RIP1K inhibitors

Abstract

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

Description

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of the earlier filing date of U.S. Provisional Application No. 63 / 004,404, filed on April 2, 2020.

[0003] field

[0004] The present disclosure relates to compounds and methods of making and using the compounds, such as for inhibiting receptor interacting protein-1 kinase ("RIP1") and for treating diseases and / or conditions associated with RIP1.

[0005] background

[0006] Receptor interacting protein-1 kinase (referred to herein as "RIP1") belongs to the tyrosine kinase-like family and is a serine / threonine protein kinase involved in innate immune signaling. RIP1 plays a central role in regulating cell signaling and its role in programmed cell death has been associated with a variety of inflammatory diseases, such as inflammatory bowel disease, psoriasis, and other diseases and / or conditions associated with inflammation and / or necrotic cell death.

[0007] Overview

[0008] Disclosed herein are compounds according to formula I

[0009]

[0010] wherein Ring B is a 5-membered or 6-membered heteroaryl group;

[0011] X is CH2 or O;

[0012] L is a heteroatom or R a , the prerequisite is that R a It is not hydrogen;

[0013] Z is for C 1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 cycloalkyl); aryl or heteroaryl, each optionally substituted by one or more R 5 group substitution;

[0014] R 1 -NR independently at each occurrence d R d , where two R d The groups, together with the nitrogen to which they are attached, provide C 3-10 Heterocyclic group; -C CH or -linker-R6 Group, wherein the linking group is a divalent C 1-10 Aliphatic moieties (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl) or C 1-10 Cycloaliphatic moiety, and R 6 YesR b ,-C(R f )3 or -C(R f )=C(R f )2;C 5-10 Aromatic group or C 3-6 Heterocyclic groups, each linker is optionally substituted by one or more halogens, R a or both replace;

[0015] R 2 and R 3 Independently R a In certain embodiments, R 2 is hydrogen or C 1-10 Aliphatic groups, such as H or C 1-6 alkyl, and in certain embodiments, R 2 It is C 1-6 Alkyl, such as CH3 or CD3;

[0016] R 4 and R 5 R independently at each occurrence e ;

[0017] R a is independently hydrogen, C 1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-6 Cycloalkyl), C 1-10 Halogenated aliphatic group, C 5-10 Aromatic group or C 3-6 Heterocyclic groups;

[0018] R b is independently -OH, -SH, -OR at each occurrence c 、-SR c 、-NR e R e 、-Si(R a )3, -C(O)OH, -C(O)OR c or -C(O)NR e R e

[0019] R cC independently at each occurrence 1-10 Alkyl (optionally with 1, 2 or 3 R e Replace), C 2-10 Alkenyl (optionally with 1, 2 or 3 R e Replace), C 2-10 Alkynyl (optionally with 1, 2 or 3 R e Replace), C 3-6 Cycloalkyl (optionally substituted by 1, 2 or 3 R e Replace) or C 5-10 Aromatic group (optionally with 1, 2 or 3 R e replace);

[0020] R d is optionally replaced by 1, 2 or 3 R a , R b and / or R e C 1-9 aliphatic groups;

[0021] R e is independently oxo (=O), -OR a 、N(R a )2. Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, or two R e The groups are linked together to form two R e The nitrogen bound to the group together provides C 3-10 Heterocyclic groups;

[0022] m is 1 to 4; and

[0023] n is 0, 1 or 2.

[0024] The foregoing and other objects, features and advantages of the present invention will become more apparent from the following detailed description.

[0025] Detailed Description

[0026] I. Overview of Terminology

[0027] The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art to practice the present disclosure. The singular forms "a", "an", and "the" represent one or more than one, unless the context clearly indicates otherwise. The term "or" represents a single element in the alternative element, or a combination of two or more elements, unless the context clearly indicates otherwise. "Comprising" as used herein means "including". Therefore, "comprising A or B" means "comprising A, B, or A and B", without excluding other elements. All references (including patents and patent applications cited herein) are incorporated by reference.

[0028] Unless otherwise indicated, all numbers expressing the amount of a component, molecular weight, percentage, temperature, time, and the like as used in this specification or claims are to be understood as being modified by the term "about". Therefore, unless otherwise implicitly or explicitly stated, the numerical parameters set forth are approximate values, which may depend on the desired performance sought and / or the detection limit under standard test conditions / methods. When the embodiment is directly and clearly distinguished from the prior art in question, the embodiment numbers are not approximate values ​​unless the word "about" is explicitly stated.

[0029] Unless otherwise explained, all technical and scientific terms used in this article have the same meaning as those of ordinary skill in the art to which the present disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods and examples are merely exemplary and are not intended to be limiting.

[0030] As used herein, the term "substituted" refers to all subsequent modifications in the term, for example, in the term "substituted aryl C 1-8 In the case of an alkyl group, substitution can occur on the aromatic C 1-8 The "C" of the alkyl group 1-8 on the "alkyl" portion, the "aryl" portion, or both.

[0031] When used to modify a specified group or part, "substituted" refers to that at least one of the specified group or part and possibly two or more hydrogen atoms are independently replaced by the same or different substituent groups defined below. In a specific embodiment, a group, part or substituent can be substituted or unsubstituted, unless explicitly defined as "unsubstituted" or "substituted". Therefore, any one of the groups specified herein can be unsubstituted or substituted, unless the context otherwise indicates or a specific structural formula excludes substitution. In a specific embodiment, a substituent may or may not be explicitly defined as substituted, but is still considered to be optionally substituted. For example, an "aliphatic" or "cyclic" part can be unsubstituted or substituted, but an "unsubstituted aliphatic" or "unsubstituted cyclic" is unsubstituted.

[0032] Unless otherwise indicated, a "substituent" or "substituent group" used to replace one or more hydrogen atoms on a saturated carbon atom in a specified group or moiety may be -R 60 , halogen, =O, -OR 70 、-SR 70 、-N(R 80 )2, haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R 70 、-SO3 - M + 、-SO3R 70 、-OSO2R 70 、-OSO3 - M + 、-OSO3R 70 、-P(O)(O - )2(M + )2. -P(O)(O - )2M 2+ 、-P(O)(OR 70 ) - M + 、-P(O)(OR 70 )2. -C(O)R 70 、-C(S)R 70 、-C(NR 70 )R 70 、-CO2 - M + 、-CO2R 70 、-C(S)OR 70 、-C(O)N(R 80 )2, -C(NR 70 )(R 80 )2. -OC(O)R 70 、-OC(S)R70 , -OCO2 - M + 、-OCO2R 70 、-OC(S)OR 70 、-NR 70 C(O)R 70 、-NR 70 C(S)R 70 、-NR 70 CO2 - M + 、-NR 70 CO2R 70 、-NR 70 C(S)OR 70 、-NR 70 C(O)N(R 80 )2.-NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R 60 It is C 1-10 An aliphatic, heteroaliphatic or cycloaliphatic group, usually C 1-6 Aliphatic groups, more usually C 1-6 Alkyl, where R 60 Optionally substituted; each R 70 is independently hydrogen or R 60 ; Each R 80 R independently at each occurrence 70 , or alternatively, two R 80 The groups together with the nitrogen atom to which they are bound form a 3- to 7-membered heterocycloaliphatic group which optionally includes 1 to 4 identical or different additional heteroatoms selected from O, N and S, wherein N optionally has R 70 substituted, such as H or C1-C3 alkyl; and each M + is a counterion with a net single positive charge. Each M + is independently at each occurrence, for example, an alkali metal ion such as K + 、Na + , Li + ; ammonium ions, such as + N(R 60 )4; protonated amino acid ions, such as lysine ions or arginine ions; or alkaline earth metal ions, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 or[Ba 2+] 0.5 (The subscript "0.5" means, for example, that one of the counterions of such a divalent alkaline earth metal ion can be the ionized form of the compound of the present invention, and other typical counterions (such as chloride ion) or two ionized compounds can serve as the counterions of such a divalent alkaline earth metal ion, or a doubly ionized compound can serve as the counterion of such a divalent alkaline earth metal ion.) As a specific example, -N(R 80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N -pyrrolidinyl, N -piperazinyl, 4 N -methyl-piperazine-1-yl, N -morpholinyl, etc. Any two hydrogen atoms on a single carbon can also be replaced by, for example, =O, =NR 70 、=N-OR 70 , =N2 or =S instead.

[0033] Unless otherwise indicated, the substituent group used to replace the hydrogen atom on the unsaturated carbon atom in the group containing unsaturated carbon is -R 60 , halogen, -O - M + 、-OR 70 、-SR 70 , -S - M + 、-N(R 80 )2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 、-SO3 - M + 、-SO3R 70 、-OSO2R 70 、-OSO3 - M + 、-OSO3R 70 、-PO3 -2 (M + )2.-PO3 - 2 M 2+ 、-P(O)(OR 70 ) - M + 、-P(O)(OR 70 )2. -C(O)R 70 、-C(S)R 70 、-C(NR 70 )R 70 、-CO2 - M + 、-CO2R 70、-C(S)OR 70 、-C(O)NR 80 R 80 、-C(NR 70 )N(R 80 )2. -OC(O)R 70 、-OC(S)R 70 , -OCO2 - M + 、-OCO2R 70 、-OC(S)OR 70 、-NR 70 C(O)R 70 、-NR 70 C(S)R 70 、-NR 70 CO2 - M + 、-NR 70 CO2R 70 、-NR 70 C(S)OR 70 、-NR 70 C(O)N(R 80 )2.-NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R 60 , R 70 , R 80 and M + As defined above. In an independent embodiment, the substituent is not -O - M + 、-OR 70 、-SR 70 or -S - M + .

[0034] Unless otherwise indicated, the substituent group used to replace a hydrogen atom on such a nitrogen atom in a group containing a nitrogen atom is -R 60 , -O - M + 、-OR 70 、-SR 70 , -S - M + 、-N(R 80 )2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R 70 、-SO3 - M + 、-SO3R70 、-OS(O)2R 70 、-OSO3 - M + 、-OSO3R 70 、-PO3 2- (M + )2.-PO3 2- M 2+ 、-P(O)(OR 70 ) - M + 、-P(O)(OR 70 )(OR 70 )、-C(O)R 70 、-C(S)R 70 、-C(NR 70 )R 70 、-CO2R 70 、-C(S)OR 70 、-C(O)NR 80 R 80 、-C(NR 70 )NR 80 R 80 、-OC(O)R 70 、-OC(S)R 70 、-OCO2R 70 、-OC(S)OR 70 、-NR 70 C(O)R 70 、-NR 70 C(S)R 70 、-NR 70 CO2R 70 、-NR 70 C(S)OR 70 、-NR 70 C(O)N(R 80 )2.-NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R 60 , R 70 , R 80 and M + As defined above.

[0035] In one embodiment, a substituted group has at least one substituent up to the number of substituents possible for the particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

[0036] In addition, in the embodiment where the group or part is substituted by a substituted substituent, the nesting of such substituted substituents is limited to three, thereby preventing the formation of polymers. Therefore, in a group or part comprising a first group (wherein the first group is a substituent on a second group, and the second group itself is a substituent on a third group), the group or part is attached to the parent structure, and the first (outermost) group can only be substituted by an unsubstituted substituent. For example, in a group comprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted by its own unsubstituted substituent.

[0037] One of ordinary skill in the art will understand that any group or moiety defined herein can be attached to any other part of a disclosed structure (such as a parent structure or core structure), such as by considering valence rules, comparison with exemplified species, and / or considering functionality, unless the context explicitly states or implies the connectivity of the group or moiety to the rest of the structure.

[0038] "Acyl" refers to the group -C(O)R, where R is H, an aliphatic group, a heteroaliphatic group, or an aromatic group (including both aryl and heteroaryl groups). Exemplary acyl moieties include, but are not limited to -C(O)H, -C(O)alkyl, -C(O)C1-C6alkyl, -C(O)C1-C6haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0039] "Aliphatic group" means a substantially hydrocarbon-based group or moiety. An aliphatic group or moiety may be acyclic, including alkyl, alkenyl or alkynyl groups (as well as alkylene, alkenylene or alkynylene groups), cyclic forms thereof, such as cycloaliphatic groups or moieties, including cycloalkyl, cycloalkenyl or cycloalkynyl, and further including straight chain and branched arrangements, as well as all stereo and positional isomers. Unless expressly stated otherwise, an aliphatic group contains from one to twenty-five carbon atoms (C 1-25 ); for example, for an acyclic aliphatic group or moiety, from one to fifteen (C 1-15 ), from one to ten (C 1-10 ), from one to six (C 1-6 ), or from one to four carbon atoms (C 1-4 ), or for a cycloaliphatic radical or moiety, from three to fifteen (C 3-15 ), from three to ten (C 3-10 ), from three to six (C 3-6 ), or from three to four (C 3-4) carbon atoms. Aliphatic groups can be substituted or unsubstituted unless explicitly referred to as "unsubstituted aliphatic groups" or "substituted aliphatic groups". Aliphatic groups can be substituted with one or more substituents (up to two substituents for each methylene carbon in the aliphatic chain, or up to one substituent for each carbon of a -C=C- double bond in the aliphatic chain, or up to one substituent for the carbon of a terminal methine group).

[0040] A "lower aliphatic group" refers to a group containing one to ten carbon atoms (C 1-10 ) aliphatic groups, such as from one to six (C 1-6 ), or from one to four (C 1-4 ) carbon atoms; or for a lower cycloaliphatic group, from three to ten (C 3-10 ) such as from three to six (C 3-6 ) carbon atoms.

[0041] "Alkoxy" refers to the group -OR, where R is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl. In certain embodiments, R is C 1-6 Alkyl group or C 3-6 Cycloalkyl groups. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In substituted alkoxy groups, R is a substituted alkyl or a substituted cycloalkyl, examples of which include haloalkoxy groups such as -OCF2H in the compounds disclosed herein.

[0042] "Alkoxyalkyl" refers to the group -alkyl-OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group; -CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl group.

[0043] "Alkyl" means a saturated aliphatic hydrocarbon group having from 1 to at least 25 carbon atoms (C 1-25 ), more typically 1 to 10 carbon atoms (C 1-10 ), such as 1 to 6 carbon atoms (C 1-6 ). The alkyl moiety may be substituted or unsubstituted. As an example, the term includes straight or branched chain hydrocarbon groups such as methyl (CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3) and neopentyl (-CH2C(CH3)3).

[0044] "Amino" means a group -NH2, -NHR or -NRR, wherein each R is independently selected from H, an aliphatic group, a heteroaliphatic group, an aromatic group (including both aryl and heteroaryl groups) or a heterocycloaliphatic group, or two R groups together with the nitrogen to which they are attached form a heterocyclic ring. Examples of such heterocyclic rings include those in which the two R groups together with the nitrogen to which they are attached form -(CH2) 2-5 - ring, which may be optionally substituted with one or two heteroatoms (such as -O- or -N(R g )) interruption, such as in the group and In which R g YesR 70 、-C(O)R 70 、-C(O)OR 60 or -C(O)N(R 80 )2.

[0045] "Amide" means the group -N(R)acyl, where R is hydrogen, a heteroaliphatic group or an aliphatic group such as an alkyl group, particularly C 1-6 alkyl.

[0046] Unless otherwise indicated, "aromatic group" means a cyclic conjugated group or moiety having from 5 to 15 ring atoms, having a single ring (e.g., phenyl, pyridyl or pyrazolyl) or multiple fused rings, in which at least one ring is aromatic (e.g., naphthyl, indolyl or pyrazolopyridinyl), that is, at least one ring and optionally multiple fused rings have a continuous delocalized π-electron system. Typically, the number of out-of-plane π electrons corresponds to Huckel's rule (4n + 2). The point of attachment to the parent structure is usually through the aromatic portion of the fused ring system. For example, However, in certain embodiments, the context or explicit disclosure may indicate that the point of attachment is through the non-aromatic portion of the fused ring system. For example, An aromatic group or moiety may contain only carbon atoms in the ring, such as in an aryl group or moiety, or it may contain one or more ring carbon atoms and one or more ring heteroatoms (e.g., S, O, N, P, or Si) containing a lone electron pair, such as in a heteroaryl group or moiety. Unless otherwise indicated, an aromatic group may be substituted or unsubstituted.

[0047] Unless otherwise indicated, "aryl" means an aromatic carbocyclic group of 6 to 15 carbon atoms, the group having a monocyclic ring (e.g., phenyl) or multiple fused rings, in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, etc.). If any aromatic ring portion contains heteroatoms, the group is a heteroaryl rather than an aryl group. An aryl group can be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise indicated, an aryl group can be substituted or unsubstituted.

[0048] "Araliphatic" means an aryl group attached to the parent through an aliphatic moiety.Araliphatic groups include aralkyl or arylalkyl groups such as benzyl and phenylethyl.

[0049] "Carboxyl" means -CO2H.

[0050] "Carboxamide" refers to a -C(O)amino group.

[0051] "Carboxyl ester" or "carboxy ester" refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0052] "Carboxylate" means -C(O)O - or a salt thereof.

[0053] "Cyano" refers to the radical -CN.

[0054] "Cycloaliphatic group" means a cyclic aliphatic group having a monocyclic ring (e.g., cyclohexyl) or a polycyclic ring (such as in a fused, bridged or spirocyclic system, the ring or at least one ring in the system is aliphatic). Typically, the point of attachment to the parent structure is the aliphatic portion through the polycyclic system. Cycloaliphatic groups include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl and cycloalkynyl. Cycloaliphatic groups can contain from three to twenty-five carbon atoms; for example, from three to fifteen, from three to ten or from three to six carbon atoms. Unless otherwise indicated, cycloaliphatic groups can be substituted or unsubstituted. Exemplary cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl or cyclohexenyl.

[0055] "Halo", "halide" or "halogen" means fluorine, chlorine, bromine or iodine.

[0056] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CH2F, -CHF2, and -CF3.

[0057] "Heteroaliphatic group" means 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 by an atom having at least one lone electron pair (usually nitrogen, oxygen, phosphorus, silicon or sulfur). The heteroaliphatic compound or group may be substituted or unsubstituted, branched or unbranched, chiral or achiral and / or acyclic or cyclic, such as a heterocycloaliphatic group.

[0058] "Unless otherwise indicated, heteroaryl" means an aromatic group or moiety having from 5 to 15 ring atoms, the ring atoms comprising at least one carbon atom and at least one heteroatom, such as N, S, O, P or Si. A heteroaryl group or moiety may comprise a monocyclic (e.g., pyridyl, pyrimidyl or pyrazolyl) or a plurality of fused rings (e.g., indolyl, benzopyrazolyl or pyrazolopyridinyl). A heteroaryl group may contain one or more non-aromatic rings fused to an aromatic moiety, and such a heteroaryl group may be connected to the remainder of the molecule by an aromatic or non-aromatic ring. A heteroaryl group or moiety may be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise indicated, a heteroaryl group or moiety may be substituted or unsubstituted.

[0059] "Heterocyclyl", "heterocyclic" and "heterocycle" refer to both aromatic and non-aromatic ring systems, and more specifically to stable three to fifteen membered ring moieties containing at least one carbon atom, and typically multiple carbon atoms and at least one (such as one to five) heteroatom. The heteroatom may be a nitrogen, phosphorus, oxygen, silicon or sulfur atom. The heterocyclyl moiety may be a monocyclic moiety, or may contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such polycyclic moieties may include fused or bridged ring systems as well as spiro ring systems; and any nitrogen, phosphorus, carbon, silicon or sulfur atom in the heterocyclyl moiety may be optionally oxidized to various oxidation states. For convenience, nitrogen, particularly but not exclusively, those defined as cyclic aromatic nitrogens, are intended to include their corresponding N-oxide forms, although not explicitly defined as such in specific embodiments. Thus, for compounds having, for example, a pyridyl ring, the corresponding pyridyl-N-oxide is included as another compound of the invention unless explicitly excluded or excluded by context. In addition, the annular nitrogen atom may be optionally quaternized. The heterocycle includes a heteroaryl moiety and a heteroalicyclic or heterocycloaliphatic moiety, which is a partially or completely saturated heterocyclic ring. Examples of heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxane, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazacycloheptatrienyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, Quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinetrienyl, azacycloheptatrienyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazine 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy,

[0060] "Hydroxy" refers to the group -OH.

[0061] "Nitro" means the radical -NO2.

[0062] "Phosphate" means the group -OP(O)(OR')2, wherein each -OR' is independently -OH; an -O-aliphatic group such as -O-alkyl or -O-cycloalkyl; an -O-aromatic group including -O-aryl and -O-heteroaryl; an -O-aralkyl group; or -OR' is -O - M + , where M + is a counterion with a single positive charge. Each M + It can be an alkali metal ion such as K + 、Na + , Li + ; ammonium ions, such as + N(R")4, wherein R" is H, an aliphatic group, a heteroaliphatic group, or an aromatic group (including both aryl and heteroaryl groups); or an alkaline earth metal ion such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 or[Ba 2+ ] 0.5 Phosphonooxyalkyl represents a group -alkyl-phosphate, such as, for example, -CH2OP(O)(OH)2 or a salt thereof, such as -CH2OP(O)(OH)2. - Na + )2, and (((dialkoxyphosphoryl)oxy)alkyl) represents a dialkyl ester of a phosphinoyloxyalkyl group, such as, for example, -CH2OP(O)(O-tert-butyl)2.

[0063] "Phosphonate" means a group -P(O)(OR')2, wherein each -OR' is independently -OH; an -O-aliphatic group such as -O-alkyl or -O-cycloalkyl; an -O-aromatic group, 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. Each M + is a positively charged counterion and may be, for example, an alkali metal ion such as K + 、Na + , Li + ; ammonium ions, such as + N(R")4, wherein R" is H, an aliphatic group, a heteroaliphatic group, or an aromatic group (including both aryl and heteroaryl groups); or an alkaline earth metal ion such as [Ca 2+ ] 0.5 , [Mg2+ ] 0.5 or[Ba 2 + ] 0.5 Phosphonoalkyl represents a group -alkyl-phosphonate, such as, for example, -CH2P(O)(OH)2, or -CH2P(O)( - Na + )2, and ((dialkoxyphosphoryl)alkyl) represents a dialkyl ester of a phosphonoalkyl group, such as, for example, -CH2P(O)(O-tert-butyl)2.

[0064] "Patient" or "subject" can generally refer to any organism, but more generally refers to mammals and other animals, particularly humans. Therefore, the disclosed methods are applicable to both human therapy and veterinary applications.

[0065] "Pharmaceutically acceptable excipient" means a substance other than the active ingredient, which is included in the composition comprising the active ingredient. As used herein, the excipient can be incorporated into the particles of the pharmaceutical composition, or it can be physically mixed with the particles of the pharmaceutical composition. For example, the excipient can be used to dilute the active agent and / or change the performance of the pharmaceutical composition. The excipient can include, but is not limited to, antiadhesives, adhesives, coatings, enteric coatings, disintegrants, flavorings, sweeteners, coloring agents, lubricants, glidants, adsorbents, preservatives, carriers or vehicles. The excipient can be starch and modified starch, cellulose and cellulose derivatives, sugars and derivatives thereof (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 tristearin, sucrose, lactose, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silicon dioxide, talc, magnesium carbonate, sodium starch glycolate, tartrate, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

[0066] "Adjuvant" is a component that modifies the effect of other agents (usually active ingredients). Adjuvants are often pharmacological and / or immunological agents. Adjuvants can alter the effect of active ingredients by increasing the immune response. Adjuvants can also serve as stabilizers for formulations. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, inactivated bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants, such as Freund's complete adjuvant or Freund's incomplete adjuvant.

[0067] "Pharmaceutically acceptable carrier" means an excipient that acts as a carrier or vehicle, such as a suspending aid, a solubilizing aid, or a nebulizing aid. 雷明顿:药学的科学与实践 , The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21st edition (2005) (incorporated herein by reference) describes exemplary compositions and formulations suitable for drug delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0068] In general, the property of the carrier will depend on the specific mode of administration adopted. For example, parenteral preparations generally include injectable fluids, which include pharmaceutically and physiologically acceptable fluids such as water, saline, balanced salt solutions, dextrose aqueous solutions, glycerol, etc. as vehicles. In certain embodiments, pharmaceutically acceptable carriers can be sterile to be suitable for administration to a subject (e.g., by parenteral, intramuscular or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical composition to be administered can contain trace amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, preservatives and pH buffers, such as sodium acetate or sorbitan monolaurate.

[0069] "Pharmaceutically acceptable salts" means pharmaceutically acceptable salts of compounds derived from various organic and inorganic counterions as known to those of ordinary skill in the art, and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, and the like. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological effectiveness of the free base when formed by an acid partner. Specifically, the disclosed compounds form salts with various pharmaceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, 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, 1-hydroxy-2-naphthoic acid, and the like. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" that are derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, meglumine, theobromine, purines, piperazine, piperidine, N -ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, e.g., S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference). In certain disclosed embodiments, the compound can be a formate salt, a trifluoroacetate salt, a hydrochloride salt, or a sodium salt.

[0070] An "effective amount" with respect to a compound or pharmaceutical composition means an amount of the compound or pharmaceutical composition sufficient to achieve a specific desired result (such as inhibition of a protein or enzyme). In certain embodiments, an "effective amount" is an amount sufficient to achieve the following results: inhibition of RIP1; induction of a desired biological or medical response in a tissue, system, subject or patient; treatment of a specified disorder or disease; amelioration or eradication of one or more of its symptoms; and / or prevention of the occurrence of a disease or disorder. One of ordinary skill in the art will appreciate that the amount of a compound that constitutes an "effective amount" may vary with the compound, the desired result, the disease state and its severity, the size, age and sex of the patient to be treated, and the like.

[0071] "Prodrug" refers to a compound that is transformed in vivo to produce a biologically active compound, or a compound that is more biologically active than the parent compound. For example, the in vivo transformation can occur by hydrolysis or enzymatic transformation. Common examples of prodrug moieties include, but are not limited to, esters and amide forms of compounds having an active form with a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the invention include, but are not limited to, esters of a phosphate group and a carboxylic acid, such as aliphatic esters, particularly alkyl esters (e.g., C 1-6 Other prodrug moieties include phosphate esters such as -CH2-OP(O)(OR')2 or salts thereof, wherein R' is H or C 1-6 Alkyl. Acceptable esters also include cycloalkyl esters and arylalkyl esters, such as, but not limited to benzyl esters. 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 one to about six carbons). Amides and esters according to the disclosed exemplary embodiments of the compounds of the present invention can be prepared according to conventional methods. A thorough discussion of prodrugs is provided in the following literature: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0072] "Solvate" means a complex formed by the combination of solvent molecules and molecules or ions of a solute. The solvent may be an organic solvent, an inorganic solvent, or a mixture of the two. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, propanol; amides such as N,N-dialiphatic amides such as N,N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides such as dimethyl sulfoxide; water; and combinations thereof. When combined with a pharmaceutically acceptable or unacceptable solvent (such as water, ethanol, etc.), the compounds described herein may exist in unsolvated as well as solvated forms. The solvated forms of the compounds disclosed herein are within the scope of the embodiments disclosed herein.

[0073] "Sulfonamide" means the group or moiety -SO2amino or -N(R)sulfonyl, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0074] "Sulfanyl" means a group or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic (including both -S-aryl and -S-heteroaryl).

[0075] "Sulfinyl" means 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).

[0076] "Sulfonyl" refers to the radical: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including -SO2aryl and -SO2heteroaryl).

[0077] As used herein, "treating" or "treatment" refers to treating a target disease or condition in a patient or subject, particularly a human having a target disease or condition, and includes, by way of example, but not limitation:

[0078] (i) preventing the disease or disorder from occurring in a patient or subject, in particular, when such patient or subject is susceptible to the disorder but has not yet been diagnosed as having it;

[0079] (ii) inhibiting the disease or condition, e.g. arresting or slowing its progression;

[0080] (iii) alleviating the disease or condition, for example, causing a reduction in symptoms or regression of the disease or condition or its symptoms; or

[0081] (iv) stabilizing the disease or condition.

[0082] As used herein, the terms "disease" and "disorder" may be used interchangeably or may be different in that a particular disease or disorder may not have a known causative agent (so the cause has not yet been determined) and is therefore not yet considered a disease, but rather merely an undesirable condition or syndrome in which a more or less specific collection of symptoms is identified by the clinician.

[0083] The above definitions and the following formulae are not intended to include impermissible substitution patterns (eg, a methyl group substituted with 5 fluoro groups). One of ordinary skill in the art would readily recognize such impermissible substitution patterns.

[0084] Those of ordinary skill in the art will appreciate that compounds can exhibit tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may include one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, certain disclosed compounds may exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Since the various compound names and compound structural formulas in the specification and claims may represent only one of possible tautomerism, conformational isomerism, optical isomerism, or geometric isomerism, those of ordinary skill in the art will appreciate that disclosed compounds encompass any tautomerism, conformational isomerism, optical isomerism, and / or geometric isomerism of the compounds described herein, as well as mixtures of these various different isomeric forms. Mixtures of different isomeric forms (including mixtures of enantiomers and / or stereoisomers) can be separated using techniques known to those of ordinary skill in the art, particularly with the benefit of this disclosure, to provide each individual enantiomer and / or stereoisomer. In the case of limited rotation (e.g., around an amide bond or between two directly connected rings (such as a pyridyl ring, a biphenyl group, etc.), atropisomers are also possible and are also specifically included in the compounds of the invention.

[0085] As will be appreciated by those skilled in the art, hydrogen can exist in any of the three isotopes (i.e., protium, deuterium, and tritium). In certain embodiments, any or all of the hydrogen present in a compound or in a particular group or moiety within a compound may be enriched with deuterium or tritium relative to the natural abundance of such isotopes. Thus, the enumeration of alkyl groups includes compounds that are enriched with deuterium relative to protium. A deuterated alkyl group may have one or more protium atoms replaced by deuterium. For example, ethyl represents C2H5 or C2H5 in which 1 to 5 protium atoms are replaced by deuterium, such as in C2D x H 5-x middle.

[0086] II. RIP1-active compounds and pharmaceutical compositions containing RIP1-active compounds

[0087] A. Compounds

[0088] Disclosed herein are compounds useful for inhibiting RIP1 and / or for treating diseases and / or conditions associated with RIP1 and pharmaceutical compositions comprising such compounds. In certain embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds inhibit RIP1 relative to RIP2, RIP3, or both RIP2 and RIP3. In certain embodiments, the compounds of the present disclosure may have a structure satisfying Formula I

[0089]

[0090] One of ordinary skill in the art will appreciate that the formulae disclosed herein include within their scope all hydrates, solvates, physical forms, stereoisomers, N - Oxides, tautomers and prodrugs.

[0091] Reference Formula I:

[0092] Ring B is a 5-membered or 6-membered heteroaryl group;

[0093] X is CH2 or O;

[0094] L is a heteroatom or R a , the prerequisite is that R a It is not hydrogen;

[0095] Z is for C 1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 cycloalkyl); aryl or heteroaryl, each optionally substituted by one or more R 5 group substitution;

[0096] R 1 -NR independently at each occurrence d R d , where two R d The groups, together with the nitrogen to which they are attached, provide C 3-10 Heterocyclic group; -C CH or -linker-R 6 Group, wherein the linking group is a divalent C 1-10 Aliphatic moieties (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl) or C 1-10Cycloaliphatic moiety, and R 6 YesR b ,-C(R f )3 or -C(R f )=C(R f )2;C 5-10 Aromatic group or C 3-6 Heterocyclic groups, each linker is optionally substituted by one or more halogens, R a or both replace;

[0097] R 2 and R 3 Independently R a In certain embodiments, R 2 is hydrogen or C 1-10 Aliphatic groups, such as H or C 1-6 alkyl, and in certain embodiments, R 2 It is C 1-6 Alkyl, such as CH3 or CD3;

[0098] R 4 and R 5 R independently at each occurrence e ;

[0099] R a is independently hydrogen, C 1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-6 Cycloalkyl), C 1-10 Halogenated aliphatic group, C 5-10 Aromatic group or C 3-6 Heterocyclic groups;

[0100] R b is independently at each occurrence -OH, -SH, -OR c 、-SR c 、-NR e R e 、-Si(R a )3, -C(O)OH, -C(O)OR c or -C(O)NR e R e

[0101] R c C independently at each occurrence 1-10 Alkyl (optionally with 1, 2 or 3 R e Replace), C 2-10 Alkenyl (optionally with 1, 2 or 3 R e Replace), C2-10 Alkynyl (optionally with 1, 2 or 3 R e Replace), C 3-6 Cycloalkyl (optionally substituted with 1, 2 or 3 R e Replace) or C 5-10 Aromatic group (optionally with 1, 2 or 3 R e replace);

[0102] R d is optionally replaced by 1, 2 or 3 R a , R b and / or R e C 1-9 aliphatic groups;

[0103] R e is independently oxo (=O), -OR a 、N(R a )2. Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, or two R e The groups are linked together to form two R e The nitrogen bound to the group together provides C 3-10 Heterocyclic groups;

[0104] m is 1 to 4; and

[0105] n is 0, 1 or 2.

[0106] In certain embodiments, when R 1 Yes - NR d R d When two R d The groups, together with the nitrogen to which they are attached, provide C 3-10 The heterocyclic group, the C 3-10 The heterocyclic group optionally includes one, two or three additional heteroatoms selected from nitrogen and oxygen. 3-10 The heterocyclic group is replaced by one or more R e The group is substituted, the R e The groups are linked together to provide C 3-10 A heterocyclic group, and the C 3-10 Heterocyclic group and R b The groups together may provide a spirocyclic group or a bridged or unbridged bicyclic group.

[0107] As illustrated in Formula I, R 1 can be located on any suitable carbon atom of the phenyl ring A, such as at position 1, 2, 3 or 4. In certain embodiments, one R 1YesR a , where R a It is C1-C 10 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl), and the second R 1 YesR b , where R b is halogen (e.g., Br, F, I, or Cl) or -NR d R d , where two R d The groups together with the nitrogen to which they are attached provide C 4-9 In certain embodiments, the C 4-9 The heterocyclic group is replaced by one or more R e Groups substituted and / or in addition to the two R d The compound has one or more additional heteroatoms other than the nitrogen to which the group is attached. b R 1 Group, where R b Yes - NR d R d , where (i) each R d Independently R a or R e ; or (ii) two R d The groups, together with the nitrogen to which they are attached, provide C 4-9 In certain embodiments, R b Yes - NR d R d , one of which R d YesR a , where R a is H, and the other R d YesR e , where R e It is C 1-6 In certain embodiments, the heterocyclic group contains 1 or 2 heteroatoms (including R b Certain heterocyclic groups contain R b In certain compound embodiments, the heterocyclic group is R b The nitrogen atom of the group is bound to the ring A phenyl ring of Formula I. In certain embodiments, the heterocyclic group is surrounded by two R e Group substitution, where R e C independently at each occurrence 1-6 A haloalkyl group (e.g., -CH2Cl) or a C 1-6Heteroalkyl (e.g., CH2OH). The heterocyclic group is a 6-membered or 7-membered heterocyclic group. In an exemplary embodiment, the heterocyclic group is

[0108] .

[0109] wherein each n is independently an integer in the range of 0 to 4, such as 0, 1, 2, 3 or 4; and R 6 Selected from hydrogen; aliphatic groups such as C 1-10 Aliphatic groups; aromatic groups, such as C 5-10 Aromatic groups; or heteroaliphatic groups, such as C 1-10 Heteroaliphatic groups.

[0110] In certain embodiments, R 1 YesR b , where R b Yes - NR d R d And two R d The groups together with the nitrogen to which they are attached provide a e C 4-9 A heterocyclic group, wherein two R e The groups are linked together to form b The groups together provide C 3-10 In such an embodiment, two R e The groups may be linked together to provide a bicyclic group or a spirocyclic group (wherein one ring of the bicyclic group or spirocyclic group is represented by R b The other ring of the bicyclic group or spirocyclic group is provided by two R e Groups are provided). In the embodiment comprising a spirocyclic group, each ring of the spirocyclic group can have the same number of atoms or different numbers of atoms. In a specific embodiment, the spirocyclic group comprises at least two rings, wherein the first ring and the second ring of the spirocyclic group have different numbers of carbon atoms, different numbers of heteroatoms or both. In certain embodiments, the two rings of the spirocyclic group comprise the same number of carbon atoms, the same number of heteroatoms or both. In certain embodiments, each ring of the spirocyclic group comprises a heteroatom in the ring, and the heteroatom can be the same in each ring, or each ring of the spirocyclic group can have different heteroatoms in the ring. The spirocyclic group can comprise the first ring coupled to the carbon atom of the ring A phenyl group, wherein the first ring has 3 to 7 atoms, and the second ring has 3 to 7 atoms. In certain embodiments, except R b In addition to the nitrogen atom of the group, the spirocyclic group also includes at least one oxygen atom. For specific embodiments containing 9 total atoms in the spirocyclic system, the spirocyclic group can contain greater than 7 total atoms in the spirocyclic system. In exemplary embodiments, Rb With two R e The groups together can provide the following spirocycles:

[0111]

[0112] Where R 6 Selected from hydrogen; aliphatic groups such as C 1-10 Aliphatic groups; aromatic groups, such as C 5-10 Aromatic groups; or heteroaliphatic groups, such as C 1-10 Heteroaliphatic groups.

[0113] As an example of such a moiety, in certain embodiments, R 1 Selected from

[0114]

[0115]

[0116] wherein each n is independently an integer in the range of 0 to 4, such as 0, 1, 2, 3 or 4; and R 6 independently selected from hydrogen; aliphatic groups such as C 1-10 Aliphatic groups; aromatic groups, such as C 5-10 Aromatic groups; or heteroaliphatic groups, such as C 1-10 Heteroaliphatic groups.

[0117] In certain embodiments, R 1 Yes-Linker-R 6 Groups such as C 2-10 Alkynyl moiety. Such C 2-10 The alkynyl moiety can be linear, branched and / or cyclic and have one, two or three substituents. Exemplary substituents include cycloalkyl and OH. In certain embodiments, one substituent is oxetanyl, azetidinyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, amino or phosphate, and / or in certain embodiments, one substituent is -OC(O)-R 8 . The C 2-10 Alkynes may contain straight and / or branched chain portions and cyclic portions, such as in or Some compounds contain a linker, wherein the linker is a C1 group and is R b R 6 Group, where R b Yes - NR d R d , one of which R d is H and the other R d is pyridyl, or two R dThe groups, together with the nitrogen to which they are attached, provide C 5-10 heteroaryl; or R b Yes OR c , where R c is a C substituted with a pyridyl group 1-4 In certain embodiments, R b yes

[0118] .

[0119] In certain embodiments, R 1 Can be selected from any of the following:

[0120]

[0121]

[0122] .

[0123] In certain embodiments, R 1 Selected from

[0124] .

[0125] In certain embodiments, R 2 and R 3 Each of which is independently R a , where R a is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl at each occurrence. In certain embodiments, R 2 and R 3 Each of which is independently R a , the R a is independently hydrogen, methyl or ethyl at each occurrence. In an exemplary embodiment, R 2 is methyl and R 3 It's hydrogen.

[0126] With reference to each of the embodiments described above, X is CH2 or O.

[0127] In certain embodiments of Formula I, including those described above, the B ring heteroaryl group is five-membered. Such a five-membered heteroaryl group may have a group satisfying the formula wherein at least one W is nitrogen and each remaining W is independently selected from C, -C(R a )-, CH, oxygen, sulfur, nitrogen or NH. In certain embodiments, the 5-membered heteroaryl group is a triazole, a diazole, such as imidazole or pyrazole, an oxazole or an oxadiazole.

[0128] Exemplary diazoles and triazoles include any of the following:

[0129]

[0130] Exemplary oxazoles include any of the following:

[0131] .

[0132] In other embodiments, B is a six-membered heteroaryl such as pyridine, pyridazine, pyrimidine, or pyrazine.

[0133] In certain embodiments, L is a divalent C 1-10 an aliphatic group; such as a C1-C4 alkylene linker (eg, -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-). In certain embodiments, L is -CH2-.

[0134] Continuing with reference to Formula I, Z can be an aryl group, such as a phenyl group or a heteroaryl group. In embodiments where Z is a heteroaryl group, Z can be a 5-membered or 6-membered heteroaryl group, such as a 5-membered or 6-membered nitrogen-containing heteroaryl group, for example, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, or a triazolyl group. In certain such embodiments, Z is a 6-membered nitrogen-containing heteroaryl group, and can be a pyridyl group, a pyrimidinyl group, or a pyridazinyl group.

[0135] In certain embodiments, Z is aryl, such as , where R 5 R independently at each occurrence e and p is 0, 1, 2, 3, 4 or 5. In other embodiments, Z is a heteroaryl group such as

[0136] Certain disclosed compounds contain R a R 5 Group, where R a is a C1-C4 aliphatic group, or is R b R 5 Group, where R b is a halogen, such as fluorine, R 2 YesR a , where R a is a C1-C4 aliphatic group, and R 3 YesR a , where R a It's hydrogen.

[0137] The compound of Formula I may also have a structure satisfying any one or more of Formulas II and IIA - IIF, IIG and IIH.

[0138]

[0139]

[0140] Reference Formula II and IIA - IIH, R 1 , X, W, and R 5 Each of R is as described above for Formula I. In certain embodiments, 0, 1 or 2 R 5 The group exists. 5 It can be R e , where R e is fluorine or chlorine. In other specific embodiments, R 5 Absent. Referring to Formulas IIA-IIF, each W is independently nitrogen or oxygen, and particularly nitrogen. In certain embodiments, Formula IIE has Formula IIK.

[0141]

[0142] wherein W is O or N. One of ordinary skill in the art will appreciate that when W in Formula IIK is N, the N has an open valence and can be replaced by hydrogen or, with reference to Formula I, by R e As an example, suitable Re groups for nitrogen substitution in this case include C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl.

[0143] Certain exemplary compounds within the scope of one or more of Formulas I, II, and IIA-IIG, IIH, and IIK include:

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153] In certain embodiments, one or more compounds may be included in a pharmaceutical composition or medicine, and in certain embodiments, the one or more compounds may be in the form of a parent compound or a pharmaceutically acceptable salt thereof, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope or a prodrug. The pharmaceutical composition typically includes at least one additional component in addition to the disclosed one or more compounds, such as a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent (described in the following section) or any combination thereof.

[0154] Pharmaceutically acceptable excipients can be included in pharmaceutical compositions for a variety of purposes, such as for diluting the pharmaceutical composition for delivery to a subject, for facilitating processing of the formulation, for providing favorable material properties to the formulation, for facilitating dispersion from a delivery device, for stabilizing the formulation (e.g., antioxidants or buffers), for providing a pleasant or palatable taste or consistency to the formulation, etc. Pharmaceutically acceptable excipients may include pharmaceutically acceptable carriers. Exemplary excipients include, but are not limited to: monosaccharides, disaccharides and polysaccharides, sugar alcohols and other polyols, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitol, diphosphatidylcholine, and lecithin; bulking agents, such as sorbitol, diphosphatidylcholine, and lecithin; agents); buffers such as phosphate and citrate buffers; anti-adherents such as magnesium stearate; binders such as sugars (including disaccharides such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinyl pyrrolidone, polyalkylene glycols); coating agents (such as cellulose ethers including hydroxypropyl methylcellulose, shellac, zein zein and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, crosslinked sodium carboxymethyl cellulose and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose , glucose, mannitol, sorbitol, calcium carbonate and magnesium stearate); flavoring and sweetening agents (such as mint, cherry, anise, peach, apricot or licorice, raspberry and vanilla); lubricants (such as minerals, for example talc or silicon dioxide; fats, for example vegetable tristearate, magnesium stearate or stearic acid); preservatives (such as antioxidants, for example vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium; amino acids, for example cysteine ​​and methionine; citric acid and sodium citrate; parabens, for example methylparaben and propylparaben); coloring agents; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0155] III. Methods of Using the Compounds

[0156] A. Disease / Disorder

[0157] The disclosed compounds, and combinations and / or pharmaceutical compositions thereof can be used to inhibit RIP1 kinase by contacting RIP1 kinase with one or more compounds of the disclosure, or compositions comprising one or more compounds of the disclosure, in vivo or in vitro. The disclosed one or more compounds, or compositions comprising one or more compounds of the disclosure, can also be used to improve, 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 used to treat conditions in which inhibition of RIP1 or pathways involving RIP1 is therapeutically useful. In certain embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds can be used to treat autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, renal diseases, cancers, ischemic conditions, red blood cell deficiency, lung and brain damage (e.g., induced by ischemia-reperfusion or cisplatin and / or cerebrovascular accident), and bacterial and viral infections.

[0158] In certain 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.

[0159] The disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof may also be used to treat immunoregulatory disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunoregulatory disorders that may be treated with the compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, organ or tissue transplantation, graft-versus-host disease resulting from transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, 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, Corneal epithelial dystrophy, Corneal leukoma, Ocular pemphigus, Moren's ulcer, Scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, Sarcoidosis, Pollen allergy, Reversible obstructive airway disease, Bronchial asthma, Allergic asthma, Intrinsic asthma, Exogenous asthma, Dust asthma, Chronic or refractory asthma, Late-onset asthma and airway hyperresponsiveness, Bronchitis, Gastric ulcer, Vascular damage due to ischemic disease and thrombosis, Ischemic bowel disease, Ischemia-reperfusion injury, Inflammatory bowel disease, Necrotizing enterocolitis, Intestinal damage associated with thermal burns, Celiac disease, Proctitis, Eosinophilic gastroenteritis, Mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, simple red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoiesis, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, Chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa,Non-inflammatory cardiomyopathy or myocardial infarction, Scleroderma (including systemic scleroderma), Antiphospholipid syndrome, Wegener's necrotizing granulomatosis, Sjögren's syndrome, Obesity, Eosinophilic fasciitis, Damage to the gums, periodontium, alveolar bone, cementum, Glomerulonephritis, Male pattern baldness or senile alopecia (by preventing hair loss or providing hair initiation and / or promoting hair production and hair growth), Muscular dystrophy, Pyoderma and Sezary syndrome, Addison's disease, Ischemia-reperfusion injury of organs following preservation, transplantation or ischemic disease, Endotoxic shock, Pseudomembranous colitis, Colitis caused by drugs or radiation, Ischemic acute renal insufficiency, Chronic renal insufficiency, Toxin disease caused by pulmonary oxygen or drugs, Lung cancer, Emphysema, Cataract, Siderosis, Retinitis pigmentosa, Retinal degeneration, Retinal detachment, Age-related macular degeneration, Vitreous scarring, Corneal alkali burns, Erythematosus multiforme, Linear IgA bullous dermatitis and refractory dermatitis, Gingivitis, Periodontitis, Sepsis, Pancreatitis, Diseases caused by environmental pollution, Aging, Carcinogenesis, Metastasis and hypotension, Diseases caused by histamine or leukotriene-C4 release, Behcet's disease, Autoimmune hepatitis, Primary biliary cirrhosis, Sclerosing cholangitis, Partial hepatectomy, Acute liver necrosis, Necrosis caused by toxins, Viral hepatitis, Shock, or hypoxia, Hepatitis B, Non-A / Non-B hepatitis, Cirrhosis, Alcoholic liver disease, including alcoholic cirrhosis, Alcoholic steatohepatitis, Non-alcoholic steatohepatitis (NASH), Autoimmune hepatobiliary disease, Acetaminophen toxicity, Hepatotoxicity, Hepatic failure, Fulminant hepatic failure, Delayed hepatic failure, "acute-on-chronic" hepatic failure, Chronic renal disease, Renal impairment / injury (caused by, e.g., nephritis, renal transplantation, surgery, administration of nephrotoxic drugs, acute renal injury), Increased effects of chemotherapy, Cytomegalovirus infection, HCMV infection, AIDS, Cancer, Alzheimer's disease, Parkinson's disease, Trauma, or chronic bacterial infection.

[0160] In certain embodiments, the Compounds of the Disclosure are useful for treating neurological pain, including neuropathic pain and inflammation-induced pain.

[0161] In certain embodiments, the compounds can be used to treat interleukin-1 converting enzyme-associated febrile 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, α-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, Fucus glycosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorder, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage diseases, Tay-Sach disease, and Wolman disease).

[0162] In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof are useful for treating and / or preventing rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis (particularly pustular psoriasis), type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia d and periodic fever syndromes, cryopyrin-associated periodic syndromes, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gouty attacks, pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of 11-1 receptor antagonists), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0163] Proliferative diseases that may be treated by the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof include benign or malignant tumors, solid tumors, cancer of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone, or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, particularly colon cancer or colorectal adenoma, tumors of the neck and head, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, MyD88 driven disorders (such as ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Hodgkin lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), smoldering or indolent multiple myeloma, or hematologic malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, ABCDLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, chronic myeloid leukemia (CML), primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic / myeloproliferative neoplasms (MDS / MPN) such as chronic myelomonocytic leukemia (CMML, including CMML-0, CMML-1 and CMML-2), Myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds disclosed herein can be used to treat drug-resistant malignancies, such as JAK inhibitor-resistant malignancies, ibrutinib-resistant malignancies, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenstrom's macroglobulinemia.

[0164] Although CMML shares some clinical and pathological features of both myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs), CMML is classified by the World Health Organization (WHO) as a separate category within the MDS / MPN overlap group. (Arber et al. “ 世界卫生组织 2016年髓系肿瘤和急性白血病分类修订版Blood, Vol. 127, No. 20, pp. 2391-2405, May 19, 2016). According to the WHO, the diagnosis of CMML now requires ≥ 1 × 10 9 / L and the presence of both persistent peripheral blood monocytosis and monocytes accounting for ≥10% of the white blood cell (WBC) differential count. In addition, CMML can only be diagnosed according to the definition when rearrangements in the PDGFRA, PDGFRB, or FGFR1 genes have been excluded, and in the 2016 update, the PCM1-JAK2 fusion gene was added as an exclusion criterion. In certain embodiments, the method of treating CMML includes identifying a patient with the WHO diagnostic criteria (i.e., ≥1×10 9 / L and monocytes accounting for ≥10% of the white blood cell differential count) and excluding rearrangements in the PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2 genes), and treating the subject by administering a RIP1 inhibitor disclosed herein, a combination of such compounds, and / or a composition thereof.

[0165] Examples of allergic disorders that can be treated using the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, idiopathic asthma, true asthma, intrinsic asthma caused by pathophysiological disturbances, idiopathic asthma of unknown or unexplained cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, extrinsic asthma caused by environmental factors, cold air-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoan, or viral infection, incipient asthma, wheezing infant syndrome, bronchiolitis, cough variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, Postnasal drip, purulent or nonpurulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis.

[0166] As another example, rheumatoid arthritis (RA) usually causes swelling, pain, loss of mobility and tenderness of target joints throughout the body. RA is characterized by a chronic inflammatory synovium of dense lymphocytes. The synovium, which is usually one cell layer thick, becomes densely packed with cells and presents a form similar to lymphoid tissue, including dendritic cells, T cells, B cells and NK cells, macrophages and plasma cell clusters. This process and a large number of immunopathological mechanisms including the formation of antigen-immunoglobulin complexes ultimately lead to the destruction of the integrity of the joint, resulting in deformity, permanent loss of function and / or bone erosion at or near the joint. Disclosed compounds, combinations of disclosed compounds or their pharmaceutical compositions can be used to treat, improve or prevent any one, several or all of these symptoms of RA. Therefore, in the context of RA, when achieving the mitigation or improvement of any symptom usually associated with RA, it is believed that the compound provides a therapeutic benefit, regardless of whether the treatment results in the concomitant treatment of radical RA and / or the reduction of the amount of circulating rheumatoid factor ("RF").

[0167] The American College of Rheumatology (ACR) has developed criteria for defining improvement and clinical remission of RA. Once such parameters, ACR20 (ACR criteria for 20% clinical improvement) requires 20% improvement in tender and swollen joint counts, and 20% improvement in 3 of the following 5 parameters: patient global assessment, physician global assessment, patient pain assessment, disability level, and acute phase reactant levels. These criteria were expanded to 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include Paulu's criteria and radiographic progress (e.g., Sharp score).

[0168] In certain embodiments, a therapeutic benefit is achieved in patients suffering from RA when the patient exhibits an ACR of 20. In specific embodiments, an ACR improvement of ACR 50 or even ACR 70 may be achieved.

[0169] B. Combinations of Therapeutic Agents

[0170] The compounds described herein can be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjuvant to other established therapies or in combination with the therapies. The compound or a composition comprising the one or more compounds can be administered once or multiple times. In certain embodiments, the compounds of the present invention can be used in combination with other therapeutic agents useful for the disorder or condition being treated. These other therapeutic agents can be administered simultaneously, sequentially in any order, by the same route of administration as the compounds disclosed herein or by different routes of administration. For sequential administration, the one or more compounds and the one or more therapeutic agents can be administered so that the effective time period of at least one compound and therapeutic agent overlaps with the effective time period of at least one other compound and / or therapeutic agent. In an exemplary embodiment of a combination comprising four components, the effective time period of the first component administered can overlap with the effective time period of the second, third, and fourth components, but the effective time periods of the second, third, and fourth components independently can overlap or not overlap with each other. In another exemplary embodiment of a combination comprising four components, the effective time period of the first component administered overlaps with the effective time period of the second component, but does not overlap with the effective time period of the third or fourth component; the effective time period of the second component overlaps with the effective time periods of the first and third components; and the effective time period of the fourth component overlaps only with the effective time period of the third component. In certain embodiments, the effective time periods of all compounds and / or therapeutic agents overlap with each other.

[0171] In certain embodiments, the compound is administered together with another therapeutic agent (such as an analgesic, antibiotic, anticoagulant, antibody, anti-inflammatory agent, immunosuppressant, guanylate cyclase-C agonist, intestinal secretagogue, antiviral agent, anticancer agent, antifungal agent or a combination thereof). The anti-inflammatory agent can be a steroidal or non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylate, 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 certain embodiments, the immunosuppressant is a mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an antilymphocyte globulin, an antithymocyte globulin, an anti-T-cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0172] In certain embodiments, the compounds of the present invention can be used together with an anticancer agent or a cytotoxic agent. Various types of anticancer and anti-neoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkaloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents, such as DNMT inhibitors, such as azacitidine and decitabine. Exemplary alkylating agents include, but are not limited to, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimine, methylmelamine, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, by way of example and not limitation, the folic acid analog methotrexate; the pyrimidine analogs fluorouracil, cytarabine; the purine analogs mercaptopurine, thioguanine, and thioazapurine. Exemplary vinca alkaloids 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 adrenocortical steroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progesterone compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

[0173] These and other useful anticancer compounds are described in the Merck Index, 13th Edition (O'Neil MJ et al., eds.) Merck Publishing Group (2001) and in Goodman and Gilman, The Pharmacological Basis of Therapeutics, 12th Edition, Brunton LL, ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0174] Among the CTLA4 antibodies, ipilimumab, which is marketed by Bristol-Myers Squibb as YERVOY ® sell.

[0175] Other chemotherapeutic agents for combination include immuno-oncology agents such as checkpoint pathway inhibitors, e.g., PD-1 inhibitors such as nivolumab and pembrolizumab, 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).

[0176] Other chemotherapeutic agents for use in combination with the inhibitors disclosed herein include anti-SLAMF7 agents, such as the humanized monoclonal antibody eloizumab (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 usulelumab (BMS-663513).

[0177] The compounds disclosed herein may also be advantageously used with CAR-T therapies. Examples of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

[0178] Additional anti-proliferative compounds useful in combination with the compounds of the invention include, by way of example and not limitation, antibodies directed against growth factor receptors (eg, anti-Her2); and cytokines such as interferon-α and -γ, interleukin-2, and GM-CSF.

[0179] Additional chemotherapeutic agents useful in combination with the compounds of the invention include proteasome inhibitors such as bortezomib, carfilzomib, marizomib, and the like.

[0180] Examples of kinase inhibitors useful in combination with the compounds disclosed herein, particularly in the treatment of malignancies, include: Btk inhibitors such as ibrutinib; CDK inhibitors such as palbociclib; EGFR inhibitors such as afatinib, erlotinib, gefitinib, lapatinib, osimertinib, and vandetinib; Mek inhibitors such as trametinib; Raf inhibitors such as dabrafenib, sorafenib, and vemurafenib; VEGFR inhibitors such as axitinib, 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 fuzotinib.

[0181] In other embodiments, the second therapeutic agent may be selected from any of the following:

[0182] pain relievers, including morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, and dipipanone;

[0183] Antibiotics, including aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromomycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefdroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefmandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (e.g., teicoplanin, vastatin, lincosamides (e.g., clindamycin and incomysin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spectinomycin), monobactams (e.g., aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin), penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), penicillins combinations (e.g., amoxicillin / clavulanate, ampicillin / sulbactam, piperacillin / tazobactam, and ticarcillin / clavulanate), peptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomifloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide, sulfachloridine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethoxazole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfadiazine), sulfamethoxazole, trimethoprim, and trimethoprim-sulfamethoxazole), tetracyclines (e.g., desmethylclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifampin, rifabutin, rifapentine, and streptomycin), and others, such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platelet mycin, quinupristin / dalfopristin, rifaximin, thiamphenicol, tigecycline, and tinidazole;

[0184] Antibodies, including anti-TNF-α antibodies, such as infliximab ( TM), adalimumab, golimumab, certolizumab; anti-B cell antibodies, for example, rituximab; anti-IL-6 antibodies, for example, tocilizumab; anti-IL-1 antibodies, for example, anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, for example, nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; inotuzumab, brodalumab, ofatumumab, sirukumab, cliniximab, clazakizumab, fezanukumab, furilukumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, tocilizumab, zalumab;

[0185] Anticoagulants, including warfarin ( TM ), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, edaparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin;

[0186] anti-inflammatory agents, including steroids, e.g., budesonide, nonsteroidal anti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine, mesalamine, olsalamine, 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;

[0187] Immunosuppressants, including mercaptopurines, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus and tacrolimus, inosine monophosphate dehydrogenase inhibitors (IMPDH) such as mycophenolate mofetil, mycophenolate mofetil and azathioprine, and agents designed to suppress cellular immunity while preserving the integrity of the recipient's humoral immunological response, including various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3)) and irradiation. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trade name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name Purinethol; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune; tacrolimus is currently available from Fujisawa under the trade name Prograf; cyclosporine is currently available from Novartis under the trade name Sandimmune and from Abbott under the trade name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the trade name Cellcept and from Novartis under the trade name Myfortic; azathioprine is currently available from Glaxo Smith under the trade name Imuran. Kline; and the antibody is 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

[0188] Guanylate cyclase-C receptor agonists or intestinal secretagogues, such as linaclotide, which is sold under the name Linzess.

[0189] These various agents can be used according to their standard or conventional dosages as indicated in the prescribing information of commercially available forms of the accompanying medications (see also, prescribing information in the 2006 edition of The Physician's Desk Reference), the disclosure of which is incorporated herein by reference.

[0190] IV. Methods of Preparing Compounds

[0191] The compounds may be prepared by any suitable method as would be appreciated by one of ordinary skill in the art. An exemplary suitable method is provided below with reference to specific compounds in the Examples, and may include the following first reaction step according to Scheme 1.

[0192]

[0193] Referring to Scheme 1, a metal-mediated cross-coupling reaction can be used to couple the protected amine precursor 100 with R 1 The group 102 is coupled, the latter comprising "R 6 -linker" group to provide a cross-coupled product 104. In certain embodiments, a metal-mediated cross-coupling reaction can be performed using a transition metal catalyst, such as a palladium catalyst. Exemplary palladium catalysts include, but are not limited to, Pd(0) catalysts (e.g., Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, etc.) or Pd(II) catalysts (e.g., XPhos Pd 2nd or 3rd generation, PdCl2, Pd(OAc)2, etc.). In certain embodiments, the palladium catalyst can be used in combination with another co-catalyst (such as CuI) to promote the cross-coupling reaction, such as in the Sonogoshira reaction. The metal-mediated cross-coupling can also include the use of a base, such as an amine base (e.g., Et3N) or an inorganic base (e.g., Cs2CO3, Na2CO3, K2CO3, etc.) and a solvent (e.g., dimethylformamide). Referring to Scheme 1, X is a suitable group for metal-mediated cross-coupling, such as a halogen or trifluoromethylsulfonate group, and PG is an amine protecting group, which can be selected from, but is not limited to, a 9-fluorenylmethoxycarbonyl ("Fmoc") group, a tert-butyloxycarbonyl ("Boc") group, a trityl ("Tr") group, an allyloxycarbonyl ("Alloc") group, a benzyloxycarbonyl ("Cbz") group, and the like.

[0194] Synthesis of tert-butyl (S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 8 and tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 9

[0195]

[0196] In other schemes herein, intermediates 8 and 9 are referred to as intermediates II and I, respectively.

[0197] Synthesis of N-(tert-Butyloxycarbonyl)-O-(2-nitropyridin-3-yl)-L-serine (3)

[0198] At 0°C to (tert-butoxycarbonyl)- L -serine 2 (5.13 g, 25.0 mmol) in anhydrous DMF (100 mL) was added sodium hydride (2.0 g, 60% in oil, 50 mmol). The resulting solution was stirred at this temperature for 2 hours, and then 3-fluoro-2-nitropyridine 1 (3.60 g, 25.3 mmol) was added. The resulting solution was warmed to ambient temperature over 8 hours and slowly quenched with aqueous HCl (3N, 25 mL) until the pH of the solution was about 4. The reaction solution was extracted with ethyl acetate (3 x 120 mL) and the combined organic layers were washed with brine (40 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a 0-10% gradient of methanol in dichloromethane to provide N -(tert-Butyloxycarbonyl)- O -(2-Nitropyridin-3-yl)- L -Serine 3 (5.35 g, 65%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 - 8.08 (m, 1H), 7.57 (d, J = 3.3 Hz, 2H),5.60 (d, J = 7.9 Hz, 1H), 4.76 (d, J = 7.8 Hz, 1H), 4.64 (dd, J = 9.3, 2.9 Hz, 1H),4.46 (dd, J = 9.3, 3.1 Hz, 1H), 1.46 (s, 9H). MS (ESI, 质荷比 ) Calculated value 327.1066; Found 228.1 [M-Boc+H] + .

[0199] O -(2-aminopyridin-3-yl)- N -(tert-Butyloxycarbonyl)- L -Synthesis of Serine (4)

[0200] Towards N -(tert-Butyloxycarbonyl)- O -(2-Nitropyridin-3-yl)- L-serine 3 (4.81 g, 14.72 mmol) was added to a solution of 5% palladium on carbon (950 mg) in methanol (100 mL). The resulting solution was hydrogenated at 60 PSI for 16 hours in a Parr-Shaker, filtered through celite, and washed with methanol. The filtrate was concentrated under reduced pressure to provide a crude product as a pale yellow solid. O -(2-aminopyridin-3-yl)- N -(tert-Butyloxycarbonyl)- L -serine 4 (4.40 g, >95% yield) was used directly in the next step without purification. MS (ESI, 质荷比 ) Calculated value 297.1325; Found 298.0 [M+H] + .

[0201] Synthesis of tert-butyl (S)-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate (5)

[0202] Towards rough O -(2-aminopyridin-3-yl)- N -(tert-Butyloxycarbonyl)- L -serine 4 (4.40g, 14.72mmol) in anhydrous DMF (300 mL) solution is added diisopropylethylamine (2.09 g, 2.80 mL, 16.19mmol), followed by HATU (6.16 g, 16.19 mmol). The resulting solution is stirred at ambient temperature for 2 days, then water (200 mL) is added, and the aqueous solution is extracted with ethyl acetate (4 x 200 mL). The combined organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography using 0-5% methanol gradient in dichloromethane to provide (S)-(4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazacycloheptatriene-3-yl) tert-butyl carbamate 5 (899 mg, 22% over 2 steps) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ8.86 (s, 1H), 8.16 (dd, J = 4.7, 1.5 Hz, 1H), 7.42 (dd, J = 8.0, 1.5 Hz, 1H),7.08 (dd, J= 8.0, 4.7 Hz, 1H), 5.64 (s, 1H), 4.73 - 4.47 (m, 2H), 4.17 (dd, J =10.7, 9.4 Hz, 1H), 1.46 (s, 9H). MS (ESI, 质荷比 ) Calculated value 279.1219; Found 280.1 [M+H] + .

[0203] Synthesis of tert-butyl (S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate (6)

[0204] To a solution of (S)-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamic acid tert-butyl ester 5 (796 mg, 2.85 mmol) in anhydrous DMF (28 mL) was added anhydrous cesium carbonate (930 mg, 2.85 mmol), followed by iodomethane (368 mg, 162 μL, 2.59 mmol). The resulting solution was stirred at ambient temperature for 2 days, followed by the addition of water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was then washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a residue in a DMF solution (approximately 12 mL). The crude product is purified by reversed-phase HPLC using 0-50% acetonitrile gradient in water (buffered with 0.1% formic acid). The desired fractions are merged, alkalized with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The combined organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide (S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxa-azepine-3-yl) tert-butyl carbamate 6 (434 mg, 57%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.28(dd, J = 4.8, 1.6 Hz, 1H), 7.47 (dd, J = 7.9, 1.6 Hz, 1H), 7.14 (dd, J = 7.9, 4.7Hz, 1H), 5.59 (d, J= 5.2 Hz, 1H), 4.73 - 4.53 (m, 2H), 4.31 - 4.12 (m, 1H), 3.51 (s, 3H), 1.41 (s, 9H). MS (ESI, 质荷比 ) Calculated value 293.1376; Found 194.1 [M-Boc+H] + .

[0205] ( S )-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of ][1,4]oxazacycloheptatriene 6-oxide (7)

[0206] To a solution of (S)-tert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 6 (429 mg, 1.46 mmol) in anhydrous dichloromethane (5 mL) was added mCPBA (730 mg, 77% maximum purity, 2.93 mmol). The resulting solution was stirred at ambient temperature for 20 hours, diluted with dichloromethane (200 mL), and washed with saturated aqueous sodium carbonate solution (20 mL) and saturated sodium thiosulfate solution (20 mL). The resulting organic layer was separated, washed with brine (2 x 30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a 0-5% gradient of methanol in dichloromethane to provide ( S )-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine 6-oxide 7 (303 mg, 67%). MS (ESI, 质荷比 ) Calculated value 309.1325; Found 310.0 [M+H] + The starting material (S)-tert-butyl(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 6 (139 mg, 32%) was partially recovered.

[0207] Synthesis of tert-butyl (S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate (8) and tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate (9)

[0208] Towards( S )-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b To a solution of ][1,4]oxazepine 6-oxide 7 (303 mg, 0.98 mmol) in anhydrous 1,2-dichloroethane (20 mL) was added 4Å molecular sieves (303 mg) followed by n-tetrabutylammonium bromide (474 ​​mg, 1.47 mmol). The reaction solution was stirred at ambient temperature for 10 minutes and then 4-methylbenzenesulfonic anhydride (480 mg, 1.47 mmol) was added. The resulting reaction mixture was then stirred at ambient temperature for 17 hours and heated at 65°C for 8 hours, cooled to ambient temperature, filtered through celite, and washed with dichloromethane (about 100 mL). The filtrate was then washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a 0-10% gradient of methanol in dichloromethane to provide the less polar isomer of (S)-tert-butyl(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 9 as a white solid (67 mg, 18%). 1 H NMR (400 MHz, 二甲基亚砜 - d 6 ) δ 7.59 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz,1H), 7.30 (d, J = 7.0 Hz, 1H), 4.50 - 4.21 (m, 3H), 3.27 (s, 3H), 1.33 (s, 9H). MS (ESI, 质荷比 ) Calculated value 371.0481; Found 372.0 [M+H] +Additional impure fractions were combined and further purified by reverse phase HPLC using a 35-80% acetonitrile gradient in water (buffered with 0.1% formic acid). The desired fractions were combined and lyophilized to provide the higher polar isomer of (S)-tert-butyl (9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 8 as a white solid (85 mg, 23%). 1 H NMR (400 MHz, 二甲基亚砜 - d 6 ) δ 8.19 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 5.2 Hz, 1H), 7.38 -7.27 (m, 1H), 4.51 - 4.32 (m, 3H), 3.32 (s, 3H), 1.35 (s, 9H). MS (ESI, 质荷比 ) Calculated value 371.0481; Found 372.0 [M+H] + The starting material is also partially recovered ( S )-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine 6-oxide 7 (61 mg, 20%).

[0209] ( S )- N -(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypyridineamide 14

[0210]

[0211] Synthesis of tert-butyl (S)-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 11

[0212] Towards( S )-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b[1,4]Oxazepine 6-oxide 7 (24.5 mg, 0.079 mmol) and 8-oxa-2-azaspiro[4.5]decane 10 (14.6 mg, 0.103 mmol) in anhydrous dichloroethane (1 mL) were added diisopropylethylamine (41 mg, 55 μL, 0.317 mmol) followed by PyBrOP (48 mg, 0.103 mmol). The resulting solution was stirred at ambient temperature for 19 hours and then heated at 60 °C for 2 days. All solvents were removed under reduced pressure and the resulting residue was purified by reverse phase HPLC using a gradient of 0-80% acetonitrile in water (buffered with 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate, and the solution was washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide tert-butyl (S)-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 11 (2.8 mg, 8%). MS (ESI, 质荷比 ) Calculated value 432.2373; Found 433.2 [M+H] + .

[0213] ( S )-3-amino-5-methyl-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H Synthesis of )-Keto Hydrochloride 12

[0214] Hydrogen chloride solution (0.5 mL, 4.0 M in dioxane, 2 mmol) was added to a vial containing tert-butyl (S)-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 11 (2.8 mg), and the resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to provide the crude product ( S )-3-amino-5-methyl-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H )-ketone hydrochloride 12 (2.4 mg, >95% yield) was used directly in the next step. MS (ESI, 质荷比) Calculated value 332.1848; Found 333.1 [M+H] + .

[0215] ( S )- N -(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypyridineamide 14

[0216] Towards( S )-3-amino-5-methyl-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H To a solution of 4-phenoxypicolinic acid 13 (2.8 mg, 13 μmol) in anhydrous DMF (0.5 mL) was added diisopropylethylamine (4.2 mg, 5.6 μL, 32 μmol) followed by HATU (4.9 mg, 13 μmol). The resulting solution was stirred at ambient temperature for 16 hours. A drop of water was added to quench the reaction and the resulting solution was directly purified by reverse phase HPLC using a 40-100% acetonitrile gradient in water (buffered with 0.1% formic acid). The desired fractions were combined and diluted with ethyl acetate (60 mL). The solution was washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide ( S )-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydropyrido[3,2- b [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypicolinamide 14 (2.2 mg, 64%). MS (ESI, 质荷比 ) Calculated value 529.2325; Found 530.2 [M+H] + .

[0217] ( S )- N -(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypyridineamide 18

[0218]

[0219] Synthesis of tert-butyl (S)-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 16

[0220] To a solution of tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 9 (32 mg, 85 μmol), Pd2(dba)3 (7.8 mg, 8.5 μmol), xantphos (4.9 mg, 8.5 μmol) and cesium carbonate (56 mg, 170 μmol) in anhydrous 1,4-dioxane (1 mL) was added 7-oxa-2-azaspiro[3.5]nonane (13 mg, 102 μmol). The reaction solution was purged with nitrogen for 1 minute, sealed and heated at 90 °C for 16 hours. The reaction solution was cooled to ambient temperature and diluted with ethyl acetate (50 mL). The resulting solution was washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC using a 30-80% acetonitrile gradient in water (buffered with 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide tert-butyl (S)-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonane-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxaazepine-3-yl)carbamate 16 (35 mg, >95% yield) as a light liquid. MS (ESI, 质荷比 ) Calculated value 418.2216; Found 419.2 [M+H] + .

[0221] ( S )-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H Synthesis of )-Keto Hydrochloride 17

[0222] Hydrogen chloride solution (0.5 mL, 4M in dioxane, 2 mmol) was added to a vial containing tert-butyl (S)-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 16 (35 mg, 0.085 mmol) and the reaction mixture was stirred at ambient temperature for 16 h. All solvents were removed under reduced pressure to provide the azetidine ring-opening byproduct and the desired product ( S )-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H )-ketone hydrochloride 17 was used in the next step without purification. MS (ESI, 质荷比 ) Calculated value 318.1692; Found 319.1 [M+H] + .

[0223] ( S )- N -(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypyridineamide 18

[0224] The crude product ( S )-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H )-Keto hydrochloride 17 and 4-phenoxypicolinic acid 13 (27.5 mg, 0.128 mmol) were dissolved in anhydrous DMF (1 mL) and diisopropylethylamine (55 mg, 74 μL, 0.425 mmol) was added followed by HATU (48.5 mg, 0.128 mmol). The resulting solution was stirred at ambient temperature for 16 hours. Two drops of water were added to quench the reaction and the resulting solution was directly purified by reverse phase HPLC using a 40-80% acetonitrile gradient in water (buffered with 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate (60 mL) and the resulting organic solution was washed with saturated aqueous sodium bicarbonate solution (5 mL), brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting product was dissolved in 80% acetonitrile / water and lyophilized to provide (S )- N -(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2- b [1,4]oxazepine-3-yl)-4-phenoxypicolinamide 18 (5.7 mg, 13% over 2 steps). MS (ESI, 质荷比 ) Calculated value 515.2169; Found 516.1 [M+H] + .

[0225] General Procedure for the Preparation of 9-Substituted Pyridooxazepines

[0226]

[0227] Exemplary 9-substituted pyridooxazazepine compounds are prepared according to the general procedure described above. Universal intermediate II can be coupled to a variety of groups by metal-catalyzed (e.g., palladium-catalyzed) cross-coupling reactions known to those skilled in the art. Specifically, according to this general scheme, alkynyl groups can be easily coupled to pyridooxazazepine rings by adjusting the procedures given below. As an example, compounds I-14, I-15, and I-16 were synthesized by this method.

[0228] Step 1: Synthesis of intermediate (III)

[0229] To intermediate II (0.1 mmol, 1 equivalent (eq)), substituted acetylene (0.2-0.3 mmol, 2-3 equivalents), Pd(PPh3)4 (0.01 mmol, 0.1 equivalent) and CuI (0.01 mmol, 0.1 equivalent) in anhydrous DMF (1 mL) in a vial was added Et3N (0.4 mmol, 4 equivalents). The reaction solution was purged with nitrogen for 1 minute, then sealed and heated at 70°C for 14 to 24 hours. The reaction solution was cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse phase HPLC (mobile phase A: water containing 0.1% HCOOH; mobile phase B: acetonitrile containing 0.1% HCOOH) to provide intermediate III.

[0230] Step 2: Synthesis of intermediate (IV)

[0231] Intermediate III (1 equivalent) is dissolved in dichloromethane, then TFA (concentration: 10% in dichloromethane) or HCl (40 equivalents, 4N in dioxane) is added. The resulting solution is stirred at ambient temperature until all starting materials disappear (monitored by reversed-phase HPLC). All solvents are removed under reduced pressure to provide a crude product of intermediate IV, which is directly used in the next step.

[0232] Step 3: Synthesis of final product (V)

[0233] Intermediate IV (1 equivalent), corresponding acid (1.2 equivalents) and diisopropylethylamine (5 equivalents) are dissolved in DMF (concentration 0.05M to 0.1M), and HATU (1.2 equivalents) is then added. The resulting solution is stirred at ambient temperature for 14 to 24 hours. The reaction solution is added to saline and ethyl acetate. The organic layer is separated and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography or reversed phase HPLC (mobile phase A: water containing 0.1% HCOOH; mobile phase B: acetonitrile containing 0.1% HCOOH) to provide the final product (V).

[0234] ( S )- N -(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypyridineamide 21

[0235]

[0236] ( S )-3-amino-9-bromo-5-methyl-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H Synthesis of )-Keto Hydrochloride 20

[0237] Hydrogen chloride solution (1 mL, 4M in dioxane, 4 mmol) was added to a vial containing tert-butyl (S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 8 (52 mg, 0.139 mmol). The resulting solution was stirred at ambient temperature for 19 hours. All solvents were removed under reduced pressure to provide ( S )-3-amino-9-bromo-5-methyl-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H)-Ketone hydrochloride 20 (43 mg, 100%). MS (ESI, 质荷比 ) Calculated value 270.9956; Found 272.0 [M+H] + .

[0238] ( S )- N -(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine-3-yl)-4-phenoxypyridineamide 21

[0239] Towards( S )-3-amino-9-bromo-5-methyl-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H To a solution of 2-oxo-1-pyridinecarboxylic acid 13 (45 mg, 0.209 mmol) in anhydrous DMF (1.4 mL) was added diisopropylethylamine (135.2 mg, 0.18 mL, 1.05 mmol) followed by HATU (79.5 mg, 0.209 mmol). The resulting solution was stirred at ambient temperature for 16 hours. Water (0.1 mL) was then added and the solution was directly purified by reverse phase HPLC using a 37-90% acetonitrile gradient in water (buffered with 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate (100 mL) and the resulting solution was washed with saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide ( S )- N -(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypicolinamide 21 (50 mg, 77%). MS (ESI, 质荷比 ) Calculated value 468.0433; Found 469.0 [M+H] + .

[0240] ( S )- N -(9-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypyridineamide 23 (I-15)

[0241]

[0242] Towards( S )- N -(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b To a solution of [1,4]oxazepine-3-yl)-4-phenoxypicolinamide 21 (25 mg, 53 μmol), 3-ethynyloxetane-3-ol 22 (15.7 mg, 0.160 mmol), CuI (1 mg, 5.3 μmol) and Pd(PPh3)4 (6.2 mg, 5.3 μmol) in anhydrous DMF (1 mL) was added triethylamine (32.4 mg, 45 μL, 0.320 mmol). The reaction solution was purged with nitrogen for 1 minute, then sealed and heated at 70°C for 16 hours, cooled to ambient temperature and diluted with ethyl acetate (60 mL). The diluted reaction mixture was then washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC using a gradient of 27-67% acetonitrile in water (buffered with 0.1% formic acid). The desired fractions were combined and lyophilized to provide ( S )- N -(9-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypyridineamide 23 (8.5 mg, 33%). MS (ESI, 质荷比 ) Calculated value 486.1539; Found 487.1 [M+H] + .

[0243] ( S )- N -(9-((4-Hydroxytetrahydro-2 H -pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of [1,4]oxazepine-3-yl)-4-phenoxypyridineamide 25 (I-16)

[0244]

[0245] Towards( S )- N -(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b[1,4]oxazacycloheptatrien-3-yl)-4-phenoxypicolinamide 21 (24 mg, 51 μmol), 4-ethynyltetrahydro-2 H To a solution of -pyran-4-ol 24 (19.4 mg, 0.153 mmol), CuI (1 mg, 5.1 μmol) and Pd(PPh3)4 (5.9 mg, 5.1 μmol) in anhydrous DMF (1 mL) was added triethylamine (31 mg, 43 μL, 0.307 mmol). The reaction mixture was then purged with nitrogen for 1 minute, sealed and heated at 70°C for 16 hours, cooled to ambient temperature and diluted with ethyl acetate (60 mL). The reaction mixture was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC using a 27-67% acetonitrile gradient in water (buffered with 0.1% formic acid). The desired fractions were combined and lyophilized to provide ( S )- N -(9-((4-Hydroxytetrahydro-2 H -pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypicolinamide 25 (13.6 mg, 52%). MS (ESI, 质荷比 ) Calculated value 514.1852; Found 515.1 [M+H] + .

[0246] ( S )- N -(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of [1,4]oxazepine-3-yl)-4-phenoxypyridineamide 29 (I-14)

[0247]

[0248] Synthesis of tert-butyl (S)-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 27

[0249] To a solution of (S)-tert-butyl (9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 8 (32 mg, 0.086 mmol) and 2-methylbut-3-yn-2-ol 26 (22 mg, 0.257 mmol) in anhydrous DMF (1 mL) was added Pd(PPh3)4 (9.9 mg, 8.6 μmol), CuI (1.6 mg, 8.6 μmol) and triethylamine (52 mg, 72 μL, 0.515 mmol). The reaction mixture was then purged with nitrogen for 1 min, sealed and heated at 70 °C for 22 h, cooled to ambient temperature and diluted with ethyl acetate (80 mL). The resulting organic mixture was washed with water (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC using a 20-70% acetonitrile gradient in water (buffered with 0.1% formic acid). The desired fractions were combined and diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide (S)-tert-butyl (9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 27 (32 mg, >95% yield). MS (ESI, 质荷比 ) Calculated value 375.1794; Measured value 320.0 [M- t Bu+H] + .

[0250] ( S )-3-amino-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydropyrido[3,2- b Synthesis of ][1,4]oxazacycloheptatriene-4(5H)-one hydrochloride 28

[0251] To a solution of tert-butyl (S)-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 27 (32 mg, 0.086 mmol) in anhydrous 1,4-dioxane (2 mL) was added hydrogen chloride solution (0.2 mL, 4M in dioxane, 0.8 mmol). The reaction mixture was stirred at ambient temperature for 15 hours, then an additional amount of hydrogen chloride solution (0.6 mL, 4M in dioxane, 2.4 mmol) was added and the reaction mixture was stirred for an additional 9 hours. All solvents were removed under reduced pressure to provide (S)-tert-butyl (9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 27 (32 mg, 0.086 mmol) in anhydrous 1,4-dioxane (2 mL). S )-3-amino-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H )-ketone hydrochloride 28 (27 mg, 100%) was used directly in the next step. MS (ESI, 质荷比 ) Calculated value 275.1270; Found 276.1 [M+H] + .

[0252] ( S )- N -(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypyridineamide 29

[0253] Towards( S )-3-amino-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H To a solution of 2-oxo-1-pyridinecarboxylic acid 13 (28 mg, 0.129 mmol) in anhydrous DMF (1.4 mL) was added diisopropylethylamine (55.5 mg, 74 μL, 0.429 mmol) followed by HATU (48.9 mg, 0.129 mmol). The resulting reaction mixture was stirred at ambient temperature for 14 hours. A drop of water was added and the solution was directly purified by reverse phase HPLC using a 40-80% acetonitrile gradient in water (buffered with 0.1% formic acid). The desired fractions were combined and lyophilized to provide (S )- N -(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]oxazepine-3-yl)-4-phenoxypicolinamide 29 (22.1 mg, 55%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.96(d, J = 7.1 Hz, 1H), 8.46 (dd, J = 5.6, 0.5 Hz, 1H), 8.23 ​​(d, J = 5.0 Hz, 1H), 7.62(dd, J = 2.6, 0.5 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.31 - 7.22 (m, 1H), 7.19 (d, J =5.0 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.97 (dd, J = 5.6, 2.5 Hz, 1H), 5.03 (dt, J =11.3, 7.2 Hz, 1H), 4.89 (dd, J = 9.6, 7.2 Hz, 1H), 4.39 (dd, J = 11.3, 9.6 Hz, 1H), 3.52 (s, 3H), 1.63 (s, 6H). MS (ESI, 质荷比 ) Calculated value 472.1747; Found 473.1 [M+H] + .

[0254] General Procedure for the Preparation of 7-Substituted Pyridooxazepines Compound VIII

[0255] Method A:

[0256]

[0257] 7-substituted pyridooxazepine compounds are prepared according to the general procedure of Method A given above. Universal intermediate I can be coupled to a variety of groups by metal-catalyzed (e.g., palladium-catalyzed) cross-coupling reactions known to those skilled in the art. Specifically, according to this general scheme, alkynyl groups can be easily coupled to pyridooxezepine rings by adjusting the following procedures. As examples, compounds prepared by Method A include I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-41, I-42, I-43, I-44, I-45, I-46, and I-47.

[0258] (S)-N-(7-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-32)

[0259]

[0260] This compound is derived from the corresponding aldehyde, which is obtained by oxidation of (S)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide. MS (ESI, m / z) Calcd. 506.1766; Found [M+1] + 507.1. 1H NMR (400 MHz, chloroform-d) δ (ppm) 8.93 (d, J = 7.0 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.49 (d, J= 8.1 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.10 - 7.05 (m, 2H), 6.96 (dd, J =5.6, 2.5 Hz, 1H), 5.25 (dd, J = 48.3,10.7 Hz, 1H), 5.02 (dt, J = 11.4, 6.9Hz, 1H), 4.79 (ddd, J = 9.7, 6.8, 1.3 Hz, 1H), 4.37 (dd, J = 11.4, 9.7 Hz,1H), 3.53 (s, 3H), 1.62 - 1.59 (m, 3H), 1.55 -1.51 (m, 3H).

[0261] N-((3S)-5-methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-33)

[0262]

[0263] MS (ESI, m / z) calcd. 512.1308; found [M+1] + 513.0. 1H NMR (400 MHz, chloroform-d)δ(ppm) 9.03 - 8.89 (m, 1H), 8.45 (dt, J = 5.7, 0.6 Hz, 1H), 7.61 (dt, J =2.6, 0.7 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.46 - 7.38 (m, 2H), 7.35 (dd, J =8.1, 4.8Hz, 1H), 7.28 - 7.24 (m, 1H), 7.10 - 7.04 (m, 2H), 6.96 (dd, J = 5.6,2.5 Hz, 1H), 5.18 - 4.99 (m, 1H), 4.94 (t, J = 6.3 Hz, 1H), 4.81 (dt, J =9.7, 7.2 Hz,1H), 4.43 - 4.31 (m, 1H), 3.54 - 3.46 (m, 3H), 3.23 - 2.86 (m,1H).

[0264] (S)-5-(2-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-34)

[0265]

[0266] MS (ESI, m / z) calcd. 478.1765; found [M+1] + 479.1. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 12.18 (s, 1H), 8.10 (d, J = 7.0 Hz, 1H), 7.44 (s, 1H), 7.27 (d, J =8.1 Hz, 1H), 7.26 - 7.18 (m, 2H), 7.10 - 6.97 (m, 2H), 5.01 (dt, J = 11.4,7.0 Hz,1H), 4.75 (dd, J = 9.8, 7.0 Hz, 1H), 4.32 (dd, J = 11.4, 9.8 Hz, 1H), 4.20 (s, 2H), 3.50 (s, 3H), 1.64 (s, 6H).

[0267] (S)-5-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-35)

[0268]

[0269] MS (ESI, m / z) calcd. 478.1765; found [M+1] + 479.1.

[0270] (S)-5-Benzyl-N-(7-((3,3-difluoro-1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-36)

[0271]

[0272] MS (ESI, m / z) calcd. 508.1671; found [M+1] + 509.5. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 12.33 (s, 1H), 8.11 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H),7.31 - 7.17 (m, 6H), 5.02 (dt, J = 11.3, 6.9 Hz, 1H), 4.73 (dd, J = 9.8, 6.9Hz, 1H), 4.33 (dd, J = 11.4, 9.8 Hz, 1H), 4.14 (s, 2H), 3.51 (s, 1H), 3.46 (s,3H), 3.27 - 3.11 (m, 2H), 2.99 (dtd, J = 13.0, 11.7, 4.0 Hz, 2H).

[0273] 5-Benzyl-N-((3S)-5-methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-37)

[0274]

[0275] MS (ESI, m / z) calcd. 500.1420; found [M+1] + 501.5. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 9.20 (s, 0.5H), 8.11 (dd, J = 6.9, 3.2 Hz, 1H), 7.47 (dd, J = 8.1, 1.2Hz, 1H), 7.36 - 7.29 (m, 3H), 7.28 (d, J = 4.0 Hz, 2H), 6.27 (q, J = 5.7 Hz,0.5H), 5.13 - 4.89 (m, 2H), 4.78 (ddd, J = 9.8, 6.8, 3.0 Hz, 1H), 4.35 (ddd,J = 11.3, 9.9, 1.2 Hz, 1H), 4.16 (s, 2H), 3.48 (m, 3H).

[0276] (S)-4-Fluoro-1-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide (I-38)

[0277]

[0278] MS (ESI, m / z) calcd 495.1718; found [M+1] + 496.5. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 7.64 (d, J = 6.4 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.25 - 7.16 (m,4H),7.07 - 6.98 (m, 2H), 5.17 (s, 2H), 5.00 (dt, J = 11.3, 6.7 Hz, 1H), 4.82 (dd, J = 9.7, 6.9 Hz, 1H), 4.28 (dd, J = 11.3, 9.7 Hz, 1H), 3.49 (s, 3H), 1.62 (s, 6H).

[0279] (S)-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-(3-fluorophenoxy)picolinamide (I-39)

[0280]

[0281] This compound is obtained from ( S Desilylation of )-4-(3-fluorophenoxy)-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)picolinamide. MS (ESI, m / z) Calcd. 432.1234; Found [M+1] + 433.1. 1 H NMR (400 MHz, chloroform-d) δ(ppm) 8.94 (d, J = 7.0 Hz, 1H), 8.49 (dd, J = 5.6, 0.5 Hz, 1H), 7.63 (dd, J =2.5, 0.5 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.02 - 6.94(m, 2H), 6.88 (ddt, J = 8.1, 2.2, 0.8 Hz, 1H), 6.82 (dt, J = 9.3, 2.3 Hz,1H), 5.03 (dt, J = 11.4, 6.9 Hz, 1H), 4.79 (dd, J = 9.7, 6.9 Hz, 1H), 4.38 (dd, J =11.4, 9.7 Hz, 1H), 3.54 (s, 3H), 3.17 (s, 1H).

[0282] (S)-4-Fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(prop-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide (I-41)

[0283]

[0284] MS (ESI, m / z) calcd. 451.1456; found [M+1] + 452.1. 1H NMR (400 MHz, chloroform-d)δ(ppm) 7.66 (d, J = 6.4 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 1.2Hz, 1H), 7.21 (td, J = 4.3, 1.4 Hz, 3H), 7.09 - 6.97 (m, 2H), 5.19 (s, 2H),5.01(dt, J = 11.2, 6.7 Hz, 1H), 4.83 (dd, J = 9.7, 7.0 Hz, 1H), 4.29 (dd, J =11.3, 9.7 Hz, 1H), 3.51 (s, 3H), 2.08 (s, 3H).

[0285] (S)-4-Fluoro-1-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-4-oxo-7-(prop-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide (I-42)

[0286]

[0287] MS (ESI, m / z) calcd. 452.1408; found [M+1] + 453.1. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 7.85 - 7.75 (m, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.50 (d, J = 4.7 Hz,1H), 7.44 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.06 - 7.00 (m, 1H), 6.94 -6.88 (m, 1H), 5.28 (s, 2H), 5.02 (dt, J = 11.2, 6.7 Hz, 1H), 4.83 (dd,J = 9.7, 6.9 Hz, 1H), 4.29 (dd, J = 11.2, 9.7 Hz, 1H), 3.52 (s, 3H), 2.09 (s, 3H).

[0288] N-((3S)-5-methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxy-3-methylbut-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-43)

[0289]

[0290] MS (ESI, m / z) calcd. 526.1464; found [M+1] + 527.3. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 9.01 (dd, J = 23.0, 6.7 Hz, 1H), 8.44 (dt, J = 5.6, 0.7 Hz, 1H), 7.62 (ddd, J = 3.3, 2.5, 0.5 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.45 - 7.38 (m,2H),7.30 - 7.26 (m, 1H), 7.25 - 7.21 (m, 1H), 7.07 (dq, J = 7.3, 1.0 Hz, 2H), 6.94 (ddd, J = 5.6, 2.5, 1.5 Hz, 1H), 5.19 (ddt, J = 51.2, 11.3, 6.7 Hz, 1H),4.85(ddd, J = 19.7, 9.7, 6.7 Hz, 1H), 4.35 (ddd, J = 11.5, 9.7, 1.8 Hz, 1H),3.49 - 3.37 (m, 3H), 1.80 - 1.72 (m, 3H).

[0291] (S)-N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-44)

[0292]

[0293] MS (ESI, m / z) calcd 470.1590; found [M+1] + 471.1. 1H NMR (400 MHz, chloroform-d)δ(ppm) 8.92 (d, J = 7.0 Hz, 1H), 8.44 (dd, J = 5.6, 0.5 Hz, 1H), 7.61 (dd, J= 2.5, 0.5 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.28 (d, J=8.1 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.09 - 7.04 (m, 2H), 6.95 (dd, J = 5.6,2.6 Hz, 1H), 5.01 (dt, J = 11.4, 7.0 Hz, 1H), 4.86 (dq, J = 7.4, 5.6 Hz, 4H), 4.78 (dd, J = 9.7, 6.9 Hz, 1H), 4.34 (dd, J = 11.4, 9.7 Hz, 1H), 4.11 (tt, J =8.5, 7.4 Hz, 1H), 3.52 (s, 3H).

[0294] (S)-N-(7-(3,3-difluoro-3-(oxetane-3-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-45)

[0295]

[0296] MS (ESI, m / z) calcd. 520.1558; found [M+1] + 521.1. 1H NMR (400 MHz, chloroform-d)δ(ppm) 8.92 (d, J = 6.9 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 2.5Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.46 - 7.37 (m, 3H), 7.29 - 7,23 (m, 1H),7.11 -7.04 (m, 2H), 6.96 (dd, J = 5.6, 2.5 Hz, 1H), 5.02 (dt, J = 11.4, 6.8Hz, 1H), 4.88 - 4.75 (m, 5H), 4.39 (dd, J = 11.4, 9.8 Hz, 1H), 3.73 (dtdd, J= 14.6,12.5, 8.1, 6.5 Hz, 1H), 3.54 (s, 3H).

[0297] N-((3S)-7-(3-amino-4,4,4-trifluoro-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-46)

[0298]

[0299] MS (ESI, m / z) calcd. 525.1624; found [M+1] + 526.0. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 8.91 (d, J = 7.0 Hz, 1H), 8.44 (d, J = 5.6 Hz, 1H), 7.61 (d, J = 2.4Hz, 1H), 7.50 - 7.37 (m, 3H), 7.31 (d, J = 8.2 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.10 -7.03 (m, 2H), 6.95 (dd, J = 5.6, 2.5 Hz, 1H), 5.00 (dt, J = 11.4, 6.9Hz, 1H), 4.78 (dd, J = 9.7, 6.8 Hz, 1H), 4.35 (dd, J = 11.4, 9.7 Hz, 1H), 3.52 (s, 3H), 1.92 (s, 2H), 1.66 (s, 3H).

[0300] (S)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-47)

[0301]

[0302] MS (ESI, m / z) calcd. 498.1903; found [M+1] + 499.1. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 8.92 (d, J = 7.0 Hz, 1H), 8.44 (dd, J = 5.6, 0.5 Hz, 1H), 7.61 (dd, J= 2.5, 0.5 Hz, 1H), 7.47 - 7.37 (m, 3H), 7.29 - 7.22 (m, 2H), 7.10 - 7.03 (m,2H), 6.95 (dd, J = 5.6, 2.5 Hz, 1H), 5.01 (dt, J = 11.3, 6.9 Hz, 1H), 4.78(dd, J = 9.7, 6.9 Hz, 1H), 4.33 (dd, J = 11.4, 9.7 Hz, 1H), 3.96 (ddd, J =11.7,5.3, 3.8 Hz, 2H), 3.59 - 3.49 (m, 5H), 2.88 (tt, J = 8.7, 4.1 Hz, 1H),1.98 - 1.87 (m, 2H), 1.81 (ddt, J = 13.7, 9.2, 4.4 Hz, 2H).

[0303] Step 1: Synthesis of intermediate (VI)

[0304] To intermediate I (0.1 mmol, 1 eq.), substituted acetylene (0.2-0.3 mmol, 2 to 3 eq.), Pd(PPh3)4 (0.01 mmol, 0.1 eq.) and CuI (0.01 mmol, 0.1 eq.) in anhydrous DMF (1 mL) in a vial was added Et3N (0.4 mmol, 4 eq.). The reaction solution was purged with nitrogen for 1 minute, then sealed and heated at 70°C for 14 to 24 hours. The reaction solution was cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse phase HPLC (mobile phase A: water containing 0.1% HCOOH; mobile phase B: acetonitrile containing 0.1% HCOOH) to provide intermediate VI.

[0305] Step 2: Synthesis of intermediate (VII)

[0306] Intermediate VI (1 equivalent) is dissolved in dichloromethane, then TFA (concentration: 10% in dichloromethane) or HCl (40 equivalents, 4N in dioxane) is added. The resulting solution is stirred at ambient temperature until all starting materials disappear (monitored by reversed-phase HPLC). All solvents are removed under reduced pressure to provide a crude product of intermediate VII, which is directly used in the next step.

[0307] Step 3: Synthesis of final product (VIII)

[0308] Intermediate VII (1 equivalent), corresponding acid (1.2 equivalents) and diisopropylethylamine (5 equivalents) are dissolved in DMF (concentration 0.05M to 0.1M), and HATU (1.2 equivalents) is then added. The resulting solution is stirred at ambient temperature for 14 to 24 hours. The reaction solution is added to saline and ethyl acetate. The organic layer is separated and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography or reversed-phase HPLC (mobile phase A: water containing 0.1% HCOOH; mobile phase B: acetonitrile containing 0.1% HCOOH) to provide final product (VIII).

[0309] Exemplary 7-substituted pyridooxazepine compounds were also prepared according to the general procedure Method B described below.

[0310] Method B:

[0311]

[0312] Step 1: Synthesis of Intermediate IX

[0313] Intermediate I was dissolved in 10% trifluoroacetic acid / dichloromethane (0.1 M) and stirred at room temperature for about 3 hours. All solvents were removed under reduced pressure to provide a crude trifluoroacetate salt of IX, which was used directly in the next step. MS (ESI, m / z) calculated value 270.9956; found value [M+1] + 271.9.

[0314] Step 2: Synthesis of intermediate X

[0315] Intermediate IX (1 equivalent), corresponding acid (1.2 equivalents) and diisopropylethylamine (5 equivalents) are dissolved in DMF (concentration 0.05M to 0.1M), and HATU (1.2 equivalents) is then added. The resulting solution is stirred at ambient temperature for 14 to 24 hours. The reaction solution is added to saline and ethyl acetate. The organic layer is separated and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography or reversed-phase HPLC (mobile phase A: water containing 0.1%HCOOH; mobile phase B: acetonitrile containing 0.1%HCOOH) to provide intermediate (X).

[0316] Step 2: Synthesis of final product VIII

[0317] To intermediate X (0.1 mmol, 1 eq.), substituted acetylene (0.2 to 0.3 mmol, 2 to 3 eq.), Pd(PPh3)4 (0.01 mmol, 0.1 eq.) and CuI (0.01 mmol, 0.1 eq.) in anhydrous DMF (1 mL) in a vial was added Et3N (0.4 mmol, 4 eq.). The reaction solution was purged with nitrogen for 1 minute, then sealed and heated at 70°C for 14 to 24 hours. The reaction solution was cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse phase HPLC (mobile phase A: water containing 0.1% HCOOH; mobile phase B: acetonitrile containing 0.1% HCOOH) to provide the final product VIII.

[0318] Compounds synthesized by Method B include compounds I-17, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30 and I-40.

[0319] ((S)-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-17)

[0320]

[0321] MS (ESI, m / z) calcd 486.1539; found [M+1] + 487.1.

[0322] (S)-4-(4-Fluorophenoxy)-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)picolinamide (I-19)

[0323]

[0324] MS (ESI, m / z) calcd. 504.1445; found [M+1] + 505.1.

[0325] (S)-N-(7-((3-fluorooxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2,b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-20)

[0326]

[0327] To a solution of ((S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (9.5 mg, 0.0195 mmol) in anhydrous dichloromethane (1 mL) at -78 °C was added Deoxo-Fluor (8.6 mg, 7.2 uL, 0.039 mmol). The resulting solution was stirred at this temperature for 30 minutes, then additional Deoxo-Fluor (4.3 mg, 3.6 uL, 0.020 mmol) was added and stirred for another 15 minutes. Saturated sodium bicarbonate solution (0.1 mL) was added, followed by dichloromethane (60 mL). The solution was washed with water (15 mL), washed with brine (15 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (40-70% acetonitrile in water containing 0.1% formic acid / ). The desired fractions were combined, diluted with ethyl acetate, washed with a small amount of saturated sodium bicarbonate aqueous solution, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide (S)-N-(7-((3-fluorooxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2,b][1,4]oxazazepine-3-yl)-4-phenoxypyridineamide (2.5 mg, 26%) as a white solid. MS (ESI, m / z) calculated value 488.1496; found value [M+1] + 489.1. 1 H NMR (400MHz, chloroform-d) δ (ppm) 8.98 - 8.87 (m, 1H), 8.48 - 8.37 (m, 1H), 7.64 - 7.52(m, 1H), 7.50 (d, J = 8.1 Hz,1H), 7.46 - 7.39 (m, 2H), 7.39 - 7.33 (m, 1H), 7.08 (dd, J = 2.0, 1.3 Hz, 1H), 7.07 (dd, J = 2.1, 1.0 Hz, 1H), 7.05 - 7.01(m, 1H), 6.96 (dd, J = 5.6, 2.6 Hz,1H), 5.12 - 4.86 (m, 5H), 4.79 (dd, J =9.7, 6.8 Hz, 1H), 4.38 (dd, J = 11.4, 9.7 Hz, 1H), 3.55 (m, 3H).

[0328] (S)-4-(3-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)picolinamide (I-21)

[0329]

[0330] MS (ESI, m / z) calcd. 490.1652; found [M+1] + 491.1. 1 H NMR (400 MHz, chloroform-d)δ(ppm) δ 8.93 (d, J = 7.0 Hz, 1H), 8.48 (dd, J = 5.6, 0.6 Hz, 1H), 7.62 (dd,J = 2.5, 0.5 Hz, 1H), 7.38 (td, J = 8.3, 6.5 Hz, 1H), 7.29 (s, 1H), 7.01 -6.92 (m, 2H), 6.87 (ddt, J = 8.2, 2.2, 0.8 Hz, 1H), 6.81 (dt, J = 9.4, 2.4Hz, 1H), 5.02 (dt, J = 11.4, 7.0 Hz, 1H), 4.83 - 4.71 (m, 1H), 4.34 (dd, J =11.4, 9.7 Hz, 1H), 3.53 (s, 3H), 1.64 (s, 6H).

[0331] (S)-4-(3-Fluorophenoxy)-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)picolinamide (I-22)

[0332]

[0333] MS (ESI, m / z) calcd. 504.1445; found [M+1] + 505.1. 1H NMR (400 MHz, chloroform-d)δ(ppm) 9.01 - 8.86 (m, 1H), 8.53 - 8.41 (m, 1H), 7.65 - 7.54 (m, 1H), 7.53 -7.46 (m, 1H), 7.38 (td, J = 8.3, 6.5 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.14 -6.92(m, 2H), 6.87 (ddt, J = 8.2, 2.3, 0.8 Hz, 1H), 6.84 - 6.78 (m, 1H), 5.06(dt, J = 11.4, 6.9 Hz, 1H), 4.97 (td, J = 6.2, 5.8, 0.9 Hz, 2H), 4.86 - 4.76(m, 3H), 4.71 (dt, J = 6.9, 0.7 Hz, 1H), 4.37 (dd, J = 11.4, 9.7 Hz, 1H), 3.54(d, J = 13.5 Hz, 3H).

[0334] (S)-N-(7-((3-fluorooxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-(3-fluorophenoxy)picolinamide (I-23)

[0335]

[0336] To a solution of (S)-4-(3-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)picolinamide (12.4 mg, 0.0246 mmol) in anhydrous dichloromethane (1 mL) at -78°C was added Deoxo-Fluor (16.3 mg, 14 uL, 0.0737 mmol). The resulting solution was stirred at this temperature for 30 minutes, then saturated sodium bicarbonate solution (0.2 mL) was added, followed by dichloromethane (80 mL). The solution was washed with water (15 mL), brine (15 mL) and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (40-70% acetonitrile in water containing 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate, washed with a small amount of saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide (S)-N-(7-((3-fluorooxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-(3-fluorophenoxy)picolinamide (4.7 mg, 38%) as a white solid. MS (ESI, m / z) calcd 506.1402; found [M+1] + 507.0. 1 H NMR (400 MHz, chloroform-d) δ(ppm) 8.99 - 8.85 (m, 1H), 8.53 - 8.41 (m,1H), 7.67 - 7.60 (m, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.03- 6.92 (m, 2H), 6.92 - 6.85 (m, 1H), 6.85 - 6.79 (m, 1H), 5.10 - 4.88 (m, 5H), 4.81 (dd, J = 9.7, 6.8 Hz, 1H), 4.39 (dd, J = 11.4, 9.7 Hz, 1H), 3.65 - 3.40(m, 3H).

[0337] (S)-5-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-24)

[0338]

[0339] MS (ESI, m / z) calcd 460.1859; found [M+1] + 461.1. 1 H NMR (400 MHz, methanol-d4) δ (ppm)7.61 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.35 - 7.15(m, 5H), 5.03 (dd, J = 11.5, 7.1 Hz, 1H), 4.67 (dd, J = 9.8, 7.1 Hz, 1H), 4.51 (dd, J = 11.6, 9.8 Hz, 1H), 4.17 (s, 2H), 3.45 (s, 3H), 1.58 (s, 6H).

[0340] (S)-5-Benzyl-N-(7-((3-hydroxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-25)

[0341]

[0342] MS (ESI, m / z) calcd. 474.1652; found [M+1] + 475.1. 1 H NMR (400 MHz, methanol-d4) δ(ppm) 7.64 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.36 - 7.20(m, 5H), 5.04 (dd, J = 11.5, 7.0 Hz, 1H), 4.89 (d, J = 0.9 Hz, 2H), 4.73 -4.69 (m, 2H), 4.67 (dd, J = 7.2, 2.7 Hz, 1H), 4.52 (dd, J = 11.6, 9.8 Hz, 1H), 4.16 (s, 2H), 3.46 (s, 3H).

[0343] (S)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-26)

[0344]

[0345] MS (ESI, m / z) calcd. 484.1747; found [M+1] + 485.1. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 8.93 (d, J = 7.0 Hz, 1H), 8.44 (d, J = 5.6 Hz, 1H), 7.61 (d, J = 2.5Hz, 1H), 7.50 - 7.37 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.11 -7.03 (m, 2H), 6.95 (dd, J = 5.6, 2.5 Hz, 1H), 5.03 (dt, J = 11.4, 6.9Hz, 1H), 4.79 (dd, J = 9.7, 7.0 Hz, 1H), 4.35 (dd, J = 11.4, 9.7 Hz, 1H), 3.52 (s, 3H), 2.65 - 2.52 (m, 2H), 2.44 (s, 1H), 2.40 - 2.30 (m, 2H), 1.96 -1.85 (m, 2H).

[0346] (S)-4-(4-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)picolinamide (I-27)

[0347]

[0348] MS (ESI, m / z) calcd. 490.1652; found [M+1] + 491.1. 1H NMR (400 MHz, chloroform-d)δ(ppm) 8.92 (d, J = 7.0 Hz, 1H), 8.45 (dd, J = 5.6, 0.6 Hz, 1H), 7.57 (dd, J= 2.6, 0.5 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.14-7.08 (m, 2H), 7.08 - 7.02 (m, 2H), 6.93 (dd, J = 5.6, 2.6 Hz, 1H), 5.01 (dt,J = 11.3, 7.0 Hz, 1H), 4.82 - 4.72 (m, 1H), 4.34 (dd, J = 11.4, 9.7 Hz, 1H), 3.52 (d, J = 1.3 Hz, 3H).

[0349] (S)-4-(2-Fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)picolinamide (I-28)

[0350]

[0351] MS (ESI, m / z) calcd. 490.1652; found [M+1] + 491.1. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 8.95 (d, J = 7.0 Hz, 1H), 8.48 (dd, J = 5.6, 0.5 Hz, 1H), 7.59 (dt, J= 2.6, 0.6 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.30 - 7.23 (m, 4H), 7.23 -7.21(m, 1H), 7.21 - 7.17 (m, 2H), 6.98 (ddd, J = 5.6, 2.6, 0.5 Hz, 1H), 5.03(dt, J = 11.4, 6.9 Hz, 1H), 4.79 (dd, J = 9.7, 6.9 Hz, 1H), 4.35 (dd, J =11.4, 9.7Hz, 1H), 4.13 (q, J = 7.1 Hz, 1H), 3.53 (s, 3H), 1.65 (s, 6H).

[0352] (S)-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-fluoro-1-(4-fluorobenzyl)-1H-pyrazole-3-carboxamide (I-40)

[0353]

[0354] This compound was obtained from the desilylation of (S)-4-fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide. MS (ESI, m / z) Calcd. 437.1299; Found [M+1] + 438.1. 1 H NMR (400MHz, chloroform-d) δ (ppm) 7.66 (d, J = 6.4 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.25 -7.18 (m, 3H), 7.11 - 7.01 (m, 2H), 5.19 (s, 2H), 5.03 (dt, J = 11.3, 6.7 Hz, 1H), 4.84 (dd, J = 9.7, 6.8 Hz, 1H), 4.32 (dd, J= 11.3, 9.7 Hz, 1H), 3.53 (s,3H), 3.16 (s, 1H).

[0355] General Synthesis of 7-Ethynylpyridoazepine Compound XI

[0356]

[0357] Those skilled in the art will readily appreciate that the illustrated synthesis of compound XI is applicable to compounds having a variety of R groups.

[0358] 6-Amino-5-bromopyridin-2-ol

[0359] 6-Aminopyridine-2-ol (11 g, 0.1 mmol) was dissolved in acetic acid (220 mL), and bromine (16 g, 5.12 mL, 0.1 mmol) was then added at ambient temperature. The resulting solution was stirred at this temperature for 40 minutes. Water (200 mL) was added, and the solution was filtered through celite. The filtrate was extracted with ethyl acetate (3 x 400 mL). The combined organic layers were washed with water (2 x 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the crude product 6-amino-5-bromopyridine-2-ol (8.3 g) as a light brown solid, which was used directly in the next step without further purification. MS (ESI, m / z) calculated value 187.9585; found value [M+1] + 188.9. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.79 (s,1H), 7.38 (d, J = 8.8Hz, 1H), 5.93 (s, 2H), 5.60 (d, J = 8.8 Hz, 1H).

[0360] 3-Bromo-6-methoxypyridin-2-amine

[0361] The crude material (8.3 g, 43.9 mmol) of 6-amino-5-bromopyridine-2-ol was dissolved in acetone (130 mL), followed by potassium hydroxide (7.4 g, 0.132 mol), followed by dimethyl sulfate (7.20 g, 5.4 mL, 57.1 mmol). The reaction solution was stirred at ambient temperature for 4 hours. All solvents were removed under reduced pressure. The residue was added to brine (100 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0-30% ethyl acetate in hexane to provide 3-bromo-6-methoxypyridine-2-amine (4.09 g, 20% over 2 steps) as a white solid. MS (ESI, m / z) calculated value 201.9742; found value [M+1] + 202.9. 1 H NMR (400 MHz, CHLOROFORM-d) δ(ppm) 7.48 (d, J = 8.4 Hz, 1H), 6.02 (d, J = 8.3 Hz, 1H), 4.73 (s, 2H), 3.82 (s, 3H).

[0362] 6-Methoxy-3-vinylpyridin-2-amine

[0363] Pd(PPh3)4(1.17 g, 1.01 mmol) was added to a solution of 3-bromo-6-methoxypyridine-2-amine (4.09 g, 20.3mmol) and tributyl(vinyl)stannane (9.64 g, 30.4 mmol) in anhydrous toluene (66 mL). The solution was purged with nitrogen for 1 min, then sealed and heated at 110°C for 16 hours. The reaction solution was cooled to ambient temperature. Potassium fluoride aqueous solution (100 mL, 1M) was added, followed by ethyl acetate (500 mL). The solution was filtered through diatomaceous earth and washed with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography using a gradient of 0-10% ethyl acetate in hexane to provide 6-methoxy-3-vinylpyridine-2-amine (2.09 g, 69%) as a light yellow liquid. MS (ESI, m / z) calcd. 150.0793; found [M+1] + 150.9. 1 H NMR (400 MHz, chloroform-d) δ(ppm) 7.46 (dd, J = 8.2, 0.6 Hz, 1H), 6.57 (ddt, J = 17.4, 11.1, 0.6 Hz, 1H), 6.14 (dd, J = 8.2, 0.6 Hz, 1H), 5.49 (dd, J = 17.4, 1.2 Hz, 1H), 5.21 (dd, J =11.1, 1.2 Hz, 1H), 4.45 (s, 2H), 3.85 (s, 3H).

[0364] (S)-tert-Butyl 2-(((Benzyloxy)carbonyl)amino)but-3-enoate

[0365] To a solution of (S)-4-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (20 g, 59.3 mmol) in anhydrous benzene (600 mL) was added copper (II) acetate (2.7 g, 14.8 mmol). The resulting solution was stirred at ambient temperature under nitrogen for 2 hours, then lead tetraacetate (55.3 g, 0.119 mol) was added. The resulting solution was refluxed under nitrogen for 14 hours, then it was cooled to ambient temperature. The reaction solution was filtered through celite and washed with ethyl acetate (1200 mL). The organic layer was washed with water (2 x 300 mL), brine (300 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a 0-10% gradient of ethyl acetate in hexanes to provide (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)but-3-enoate (4.3 g, 25%) as a light yellow liquid. MS (ESI, m / z) calcd. 291.1471; found [M- t Bu+1] + 236.0. 1 H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.44 - 7.27 (m, 5H), 5.90 (ddd, J = 16.3, 10.4, 5.3 Hz, 1H), 5.44 (d,J = 8.1 Hz, 1H),5.34 (ddd, J = 17.2, 1.8, 0.7 Hz, 1H), 5.24 (ddd, J = 10.4,1.8, 0.7 Hz, 1H), 5.12 (s, 2H), 4.86 - 4.74 (m, 1H), 1.46 (s, 9H).

[0366] (S)-2-(((Benzyloxy)carbonyl)amino)but-3-enoic acid

[0367] To a solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)but-3-enoate (4.3 g, 14.8 mmol) in anhydrous dichloromethane (340 mL) at 0°C was added trifluoroacetic acid (50.5 g, 34 mL, 0.443 mol). The resulting solution was stirred at ambient temperature for 16 hours. All solvents were removed under reduced pressure to provide (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoic acid (3.3 g, 95%) as a white solid. MS (ESI, m / z) Calcd. 235.0845; Found [M-1] + 234.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm) δ12.80 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.42 - 7.25 (m, 5H), 5.91 (ddd, J = 16.8, 10.4, 6.1 Hz, 1H), 5.33 (dt, J= 17.2, 1.5 Hz, 1H), 5.21 (dt, J = 10.4,1.4 Hz, 1H), 5.05 (s, 2H), 4.62 (ddt,J = 7.8, 6.1, 1.7 Hz, 1H).

[0368] (S)-Benzyl (1-((6-methoxy-3-vinylpyridin-2-yl)amino)-1-oxobut-3-en-2-yl)carbamate

[0369] To a cloudy solution of (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoic acid (1.75 g, 7.55 mmol) in anhydrous dichloromethane (35 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.01 g, 1 mL, 7.55 g) dropwise at 0°C and stirred at this temperature for 30 minutes. 6-methoxy-3-vinylpyridin-2-amine (1.03 g, 6.87 mmol) in anhydrous dichloromethane (5 mL) was then added dropwise followed by triethylamine (0.76 g, 1.05 mL, 7.55 mmol). The resulting solution was stirred at ambient temperature for an additional 2 hours and dichloromethane (150 mL) was added. The solution was washed with a small amount of aqueous HCl (1 N), aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a 0-50% gradient of ethyl acetate in hexanes to provide benzyl (S)-(1-((6-methoxy-3-vinylpyridin-2-yl)amino)-1-oxobut-3-en-2-yl)carbamate (568 mg, 23%) as a light yellow liquid. MS (ESI, m / z) calcd. 367.1532; found [M+1] + 368.1. 1H NMR (400MHz, chloroform-d) δ(ppm) 7.75 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.43 - 7.27 (m,5H), 6.63 (d, J = 8.5 Hz, 1H), 6.54 (dd, J = 17.5, 11.1 Hz, 1H), 6.02 (ddd, J= 16.9, 10.2, 6.3Hz, 1H), 5.79 (s, 1H), 5.59 (dd, J = 17.4, 0.9 Hz, 1H), 5.47(d, J = 17.0 Hz, 1H), 5..37 (d, J = 10.1 Hz, 1H), 5.30 (d, J = 11.0 Hz, 1H), 5.14 (d, J = 1.3Hz, 2H), 3.98 - 3.72 (s, 3H).

[0370] (S)-Benzyl (2-methoxy-8-oxo-8,9-dihydro-7H-pyrido[2,3-b]azepine-7-yl)carbamate

[0371] To a suspension of (S)-(1-((6-methoxy-3-vinylpyridin-2-yl)amino)-1-oxobut-3-en-2-yl)carbamic acid benzyl ester (573 mg, 1.56 mmol) in anhydrous toluene (78 mL) was added Grubb's 2nd generation catalyst (133 mg, 0.156 mmol). The solution was purged with nitrogen for 1 minute and then heated at 80°C under nitrogen for 15 hours. The reaction solution was cooled to ambient temperature. All solvents were removed under reduced pressure. The resulting residue was purified by silica gel chromatography using a 0-30% gradient of ethyl acetate in hexanes to provide (S)-(2-methoxy-8-oxo-8,9-dihydro-7H-pyrido[2,3-b]azepine-7-yl)carbamic acid benzyl ester (343 mg, 65%) as a white solid. MS (ESI, m / z) calcd. 339.1219; found [M+1] + 340.0. 1H NMR (400 MHz, chloroform-d) δ (ppm) 7.97 (s, 1H),7.55 (d, J = 8.4 Hz, 1H), 7.44 - 7.27 (m, 5H), 6.63 - 6.53 (m, 2H), 6.22(d, J= 6.2 Hz, 1H), 5.67 (dd, J = 10.0, 4.4 Hz, 1H), 5.14 (s, 2H), 4.41 (d, J =6.7 Hz, 1H), 3.91 (s, 3H).

[0372] (S)-tert-Butyl (2-methoxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)carbamate

[0373] To (S)-(2-methoxy-8-oxo-8,9-dihydro-7H-pyrido [2,3-b] azepine-7-yl) benzyl carbamate (341 mg, 1mmol) in MeOH solution, add 10% palladium on carbon (110mg) and di-tert-butyl carbonate (537 mg, 2 mmol). The reactant was hydrogenated under 50PSI hydrogen pressure in Parr-Shaker for 15 hours. The reaction solution was filtered through diatomite and washed with MeOH. All solvents were removed under reduced pressure. The obtained residue was purified by silica gel chromatography using 0-40% ethyl acetate gradient in hexane to provide (S)-(2-methoxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) tert-butyl carbamate (151 mg, 49%) as a white solid. MS (ESI, m / z) calcd. 307.1532; found [M+1-Boc] + 208.0. 1 H NMR (400 MHz, chloroform-d) δ(ppm) 7.82 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 8.2 Hz, 1H), 5.53(d, J = 7.5 Hz,1H), 4.29 (dt, J = 11.5, 7.2 Hz, 1H), 3.85 (s, 3H), 2.87 -2.73 (m, 1H), 2.73 - 2.55 (m, 2H), 2.02 - 1.89 (m, 1H), 1.39 (s, 9H).

[0374] (S)-tert-Butyl (2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)carbamate

[0375] To a solution of (S)-(2-methoxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)carbamic acid tert-butyl ester (150 mg, 0.489 mmol) in anhydrous DMF (4 mL) was added iodomethane (69.3 mg, 30.4 uL, 0.489 mmol) followed by cesium carbonate (159 mg, 0.489 mmol). The resulting solution was stirred at ambient temperature for 2 days. The reaction solution was diluted with ethyl acetate (150 mL), washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a 0-30% gradient of ethyl acetate in hexanes to provide (S)-tert-butyl (2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)carbamate (147 mg, 94%) as a white solid. MS (ESI, m / z) calcd. 321.1689; found [M+1-Boc] + 222.0. 1 H NMR (400 MHz, chloroform-d) δ(ppm) 7.40 (d, J =8.1 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 5.53 (d, J = 7.7 Hz, 1H), 4.26 (dt, J= 11.2, 7.4 Hz, 1H), 3.89 (s, 3H), 3.45 (s, 3H), 2.77 - 2.56 (m, 2H), 2.52 (dd, J = 12.3, 6.4 Hz, 1H), 2.02 - 1.84 (m, 1H), 1.40 (s, 9H).

[0376] (S)-7-Amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepine-8-one

[0377] To a solution of (S)-tert-butyl (2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)carbamate (35 mg, 0.11 mmol) in anhydrous dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL). The resulting solution was stirred at ambient temperature for 3 hours. Anhydrous 1,2-dichloroethane (1 mL) was then added. All solvents were removed under reduced pressure to provide a crude trifluoroacetate salt of (S)-7-amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepine-8-one. The resulting residue was used directly in the next step. MS (ESI, m / z) Calcd. 221.1164; Found [M+1] + 222.1.

[0378] (S)-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide

[0379] To a solution of the crude trifluoroacetate salt of (S)-7-amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepine-8-one (0.11 mmol) and 4-phenoxypicolinic acid (28 mg, 0.13 mmol) in anhydrous DMF (1 mL) was added diisopropylethylamine (56 mg, 75 uL, 0.43 mmol) followed by HATU (49.4 mg, 0.13 mmol). The resulting solution was stirred at ambient temperature for 19 hours. A drop of water was added to quench the reaction. The solution was directly purified by reverse phase HPLC (30-70% acetonitrile in water containing 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide (S)-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (43 mg, 95%) as a white solid. MS (ESI, m / z) Calcd. 418.1641; Found [M+1] + 419.1. 1H NMR (400 MHz, chloroform-d) δ(ppm) 8.90 (d, J = 7.6Hz, 1H), 8.43 (dd, J = 5.6, 0.5 Hz, 1H), 7.62 (dd, J = 2.5, 0.5 Hz, 1H), 7.46(d, J = 8.2 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.26 - 7.20(m, 1H), 7.10 - 7.04 (m,2H), 6.93 (dd, J = 5.6, 2.6 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 4.66 (dt, J =11.4, 7.5 Hz, 1H), 3.90 (s, 3H), 3.48 (s, 3H), 2.83 -2.69 (m, 2H), 2.64 -2.52 (m, 1H), 2.15 - 2.02 (m, 1H).

[0380] (S)-N-(2-Hydroxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide

[0381] To a solution of (S)-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (29 mg, 0.069 mmol) in anhydrous acetonitrile (1 mL) was added phosphorus tribromide (56 mg, 20 uL, 0.21 mmol). The resulting solution was heated at 80° C. for 3 hours. The reaction solution was cooled to ambient temperature and methanol was carefully added to quench the reaction. All solvents were removed under reduced pressure. The crude solid was dissolved in DMSO and purified by reverse phase HPLC (20-56% acetonitrile in water containing 0.1% formic acid). The desired fractions were combined and lyophilized to provide (S)-N-(2-hydroxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (24 mg, 87%) as a white solid. MS (ESI, m / z) Calcd. 404.1485; Found [M+1] + 405.1.

[0382] (S)-9-methyl-8-oxo-7-(4-phenoxypyridinylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-2-yl trifluoromethanesulfonate

[0383] To a solution of (S)-N-(2-hydroxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (24.2 mg, 0.06 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (25.6 mg, 0.072 mmol) in anhydrous DMF (1 mL) was added anhydrous potassium carbonate (17.4 mg, 0.126 mmol). The resulting solution was stirred at ambient temperature for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a 0-50% gradient of ethyl acetate in hexanes to provide (S)-9-methyl-8-oxo-7-(4-phenoxypyridinylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-2-yl trifluoromethanesulfonate (30 mg, 92%) as a white solid. MS (ESI, m / z) Calcd. 536.0977; Found [M+1] + 537.0.

[0384] General procedure for the preparation of 7-ethynylpyridoazepine compounds XI

[0385] To (S)-9-methyl-8-oxo-7-(4-phenoxypicolinamido)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-2-yl trifluoromethanesulfonate (0.03 mmol, 1 eq.), substituted acetylene (0.06 to 0.09 mmol, 2 to 3 eq.), Pd(PPh3)4 (0.01 mmol, 0.1 eq.), and CuI (0.01 mmol, 0.1 eq.) in anhydrous DMF (0.5 mL) in a vial was added Et3N (0.4 mmol, 4 eq.). The reaction solution was purged with nitrogen for 1 minute, then sealed and heated at 70°C for 14 to 24 hours. The reaction solution was cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography or reverse phase HPLC (mobile phase A: water containing 0.1% HCOOH; mobile phase B: acetonitrile containing 0.1% HCOOH) to provide the intermediate final product XI. Compounds I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59 and I-60 are exemplary compounds synthesized by this general method. Those skilled in the art will readily appreciate that the pyridine amide ring ('B' ring according to the formula shown herein) can be replaced with other heteroaryl groups in the general synthesis of the above-mentioned XI. For example, the pyridine amide moiety can be replaced with another 5- or 6-membered heteroaryl ring described herein. As an example of such a replacement, compound I-54 contains a triazole in the 'B' ring position. The general synthesis presented above is modified according to the following working examples.

[0386] Synthesis of (S)-5-benzyl-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-1H-1,2,4-triazole-3-carboxamide (I-54)

[0387]

[0388] Step 1 (S)-5-Benzyl-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-1H-1,2,4-triazole-3-carboxamide

[0389] To a solution of (S)-7-amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepine-8-one (0.0523 mmol) and 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (10.6 mg, 0.0523 mmol) in anhydrous DMF (0.5 mL) was added diisopropylethylamine (27 mg, 37 uL, 0.209 mmol) followed by HATU (21.9 mg, 0.0575 mmol). The resulting solution was stirred at ambient temperature for 19 hours. A drop of water was added to quench the reaction. The solution was directly purified by reverse phase HPLC (15 to 52% acetonitrile in water containing 0.1% formic acid). The desired fractions were combined and lyophilized to provide (S)-5-benzyl-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-1H-1,2,4-triazole-3-carboxamide (21 mg, 97%) as a white solid. MS (ESI, m / z) Calcd. 406.1753; Found [M+1] + 407.1.

[0390] Step 2 (S)-5-Benzyl-N-(2-hydroxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-1H-1,2,4-triazole-3-carboxamide

[0391] To a solution of (S)-5-benzyl-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-1H-1,2,4-triazole-3-carboxamide (21 mg, 0.051 mmol) in anhydrous acetonitrile (1 mL) was added phosphorus tribromide (41 mg, 14 uL, 0.15 mmol). The resulting solution was heated at 80 ° C for 3 hours. The reaction solution was cooled to ambient temperature, and methanol was carefully added to quench the reaction. All solvents were removed under reduced pressure. The crude solid was dissolved in DMSO and purified by reverse phase HPLC (10 to 40% acetonitrile in water containing 0.1% formic acid). The desired fractions were combined and lyophilized to provide (S)-5-benzyl-N-(2-hydroxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-1H-1,2,4-triazole-3-carboxamide (18 mg, 91%) as a white solid. MS (ESI, m / z) Calcd. 392.1597; Found [M+1] + 393.1.

[0392] Step 3: (S)-7-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-2-yl trifluoromethanesulfonate

[0393] To a solution of (S)-5-benzyl-N-(2-hydroxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-1H-1,2,4-triazole-3-carboxamide (18 mg, 0.046 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (19.7 mg, 0.055 mmol) in anhydrous DMF (1 mL) was added anhydrous potassium carbonate (15.2 mg, 0.11 mmol). The resulting solution was stirred at ambient temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient of 0 to 50% acetone in hexanes to provide (S)-7-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-2-yl trifluoromethanesulfonate (22 mg, 92%) as a white solid. MS (ESI, m / z) Calcd. 524.1090; Found [M+1] + 525.0.

[0394] Step 4 (S)-5-Benzyl-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-1H-1,2,4-triazole-3-carboxamide

[0395] To (S)-7-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-2-yl trifluoromethanesulfonate (22 mg, 0.0422 mmol), 2-methylbut-3-yn-2-ol (11.6 mg, 0.0138 mmol), Pd(PPh3)4 (5.3 mg, 0.0046 mmol) and CuI (0.9 mg, 0.0046 mmol) in anhydrous DMF (1 mL) in a vial was added Et3N (18.6 mg, 26 uL, 0.184 mmol). The reaction solution was purged with nitrogen for 1 minute, then sealed and heated at 70°C for 14 hours. The reaction solution is cooled to ambient temperature, diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue is purified by reverse phase HPLC (15% to 47% acetonitrile in water containing 0.1% formic acid). The desired fractions are merged, diluted with ethyl acetate, washed with a small amount of saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide (S)-5-benzyl-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl)-1H-1,2,4-triazole-3-carboxamide (4.0 mg, 21%) as a white solid. MS (ESI, m / z) calculated value 458.2066; Measured value [M+1] + 459.1. 1 H NMR (400MHz, chloroform-d) δ (ppm) 8.12 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.35- 7.25 (m, 5H), 7.23 (d, J =7.7 Hz, 1H), 4.57 (dt, J = 12.1, 6.9 Hz, 1H), 4.14 (s, 2H), 3.50 (s, 3H), 2.90 - 2.73 (m, 2H), 2.71- 2.57 (m, 1H), 2.20 (s,1H), 2.13 - 2.03 (m, 1H), 1.63 (s,6H).

[0396] (S)-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (I-52)

[0397]

[0398] MS (ESI, m / z) calcd 470.1954; found [M+1] + 471.1. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 8.93 (d, J = 7.3 Hz, 1H), 8.43 (dd, J = 5.6, 0.5 Hz, 1H), 7.62 (dd, J= 2.6, 0.5 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.26 -7.21(m, 2H), 7.11 - 7.03 (m, 2H), 6.93 (dd, J = 5.6, 2.6 Hz, 1H), 4.59 (dt, J= 11.1, 7.2 Hz, 1H), 3.52 (s, 3H), 2.93 - 2.73 (m, 2H), 2.73 - 2.58 (m, 1H), 2.14 (s, 1H), 2.13 - 1.99 (m, 1H), 1.65 (s, 6H).

[0399] (S)-N-(2-((3-hydroxyoxetane-3-yl)ethynyl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (I-53)

[0400]

[0401] MS (ESI, m / z) calcd. 484.1747; found [M+1] + 485.1. 1H NMR (400 MHz, chloroform-d)δ(ppm) 8.94 (d, J = 7.3 Hz, 1H), 8.44 (dd, J = 5.6, 0.6 Hz, 1H), 7.62 (dd, J= 2.6, 0.5 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.11 - 7.04 (m, 2H), 6.93 (dd, J = 5.6,2.5 Hz, 1H), 4.98 (dd, J = 6.6, 1.0 Hz, 2H), 4.80 (dt, J = 6.8, 0.7 Hz, 2H), 4.61 (dt, J = 11.1, 7.3 Hz, 1H), 3.52 (s, 3H), 2.89 (s, 1H), 2.88 - 2.75 (m,2H), 2.75 - 2.62 (m, 1H), 2.18 - 2.04 (m, 1H).

[0402] N-((7S)-9-methyl-8-oxo-2-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (I-55)

[0403]

[0404] MS (ESI, m / z) calcd. 510.1515; found [M+1] + 511.0. 1H NMR (400 MHz, chloroform-d)δ(ppm) 9.01 (dd, J = 20.7, 7.2 Hz, 1H), 8.42 (dd, J = 5.6, 1.2 Hz, 1H), 7.63- 7.53 (m, 2H), 7.45 - 7.35 (m, 2H), 7.31 - 7.25 (m, 1H), 7.24 - 7.18 (m,1H),7.09 - 7.00 (m, 2H), 6.92 (dd, J = 5.6, 2.5 Hz, 1H), 4.91 (d, J = 6.4 Hz,1H), 4.80 - 4.52 (m, 1H), 3.97 - 3.77 (m, 0.5H), 3.66 - 3.52 (m, 0.5H), 3.52 - 3.34 (m, 3H), 2.97 - 2.76 (m, 2H), 2.76 - 2.59 (m, 1H), 2.19 - 2.00 (m, 1H).

[0405] N-((7S)-9-methyl-8-oxo-2-(4,4,4-trifluoro-3-hydroxy-3-methylbut-1-yn-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (I-56)

[0406]

[0407] MS (ESI, m / z) calcd. 524.1671; found [M+1] + 525.2. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 8.97 (dd, J = 12.6, 7.2 Hz, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.64 - 7.54(m, 2H), 7.46 - 7.35 (m, 2H), 7.32 - 7.18 (m, 2H), 7.10 - 7.01 (m, 2H), 6.96-6.87 (m, 1H), 4.64 (ddt, J = 20.4, 11.3, 7.1 Hz, 1H), 3.55 - 3.39 (m, 3.5H), 3.23 (s, 0.5H), 2.93 - 2.76 (m, 2H), 2.75 - 2.63 (m, 1H), 2.19 - 1.98 (m, 1H), 1.74 (s, 3H).

[0408] (S)-N-(2-((3,3-difluoro-1-hydroxycyclobutyl)ethynyl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (I-57)

[0409]

[0410] MS (ESI, m / z) calcd. 518.1766; found [M+1] + 519.1. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 8.95 (d, J = 7.3 Hz, 1H), 8.43 (dd, J = 5.6, 0.6 Hz, 1H), 7.62 (dd, J= 2.6, 0.5 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.27 (d, J=5.2 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.10 - 7.04 (m, 2H), 6.93 (dd, J = 5.6,2.5 Hz, 1H), 4.61 (dt, J = 11.1, 7.1 Hz, 1H), 3.52 (s, 3H), 3.29 - 3.14 (m, 2H), 3.07 - 2.92 (m, 2H), 2.84 (dtd, J = 15.2, 7.5, 5.6 Hz, 2H), 2.75 - 2.59(m, 1H), 2.19 - 2.03 (m, 1H).

[0411] (S)-N-(9-methyl-2-(oxetan-3-ylethynyl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (I-58)

[0412]

[0413] MS (ESI, m / z) calcd. 468.1798; found [M+1] + 469.1. 1H NMR (400 MHz, chloroform-d)δ(ppm) 8.94 (d, J = 7.3 Hz, 1H), 8.43 (dd, J = 5.6, 0.5 Hz, 1H), 7.62 (dd, J= 2.5, 0.5 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.45 - 7.35 (m, 2H), 7.27 -7.22 (m, 3H), 7.10 - 7.04 (m, 2H), 6.93 (dd, J = 5.6, 2.6 Hz, 1H), 4.92 -4.79 (m,4H), 4.60 (dt, J = 11.2, 7.3 Hz, 1H), 4.12 (tt, J = 8.5, 7.4 Hz, 1H), 3.52 (s, 3H), 2.94 - 2.73 (m, 2H), 2.73 - 2.61 (m, 1H), 2.19 - 2.03 (m, 1H).

[0414] (S)-N-(2-(3,3-difluoro-3-(oxetane-3-yl)prop-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (I-59

[0415]

[0416] MS (ESI, m / z) calcd. 518.1766; found [M+1] + 519.1. 1H NMR (400 MHz, chloroform-d)δ(ppm) 8.93 (d, J = 7.3 Hz, 1H), 8.44 (d, J = 5.6 Hz, 1H), 7.65 - 7.59 (m,2H), 7.45 - 7.35 (m, 3H), 7.26 - 7.20 (m, 1H), 7.10 - 7.04 (m, 2H), 6.94 (dd,J =5.6, 2.5 Hz, 1H), 4.90 - 4.74 (m, 4H), 4.59 (dt, J = 11.3, 7.2 Hz, 1H), 3.83 - 3.62 (m, 1H), 3.53 (s, 3H), 2.96 - 2.76 (m, 2H), 2.72 (dd, J = 11.9, 6.2 Hz, 1H), 2.20 - 2.06 (m, 1H).

[0417] N-((7S)-2-(3-amino-4,4,4-trifluoro-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-7-yl)-4-phenoxypicolinamide (I-60)

[0418]

[0419] MS (ESI, m / z) calcd. 523.1831; found [M+1] + 524.1. 1 H NMR (400 MHz, chloroform-d)δ(ppm) 8.93 (d, J = 7.3 Hz, 1H), 8.43 (dd, J = 5.6, 0.6 Hz, 1H), 7.62 (dd, J= 2.6, 0.5 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.30 -7.21(m, 2H), 7.09 - 7.04 (m, 2H), 6.93 (dd, J = 5.6, 2.5 Hz, 1H), 4.58 (dt, J= 11.1, 7.2 Hz, 1H), 3.52 (s, 3H), 2.93 - 2.75 (m, 2H), 2.75 - 2.63 (m, 1H), 2.17- 2.02 (m, 1H), 2.02 - 1.81 (m, 2H), 1.67 (d, J = 0.9 Hz, 3H).

[0420] ( S )-5-Benzyl- N -(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine-3-yl)-4 H -1,2,4-Triazole-3-carboxamide (I-1)

[0421]

[0422] 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 8.30 (dd, J = 4.7, 1.6 Hz, 1H), 8.06 (d, J = 7.0Hz, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 1H), 7.32 - 7.21 (m, 5H), 7.18 (dd, J = 8.0,4.7 Hz, 1H), 4.99 (dt, J = 11.3, 7.0 Hz, 1H), 4.76 (dd, J = 9.8, 7.1 Hz, 1H),4.32 (dd, J = 11.3, 9.8 Hz, 1H), 4.17 (d, J = 2.1 Hz, 2H), 3.49 (s, 3H). HRMS (TOFMS ES+) accurate mass C 19 H 18 N6O3378.1440, measured value 379.1566.

[0423] ( S )-5-Benzyl- N -(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine-3-yl)-1,3,4-oxadiazole-2-carboxamide (I-2)

[0424]

[0425] MS (ESI, 质荷比 ) Calculated value 379.1281; Found 380.0 [M+H] +.

[0426] ( S )-5-Benzyl- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine-3-yl)-4 H -1,2,4-Triazole-3-carboxamide (I-3)

[0427]

[0428] MS (ESI, 质荷比 ) Calculated value 460.1859; Found 443.1 [M-H2O+H] + .

[0429] ( S )-5-Benzyl- N -(5-methyl-8-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine-3-yl)-1,3,4-oxadiazole-2-carboxamide (I-5)

[0430]

[0431] MS (ESI, 质荷比 ) Calculated value 502.1965; Found 503.1 [M+H] + .

[0432] ( S )-3-amino-8-bromo-5-methyl-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H Synthesis of )-Keto Hydrochloride (I-6)

[0433]

[0434] The 8-bromo compound illustrated as structure 4 in the above scheme is compound 1-6 of the present disclosure. In addition to exhibiting RIP1K inhibitory activity, compound 1-6 can be used as an intermediate for the synthesis of 8-substituted pyridooxazepines. For example, as known to those skilled in the art, compound 1-6 can be cross-coupled with amino moieties and unsaturated groups, for example, under palladium catalysis.

[0435] Hydrogen chloride solution (1 mL, 4M in dioxane, 4 mmol) was added to a vial containing tert-butyl (S)-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)carbamate 1 (prepared as described in WO2020239074, 52 mg, 0.139 mmol). The resulting solution was stirred at ambient temperature for 19 hours. All solvents were removed under reduced pressure to provide ( S )-3-amino-8-bromo-5-methyl-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H )-Keto hydrochloride 2 (43 mg, 100%). MS (ESI, 质荷比 ) Calculated value 270.9956; Found 272.0 [M+H] + .

[0436] ( S )- N -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b Synthesis of [1,4]oxazacycloheptatrien-3-yl)-4-phenoxypyridineamide (4)

[0437] Towards( S )-3-amino-8-bromo-5-methyl-2,3-dihydropyrido[3,2- b [1,4]Oxazacycloheptatriene-4(5 H To a solution of 2-oxo-1-pyridinecarboxylic acid 3 (45 mg, 0.21 mmol) in anhydrous DMF (1.4 mL) was added diisopropylethylamine (135 mg, 0.18 mL, 1.1 mmol) followed by HATU (80 mg, 0.21 mmol). The resulting solution was stirred at ambient temperature for 16 hours. Water (0.1 mL) was then added and the solution was directly purified by reverse phase HPLC using a 37 to 90% acetonitrile gradient in water (buffered with 0.1% formic acid). The desired fractions were combined, diluted with ethyl acetate (100 mL) and the resulting solution was washed with saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide ( S )- N -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b[1,4]oxazacycloheptatrien-3-yl)-4-phenoxypyridineamide 4 (50 mg, 77%). MS (ESI, 质荷比 ) Calculated value 468.0433; Found 468.9 [M+H] + .

[0438] ( S )- N -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine-3-yl)-4-phenoxypyridineamide (I-6)

[0439]

[0440] MS (ESI, 质荷比 ) Calculated value 468.0433; Found 468.9 [M+H] + . (I-6)

[0441] ( S )- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine-3-yl)-4-phenoxypyridineamide (I-7)

[0442]

[0443] MS (ESI, 质荷比 ) Calculated value 472.1747; Found 473.1 [M+H] + .

[0444] (S)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-18)

[0445]

[0446] MS (ESI, m / z) calcd. 472.1747; found [M+1] + 473.1. 1H NMR (400 MHz, methanol-d4) δ (ppm) 8.52 (dd, J = 5.7, 0.5 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.52 -7.44 (m, 3H), 7.36 (d, J = 8.2 Hz, 1H), 7.34 - 7.27 (m, 1H),7.17 - 7.12 (m,2H), 7.09 (dd, J = 5.6, 2.6 Hz, 1H), 5.00 (dd, J = 11.5, 7.0 Hz, 1H), 4.69 (dd, J = 9.8, 7.0 Hz, 1H), 4.49 (dd, J = 11.5, 9.8 Hz, 1H), 3.46(s, 3H), 1.57(s, 6H).

[0447] (S)-N-(7-((3,3-difluoro-1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-30)

[0448]

[0449] MS (ESI, m / z) calcd. 520.1558; found [M+1] + 521.1. 1H NMR (400 MHz, chloroform-d)δ(ppm) 8.97 (d, J = 6.9 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.61 (d, J = 2.5Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.29 (d, J = 8.1 Hz,1H), 7.24 (t, J = 1.2 Hz, 1H), 7.11 - 7.04 (m, 2H), 6.96 (dd, J = 5.6, 2.5 Hz,1H), 5.09 (dt, J = 11.4, 6.8 Hz, 1H), 4.81 (dd, J = 9.7, 6.8 Hz, 1H), 4.36 (dd, J =11.4, 9.7 Hz, 1H), 3.50 (s, 3H), 3.22 (tdd, J = 11.9, 9.3, 3.7 Hz, 2H), 3.08 - 2.86 (m, 3H).

[0450] (S)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4-phenoxypicolinamide (I-31)

[0451]

[0452] MS (ESI, m / z) calcd 486.1903; found [M+1] + 487.1. 1H NMR (400 MHz, chloroform-d)δ(ppm) 8.92 (d, J = 7.0 Hz, 1H), 8.44 (d, J = 5.6 Hz, 1H), 7.61 (d, J = 2.5Hz, 1H), 7.47 - 7.37 (m, 3H), 7.28 (d, J = 1.1 Hz, 1H), 7.25 (d, J = 5.9 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.96 (dd, J = 5.6, 2.5 Hz, 1H), 5.00 (dt, J = 11.4,7.0 Hz, 1H), 4.78 (dd, J = 9.7, 7.0 Hz, 1H), 4.34 (dd, J = 11.4, 9.7 Hz, 1H), 3.54 (s, 2H), 3.53 (s, 3H), 1.34 (s, 6H).

[0453] (S)- N -(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b [1,4]Oxazepine-3-yl)-4-phenoxypyridineamide (I-31)

[0454]

[0455] 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 8.74 (d, J = 7.2 Hz, 1H), 8.47 (dd, J = 5.6, 0.5Hz, 1H), 7.56 (dd, J = 2.6, 0.5 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.31 - 7.25 (m,3H), 7.14 - 7.08 (m, 3H), 6.98 (dd, J = 5.6, 2.6 Hz, 1H), 4.97 (dt, J = 11.2, 7.3Hz, 1H), 4.69 (dd, J = 9.7, 7.3 Hz, 1H), 4.25 (dd, J= 11.3, 9.7 Hz, 1H), 3.48(s, 2H), 3.40 (s, 3H), 1.87 (s, 1H), 1.29 (s, 6H). HRMS (TOFMS ES+) accurate mass C 28 H 27 N3O5485.1951, measured value 486.2024.

[0456] ( S )- N -(8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine-3-yl)-4-phenoxypyridineamide (I-8)

[0457]

[0458] 1 H NMR (400 MHz, CDCl 3 ) δ 8.91 (d, J = 7.0 Hz, 1H), 8.44 (d, J = 5.6 Hz,1H), 8.30 (d, J = 1.9 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H),7.41 (td, J = 8.9, 7.2 Hz, 2H), 7.27 - 7.24 (m, 1H), 7.12 - 7.03 (m, 2H), 6.95(dd, J = 5.6, 2.5 Hz, 1H), 5.00 (dt, J = 11.4, 7.0 Hz, 1H), 4.76 (dd, J = 9.7, 7.0Hz, 1H), 4.34 (dd, J = 11.4, 9.7 Hz, 1H), 3.54 (s, 2H), 3.51 (s, 3H), 1.91 (s,1H), 1.33 (s, 6H). HRMS (TOFMS ES+) accurate mass C 27 H 26 N4O5486.1903, measured value 487.1988.

[0459] ( S )- N -(5-methyl-4-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydropyrido[3,2- b [1,4]Oxazepine-3-yl)-4-phenoxypyridineamide (I-9)

[0460]

[0461] HRMS (TOFMS ES+) Accurate Mass C 28 H 21 N5O4491.1594, measured value 492.1680.

[0462] Kinase inhibition

[0463] In this example, ADP-Glo ​​was used. TM Technology, compounds of the disclosure were evaluated using biochemical assays.

[0464] ADP-Glo™ (Promega, Madison, WI, USA) reagent was thawed at ambient temperature. Kinase assay reagent was prepared by mixing kinase assay buffer with lyophilized kinase assay substrate.

[0465] Prepare a 500 ml stock volume of 5X reaction kinase buffer by mixing 1000 μl 1M MgCl2, 500 μl 1M Tris-HCL pH 7.4, 0.5 mg / ml (25 mg) BSA and 3475 μl distilled H2 O. Prepare a 3 ml 2X working stock volume of reaction kinase buffer containing a final concentration of 100 μM DTT and 4 mM MnCl2.

[0466] Thaw the components of RIPK1 enzyme (Rigel Pharmaceuticals, South San Francisco, CA, USA) on ice. Prepare diluted RIPK1 to 31 ng / well in 1X kinase reaction buffer (diluted from 2X buffer). Prepare 166 μM working stock ATP assay solution in 1X kinase reaction buffer (diluted from 2X buffer).

[0467] In a 96-well plate, compounds were serially diluted in DMSO from 250uM in 4-fold dilutions and then diluted 1:5 in 2X reaction buffer. 1.0ul of diluted compound was added to a 384-well plate in duplicate. 2 μl of diluted active RIPK1 was added to a 384-well plate (not added to column 1), and 2X reaction buffer was added to column 1. 150nM AKT (Anaspec, Fremont, CA, USA) was combined with ATP working stock solution in equal volumes and added to a 384-well plate at 2ul / well. The final reaction volume was 5.0 μl.

[0468] The plate was centrifuged briefly and the reaction was incubated at 30°C for 30 minutes. 5 μl ADP-Glo TM The reaction was terminated. The plate was centrifuged quickly and the reaction was incubated at room temperature for 40 minutes. The kinase detection reagent was then added and incubated at room temperature for 30 minutes. The relative light units (RLU) of the kinase reaction were determined by luminescence (luminescence 0.1 s) using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA). Table 1 provides the IC values ​​obtained from this example. 50 value.

[0469]

[0470]

[0471]

[0472] Whole cell assay data

[0473] In this example, U937 and L929 cells were exposed to compounds of the disclosure and subjected to necroptosis assays to evaluate the activity of the compounds against human and murine RIP1.

[0474] U937 and L929 cells were obtained from the American Type Culture Collection (Manassa, VA, USA). Both cells were maintained in the logarithmic growth phase at 37°C and 5% CO2 in complete RPMI 1640 medium (Sigma, ST Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis, MO, USA). For programmed necrosis assay, L929 cells were plated at 10,000 cells / well in 100 μL / well culture medium in Costar 96-well black transparent bottom plates (FisherScientific, Hampton, NH, USA) for 18 hours; on the day of the assay, U937 cells were plated at 50,000 cells / well in 50 μL / well culture medium containing 60uM zVAD-fmk (Lonza, Basel, Switzerland). Remove the culture medium from L929 cells from 96-well plates and replace with new culture medium containing 40uM zVAD-fmk in 50 μL / wells. Each compound of the present disclosure evaluated in this embodiment was serially diluted from 2.5mM in DMSO by 4-fold dilution, and then diluted 1:125 in complete medium. Then 50 μL / well of 2x compound was added to the cells in the plate. Cells were pre-incubated with the compound at 37°C and 5%CO2 for 1 hour, and then 10 μL / well of 11x TNFa (Peprotech, Rocky Hill, NJ, the U.S.) was added to obtain a final concentration of TNFa of 2ng / mL. After TNFa stimulation for 18 hours at 37°C and 5% CO2, the relative amount of programmed necrosis cells was determined by luminescence using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA) and CellTiter-Glo® luminescent cell viability reagent assay (Promega, Madison, WI, USA) (added according to the manufacturer's instructions). The results from this example are summarized in Table 2. This example determines that embodiments of the compounds described herein have unexpectedly potent activity against human RIP1 and mouse RIP1, which allows them to be evaluated in an in vivo mouse model of the disease. These results can be used to determine safe and effective doses for humans.

[0475]

[0476]

[0477] Acute in vivo assay

[0478] In this example, an acute hypothermia mouse model assay was used to evaluate the ability of compounds disclosed herein to inhibit TNF-α-induced hypothermia.

[0479] Female C57BL / 6 mice were randomized and weighed on day -1. On the day of the study (day 0), the mice were administered vehicle or test article by oral gavage. Fifteen minutes after oral administration of the test agent, each mouse was administered an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor alpha (TNF-a, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured at hour 0 (before intraperitoneal injection) and every hour via a rectal probe temperature measurement device. Three (3) hours after intraperitoneal injection of TNF-a and zVAD / FMK, mice were euthanized by CO2 asphyxiation and blood was collected via cardiac puncture. Serum and plasma were harvested for determination of cytokine and compound levels, respectively. A separate group of mice (satellite mice) was included to determine compound levels in plasma at the time of administration of TNFa / zVAD-FMK. The compounds of the present disclosure inhibit TNF-a-induced hypothermia.

[0480] Brain Infiltration

[0481] Certain embodiments of the present invention provide a compound, a plurality of compounds, or a combination thereof that crosses the blood-brain barrier. The disclosed compound and composition embodiments exhibit sufficient brain penetration as potential therapeutic agents for neurological diseases. Brain penetration can be assessed by evaluating the brain / plasma ratio (B / P) (as measured by in vivo pharmacokinetic studies in rodents) and determining the free fraction in the rodent brain in vitro. As an example, compound I-44 exhibits a B / P ratio of 1.6, and compound I-58 exhibits a B / P ratio of 0.44. Other embodiments exhibit higher distribution ratios. Without being limited 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 of ordinary skill in the art. See, for example, Liu, X. et al., J.Pharmacol. Exp. Therap., 325:349-56, 2008. 1I - MDR1通透性。 In this method, the passive membrane permeability (Papp) and P-gp (P-glycoprotein) substrate efflux potential were 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 less than or equal to 2.5 may exhibit the ability to cross the blood-brain barrier.

[0482] Brain free fraction is a predictive marker for assessing the potential of potential therapeutics in the central nervous system. See, Read KD; Braggio S. Assessing brain free fraction in early drug discovery. 专家意见:药物代谢与毒理学 . 2010, 6, 337-344.

[0483] Therefore, the brain free fractions of representative compounds are provided in Table 3:

[0484]

[0485] The determination of brain free fraction is known, and thus one skilled in the art can determine the brain free fraction of other compounds disclosed herein. See, Srinivas, Nithya et al. "Clinical Pharmacokinetics and Pharmacodynamics of Drugs in the Central Nervous System." 临床 药代动力学 Vol. 57, 9 (2018): 1059-1074. doi:10.1007 / s40262-018-0632-y. The brain free fractions reported in Table 3 indicate that the exemplary compounds exhibit characteristics of central nervous system active compounds.

[0486] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are merely preferred examples of the invention and should not be viewed as limiting the scope of the invention. Instead, the scope of the invention is defined by the following claims. We therefore claim that all that falls within the scope and spirit of these claims is our invention.

Claims

1. Compounds according to formula I wherein Ring B is triazole, diazole, oxazole, oxadiazole, pyrazolyl or pyridinyl; X is CH2 or O; L is O or CH2; Z is for C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 Cycloalkyl, phenyl, pyridyl, pyrimidinyl or pyrazolyl, each optionally substituted by one or more R 5 group substitution; R 1 In each occurrence, independently R 2 It is CH3; R 3 It is H; R 4 It is a halogen; R 5 It is a halogen; m is 1; and n is 0 or 1.

2. The compound of claim 1, wherein Ring B is triazole, oxadiazole, oxazole or oxadiazole.

3. The compound of claim 1, wherein ring B is pyrazolyl, and the -N(R 3 The )C(O)- moiety is attached to ring B at a ring nitrogen atom on ring B.

4. The compound of claim 1, wherein ring B is pyridyl.

5. The compound of claim 1, wherein n is 0.

6. The compound of claim 1, wherein n is 1.

7. The compound of claim 1, wherein at least one R 4 It's fluorine.

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

9. The compound of claim 1, wherein X is -CH2-.

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

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

12. The compound of claim 1 having formula II 13. The compound of claim 1 having formula IIA 14. The compound of claim 1 having the formula IIF, IIG, IIH 15. The compound of claim 1, wherein R 1 yes:

16. The compound of claim 1, wherein R 1 yes 17. The compound of claim 1, wherein at least one R 1 yes 18. The compound of claim 1, having the formula 19. The compound of claim 1 having the formula 20. Use of the compound according to any one of claims 1 to 19 or a pharmaceutical composition containing the compound according to any one of claims 1 to 19 for preparing a medicament for treating a disease, wherein the disease is a disease involving receptor interacting protein-1 kinase.

21. The use according to claim 20, wherein the disease is an inflammatory or immunoregulatory disorder.

22. The use according to claim 20, wherein the disease is a senile disorder.

23. The use according to claim 20, wherein the disease is selected from amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease or Alzheimer's disease.

24. The use of claim 20, wherein the disease is atopic dermatitis, rheumatoid arthritis or ankylosing spondylitis.

25. The use of claim 20, wherein the disease is myelodysplastic syndrome.

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