-7.31(m,4H),7.11(d,J=8.6H) z,1H),4.88(dt,J=11.2,7.3Hz,1H),4.70(dd,J=9.8,7.3Hz,1H),4.30(dd,J=11.3,9.8Hz,1H),4.22(d,J=0.8Hz,2H),3.41(s,3H). LC / MS: Purity 97%, MS(m / e)458(M+H) + .

[0263] (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]oxazepin-3-yl)picolinamide (I-26) [ka] 1H 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, 2H, H-4 of oxetane H-2), 4.80-4.48 (2H, m, 2H, H-4 of oxetane H-2), 4.71 (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), 4.02 (2H, s, pyCH2Fpy), 3.41 (3H, s, NCH3); 19 F NMR(380MHz,CDCl3)δ-71.1(d,J 9.5Hz);m / z:503[M+H] + (Measured value [M+H] + ,503.1746,C 27 H 23 FN4O5 is [M+H] + 503.1725).

[0264] (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]oxazepin-3-yl)picolinamide (I-27) [ka] 1H 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, oxobenzoxazapine H-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(CH3)2OH); 19 F NMR(380MHz,CDCl3)δ-71.1(d,J 9.5Hz);m / z:489[M+H] + ,471[M+H-H2O] + (Measured value [M+H] + ,489.1938,C 27 H 25 FN4O4 is [M+H] + 489.1933 required).

[0265] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxamide (I-28) [ka] 1H NMR(400MHz, methylene chloride-d2)δ 8.52-8.46(m,2H),7.93(q,J=0.9Hz,1H),7.90(d,J=7.4Hz,1H),7.52(d, J=0.9Hz,1H),7.43(d,J=2.3Hz,1H),7.39(dd,J=8.5,2.3Hz,1H),7.17-7. 13(m,2H),7.12(d,J=8.5Hz,1H),4.88(dt,J=11.1,7.2Hz,1H),4.70(dd,J =9.8,7.4Hz,1H),4.31(dd,J=11.3,9.8Hz,1H),3.85(s,2H),3.41(s,3H). LC / MS: Purity 99%, MS(m / e)457(M+H) + .

[0266] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxamide (I-29) [ka] 1 H NMR(400MHz, methylene chloride-d2)δ 8.53(s,2H),7.96-7.90(m,2H),7.51(d,J=0.8Hz,1H),7.32(d,J=1.9Hz,1H),7.28(dd,J=8.3,1.9Hz,1H),7.18-7.11(m,3H),4 .87(dt,J=11.2,7.2Hz,1H),4.71(dd,J=9.7,7.3Hz,1H),4.32(dd,J=11.3,9.8Hz,1H),3.84(s,2H),3.40(s,3H),1.60(s,6H). LC / MS: Purity 98%, MS(m / e)460(M+H) + .

[0267] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyrimidin-2-ylmethyl)-1H-pyrazole-1-carboxamide (I-30) [ka] 1 H NMR (400 MHz, methylene chloride-d2) δ 8.65 (d, J = 4.9 Hz, 2H), 8.04 (app q,J=0.9Hz,1H),7.89(d,J=7.2Hz,1H),7.65(d,J=0.8Hz,1H),7.41(d,J=2.3Hz,1H),7.36(dd,J=8.5,2.3Hz,1H),7.15(t,J=4.9Hz,1H), 7.09(d,J=8.5Hz,1H),4.87(dt,J=11.2,7.3Hz,1H),4.68(dd,J=9.8,7.4Hz,1H),4.30(dd,J=11.3,9.8Hz,1H),4.13(s,2H),3.39(s,3H). LCMS: Purity 96%, MS(m / e)457 / 459(M+H) + .

[0268] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyrimidin-2-ylmethyl)-1H-pyrazole-1-carboxamide (I-31) [ka] 1 H NMR (400 MHz, chloroform-d) δ 8.66 (d, J = 4.9 Hz, 2H), 8.05 (app q,J=0.8Hz,1H),7.95(d,J=7.2Hz,1H),7.62(d,J=0.8Hz,1H),7.25(dd,J=4.8,1.9Hz,2H),7.14(t,J=4.9Hz,1H),7.12-7.08(m,1H),4.8 5(dt,J=11.3,7.3Hz,1H),4.66(dd,J=9.8,7.3Hz,1H),4.28(dd,J=11.3,9.8Hz,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) + .

[0269] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-32) [ka] 1 H NMR(400MHz, methylene chloride-d2)δ 7.97(app q,J=0.9Hz,1H),7.90(d,J=7.0Hz,1H),7.72(td,J=8.3,7.4Hz,1H),7.59(d,J=0.8Hz,1H),7.38(d,J=1. 9Hz,1H),7.35(dd,J=8.2,2.0Hz,1H),7.18(d,J=8.2Hz,1H),7.05(ddd,J=7.4,2.6,0.7Hz,1H),6.78(app dd,J=8.1,2.9Hz,1H),4.93-4.82(m,3H),4.76-4.67(m,3H),4.32(dd,J=11.3,9.8Hz,1H),3.93(s,2H),3.41(s,3H),2.71(s,1H). 19 F NMR (376 MHz, methylene chloride-d2) δ -68.27 (d, J = 8.2 Hz). LCMS: Purity 98%, MS (m / e) 492 (M+H). + .

[0270] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-33) [ka] 1H NMR(400MHz, methylene chloride-d2)δ 7.97(app q,J=0.8Hz,1H),7.89(d,J=7.1Hz,1H),7.72(td,J=8.3,7.4Hz,1H),7.58(d,J=0.8Hz,1H),7.3 5-7.31(m,2H),7.16(dd,J=8.2,0.5Hz,1H),7.05(ddd,J=7.4,2.5,0.7Hz,1H),6.82-6.73(app m,1H),4.86(dt,J=11.3,7.2Hz,1H),4.70(dd,J=9.8,7.3Hz,1H),4.31(dd,J=11.3,9.8Hz,1H),3.93(s,2H),3.92-3.86(m ,2H),3.68(ddd,J=11.8,9.0,2.9Hz,2H),3.41(s,3H),2.22(s,1H),2.04-1.98(m,2H),1.84(ddd,J=13.0,9.1,4.0Hz,2H). 19 F NMR (376 MHz, methylene chloride-d2) δ -68.27 (d, J = 8.2 Hz). LCMS: Purity 97%, MS (m / e) 520 (M+H). + .

[0271] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-34) [ka] 1H NMR(400MHz, methylene chloride-d2)δ 7.97(q,J=0.9Hz,1H),7.89(d,J=7.1Hz,1H),7.72(td,J=8.2,7.4Hz,1H),7.58(d,J=0.8Hz,1H),7.33-7.24(m,2 H),7.13(dd,J=8.2,0.4Hz,1H),7.05(ddd,J=7.4,2.5,0.7Hz,1H),6.78(ddd,J=8.2,2.8,0.7Hz,1H),4.85(dt,J =11.2,7.2Hz,1H),4.69(dd,J=9.8,7.3Hz,1H),4.29(dd,J=11.2,9.8Hz,1H),3.92(s,2H),3.92-3.88(m,2H),3. 50(ddd,J=11.7,8.9,2.9Hz,2H),3.40(s,3H),2.84(tt,J=8.7,4.1Hz,1H),1.93-1.86(m,2H),1.79-1.67(m,2H). 19 F NMR (376 MHz, methylene chloride-d2) δ -68.27 (d, J = 8.2 Hz). LCMS: Purity 91%, MS (m / e) 504 (M+H) + .

[0272] (S)-N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-35) [ka] 1H NMR (400 MHz, methylene chloride-d2) δ 7.97 (app q,J=0.8Hz,1H),7.86(d,J=7.5Hz,1H),7.71(td,J=8.2,7.4Hz,1H),7.56(d,J= 0.9Hz,1H),7.41-7.33(m,2H),7.17(d,J=8.0Hz,1H),7.04(ddd,J=7.4,2.5,0. 7Hz,1H),6.78(ddd,J=8.2,2.8,0.7Hz,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, methylene chloride-d2) δ -68.34 (d, J = 8.2 Hz). LCMS: purity 94%, MS (m / e) 472 / 474 (M+H) + .

[0273] (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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-36) [ka] 1 H NMR(400MHz,chloroform-d)δ 7.97(q,J=0.9Hz,1H),7.95(s,1H),7.68(td,J=8.2,7.4Hz,1H),7.53(d,J=0.8Hz,1H),7.3 0-7.25(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=6.6,0.8Hz,2H),4.79(dd,J=6.6,0.9Hz,2H),4.45(dt,J=11.4,7.4Hz,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). 19F NMR (376MHz, chloroform-d) δ-67.08 (d,J=8.2Hz). LCMS: Purity 97%, MS(m / e)490(M+H) + .

[0274] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-37) [ka] 1 H NMR (400MHz, methylene chloride-d2) δ 7.98(app q,J=0.9Hz,1H),7.89(d,J=7.1Hz,1H),7.72(app td,J=8.3,7.4Hz,1H),7.58(d,J=0.8Hz,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=8.2,2.8,0.7Hz,1H),4.84(dt, J=11.2,7.2Hz,1H),4.69(dd,J=9.8,7.3Hz,1H),4.29(dd,J=11.3,9.8Hz,1H),3. 93(s,2H),3.48(d,J=5.9Hz,2H),3.40(s,3H),1.83(t,J=6.8Hz,1H),1.29(s,6H). 19 F NMR (376 MHz, methylene chloride-d2) δ -68.27 (d, J = 8.2 Hz). LCMS: Purity 98%, MS (m / e) 492 (M+H). + .

[0275] (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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-38) [ka] 1 H NMR (400 MHz, methylene chloride-d2) δ 7.97(t,J=0.9Hz,1H),7.88(d,J=7.4Hz,1H),7.71(td,J=8.2,7.4Hz,1H),7.5 5(d,J=0.8Hz,1H),7.28-7.23(m,3H),7.04(ddd,J=7.4,2.5,0.6Hz,1H),6.77 (ddd,J=8.2,2.9,0.6Hz,1H),4.39(dt,J=11.4,7.4Hz,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, methylene chloride-d2) δ -68.35 (d, J = 8.1 Hz). LCMS: Purity 95%, MS (m / e) 476 (M+H). + .

[0276] (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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-39) [ka] 1H NMR(400MHz, methylene chloride-d2)δ 7.97(q,J=0.9Hz,1H),7.87(d,J=7.4Hz,1H),7.71(td,J=8.2,7.4Hz,1H),7.55(d,J=0.8Hz,1H ),7.28-7.18(m,3H),7.04(ddd,J=7.4,2.6,0.7Hz,1H),6.77(ddd,J=8.1,2.8,0.7Hz,1H),4.38 (dt,J=11.5,7.4Hz,1H),3.92(s,2H),3.48(d,J=6.8Hz,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=11.5,8.0Hz,1H),1.82(t,J=6.9Hz,1H),1.29(s,6H). 19 F NMR (376 MHz, methylene chloride-d2) δ -68.35 (d, J = 8.3 Hz). LCMS: Purity 94%, MS (m / e) 490 (M+H). + .

[0277] (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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-40) [ka] 1H NMR (400 MHz, methylene chloride-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=7.4,2.5Hz,1H),6.77(dd,J=8.2,2.8Hz,1H),4.39(dt,J=11.5,7.3Hz,1H),3.92(s,2H),3.90-3. 86(m,1H),3.68(ddd,J=11.8,9.1,2.9Hz,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, methylene chloride-d2) δ -68.30 (d, J = 8.5 Hz). LCMS: Purity 97%, MS (m / e) 518 (M+H). + .

[0278] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((1-hydroxycyclobutyl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-41) [ka] 1 H NMR(400MHz,chloroform-d)δ 7.97(q,J=0.9Hz,1H),7.95(s,1H),7.67(td,J=8.2,7.4Hz,1H),7.53(d,J=0.9Hz,1H),7.27 (d,J=6.9Hz,2H),7.22-7.15(m,1H),6.98(dd,J=7.5,2.4Hz,1H),6.76(dd,J=8.2,2.9Hz,1H ),4.45(dt,J=11.0,7.3Hz,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) + .

[0279] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-fluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (I-42) [ka] 1 H NMR(400MHz,chloroform-d)δ 8.09(d,J=5.0Hz,1H),7.97(d,J=7.3Hz,1H),7.93(s,1H),7.55(ddd,J=9.7,7.4,1.9Hz,1H),7.51(s,1H),7.39-7.31(m,2H),7.12(ddd,J =7.1,4.9,1.7Hz,1H),4.88(dt,J=11.3,7.3Hz,1H),4.67(dd,J=9.8,7.4Hz,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) + .

[0280] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-43) [ka] 1 H NMR(400MHz,chloroform-d)δ 8.06(d,J=4.7Hz,1H),7.97(d,J=7.2Hz,1H),7.91(s,1H),7.52(t,J=8.5Hz,1H),7.48(s,1H),7.26-7.20(m,2H),7.12-7.05(m,2H) ),4.84(dt,J=11.2,7.2Hz,1H),4.65(dd,J=9.8,7.3Hz,1H),4.29(dd,J=11.3,9.8Hz,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 = 4.2 Hz), 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) + .

[0281] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-44) [ka] 1 H NMR(400MHz,chloroform-d)δ 8.05(d,J=4.8Hz,1H),7.95(d,J=7.3Hz,1H),7.90(d,J=1.0Hz,1H),7.52(ddd,J=9.5,7. 3,2.0Hz,1H),7.48(s,1H),7.29-7.23(m,2H),7.14-7.05(m,2H),6.19(d,J=16.0Hz,1H) ,5.77(d,J=16.0Hz,1H),4.84(dt,J=11.3,7.3Hz,1H),4.64(dd,J=9.8,7.3Hz,1H),4.29 (dd,J=11.3,9.8Hz,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) δ 168.47, 162.88, 160.50, 150.08 (d, J = 15.7 Hz), 149.03, 145.88 (d, J = 14.5 Hz), 143.04, 140.74 (d, J = 5.4 Hz), 136.19, 131.13, 127.12, 126.65, 123.25, 121.99 (d ,J=30.5Hz),121.76(d,J=4.4Hz),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) + .

[0282] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-45) [ka] 1 H NMR(400MHz,chloroform-d)δ 8.07(s,1H),7.96(d,J=7.2Hz,1H),7.91(s,1H),7.52(t,J=9.9Hz,1H),7.49(s,1H),7.28-7.21(m ,2H),7.13-7.05(m,2H),4.85(dt,J=11.2,7.3Hz,1H),4.66(dd,J=9.8,7.3Hz,1H),4.28(dd,J=11 .3,9.8Hz,1H),3.92(ddd,J=11.6,5.4,3.7Hz,2H),3.80(s,2H),3.52(ddd,J=11.7,8.8,2.9Hz,2H ),3.40(s,3H),2.82(tt,J=8.5,4.1Hz,1H),1.96-1.83(m,2H),1.74(dtd,J=12.8,8.8,3.7Hz,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) + .

[0283] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-46) [ka] 1H NMR(400MHz,chloroform-d)δ 8.10-8.03(m,1H),7.96(d,J=7.2Hz,1H),7.91(s,1H),7.52(ddd,J=9.6,7.3,1.9Hz,1H),7.49(s,1H),7.28-7.18(m,2H),7.12-7.06(m,2H), 4.84(dt,J=11.2,7.3Hz,1H),4.66(dd,J=9.7,7.3Hz,1H),4.28(dd,J=11.3,9.8Hz,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 = 5.3 Hz), 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) + .

[0284] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-47) [ka] 1H NMR (400 MHz, chloroform-d) δ 8.10-8.03(m,1H),7.98(d,J=7.2Hz,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=11.3,7.3Hz,1H),4.81-4.77(m,2H),4.67(dd,J=9.7,7.3H z,1H),4.32(dd,J=11.3,9.8Hz,1H),3.85(s,1H),3.81(s,2H),3.40(s,3H). 13 C NMR (101 MHz, chloroform-d) δ 168.37,162.80,160.42,150.35,148.95,145.81(d,J=14.5Hz),145.37(d ,J=14.3Hz),142.96,140.64(d,J=5.3Hz),136.17,133.20,131.00,127.03 ,126.58,123.28,121.90(d,J=30.5Hz),121.67(d,J=4.4Hz),121.57(d,J= 4.4Hz), 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) + .

[0285] (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-48) [ka] 1H NMR (400 MHz, chloroform-d) δ 8.07(d,J=5.0Hz,1H),7.97(d,J=7.2Hz,1H),7.92(s,1H),7.53(ddd,J=9.5,7. 3,2.0Hz,1H),7.50(s,1H),7.30-7.26(m,2H),7.13-7.08(m,2H),4.86(dt,J=1 1.2,7.2Hz,1H),4.67(dd,J=9.8,7.3Hz,1H),4.30(dd,J=11.3,9.8Hz,1H),3.8 1(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) + .

[0286] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2,6-difluoropyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (I-49) [ka] 1H NMR(400MHz,DMSO-d6)δ 8.54-8.47(m,1H),8.09(s,1H),8.02(dt,J=9.9,8.0Hz,1H),7.73(d,J=2.4Hz,1H),7.71(s,1H),7.43(dd,J=8.6,2. 4Hz,1H), 7.17(d,J=8.5Hz,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-d6)δ 168.76,161.97-159.22(m),158.38(d,J=13.7Hz),149.36,149.18,147.11(dd,J=7.8,5.5Hz),143.27,138.48,130.33,127 .88,126.75,124.93,121.79,119.49(dd,J=28.0,5.5Hz),117.79,107.19(dd,J=34.3,5.4Hz),76.09,50.62,35.27,22.24. 19 F NMR (376MHz, DMSO-d6) 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) + .

[0287] (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]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-50) [ka] 1H NMR(400MHz,chloroform-d)δ 7.98(d,J=7.2Hz,1H),7.92(s,1H),7.63(dt,J=9.5,7.8Hz,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=11.2,7.2Hz,1H),4.67(dd,J=9.8,7.3Hz,1H),4.30(dd,J=11.3,9.8Hz,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 = 10.0 Hz), 130.94, 128.51 ( d,J=12.1Hz),126.98,126.51,123.03,121.04,120.54,118.19(dd,J=28.4,6.0Hz), 106.23(dd,J=34.4,5.7Hz),94.74,80.48,77.09,65.51,50.04,35.50,31.39,22.67. 19 F NMR (376MHz, 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) + .

[0288] (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]oxazepin-3-yl)picolinamide (I-51) [ka] 1H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.51 (1H, dd, J 5.0, 0.5 Hz, pyrH-6), 8.10 (1H, dt, J 4.5, 1.5 Hz, F pyrH-4 or H-6), 7.92 (1H, br d, J 1.0 Hz, pyrH-3), 7.53 (ddd, J 9.5, 7.5, 2.0 Hz, F pyrH-4 or H-6), 7.27-7.24 (3H, m, pyrH-5, oxobenzoxazapine H-6, H-8), 7.13-7.10 (1H, m, pyrH-5), 7.10 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 5.03 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H,dd,J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H,dd,J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.01 (2H,s,pyCH2Fpy), 3.94 (2H,ddd,J 11.5, 5.5, 4.0 Hz, 2H of pyran H-2, H-6), 3.53 (2H,ddd,J 11.5, 9.0, 3.0 Hz, 2H,H-6 of pyran H-2), 3.41 (3H,s,NCH3), 2.85-2.80 (1H,m,pyran H-4), 1.94-1.87 (2H,m,2H,H-5 of pyran H-3), 1.79-1.71 (2H,m,2H,H-5 of pyran H-3); 19 F NMR(380MHz,CDCl3)δ-77.1(d,J 9.5Hz);m / z:516[M+H] + (Measured value [M+H] + ,515.2092,C 29 H 27 FN4O4 is [M+H] + 515.2089).

[0289] (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-52) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.51 (1H, d, J 5.0 Hz, pyrH-6), 8.11 (1H, dt, J 4.5, 1.5 Hz, F pyrH-4 or H-6), 7.92 (1H, br d, J 1.0 Hz, pyrH-3), 7.54 (1H, ddd, J 9.5, 7.5, 2.0 Hz, F pyrH-4 or H-6), 7.28-7.24 (3H, m, oxobenzoxazapine H-6, H-8, pyrH-5), 7.14-7.11 (1H, m, F pyrH-5), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.88 (2H, dd, J 8.5, 5.5 Hz, 2H, H-4 of oxetane H-2), 4.80 (2H, dd, J 7.5, 5.5 Hz, 2H, H-4 of oxetane H-2), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.10-4.04 (1H, m, oxetane H-3), 4.02 (2H, s, pyCH2py), 3.41 (3H, s, NCH3); 19 F NMR(380MHz,CDCl3)δ-71.1(d,J 9.5Hz);m / z:488[M+H] + (Measured value [M+H] + ,487.1780,C 27 H 23 FN4O4 is [M+H] + (Requires 487.1776).

[0290] (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]oxazepin-3-yl)picolinamide (I-53) [ka] 1H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.0 Hz, NH), 8.51 (1H, dd, J 5.0, 0.5 Hz, pyH-6), 7.95 (1H, dd, J 2.0, 1.0 Hz, pyH-3), 7.72-7.66 (1H, m, FpyH-4), 7.34 (1H, dd, J 5.0, 2.0 Hz, pyH-5), 7.27-7.24 (2H, m, 2H, H-8 of oxobenzoxazapine H-6), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.99 (1H, dd, J 7.5, 2.5 Hz, FpyH-3 or H-5), 4.78 (1H, dd, J 8.0, 2.5 Hz, FpyH-3 or H-5), 5.04 (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), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.10 (2H, s, pyCH2Fpy), 3.94 (2H, ddd, J 11.5, 5.5, 3.5 Hz, 2H of pyran H-2, H-6), 3.54 (2H, ddd, J 11.5, 8.5, 3.0 Hz, 2H,H-6 of pyran H-2), 3.43 (3H,s,NCH3), 2.87-2.81 (1H,m,pyran H-4), 1.94-1.88 (2H,m,2H,H-5 of pyran H-3), 1.80-1.71 (2H,m,2H,H-5 of pyran H-3); 19 F NMR(380MHz,CDCl3)δ-66.6(d,8.0Hz);m / z:516[M+H] + (Measured value [M+H] + ,515.2094,C 29 H 27 FN4O4 is [M+H] + 515.xxxx).

[0291] (S)-4-((2-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]oxazepin-3-yl)picolinamide (I-54) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.0 Hz, NH), 8.50 (1H, d, J 5.5 Hz, pyrH-6), 8.11 (1H, ddd, J 5.0, 2.0, 1.5 Hz, F pyrH-6), 7.59 (1H, ddd, J 9.5, 8.0, 2.0 Hz, F pyrH-4), 7.54 (1H, d, J 2.5 Hz, pyrH-3), 7.28-7.25 (3H, m, oxobenzoxazapine H-6, H-8, F pyrH-5), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-99), 6.97 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (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), 3.41 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2OH); 19 F NMR(380MHz,CDCl3)δ-79.8(d,J 9.5Hz);m / z:492[M+H] + (Measured value [M+H] + ,491.1729,C 26 H 23 FN4O5 is [M+H] + (Requires 491.1725).

[0292] (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-55) [ka] IR(film)ν 3363,2958,2881,1665,1590,1574,1505,1452,1363,1300,1236,1178,1103,979,915,840,732cm -1 ;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-6), 8.12 (1H, dt, J 5.0, 1.5 Hz, FpyH-6), 7.59 (1H, ddd, J 9.5, 8.0, 2.0 Hz, FpyH-4), 7.56 (1H, d, J 2.5 Hz, pyH-3), 7.29-7.25 (3H, m, oxobenzoxazapine H-6, H-8, FpyH-5), 7.12 (1H, d, J 9.0 Hz, 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), 4.87 (2H, dd, J 8.5, 5.5 Hz, 2H, H-4 of oxetane H-2), 4.80 (2H, dd, J 7.0, 5.5 Hz, 2H, H-4 of oxetane H-2), 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), 4.10-4.02 (1H, m, oxetane H-3), 3.42 (3H, s, NCH3); 13 C NMR(100MHz,CDCl3)δ 168.9,164.7,163.2,155.6(d,J 242.0Hz),151.7,150.4,149.9,144.0(d,J 13.5Hz),136.2,136.1(d,J 27.0Hz),133.0(d,J 3.0Hz),130.8,126.4,123.1,122.6(d,J 4.5Hz),120.6,113.9,109.7,89.0,82.7,77.1,77.0,49.4,35.4,26.4; 19 F NMR(380MHz,CDCl3)δ-79.8(d,J 9.5Hz);m / z:489[M+H] + (Measured value [M+H] + ,489.1569,C 26 H 21 FN4O5 is [M+H] + (Requires 489.1569).

[0293] (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-56) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.50 (1H, d, J 5.5 Hz, pyrH-6), 8.12 (1H, dt, J 5.0, 1.5 Hz, F pyrH-6), 7.59 (1H, ddd, J 9.5, 8.0, 2.0 Hz, F pyrH-4), 7.56 (1H, d, J 2.5 Hz, pyrH-3), 7.32-7.24 (3H, m, oxobenzoxazapine H-6, H-8, F pyrH-3), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.97 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.78 (2H, dd, J 7.0, 0.5 Hz, 2H, H-4 of oxetane H-2), 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), 3.42 (3H, s, NCH3); 19 F NMR(380MHz,CDCl3)δ-79.8(d,J 9.5Hz);m / z:505[M+H] + (Measured value [M+H] + ,505.1502,C 26 H 21 FN4O6 is [M+H] + 505.1518).

[0294] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide (I-57) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.52 (1H, dd, J 4.5, 1.5 Hz, OpyH-6), 8.49 (1H, d, J 5.5 Hz, OpyH-6), 8.45 (1H, d, J 2.5 Hz, OpyH-2), 7.60 (1H, d, J 2.5 Hz, OpyH-3), 7.42 (1H, ddd, J 8.0, 2.5, 1.5 Hz, OpyH-4), 7.37 (1H, dd, J 8.0, 4.5 Hz, OpyH-5), 7.31-7.28 (2H, m, oxobenzoxazapine H-6, H-8), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.98 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.78 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.30 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.42 (3H, s, NCH3); m / z: 487 [M+H] + (Measured value [M+H] + ,487.1624,C 26 H 22 N4O6 is [M+H] + (Requires 487.1612).

[0295] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide (I-58) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.0 Hz, NH), 8.52 (1H, dd, J 4.5, 1.5 Hz, OpyH-2 or H-6), 8.48 (1H, d, J 5.5 Hz, OpyH-6), 8.45 (1H, d, J 2.5 Hz, OpyH-2 or H-6), 7.60 (1H, d, J 2.5 Hz, OpyH-3), 7.41 (1H, ddd, J 8.0, 2.5, 1.5 Hz, OpyH-4 or H-5), 7.36 (1H, ddd, J 8.0, 4.5, 0.5 Hz, OpyH-4 or H-5), 7.27-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.98 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (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, oxobenzoxazapine H-2 (1H), 3.41 (3H, s, NCH), 1.61 (6H, s, C(CH)OH); m / z: 455 [M + H-H0] + (Measured value [M+H] + ,473.1833,C 26 H 24 N4O5 is [M+H] + 473.1819 required).

[0296] (S)-4-((5-fluoropyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-59) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.23 ​​(1H, d, J 5.5 Hz, pyrH-6), 8.41 (1H, br s, Opy 1H), 8.30 (1H, br s, Opy 1H), 7.63 (1H, d, J 2.5 Hz, pyrH-3), 7.32-7.29 (2H, m, oxobenzoxazapine H-6, H-8), 7.18-7.15 (1H, m, Opy 1H), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.02 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H,d,J 7.0 Hz, 2H,H-4 of oxetane H-2), 4.78 (2H,d,J 6.5 Hz, 2H,H-4 of oxetane H-2), 4.71 (1H,dd,J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H,dd,J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.42 (3H,s,NCH3); 19 F NMR(380MHz,CDCl3)δ-123.3(d,J 8.0Hz);m / z:505[M+H] + (Measured value [M+H] + ,505.1519,C 26 H 21 FN4O6 is [M+H] + 505.1518).

[0297] (S)-4-((5-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]oxazepin-3-yl)picolinamide (I-60) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.52 (1H, d, J 5.5 Hz, pyrH-6), 8.40 (1H, d, J 2.5 Hz, OpyH), 8.29 (1H, d, J 2.0 Hz, OpyH), 7.63 (1H, d, J 2.5 Hz, pyrH-3), 7.28-7.18 (2H, m, oxobenzoxazapine H-6, H-8), 7.17 (1H, dt, J 9.0, 2.5 Hz, OpyH), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.02 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.5, 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), 3.42 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2OH); 19 F NMR(380MHz,CDCl3)δ-123.3(d,J 8.0Hz);m / z:491[M+H] + ,473[M+H-H2O] + (Measured value [M+H] + ,491.1741,C 26 H 23 FN4O5 is [M+H] + (Requires 491.1725).

[0298] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-ylmethyl)picolinamide (I-61) [ka] 1H NMR(400MHz,CDCl3)δ 8.85(1H,d,J 7.0Hz,NH),8.49(1H,d,J 5.0Hz,pyH-6),8.49-8.45(2H,m,CH2pyH-2,H-6),7.92(1H,br d,J 1.0Hz,pyH-3),7.42(1H,br d,J 8.0Hz,CH2pyH-5),7.27-7.25(2H,m,oxobenzoxazapine H-6,H-8),7.23-7.7.20(1H,m,CH2pyH-4),7.19(1H,dd,J 5.0,2.0Hz,pyH-5),7.11(1H,d,J 9.0 Hz, oxobenzoxazapine H-9), 5.02 (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), 4.00 (2H, s, CH2py), 3.41 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2OH); m / z: 453 [M + H - HO] + (Measured value [M+H] + ,471.2020,C 27 H 26 N4O4 is [M+H] + 471.2027).

[0299] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-ylmethyl)picolinamide (I-62) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.50 (1H, d, J 5.5 Hz, pyH-6), 8.94-8.46 (2H, m, CH2pyH-2, H-6), 7.92 (1H, br d, J 1.0 Hz, pyH-3), 7.45 (1H, br d, J 8.0 Hz, CH2pyH-5), 7.30-7.27 (2H, m, oxobenzoxazapine H-6, H-8), 7.26-7.23 (1H, m, CH2pyH-4), 7.20 (1H, dd, J 5.0, 2.0 Hz, pyH-5), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.03 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, dd, J 6.5, 2.0 Hz, 2H, H-4 of oxetane H-2), 4.78 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 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), 4.01 (2H, s, CH2Py), 3.40 (3H, s, NCH3); 13 C NMR(100MHz,CDCl3)δ 168.9,163.9,150.5,150.3,149.9,149.4,148.8,148.2,136.5,136.4,134.1,110.9,126.7,12 6.5,123.8,123.3,122.5,119.4,88.9,84.6,84.6,77.2,67.4,49.3,38.4,35.4;m / z:485[M+H] + (Measured value [M+H] + ,485.1829,C 27 H 24 N4O5 is [M+H] + (Requires 485.1819).

[0300] (S)—N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide (I-63) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.52 (1H, dd, J 4.5, 1.5 Hz, OpyH-6), 8.47 (1H, d, J 5.5 Hz, OpyH-6), 8.45 (1H, d, J 2.5 Hz, OpyH-2), 7.60 (1H, d, J 2.5 Hz, OpyH-3), 7.41 (1H, ddd, J 8.5, 2.5, 1.5 Hz, OpyH-5), 7.36 (1H, dd, J 8.0, 4.5 Hz, OpyH-4), 7.62-7.24 (2H, m, oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.97 (1H, dd, J 5.5, 2.5 Hz, pyran H-5), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.93 (2H, ddd, J 13.0, 5.5, 4.0 Hz, 2H of pyran H-2, H-6), 3.52 (2H, ddd, J 11.5, 8.5, 3.0 Hz, 2H, H-6 of pyran H-2), 3.42 (3H, s, NCH3), 2.86-2.79 (1H, m, pyran H-4), 1.93-1.87 (2H, m, 2H, H-5 of pyran H-3), 1.79-1.70 (2H, m, 2H, H-5 of pyran H-3); m / z: 499 [M+H] + (Measured value [M+H] + ,499.1975,C 28 H 26 N4O5 is [M+H] + 499.1976 required).

[0301] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-ylmethyl)picolinamide (I-64) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.54-8.52 (1H, m, CH2pyH-6), 8.49 (1H, d, J 5.5 Hz, pyH-6), 7.96 (1H, br d, J 1.0 Hz, pyH-3), 7.60 (1H, td, J 7.5, 2.0 Hz, CH2pyH-4), 7.33 (1H, dd, J 5.0, 2.0 Hz, pyH-5), 7.30-7.27 (2H, m, oxobenzoxazapine H-6, H-8), 7.16-7.11 (3H, m, oxobenzoxazapine H-9, CH2pyH-3, H-5), 5.04 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, dd, J 7.0, 1.0 Hz, 2H, H-4 of oxetane H-2), 4.78 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.70 (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), 4.18 (2H, s, CHpy), 3.41 (3H, s, NCH); m / z: 485 [M+H] + (Measured value [M+H] + ,485.1810,C 27 H 24 N4O5 is [M+H] + (Requires 485.1819).

[0302] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide (I-65) [ka] 1H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.49 (1H, d, J 5.0 Hz, pyrH-6), 7.94 (1H, br d, J 1.0 Hz, pyrH-3), 7.31 (1H, dd, J 5.0, 2.0 Hz, pyrH-5), 7.26-7.24 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.72 (1H, s, thiazole H-5), 5.03 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, oxobenzoxazapine H-2 1H), 4.28 (1H, dd, J 11.5, 9.5 Hz, oxobenzoxazapine H-2 1H), 4.10 (2H, s, pyroCH2 thiazole), 3.41 (3H, s, NCH3), 2.65 (3H, s, thiazoleCH3), 1.60 (6H, s, C(CH3)2)OH); m / z: 491 [M+H] + (Measured value [M+H] + ,491.1750,C 26 H 26 N4O4S is [M+H] + (Requires 491.1748).

[0303] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide (I-66) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.49 (1H, d, J 5.0 Hz, pyrH-6), 7.94 (1H, br d, J 1.0 Hz, pyrH-3), 7.32 (1H, dd, J 5.0, 1.5 Hz, pyrH-5), 7.29-7.24 (2H, m, oxobenzoxazapine H-6, H-8), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.72 (1H, s, thiazole H-5), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.91 (2H, dd, J 6.5, 2.5 Hz, 2H, H-4 of oxetane H-2), 4.77 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.70 (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), 4.10 (2H, s, pyCH2 thiazole), 3.40 (3H, NCH3), 2.65 (3H, s, thiazole CH3); m / z: 505 [M+H] + (Measured value [M+H] + ,505.1545,C 26 H 24 N4O5S is [M+H] + 505.1540).

[0304] (S)-4-((5-fluoropyridin-3-yl)oxy)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-67) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.53 (1H, dd, J 5.5, 0.5 Hz, pyrH-6), 8.41 (1H, d, J 2.5 Hz, Opy 1H), 8.29 (1H, d, J 2.0 Hz, Opy 1H), 7.63 (1H, d, J 2.5 Hz, pyrH-3), 7.28-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.17 (1H, dt, J Hz, Opy 1H), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.02 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.02 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.87 (2H, dd, J 8.5, 5.5 Hz, 2H, H-4 of oxetane H-2), 4.80 (2H, dd, J 6.5, 5.5 Hz, 2H, H-4 of oxetane H-2), 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), 4.10-4.02 (1H, m, oxetane H-3), 3.42 (3H, s, NCH3); 19 F NMR(380MHz,CDCl3)δ-123.3(d,J 9.5Hz);m / z:489[M+H] + (Measured value [M+H] + ,489.1565,C 26 H 21 FN4O5 is [M+H] + (Requires 489.1569).

[0305] (S)-4-((3,5-dimethylisoxazol-4-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-68) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.49 (1H, d, J 5.0 Hz, pyrH-6), 7.86 (1H, d, J 1.0 Hz, pyrH-3), 7.28-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.12-7.10 (1H, m, pyrH-5), 5.03 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, oxobenzoxazapine H-2 (1H), 3.70 (2H,s, CH2 isoxazole), 3.41 (3H,s, NCH3), 2.29 (3H,s, 1 x isoxazole CH3), 2.04 (3H,s, 1 x isoxazole CH3), 1.61 (6H,s, C(CH3)2OH); m / z: 471 [M + H-H2O] + (Measured value [M+H] + ,489.1246,C 27 H 28 N4O5 is [M+H] + 489.1232).

[0306] (S)-4-((3,5-dimethylisoxazol-4-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-69) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.49 (1H, dd, J 5.0, 0.5 Hz, pyrH-6), 7.86 (1H, d, J 1.0 Hz, pyrH-3), 7.32-7.29 (2H, m, oxobenzoxazapine H-6, H-8), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.11 (1H, dd, J 5.0, 2.0 Hz, pyrH-5), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, ddd, J 6.5, 2.5 Hz, 2H, H-4 of oxetane H-2), 4.91 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.71 (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), 3.71 (2H, s, CH2 isoxazole), 3.43 (3H, s, NCH3), 2.29 (3H, s, 1 x isoxazole CH3), 2.04 (3H, s, 1 x isoxazole CH3); m / z: 525 [M+Na] + ,503[M+H] + ,485[M+H-H2O] + (Measured value [M+H] + ,503.1924,C 27 H 26 N4O6 is [M+H] + 503.1925).

[0307] (S)-4-((1H-pyrazol-1-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-70) [ka] 1H NMR (400 MHz, CDCl3) δ 8.83 (1H, d, J 7.5 Hz, NH), 8.53 (1H, d, J 5.5 Hz, pyrH-6), 7.85 (1H, d, J 1.0 Hz, pyrH-3), 7.57 (1H, d, J 1.5 Hz, pyrazole H-3 or H-5), 7.43 (1H, d, J 2.0 Hz, pyrazole H-3 or H-5), 7.31-7.28 (2H, m, oxobenzoxazapine H-6, H-8), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.09 (1H, dt, J 5.0, 1.0 Hz, pyrH-5), 6.32 (1H, dd, J 2.5, 2.0 Hz, pyrazole H-4), 5.38 (2H, s, pyrazole H-4), 5.03 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.91 (2H, dd, J 7.0, 2.0 Hz, 2H, H-4 of oxetane H-2), 4.77 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 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), 3.41 (3H, s, NCH); m / z: 474 [M+H] + (Measured value [M+H] + ,474.1765,C 25 H 23 N5O5 is [M+H] + (Requires 474.1772).

[0308] (S)-4-((1H-pyrazol-1-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-71) [ka] 1H NMR (400 MHz, CDCl3) δ 8.83 (1H, d, J 7.0 Hz, NH), 8.52 (1H, dd, J 5.0, 0.5 Hz, pyrazole H-6), 7.86 (1H, dd, J 2.0, 0.5 Hz, pyrazole H-3), 7.56 (1H, d, J 2.0 Hz, pyrazole H-3 or H-5), 7.43 (1H, dd, J 2.5, 0.5 Hz, pyrazole H-3 or H-5), 7.28-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.08 (1H, dt, J 5.0, 1.0 Hz, pyrazole H-5), 6.32 (1H, dd, J 2.5, 2.0 Hz, pyrazole H-4), 5.37 (2H, s, pyrazole H-4), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.07 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.41 (3H, s, NCH), 1.61 (6H, s, C(CH)OH); m / z: 442 [M+H] + (Measured value [M+H] + ,460.1984,C 25 H 25 N5O4 is [M+H] + 460.1979 required).

[0309] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)methyl)picolinamide (I-72) [ka] 1H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.47 (1H, d, J 5.0 Hz, pyrH-6), 8.34 (1H, d, J 2.0 Hz, MepyH-2), 7.90 (1H, d, J 1.0 Hz, pyrH-3), 7.30 (1H, dd, J 8.0, 2.5 Hz, Mepy-4), 7.26-7.22 (2H, m, oxobenzoxazapine H-6, H-8), 7.18 (1H, dd, J 5.0, 1.5 Hz, pyrH-5), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.06 (1H, d, J 8.0 Hz, MepyH-5), 5.02 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.95 (2H, s, pyCH2MePy), 3.40 (3H, s, NCH3), 2.50 (3H, s, pyCH3), 1.61 (6H, s, C(CH3)2OH); m / z: 486 [M+H] + ,468[M+H-H2O] + (Measured value [M+H] + ,485.2190,C 28 H 28 N4O4 is [M+H] + (Requires 485.2183).

[0310] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)methyl)picolinamide (I-73) [ka] 1H NMR (400 MHz, CDCl3) δ 8.83 (1H, d, J 7.5 Hz, NH), 8.47 (1H, d, J 5.0 Hz, pyrH-6), 8.33 (1H, d, J 2.0 Hz, MepyH-2), 7.90 (1H, d, J 1.0 Hz, pyrH-3), 7.31 (1H, dd, J 8.0, 2.0 Hz, MepyH-4), 7.27-7.18 (2H, m, oxobenzoxazapine H-6, H-8), 7.17 (1H, dd, J 5.0, 2.0 Hz, pyrH-5), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.07 (1H, d, J 8.0Hz, MepyH-5), 5.02 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapine H-3), 4.92 (2H, dd, J 6.5, 1.0Hz, 2H, H-4 of oxetane H-2), 4.79 (2H, d, J 6.5Hz, 2H, H-4 of oxetane H-2), 4.69 (1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.0, 9.5Hz, 1H of oxobenzoxazapine H-2), 3.95 (2H, s, pyCH2MePy), 3.39 (3H, s, NCH3), 2.51 (3H, s, pyCH3); 13 C NMR(100MHz,CDCl3)δ 168.9,164.0,157.0,150.7,150.5,149.1,148.7,147.1,136.9,136.4,130.9,130.8,130.9,130.8,126.6,1 m / z:499[M+H] + (Measured value [M+H] + ,499.1997,C 28 H 26 N4O5 is [M+H] + 499.1976 required).

[0311] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylpyridin-3-yl)oxy)picolinamide (I-74) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.46 (1H, d, J 5.5 Hz, pyrH-6), 8.43 (1H, dd, J 4.5, 1.0 Hz, MepyH-6), 7.52 (1H, d, J 2.5 Hz, pyrH-3), 7.31 (1H, dd, J 8.0, 1.0 Hz, MepyH-4), 7.27-7.24 (2H, m, oxobenzoxazapine H-6, H-8), 7.20 (1H, dd, J 8.0, 4.5 Hz, MepyH-5), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.87 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.00 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.41 (3H, s, NCH3), 2.39 (3H, s, pyrCH3), 1.61 (6H, s, C(CH3)2OH); m / z: 488 [M+H] + ,470[M+H-H2O] + (Measured value [M+H] + ,487.1985,C 27 H 27 N4O5 is [M+H] + 487.1976 required).

[0312] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylpyridin-3-yl)oxy)picolinamide (I-75) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.46 (1H, d, J 5.5 Hz, pyrH-6), 8.43 (1H, dd, J 4.5, 1.5 Hz, MepyH-6), 7.52 (1H, d, J 2.5 Hz, pyrH-3), 7.33-7.29 (3H, m, MepyH-4, oxobenzoxazapine H-6, H-8), 7.21 (1H, dd, J 8.0, 4.5 Hz, MepyH-5), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.88 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H,d,J 6.5 Hz, 2H,H-4 of oxetane H-2), 4.79 (2H,dd,J 6.5, 1.0 Hz, 2H,H-4 of oxetane H-2), 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), 3.42 (3H,s,NCH3), 2.40 (3H,s,pyCH3); 13 C NMR(100MHz,CDCl3)δ 168.9,165.2,163.4,152.0,151.5,150.5,150.4,148.2,146.5,136.3,130.9,128.7,126.5,12 3.3,122.6,119.4,113.8,110.0,88.8,84.7,84.5,77.1,67.4,49.3,35.4,19.2;m / z:501[M+H] + (Measured value [M+H] + ,501.1771,C 27 H 24 N4O6 is [M+H] + 501.1769).

[0313] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(thiazol-4-ylmethyl)picolinamide (I-76) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.76 (1H, d, J 1.0 Hz, thiazole H-2), 8.51 (1H, d, J 5.0 Hz, pyrH-6), 7.95 (1H, s, pyrH-3), 7.33 (1H, dd, J 4.5, 1.0 Hz, pyrH-5), 7.30-7.27 (2H, m, oxobenzoxazapine H-6, H-8), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.99 (1H, s, thiazole H-5), 5.04 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.91 (2H, dd, J 6.5, 3.0 Hz, 2H, H-4 of oxetane H-2), 4.77 (2H, d, J 6.5, Hz, 2H, H-4 of oxetane H-2), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.21 (2H, s, pyCH2 thiazole), 3.40 (3H, s, NCH3); m / z: 513 [M+H] + ,491[M+H] + (Measured value [M+H] + ,491.1391,C 25 H 22 N4O5S is [M+H] + (Requires 491.1384).

[0314] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(thiazol-4-ylmethyl)picolinamide (I-77) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.76 (1H, d, J 2.0 Hz, thiazole H-2), 8.50 (1H, dd, J 5.0, 0.5 Hz, pyrH-6), 7.96 (1H, d, J 1.0 Hz, pyrH-3), 7.33 (1H, dd, J 5.0, 2.0 Hz, pyrH-5), 7.27-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.98 (1H, d, J 2.0 Hz, thiazole H-5), 5.03 (1H, td, J 11.5, 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 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.21 (2H, s, pyrCH2 thiazole), 3.41 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2OH); m / z: 499 [M+Na] + ,477[M+H] + ,459[M+H-H2O] + (Measured value [M+H] + ,477.1588,C 25 H 24 N4O4S is [M+H] + (Requires 477.1591).

[0315] (S)-4-((2,6-dimethylpyridin-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]oxazepin-3-yl)picolinamide (I-78) [ka] 1H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.44 (1H, dd, J 5.5, 0.5 Hz, pyrH-6), 7.50 (1H, d, J 2.0 Hz, pyrH-3), 7.27-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.20 (1H, d, J 8.0 Hz, pyrH-4 or H-5), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.03 (1H, d, J 8.0 Hz, pyrH-4 or pyrH-5), 6.86 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.00 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.41 (3H, s, NCH3), 2.54 (3H, s, 1 x OpyCH3), 2.33 (3H, s, 1 x OpyCH3), 1.61 (6H, s, C(CH3)2OH); m / z: 501 [M+H] + ,483[M+H-H2O] + .

[0316] (S)-4-((2,6-dimethylpyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-79) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5 Hz, pyrH-6), 7.49 (1H, d, J 2.5 Hz, pyrH-3), 7.30-7.28 (2H, m, oxobenzoxazapine H-6, H-8), 7.20 (1H, d, J 8.0 Hz, pyrH-4 or H-5), 7.14 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 7.04 (1H, d, J 8.5 Hz, pyrH-4 or H-5), 6.86 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, dd, J 7.0, 1.0 Hz, 2H, H-4 of oxetane H-2), 4.78 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.92 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.41 (3H, s, NCH3), 2.54 (3H, s, 1 x OpyCH3), 2.34 (3H, s, 1 x OpyCH3); m / z: 515 [M+H] + (Measured value [M+H] + ,515.1934,C 28 H 26 N4O6 is [M+H] + 515.1925 required).

[0317] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide (I-80) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.55 (1H, d, J 5.5 Hz, pyH-6), 8.53 (1H, d, J 2.5 Hz, CF3pyH-6), 7.54 (1H, d, J 9.0 Hz, CF3pyH-3), 7.65 (1H, d, J 2.5 Hz, pyH-3), 7.53 (1H, dd, J 8.5, 2.5 Hz, CF3pyH-4), 7.27-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.05 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (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), 3.42 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2OH); 19 F NMR(380MHz,CDCl3)δ-67.4;m / z:541[M+H] + ,523[M+H-H2O] + (Measured value [M+H] + ,541.1689,C 27 H 23 F3N4O5 is [M+H] + (Requires 541.1693).

[0318] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide (I-81) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.56 (1H, d, J 5.5 Hz, pyH-6), 8.53 (1H, d, J 2.5 Hz, CF3pyH-6), 7.74 (1H, d, J 8.5 Hz, CF3pyH-3), 7.65 (1H, d, J 2.0 Hz, pyH-3), 7.53 (1H, dd, J 8.5, 2.5 Hz, CF3pyH-4), 7.32-7.29 (2H, m, oxobenzoxazapine H-6, H-8), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.05 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, dd, J 7.0, 1.0 Hz, 2H, H-4 of oxetane H-2), 4.78 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3); 13 C NMR(100MHz,CDCl3)δ 168.8,164.3,163.1,152.8,152.0,150.7,150.5,144.8(q,J 35.5Hz),142.8,136.3,131.0,128.1,126.5,123.3,122.0(q,J 2.5Hz),119.4,115.2,111.1,88.6,84.8,84.4(2C),77.1,67.5,49.4,35.5; 19 F NMR(380MHz,CDCl3)δ-67.4;m / z:555[M+H] + (Measured value [M+H] + ,555.1494,C 27 H 21 F3N4O6 is [M+H] + (Requires 555.1486).

[0319] (S)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylpyridin-3-yl)oxy)picolinamide (I-82) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.46 (1H, d, J 5.5 Hz, pyH-6), 8.43 (1H, dd, J 4.5, 1.5 Hz, CH3pyH-6), 7.52 (1H, d, J 2.5 Hz, pyH-3), 7.33-7.28 (3H, m, oxobenzoxazapine H-6, H-8, CH3pyH-4), 7.21 (1H, dd, J 8.0, 4.5 Hz, CH3pyH-5), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.88 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 2.56-2.50 (2H, m, cBu 2H), 2.39 (3H, s, pyCH3), 2.38-2.30 (2H, m, cBu 2H), 1.90-1.85 (2H, m, cBu 2H); m / z: 521 [M+Na] + ,499[M+H] + (Measured value [M+H] + ,499.1991,C 28 H 26 N4O5 is [M+H] + 499.1976 required).

[0320] (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-83) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.50 (1H, d, J 5.5 Hz, pyrH-6), 8.12 (1H, dt, J 4.5, 1.5 Hz, FpyH), 7.59 (1H, ddd, J 9.5, 8.0, 2.0 Hz, FpyH), 7.56 (1H, d, J 2.5 Hz, pyrH-3), 7.31-7.25 (3H, m, oxobenzoxazapine H-6, H-8, FpyH), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.97 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.01 (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), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 2.56-2.50 (2H of 2H, m, cBu), 2.38-2.30 (2H of 2H, m, cBu), 1.92-1.85 (2H, m, cBu 2H); 19 F NMR(380MHz,CDCl3)δ-79.8(d,J 9.5Hz);m / z:525[M+Na]+,503[M+H] + (Measured value [M+H] + ,503.1733,C 27 H 23 FN4O5 is [M+H] + 503.1725).

[0321] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-84) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.0 Hz, NH), 8.51 (1H, d, J 5.0 Hz, PyH-6), 7.95 (1H, d, J 1.0 Hz, PyH-3), 7.69 (1H, dd, J 15.5, 8.0 Hz, F PyH-3), 7.35 (1H, dd, J 5.0, 2.0 Hz, PyH-5), 7.28-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.99 (1H, dd, J 7.5, 2.5 Hz, F PyH-5), 6.78 (1H, dd, J 8.0, 2.5 Hz, FpyH-4), 5.05 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.88 (2H, dd, J 8.5, 5.5 Hz, 2H, H-4 of oxetane H-2), 4.80 (2H, dd, J 7.5, 5.5 Hz, 2H, H-4 of oxetane H-2), 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), 4.11 (2H, s, CHpy), 4.10-4.04 (1H, m, oxetane H-3), 3.42 (3H, s, NCH); 13 C NMR(100MHz,CDCl3)δ 169.0,164.0,163.2(d,J 240.0Hz),157.3(d,13.0Hz),150.0,149.3,149.1,148.7,141.7(d,J 7.5Hz),136.3,130.7,127.1,126.4,123.1,122.7,120.5(d,J 8.0Hz),120.4,107.7(d,J 37.0Hz,),89.0,82.7,77.2,49.3,43.0,35.4,26.4; 19F NMR(380MHz,CDCl3)δ-66.5(d,J 8.0Hz);m / z:509[M+Na] + ,487[M+H] + (Measured value [M+H] + ,487.1783,C 27 H 23 FN4O4 is [M+H] + (Requires 487.1776).

[0322] (S)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide (I-85) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.50 (1H, d, J 5.0 Hz, pyrH-6), 7.94 (1H, d, J 1.0 Hz, pyrH-3), 7.32 (1H, dd, J 5.0, 2.0 Hz, pyrH-5), 7.29-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.73 (1H, s, thiazole H-5), 5.05 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.88 (2H, dd, J 8.5, 5.5 Hz, 2H, H-4 of oxetane H-2), 4.80 (2H, dd, J 7.5, 5.5 Hz, 2H, H-4 of oxetane H-2), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.10 (2H, s, pYCH2 thiazole), 4.10-4.02 (1H, m, oxetane H-3), 3.42 (3H, s, NCH3), 2.65 (3H, s, thiazole CH3); m / z: 489 [M+H] + (Measured value [M+H] + ,489.1597,C 26 H24 N4O4S is [M+H] + (Requires 489.1591).

[0323] (S)-4-Hydroxy-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-86) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.82 (1H, m, NH), 8.28-8.10 (1H, br m, py of 1H), 7.54-7.38 (1H, br m, py of 1H), 7.25-7.21 (2H, m, oxobenzoxazapine H-6, H-8), 7.07 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 6.84-6.72 (1H, br m, py of 1H), 5.01 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.60 (1H, dd, J 10.0, 7.5 Hz, oxobenzoxazapine H-2), 4.36 (1H, dd, J 10.5, 9.5 Hz, oxobenzoxazapine H-2 (1H), 3.38 (3H, s, NCH), 1.61 (6H, s, C(CH)OH); m / z: 378 [M + H-H0] + (Measured value [M+H] + ,396.1572,C 21 H 21 N3O5 is [M+H] + 396.1554).

[0324] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide (I-87) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.0 Hz, NH), 8.60 (1H, dd, J 4.5, 1.0 Hz, CF3pyH-6), 8.53 (1H, d, J 5.5 Hz, pyH-6), 7.59-7.56 (2H, m, pyH-3, CF3pyH-5), 7.50 (1H, d, J 8.0 Hz, CF3pyH-4), 7.28-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.01 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.00 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.41 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2OH); 19 F NMR(380MHz,CDCl3)δ-65.8;m / z:541[M+H] + ,523[M+H-H2O] + (Measured value [M+H] + ,541.1700,C 27 H 23 F3N4O5 is [M+H] + (Requires 541.1693).

[0325] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide (I-88) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.60 (1H, dd, J 4.5, 1.0 Hz, CF3pyH-6), 8.53 (1H, d, J 5.5 Hz, pyH-6), 7.59-7.56 (2H, m, pyH-3, CF3pyH-5), 7.51 (1H, d, J 7.5 Hz, CF3pyH-4), 7.31-7.29 (2H, m, oxobenzoxazapine H-6, H-8), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.01 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.92-4.90 (2H, m, 2H, H-4 of oxetane H-2), 4.78 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.30 (1H, dd, J 10.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.42 (3H, s, NCH3); 19 F NMR(380MHz,CDCl3)δ-65.8;m / z:555[M+H] + (Measured value [M+H] + ,555.1476,C 27 H 21 F3N4O6 is [M+H] + (Requires 555.1486).

[0326] (S)-4-Hydroxy-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-89) [ka] 1H NMR (400 MHz, CD3OD) δ 8.18 (1H, br m, 1H of pyOH), 7.53 (1H, d, J 2.0 Hz, oxobenzoxazapine H-6), 7.38 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.31 (1H, br m, 1H of pyOH), 7.21 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 6.79 (1H, br m, 1H of pyOH), 5.00 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.86 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.70 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.59 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.42 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.40 (3H, s, NCH3); m / z: 410 [M+H] + (Measured value [M+H] + ,410.1335,C 21 H 19 N3O6 is [M+H] + 410.1347).

[0327] (S)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide (I-90) [ka] 1H NMR (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.49 (1H, d, J 4.5 Hz, pyH-3), 7.94 (1H, s, pyH-3), 7.31 (1H, d, J 4.5 Hz, pyH-5), 7.26-7.24 (2H, m, oxobenzoxazapine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.72 (1H, s, thiazole H-5), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, t, J 10.5 Hz, 1H of oxobenzoxazapine H-2), 4.10 (2H, s, pyCH2 thiazole), 3.94 (2H, dt, J 12.0, 4.5 Hz, 2H of pyran H-2, H-6), 3.54 (2H, ddd, J 11.5, 9.0, 3.0 Hz, 2H,H-6 of pyran H-2), 3.41 (3H,s,NCH3), 2.86-2.80 (1H,m, pyran H-4), 2.65 (3H,s, thiazole CH3), 1.92-1.87 (2H,m, 2H,H-5 of pyran H-3), 1.79-1.71 (2H,m, 2H,H-5 of pyran H-3); m / z: 518 [M+H] + (Measured value [M+H] + ,517.1914,C 28 H 28 N4O4S is [M+H] + 517.1904).

[0328] (S)-4-((2-cyanopyridin-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]oxazepin-3-yl)picolinamide (I-91) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.60-8.58 (2H, m, pyH-6, CNpyH-6), 7.62 (1H, d, J 2.5 Hz, pyH-3), 7.57 (1H, dd, J 8.5, 4.5 Hz, CNpyH-5), 7.48 (1H, dd, J 8.5, 1.5 Hz, CNpyH-4), 7.28-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.13 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.00 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2OH); m / z: 498 [M+H] + (Measured value [M+H] + ,498.1777,C 27 H 23 N5O5 is [M+H] + (Requires 498.1772).

[0329] (S)-4-((2-cyanopyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-92) [ka] 1H NMR (400 MHz, CDCl3) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.61-8.59 (2H, m, pyH-6, CNpyH-6), 7.62 (1H, d, J 2.5 Hz, pyH-3), 7.57 (1H, dd, J 8.5, 4.5 Hz, CNpyH-5), 7.49 (1H, dd, J 8.5, 1.5 Hz, CNpyH-4), 7.32-7.30 (2H, m, oxobenzoxazapine H-6, H-8), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.13 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.78 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3); m / z: 512 [M+H] + (Measured value [M+H] + ,512.1584,C 27 H 21 N5O6 is [M+H] + 512.1565).

[0330] (S)-4-((6-cyanopyridin-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]oxazepin-3-yl)picolinamide (I-93) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.0 Hz, NH), 8.53 (1H, d, J 5.0 Hz, pyH-6), 7.94 (1H, s, pyH-3), 7.74 (1H, dd, J 8.0, 7.5 Hz, CN-pyH-4), 7.56 (1H, d, J 7.5 Hz, CN-pyH-3 or H-5), 7.38-7.32 (2H, m, pyH-5, CN-pyH-3 or H-5), 7.28-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.03 (1H, dt, J 11.5, 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, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.21 (2H, s, pyCH2py), 3.42 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2OH); m / z: 496 [M+H] + ,478[M+H-H2O] + (Measured value [M+H] + ,496.1998,C 28 H 25 N5O4 is [M+H] + 496.1979).

[0331] (S)-4-((6-cyanopyridin-2-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-94) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.0 Hz, NH), 8.53 (1H, d, J 5.0 Hz, pyH-6), 7.94 (1H, s, pyH-3), 7.74 (1H, dd, J 8.0, 7.5 Hz, CN-pyH-4), 7.56 (1H, d, J 7.5 Hz, CN-pyH-3 or H-5), 7.36-7.34 (2H, m, pyH-5, CN-pyH-3 or H-5), 7.32-7.30 (2H, m, oxobenzoxazapine H-6, H-8), 7.15 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 5.05 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, d, J 7.0 Hz, 2H, H-4 of oxetane H-2), 4.78 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.71 (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), 4.22 (2H, s, pyCH2py), 3.42 (3H, s, NCH3); m / z: 510 [M+H] + (Measured value [M+H] + ,510.1774,C 28 H 23 N5O5 is [M+H] + (Requires 510.1772).

[0332] (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-fluoropyridin-3-yl)oxy)picolinamide (I-95) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.51 (1H, d, J 5.5 Hz, PyH-6), 8.13 (1H, dt, J 5.0, 1.5 Hz, FpyH-6), 7.60 (1H, ddd, J 9.5, 8.0, 2.0 Hz, FpyH-4), 7.57 (1H, d, J 2.5 Hz, PyH-3), 7.27 (1H, ddd, J 8.0, 5.0, 1.0 Hz, FpyH-5), 7.26-7.23 (2H, m, oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.98 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.00 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 1.31 (9H, s, C(CH3)3); 19 F NMR(380MHz,CDCl3)δ-79.8(d,J 9.5Hz);m / z:490[M+H] + (Measured value [M+H] + ,489.1938,C 27 H 25 FN4O4 is [M+H] + 489.1933 required).

[0333] (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide (I-96) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.50 (1H, dd, J 5.0, 0.5 Hz, pyrH-3), 7.95 (1H, d, J 1.0 Hz, pyrH-3), 7.32 (1H, dd, J 5.0, 2.0 Hz, pyrH-5), 7.25-7.22 (2H, m, oxobenzoxazapine H-6, H-8), 7.08 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.73 (1H, s, thiazole H-4), 5.03 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, oxobenzoxazapine H-2 1H), 4.27 (1H, dd, J 11.0, 9.5 Hz, oxobenzoxazapine H-2 1H), 4.11 (2H, s, pyroCH2 thiazole), 3.42 (3H, NCH3), 2.66 (3H, s, thiazoleCH3), 1.31 (9H, s, C(CH3)3); m / z: 490 [M+H] + (Measured value [M+H] + ,489.1954,C 27 H 28 N4O3S is [M+H] + 489.1955 required).

[0334] (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)picolinamide (I-97) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.52 (1H, d, J 5.0 Hz, pyrH-3), 7.96 (1H, d, J 1.0 Hz, pyrH-3), 7.70 (1H, dd, J 8.0, 7.5 Hz, F pyrH-4), 7.35 (1H, dd, J 5.0, 2.0 Hz, pyrH-5), 7.26-7.23 (2H, m, oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.00 (1H, dd, J 7.5, 2.0 Hz, F pyrH-4 or H-5), 6.79 (1H, dd, J 8.0, 2.5 Hz, FpyH-3 or H-5), 5.03 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.27 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.11 (2H, s, pyCH2Fpy), 3.42 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3); 19 F NMR(380MHz,CDCl3)δ-66.6(d,J 8.0Hz);m / z:488[M+H] + (Measured value [M+H] + ,487.2153,C 28 H 27 FN4O3 is [M+H] + 487.2140 required).

[0335] (S)-4-((2-ethylthiazol-4-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-98) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.50 (1H, d, J 4.5 Hz, pyrH-6), 7.96 (1H, d, J 1.0 Hz, pyrH-3), 7.33 (1H, dd, J 4.5, 1.5 Hz, pyrH-5), 7.27-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.72 (1H, s, thiazole H-4), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, oxobenzoxazapine H-2 1H), 4.29 (1H, dd, J 11.0, 9.5 Hz, oxobenzoxazapine H-2 1H), 4.12 (2H, s, pyCH2 thiazole), 3.42 (3H, s, NCH3), 2.98 (2H, q, J 7.5 Hz, CH2CH3), 1.42 (6H, s, C(CH3)2OH), 1.35 (3H, t, J 7.5 Hz, CH2CH3); m / z: 505 [M+H] + ,487[M+H-H2O] + (Measured value [M+H] + ,505.1902,C 27 H 28 N4O4S is [M+H] + 505.1904).

[0336] (S)-4-((2-ethylthiazol-4-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-99) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.51 (1H, dd, J 5.0, 0.5 Hz, pyrH-6), 7.96 (1H, d, J 1.0 Hz, pyrH-3), 7.33 (1H, dd, J 5.0, 2.0 Hz, pyrH-5), 7.31-7.28 (2H, m, oxobenzoxazapine H-6, H-8), 7.15 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 6.73 (1H, s, thiazole H-4), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, ddd, J 6.5, 2.0, 1.0 Hz, 2H, H-4 of oxetane H-2), 4.79 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.12 (2H, s, pYCH2 thiazole), 3.42 (3H, s, NCH3), 2.98 (2H, q, J 7.5 Hz, CH2CH3), 1.35 (3H, t, J 7.5 Hz, CH2CH3); m / z: 519 [M+H] + (Measured value [M+H] + ,519.1712,C 27 H 26 N4O5S is [M+H] + 519.1697).

[0337] (S)-4-((5-fluoropyridin-3-yl)oxy)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-100) [ka] 1H NMR (400 MHz, CDCl3) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.54 (1H, d, J 5.5 Hz, pyrH-6), 8.42 (1H, d, J 2.5 Hz, F pyrH-2, H-4 or H-6), 8.30 (1H, d, J 2.0 Hz, F pyrH-2, H-4 or H-6), 7.64 (1H, d, J 2.5 Hz, pyrH-3), 7.31-7.29 (2H, m, oxobenzoxazapine H-6, H-8), 7.18 (1H, dt, J 9.0, 2.5 Hz, F pyrH-2, H-4, H-6), 7.13 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 7.03 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.72 (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), 3.43 (3H, s, NCH3), 2.57-2.51 (2H, m, cBu 2H), 2.38-2.31 (2H, m, cBu 2H), 1.93-1.86 (2H, m, cBu 2H); 19 F NMR(380MHz,CDCl3)δ-123.3(J 8.0Hz);m / z:503[M+H] + ,485[M+H-H2O] + (Measured value [M+H] + ,503.1731,C 27 H 23 FN4O5 is [M+H] + 503.1725).

[0338] (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((5-fluoropyridin-3-yl)oxy)picolinamide (I-101) [ka] 1H NMR (400 MHz, CDCl3) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.53 (1H, d, J 5.5 Hz, pyrH-6), 8.41 (1H, d, J 2.5 Hz, F pyrH-2, H-4 or H-6), 8.30 (1H, d, J 2.0 Hz, F pyrH-2, H-4 or H-6), 7.64 (1H, d, J 2.5 Hz, pyrH-3), 7.26-7.22 (2H, m, oxobenzoxazapine H-6, H-8), 7.18 (1H, dt, J 9.0, 2.5 Hz, F pyrH-2, H-4 or H-6), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.03 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.5, 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 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3); 19 F NMR(380MHz,CDCl3)δ-123.2(d,J 8.0Hz);m / z:489[M+H] + (Measured value [M+H] + ,489.1932,C 27 H 25 FN4O4 is [M+H] + 489.1933 required).

[0339] (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide (I-102) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.53 (1H, dd, J 4.6, 1.5 Hz, OpyH-6), 8.49 (1H, d, J 5.5 Hz, OpyH-6), 8.46 (1H, d, J 2.5 Hz, OpyH-2), 7.61 (1H, d, J 2.5 Hz, OpyH-3), 7.42 (1H, ddd, J 8.0, 2.5, 1.5 Hz, OpyH-4), 7.37 (1H, ddd, J 8.0, 4.5, 0.5 Hz, OpyH-5), 7.26-7.22 (2H, m, oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.98 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (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), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.42 (3H, s, NCH3), 1.31 (9H, s, C(CH3)3); m / z: 471 [M+H] + (Measured value [M+H] + ,471.2039,C 27 H 26 N4O4 is [M+H] + 471.2027).

[0340] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-103) [ka] 1H NMR(400MHz,chloroform-d)δ 7.96(d,J=7.1Hz,1H),7.93(d,J=0.9Hz,1H),7.55(s,1H),7.47(t,J=7.7Hz,1H),7. 35-7.27(m,2H),7.15(d,J=8.8Hz,1H),6.99(d,J=7.7Hz,1H),6.90(d,J=7.7Hz,1H), 4.93(d,J=6.6Hz,2H),4.90-4.83(m,1H),4.79(dd,J=6.5,0.9Hz,2H),4.69(dd,J=9 .8,7.2Hz,1H),4.32(dd,J=11.3,9.8Hz,1H),3.94(s,2H),3.42(s,3H),2.52(s,3H). LCMS: Purity 97%, MS(m / e)488(M+H) + .

[0341] (S)—N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-104) [ka] 1 H NMR(400MHz,chloroform-d)δ 7.95(d,J=7.2Hz,1H),7.92(d,J=0.9Hz,1H),7.54(s,1H),7.51-7.43(m,1H),7.28-7.25(m,2H),7. 10(d,J=8.8Hz,1H),7.02-6.95(m,1H),6.89(d,J=7.7Hz,1H),4.87(dt,J=11.2,7.3Hz,1H),4.67(d d,J=9.8,7.3Hz,1H),4.29(dd,J=11.3,9.8Hz,1H),3.97-3.91(m,4H),3.54(ddd,J=11.7,8.8,2.9H z,2H),3.41(s,3H),2.83(dq,J=8.5,4.3Hz,1H),2.52(s,3H),1.94-1.87(m,2H),1.80-1.71(m,2H). LCMS: Purity 94%, MS(m / e)500(M+H) + .

[0342] (±)-4-((6-fluoropyridin-2-yl)methyl)-N-((3S)-5-methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-105) [ka] 1 H NMR (400 MHz, methylene chloride-d2) δ 7.97 (app s, 1H), 7.89 (d, J = 7.0 Hz, 1H), 7.72 (app td,J=8.3,7.4Hz,1H),7.59(d,J=0.8Hz,1H),7.46-7.34(m,2H),7.19(d,J=8.1Hz,1H),7.05(dd,J=7.3,2.5Hz,1H),6.78(dd,J=8.2,2. 8Hz,1H), 4.97(q,J=5.8Hz,1H),4.86(dt,J=11.2,7.1Hz,1H),4.71(dd,J=9.8,7.2Hz,1H),4.38-4.27(m,1H),3.93(s,2H),3.41(s,3H). 19 F NMR (376 MHz, methylene chloride-d) δ -68.29 (d, J = 8.2 Hz), -79.65 (d, J = 5.8 Hz). LCMS: purity 91%, MS (m / e) 518 (M+H). + .

[0343] (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-106) [ka] 1H NMR(400MHz, methylene chloride-d2)δ 7.98(app q,J=0.8Hz,1H),7.90(d,J=7.1Hz,1H),7.73(td,J=8.3,7.4Hz,1H),7.59(d,J= 0.9Hz,1H),7.28(dd,J=1.9,0.4Hz,1H),7.25(dd,J=8.2,2.0Hz,1H),7.12(app dd,J=8.2,0.4Hz,1H),7.05(app ddd,J=7.4,2.5,0.7Hz,1H),6.79(ddd,J=8.2,2.8,0.6Hz,1H),4.85(dt,J=11.2,7.2Hz,1H),4. 69(dd,J=9.8,7.3Hz,1H),4.28(dd,J=11.2,9.7Hz,1H),3.93(s,2H),3.41(s,3H),1.32(s,9H). 19 F NMR (376 MHz, methylene chloride-d2) δ -68.29 (d, J = 8.4 Hz). LCMS: Purity 98%, MS (m / e) 476 (M+H). + .

[0344] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-7-(3-methyl-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-107) [ka] 1H NMR (400 MHz, methylene chloride-d2) δ 7.98 (app s, 1H), 7.89 (d, J = 7.1 Hz, 1H), 7.72 (td, J = 8.2, 7.3 Hz, 1H), 7.59 (s, 1H), 7.31-7.23 (m, 2H), 7.13 (d, J = 8.3 Hz, 1H), 7.05 (app dd, J = 7.4, 2.5 Hz, 1H), 6.79 (app dd,J=8.2,2.8Hz,1H),4.85(dt,J=11.2,7.2Hz,1H),4.69(dd,J=9.8,7.3Hz,1H),4.29(dd,J =11.2,9.8Hz,1H),4.05-3.95(m,2H),3.93(s,2H),3.41(s,3H),3.40-3.32(m,2H),1.76(app d,J=3.3Hz,1H),1.64-1.43(m,4H),1.27(s,6H). 19 F NMR (376 MHz, methylene chloride-d2) δ -68.26 (d, J = 8.2 Hz). LCMS: Purity 96%, MS (m / e) 546 (M+H) + .

[0345] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-108) [ka] 1 H NMR (400 MHz, chloroform-d) δ 8.00-7.94 (m, 2H), 7.68 (app td, J = 8.2, 7.4 Hz, 1H), 7.55 (app s, 1H), 7.30-7.23 (m, 2H), 7.15-7.08 (m, 1H), 6.99 (dd, J = 7.3, 2.4 Hz, 1H), 6.77 (dd, J = 8.2, 2.8 Hz, 1H). 4.93-4.83(m,3H),4.80(dd,J=7.3,5.5Hz,2H),4.68(dd,J=9.8,7.3Hz,1H) ,4.30(dd,J=11.3,9.8Hz,1H),4.15-4.00(m,1H),3.92(s,2H),3.41(s,3H).19 F NMR (376 MHz, chloroform-d) δ -66.97 (d, J = 8.0 Hz). LCMS: Purity 97%, MS (m / e) 476 (M+H). + .

[0346] (S)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-109) [ka] 1 H NMR(400MHz, methylene chloride-d2)δ 7.98(s,1H),7.89(d,J=7.1Hz,1H),7.61(s,1H),7.34(d,J=1.9Hz,1H),7.31(dd,J=8.2,2.0Hz,1H),7.15(d,J=8.2Hz,1H),7.12- 6.94(m,3H),4.92-4.81(m,3H),4.76(dd,J=7.2,5.5Hz,2H),4.70(dd,J=9.8,7.3Hz,1H),4.30(dd,J=11.3,9.8Hz,1H),4.07(app tt,J=8.5,7.2Hz,3H),3.41(s,3H),2.57(s,3H). LCMS: Purity 97%, MS(m / e)472(M+H) + .

[0347] (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-2-yl)oxy)-1H-pyrazole-1-carboxamide (I-110) [ka] 1H NMR(400MHz, methylene chloride-d2)δ 8.27(d,J=0.8Hz,1H),7.95(d,J=7.1Hz,1H),7.82(q,J=8.0Hz,1H),7.73(d,J=0.9Hz,1 H),7.44(d,J=2.3Hz,1H),7.39(dd,J=8.6,2.3Hz,1H),7.13(d,J=8.5Hz,1H),6.86(app dd,J=8.3,1.8Hz,1H),6.67(app dd,J=7.5,2.8Hz,1H). ,4.90(dt,J=11.2,7.3Hz,1H),4.73(dd,J=9.8,7.4Hz,1H),4.33(dd,J=11.3,9.8Hz,1H),3.42(s,3H). 19 F NMR (376 MHz, methylene chloride-d2) δ -69.89 (d, J = 8.3 Hz). LCMS: Purity 99%, MS (m / e) 477 (M+H) + .

[0348] (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-111) [ka] 1H NMR(400MHz, methylene chloride-d2)δ 8.27(d,J=0.8Hz,1H),7.96(d,J=7.0Hz,1H),7.82(q,J=8.0Hz,1H),7.73(s,1H),7.32(d,J=1.9Hz,1H) ,7.30(dd,J=8.2,2.0Hz,1H),7.15(d,J=8.2Hz,1H),6.86(d,J=7.9Hz,1H),6.67(dd,J=7.2,2.5Hz,1H). ,4.89(dt,J=11.2,7.2Hz,1H),4.73(dd,J=9.8,7.3Hz,1H),4.32(dd,J=11.2,9.8Hz,1H),3.92(app dt,J=11.6,4.4Hz,2H),3.52(app ddd,J=11.6,8.9,2.8Hz,2H),3.43(s,3H),2.85(app tt,J=8.7,4.1Hz,1H),1.91-1.62(m,4H). 19 F NMR (376 MHz, methylene chloride-d2) δ -69.89 (d, J = 8.3 Hz). LCMS: Purity 96%, MS (m / e) 506 (M+H) + .

[0349] (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-112) [ka] 1H NMR (400 MHz, methylene chloride-d2) δ 8.27(s,1H),7.97(d,J=7.0Hz,1H),7.82(q,J=8.0Hz,1H),7.35(d,J=1.9Hz ,1H),7.31(dd,J=8.2,2.0Hz,1H),7.17(d,J=8.3Hz,1H),6.86(dd,J=8.1,1. 5Hz,1H),6.67(dd,J=7.8,2.5Hz,1H),4.89(dt,J=11.2,7.2Hz,1H),4.74(dd ,J=9.8,7.3Hz,1H),4.33(dd,J=11.2,9.7Hz,1H),3.43(s,3H),1.60(s,6H). 19 F NMR (376 MHz, methylene chloride-d2) δ -69.88 (d, J = 8.2 Hz). LCMS: Purity 96%, MS (m / e) 502 (M + Na). + .

[0350] (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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-113) [ka] 1 H NMR(400MHz,chloroform-d)δ 7.97(q,J=0.9Hz,1H),7.95(s,1H),7.68(td,J=8.2,7.4Hz,1H),7.53(d,J=0.8Hz,1H),7.3 0-7.25(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=6.6,0.8Hz,2H),4.79(dd,J=6.6,0.9Hz,2H),4.45(dt,J=11.4,7.4Hz,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). 19F NMR (376MHz, chloroform-d) δ-67.08 (d,J=8.2Hz). LCMS: Purity 97%, MS(m / e)490(M+H) + .

[0351] (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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-114) [ka] 1 H NMR (400 MHz, methylene chloride-d2) δ 7.97(t,J=0.9Hz,1H),7.88(d,J=7.4Hz,1H),7.71(td,J=8.2,7.4Hz,1H),7.5 5(d,J=0.8Hz,1H),7.28-7.23(m,3H),7.04(ddd,J=7.4,2.5,0.6Hz,1H),6.77 (ddd,J=8.2,2.9,0.6Hz,1H),4.39(dt,J=11.4,7.4Hz,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, methylene chloride-d2) δ -68.35 (d, J = 8.1 Hz). LCMS: Purity 95%, MS (m / e) 476 (M+H). + .

[0352] (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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-115) [ka] 1H NMR(400MHz, methylene chloride-d2)δ 7.97(q,J=0.9Hz,1H),7.87(d,J=7.4Hz,1H),7.71(td,J=8.2,7.4Hz,1H),7.55(d,J=0.8Hz,1H ),7.28-7.18(m,3H),7.04(ddd,J=7.4,2.6,0.7Hz,1H),6.77(ddd,J=8.1,2.8,0.7Hz,1H),4.38 (dt,J=11.5,7.4Hz,1H),3.92(s,2H),3.48(d,J=6.8Hz,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=11.5,8.0Hz,1H),1.82(t,J=6.9Hz,1H),1.29(s,6H). 19 F NMR (376 MHz, methylene chloride-d2) δ -68.35 (d, J = 8.3 Hz). LCMS: Purity 94%, MS (m / e) 490 (M+H). + .

[0353] (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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-116) [ka] 1H NMR (400 MHz, methylene chloride-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=7.4,2.5Hz,1H),6.77(dd,J=8.2,2.8Hz,1H),4.39(dt,J=11.5,7.3Hz,1H),3.92(s,2H),3.90-3. 86(m,1H),3.68(ddd,J=11.8,9.1,2.9Hz,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, methylene chloride-d2) δ -68.30 (d, J = 8.5 Hz). LCMS: Purity 97%, MS (m / e) 518 (M+H). + .

[0354] (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((1-hydroxycyclobutyl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-117) [ka] 1 H NMR(400MHz,chloroform-d)δ 7.97(q,J=0.9Hz,1H),7.95(s,1H),7.67(td,J=8.2,7.4Hz,1H),7.53(d,J=0.9Hz,1H),7.27 (d,J=6.9Hz,2H),7.22-7.15(m,1H),6.98(dd,J=7.5,2.4Hz,1H),6.76(dd,J=8.2,2.9Hz,1H ),4.45(dt,J=11.0,7.3Hz,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) + .

[0355] (S)-N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-118) [ka] 1 H NMR(400MHz,chloroform-d)δ 7.96-7.88(app m,2H),7.52(d,J=0.8Hz,1H),7.46(t,J=7.7Hz,1H),7.35-7.30(m,2H),7.14-7.08(app m,1H),6.97(d,J=7.6Hz,1H),6.89(d,J=7.7Hz,1H),4.45(app dt,J=11.1,7.4Hz,1H),3.94(s,2H),3.39(s,3H),2.88-2.74(m,1H),2.74-2.60(m,2H),2.52(s,3H),2.12-1.95(m,1H). LCMS: Purity 99%, MS(m / e)470(M+H) + .

[0356] (S)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-119) [ka] 1H NMR(400MHz,chloroform-d)δ 7.97-7.91(app m,2H),7.52(d,J=0.8Hz,1H),7.46(t,J=7.7Hz,1H),7.27-7.14(m,3H),6.98(d,J=7.6Hz,1H),6.89(d,J=7.7Hz,1H),4.44(app dt,J=11.1,7.4Hz,1H),3.94(s,2H),3.40(s,3H),2.93-2.78(m,1H),2.7 7-2.60(m,2H),2.52(s,3H),2.10-2.04(m,1H),2.03(s,1H),1.61(s,6H). LCMS: Purity 92%, MS(m / e)472(M+H) + .

[0357] (S)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-120) [ka] 1 H NMR(400MHz,chloroform-d)δ 7.97-7.91(m,2H),7.52(d,J=0.8Hz,1H),7.46(t,J=7.7Hz,1H),7.27(s,2H),7.24- 7.18(m,1H),6.98(d,J=7.6Hz,1H),6.89(d,J=7.7Hz,1H),4.93(d,J=6.7Hz,2H),4. 79(dd,J=6.6,0.9Hz,2H),4.44(dt,J=11.4,7.5Hz,1H),3.94(s,2H),3.40(s,3H),2 .95-2.80(m,1H),2.75(d,J=16.6Hz,1H),2.73-2.59(m,2H),2.52(s,3H),2.08(app td,J=11.4,7.7Hz,1H). LCMS: Purity 92%, MS(m / e)486(M+H) + .

[0358] (S)-N-(6-fluoro-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-121) [ka] 1 H NMR (400 MHz, chloroform-d) δ 7.98(s,1H),7.93(d,J=7.6Hz,1H),7.68(s,1H),7.53(d,J=0.9Hz,1H),7.0 7-7.01(m,2H),7.01-6.96(m,1H),6.78-6.74(m,1H),4.45(dt,J=11.3,7.7 Hz,1H),3.92(s,2H),3.39(s,3H),3.10(dd,J=13.5,6.6Hz,1H),2.72-2.58 (m,1H),2.51(tdd,J=13.4,7.6,2.3Hz,1H),2.13-2.00(m,1H),1.61(s,6H). 19 F NMR (376 MHz, chloroform-d) δ -67.09, -116.77. LCMS: Purity 95%, MS (m / z) 516.0 (M+Na) + .

[0359] (S)-N-(6-fluoro-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide (I-122) [ka] 1H NMR (400 MHz, chloroform-d) δ 7.98 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.68 (q, J = 7.4 Hz, 1H), 7.53 (s, 1H), 7.06-7.00 (m, 2H), 6.98 (ddd, J = 7.4, 2.4, 0.7 Hz, 1H), 6.79-6.74 (m, 1H), 4.44 (dt, J = 11.3, 7.0). 7Hz,1H),3.92(s,2H),3.50(s,2H),3.39(s,3H),3.09(dd,J=13.5,6.6Hz,1H),2.7 2-2.58(m,1H),2.50(tdd,J=13.4,7.5,2.3Hz,1H),2.12-2.01(m,1H),1.29(s,6H). 19 F NMR (376 MHz, chloroform-d) δ -67.09, -117.08. LCMS: Purity 99%, MS (m / z) 530.1 (M+Na) + .

[0360] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)thiazol-4-yl)methyl)picolinamide (I-123) [ka] 1H NMR (400 MHz, CDCl3) δ 8.88 (1H, d, J 7.5 Hz, NH), 8.55 (1H, d, J 5.0 Hz, pyrH-6), 7.98 (1H, br s, pyrH-3), 7.36 (1H, dd, J 5.0, 1.5 Hz, pyrH-5), 7.29-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.15 (1H, s, thiazole H-4), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.05 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.30 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapine H-2), 4.24 (2H, s, pyCH2 thiazole), 3.43 (3H, s, NCH3), 1.63 (6H, s, C(CH3)2OH); 19 F NMR(380MHz,CDCl3)δ-61.1;m / z:545[M+H] + ,527[M+H-H2O] + (Measured value [M+H] + ,545.1483,C 26 H 23 F3N4O4S is [M+H] + (Requires 545.1465).

[0361] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)thiazol-4-yl)methyl)picolinamide (I-124) [ka] 1H NMR (400 MHz, CDCl3) δ 8.88 (1H, d, J 7.5 Hz, NH), 8.55 (1H, d, J 5.0 Hz, pyrH-6), 7.98 (1H, s, pyrH-3), 7.36 (1H, dd, J 5.0, 1.5 Hz, pyrH-5), 7.33-7.31 (2H, m, oxobenzoxazapine H-6, H-8), 7.16 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.16 (1H, s, thiazole H-4), 5.07 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.93 (2H, dd, J 6.5, 1.5 Hz, 2H,H-4 of oxetane H-2), 4.80 (2H,d,J 7.0 Hz, 2H,H-4 of oxetane H-2), 4.73 (1H,dd,J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.32 (1H,dd,J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 4.24 (2H,s,pyCH2 thiazole), 3.43 (3H,s,NCH3); 19 F NMR(380MHz,CDCl3)δ-61.1;m / z:559[M+H] + (Measured value [M+H] + ,559.1273,C 26 H 21 F3N4O5S is [M+H] + 559.1258).

[0362] (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-125) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.51 (1H, d, J 6.6 Hz, pyrH-6), 8.13 (1H, br d, J 5.0 Hz, O pyrH-6), 7.63-7.57 (1H, m, O pyrH-4 or H-5), 7.57 (1H, d, J 2.5 Hz, pyrH-3), 7.29-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.98 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.02 (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, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.95 (2H, ddd, J 12.5, 5.5, 4.0 Hz, 2H of pyran H-2, H-6), 3.55 (2H, ddd, J 11.5, 8.5, 3.0 Hz, 2H,H-6 of pyran H-2), 3.43 (3H,s,NCH3), 2.87-2.82 (1H,m,pyran H-4), 1.96-1.88 (2H,m,2H,H-5 of pyran H-3), 1.80-1.74 (2H,m,2H,H-5 of pyran H-3); 19 F NMR(380MHz,CDCl3)δ-79.8(d,J 9.5Hz);m / z:517[M+H] + (Measured value [M+H] + ,517.xxxx,C 28 H 25 FN4O5 is [M+H] + 517.xxxx).

[0363] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide (I-126) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5 Hz, pyrH-6), 7.66 (1H, d, J 2.5 Hz, pyrH-3), 7.35 (1H, d, J 1.0 Hz, pyrazole H-3 or H-5), 7.31 (1H, s, pyrazole H-3 or H-5), 7.29-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.03 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.03 (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), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.91 (3H, s, pyrazole CH3), 3.43 (3H, s, NCH3), 1.63 (6H, s, C(CH3)2OH); m / z: 476 [M+H] + (Measured value [M+H] + ,476.xxxx,C 25 H 23 N5O5 is [M+H] + 476.xxxx).

[0364] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide (I-127) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5 Hz, pyrH-6), 7.66 (1H, d, J 2.5 Hz, pyrH-3), 7.35 (1H, s, pyrazole H-3 or H-5), 7.33-7.30 (3H, m, oxobenzoxazapine H-6, H-8, pyrazole H-3 or H-5), 7.16 (1H, d, J 8.5 Hz, oxobenzoxazapine H-9), 7.03 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.03 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.93 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.79 (2H, dd, J 7.0, 0.5 Hz, 2H, H-4 of oxetane H-2), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.90 (3H, s, pyrazole CH3), 3.43 (3H, s, NCH3); m / z: 490 [M+H] + (Measured value [M+H] + ,490.xxxx,C 25 H 23 N5O6 is [M+H] + 490.xxxx).

[0365] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-yloxy)picolinamide (I-128) [ka] 1H NMR (400 MHz, CDCl3) δ 8.88 (1H, d, J 7.0 Hz, NH), 8.73 (1H, d, J 5.5 Hz, pyH-6), 8.09 (1H, d, J 2.0 Hz, pyH-3), 7.68 (1H, dd, J 5.5 Hz, pyH-5), 7.41 (1H, ddd, J 9.5 Hz, pyH-6), 7.32 (1H, ddd, J 7.0 Hz, pyH-2), 7.29–7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.65 (1H, dd, J 9.5 Hz, OpyH-3), 6.30 (1H, td, J 7.0, 1.0 Hz, OpyH-5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.74 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.44 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2)OH); m / z: 455 [M+H] + (Measured value [M+H-H2O] + ,473.xxxx,C 26 H 24 N4O5 is [M+H] + 473.xxxx).

[0366] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-yloxy)picolinamide (I-129) [ka] 1H NMR (400 MHz, CDCl3) δ 8.88 (1H, d, J 7.5 Hz, NH), 8.73 (1H, dd, J 5.5, 0.5 Hz, pyrH-6), 8.09 (1H, d, J 2.5 Hz, pyrH-3), 7.67 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 7.41 (1H, ddd, J 9.0, 6.5, 2.0 Hz, pyrH-4), 7.33-7.29 (3H, m, oxobenzoxazapine H-6, H-8, pyrH-6), 7.16 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.65 (1H, br d, J 9.0 Hz, pyrH-3), 6.31 (1H, td, J 7.0, 1.0 Hz, OpyH-5), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.92 (2H, ddd, J 7.0, 2.0, 0.5 Hz, oxetane H-2, H-4), 4.78 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.32 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3); 13 C NMR(100MHz,CDCl3)δ 168.8,163.0,161.4,151.1,150.5,149.6,149.1,140.5,136.3,136.1,130.9,126.6,124.1 ,123.3,122.3,119.4,119.3,107.1,88.8,84.7,84.5,77.1,67.4,49.4,35.5;m / z:487[M+H] + (Measured value [M+H] + ,487.xxxx,C 26 H 22 N4O6 is [M+H] + 487.xxxx).

[0367] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)oxy)picolinamide (I-130) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.88 (1H, d, J 7.5 Hz, NH), 8.51 (1H, d, J 6.0 Hz, pyrH-6), 7.77 (1H, d, J 2.5 Hz, pyrH-3), 7.66 (1H, t, J 8.0 Hz, MepyH-4), 7.28-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.17 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 7.12 (1H, dd, J 7.5, 1.0 Hz, oxobenzoxazapine H-9), 7.00 (1H, d, J 7.5 Hz, MepyH-3 or H-5), 7.79 (1H, d, J 8.0 Hz, MepyH-3 or H-5), 5.04 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 2.45 (3H, s, pyCH3), 1.62 (6H, s, C(CH3)2OH); m / z: 487 [M+H] + ,469[M+H-H2O] + (Measured value [M+H] + ,487.xxxx,C 27 H 26 N4O5 is [M+H] + 487.xxxx).

[0368] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)oxy)picolinamide (I-131) [ka] 1H NMR (400 MHz, CDCl3) δ 8.88 (1H, d, J 7.5 Hz, NH), 8.51 (1H, d, J 5.5 Hz, pyrH-6), 7.77 (1H, d, J 2.5 Hz, pyrH-3), 7.66 (1H, t, J 8.0 Hz, MepyH-4), 7.31-7.29 (2H, m, oxobenzoxazapine H-6, H-8), 7.18 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.00 (1H, d, J 7.5 Hz, MepyH-3 or H-5), 6.79 (1H, d, J 8.0 Hz, Mepy H-3 or H-5), 5.06 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.93 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.79 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.33 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 2.45 (3H, s, pyCH3); m / z: 501 [M+H] + (Measured value [M+H] + ,501.xxxx,C 27 H 24 N4O6 is [M+H] + 501.xxxx).

[0369] (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide (I-132) [ka] 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyrH-6), 7.66 (1H, d, J 2.5 Hz, pyrH-3), 7.35 (1H, s, pyrazole H-3 or H-5), 7.31 (1H, s, pyrazole H-3 or H-5), 7.26-7.23 (2H, m, oxobenzoxazapine H-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.02 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.01 (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), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.90 (3H, s, pyrazole CH3), 3.43 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3); m / z: 474 [M+H] + (Measured value [M+H] + ,474.xxxx,C 26 H 27 N5O4 is [M+H] + 474.xxxx).

[0370] (S)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide (I-133) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyrH-6), 7.66 (1H, d, J 2.5 Hz, pyrH-3), 7.35 (1H, d, J 1.0 Hz, pyrazole H-3 or H-5), 7.31-7.28 (3H, m, pyrazole H-3 or H-5, oxobenzoxazapine H-6, H-8), 7.13 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.02 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.03 (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), 3.90 (3H, s, pyrazole CH3), 3.43 (3H, s, NCH3), 2.57-2.51 (2H, H-4 of 2H, m, cBuH-2), 2.39-2.31 (2H, H-4 of 2H, m, cBuH-2), 1.93-1.86 (2H, m, cBuH-3); 13 C(100MHz,CDCl3)δ168.9,166.7,163.6,151.1,150.0,137.6,136.2,131.2,130.9,126.5,123.1 ,121.4,120.3,113.5,109.4,93.3,82.0,77.2,68.2,49.4,39.8,38.6,35.4,13.0;m / z:488[M+H] + (Measured value [M+H] + ,488.xxxx,C 26 H 25 N5O5 is [M+H] + 488.xxxx).

[0371] (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-134) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.88 (1H, d, J 7.5 Hz, NH), 8.57 (1H, d, J 5.5 Hz, pyH-6), 7.85 (1H, q, J 8.0 Hz, FpyH-4), 7.81 (1H, d, J 2.0 Hz, pyH-3), 7.28-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.24 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.89 (1H, dd, J Hz, J 8.0, 1.0 Hz, FpyH-3 or H-5), 6.74 (1H, dd, J Hz, J 8.0, 2.5 Hz, FpyH-3 or H-5), 5.04 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.30 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2OH); 19 F NMR(380MHz,CDCl3)δ-67.3(d,J 8.0Hz);m / z:490[M+H] + (Measured value [M+H] + ,490.xxxx,C 26 H 23 FN4O5 is [M+H] + 490.xxxx).

[0372] (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-135) [ka] 1H NMR (400 MHz, CDCl3) δ 8.88 (1H, d, J 7.5 Hz, NH), 8.57 (1H, d, J 5.5 Hz, pyrH-6), 7.85 (1H, q, J 8.0 Hz, F pyrH-4), 7.81 (1H, d, J 2.5 Hz, pyrH-3), 7.32-7.30 (2H, m, oxobenzoxazapine H-6, H-8), 7.25 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 7.16 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.90 (1H, dd, J 8.0, 1.5 Hz, F pyrH-3 or H-5), 6.74 (1H, dd, J 8.0, 2.5 Hz, FpyH-3 or H-5), 5.05 (1H, dt, J 11.0, 7.0 Hz, oxobenzoxazapine H-3), 4.93 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.79 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.33 (1H, dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.43 (3H, s, NCH3); 19 F NMR(380MHz,CDCl3)δ-67.3(d,J 8.0Hz);m / z:505[M+H] + (Measured value [M+H] + ,505.xxxx,C 26 H 21 FN4O6 is [M+H] + 505.xxxx).

[0373] (S)-4-((1-methyl-1H-pyrazol-4-yl)oxy)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-136) [ka] 1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5 Hz, pyrH-6), 7.67 (1H, d, J 2.5 Hz, pyrH-3), 7.35 (1H, d, J 0.5 Hz, pyrazole H-3 or H-5), 7.31 (1H, s, pyrazole H-3 or H-5), 7.28-7.25 (2H, m, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 7.03 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.03 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.29 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.95 (2H, ddd, J 11.5, 5.5, 4.0 Hz, 2H of pyran H-2, H-6), 3.90 (3H, s, pyrazole NCH3), 3.52 (2H, ddd, J 11.5, 9.0, 3.0 Hz, 2H,H-6 of pyran H-2), 3.43 (3H,s,NCH3), 2.88-2.81 (1H,m,pyran H-4), 1.94-1.88 (2H,m,2H,H-5 of pyran H-3), 1.80-1.72 (2H,m,2H,H-5 of pyran H-3); 13 C NMR(100MHz,CDCl3)δ169.0,166.7,163.6,151.4,150.0,149.7,137.6,136.2,131.3,130.8,126.4,1 23.0,121.5,121.2,113.5,109.4,93.0,80.1,77.2,66.4,49.4,39.9,35.4,32.2,26.8;m / z:502[M+H] + (Measured value [M+H] + ,502.xxxx,C 27 H 27 N5O5 is [M+H] + 502.xxxx).

[0374] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(oxazol-4-ylmethyl)picolinamide (I-137) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.52 (1H, dd, J 5.0, 0.5 Hz, pyrH-6), 7.96 (1H, d, J 2.0 Hz, pyrH-6), 7.84 (1H, s, oxazole H-2 or H-5), 7.43 (1H, d, J 1.0 Hz, oxazole H-2 or H-5), 7.34 (1H, dd, J 5.0, 2.0 Hz, pyrH-5), 7.28-7.26 (2H, m, oxobenzoxazapine H-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.04 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.72 (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), 3.94 (2H, s, pyrCH2 oxazole), 3.42 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2OH); m / z: 461 [M+H] + ,443[M+H-H2O] + (Measured value [M+H] + ,461.xxxx,C 25 H 24 N4O5 is [M+H] + 461.xxxx).

[0375] (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(oxazol-4-ylmethyl)picolinamide (I-138) [ka] 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, pyrH-6), 7.96 (1H, dd, J 2.0, 0.5 Hz, pyrH-3), 7.84 (1H, s, oxazole H-2 or H-5), 7.44 (1H, d, J 1.0 Hz, oxazole H-2 or H-5), 7.35 (1H, dd, J 5.0, 2.0 Hz, pyrH-5), 7.33-7.30 (2H, m, oxobenzoxazapine H-6, H-8), 7.16 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 5.06 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapine H-3), 4.93 (2H, ddd, J 6.5, 2.0, 1.0 Hz, 2H, H-4 of oxetane H-2), 4.79 (2H, d, J 6.5 Hz, 2H, H-4 of oxetane H-2), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.31 (1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapine H-2), 3.94 (2H, s, pyCH2 oxazole), 3.43 (3H, s, NCH3); 13 C NMR(100MHz,CDCl3)δ169.0,164.0,151.5,150.6,149.3,149.0,148.7,137.4,136.4,135.6,130.9,1 26.8,126.6,123.3,122.5,119.3,88.6,84.3,84.5(2C),77.2,67.5,49.3,35.5,31.9;m / z:475[M+H] + (Measured value [M+H] + ,475.xxxx,C 25 H 22 N4O6 is [M+H] + 475.xxxx).

[0376] tert-Butyl (S)-4-((3-(4-((2-fluoropyridin-3-yl)oxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)piperidine-1-carboxylate (I-139) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.51 (1H, d, J 5.5 Hz, pyrH-6), 8.12 (1H, dt, J 4.5, 1.5 Hz, F pyrH-6), 7.60 (1H, ddd, J 9.5, 8.0, 2.0 Hz, F pyrH-4 or H-5), 7.56 (1H, d, J 2.5 Hz, pyrH-3), 7.29-7.24 (3H, m, F pyrH-4 or H-5, oxobenzoxazapine H-6, H-8), 7.10 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.98 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 5.01 (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, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.79-3.71 (2H, m, 2H of piperidine H-2, H-6), 3.42 (3H, s, NCH3), 3.22 (2H, ddd, J 13.5, 9.0, 3.5 Hz, 2H,H-6 of piperidine H-2), 2.82-2.74 (1H,m, piperidine H-4), 1.88-1.83 (2H,m, 2H,H-5 of piperidine H-3), 1.70-1.64 (2H,m, 2H,H-5 of piperidine H-3), 1.46 (9H,s, C(CH3)3); 19 F NMR(380MHz,CDCl3)δ-79.8(d,J 9.5Hz),;m / z:560[M+H-C4H8] + ,516[M+H-C4H8-CO2] + (Measured value [M+H] + ,504.xxxx,C 33 H 34FN5O6 is [M+H] + 504.xxxx).

[0377] (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-7-((1-methylpiperidin-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-140) [ka] 1 H NMR (400 MHz, CD3OD) δ 8.57 (1H, d, J 5.5 Hz, pyrH-3), 8.14 (1H, ddd, J 4.5, 2.0, 1.5 Hz, F pyrH-6), 7.85 (1H, ddd, J 9.5, 9.0, 2.0 Hz, F pyrH-4 or H-5), 7.50 (1H, d, J 2.5 Hz, pyrH-3), 7.44-7.41 (2H, m, oxobenzoxazapine H-6, F pyrH-4 or H-5), 7.29 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapine H-8), 7.16 (1H, d, J 8.0 Hz, oxobenzoxazapine H-9), 7.15 (1H, dd, J 5.5, 2.5 Hz, pyrH-5), 4.97 (1H, dd, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.61 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.39 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapine H-2), 3.39 (3H, s, NCH3), 3.10 (2H, ddd, J 12.5, 6.0, 4.0 Hz, 2H of piperidine H-2, H-6), 2.85-2.78 (1H, m, piperidine H-4), 2.76 (2H, ddd, J 12.5, 9.0, 3.0 Hz, 2H,H-6 of piperidine H-2), 1.98-1.91 (2H,m, 2H,H-5 of piperidine H-3), 1.74-1.65 (2H,m, 2H,H-5 of piperidine H-3); 19 F NMR(380MHz,CD3OD)δ-83.6(d,J 9.5Hz);m / z:516[M+H] + (Measured value [M+H] +,516.xxxx,C 28 H 26 FN5O3 is [M+H] + 516.xxxx).

[0378] (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-4-oxo-7-(piperidin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-141) [ka] 1 H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.51 (1H, d, J 5.5 Hz, pyrH-6), 8.12 (1H, dt, J 4.5, 1.5 Hz, F pyrH-6), 7.60 (1H, ddd, J 9.5, 8.0, 2.0 Hz, F pyrH-4 or H-5), 7.56 (1H, d, J 2.5 Hz, pyrH-3), 7.29-7.24 (3H, m, F pyrH-4 or H-5, oxobenzoxazapine H-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapine H-9), 6.98 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapine H-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapine H-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, oxobenzoxazapine H-2 (1H), 3.42 (3H, s, NCH3), 2.85-2.76 (2H, m, piperidine H-2 (2H, H-6), 2.73-2.65 (1H, m, piperidine H-4), 2.44-2.32 (5H, m, piperidine H-2 (2H, H-6, NCH3), 2.05-2.00 (2H, m, piperidine H-3 (2H, H-5), 1.87-1.79 (2H, m, piperidine H-3 (2H, H-5)); 19 F NMR(380MHz,CDCl3)δ-79.8(d,J 8.0Hz);m / z:530[M+H] + (Measured value [M+H] + ,530.xxxx,C29 H 28 FN5O3 is [M+H] + 530.xxxx).

[0379] Example 12 In this example, the disclosed compounds were evaluated using a biochemical assay employing ADP-Glo™ technology.

[0380] ADP-Glo™ (Promega, Madison, WI, USA) reagent was thawed at ambient temperature. Kinase detection reagent was prepared by mixing kinase detection buffer with lyophilized kinase detection substrate.

[0381] A 500 ml stock volume of 5x reaction kinase buffer was made by mixing 1000 μl of 1 M MgCl, 500 μl of 1 M Tris-HCl (pH 7.4), 0.5 mg / ml (25 mg) BSA, and 3475 μl of distilled H O. A 3 ml 2x working stock volume of reaction kinase buffer was made containing final concentrations of 100 μM DTT and 4 mM MnCl.

[0382] RIPK1 enzyme (Rigel Pharmaceuticals, South San Francisco, CA, USA) components were thawed on ice. RIPK1 was diluted in 1x kinase reaction buffer (diluted from 2x buffer) to 31 ng / well. A 166 μM working stock ATP assay solution was prepared in 1x kinase reaction buffer (diluted from 2x buffer).

[0383] Compounds were serially diluted in DMSO starting at 250 μM in 4-fold dilutions, then diluted 1:5 in 2x reaction buffer in a 96-well plate. 1.0 μl of diluted compound was added to a duplicate 384-well plate. 2 μl of diluted active RIPK1 was added to the 384-well plate (not to column 1), and 2x rxn buffer was added to column 1. 150 nM AKT (Anaspec, Fremont, CA, USA) was combined with an equal volume of ATP working stock and added 2 μl / well to the 384-well plate. The final reaction volume was 5.0 μl.

[0384] The plate was quickly centrifuged and the reaction was incubated at 30°C for 30 minutes. 5 μl of ADP-Glo™ was added to terminate the reaction. The plate was quickly centrifuged and the reaction was incubated at room temperature for 40 minutes. Kinase detection reagent was then added and incubated at room temperature for 30 minutes. Relative light units (RLU) of the kinase reaction were determined by luminescence (Luminescence 0.1 s) using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, MA, USA). IC obtained from this example 50 The values ​​are provided in Table 1.

[0385] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0386] Example 13 In this example, U937 and L929 cells were exposed to compounds of the present disclosure and a cell necroptosis assay was performed to evaluate the activity of the compounds against human RIP1 and mouse RIP1.

[0387] U937 and L929 cells were obtained from the American Type Culture Collection (Manassa, VA, USA). Both cells were maintained in logarithmic growth phase in complete RPMI 1640 medium (Sigma, St. Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, St. Louis, MO, USA) at 37°C with 5% CO2. For necroptosis assays, L929 cells were seeded at 10K cells / well in 100 μL / well medium in Costar 96-well black clear-bottom plates (Fisher Scientific, Hampton, NH, USA) for 18 hours. U937 cells were seeded at 50K cells / well in 50 μL / well medium containing 60 μM zVAD-fmk (Lonza, Basel, Switzerland) on the day of the assay. The L929 cell medium was removed from the 96-well plate and replaced with 50 μL / well of fresh medium containing 40 μM zVAD-fmk. Each compound of the present disclosure evaluated in this example was serially diluted in DMSO starting at 2.5 mM in 4-fold dilutions, then diluted 1:125 in complete medium. 50 μL / well of 2× compound was then added to the plated cells. After preincubating the cells with compound for 1 hour at 37°C and 5% CO2, 10 μL / well of 11× TNFα (Peprotech, Rocky Hill, NJ, USA) was added to bring the final TNFα concentration to 2 ng / mL. The relative amount of necroptotic cells was determined 18 hours after TNFα stimulation at 37°C and 5% CO2 by luminescence using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, MA, USA) and CellTiter-Glo® Luminescent Cell Viability Reagent Assay (Promega, Madison, WI, USA) added according to the manufacturer's instructions. The results of this example are summarized in Table 2. This example establishes that embodiments of the compounds described herein have unexpectedly potent activity against human RIP1 and mouse RIP1, enabling their evaluation in in vivo mouse models of disease. These results are useful for determining safe and effective dosing in humans.

[0388] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] * ND indicates that no activity was detected or the inhibition curve showed artifacts. This value does not necessarily indicate an inactive compound, but indicates that the experiment was unable to obtain data for some reason. For example, an insoluble compound or other experimental artifact may result in a value of "ND."

[0389] Example 14 In this example, an acute hypothermia mouse model assay was used to assess the ability of compounds disclosed herein to inhibit TNF-alpha-induced hypothermia.

[0390] Female C57BL / 6 mice were randomly divided into groups and weighed on day 1. On the day of the study (day 0), mice were orally gavaged with vehicle or test article. 15 minutes after oral administration of the test agent, each mouse received an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor alpha (TNF-α, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured at time 0 (before IP injection) and every hour via a rectal probe temperature measurement device. Three hours after IP injection of TNF-α and zVAD / FMK, mice were euthanized by CO2 asphyxiation, and blood was collected via cardiac puncture. Serum and plasma were collected for determination of cytokine and compound levels, respectively. A separate group of mice (satellite mice) was included to determine plasma compound levels upon TNFα / zVAD-FMK administration.

[0391] Certain embodiments of the invention provide a compound, a plurality of compounds, or compositions thereof for crossing the blood-brain barrier. Disclosed compound and composition embodiments exhibit sufficient brain penetration for potential therapeutic use in neurological disorders. Brain penetration can be assessed by evaluating the brain-free / plasma ratio (Bu / Pu) measured in in vivo pharmacokinetic studies in rodents. As an example, compound I-104 exhibited a Bu / Pu ratio of 1.7. Other examples exhibited higher distribution ratios, e.g., compound I-120 exhibited a Bu / Pu distribution ratio of 10.98. Without being bound by theory, it is believed that compounds with higher brain / plasma distribution ratios may be more pharmacologically active against neurological disorders. Other methods for assessing brain penetration are known to those skilled in the art. See, e.g., Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008. I-MDR1 permeability. In this method, passive membrane permeability (Papp) and P-gp (P-glycoprotein) substrate efflux potential are determined using the MDCKII-MDR1 cell line as an in vitro model of effective permeability of compounds across the BBB. Compounds with an MDCKII-MDR1 efflux ratio of 2.5 or less may exhibit the ability to cross the blood-brain barrier.

[0392] Example 15 2-((trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol [ka] A two-neck flask containing a stir bar was heated, cooled to room temperature under vacuum, and backfilled with argon via a balloon. Trimethylsilylacetylene (1.4 mL, 1.0 g, 10.2 mmol) was transferred to the flask, followed by dry THF, and the resulting mixture was cooled to -78°C. ℃The mixture was cooled to RT. To the above stirred solution, n-BuLi (1.6 M solution in hexane, 7.0 mL, 11.2 mmol) was added dropwise over a period of 15 min. After 30 min, spiro[3.3]heptanone (1.0 mL, 1.0 g, 9.09 mmol) was added to the reaction solution over 15 min and stirred at the same temperature for 1 h and at 0 °C for 1 h. The reaction solution was slowly quenched with ice-cold aqueous NH4Cl (5 mL), concentrated to remove volatiles, and diluted with Et2O (30 mL) and HO (10 mL). After separating 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 with anhydrous Na2SO4, polished filtered, and concentrated. The crude concentrate was dried under high vacuum to give 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. 1 H 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). (The reaction progress was monitored using PMA, KMnO, and ammonium molybdate dye.)

[0393] 2-ethynylspiro[3.3]heptan-2-ol [ka] To a stirred solution of 2-((trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol (1.71 g, 8.2 mmol) in dry EtO (30 mL) at 0 °C under nitrogen, solid n-BuNF.3HO was added all at once. After 2 h, the clear, light brown reaction solution was slowly quenched with saturated aqueous NHCl (10 mL) over a 10 min period, warmed to room temperature, and diluted with HO (6 mL) and EtO (20 mL). The organic layer was separated and the aqueous layer was extracted with additional EtO (3 × 20 mL). The combined organic layers were washed successively with water (10 mL), aqueous NaHCO (10 mL), and brine, and the organic layer was separated, stirred with anhydrous NaSO, polished filtered, and concentrated to give ethynylspiro[3.3]heptan-2-ol as a slightly brown liquid (1.11 g, 99%). The title compound thus obtained was used in the next step without further purification. 1 H 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). (The reaction progress was monitored using PMA, KMnO, and ammonium molybdate dye.)

[0394] 6-((trimethylsilyl)ethynyl)-2-oxaspiro[3.3]heptan-6-ol [ka] Analogous to the preparation of 2-((trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol, reaction of trimethylsilyllithium acetylide with 2-oxaspiro[3.3]heptan-6-one gave 6-((trimethylsilyl)ethynyl)-2-oxaspiro[3.3]heptan-6-ol as a crude light brown solid, which was used in the next step without further purification. 1 H 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).

[0395] 6-ethynyl-2-oxaspiro[3.3]heptan-6-ol [ka] 6-Ethynyl-2-oxaspiro[3.3]heptan-6-ol was prepared in a similar manner to the preparation 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. 1 H 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).

[0396] 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine [ka] 1-Methyl-4-(2-methylbut-3-yn-2-yl)piperazine was prepared according to a modified procedure of Imada, Y.; Yurasa, M.; Nakamura, I.; Murahashi, S. - iJ Org. Chem. 1998, 63, 2342-2347. To a stirred light green solution of CuCl (0.10 g, 10 mmol) in dry THF at room temperature under argon, 1-methylpiperazine (1.10 g, 1.22 mL, 11 mmol) and NEt (1.11 g, 1.53 mL, 11 mmol) were added successively over 20 min. After stirring the blue heterogeneous mixture for 10 min, 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 dry THF (5 mL) was added slowly over 20 min, resulting in a mild exotherm. The reaction mixture was continued to stir for 30 min, heated at 58 °C for 7 h, and cooled. The brownish-red reaction mixture was diluted with EtO (70 mL) and aqueous NaHCO (40 mL). After separating the organic layer, the red heterogeneous aqueous layer was extracted with EtO (3 × 75 mL). The combined light green organic layers were washed successively with aqueous NaHCO (40 mL) and then aqueous NaCl, stirred with anhydrous NaSO, and filtered through Celite. The filtrate was concentrated to give the title compound as a crude yellow solid (1.16 g). Further purification by silica gel chromatography (Com...

Claims

1. I-51: (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]oxazepin-3-yl)picolinamide; I-52: (S)-4-((2-fluoropyridin-3-yl)methyl)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide; I-53: (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]oxazepin-3-yl)picolinamide; I-54: (S)-4-((2-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]oxazepin-3-yl)picolinamide I-55: (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-56: (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-57: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide I-58: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide I-59: (S)-4-((5-fluoropyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-60: (S)-4-((5-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]oxazepin-3-yl)picolinamide I-61: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-ylmethyl)picolinamide I-62: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-ylmethyl)picolinamide I-63: (S)—N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide I-64: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-ylmethyl)picolinamide I-65: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide I-66: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide I-67: (S)-4-((5-fluoropyridin-3-yl)oxy)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-68: (S)-4-((3,5-dimethylisoxazol-4-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-69: (S)-4-((3,5-dimethylisoxazol-4-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-70: (S)-4-((1H-pyrazol-1-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-71: (S)-4-((1H-pyrazol-1-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-72: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)methyl)picolinamide I-73: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl)methyl)picolinamide I-74: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylpyridin-3-yl)oxy)picolinamide I-75: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylpyridin-3-yl)oxy)picolinamide I-76: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(thiazol-4-ylmethyl)picolinamide I-77: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(thiazol-4-ylmethyl)picolinamide I-78: (S)-4-((2,6-dimethylpyridin-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]oxazepin-3-yl)picolinamide I-79: (S)-4-((2,6-dimethylpyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-80: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide I-81: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide I-82: (S)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylpyridin-3-yl)oxy)picolinamide I-83: ​​(S)-4-((2-fluoropyridin-3-yl)oxy)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-84: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-85: (S)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide I-86: (S)-4-hydroxy-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-87: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide I-88: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)pyridin-3-yl)oxy)picolinamide I-89: (S)-4-hydroxy-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-90: (S)—N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide I-91: (S)-4-((2-cyanopyridin-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]oxazepin-3-yl)picolinamide I-92: (S)-4-((2-cyanopyridin-3-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-93: (S)-4-((6-cyanopyridin-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]oxazepin-3-yl)picolinamide I-94: (S)-4-((6-cyanopyridin-2-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-95: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-fluoropyridin-3-yl)oxy)picolinamide I-96: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-methylthiazol-4-yl)methyl)picolinamide I-97: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)picolinamide I-98: (S)-4-((2-ethylthiazol-4-yl)methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-99: (S)-4-((2-ethylthiazol-4-yl)methyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-100: (S)-4-((5-fluoropyridin-3-yl)oxy)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-101: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((5-fluoropyridin-3-yl)oxy)picolinamide I-102: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-yloxy)picolinamide I-103: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-104: (S)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-105: (±)-4-((6-fluoropyridin-2-yl)methyl)-N-((3S)-5-methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide I-106: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-107: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-7-(3-methyl-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide I-108: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide I-109: (S)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-111: (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide I-112: (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide I-117: (S)-4-((6-fluoropyridin-2-yl)methyl)-N-(8-((1-hydroxycyclobutyl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide I-119: (S)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-120: (S)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-methylpyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-121: (S)-N-(6-fluoro-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-122: (S)-N-(6-fluoro-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-((6-fluoropyridin-2-yl)methyl)-1H-pyrazole-1-carboxamide I-123: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)thiazol-4-yl)methyl)picolinamide I-124: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((2-(trifluoromethyl)thiazol-4-yl)methyl)picolinamide I-125: (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-126: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide I-127: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide I-128: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-yloxy)picolinamide I-129: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-yloxy)picolinamide I-130: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)oxy)picolinamide I-131: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl)oxy)picolinamide I-132: (S)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide I-133: (S)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)picolinamide I-134: (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-135: (S)-4-((6-fluoropyridin-2-yl)oxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-136: (S)-4-((1-methyl-1H-pyrazol-4-yl)oxy)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide I-137: (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(oxazol-4-ylmethyl)picolinamide I-138: (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(oxazol-4-ylmethyl)picolinamide I-139: tert-butyl (S)-4-((3-(4-((2-fluoropyridin-3-yl)oxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)piperidine-1-carboxylate I-140: A compound which is (S)-4-((2-fluoropyridin-3-yl)oxy)-N-(5-methyl-7-((1-methylpiperidin-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide, or a pharma- ceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof.

2. A pharmaceutical composition comprising the compound of claim 1, or a pharma- ceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof, and one or more pharmacologically acceptable excipients.

3. The pharmaceutical composition of claim 2 for use in treating a disease, wherein the disease is a disease involving receptor interacting protein-1 (RIP1) kinase.

4. A pharmaceutical composition as described in claim 2 for use in treating a disease, wherein the disease is an inflammatory or immunoregulatory disorder.

5. A pharmaceutical composition as described in claim 2 for use in treating a disease, wherein the disease is amyotrophic lateral sclerosis (ALS), Parkinson's disease, or Alzheimer's disease.

6. A pharmaceutical composition as described in claim 2 for use in treating a disease, wherein the disease is atopic dermatitis, rheumatoid arthritis, or ankylosing spondylitis.

7. A pharmaceutical composition as described in claim 2 for use in treating a disease, wherein the disease is myelodysplastic syndrome.

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