Methods for Treating Migraine with MNK Inhibitors

Abstract

Methods are provided for treating migraine and migraine-related symptoms comprising administering a therapeutically effective amount of a compound having activity as an inhibitor of MNK. One embodiment provides a compound having the structure (II), or a pharma- ceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 2 , X, Y, and L are as defined herein.

Description

[Technical Field]

[0001] The present disclosure describes compounds and methods useful as mitogen-activated protein kinase-interacting kinase ("MNK") inhibitors, useful in the treatment of migraine and related conditions. [Background technology]

[0002] 2. Description of Related Art Migraines affect approximately 35 million people each year in the United States alone. 45% of women and 18% of men will experience a migraine at some point in their lifetime. Not only are migraines painful, they can seriously impair a migraine sufferer's ability to perform life's most basic functions. To make matters worse, migraines are most typical in people between the ages of 35 and 45, which are often the prime years of paid work and child-rearing, and migraines often affect more than just a person's well-being.

[0003] The causes of migraine are still poorly understood, and although treatments have certainly improved in recent years, many common therapies have serious side effects or are simply ineffective for many migraine sufferers.

[0004] Thus, there is a need to develop compounds that are effective in treating migraine. Embodiments of the present disclosure fulfill this need and provide further related advantages. Summary of the Invention

[0005] Briefly, embodiments of the present disclosure provide compounds, including pharmaceutically acceptable salts, stereoisomers, tautomers and prodrugs thereof, that are useful for the treatment of migraine headaches.

[0006] In one embodiment, the compound has the following structure (I): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a, R 1b , and R 3 each of which is as defined herein.

[0007] In another embodiment, the compound has the following structure (II): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 2 , X, Y, and L are as defined herein.

[0008] In yet another embodiment, the compound has the following structure (III): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 2 , R 3 , Z 1 , and Z 2 is as defined herein.

[0009] In yet another embodiment, the compound has the following structure (IX): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4c , R 4d , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , Z1 , n, z, and q are as defined herein. [Brief explanation of the drawings]

[0010] [Figure 1] 1 shows an analytical scale chromatogram of the first eluting peak (i.e., "Enantiomer 1 of 4ET-01-027") from the separation of a racemic mixture of 4ET-01-027 ("rac-4ET-01-027"). [Figure 2] 1 shows an analytical scale chromatogram of the second eluting peak (i.e., "Enantiomer 2 of 4ET-01-027") from the separation of a racemic mixture of 4ET-01-027 ("rac-4ET-01-027"). [Figure 3A] We show that genetic inhibition of MNK partially attenuates facial hypersensitivity and hyperalgesic priming induced by dural interleukin-6 ("IL-6"). [Figure 3B] We show that genetic inhibition of MNK partially attenuates facial hypersensitivity and hyperalgesic priming induced by dural interleukin-6 ("IL-6"). [Figure 4A] Figure 1 shows that MNK1 knockout ("KO") mice fail to prime to low doses of NO donors after repeated stress. [Figure 4B] Figure 1 shows that MNK1 knockout ("KO") mice fail to prime to low doses of NO donors after repeated stress. [Figure 5A] We show how eFT508 reduces dural IL-6-induced facial hypersensitivity and prevents priming to pH 7.0. [Figure 5B] We show how eFT508 reduces dural IL-6-induced facial hypersensitivity and prevents priming to pH 7.0. [Figure 6] 1 shows that rac-4ET-01-027, enantiomer 1 of 4ET-01-027, and 4ET-04-023 reduce maternal IL-6-induced facial grimacing. DETAILED DESCRIPTION OF THE INVENTION

[0011] The compounds of the present disclosure can treat and prevent migraine and related migraine symptoms.It has been discovered that MNK plays an important role in migraine and migraine-related symptoms.As a result, these MNK inhibitors are useful for treating migraine and migraine-related symptoms.

[0012] Throughout this specification, when a composition is described as having, containing, or comprising particular ingredients, or a process is described as having, including, or comprising particular process steps, it is contemplated that the compositions of the present teachings also consist essentially of or consist of the recited ingredients, and that the processes of the present teachings also consist essentially of or consist of the recited process steps.

[0013] In this application, when an element or component is said to be included in and / or selected from a list of enumerated elements or components, it should be understood that the element or component can be any one of the listed elements or components, or can be selected from a group consisting of two or more of the listed elements or components.

[0014] The present disclosure is directed to MNK inhibitors and the treatment of migraine and migraine-related symptoms.

[0015] In the following description, specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details.

[0016] Unless the context otherwise requires, throughout this specification and the claims that follow, the word "comprise" and variations thereof (such as "comprises" and "comprising") are to be construed in an open-ended and inclusive sense, i.e., "including, but not limited to."

[0017] As used herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and fractions thereof (such as tenths and hundredths of integers), where appropriate, unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure, unless otherwise indicated. The use of alternative terms (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0018] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described with respect to an embodiment of the present disclosure is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0020] As used herein, the term "MNK" is intended to mean mitogen-activated protein (MAP) kinase (MAPK)-interacting kinase.

[0021] "Amino" refers to the -NH2 radical.

[0022] "Carboxy" or "carboxyl" refers to the -CO2H radical.

[0023] "Cyano" refers to the -CN radical.

[0024] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0025] "Nitro" refers to the -NO2 radical.

[0026] "Oxo" refers to the =O substituent.

[0027] "Thiol" refers to an --SH substituent.

[0028] "Thioxo" refers to =S.

[0029] "Alkyl" means an alkyl group consisting solely of carbon and hydrogen atoms and having 1 to 12 carbon atoms (C1-C 12 "C" refers to a saturated straight or branched hydrocarbon chain radical having 1 to 8 carbon atoms (C-C alkyl), 1 to 8 carbon atoms (C-C alkyl), or 1 to 6 carbon atoms (C-C alkyl), or any value within these ranges, e.g., C-C alkyl, which is attached to the rest of the molecule by a single bond, and includes, for example, methyl, ethyl n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. The carbon numbers referred to refer to the carbon backbone and carbon branches, but do not include carbon atoms belonging to any substituents. Unless specifically stated otherwise in the specification, alkyl groups are optionally substituted.

[0030] "Alkenyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, and having 2 to 12 carbon atoms (C-C 12"Alkenyl" refers to an unsaturated straight or branched hydrocarbon chain radical having 2 to 8 carbon atoms (C2-C8 alkenyl), 2 to 6 carbon atoms (C2-C6 alkenyl), or any value within these ranges, which is attached to the rest of the molecule by a single bond, and includes, for example, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. The carbon numbers referred to refer to the carbon backbone and carbon branches, but do not include carbon atoms belonging to any substituents. Unless specifically stated otherwise in the specification, alkenyl groups are optionally substituted.

[0031] The term "alkynyl" refers to an alkynyl group having 2 to 12 carbon atoms (C2-C 12 "Alkynyl" refers to an unsaturated straight or branched chain hydrocarbon radical having 2 to 9 carbon atoms (C2-C9 alkynyl), or 2 to 6 carbon atoms (C2-C6 alkynyl), or any value within these ranges, and having at least one carbon-carbon triple bond. Examples of alkynyl groups may be selected from the group consisting of ethynyl, propargyl, but-1-ynyl, but-2-ynyl, and the like. The carbon numbers referred to refer to the carbon backbone and carbon branches, but do not include carbon atoms belonging to any substituents. Unless specifically stated otherwise in the specification, alkynyl groups are optionally substituted.

[0032] "Alkoxy" means a group of the formula -OR a where R a is a group of 1 to 12 carbon atoms (C1-C 12 and alkyl radicals as defined above having 1 to 8 carbon atoms (C1-C8 alkoxy), 1 to 6 carbon atoms (C1-C6 alkoxy), or any value within these ranges. Unless specifically stated otherwise in the specification, an alkoxy group is optionally substituted.

[0033] "Aminyl" means a group of the formula -NR a R b where R a is H or C1-C6 alkyl, and Rb is C1-C6 alkyl as defined above. The C1-C6 alkyl portion of an aminyl group is optionally substituted unless otherwise specified.

[0034] An "aminoalkylcycloalkyl" is a group of the formula -R a R b NR c R d where R a is cycloalkyl as defined herein, and R b is C1-C6 alkyl, and R c is H or C1-C6 alkyl, and R d is C1-C6 alkyl as defined above. The cycloalkyl and each C1-C6 alkyl portion of an aminylalkylcycloalkyl group is optionally substituted unless otherwise specified.

[0035] "Aromatic ring" refers to a cyclic, planar molecule or portion of a molecule (i.e., radical) having a resonance-bonded ring that exhibits increased stability compared to other bonding arrangements with the same set of atoms. Generally, aromatic rings contain a set of covalently bonded, coplanar atoms and contain an even number of π electrons (i.e., 4n+2 π electrons, n=0, 1, 2, 3, etc.) (e.g., alternating double and single bonds) that is not a multiple of four. Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, and pyrimidonyl. Unless specifically stated otherwise in this specification, "aromatic ring" includes all optionally substituted radicals.

[0036] "Aryl" refers to an alkyl group having 6 to 18 carbon atoms, e.g., 6 to 10 carbon atoms (C6-C 10"(aryl)" refers to a carbocyclic ring system radical containing at least one carbocyclic aromatic ring. For purposes of embodiments of the present disclosure, an aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.

[0037] As used herein, "aryl" includes fused ring systems containing non-aromatic moieties. For example, in some embodiments, aryl has the following structure: [ka] The signal may have one of the following:

[0038] Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.

[0039] The term "arylalkyl" or "aralkyl" refers to the group -alkyl-aryl, where alkyl and aryl groups are as defined herein. Aralkyl groups of the present disclosure are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, and the like.

[0040] "Cyanoalkyl" refers to an alkyl group that includes at least one cyano substituent. The -CN substituent may be on a primary, secondary, or tertiary carbon. Unless otherwise specifically stated in the specification, a cyanoalkyl group is optionally substituted.

[0041] "Carbocyclic" or "carbocycle" refers to a ring system in which each of the ring atoms is carbon.

[0042] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic radical, consisting solely of carbon and hydrogen atoms, including 3 to 15 ring carbon atoms (C3-C4). 15 Cycloalkyl), 3 to 10 ring carbon atoms (C3-C 10 Cycloalkyl radicals may include fused or bridged ring systems having 3 to 8 ring carbon atoms (C-C cycloalkyl), or 3 to 8 ring carbon atoms (C-C cycloalkyl), or any value within these ranges, e.g., 3 to 4 carbon atoms (C-C cycloalkyl), which may be saturated or partially unsaturated and are attached to the remainder of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in the specification, cycloalkyl groups are optionally substituted.

[0043] "Alkylcycloalkyl" refers to a group of the formula -R a R b where R a is a cycloalkyl group, and R b is an alkyl group as defined above. Unless stated otherwise specifically in the specification, an alkylcycloalkyl group is optionally substituted.

[0044] "Fused" refers to any ring structure described herein that is fused to another ring structure.

[0045] "Halo" refers to bromo, chloro, fluoro, or iodo.

[0046] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0047] "Halocycloalkyl" refers to a cycloalkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted.

[0048] A "haloalkylcycloalkyl" is a group of the formula -R a R b where R a is a cycloalkyl group, and R b is a haloalkyl group as defined above. Unless stated otherwise specifically in the specification, a haloalkylcycloalkyl group is optionally substituted.

[0049] "Halocycloalkylalkyl" refers to a group of the formula -R a R b where R a is an alkyl group, and R b is a halocycloalkyl group as defined above. Unless stated otherwise specifically in the specification, a halocycloalkylalkyl group is optionally substituted.

[0050] A "heterocyclylcycloalkyl" is a group of the formula -R a R b where R a is a cycloalkyl group, and Rb is a heterocyclyl group as defined herein. Unless stated otherwise in the specification, a heterocyclylcycloalkyl group is optionally substituted.

[0051] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyl radicals, as defined above. The hydroxyalkyl group is attached to the main chain via an alkyl carbon atom. Unless otherwise specifically stated in the specification, the hydroxylalkyl group is optionally substituted.

[0052] "Heterocyclyl," "heterocyclic," or "heterocycle" refers to a 3- to 18-membered, e.g., 3- to 10-membered or 3- to 8-membered, non-aromatic ring radical having 1 to 10, e.g., 2 to 10, ring carbon atoms and 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, a heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, spiro, and / or bridged ring systems. The nitrogen, carbon, and sulfur atoms in the heterocyclyl radical are optionally oxidized, and the nitrogen atom can be optionally quaternized. Non-limiting examples of heterocyclic units having a single ring include aziridinyl, aziridinyl, uralyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinone, oxathiazolinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclic units having two or more rings include hexahydro-1H-pyrrolidinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl. As used herein, "heterocyclyl" includes fused ring systems containing additional non-heterocyclyl components. For example, in some embodiments, heterocyclyl has the following structure: [ka] The signal may have one of the following:

[0053] Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted.

[0054] "Haloheterocyclyl" refers to a heterocyclyl group containing at least one halo substituent. The halo substituent may be on a primary, secondary, or tertiary carbon. Unless stated otherwise specifically in the specification, a haloheterocyclyl group is optionally substituted.

[0055] "Haloheterocyclylalkyl" refers to a group of the formula -R a R b where R a is an alkyl group, and R b is a haloheterocyclyl group as defined herein. Unless stated otherwise in the specification, a haloheterocyclylalkyl group is optionally substituted.

[0056] "Heterocyclylalkyl" refers to a group of the formula -R a R b where R a is an alkyl group, and R b is a heterocyclyl group as defined herein. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[0057] "Heteroaryl" refers to a 5- to 18-membered, e.g., 5- or 6-membered, ring system radical containing 1 to 13 ring carbon atoms, 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. The heteroaryl radical can be monocyclic, bicyclic, tricyclic, or tetracyclic, which can include fused or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzothiadiazolyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, and isoindoline. Examples of aryl include, but are not limited to, aryl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). As used herein, "heteroaryl" includes fused ring systems in which the heteroatom (e.g., oxygen, sulfur, nitrogen, etc.) is not part of the aryl moiety. For example, in some embodiments, a heteroaryl can have the following structure: [ka]

[0058] Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[0059] Non-limiting examples of heteroaryl rings, including monocyclic rings, include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl.

[0060] A non-limiting example of the above-mentioned heteroaryl group is C1-C5 heteroaryl having 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom independently selected from nitrogen (N), oxygen (O), or sulfur (S) (preferably 1 to 4 additional ring atoms that are heteroatoms). Examples of C1-C5 heteroaryl include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0061] Unless otherwise specified, when two substituents combine to form a ring having a specified number of ring atoms (e.g., R 2 and R 3 are combined with the nitrogen (N) to which they are attached to form a ring having 3 to 7 ring members, the ring can have carbon atoms and, optionally, one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring can be saturated or partially saturated and can be optionally substituted.

[0062] For purposes of this disclosure, fused ring units containing a single heteroatom, as well as spirocyclic rings, bicyclic rings, and the like, are considered to belong to the ring family corresponding to the heteroatom-containing ring. For example, 1,2,3,4-tetrahydroquinoline having the formula: [ka] is considered a heterocyclic unit for the purposes of this disclosure. 6,7-dihydro-5H-cyclopentapyrimidine having the formula: [ka] is considered a heteroaryl unit for purposes of this disclosure. When a fused ring unit contains heteroatoms in both the saturated ring and the aryl ring, the aryl ring predominates and determines the type of category to which the ring is assigned. For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula: [ka] is considered a heteroaryl unit for the purposes of this disclosure.

[0063] Whenever a term or any of its prefix roots appears in a name of a substituent, that name should be interpreted as including those limitations provided herein. For example, whenever the term "alkyl" or "aryl" or any of their prefix roots appears in a name of a substituent (e.g., arylalkyl, alkylamino), that name should be interpreted as including those limitations given above for "alkyl" and "aryl."

[0064] The term "substituted" is used throughout this specification. The term "substituted" is defined herein as a moiety, whether acyclic or cyclic, in which one or more hydrogen atoms have been replaced by a substituent or several (e.g., 1 to 10) substituents, as defined below. Substituents can replace one or two hydrogen atoms of a single moiety at a time. Furthermore, these substituents can replace two hydrogen atoms on two adjacent carbons to form the substituent, new moiety, or unit. For example, substitution units requiring a single hydrogen atom replacement include halogen, hydroxyl, etc. Replacement of two hydrogen atoms includes carbonyl, oximino, etc. Replacement of two hydrogen atoms from adjacent carbon atoms includes epoxy, etc. The term "substituted" is used throughout this specification to indicate that one or more hydrogen atoms of a moiety can be replaced by a substituent. When a moiety is described as "substituted," any number of hydrogen atoms can be replaced. For example, difluoromethyl is a substituted C1 alkyl, trifluoromethyl is a substituted C1 alkyl, 4-hydroxyphenyl is a substituted aromatic ring, (N,N-dimethyl-5-amino)octanyl is a substituted C8 alkyl, 3-guanidinopropyl is a substituted C3 alkyl, and 2-carboxypyridinyl is a substituted heteroaryl.

[0065] Variable groups defined herein, for example, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle, and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups are as indicated.

[0066] In some embodiments, the substituent is i)-OR x+2 , for example, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, ii)-C(O)R x+2, for example, -COCH3, -COCH2CH3, -COCH2CH2CH3, iii)-C(O)OR x+2 , for example, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3, iv)-C(O)N(R x+2 )2, for example, -CONH2, -CONHCH3, -CON(CH3)2, v)-N(R x+2 )2, for example, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), vi) the halogens, -F, -Cl, -Br, and -I; vii)-CH e X g (wherein X is a halogen, m is 0 to 2, and e+g=3), for example, —CHF, —CHF, —CF, —CCl, or —CBr; viii)-SO2R x+2 , for example, -SO2H, -SO2CH3, -SO2C6H5, ix) C1-C6 straight, branched, or cyclic alkyl; x) Cyano xi) nitro, xii)N(R x+2 )C(O)R x+2 , xiii) oxo (=O), xiv) heterocycles, and xv) heteroaryl; Each R x+2 are independently hydrogen, optionally substituted C1-C6 straight or branched chain alkyl (e.g., optionally substituted C1-C4 straight or branched chain alkyl), or optionally substituted C3-C6 cycloalkyl (e.g., optionally substituted C3-C4 cycloalkyl), or two R x+2 The units can, together, form a ring containing 3 to 7 ring atoms. In certain embodiments, each R x+2 are independently halogen or C 3- C6 cycloalkyl or hydrogen optionally substituted with C3-C6 cycloalkyl, C1-C6 straight or branched chain alkyl.

[0067] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0068] "Patient" or "subject" refers to an animal, such as a mammal, e.g., a human. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human. Other subjects include mammals that do not tolerate opioids well, or mammals that are common pets or livestock (e.g., dogs, cats, and horses).

[0069] "Mammal" includes humans and both domestic animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals.

[0070] "Pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.

[0071] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent.

[0072] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0073] A "pharmaceutically acceptable acid addition salt" refers to a salt that retains the biological effectiveness of the free base and is biologically acceptable or otherwise biologically suitable for administration to a subject. See generally S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic response. "Pharmaceutically acceptable acid addition salts" are those which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and include inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, glutamic ... It refers to salts formed with organic acids such as conic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0074] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness of the free acid and is biologically acceptable or otherwise biologically suitable for administration to a subject. See generally S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic reaction. Pharmaceutically acceptable base addition salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts.Salts derived from 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 ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dianol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0075] "Drug" refers to a compound that is biologically active and provides a desired physiological effect after administration to a patient in need thereof.

[0076] "Prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., a compound of structures (I)-(XLIX)). Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. The term "prodrug" is also intended to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds, as described herein, are typically prepared by modifying functional groups present in the active compound, such that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent active compound. Prodrugs include compounds of the present disclosure in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to restore the free hydroxy, amino, or mercapto group, respectively, when a prodrug of the present disclosure is administered to a mammalian subject.Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of hydroxy functional groups, or acetamide, formamide and benzamide derivatives of amine functional groups in the active compounds.

[0077] Furthermore, embodiments of the present disclosure may provide prodrugs of MNK inhibitors. Prodrugs are compounds that can be converted into active drugs. Generally, prodrugs are administered to a patient and then converted in vivo to the physiologically active form of the compound. In some cases, prodrugs may have a desired physiological effect. Prodrugs of the present disclosure may contain functional groups including esters, amides, phosphate esters, sulfonamides, or combinations thereof.

[0078] "Derivative" refers to a compound that can be synthesized from a parent compound by replacing one atom with another atom or group of atoms.

[0079] "Migraine" refers to a headache or aura resulting from abnormal brain activity, but not caused by a tumor, other serious medical problems, or a viral or bacterial infection of the sinuses or nasal passages. Currently, there are no blood tests or scans that can diagnose migraine. As a result, a diagnosis is often made by a qualified physician after ruling out other causes of headache and taking into account migraine symptoms and a family history of migraine. Migraine symptoms often include moderate to severe pain, intense pain, inability to perform activities of daily living while experiencing the headache, aura, a pulsating, throbbing, or pulsating sensation in the head, pain worsened by physical activity, pain worsened by any movement, nausea and / or vomiting, sensitivity to sound, light, or smell, and duration of more than four hours.

[0080] Migraine headaches are often considered to have four stages: prodrome, aura, headache, and post-onset symptoms.

[0081] Late symptoms are often characterized by extreme fatigue and yawning, irritability or moodiness, difficulty concentrating, and food cravings.

[0082] Auras are most typically visual. Visual auras include flashing lights, blind spots, bright spots, wavy, zigzag, or C-shaped lines, bright geometric lines and / or shapes in the visual field, blurred vision, or visual hallucinations. Sensory auras, such as tingling or numbness in the extremities, face, or tongue, and speech-impaired auras, are also sometimes observed. Migraines may also be diagnosed, at least in part, by their occurrence in response to triggers such as caffeine withdrawal, hormonal changes, lack of sleep, alcohol, exercise or physical stress, loud noises, bright lights, dietary deprivation, odors, perfumes, smoking or smoke exposure, stress, anxiety, and / or eating common trigger foods such as chocolate, dairy products, especially cheese, MSG, foods containing tyramine, especially red wine, aged cheeses, smoked fish, chicken liver, figs, and beans, fruits, especially avocados, bananas, or citrus fruits, meats containing nitrates such as bacon, hot dogs, salami, and cured meats, onions, peanuts and other nuts and seeds, fermented foods, and pickled foods.

[0083] Late symptoms are often characterized by fatigue, body aches, difficulty concentrating, dizziness, and sensitivity to light.

[0084] Not all patients experience prodromal and / or post-symptoms. Furthermore, not all patients experience an aura, or some experience it along with a headache. Some patients experience the aura alone, or the aura with prodromal and / or post-symptoms but without headache. Any patient experiencing an aura and / or headache is typically considered to be suffering from a migraine.

[0085] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that is sufficient to achieve the intended application, including but not limited to, the treatment of diseases as defined below. A therapeutically effective amount may vary depending on the intended therapeutic application (in vivo), or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a specific response in target cells, such as reduced platelet adhesion and / or cell migration. Specific doses will vary depending on the particular compound selected, the administration regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is delivered.

[0086] As used herein, "treatment" or "treating" refers to an approach to obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic effect and / or a prophylactic effect. A therapeutic effect refers to the eradication or amelioration of the underlying disease being treated. A therapeutic benefit is also achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in a subject, even though the subject may still be afflicted with the underlying disease. A prophylactic effect includes delaying or eliminating the appearance of the disease or condition, delaying or eliminating the onset of symptoms of the disease or condition, slowing, halting, or reversing the progression of the disease or condition, or any combination thereof. In certain embodiments, for prophylactic benefit, a composition is administered to a subject at risk of developing a particular disease or reporting one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0087] As used herein, the terms "co-administration," "administered in combination," and their grammatical equivalents include the administration of two or more agents to an animal, including a human, such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0088] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide salts (eg, methyl bromide).

[0089] The term "in vivo" refers to events that take place inside a subject's body.

[0090] The embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of structures (I) through (XLIX).

[0091] Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, and the like, of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments encompass compounds produced by a process comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the present disclosure to an animal, e.g., a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0092] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0093] In many cases, crystallization produces solvates of the compounds of the present disclosure. As used herein, the term "solvate" refers to an aggregate containing one or more compounds of the present disclosure together with one or more solvent molecules. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present disclosure can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvate forms. In some aspects, the compounds of the present disclosure are true solvates, while in other cases, the compounds of the present disclosure are simply mixtures of water and some extraneous solvent, even if they retain extraneous water.

[0094] "Any" or "optionally" means that the subsequently described circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that the description includes both substituted aryl radicals and aryl radicals with no substitution.

[0095] A "pharmaceutical composition" refers to a medium generally accepted in the art for the formulation of a compound of the present disclosure and delivery of the compound to a mammal, e.g., a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0096] "Stereoisomers" refer to compounds consisting of the same atoms joined by the same bonds, but having different, non-interchangeable three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0097] The compounds of the present disclosure (i.e., compounds of structures (I) through (XLIX)), or pharmaceutically acceptable salts thereof, may contain one or more centers of geometric asymmetry and thus give rise to stereoisomers, enantiomers, diastereomers, and other stereoisomeric forms defined with respect to absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, as (D)- or (L)-. Accordingly, embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0098] The embodiments of the present disclosure include all manner of rotamers and conformationally restricted states of the compounds of the present disclosure. Also included are atropisomers, which are stereoisomers that arise due to hindrance of rotation around a single bond, where the energy difference due to steric strain or other contributing factors creates a barrier to rotation high enough to allow the isolation of individual conformers. As an example, certain compounds of the present disclosure can exist as a mixture of atropisomers, or can be purified or enriched for the presence of a single atropisomer.

[0099] In some embodiments, the compounds of structures (I)-(XLIX) are mixtures of enantiomers or diastereomers. In other embodiments, the compounds of structures (I)-(XLIX) are substantially one enantiomer or diastereomer.

[0100] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. Thus, embodiments include tautomers of the disclosed compounds.

[0101] The chemical naming protocols and structural diagrams used herein are modifications of the IUPAC naming system using the ACD / Name version 9.07 software program and / or the ChemDraw Professional version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names used herein, a substituent is typically named before the group to which it is attached. For example, cyclopropylethyl contains an ethyl skeleton with a cyclopropyl substituent. Except as noted below, all bonds are identified in the chemical structural diagrams herein, except that all bonds on some carbon atoms are assumed to be attached to sufficient hydrogen atoms to complete valence.

[0102] compound The present disclosure is directed to MNK inhibitors used to treat, prevent, or alleviate the effects of migraine and related conditions.

[0103] In some embodiments, the MNK inhibitor has the following structure (Ia): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R 1a and R 1b are each independently alkyl. In some embodiments, R 1a and R 1b are the same. In certain embodiments, R 1a and R 1b are different. R 1a or R 1b R can be an alkyl group such as a methyl, ethyl, propyl, isopropyl, or tert-butyl group. 1a or R1b The substituents can be the same or different alkyl groups. For example, R 1a can be a methyl group, while R 1b can be an ethyl group. 1a can be an isopropyl group, while R 1b may be a tert-butyl group. 1a or R 1b Any combination of alkyl groups may be used.

[0104] In some embodiments, R 1a and R 1b are linked together to form a cyclic moiety. In certain embodiments, the compound has the following structure (Ib): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R 1a and R 1b may be joined together to form ring A.

[0105] Structure (Ib), substituent R 1a or R 1bcan be bonded together to form a cyclic compound, designated as cyclic moiety A. For example, cyclic moiety A in structure (Ib) can include a five-membered ring. cyclic moiety A in structure (Ib) can be an unsubstituted cyclic compound. For example, cyclic moiety A can be an unsubstituted five-membered ring, such as cyclopentane. Furthermore, cyclic moiety A in structure (Ib) can have one or more alkyl substitutions. For example, alkyl substitutions on cyclic moiety A can include methyl, ethyl, propyl, isopropyl, cyclopropyl, or tert-butyl groups. The substitution position can be at the 2-, 3-, 4-, or 5-position of the cyclopentane. The degree of substitution can include mono-, di-, tri-, or tetra-substitution. For example, cyclic moiety A can be 2,2,5,5-tetramethylcyclopentane. Different substitution patterns can be introduced on the cyclopentane ring using synthetic routes. For example, cyclic moiety A can be 3,3,4,4-tetramethylcyclopentane.

[0106] Furthermore, the cyclic moiety A may have fused rings. A portion of the cyclic moiety A may include a fused benzene ring. For example, the cyclic moiety A may include a benzene ring fused with a cyclopentyl or cyclohexyl ring. For example, a synthetic route to prepare a benzene-fused cyclohexyl compound may include the use of 1-tetralone. Furthermore, the cyclic moiety A may include a cyclopentyl or cyclohexyl ring fused with another cyclic structure.

[0107] The cyclic moiety A can include a six-membered ring. The cyclic moiety A can be an unsubstituted cyclic moiety. For example, the cyclic moiety A can be an unsubstituted six-membered ring such as cyclohexane. Furthermore, the cyclic moiety A can have one or more alkyl substitutions. For example, the alkyl substitution on the cyclic moiety A can include methyl, ethyl, propyl, isopropyl, cyclopropyl, or tert-butyl groups. The cyclic moiety A can have one or more heteroatom-containing substituents (e.g., alcohol, sulfonamide, or carboxylic acid). The substitution position can be the 2-, 3-, 4-, 5-, or 6-position of the cyclohexane. The degree of substitution can include mono-, di-, tri-, or tetra-substitution. For example, the cyclic moiety A can be 3,5-dimethylcyclohexane. Different substitution patterns can be introduced on the cyclohexane ring using synthetic routes. For example, the cyclic moiety A can be 2,3,4,5,6-pentamethylcyclohexane.

[0108] The cyclic moiety A can include a heterocyclic compound. A heterocyclic compound is a cyclic compound having atoms of at least two different elements, such as carbon and oxygen atoms. For example, the cyclic moiety A can be tetrahydropyran. Tetrahydropyran contains one oxygen atom and five carbon atoms in a six-membered ring. The heterocyclic compound can be further substituted with alkyl substituents or functional groups at various positions with various degrees of substitution. Note that while some of the structures shown in this disclosure include oxygen atoms in the cyclic compound, such structures are provided for illustrative purposes only. Different heteroatoms can be introduced into the cyclic compound using synthetic routes. For example, the cyclic moiety A in structure (Ib) can include a piperidine (nitrogen atom), a phosphinate (phosphorus atom), a silinane (silicon atom), or a thiane (sulfur atom).

[0109] The cyclic moiety A can be unsaturated. Unsaturated cyclic compounds can include aromatic cyclic compounds such as benzene, pyridine, diazine, oxazine, dioxin, or thiazine. Alternatively, the cyclic moiety A can be saturated.

[0110] The cyclic moiety A may have one or more functional group substitutions. For example, the functional group may include hydroxyl, amine, amide, carboxylic acid, ether, or sulfonamide. Thus, the cyclic moiety A may include 4-hydroxycyclohexane, 4-carboxylic acid cyclohexane, 4-methoxylcyclohexane, or 4-alkylsulfonamide cyclohexane. The substitution position may be the 2-, 3-, 4-, 5-, or 6-position of the cyclohexane. The degree of substitution may include mono-, di-, tri-, tetra-, or penta-substitution. One or more functional groups may be introduced onto the heterocyclic compound at various substitution positions and degrees.

[0111] The substituent R of structures (Ia) and (Ib) 2 may contain nitrogen-containing functional groups. For example, the substituent R 2 The nitrogen-containing functional group of may include an amide, amidine, amine, amine oxide, azo, carbamate, carbodiimide, enamine, aromatic heterocycle, non-aromatic heterocycle, hydrazone, hydroxamic acid, imide, imine, nitrile, sulfonamide, or urea. For example, the aromatic heterocycle may include a pyrrole, imidazole, pyrazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine. The substituent R 2 The nitrogen-containing functional group in may be unsubstituted or substituted. For example, pyridazine may be substituted with an amine group at the 3-position, as shown in 4ET-004-006 below. In another example, pyridazine may be substituted with an amide containing a cyclopropyl ring at the 3-position, as shown in 4ET-004-003 below. The degree and position of substitution on the nitrogen-containing functional group may vary. The substituent R 2 The nitrogen-containing functional group is -C n H 2n -, where n is 0 to 5. In this regard, the substituent R 2 and the nitrogen-containing functional groups of skeletal structures (Ia) and (Ib) are separated by n carbon atoms.

[0112] The substituent R of structures (Ia) and (Ib) 2may include an aromatic heterocycle. For example, in some embodiments, the substituent R 2 may contain a 4-aminopyrimidinyl moiety. In some specific embodiments, the compound is a compound of structure (Ic): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R 3 may comprise an amine.

[0113] In some embodiments, the amine is a primary amine. In some embodiments, R 3 is -NH2.

[0114] In some embodiments, R 3 may contain a secondary amine. When the amine is a secondary amine, R 3 may further comprise a functional group at one end. For example, the functional group may include a hydroxyl, sulfonamide, carboxylic acid, ester, amine, amide, morpholine, piperazine, or thiomorpholine. The secondary amine and functional group may be -C n H 2n -, where n is 1 to 5. That is, the substituent R 3 The secondary amine and functional group may be separated by n carbon atoms. For example, a secondary amine attached to a hydroxyl group separated by a carbon atom forms an aminoalcohol (HO-C2H4NH-), which is shown below as Examples 4ET-02-001, 4ET-03-004, 4ET-03-007, and 4ET-03-011. As another example, a secondary amine attached to a sulfonamide group separated by two carbon atoms forms an aminosulfonamide (CH3SO2NHC2H4NH-), which is shown below as Examples 4ET-02-004, 4ET-03-012, 4ET-03-013, and 4ET-03-014.

[0115] Substituent R3 The amine in the substituent R may include a tertiary amine. 3 The tertiary amine of the substituent R may be cyclic. 3 The cyclic tertiary amine of formula (I) can be part of a saturated five-membered or six-membered ring. For example, the substituent R 3 The cyclic tertiary amine of the formula (I) can be pyrrolidine, imidazolidine, or pyrazolidine. The substituent R in the saturated six-membered ring 3 The cyclic tertiary amine may be piperidine or piperazine.

[0116] The tertiary amine may further include a functional group at one end. For example, the functional group may include a hydroxyl, sulfonamide, carboxylic acid, ester, amide, amine, morpholine, piperazine, or thiomorpholine. The tertiary amine and the functional group may be -C n H 2n -, where n is 1 to 5. That is, the substituent R 3 The tertiary amine and the functional group may be separated by n carbon atoms.

[0117] Substituent R 3 The tertiary amine of the substituent R may be cyclic. 3 The cyclic tertiary amine of formula (I) can be part of an unsaturated five- or six-membered ring. For example, the substituent R 3 The cyclic tertiary amine of formula (I) can be a pyrazole, imidazole, or oxazole. The substituent R in the unsaturated six-membered ring 3 The cyclic tertiary amine may be a pyridine, diazine, triazine, or oxazine.

[0118] Substituent R 3 The amine of the substituent R may also contain an amide group. 3 The amide group may further include a functional group at one end, for example, the functional group may include a hydroxyl, sulfonamide, carboxylic acid, ester, amine, amide, morpholine, piperazine, or thiomorpholine.

[0119] Substituent R 3 The amide and functional groups are -Cn H 2n -, where n is 0 to 5. That is, the substituent R 3 The amide and functional group may be separated by n carbon atoms. For example, an amide linked to a morpholine group by one methylene forms a morpholine amide, which is shown below as Examples 4ET-02-007, 4ET-03-027, and 4ET-03-028. An amide linked to a morpholine group by two methylenes forms a morpholine amide, which is shown below as Example 4ET-02-031. The substituent R 3 The amide of may also be directly attached to one of the functional groups.

[0120] Substituent R 3 The amide of the formula (I) can be directly attached to the cyclic structure. For example, the substituent R 3 The amide may be directly attached to the cyclopropane. In this case, there is no carbon atom between the amide and the cyclopropane. 3 Examples of structures having an amide group directly bonded to the cyclopropane as part of the formula include the following: 4ET-02-003, 4ET-02-009, 4ET-02-010, 4ET-02-011, 4ET-02-012, 4ET-02-016, 4ET-03-002, 4ET-03-009, 4ET-03-017, 4ET-03-019, 4ET-03-020, 4ET-03-023, 4ET-03-026, 4ET-03-034, and 4ET-04-003. The cyclopropane may be unsubstituted or substituted with one or more functional groups. For example, a substituted cyclopropane may contain a fluorine, hydroxyl, hydroxylmethylene, alkyl, carboxylic acid, amine, aminomethylene, ester, ether, amide, sulfonamide, morpholine, piperazine, or thiomorpholine group attached to the cyclopropane ring. The substitution position on the cyclopropane to which the functional group is attached may be the 1-, 2-, or 3-position. A functional group attached to the cyclopropane may have an additional alkyl chain (-C n H 2n-), where n is 0 to 5. When n is equal to 0, there is no methylene between the functional group and the cyclopropane. That is, the functional group can be directly attached to the 1-, 2-, or 3-position of the cyclopropane. Similarly, when n is equal to 1, there is one methylene between the functional group and the cyclopropane. In this case, the functional group is one carbon away from the cyclopropane, which provides additional flexibility in the structure. The substituent R 3 Examples of structures having an amide group directly bonded to a substituted cyclopropane as part of the formula include the following: 4ET-02-009, 4ET-02-010, 4ET-02-011, 4ET-02-012, 4ET-02-016, 4ET-03-019, 4ET-03-020, 4ET-03-023, 4ET-03-026, and 4ET-03-034.

[0121] Substituent R 3 The amide may be directly attached to the cyclobutane. In this case, there is no carbon atom between the amide and the cyclobutane. The cyclobutane may further have a functional group. For example, the functional group may include hydroxyl, alkyl, carboxylic acid, amine, ester, ether, amide, sulfonamide, morpholine, piperazine, or thiomorpholine. The substitution position on the cyclobutane where the functional group is attached may be the 1-, 2-, 3-, or 4-position. The functional group may also be attached by inserting an additional alkyl chain (C n H 2n ), where n is 0 to 5.

[0122] The ring structure bonded to the amide, either directly or via an alkyl chain, may contain at least one heteroatom to form a heterocyclic compound. The heterocyclic compound may include a three-membered ring with one heteroatom or a four-membered ring with one heteroatom. For example, a three-membered ring with one heteroatom may include aziridine or ethylene oxide. As another example, a four-membered ring with one heteroatom may include azetidine or oxetane. An azetidine bonded directly to an amide is shown, for example, in 4ET-02-017 below. As noted above, functional groups may be attached to the heterocyclic compound. In the case of ethylene oxide (epoxide), Sharpless epoxidation may be used to generate a chiral epoxide.

[0123] Although the examples herein have only one substitution on the ring structure, such an arrangement is provided for illustrative purposes only. Embodiments of the present disclosure also include disubstituted ring structures. For example, a total of two amine groups may be attached to the cyclopropane, with the first amine group being attached to the 1-position of the cyclopropane and the second amine group being attached to the 2-position of the cyclopropane.

[0124] Substituent R 3 The amide of the substituent R may be a reverse amide. 3 Instead of the nitrogen atom of the amide being directly bonded to structure (Ic), the substituent R 3 The carbon atom of the amide may be attached to structure (Ic). An inverse amide attached to structure (Ic) is shown, for example, in 4ET-03-024 below. Substituent R 3 The above-described embodiments of the present disclosure that include an amide may be replaced with a reverse amide. For example, the amide group in examples such as 4ET-02-003, 4ET-02-009, 4ET-02-010, 4ET-02-011, 4ET-02-012, 4ET-02-016, 4ET-03-002, 4ET-03-009, 4ET-03-017, 4ET-03-019, 4ET-03-020, 4ET-03-023, 4ET-03-026, 4ET-03-034, 4ET-04-003, 4ET-02-007, 4ET-03-027, 4ET-03-028, and 4ET-02-031 may be replaced with a reverse amide.

[0125] Structure (Ic) is a group containing a substituent R 3 For example, a thioamide group may be used in place of the amide group shown in 4ET-02-013 below. Similar to the amide substituent, the thioamide group may be replaced with the reverse thioamide. In this regard, the substituent R 3 Instead of the nitrogen atom of the thioamide being directly bonded to structure (Ic), the substituent R 3 The carbon atom of the thioamide may be bonded to structure (Ic).

[0126] Furthermore, the substituent R 3 Other amide analogs of structure (Ic) may be used. For example, a urea group may be used in place of the amide group shown in 4ET-02-015 below. As another example, a thiourea group may be used in place of the amide group. The substituent R 3 Amides, reverse amides, thioamides, reverse thioamides, ureas, and thioureas as part of are interchangeable in structure (Ic).

[0127] In some MNK inhibitors of the present disclosure, the 4-aminopyrimidine moiety in structure (Ic) can be modified. The pyrimidine moiety and the parent structure shown in structure (Ia) or (Ib) are connected via an amine linker (-NH-) in structure (Ic). The amine linker can be extended. For example, the amine linker can include an additional alkyl chain (-C) between the amine and pyrimidine moieties. n H 2n -), where n is 1 to 5. For example, as shown in 4ET-04-004, one extra carbon atom (n=1) can be added so that the amine linker and pyrimidine are one carbon away from the parent structure, giving structure (Ic) more structural flexibility through an additional degree of freedom. Insertion of a methylene unit, a one carbon extension between the amine and pyrimidine moieties, provides a benzylpyrimidine moiety. As another example, an amine linker can be added by inserting an additional alkyl chain (-C) between the amine and the parent structure shown as structure (Ia) or (Ib). n H 2n-), where n is 1 to 5. For example, as shown in 4ET-04-015, one extra carbon atom (n=1) can be added so that the amine linker and the parent structure shown as structure (Ia) or (Ib) are one carbon away from the parent structure. A one-carbon extension, the insertion of a methylene unit, between the amine and structure (Ia) or (Ib) provides a methylaminopyrimidine moiety. In this regard, methylene units can be added to both sides of the amine linker of structure (Ic). Amine linker extensions with extra methylene units can be used in conjunction with any of the other variations of structures (Ia), (Ib), and (Ic) disclosed herein.

[0128] Additionally, the pyrimidine moiety in structure (Ic) may be modified to replace two nitrogen atom isomers to form different unsaturated six-membered rings, such as 1,2-diazines (pyridazines) or 1,4-diazines (pyrazines). For example, 1,2-diazines (pyridazines) may be used instead of 1,3-diazines (pyrimidines) in structure (Ic) shown in Examples 4ET-04-003 and 4ET-04-006 below. These modifications may be used in combination with any of the other variations of structures (Ia), (Ib), and (Ic) disclosed herein.

[0129] The pyrimidine in structure (Ic) can be replaced with a 5-membered heterocyclic compound. The pyrimidine is a 6-membered heterocyclic compound having two nitrogen atoms. Generally, 5-membered heterocyclic compounds have different chemical and physical properties from 6-membered heterocyclic compounds. Some MNK inhibitors of the present disclosure can utilize such differences between 5-membered and 6-membered heterocyclic compounds. For example, a 5-membered heterocyclic compound can contain a nitrogen atom and a sulfur atom. For example, a 5-membered heterocyclic compound having N and S atoms can include thiazole, as shown in Example 4ET-04-001 below. As another example, a 5-membered heterocyclic compound having S atoms can include thiophene. A 5-membered heterocyclic compound can contain a nitrogen atom and an oxygen atom. For example, a 5-membered heterocyclic compound having N and O atoms can include oxazole or isoxazole. In yet another example, a 5-membered heterocyclic compound can contain two nitrogen atoms. For example, a 5-membered heterocyclic compound having two nitrogen atoms can include imidazole or pyrazole. These modifications may be used in combination with any of the other variations of structures (Ia), (Ib), and (Ic) disclosed herein.

[0130] As an example of how the various modifications disclosed herein can be used in combination with one another, an amine linker with an additional carbon atom can be attached to a pyridazine moiety, which can be linked to a pyridone backbone bearing an amine or sulfonamide. As another example, an amine linker with an additional carbon atom can be attached to a pyridazine moiety, which can be attached directly to an amino group.

[0131] In some MNK inhibitors of the present disclosure, the 4-aminopyrimidine moiety and the parent structure, such as the pyridone moiety in structure (Ic), may be linked via other nitrogen-containing linkers. The pyrimidine moiety and parent structure shown in structure (Ia) or (Ib) are connected via an amine linker (—NH—) in structure (Ic). Embodiments of the present disclosure may be configured to introduce an amide group between the 4-aminopyrimidine moiety and the parent structure. This can be synthesized by using an amide-containing starting material in the Buchwald-Hartwig amination described in Example 1, Synthesis of MNK Inhibitors. For example, the resulting MNK inhibitor may contain an amide between the 4-aminopyrimidine moiety and the parent structure, such as shown in Example 4ET-04-013 below, or a reverse amide, such as shown in Example 4ET-04-014.

[0132] Furthermore, embodiments of the present disclosure can be configured to introduce a sulfonamide group between the 4-aminopyrimidine moiety and the parent structure. This can be synthesized by using a sulfonamide-containing starting material in the Buchwald-Hartwig amination described in Example 1, Synthesis of MNK Inhibitors. Another approach involves the use of sulfonyl chloride reagents or intermediates. For example, the resulting MNK inhibitor can contain a sulfonamide between the 4-aminopyrimidine moiety and the parent structure, as shown in Examples 4ET-04-010 and 4ET-04-011 below, or a reverse sulfonamide as shown in Example 4ET-04-012.

[0133] Additionally, embodiments of the present disclosure can be configured to introduce an ether group between the 4-aminopyrimidine moiety and the parent structure, which can be synthesized by using an alcohol-containing starting material in a Buchwald-Hartwig amination as described in the synthesis of the MNK inhibitor in Example 1. Another approach involves using an alcohol-containing starting material in an Ullmann-type coupling reaction.

[0134] Substituent R of structure (Ic) 1a or R 1bcan be an alkyl group as described above in structure (Ia). Alternatively, the substituent R 1a or R 1b may be linked together to form a cyclic compound shown below as ring structure A. A detailed description of ring structure A in structure (Ib) is given in structure (Id): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R 3 may comprise an amine.

[0135] One embodiment is a compound having the following structure (II): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R 1a is C1-C6 alkyl or aryl, R 1b is C1-C6 alkyl or aryl; Alternatively, R 1a and R 1b are joined together with the carbon to which they are both attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; R 2 -NHR 3a , -NHC(=O)R 3b , -NHC(=S)R 3b , or -C(=O)R 3c and R 3a is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, each of which is optionally selected from hydroxyl, C3-C6 cycloalkyl, —NHS(O)2CH3, heterocyclyl, —C(═O)OH, —C(═O)N(R 3d )R 3d, or -N(R 3d )R 3d and is substituted with one or more substituents selected from the group consisting of R 3b is C1-C6 alkyl, C3-C6 cycloalkyl, or heterocyclyl, each of which is optionally selected from hydroxyl, halo, C1-C6 alkyl, C3-C6 cycloalkyl, —NHS(O)2CH3, —N(R 3d )R 3d , heterocyclyl, -C(=O)OH, -C(=O)N(R 3d )R 3d , -NHC(=O)CH3, -CH2C(=O)OH; R 3c is -N(R 3d )R 3d or heterocyclyl, R 3d is independently in each occurrence hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; L is -NH- or -CHNH-; X is N and Y is CH, or X is CH and Y is N; however, R 1a and R 1b are both -CH3, or R 1a and R 1b When R are linked to form a 5- or 6-membered cycloalkoxy or heterocyclyl, 2 But the following structure: -NH2 or [ka] The condition is that the applicant does not have

[0136] In some embodiments, R 1a is C1-C6 alkyl. In some embodiments, R 1a is methyl. In certain embodiments, R 1a is aryl. In certain embodiments, R 1ais phenyl.

[0137] In certain embodiments, R 1b is C1-C6 alkyl. In some embodiments, R 1b is methyl. In some embodiments, R 1a and R 1b are joined together with the carbon to which they are both attached to form a cycloalkyl. In more specific embodiments, the cycloalkyl is cyclopentyl or cyclohexyl. In some embodiments, R 1a and R 1b are bonded together with the carbon to which they are both attached to form a cycloalkenyl. In some embodiments, the cycloalkenyl is cyclopentenyl, cyclohexenyl, or cycloheptenyl. In certain embodiments, R 1a and R 1b are attached together with the carbon to which they are both attached to form a heterocyclyl. In some particular embodiments, R 1a and R 1b are bonded together with the carbon to which they are both attached to form an aryl. In some embodiments, R 1a and R 1b are attached together with the carbon to which they are both attached to form a heteroaryl.

[0138] In more specific embodiments, the compound has the following structure: [ka] [ka] One of the or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: [ka] represents a double bond or a single bond, R4 is independently, at each occurrence, C1-C6 alkyl, C3-C6 cycloalkyl, halo, haloalkyl, hydroxyl, -NHS(O)2CH3, or -C(O)OH; or two R 4 are bonded together with the carbon to which they are both attached to form a cycloalkyl, W is N or O; Z is C or O; n is 0, 1, 2, 3, or 4.

[0139] In some embodiments, n is 0, 1, or 2. In some more specific embodiments, [ka] is a double bond and the rest are single bonds. In some embodiments, the compound has the following structure: [ka] It has.

[0140] In some more specific embodiments, the compound has the following structure: [ka] It has.

[0141] In some embodiments, the compound has the following structure: [ka] It has one of the following.

[0142] In some embodiments, R 2 is H. In more specific embodiments, R 2 -NHR 3a In more specific embodiments, R 2 is H or -NHR 3a In more specific embodiments, R 2is H or has the following structure: -NH2, [ka] It has one of the following.

[0143] In some embodiments, R 2 is -NHC(=O)R 3b In some embodiments, R 2 is H or -NHC(=O)R 3b In more specific embodiments, R 2 has the following structure: [ka] It has one of the following.

[0144] In certain embodiments, R 2 is -NHC(=S)R 3b In certain embodiments, R 2 has the following structure: [ka] It has.

[0145] In certain embodiments, R 2 is -C(=O)R 3c In some embodiments, R 2 has the following structure: [ka] It has one of the following.

[0146] In some embodiments, R 2 has the following structure: -NH2, [ka] It has one of the following.

[0147] In certain specific embodiments, R 2 has the following structure: -NH2 or [ka] It has one of the following.

[0148] In some embodiments, X is CH and Y is N. In certain embodiments, X is N and Y is CH. In some embodiments, L is -NH-. In further embodiments, L is -CHNH-.

[0149] In some embodiments, R 3a is a branched C1-C6 alkyl. In some embodiments, R 3a is isopropyl.

[0150] In various different embodiments, the compound has one of the structures set forth below in Table 1, or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof. The compounds in Table 1 were prepared as described in the Examples and / or by methods known in the art. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

[0151] One embodiment is a compound having the structure: [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof.

[0152] In some embodiments, the MNK inhibitor has the following structure (III): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R 1 is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Cyano, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, hydroxy, and halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyalkyl 3-6 cycloalkyl; R 2 teeth, [ka] is selected from the group consisting of R3 is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Cyano, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, hydroxy, and halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyalkyl 3-6 cycloalkyl; R 1a and R 1b are taken together to form a 3- to 7-membered ring having 0 to 2 heteroatoms selected from the group consisting of N, O, and S, and the 3- to 7-membered ring is 1-6 Alkyl, R 8 , and -C(=O)OR 9 and optionally further substituted with one or more substituents selected from the group consisting of: Z 1 and Z 2 are each independently a direct bond or -{C(R 4a )(R 4b )} p -Y-, where p is 0, 1, 2, 3, 4, or 5, and Y is a direct bond, -O-, or -N(R 8 )- and R 4a is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHCO(C 3-7 cycloalkyl), NHSO2(C 1-6alkyl), NHSO2(C 3-7 Branched alkyl), and NHSO2(C 3-7 cycloalkyl), or two R 4a is attached to two adjacent carbons to form a direct bond, R 4b is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHCO(C 3-7 cycloalkyl), NHSO2(C 1-6 alkyl), NHSO2(C 3-7 Branched alkyl), and NHSO2(C 3-7 cycloalkyl), R 5 is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Alkoxyl, C 3-7 selected from the group consisting of branched alkoxy and hydroxy; R 6 is hydrogen, NH2, NHR 6a , NHCH2CH2OH, NHCH2CH2NHSO2Me, C 1-6 Alkoxyl, C 3-7 selected from the group consisting of branched alkoxy and hydroxy; R 6a is -(CO)C 1-6 Alkyl, -(CO)C 3-7 Branched alkyl, -(CO)C 1-6 hydroxyalkyl, [ka] is selected from the group consisting of q is 1, 2, 3, 4, 5, or 6; e is 1, 2, 3, 4, 5, or 6; X 2 is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, hydroxy, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Branched alkoxy, C 1-6 Haloalkoxy, C 3-7 Branched haloalkoxy, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2, C 1-5 (COOH), C 1-6 (NHSOMe), X 3 is hydrogen, halogen, C 1-5 Alkyl, C 3-7 Branched alkyl, C 1-5 Haloalkyl, C 3-7 Branched haloalkyl, hydroxy, C 1-5 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, C 1-5 Alkoxy, C 3-7 Branched alkoxy, C 1-5 Haloalkoxy, C 3-7 Branched haloalkoxy, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2, COOH, C 1-5 (COOH), NHSO2Me, C 1-5 (NHSOMe), R 7 is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Alkoxyl, C 3-7selected from the group consisting of branched alkoxy and hydroxyl; R 8 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, CO(C 1-6 alkyl), CO(C 3-7 Branched alkyl), SO2(C 1-6 alkyl), and SO2(C 3-7 branched alkyl), R 9 is hydrogen, C 1-6 It is selected from the group consisting of alkyl, and aralkyl.

[0153] In a more specific embodiment, the compound has the following structure (IV): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: Z 1 teeth, [ka] is selected from the group consisting of R 1 is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Cyano, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, hydroxy, and halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6C optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyalkyl 3-6 cycloalkyl; R 2 is selected from the group consisting of: [ka] R 3 is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Cyano, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, hydroxy, and halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyalkyl 3-6 cycloalkyl; R 4a is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHCO(C 3-7 cycloalkyl), NHSO2(C 1-6 alkyl), NHSO2(C 3-7 Branched alkyl), and NHSO2(C 3-7 cycloalkyl), R 4b is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C3-7 Branched haloalkyl, hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHCO(C 3-7 cycloalkyl), NHSO2(C 1-6 alkyl), NHSO2(C 3-7 Branched alkyl), and NHSO2(C 3-7 cycloalkyl), R 4c is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHCO(C 3-7 cycloalkyl), NHSO2(C 1-6 alkyl), NHSO2(C 3-7 Branched alkyl), and NHSO2(C 3-7 cycloalkyl), R 4d is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHCO(C 3-7 cycloalkyl), NHSO2(C 1-6 alkyl), NHSO2(C3-7 Branched alkyl), and NHSO2(C 3-7 cycloalkyl), R 4e is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, and C 3-7 is a branched haloalkyl; R 4f is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, and C 3-7 is a branched haloalkyl; R 1a and R 1b together optionally forming part of a ring, X 1 forming an optionally substituted 3- to 7-membered ring containing a group, X 1 is -C(F) 2- , -CH(COR 12 )-, -O-, -NH-, -N(R 8 )- and -S(=O) 2- is selected from the group consisting of m is 0, 1, or 2; n is 1, 2, or 3; R 5 is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Alkoxyl, C 3-7 selected from the group consisting of branched alkoxy and hydroxy; R 6 is hydrogen, NH2, NHR 6a , NHCH2CH2OH, NHCH2CH2NHSO2Me, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Alkoxyl, C 3-7 selected from the group consisting of branched alkoxy and hydroxy; R 6ais -(CO)C 1-6 Alkyl, -(CO)C 3-7 Branched alkyl, -(CO)C 1-6 hydroxyalkyl, [ka] is selected from the group consisting of q is 1, 2, 3, 4, 5, or 6; e is 1, 2, 3, 4, 5, or 6; X 2 is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, hydroxy, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Branched alkoxy, C 1-6 Haloalkoxy, C 3-7 Branched haloalkoxy, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2, C 1-5 (COOH), C 1-6 (NHSOMe), X 3 is hydrogen, halogen, C 1-5 Alkyl, C 3-7 Branched alkyl, C 1-5 Haloalkyl, C 3-7 Branched haloalkyl, hydroxy, C 1-5 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, C 1-5 Alkoxy, C 3-7 Branched alkoxy, C 1-5 Haloalkoxy, C 3-7 Branched haloalkoxy, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2, COOH, C 1-5 (COOH), NHSO2Me, C 1-5 (NHSOMe), R7 is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Alkoxyl, C 3-7 selected from the group consisting of branched alkoxy and hydroxy; R 8 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, CO(C 1-6 alkyl), CO(C 3-7 Branched alkyl), SO2(C 1-6 alkyl), and SO2(C 3-7 branched alkyl), R 10 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, CO(C 1-6 alkyl), CO(C 3-7 Branched alkyl), SO2(C 1-6 alkyl), and SO2(C 3-7 branched alkyl), R 11 is hydrogen and C 1-6 is selected from the group consisting of alkyl, R 12 is hydrogen and C 1-6 alkyl.

[0154] In a more specific embodiment, the compound has the following structure (V): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , n, Z 1 , R 5 , R 6 , and R 7 is as defined herein.

[0155] In a more specific embodiment, the compound has the following structure (VI): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , n, Z 1 , and R 6 is as defined herein.

[0156] In a more specific embodiment, the compound has the following structure (VII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , n, Z 1 , and R 6 is as defined herein.

[0157] In a more specific embodiment, the compound has the following structure (VIII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , n, Z 1 , and R 6 is as defined herein.

[0158] In a more specific embodiment, the compound has the following structure (IX): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4d , R 4c , n, and Z 1 is as defined herein; R 8a is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8b is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8c is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8d is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 9ais hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl and C 3-7 branched alkoxy; R 9b is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl and C 3-7 branched alkoxy; R 9a and R 9b together form an optionally substituted 3- to 7-membered ring, q is 1, 2, or 3; z is 0, 1, or 2.

[0159] In more specific embodiments, the compound has the following structure (X): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4d , R 4c , Z 1 , X 1 and n is as defined herein; R 8a is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8b is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8c is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8d is, at each occurrence, independently hydrogen, halogen, C 1-6Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), q is 1, 2, or 3; z is 0, 1, or 2.

[0160] In a more specific embodiment, the compound has the following structure (XI): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 5 , R 6 , R 7 and n is as defined herein; R 8a is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C3-7 branched alkyl), R 8b is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8c is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8d is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 9a is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 9b is hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), q is 1, 2, or 3; z is 0, 1, or 2.

[0161] In a more specific embodiment, the compound has the following structure (XII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , n, and z are as defined herein.

[0162] In a more specific embodiment, the compound has the following structure (XIII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n, and z are as defined herein.

[0163] In a more specific embodiment, the compound has the following structure (XIV): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , R9a , R 9b , n, and z are as defined herein.

[0164] In a more specific embodiment, the compound has the following structure (XV): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 5 , R 6 , R 7 , X 1 and n is as defined herein; R 8a is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8b is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8c is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), R 8d is, at each occurrence, independently hydrogen, halogen, C 1-6 Alkyl, C 3-7 Branched alkyl, C 1-6 Haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Branched Hydroxyalkyl, Hydroxy, C 1-6 Alkoxyl, C 3-7 Branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 Branched alkyl), NHSO2(C 1-6 alkyl), and NHSO2(C 3-7 branched alkyl), q is 1, 2, or 3; z is 0, 1, or 2.

[0165] In a more specific embodiment, the compound has the following structure (XVI): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , n, and z are as defined herein.

[0166] In a more specific embodiment, the compound has the following structure (XVII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , n, and z are as defined herein.

[0167] In a more specific embodiment, the compound has the following structure (XVIII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , X1 , n, and z are as defined herein.

[0168] In a more specific embodiment, the compound has the following structure (XIX): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 5 , R 6 , R 7 , and n is as defined herein.

[0169] In some embodiments, the compound has the following structure (XX): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , and n is as defined herein.

[0170] In a more specific embodiment, the compound has the following structure (XXI): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R1b , R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , and n is as defined herein.

[0171] In a more specific embodiment, the compound has the following structure (XXII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , and n is as defined herein.

[0172] In a more specific embodiment, the compound has the following structure (XXIII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4a , R 4b , R 4d , R 4c , R 5 , R 6 , R 7 , m, and n are as defined herein.

[0173] In a more specific embodiment, the compound has the following structure (XXIV): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4a , R 4b , R 6 , m, and n are as defined herein.

[0174] In a more specific embodiment, the compound has the following structure (XXV): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4a , R 4b , R 6 , m, and n are as defined herein.

[0175] In a more specific embodiment, the compound has the following structure (XXVI): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4a , R 4b , R 6 , m, and n are as defined herein.

[0176] In a more specific embodiment, the compound has the following structure (XXVII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4d , R 4c , R 4e , R 4f , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n, q, and z are as defined herein.

[0177] In a more specific embodiment, the compound has the following structure (XXVIII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , m, n, q, and z are as defined herein.

[0178] In a more specific embodiment, the compound has the following structure (XXIX): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4d , R 4c , R 4e , R 4f , R 8a , R 8b , R 8c , R 8d , X 1 , n, q, and z are as defined herein.

[0179] In more specific embodiments, the compound has the following structure (XXX): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 8a , R 8b , R 8c , R 8d , X 1 , m, n, q, and z are as defined herein.

[0180] In a more specific embodiment, the compound has the following structure (XXXI): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 5 , R 6 , R7 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n, q, and z are as defined herein.

[0181] In a more specific embodiment, the compound has the following structure (XXXII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n, q, and z are as defined herein.

[0182] In a more specific embodiment, the compound has the following structure (XXXIII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n, q, and z are as defined herein.

[0183] In a more specific embodiment, the compound has the following structure (XXXIV): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n, q, and z are as defined herein.

[0184] In a more specific embodiment, the compound has the following structure (XXXV): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4a , R 4b , R 4d , R 4c , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , m, n, q, and z are as defined herein.

[0185] In a more specific embodiment, the compound has the following structure (XXXVI): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4a , R 4b , R 4d , R 4c , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , m, n, q, and z are as defined herein.

[0186] In a more specific embodiment, the compound has the following structure (XXXVII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4a , R 4b , R 4d , R 4c , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , m, n, q, and z are as defined herein.

[0187] In a more specific embodiment, the compound has the following structure (XXXIX): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4a , R 4b , R 4d , R4c , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , m, n, q, and z are as defined herein.

[0188] In a more specific embodiment, the compound has the following structure (XL): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , R 8d , X 1 , n, q, and z are as defined herein.

[0189] In a more specific embodiment, the compound has the following structure (XLI): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , n, q, and z are as defined herein.

[0190] In a more specific embodiment, the compound has the following structure (XLII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , n, q, and z are as defined herein.

[0191] In a more specific embodiment, the compound has the following structure (XLIII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4a , R 4b , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , R 8d , X 1 , m, n, q, and z are as defined herein.

[0192] In a more specific embodiment, the compound has the following structure (XLIV): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4a , R 4b , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , m, n, q, and z are as defined herein.

[0193] In a more specific embodiment, the compound has the following structure (XLV): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4a , R 4b , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , m, n, q, and z are as defined herein.

[0194] In more specific embodiments, the compound has the following structure: [ka] One of the or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof.

[0195] In some embodiments, Z 1 teeth, [ka] is.

[0196] In some embodiments, Z 1 teeth, [ka] is.

[0197] In some embodiments, R 1 is hydrogen.

[0198] In some embodiments, R 1 is a halogen.

[0199] In some embodiments, R 1 is C 1-6 It is alkyl.

[0200] In some embodiments, R 1 is C 3-7 It is a branched alkyl.

[0201] In some embodiments, R 1 is C 1-6 It is haloalkyl.

[0202] In some embodiments, R 1 is C 3-7 It is a branched haloalkyl.

[0203] In some embodiments, R 1 is C 1-6 It is a hydroxyalkyl.

[0204] In some embodiments, R 1 is C 3-7 It is a branched hydroxyalkyl.

[0205] In some embodiments, R 1 is cyano.

[0206] In some embodiments, R1 is C 1-6 It is alkoxyl.

[0207] In some embodiments, R 1 is C 3-7 It is a branched alkoxy.

[0208] In some embodiments, R 1 is hydroxy.

[0209] In some embodiments, R 1 is C 3-6 It is cycloalkyl.

[0210] In some embodiments, R 1 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C substituted with one substituent selected from the group consisting of hydroxyalkyl 3-6 It is cycloalkyl.

[0211] In some embodiments, R 1 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C substituted with two substituents selected from the group consisting of hydroxyalkyl 3-6 It is cycloalkyl.

[0212] In some embodiments, R 1 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C substituted with three substituents selected from the group consisting of hydroxyalkyl 3-6 It is cycloalkyl.

[0213] In some embodiments, R 2 teeth, [ka] is.

[0214] In some embodiments, R 2 teeth, [ka] is.

[0215] In some embodiments, R 2 teeth, [ka] is.

[0216] In some embodiments, R 2 teeth, [ka] is.

[0217] In some embodiments, R 2 teeth, [ka] is.

[0218] In some embodiments, R 2 teeth, [ka] is.

[0219] In some embodiments, R 2 teeth, [ka] is.

[0220] In some embodiments, R 2 teeth, [ka] is.

[0221] In some embodiments, R 2 teeth, [ka] is.

[0222] In some embodiments, R 2 teeth, [ka] is.

[0223] In some embodiments, R 2 teeth, [ka] is.

[0224] In some embodiments, R 2 teeth, [ka] is.

[0225] In some embodiments, R 2 teeth, [ka] is.

[0226] In some embodiments, R 2 teeth, [ka] is.

[0227] In some embodiments, R 2 teeth, [ka] is.

[0228] In some embodiments, R2 teeth, [ka] is.

[0229] In some embodiments, R 3 is hydrogen.

[0230] In some embodiments, R 3 is a halogen.

[0231] In some embodiments, R 3 is C 1-6 It is alkyl.

[0232] In some embodiments, R 3 is C 3-7 It is a branched alkyl.

[0233] In some embodiments, R 3 is C 1-6 It is haloalkyl.

[0234] In some embodiments, R 3 is C 3-7 It is a branched haloalkyl.

[0235] In some embodiments, R 3 is C 1-6 It is a hydroxyalkyl.

[0236] In some embodiments, R 3 is C 3-7 It is a branched hydroxyalkyl.

[0237] In some embodiments, R 3 is cyano.

[0238] In some embodiments, R 3 is C 1-6 It is alkoxyl.

[0239] In some embodiments, R 3 is C 3-7 It is a branched alkoxy.

[0240] In some embodiments, R 3 is hydroxy.

[0241] In some embodiments, R 3 is C 3-6 It is a cycloakyl.

[0242] In some embodiments, R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C substituted with one substituent selected from the group consisting of hydroxyalkyl 3-6 It is a cycloakyl.

[0243] In some embodiments, R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C substituted with two substituents selected from the group consisting of hydroxyalkyl 3-6 It is a cycloakyl.

[0244] In some embodiments, R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C substituted with three substituents selected from the group consisting of hydroxyalkyl 3-6 It is a cycloakyl.

[0245] In some embodiments, R 4a is hydrogen.

[0246] In some embodiments, R 4a is a halogen.

[0247] In some embodiments, R 4a is C1-6 It is alkyl.

[0248] In some embodiments, R 4a is C 3-7 It is a branched alkyl.

[0249] In some embodiments, R 4a is C 1-6 It is haloalkyl.

[0250] In some embodiments, R 4a is C 3-7 It is a branched haloalkyl.

[0251] In some embodiments, R 4a is hydroxy.

[0252] In some embodiments, R 4a is C 1-6 It is alkoxyl.

[0253] In some embodiments, R 4a is C 3-7 It is a branched alkoxy.

[0254] In some embodiments, R 4a is NHCO(C 1-6 alkyl).

[0255] In some embodiments, R 4a is NHCO(C 3-7 branched alkyl).

[0256] In some embodiments, R 4a is NHCO(C 3-7 cycloalkyl).

[0257] In some embodiments, R 4a is NHSO2(C 1-6 alkyl).

[0258] In some embodiments, R4a is NHSO2(C 3-7 branched alkyl).

[0259] In some embodiments, R 4a is NHSO2(C 3-7 cycloalkyl).

[0260] In some embodiments, R 4b is hydrogen.

[0261] In some embodiments, R 4b is a halogen.

[0262] In some embodiments, R 4b is C 1-6 It is alkyl.

[0263] In some embodiments, R 4b is C 3-7 It is a branched alkyl.

[0264] In some embodiments, R 4b is C 1-6 It is haloalkyl.

[0265] In some embodiments, R 4b is C 3-7 It is a branched haloalkyl.

[0266] In some embodiments, R 4b is hydroxy.

[0267] In some embodiments, R 4b is C 1-6 It is alkoxyl.

[0268] In some embodiments, R 4b is C 3-7 It is a branched alkoxy.

[0269] In some embodiments, R 4b is NHCO(C 1-6alkyl).

[0270] In some embodiments, R 4b is NHCO(C 3-7 branched alkyl).

[0271] In some embodiments, R 4b is NHCO(C 3-7 cycloalkyl).

[0272] In some embodiments, R 4b is NHSO2(C 1-6 alkyl).

[0273] In some embodiments, R 4b is NHSO2(C 3-7 branched alkyl).

[0274] In some embodiments, R 4b is NHSO2(C 3-7 cycloalkyl).

[0275] In some embodiments, R 4c is hydrogen.

[0276] In some embodiments, R 4c is a halogen.

[0277] In some embodiments, R 4c is C 1-6 It is alkyl.

[0278] In some embodiments, R 4c is C 3-7 It is a branched alkyl.

[0279] In some embodiments, R 4c is C 1-6 It is haloalkyl.

[0280] In some embodiments, R 4c is C 3-7It is a branched haloalkyl.

[0281] In some embodiments, R 4c is hydroxy.

[0282] In some embodiments, R 4c is C 1-6 It is alkoxyl.

[0283] In some embodiments, R 4c is C 3-7 It is a branched alkoxy.

[0284] In some embodiments, R 4c is NHCO(C 1-6 alkyl).

[0285] In some embodiments, R 4c is NHCO(C 3-7 branched alkyl).

[0286] In some embodiments, R 4c is NHCO(C 3-7 cycloalkyl).

[0287] In some embodiments, R 4c is NHSO2(C 1-6 alkyl).

[0288] In some embodiments, R 4c is NHSO2(C 3-7 branched alkyl).

[0289] In some embodiments, R 4c is NHSO2(C 3-7 cycloalkyl).

[0290] In some embodiments, R 4d is hydrogen.

[0291] In some embodiments, R 4dis a halogen.

[0292] In some embodiments, R 4d is C 1-6 It is alkyl.

[0293] In some embodiments, R 4d is C 3-7 It is a branched alkyl.

[0294] In some embodiments, R 4d is C 1-6 It is haloalkyl.

[0295] In some embodiments, R 4d is C 3-7 It is a branched haloalkyl.

[0296] In some embodiments, R 4d is hydroxy.

[0297] In some embodiments, R 4d is C 1-6 It is alkoxyl.

[0298] In some embodiments, R 4d is C 3-7 It is a branched alkoxy.

[0299] In some embodiments, R 4d is NHCO(C 1-6 alkyl).

[0300] In some embodiments, R 4d is NHCO(C 3-7 branched alkyl).

[0301] In some embodiments, R 4d is NHCO(C 3-7 cycloalkyl).

[0302] In some embodiments, R 4d is NHSO2(C1-6 alkyl).

[0303] In some embodiments, R 4d is NHSO2(C 3-7 branched alkyl).

[0304] In some embodiments, R 4d is NHSO2(C 3-7 cycloalkyl).

[0305] In some embodiments, R 4e is hydrogen.

[0306] In some embodiments, R 4e is a halogen.

[0307] In some embodiments, R 4e is C 1-6 It is alkyl.

[0308] In some embodiments, R 4e is C 3-7 It is a branched alkyl.

[0309] In some embodiments, R 4e is C 1-6 It is haloalkyl.

[0310] In some embodiments, R 4e is C 3-7 It is a branched haloalkyl.

[0311] In some embodiments, R 4f is hydrogen.

[0312] In some embodiments, R 4f is a halogen.

[0313] In some embodiments, R 4f is C 1-6 It is alkyl.

[0314] In some embodiments, R 4f is C 3-7 It is a branched alkyl.

[0315] In some embodiments, R 4f is C 1-6 It is haloalkyl.

[0316] In some embodiments, R 4f is C 3-7 It is a branched haloalkyl.

[0317] In some embodiments, R 1a and R 1b taken together form an optionally substituted three-membered ring.

[0318] In some embodiments, R 1a and R 1b taken together form an optionally substituted four-membered ring.

[0319] In some embodiments, R 1a and R 1b taken together form an optionally substituted 5-membered ring.

[0320] In some embodiments, R 1a and R 1b taken together form an optionally substituted 6-membered ring.

[0321] In some embodiments, R 1a and R 1b taken together form an optionally substituted seven-membered ring.

[0322] In some embodiments, R 1a and R 1b Together, X 1 The ring forms an optionally substituted three-membered ring containing the group.

[0323] In some embodiments, R 1a and R 1bTogether, X 1 The ring forms an optionally substituted four-membered ring containing the group.

[0324] In some embodiments, R 1a and R 1b Together, X 1 The ring forms an optionally substituted five-membered ring containing the group.

[0325] In some embodiments, R 1a and R 1b Together, X 1 The ring forms an optionally substituted six-membered ring containing the group.

[0326] In some embodiments, R 1a and R 1b Together, X 1 The ring forms an optionally substituted seven-membered ring containing the group.

[0327] In some embodiments, X 1 is CF2.

[0328] In some embodiments, X 1 is CHCO2R 12 is.

[0329] In some embodiments, X 1 is O.

[0330] In some embodiments, X 1 is NH.

[0331] In some embodiments, X 1 is NR 8 is.

[0332] In some embodiments, X 1 is SO2.

[0333] In some embodiments, m is 0.

[0334] In some embodiments, m is 1.

[0335] In some embodiments, m is 2.

[0336] In some embodiments, n is 1.

[0337] In some embodiments, n is 2.

[0338] In some embodiments, n is 3.

[0339] In some embodiments, R 5 is hydrogen.

[0340] In some embodiments, R 5 is a halogen.

[0341] In some embodiments, R 5 is C 1-6 It is alkyl.

[0342] In some embodiments, R 5 is C 3-7 It is a branched alkyl.

[0343] In some embodiments, R 5 is C 1-6 It is haloalkyl.

[0344] In some embodiments, R 5 is C 3-7 It is a branched haloalkyl.

[0345] In some embodiments, R 5 is C 1-6 It is alkoxyl.

[0346] In some embodiments, R 5 is C 3-7 It is a branched alkoxy.

[0347] In some embodiments, R 5 is hydroxy.

[0348] In some embodiments, R 6 is hydrogen.

[0349] In some embodiments, R 6 is NH2.

[0350] In some embodiments, R 6 is NHR 6a is.

[0351] In some embodiments, R 6 is NHCH2CH2OH.

[0352] In some embodiments, R 6 is NHCH2CH2NHSO2Me.

[0353] In some embodiments, R 6 is C 1-6 It is alkoxyl.

[0354] In some embodiments, R 6 is C 3-7 It is a branched alkoxy.

[0355] In some embodiments, R 6 is hydroxy.

[0356] In some embodiments, R 6a is —(CO)C1-6 alkyl.

[0357] In some embodiments, R 6a is -(CO)C 3-7 It is a branched alkyl.

[0358] In some embodiments, R 6a is —(CO)C1-6 hydroxyalkyl.

[0359] In some embodiments, R 6a teeth, [ka] is.

[0360] In some embodiments, R 6a teeth, [ka] is.

[0361] In some embodiments, R 6a teeth, [ka] is.

[0362] In some embodiments, R 6a teeth, [ka] is.

[0363] In some embodiments, R 6a teeth, [ka] is.

[0364] In some embodiments, R 6a teeth, [ka] is.

[0365] In some embodiments, R 6a teeth, [ka] is.

[0366] In some embodiments, R6a teeth, [ka] is.

[0367] In some embodiments, R 6a teeth, [ka] is.

[0368] In some embodiments, R 6a teeth, [ka] is.

[0369] In some embodiments, q is 1.

[0370] In some embodiments, q is 2.

[0371] In some embodiments, q is 3.

[0372] In some embodiments, q is 4.

[0373] In some embodiments, q is 5.

[0374] In some embodiments, q is 6.

[0375] In some embodiments, e is 1.

[0376] In some embodiments, e is 2.

[0377] In some embodiments, e is 3.

[0378] In some embodiments, e is 4.

[0379] In some embodiments, e is 5.

[0380] In some embodiments, e is 6.

[0381] In some embodiments, X 2 is hydrogen.

[0382] In some embodiments, X 2 is a halogen.

[0383] In some embodiments, X 2 is C 1-6 It is alkyl.

[0384] In some embodiments, X 2 is C 3-7 It is a branched alkyl.

[0385] In some embodiments, X 2 is C1-C6 haloalkyl.

[0386] In some embodiments, X 2 is C 3-7 It is a branched haloalkyl.

[0387] In some embodiments, X 2 is hydroxy.

[0388] In some embodiments, X 2 is C 1-6 It is a hydroxyalkyl.

[0389] In some embodiments, X 2 is C 3-7 It is a branched hydroxyalkyl.

[0390] In some embodiments, X 2 is C 1-6 It is an alkoxy.

[0391] In some embodiments, X 2is C 3-7 It is a branched alkoxy.

[0392] In some embodiments, X 2 is C 1-6 It is haloalkoxy.

[0393] In some embodiments, X 2 is C 3-7 It is a branched haloalkoxy.

[0394] In some embodiments, X 2 is NH2.

[0395] In some embodiments, X 2 is NH(C 1-6 alkyl).

[0396] In some embodiments, X 2 is N(C 1-6 alkyl)2.

[0397] In some embodiments, X 2 is C 1-5 (COOH).

[0398] In some embodiments, X 2 is C 1-6 (NHSO2Me).

[0399] In some embodiments, X 3 is hydrogen.

[0400] In some embodiments, X 3 is a halogen.

[0401] In some embodiments, X 3 is C 1-5 It is alkyl.

[0402] In some embodiments, X 3 is C 3-7 It is a branched alkyl.

[0403] In some embodiments, X 3 is C 1-5 It is haloalkyl.

[0404] In some embodiments, X 3 is C 3-7 It is a branched haloalkyl.

[0405] In some embodiments, X 3 is hydroxy.

[0406] In some embodiments, X 3 is C 1-5 It is a hydroxyalkyl.

[0407] In some embodiments, X 3 is C 3-7 It is a branched hydroxyalkyl.

[0408] In some embodiments, X 3 is C 1-5 It is an alkoxy.

[0409] In some embodiments, X 3 is C 3-7 It is a branched alkoxy.

[0410] In some embodiments, X 3 is C 1-5 It is haloalkoxy.

[0411] In some embodiments, X 3 is C 3-7 It is a branched haloalkoxy.

[0412] In some embodiments, X 3 is NH2.

[0413] In some embodiments, X 3 is NH(C 1-6 alkyl).

[0414] In some embodiments, X 3 is N(C 1-6 alkyl)2.

[0415] In some embodiments, X 3 is COOH.

[0416] In some embodiments, X 3 is C 1-5 (COOH).

[0417] In some embodiments, X 3 is NHSO2Me.

[0418] In some embodiments, X 3 is C 1-5 (NHSO2Me).

[0419] In some embodiments, R 7 is hydrogen.

[0420] In some embodiments, R 7 is a halogen.

[0421] In some embodiments, R 7 is C 1-6 It is alkyl.

[0422] In some embodiments, R 7 is C 3-7 It is a branched alkyl.

[0423] In some embodiments, R 7 is C 1-6 It is haloalkyl.

[0424] In some embodiments, R 7 is C 3-7 It is a branched haloalkyl.

[0425] In some embodiments, R 7 is C 1-6It is alkoxyl.

[0426] In some embodiments, R 7 is C 3-7 It is a branched alkoxy.

[0427] In some embodiments, R 7 is hydroxy.

[0428] In some embodiments, R 8 is C 1-6 It is alkyl.

[0429] In some embodiments, R 8 is C 1-6 It is haloalkyl.

[0430] In some embodiments, R 8 is C 3-7 It is a branched haloalkyl.

[0431] In some embodiments, R 8 is C 1-6 It is a hydroxyalkyl.

[0432] In some embodiments, R 8 is C 3-7 It is a branched hydroxyalkyl.

[0433] In some embodiments, R 8 is C 1-6 It is alkoxyl.

[0434] In some embodiments, R 8 is C 3-7 It is a branched alkoxy.

[0435] In some embodiments, R 8 is CO(C 1-6 alkyl).

[0436] In some embodiments, R 8 is CO(C 3-7branched alkyl).

[0437] In some embodiments, R 8 is SO2(C 1-6 alkyl).

[0438] In some embodiments, R 8 is SO2(C 3-7 branched alkyl).

[0439] In some embodiments, R 8a is hydrogen.

[0440] In some embodiments, R 8a is a halogen.

[0441] In some embodiments, R 8a is C 1-6 It is alkyl.

[0442] In some embodiments, R 8a is C 3-7 It is a branched alkyl.

[0443] In some embodiments, R 8a is C 1-6 It is haloalkyl.

[0444] In some embodiments, R 8a is C 3-7 It is a branched haloalkyl.

[0445] In some embodiments, R 8a is C 1-6 It is a hydroxyalkyl.

[0446] In some embodiments, R 8a is C 3-7 It is a branched hydroxyalkyl.

[0447] In some embodiments, R 8a is hydroxy.

[0448] In some embodiments, R 8a is C 1-6 It is alkoxyl.

[0449] In some embodiments, R 8a is C 3-7 It is a branched alkoxy.

[0450] In some embodiments, R 8a is NHCO(C 1-6 alkyl).

[0451] In some embodiments, R 8a is NHCO(C 3-7 branched alkyl).

[0452] In some embodiments, R 8a is NHSO2(C 1-6 alkyl).

[0453] In some embodiments, R 8a is NHSO2(C 3-7 branched alkyl).

[0454] In some embodiments, R 8b is hydrogen.

[0455] In some embodiments, R 8b is a halogen.

[0456] In some embodiments, R 8b is C 1-6 It is alkyl.

[0457] In some embodiments, R 8b is C 3-7 It is a branched alkyl.

[0458] In some embodiments, R 8b is C 1-6 It is haloalkyl.

[0459] In some embodiments, R 8b is C 3-7 It is a branched haloalkyl.

[0460] In some embodiments, R 8b is C 1-6 It is a hydroxyalkyl.

[0461] In some embodiments, R 8b is C 3-7 It is a branched hydroxyalkyl.

[0462] In some embodiments, R 8b is hydroxy.

[0463] In some embodiments, R 8b is C 1-6 It is alkoxyl.

[0464] In some embodiments, R 8b is C 3-7 It is a branched alkoxy.

[0465] In some embodiments, R 8b is NHCO(C 1-6 alkyl).

[0466] In some embodiments, R 8b is NHCO(C 3-7 branched alkyl).

[0467] In some embodiments, R 8b is NHSO2(C 1-6 alkyl).

[0468] In some embodiments, R 8b is NHSO2(C 3-7 branched alkyl).

[0469] In some embodiments, R 8c is hydrogen.

[0470] In some embodiments, R 8c is a halogen.

[0471] In some embodiments, R 8c is C 1-6 It is alkyl.

[0472] In some embodiments, R 8c is C 3-7 It is a branched alkyl.

[0473] In some embodiments, R 8c is C 1-6 It is haloalkyl.

[0474] In some embodiments, R 8c is C 3-7 It is a branched haloalkyl.

[0475] In some embodiments, R 8c is C 1-6 It is a hydroxyalkyl.

[0476] In some embodiments, R 8c is C 3-7 It is a branched hydroxyalkyl.

[0477] In some embodiments, R 8c is hydroxy.

[0478] In some embodiments, R 8c is C 1-6 It is alkoxyl.

[0479] In some embodiments, R 8c is C 3-7 It is a branched alkoxy.

[0480] In some embodiments, R 8c is NHCO(C 1-6 alkyl).

[0481] In some embodiments, R 8c is NHCO(C 3-7 branched alkyl).

[0482] In some embodiments, R 8c is NHSO2(C 1-6 alkyl).

[0483] In some embodiments, R 8c is NHSO2(C 3-7 branched alkyl).

[0484] In some embodiments, R 8d is hydrogen.

[0485] In some embodiments, R 8d is a halogen.

[0486] In some embodiments, R 8d is C 1-6 It is alkyl.

[0487] In some embodiments, R 8d is C 3-7 It is a branched alkyl.

[0488] In some embodiments, R 8d is C 1-6 It is haloalkyl.

[0489] In some embodiments, R 8d is C 3-7 It is a branched haloalkyl.

[0490] In some embodiments, R 8d is C 1-6 It is a hydroxyalkyl.

[0491] In some embodiments, R 8d is C 3-7 It is a branched hydroxyalkyl.

[0492] In some embodiments, R 8d is hydroxy.

[0493] In some embodiments, R 8d is C 1-6 It is alkoxyl.

[0494] In some embodiments, R 8d is C 3-7 It is a branched alkoxy.

[0495] In some embodiments, R 8d is NHCO(C 1-6 alkyl).

[0496] In some embodiments, R 8d is NHCO(C 3-7 branched alkyl).

[0497] In some embodiments, R 8d is NHSO2(C 1-6 alkyl).

[0498] In some embodiments, R 8d is NHSO2(C 3-7 branched alkyl).

[0499] In some embodiments, R 9a is hydrogen.

[0500] In some embodiments, R 9a is a halogen.

[0501] In some embodiments, R 9a is C 1-6 It is alkyl.

[0502] In some embodiments, R 9a is C 3-7 It is a branched alkyl.

[0503] In some embodiments, R 9ais C 1-6 It is haloalkyl.

[0504] In some embodiments, R 9a is C 3-7 It is a branched haloalkyl.

[0505] In some embodiments, R 9a is C 1-6 It is a hydroxyalkyl.

[0506] In some embodiments, R 9a is C 3-7 It is a branched hydroxyalkyl.

[0507] In some embodiments, R 9a is hydroxy.

[0508] In some embodiments, R 9a is C 1-6 It is alkoxyl.

[0509] In some embodiments, R 9a is C 3-7 It is a branched alkoxy.

[0510] In some embodiments, R 9b is hydrogen.

[0511] In some embodiments, R 9b is a halogen.

[0512] In some embodiments, R 9b is C 1-6 It is alkyl.

[0513] In some embodiments, R 9b is C 3-7 It is a branched alkyl.

[0514] In some embodiments, R 9b is C 1-6 It is haloalkyl.

[0515] In some embodiments, R 9b is C 3-7 It is a branched haloalkyl.

[0516] In some embodiments, R 9b is C 1-6 It is a hydroxyalkyl.

[0517] In some embodiments, R 9b is C 3-7 It is a branched hydroxyalkyl.

[0518] In some embodiments, R 9b is hydroxy.

[0519] In some embodiments, R 9b is C 1-6 It is alkoxyl.

[0520] In some embodiments, R 9b is C 3-7 It is a branched alkoxy.

[0521] In some embodiments, R 9a and R 9b together form a three-membered ring.

[0522] In some embodiments, R 9a and R 9b together form a four-membered ring.

[0523] In some embodiments, R 9a and R 9b together form a five-membered ring.

[0524] In some embodiments, R 9a and R 9b together form a six-membered ring.

[0525] In some embodiments, R 9a and R 9btogether form a seven-membered ring.

[0526] In some embodiments, R 9a and R 9b taken together form an optionally substituted three-membered ring.

[0527] In some embodiments, R 9a and R 9b taken together form an optionally substituted four-membered ring.

[0528] In some embodiments, R 9a and R 9b taken together form an optionally substituted 5-membered ring.

[0529] In some embodiments, R 9a and R 9b taken together form an optionally substituted 6-membered ring.

[0530] In some embodiments, R 9a and R 9b taken together form an optionally substituted seven-membered ring.

[0531] In some embodiments, q is 1.

[0532] In some embodiments, q is 2.

[0533] In some embodiments, q is 3.

[0534] In some embodiments, z is 0.

[0535] In some embodiments, z is 1.

[0536] In some embodiments, z is 2.

[0537] In some embodiments, R 10 is hydrogen.

[0538] In some embodiments, R 10 is C 1-6 It is alkyl.

[0539] In some embodiments, R 10 is C 1-6 It is haloalkyl.

[0540] In some embodiments, R 10 is C 3-7 It is a branched haloalkyl.

[0541] In some embodiments, R 10 is C 1-6 It is a hydroxyalkyl.

[0542] In some embodiments, R 10 is C 1-6 It is alkoxyl.

[0543] In some embodiments, R 10 is C 3-7 It is a branched alkoxy.

[0544] In some embodiments, R 10 is CO(C 1-6 alkyl).

[0545] In some embodiments, R 10 is CO(C 3-7 branched alkyl).

[0546] In some embodiments, R 10 is SO2(C 1-6 alkyl).

[0547] In some embodiments, R 10 is SO2(C 3-7 branched alkyl).

[0548] In some embodiments, R 11 is hydrogen.

[0549] In some embodiments, R 11 is C 1-6 It is alkyl.

[0550] In some embodiments, R 12 is hydrogen.

[0551] In some embodiments, R 12 is C 1-6 It is alkyl.

[0552] In some embodiments, compounds of formula (I), (I′) or substructures exclude N-(6-(((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide and / or 3-((6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)amino)propanoic acid.

[0553] In some embodiments, the compound has the following structure (XLVII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein m, n, R 3 , and R 2 is as defined herein.

[0554] R 2 , R 3 Non-limiting examples of , m, and n are shown in Table 2 below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0555] In some embodiments, the compound has the following structure (XLVIII): [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 2 , R 3 , n, and m are as defined herein. 2 , R 3 Non-limiting examples of n, m, and n are defined herein below in Table 3 below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0556] Compounds of the present disclosure include compounds having the formula (XLIX) or a pharmaceutically acceptable salt form thereof: [ka] R 3 , R 4f , and non-limiting examples of n are defined herein in Table 4 below. [Table 4]

[0557] To demonstrate how the compounds of the present disclosure are named and referenced herein, compounds having the formula: [ka] It has the chemical name 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione.

[0558] For purposes of this disclosure, compounds represented by a racemic formula are, for example, [ka] The following formula: [ka] or the following formula: [ka] or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, which stands equally well for either of the two enantiomers.

[0559] For the purposes of this disclosure, a compound represented by a racemic formula stands equally well as either of the two enantiomers or mixtures thereof, or, if a second chiral center is present, all diastereomers.

[0560] In all embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed disclosure. The compounds of the present disclosure may include any of the substituents or combinations of substituents provided herein. It is understood that combinations of substituents and / or variables in the formulas shown herein are permissible only if such combinations result in stable compounds.

[0561] In further embodiments, various compounds of the present disclosure that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of the present disclosure can be converted to their free base or acid form by standard techniques.

[0562] Pharmaceutical Composition To facilitate delivery to cells, tissues, or patients, the MNK inhibitors of the present disclosure can be formulated with pharmaceutically acceptable carriers, excipients, or diluents in various compositions. Suitable pharmaceutical carriers, excipients, and / or diluents for use in the present disclosure include, but are not limited to, lactose, sucrose, starch powder, talc powder, cellulose esters of alkanoic acid, magnesium stearate, magnesium oxide, crystalline cellulose, methylcellulose, carboxymethylcellulose, gelatin, glycerin, sodium alginate, gum arabic, gum acacia, sodium and calcium salts of phosphates and sulfates, polyvinylpyrrolidone and / or polyvinyl alcohol, saline, and water. Specific formulations of compounds for therapeutic treatment are discussed in Hoover, J.E., Remington's Pharmaceutical Sciences (Easton, Pa.: Mack Publishing Co., 1975) and Liberman and Lachman, eds. Pharmaceutical Dosage Forms (New York, NY: Marcel Decker Publishers, 1980), which are incorporated herein by reference.

[0563] Other embodiments are directed to pharmaceutical compositions. The pharmaceutical composition comprises any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still other embodiments, the pharmaceutical composition comprises a compound disclosed herein and an additional therapeutic agent. Non-limiting examples of such therapeutic agents are described herein below.

[0564] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0565] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in the form of a depot preparation or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the compounds are delivered in a target-specific drug delivery system, for example, in the form of liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target and are selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

[0566] In methods of treatment according to embodiments of the present disclosure, at least one compound of structure (I)-(XLIX) is administered in an effective amount to a subject suffering from or diagnosed with such a disease, disorder, or medical condition. An effective amount or dose may be ascertained by methods such as modeling, dose escalation studies, or clinical trials, taking into account, for example, the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, previous or ongoing treatments of the subject, the subject's health status and response to the drug, and the judgment of the treating physician.

[0567] The compounds of the present disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 10-5000 mg per day, 100-5000 mg per day, 1000 mg-4000 mg per day, and 1000-3000 mg per day are exemplary dosages used in some embodiments. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician.

[0568] In some embodiments, the compound of the present disclosure is administered in a single dose. Typically, this administration is by injection, for example, intravenous injection, to rapidly introduce the drug. However, other routes may be used as appropriate. A single dose of the compound of the present disclosure may also be used to treat acute conditions.

[0569] In some embodiments, the compound of the present disclosure is administered in multiple doses. In some embodiments, administration is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration is about once per month, once every two weeks, once per week, or once every other day. In another embodiment, the compound of the present disclosure and another agent are administered together about once per day to about six times per day. In another embodiment, administration of the compound of the present disclosure and another agent continues for less than about seven days. In yet another embodiment, administration continues for more than about six days, ten days, fourteen days, twenty-eight days, two months, six months, or one year. In some cases, continuous administration is administered and maintained as long as necessary.

[0570] Administration of the disclosed compound can be continued for as long as necessary. In some embodiments, the disclosed compound is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the disclosed compound is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the disclosed compound is administered chronically on an ongoing basis, for example, for the treatment of chronic migraine or for the prevention of migraine. In some embodiments, the disclosed compound can be administered only when migraine symptoms are evident, such as during prodromal symptoms or aura, or even during headache.

[0571] In some embodiments, the compounds of the present disclosure are administered in individual dosage forms. It is known in the art that due to inter-subject variability in the pharmacokinetics of compounds, individualization of dosing regimens is necessary for optimal treatment.

[0572] In some embodiments, the compound described herein is formulated into pharmaceutical compositions.In certain embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of the disclosed compound into pharmaceutical preparations.Suitable formulations depend on the selected route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients may be used as suitable for formulating the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0573] Provided herein are pharmaceutical compositions comprising one or more compounds of structures (I) through (XLIX) and a pharmaceutically acceptable carrier.

[0574] Provided herein are pharmaceutical compositions comprising one or more compounds selected from the compounds of structures (I)-(XLIX) and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s). In certain embodiments, the described compounds are administered as pharmaceutical compositions in which one or more compounds selected from the compounds of structures (I)-(XLIX) are mixed with other active ingredients, such as in combination therapy. Encompassed herein are all combinations of active agents described in the combination therapy section below and throughout this disclosure. In certain embodiments, the pharmaceutical composition comprises one or more compounds of structures (I)-(XLIX).

[0575] As used herein, a pharmaceutical composition refers to a mixture of one or more compounds selected from the compounds of structures (I)-(XLIX) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to a living organism. In some embodiments, a therapeutically effective amount of one or more compounds selected from the compounds of structures (I)-(XLIX) provided herein is administered in a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0576] In addition, the MNK inhibitors described herein can be formulated with another MNK inhibitor described herein, another MNK inhibitor, another pain therapeutic agent, a nerve regeneration therapeutic agent, or another small molecule or biological therapeutic agent, or any combination thereof. Exemplary pain therapeutic agents and nerve regeneration therapeutic agents are described herein with respect to methods of treatment using MNK inhibitors.

[0577] In one embodiment, one or more compounds selected from the compounds of structures (I)-(XLIX) are formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from a physiologically compatible buffer, such as, by way of example only, Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compounds selected from the compounds of structures (I)-(XLIX) are formulated for transmucosal administration. In certain embodiments, transmucosal formulations include penetrants appropriate for permeating the barrier. In still other embodiments, where the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0578] In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated into oral dosage forms, including, but not limited to, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0579] In certain embodiments, pharmaceutical preparations for oral use are prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and then processing the resulting granules to obtain tablets or dragee cores, after adding suitable excipients. Suitable excipients include, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In certain embodiments, disintegrants are optionally added. Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0580] In one embodiment, dosage forms such as dragee cores and tablets are provided with one or more suitable coatings. In certain embodiments, concentrated sugar solutions are used to coat dosage forms. The sugar solutions optionally contain additional ingredients such as, but not limited to, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes and / or pigments are also optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments are optionally used to distinguish different combinations of active compound doses.

[0581] In certain embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In certain embodiments, the push-fit capsules contain the active ingredient mixed with one or more fillers. Fillers include, by way of example only, binders such as lactose or starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers are optionally added.

[0582] In yet other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, the injectable formulations are provided in unit dosage form (e.g., ampoules) or in multi-dose containers. Preservatives are optionally added to the injectable formulation. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection formulations optionally contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. In certain embodiments, pharmaceutical formulations for parenteral administration comprise aqueous solutions of the active compounds in water-soluble form. In further embodiments, suspensions of one or more compounds selected from compounds of structure (I) or (II) are prepared as appropriate oily injection suspensions. Lipophilic solvents or vehicles suitable for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension also contains suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0583] Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent, or excipient and one or more compounds selected from the compounds of structures (I) through (XLIX) described herein as an active ingredient. The active ingredient may be in free acid or free base form, or in a pharmaceutically acceptable salt form. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Furthermore, the compounds described herein include unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered to be disclosed herein. Additionally, pharmaceutical compositions optionally contain other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, solubility enhancers, salts for regulating osmotic pressure, buffers, and / or other therapeutically useful substances.

[0584] Methods for preparing compositions containing the compounds described herein include formulating the compounds with one or more inert pharmaceutically acceptable excipients or carriers to form solids, semi-solids, or liquids. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. Pharmaceutical compositions described herein may take the form of liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to use, or emulsions. These compositions also optionally contain minor amounts of nontoxic auxiliary substances (e.g., wetting or emulsifying agents, pH buffering agents, and the like).

[0585] In some embodiments, pharmaceutical compositions comprising one or more compounds selected from the compounds of structures (I)-(XLIX) are illustratively in the form of a liquid in which the drug is present in solution, in suspension, or both. Typically, when the composition is administered as a suspension, a first portion of the drug is present in solution and a second portion of the drug is present in particulate form in suspension in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0586] In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulose polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0587] The pharmaceutical compositions also optionally include a solubilizing agent to aid in the solubility of one or more compounds selected from the compounds of structures (I)-(XLIX). The term "solubilizing agent" generally includes agents that result in the formation of a micellar or true solution of the drug. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0588] Additionally, the pharmaceutical compositions optionally contain one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid, bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane, and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride, etc. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0589] The composition also optionally contains one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions. Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0590] Other pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal, stabilized chlorine dioxide, and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0591] The composition may contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as Octoxynol 10 and Octoxynol 40.

[0592] The compositions may also contain one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0593] In certain embodiments, the aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0594] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In further embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. A variety of sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compound for several weeks to over 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stabilization are employed.

[0595] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0596] In some embodiments, the concentration of one or more compounds selected from the compounds of structures (I)-(XLIX) provided in the pharmaceutical compositions of the present disclosure is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25 ... %,16%,15.75%,15.50%,15.25%,15%,14.75%,14.50%,14.25%,14%,13.75%,13.50%,13.25%,13%,12.75%,12.50%,12.25%,12%,11.75%,11.50%,11.25%,11%,10.75%,10.50%,10.25%,10%,9.75%,9.50%,9.25%,9%,8.75%,8.50%,8.2 5%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.0 7%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0597] In some embodiments, the concentration of one or more compounds selected from the compounds of structures (I)-(XLIX) provided in the pharmaceutical compositions of the present disclosure is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%. , about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v, or v / v.

[0598] In some embodiments, the amount of one or more compounds selected from the compounds of structures (I)-(XLIX) provided in the pharmaceutical compositions of the present disclosure is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0. 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g.

[0599] In some embodiments, the amount of one or more compounds selected from the compounds of structures (I)-(XLIX) provided in the pharmaceutical compositions of the present disclosure ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0600] Packaging materials for use in packaging the pharmaceutical compositions described herein include, for example, those described in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material appropriate for the selected formulation and intended mode of administration and treatment. For example, the container(s) contain one or more compounds described herein, optionally in a composition or in combination with another agent disclosed herein. The container(s) optionally have a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper pierceable by a hypodermic injection needle). Such kits optionally contain the compound along with an identifying description or label or instructions for its use in the methods described herein.

[0601] For example, a kit typically includes one or more additional containers, each holding one or more of various materials (e.g., reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user perspective for use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packages, containers, vials, and / or tube labels listing the contents and / or instructions for use, and package inserts containing the instructions. A set of instructions for use is also typically included. The label is optionally on or associated with the container. For example, a label is on a container when letters, numbers, or other symbols forming the label are applied, molded, or etched into the container itself, whereas a label is associated with a container when the label is present in a receptacle or carrier that also holds the container, for example, as a package insert. In addition, the label is used to indicate that the contents are to be used for a particular therapeutic application. In addition, the label indicates instructions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are provided in a pack or dispenser device containing one or more unit dosage forms containing the compounds provided herein. The pack comprises, for example, metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser has a notice attached to the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the government agency of the drug form for administration to humans or animals. Such notice is, for example, the label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. In some embodiments, a composition containing the compounds provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in an appropriate container, and labeled for the treatment of the indicated condition.

[0602] Treatment method One embodiment of the present disclosure provides a method of treating a disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structures (I)-(XLIX), or a pharmaceutical composition described herein. In a more specific embodiment, the disease or disorder is migraine or a symptom associated with migraine.

[0603] Certain compounds of the present disclosure may be able to cross the blood-brain barrier. These brain-penetrating compounds may be used for administration to neurons or brain tissue.

[0604] Embodiments of the present disclosure are useful for treating migraine and migraine-related symptoms in a host species. The host species or patient may belong to any mammalian species, such as primate species, particularly humans, rodents including mice, rats, and hamsters, rabbits, horses, cows, dogs, cats, etc. Animal models are of interest for experimental studies to provide a model for the treatment of human disease.

[0605] Embodiments of the present disclosure also relate to the use of compounds according to structures (I)-(XLIX) and / or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or modulated by mitogen-activated protein kinase interacting kinase (MNK) activity. Furthermore, embodiments of the present disclosure relate to the use of compounds according to structures (I)-(XLIX) and / or physiologically acceptable salts thereof for the manufacture of a medicament for the prophylactic or therapeutic treatment and / or monitoring of diseases. A particular embodiment is the use of a compound according to structures (I)-(XLIX) or a physiologically acceptable salt thereof for the manufacture of a medicament for prophylactic or therapeutic treatment.

[0606] The compounds disclosed herein may be administered as a single dose or multiple doses.For example, when multiple doses are administered, they can be administered at intervals of 3 times per 24 hours, 2 times per 24 hours, 1 time per 24 hours, 1 time every other day, 1 time every 3 days, 1 time every 4 days, 1 time per week, 2 times per week, or 3 times per week.The compounds can also be delivered continuously, for example, via a continuous pump.The administration schedule can depend on the dose administered, the severity of the disease, the response to treatment, and other factors, or any combination thereof.

[0607] The dose can be any effective amount, however, in certain examples, the dose can be 25 mg, 50 mg, 100 mg, 200 mg, or 500 mg.

[0608] The first dose may be higher than subsequent doses, or all doses may be the same. The dose may depend on the administration schedule, the severity of the disease, the response to treatment, and other factors, or any combination thereof. The compound may be administered for a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or 3 years. The administration period may depend on the severity of the disease, the response to treatment, and other factors, or any combination thereof.

[0609] For example, a less frequent dosing schedule for the same dose may be employed when the patient responds to treatment, or the dosing schedule may remain unchanged, but the dose may be reduced when the patient responds to treatment.

[0610] In certain embodiments, the pharmaceutical composition may be administered daily or periodically, even in the absence of migraine symptoms, to prevent migraines. Such administration may be particularly useful for patients who suffer from chronic migraines, who are severely incapacitated by migraines, or whose lifestyle or occupation is severely disrupted by migraines (e.g., parents of young children, individuals employed to operate automobiles or heavy machinery, individuals performing long and visually intensive processes such as surgeons, etc.).

[0611] In other particular embodiments, the pharmaceutical composition may be administered when migraines are more likely to occur (such as during certain periods of a woman's menstrual cycle) or when migraine symptoms are present. Typically, the pharmaceutical composition may be administered prior to the headache, for example, at the onset of or during prodromal or aura symptoms.

[0612] The compounds according to the present disclosure can be administered in combination with additional therapeutic agents, including other MNK inhibitors or therapeutic agents that are not MNK inhibitors, particularly other migraine therapeutic agents. Suitable additional therapeutic agents include both small molecules and biologics. The compounds according to the present disclosure can be administered with any combination of additional therapeutic agents.

[0613] For example, the compounds of the present disclosure may be administered with one or more other pain medications and / or migraine medications. Suitable medications include mild analgesics such as ibuprofen, ketoprofen, aspirin, other salicates, and nonsteroidal anti-inflammatory drugs including naproxen and acetaminophen; triptans such as sumatriptan and rizatriptan; dihydroergotamine; lasmiditan; ubrogepant; rimegepant or other CGRP antagonists; opioids; antiemetics such as metoclopramide and prochlorperazine; beta-blockers such as propranolol or metoprolol tartrate; calcium channel blockers such as verapamil; tricyclic antidepressants such as amitriptyline; anticonvulsants such as valproate or topiramate; Botox injections; and anti-CGRP monoclonal antibodies.

[0614] When administered with another analgesic agent, the compounds according to the present disclosure may allow for a reduction in the dose or frequency of administration of the other analgesic agent, or a reduction in the total time the other therapeutic agent is administered. Such administration schedules may be particularly beneficial when the additional pain medication is addictive, such as an opioid.

[0615] The agents disclosed herein or other suitable agents are administered depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure are co-administered with other agents. When used in combination therapy, the compounds described herein are administered simultaneously with the second agent or separately. This combination administration can include simultaneous administration of two or more agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any additional agents (e.g., anti-inflammatory agents, pain-reducing agents, etc.) can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and the additional agents can be administered simultaneously, where both agents are in separate formulations. In another alternative, the additional agent can be administered immediately after the compound of the present disclosure is administered, or vice versa. In some embodiments of the separate administration protocol, the compounds of the present disclosure and the additional agent are administered several days apart, or several hours apart, or several days apart. In some embodiments, the compounds of structures (I)-(XLIX) are administered as monotherapy.

[0616] The methods of the presently disclosed embodiments can be carried out either in vitro or in vivo. The susceptibility of a particular patient, subject, or cell to treatment with a compound of structures (I)-(XLIX), whether in the course of research or clinical application, can be specifically determined by in vitro testing. [Example]

[0617] The examples and preparations provided below further describe and illustrate the compounds of the present disclosure and methods for preparing and testing such compounds. It should be understood that the scope of the present disclosure is in no way limited by the scope of the following examples and preparations. In the following examples, and throughout the specification and claims, molecules with a single stereocenter are present as a racemic mixture unless otherwise specified. Molecules with two or more stereocenters are present as a racemic mixture of diastereomers unless otherwise specified. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art. Methods for making the compounds described herein are provided below. In general, starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or can be synthesized according to sources known to those skilled in the art (e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), or can be prepared as described herein.

[0618] General Reaction Scheme 1 The following general reaction scheme includes variations of various components to achieve different synthetic targets. For example, as referenced below, compounds 6a-6f and compounds 8a-8c each have the following structures: [ka] General Reaction Scheme 1 is shown below. [ka] Any of the above reaction schemes can be modified at any step during the total synthesis of the desired compound to add and / or modify substituents or to change the order of steps as appropriate. For example, General Reaction Scheme 1 can be modified after the step to produce compounds 7a-7f according to the following General Reaction Scheme 2, where X and Y are either N or C depending on the identity of the reactants used.

[0619] General Reaction Scheme 2 [ka]

[0620] General Reaction Scheme 3 Compounds of the present disclosure may be prepared according to the processes outlined in General Reaction Schemes 3 to 20. Compound numbering corresponds to the structures shown in the schemes herein. [ka]

[0621] Compound (1), a known compound, or a compound prepared by a known method, is reacted with a compound of formula (2), a known compound, or Y 1 C 1-6The compound of formula (3) is reacted with a compound prepared by a known method, which is an alkyl group, in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid in a solvent such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, or methylene chloride, optionally with heating and optionally with microwave irradiation, to obtain a compound of formula (3). The compound of formula (3) is reacted with urea hydrogen peroxide in the presence of an acid anhydride such as trifluoroacetic anhydride or acetic anhydride in a solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran, or 1,4-dioxane, optionally with heating and optionally with microwave irradiation, to obtain a compound of formula (4). The compound of formula (4) is reacted with an acid anhydride, such as trifluoroacetic anhydride, acetic anhydride, in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating and optionally with microwave irradiation, to provide a compound of formula (5).

[0622] General Reaction Scheme 4 [ka] The compound of formula (5) is reacted with ammonium hydroxide, optionally in the presence of a solvent such as methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, with optional heating and optional microwave irradiation, to provide a compound of formula (6). The compound of formula (6) is reacted with a compound of formula (7), a known compound, or a compound prepared by a known method, in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and the like, in a solvent such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, methylene chloride, and the like, with optional heating and optional microwave irradiation, to provide a compound of formula (8).

[0623] General Reaction Scheme 5 [ka] A compound of formula (9), a known compound, or a compound prepared by a known method, is reacted with a compound of formula (10), a known compound, or a compound prepared by a known method, 2 C 1-6 The compound of formula (11) is reacted with a compound prepared by known methods, which is an alkyl group, in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid in a solvent such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, or methylene chloride, optionally with heating and optionally with microwave irradiation, to obtain a compound of formula (11). The compound of formula (11) is reacted with urea hydrogen peroxide in the presence of an acid anhydride such as trifluoroacetic anhydride or acetic anhydride in a solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran, or 1,4-dioxane, optionally with heating and optionally with microwave irradiation, to obtain a compound of formula (12). The compound of formula (12) is reacted with an acid anhydride, such as trifluoroacetic anhydride, acetic anhydride, in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, optionally with heating and optionally with microwave irradiation, to provide a compound of formula (13).

[0624] General Reaction Scheme 6 [ka] The compound of formula (13) is reacted with ammonium hydroxide, optionally in the presence of a solvent such as methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, with optional heating and optional microwave irradiation, to provide a compound of formula (14). The compound of formula (14) is reacted with a compound of formula (15), a known compound, or a compound prepared by a known method, in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and the like, in a solvent such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, methylene chloride, and the like, with optional heating and optional microwave irradiation, to provide a compound of formula (16).

[0625] General Reaction Scheme 7 [ka] The compound of formula (16) can be reacted with a compound of formula (17), a known compound, or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or bispalladium-tri(1,3-dibenzylidene)acetone, optionally with 4,5-bis( Diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)dicyclohexylphosphine ) Di-tert-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl, sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert-butylphosphino In the presence of an organic phosphine such as 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,Reaction in a solvent such as 2-dimethoxyethane, optionally in the presence of water, optionally with heating and optionally with microwave irradiation, provides a compound of formula (18).

[0626] General Reaction Scheme 8 [ka] The compound of formula (16) can be reacted with a compound of formula (19), a known compound, or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or bispalladium-tri(1,3-dibenzylidene)acetone, optionally with 4,5-bis( Diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)dicyclohexylphosphine ) Di-tert-butylphosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl, sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert-butylphosphino In the presence of an organic phosphine such as 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,Reaction in a solvent such as 2-dimethoxyethane, optionally in the presence of water, optionally with heating and optionally with microwave irradiation, provides a compound of formula (20).

[0627] General Reaction Scheme 9 [ka] The compound of formula (16) can be reacted with a compound of formula (21), a known compound, or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or bispalladium-tri(1,3-dibenzylidene)acetone, optionally with 4,5-bis( Diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)dicyclohexylphosphine ) Di-tert-butylphosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl, sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert-butylphosphino In the presence of an organic phosphine such as 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,Reaction in a solvent such as 2-dimethoxyethane, optionally in the presence of water, optionally with heating and optionally with microwave irradiation, provides a compound of formula (22).

[0628] General Reaction Scheme 10 [ka] The compound of formula (16) can be reacted with a compound of formula (23), a known compound, or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or bispalladium-tri(1,3-dibenzylidene)acetone, optionally with 4,5-bis( Diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)dicyclohexylphosphine ) Di-tert-butylphosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl, sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert-butylphosphino In the presence of an organic phosphine such as 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,Reaction in a solvent such as 2-dimethoxyethane, optionally in the presence of water, optionally with heating and optionally with microwave irradiation, provides a compound of formula (24).

[0629] General Reaction Scheme 11 [ka] The compound of formula (16) can be reacted with a compound of formula (25), a known compound, or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or bispalladium-tri(1,3-dibenzylidene)acetone, optionally with 4,5-bis( Diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)dicyclohexylphosphine ) Di-tert-butylphosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl, sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert-butylphosphino In the presence of an organic phosphine such as 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,The compound of formula (26) is reacted in a solvent such as 2-dimethoxyethane, optionally in the presence of water, optionally with heating and optionally with microwave irradiation, to obtain a compound of formula (26). The compound of formula (26) is reacted with a compound of formula (27), a known compound, or a compound prepared by a known method, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, in a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, optionally with heating and optionally with microwave irradiation, to obtain a compound of formula (28).

[0630] General Reaction Scheme 12 [ka] The compound of formula (16) can be reacted with a compound of formula (29), a known compound, or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or bispalladium-tri(1,3-dibenzylidene)acetone, optionally with 4,5-bis( Diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)dicyclohexylphosphine ) Di-tert-butylphosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl, sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert-butylphosphino In the presence of an organic phosphine such as 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,The compound of formula (30) is reacted in a solvent such as 2-dimethoxyethane, optionally in the presence of water, optionally with heating, and optionally with microwave irradiation to obtain a compound of formula (30). The compound of formula (30) is reacted with a compound of formula (31), a known compound, or a compound prepared by a known method, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, in a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, optionally with heating, and optionally with microwave irradiation to obtain a compound of formula (32).

[0631] General Reaction Scheme 13 [ka] The compound of formula (16) can be reacted with a compound of formula (33), a known compound, or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or bispalladium-tri(1,3-dibenzylidene)acetone, optionally with 4,5-bis( Diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)dicyclohexylphosphine ) Di-tert-butylphosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl, sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert-butylphosphino In the presence of an organic phosphine such as 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,The compound of formula (34) is reacted in a solvent such as 2-dimethoxyethane, optionally in the presence of water, optionally with heating, and optionally with microwave irradiation to obtain a compound of formula (34). The compound of formula (34) is reacted with a compound of formula (35), a known compound, or a compound prepared by a known method, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, in a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, optionally with heating, and optionally with microwave irradiation to obtain a compound of formula (36).

[0632] General Reaction Scheme 14 [ka] The compound of formula (16) can be reacted with a compound of formula (37), a known compound, or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or bispalladium-tri(1,3-dibenzylidene)acetone, optionally with 4,5-bis( Diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)dicyclohexylphosphine ) Di-tert-butylphosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl, sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert-butylphosphino In the presence of an organic phosphine such as 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,The compound of formula (38) is reacted with a compound of formula (39), a known compound, or a compound prepared by a known method, in a solvent such as 2-dimethoxyethane, optionally in the presence of water, optionally with heating, and optionally with microwave irradiation, to obtain a compound of formula (38). The compound of formula (38) is reacted with a compound of formula (39), a known compound, or a compound prepared by a known method, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, in a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, optionally with heating, and optionally with microwave irradiation, to obtain a compound of formula (40).

[0633] General Reaction Scheme 15 [ka] The compound of formula (41) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, optionally in the presence of ethylenediamine, optionally in the presence of water, in the presence of a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, optionally with heating and optionally with microwave irradiation to provide a compound of formula (42).

[0634] General Reaction Scheme 16 [ka] The compound of formula (43) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, optionally in the presence of ethylenediamine, optionally in the presence of water, in the presence of a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, optionally with heating and optionally with microwave irradiation to provide a compound of formula (44).

[0635] General Reaction Scheme 17 [ka] The compound of formula (45) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, optionally in the presence of ethylenediamine, optionally in the presence of water, in the presence of a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, optionally with heating and optionally with microwave irradiation to provide a compound of formula (46).

[0636] General Reaction Scheme 18 [ka] The compound of formula (47) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, optionally in the presence of ethylenediamine, optionally in the presence of water, in the presence of a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, optionally with heating and optionally with microwave irradiation to provide a compound of formula (48).

[0637] General Reaction Scheme 19 [ka] The compound of formula (49) is reacted with a compound of formula (50), a known compound, or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0) acetate, dichlorobis(triphenylphosphine)palladium(II), bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0), in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, and the like, optionally in the presence of water, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, methylene chloride, 1,2-dichloroethane, and the like, optionally with heating and optionally with microwave irradiation, to provide a compound of formula (51).

[0638] General Reaction Scheme 20 [ka] A compound of formula (52) is reacted with a compound of formula (53), a known compound, or a compound prepared by known methods in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0) acetate, dichlorobis(triphenylphosphine)palladium(II), bis(acetonitrile)dichloropalladium(II), or tris(dibenzylideneacetone)dipalladium(0), in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, or pyridine, optionally in the presence of water, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, methylene chloride, or 1,2-dichloroethane, optionally with heating and optionally with microwave irradiation, to provide a compound of formula (54). The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectroscopy, or by chromatographic methods such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC).

[0639] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

[0640] The reactions or processes described herein can be carried out in a suitable solvent, which can be easily selected by one skilled in the art of organic synthesis. A suitable solvent is typically substantially non-reactive with the reactants, intermediates, and / or products at the temperature at which the reaction is carried out, i.e., a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. A suitable solvent for a particular reaction step can be selected depending on the particular reaction step.

[0641] The examples provided below provide representative methods for preparing exemplary compounds of the present disclosure. Those of skill in the art will know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare compounds of the present disclosure.

[0642] It will also be understood by those skilled in the art that in the processes for preparing the compounds described herein, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include, but are not limited to, hydroxy, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters. Protecting groups are optionally added or removed according to standard techniques known to those skilled in the art and described herein. The use of protecting groups is described in detail in Green, T. W. and P. G. M. Hutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one skilled in the art will appreciate, the protecting group can also be a polymer resin such as a Wang resin, a Rink resin, or a 2-chlorotrityl-chloride resin.

[0643] It will also be understood by those skilled in the art that, although such protected derivatives of the compounds of the present disclosure may not themselves have pharmacological activity, they may be administered to a mammal and then metabolized in the body to form a compound of the present disclosure that is pharmacologically active. Such derivatives may therefore be described as "prodrugs." Prodrugs of the compounds of the present disclosure are included within the scope of embodiments of the present disclosure.

[0644] Features of these examples may be combined with elements of the preceding detailed description unless clearly mutually exclusive. More specific reagent conditions and results from the above general reaction schemes are detailed in the following examples.

[0645] The following abbreviations are used in the reaction schemes and synthetic examples herein. This list is not meant to be a comprehensive list of abbreviations used in this disclosure as additional standard abbreviations will be readily understood by those of skill in the art and may also be used in the synthetic schemes and examples. DMA: Dimethylacetamide DMF: dimethylformamide DMSO: dimethyl sulfoxide TFAA: Trifluoroacetic anhydride Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0646] Example 1 Synthesis of 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide [ka] To a solution of compound 1 (10 g, 42.3 mmol) in ethanol (37 mL) was added HSO (2.3 mL, 18.4 M, 42.3 mmol) at room temperature. The reaction mixture was heated at 80 °C for 16 h. The solvent was removed under reduced pressure, and EtOAc (250 mL) was added. After washing with NaHCO (200 mL × 2) and water (200 mL × 2), the organic phase was dried over NaSO, filtered, and concentrated under reduced pressure to give ethyl 5-bromo-3-methylpicolinate (2, 9.6 g, 39 mmol, 93%) as a colorless liquid. 1 H NMR(400MHz,CDCl3) δ 8.58(s,1H),7.76(s,1H),4.43(q,J=7.1Hz,2H),2.56(s,3H),1.41(t,J=7.1Hz,3H).

[0647] To a solution of compound 2 (9.6 g, 39 mmol) in CHCl (111 mL) was added urea hydrogen peroxide (6.4 g, 68.3 mmol), followed by trifluoroacetic anhydride (9.6 mL, 68.3 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h and poured into an ice / water mixture (100 mL). After extraction with CHCl (50 mL × 3), the combined organic phase was washed with NaHCO (50 mL × 3) and water (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give 5-bromo-2-(ethoxycarbonyl)-3-methylpyridine 1-oxide (3, 10.1 g, 39 mmol, 99%) as a colorless liquid. 1 H NMR(400MHz,CDCl3) δ 8.20(s,1H),7.26(s,1H),4.47(q,J=7.1Hz,2H),2.27(s,3H),1.39(t,J=7.1Hz,3H).

[0648] To a solution of compound 3 (10.1 g, 39 mmol) in DMF (30.5 mL) was added trifluoroacetic anhydride (9.6 mL, 68.3 mmol) at 0 °C. The mixture was stirred at 40 °C for 8 h and diluted with water (100 mL). After extraction with EtOAc (100 mL × 3), the combined organic phase was washed with brine (100 mL × 5), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Biotage flash chromatography (silica gel, 0% to 30% EtOAc in hexane) to give ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (4, 6.8 g, 26.1 mmol, 67%) as a white solid. 1 H NMR(400MHz,CDCl3) δ 7.83(s,1H),4.42(q,J=7.1Hz,2H),2.45(s,3H),1.41(t,J=7.1Hz,3H).

[0649] Ammonium hydroxide (130.5 mL, 28% v / v) was added to compound 4 (6.8 g, 26.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 6 hours and concentrated under reduced pressure to give 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (compound 5 of General Reaction Scheme 1, 6.0 g, 26 mmol, 99%) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 7.87(s,1H),7.84(s,1H),7.71(s,1H),2.12(s,3H).

[0650] General Procedure A Synthesis of 2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione [ka] To a solution of compound 5 (1 equiv.) in 1,4-dioxane (0.2 M) was added ketones 6a-f (4 equiv.), followed by H2SO4 (0.5 equiv.). Compounds 6a-6f are as shown in General Reaction Scheme 1.

[0651] The reaction mixture was sealed in a pressure vessel and heated at 100° C. for 16 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting crude material was purified by Biotage flash chromatography (gradient elution, 30→85% EtOAc in hexanes or 0→10% MeOH in CH2Cl2) to give compounds 7a-f.

[0652] Example 2 Synthesis of 6-bromo-3,3,8-trimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (7a) [ka] Compound 7d was synthesized according to general procedure A. Compound 7a (150 mg, 0.55 mmol, 85% yield) was produced as a white solid from compound 5 (150 mg, 0.65 mmol, 1.0 equiv), acetone (0.48 mL, 6.5 mmol, 10.0 equiv), and HSO (3 mg, 0.03 mmol, 0.05 equiv) in 1,4-dioxane (2 mL).

[0653] Example 3 Synthesis of 6'-bromo-8'-methyl-2'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (7b) [ka] Compound 7d was synthesized according to general procedure A. Compound 7b (585 mg, 1.97 mmol, 76%) was produced from compound 5 (600 mg, 2.6 mmol), cyclopentanone (6b, 0.92 mL, 10.4 mmol), and HSO (0.07 mL, 1.3 mmol) in 1,4-dioxane (5.2 mL).

[0654] Example 4 Synthesis of 6-bromo-8-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (7c) [ka] Compound 7d was synthesized according to general procedure A. Compound 7c (954 mg, 3.06 mmol, 71%) was produced from compound 5 (1 g, 4.33 mmol), cyclohexanone (6c, 1.8 mL, 17.31 mmol), and HSO (0.12 mL, 2.16 mmol) in 1,4-dioxane (16 mL).

[0655] Example 5 Synthesis of 6-bromo-8-methyl-2',3',5',6'-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-pyran]-1,5-dione (7d). [ka] Compound 7d was synthesized according to general procedure A. Compound 7d (486 mg, 1.55 mmol, 72%) was produced from compound 5 (500 mg, 2.16 mmol), tetrahydro-4H-pyran-4-one (6d, 0.8 mL, 8.65 mmol), and HSO (0.058 mL, 1.08 mmol) in 1,4-dioxane (12 mL).

[0656] Example 6 Synthesis of 6-bromo-4-hydroxy-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (7e) [ka] Compound 7e was synthesized according to general procedure A. Compound 7e (196 mg, 0.60 mmol, 46%) was produced from compound 5 (300 mg, 1.29 mmol), 4-hydroxycyclohexan-1-one (6e, 592 mg, 5.19 mmol), and HSO (0.035 mL, 0.645 mmol) in 1,4-dioxane (13 mL).

[0657] Example 7 Synthesis of N-(6'-bromo-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-4-yl)methanesulfonamide (7f) [ka] Compound 7e was synthesized according to general procedure A. The intermediate 4-amino-6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione was generated from compound 5, tert-butyl(4-oxocyclohexyl)carbamate (6f), and H2SO4 in 1,4-dioxane (13 mL). The primary amino intermediate was treated with sulfonyl chloride in CHCl2 to give the methylsulfonamide 7f (36% over two steps).

[0658] General Procedure B Synthesis of chloropyrimidinyl pyridone intermediates (9a-f) [ka] One of compounds 7a–7f (1 equiv.), 4-amino-6-chloropyrimidine 8a (1.2 equiv.), CsCO (3 equiv.), Xantphos (20 mol%), and Pd(OAc) (10 mol%) were combined in 1,4-dioxane (0.1 M), and the mixture was purged with inert gas (nitrogen or argon) for 20 min. The vessel was sealed and heated at 90 °C for 16 h. The reaction mixture was cooled to ambient temperature, washed with water, and extracted with 2-propanol / chloroform (v:v / 1:4) until complete recovery of the product was confirmed (TLC: 80% EtOAc / hexane). The extracts were combined and concentrated under reduced pressure, and the crude material was purified by either recrystallization (CHCl in hexane) or Biotage flash chromatography (gradient elution: 0% to 10% MeOH in CHCl) to give compounds 9a–f.

[0659] Example 8 Synthesis of 6-((6-chloropyrimidin-4-yl)amino)-3,3,8-trimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (9a) [ka] Compound 9a was synthesized according to general procedure B. The compound was purified and analyzed according to the following parameters: UHPLC-MS (HESI / APCI): t 1.36 minutes, m / z 320.3[M+H].

[0660] Example 9 Synthesis of 6'-((6-chloropyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (9b) [ka] Compound 9b was synthesized according to general procedure B. Compound 9b (209 mg, 0.60 mmol, 45%) was produced from compound 7b (270 mg, 1.33 mmol), 4-amino-6-chloropyrimidine 8a (150 mg, 1.6 mmol), CsCO (950 mg, 4.0 mmol), Xantphos (110 mg, 0.27 mmol), and Pd(OAc) (20 mg, 0.13 mmol) in 1,4-dioxane (4.7 mL). 1 H NMR(400MHz,DMSO-d6) δ 9.88(s,1H),9.62(s,1H),8.59(s,1H),8.50(s,1H),7.45(s,1H),2.76(m,2H), 2.40(s,3H),1.94(m,2H),1.80(m,2H),1.67(m,2H).UHPLC-MS(HESI / APCI):Rt 1.42 minutes, m / z 346.2[M+H].

[0661] Example 10 Synthesis of 6'-((6-chloropyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (9c) [ka] Compound 9c was synthesized according to general procedure B. Compound 9c (400 mg, 1.29 mmol), 4-amino-6-chloropyrimidine 8a (200 mg, 1.54 mmol), CsCO (1.25 g, 3.9 mmol), Xantphos (149 mg, 0.26 mmol), and Pd(OAc) (29 mg, 0.13 mmol) in 1,4-dioxane (16 mL) afforded compound 9c (400 mg, 1.11 mmol, 86%). 1H NMR(500MHz,DMSO) δ 8.70(s,1H),8.43(s,1H),8.25(s,1H),6.28(s,1H),5.03(s,1H),3.10(m,2H),2.84-2.76(m,2H) ,2.42(s,3H),2.04-1.94(m,2H),1.88-1.80(m,2H),1.74-1.66(m,2H).UHPLC-MS(HESI / APCI):Rt 1.48 minutes, m / z 360.2[M+H].

[0662] Example 11 Synthesis of 6-((6-chloropyrimidin-4-yl)amino)-8-methyl-2',3',5',6'-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-pyran]-1,5-dione (9d) [ka] Compound 9d was synthesized according to general procedure B. The title compound was purified and analyzed according to the following parameters. UHPLC-MS (HESI / APCI): Rt 1.37 min, m / z 362.2 [M+H].

[0663] General procedure C Synthesis of aminopyrimidinylpyridone (10) [ka] To a mixture of chloropyrimidines 9a-9f (1 equiv.) in 2-propanol or DMSO (0.1 M) was added triethylamine (5 equiv.) and the corresponding amine (5 equiv.). The reaction mixture was stirred at temperatures ranging from 100-120 °C for 16 h. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude material was purified by Biotage flash chromatography (silica gel, 0% → 10% MeOH in CHCl, C 18 , 0%-10% MeOH in water) and then purified by preparative TLC as needed to afford aminopyrimidines of general structure 10.

[0664] Example 12 Synthesis of 6'-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (4ET-02-001) [ka] Compound 4ET-02-001 was synthesized according to general procedure C. Compound 4ET-02-001 (10 mg, 0.026 mmol, 20%) was produced as a beige solid from compound 9c (48 mg, 0.13 mmol), ethanolamine (48 mg, 0.78 mmol) and triethylamine (0.13 mL, 0.93 mmol) in 2-propanol (2 mL). 1 H NMR(400MHz,DMSO) δ 9.98(br s,1H),8.54(s,1H),8.37(s,1H),8.21(s,1H),6.97(br s,1H),6.26(s,1H),4.70(t,J=5.4Hz,1H),3.57-3.46(m,2H),3.29-3.23(m ,2H),3.00(dt,J=3.9,13.0Hz,2H),2.43(s,3H),1.80-1.61(m,5H),1.44(br d,J=11.5Hz,2H),1.23(s,1H).LCMS(ES-API):Rt 3.57min,m / z 385.2[M+H].

[0665] Example 13 Synthesis of 3-((6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)amino)propanoic acid (4ET-02-006) [ka] Compound 4ET-02-006 was synthesized according to general procedure C. Compound 4ET-02-006 (4 mg, 0.009 mmol, 5%) was produced from compound 9c (70 mg, 0.19 mmol), β-alanine (87 mg, 0.97 mmol), and triethylamine (0.16 mL, 1.16 mmol) in DMSO (2.5 mL). 1 H NMR(500MHz,DMSO) δ 10.01(s,1H),8.56(s,1H),8.40(s,1H),8.19(s,1H),7.70(d,J=13.8Hz, 1H),7.07(s,1H),6.24(s,1H),5.03(s,2H),3.21(d,J=36.3Hz,3H),3.08 -2.91(m,1H),2.40(d,J=32.2Hz,1H),2.18(s,1H),2.04(s,1H),1.70(dd,J=55.2,16.1Hz,4H),1.44(d,J=11.4Hz,2H).UHPLC-MS(HESI / APCI):Rt 1.08 min, m / z 413.3[M+H].

[0666] Example 14 Synthesis of 8'-methyl-6'-((6-((2-morpholinoethyl)amino)pyrimidin-4-yl)amino)-2'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (4ET-03-006) [ka] Compound 4ET-03-006 was synthesized according to general procedure C. The title compound 4ET-03-006 (5.2 mg, 0.01 mmol, 11%) was produced from compound 9b (40 mg, 0.11 mmol), 2-morpholinoethylamine (72 mg, 0.55 mmol) and triethylamine (56 mg, 0.55 mmol) in 2-propanol (1.1 mL). 1H NMR(500MHz,DMSO-d6) δ 9.82(s,1H),8.68(s,1H),8.44(s,1H),8.22(s,1H),6.93(s,1H),6.28(s,1H),3.58(s,4H),3.32(s,2H),2. 80(m,2H),2.48-2.37(m,6H),2.44(s,3H),1.98(s,2H),1.84(s,2H),1.69(s,2H);UHPLC-MS(HESI / APCI):Rt 0.90 min, m / z 440.3[M+H].

[0667] Example 15 Synthesis of 6'-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (4ET-03-007) [ka] Compound 4ET-03-007 was synthesized according to general procedure C. The title compound 4ET-03-007 (1.1 mg, 0.003 mmol, 2%) was produced from compound 9b (41 mg, 0.12 mmol), ethanolamine (37 mg, 0.6 mmol) and triethylamine (61 mg, 0.6 mmol) in 2-propanol (1.2 mL). 1H NMR(500MHz,DMSO-d6) δ 9.82(s,1H),8.64(s,1H),8.42(s,1H),8.22(s,1H),7.02(s,1H),6.28(s,1H),4.74(s,OH),3.51(s,2H), 3.32(s,2H),2.80(m,2H),2.42(s,3H),1.98(s,2H),1.84(s,2H),1.69(s,2H);UHPLC-MS(HESI / APCI):Rt 0.46 min, m / z 371.2[M+H].

[0668] Example 16 Synthesis of N-(2-((6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)amino)ethyl)methanesulfonamide (4ET-03-013) [ka] Compound 4ET-03-013 was synthesized according to general procedure C. Compound 10e (4ET-03-013) (4 mg, 0.009 mmol, 8%) was produced from compound 9b (40 mg, 0.12 mmol), N-(2-aminoethyl)-methanesulfonamide (0.1 mL, 0.6 mmol) and triethylamine (0.1 mL, 0.7 mmol) in 2-propanol (2 mL). 1 H NMR(500MHz,CD3OD) δ 8.37(s,1H),8.26(s,1H),6.14(s,1H),4.63(s,3H),3.66(s,1H),3.54-3.43(m,2H),3.31-3.26(m,2H),3.03(s,3 H),2.97(s,1H),2.53(s,2H),2.17-2.08(m,2H),1.95-1.86(m,2H),1.83-1.74(m,2H).UHPLC-MS(HESI / APCI):Rt 1.13 minutes, m / z 448.3[M+H].

[0669] Example 17 Synthesis of N-(2-((6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)amino)ethyl)methanesulfonamide (4ET-02-004) [ka] Compound 4ET-02-004 was synthesized according to general procedure C. Compound 9c (70 mg, 0.19 mmol), ethylenediamine (0.07 mL, 0.97 mmol), and triethylamine (0.16 mL, 1.17 mmol) in 2-propanol (4 mL) gave the 1,2-diamine intermediate (20 mg, 0.052 mmol, 27%). Methanesulfonyl chloride (0.004 mL, 0.05 mmol) was added to a mixture of the diamine intermediate (20 mg, 0.05 mmol) and pyridine (5 mg, 0.057 mmol) in CHCl (0.2 mL) at 0 °C. The reaction mixture was warmed to room temperature (approximately 23.0 °C), stirred for 16 h, and then quenched with 3N NaOH. The aqueous layer was extracted with CHCl (3 × 15 mL), then a few drops of 12 N HCl were added to the aqueous mixture until it was acidic (pH 2-4) by pH paper. The aqueous layer was extracted with 3:1 (CHCl / IPA) × 3, combined with the CHCl extracts, dried (NaSO), filtered, and concentrated under reduced pressure to yield compound 4ET-02-004 (15 mg, 0.032 mmol, 63%). 1 H NMR(500MHz,CD3OD) δ 8.42(s,1H),8.03(s,1H),6.35(s,1H),3.56(s,1H),3.31-3.26(m,2H),3.21-3.10(m,2H),2.98(s, 3H),2.67-2.58(m,3H),2.54(s,3H),2.0-1.75(m,4H),1.73-1.35(m,6H).UHPLC-MS(HESI / APCI):Rt 1.19 minutes, m / z 462.3[M+H].

[0670] General Procedure D Synthesis of Amidopyrimidinylpyridones from Chloropyrimidinylpyridones and Amides [ka] A mixture of the corresponding chloropyrimidine (X = N, Y = CH) pyridone or chloropyridazine (X = CH, Y = N) pyridone (1 equivalent), amide (1.2 equivalents), CsCO (3 equivalents), Xantphos (20 mol%), Pd(OAc) (10 mol%), and 1,4-dioxane (0.1 M) was purged with inert gas (nitrogen or argon) for 20 minutes. The vessel was sealed and heated at 90 °C for 16 hours. The reaction was cooled to ambient temperature, and the solvent was removed under reduced pressure. The resulting crude material was purified by Biotage flash chromatography (gradient elution, 0% to 10% MeOH in CHCl) followed by Prep-TLC, if necessary, to afford the amidopyrimidinyl or aminopyridazinyl pyridone aminal (compound 11).

[0671] Example 18 Synthesis of N-(6-((3,3,8-trimethyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-002) [ka] Compound 4ET-03-002 was synthesized according to general procedure D. Compound 4ET-03-002 (5.5 mg, 0.015 mmol, 10%) was produced from compound 9a (50 mg, 0.16 mmol), cyclopropanecarboxamide (16 mg, 0.19 mmol), CsCO (153 mg, 0.47 mmol), Xantphos (18 mg, 0.03 mmol), and Pd(OAc) (4 mg, 0.016 mmol), and 1,4-dioxane (2 mL).

[0672] Example 19 Synthesis of N-(6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)-2-morpholinoacetamide (4ET-02-007) [ka] Compound 4ET-02-007 was synthesized according to general procedure D. Compound 4ET-02-007 (13 mg, 0.03 mmol, 10%) was produced from compound 9c (100 mg, 0.28 mmol), 2-morpholinoacetamide (48 mg, 0.33 mmol), CsCO (272 mg, 0.83 mmol), Xantphos (32 mg, 0.06 mmol), and Pd(OAc) (6 mg, 0.03 mmol) in 1,4-dioxane (3 mL). 1 H NMR(500MHz,DMSO) δ 10.07(d,J=27.4Hz,1H),9.29(s,1H),8.52(d,J=25.5Hz,2H),7.92(s,1H),3.72-3.57(m,3H),3.27-3.13(m,3H),3.01(t,J=11.3Hz ,2H),2.59-2.52(m,2H),2.44(d,J=11.5Hz,2H),1.83-1.58(m,4H),1.46(d,J=11.8Hz,2H),1.24(s,2H).UHPLC-MS(HESI / APCI):Rt 1.2 minutes, m / z 468.3[M+H].

[0673] Example 20 Synthesis of N-(6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)isobutyramide (4ET-03-005) [ka] Compound 4ET-03-005 was synthesized according to general procedure D. Compound 4ET-03-005 (3.8 mg, 0.01 mmol, 8%) was produced from compound 9b (40 mg, 0.12 mmol), isobutyramide (11 mg, 0.13 mmol), CsCO (117 mg, 0.36 mmol), Xantphos (14 mg, 0.024 mmol), and Pd(OAc) (2.7 mg, 0.012 mmol) in 1,4-dioxane (0.6 mL). 1H NMR(500MHz,DMSO-d6) δ 10.51(s,1H),9.89(s,1H),9.23(s,1H),8.53(s,1H),8.51(s,1H),7.91(s,1H),2.80(m,3H),2.4 4(s,3H),1.98(s,2H),1.84(s,2H),1.69(s,2H),1.09(d,J=6.8Hz,6H);UHPLC-MS(HESI / APCI):Rt 1.40 minutes, m / z 397.3[M+H].

[0674] General Procedure E Synthesis of Amidopyrimidinyl and Amidopyridazinyl Pyridones from Bromopyridones and Aminopyrimidines / Aminopyridazines. [ka] To a mixture of compounds 7a–7f (1 equivalent), N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide (8b) or N-(5-aminopyridazin-3-yl)cyclopropanecarboxamide (8c) (1.2 equivalents), CsCO (3 equivalents), Xantphos (20 mol%), and Pd(OAc) (10 mol%), 1,4-dioxane (0.1 M) was added, and the suspension was purged with inert gas (nitrogen or argon) for 20 minutes. The vessel was sealed and heated at 90°C for 16 hours, then cooled to ambient temperature. The crude material was purified using Biotage flash chromatography (gradient elution, 0% to 10% MeOH in CHCl) to afford the amidopyrimidinyl or amidopyridazinyl pyridone aminal (compound 12).

[0675] Example 21 Synthesis of N-(6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-02-003) [ka] Compound 4ET-02-003 was synthesized according to general procedure E. The title compound 4ET-02-003 (50 mg, 0.122 mmol, 26%) was produced from compound 7c (149 mg, 0.48 mmol), N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide (102 mg, 0.575 mmol), CsCO (468 mg, 1.44 mmol), Xantphos (56 mg, 0.096 mmol), and Pd(OAc) (11 mg, 0.048 mmol) in 1,4-dioxane (5 mL).

[0676] Example 22 Synthesis of N-(6-((8-methyl-1,5-dioxo-1,2',3',5,5',6'-hexahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-pyran]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-009) [ka] Compound 4ET-03-009 was synthesized according to general procedure E. Compound 4ET-03-009 (96 mg, 0.23 mmol, 74%) was produced from compound 7d (100 mg, 0.32 mmol), cyclopropylamidopyrimidinylamide 8b (85 mg, 0.48 mmol), CsCO (312 mg, 0.96 mmol), Xantphos (37 mg, 0.06 mmol), and Pd(OAc) (7.1 mg, 0.03 mmol) in 1,4-dioxane (3.2 mL). 1 H NMR(400MHz,DMSO-d6) δ 10.86(s,1H),10.32(s,1H),9.18(s,1H),8.53(s,1H),8.50(s,1H),7.89(s,1H),3.93(m,2H),3.69(m,2H),3.2 5(m,2H),2.45(s,3H),2.02(pent,J=6.0Hz,1H),1.43(m,2H),0.85(d,J=6.0Hz,4H);UHPLC-MS(HESI / APCI):Rt 0.71 min, m / z 411.3[M+H].

[0677] Example 23 Synthesis of N-(6-((4-hydroxy-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-015) [ka] Compound 4ET-03-015 was synthesized according to general procedure E. Compound 4ET-03-015 (99 mg, 0.23 mmol, 78%) was produced from compound 7e (100 mg, 0.30 mmol), cyclopropylamidopyrimidinylamide 8b (82 mg, 0.45 mmol), CsCO (300 mg, 0.92 mmol), Xantphos (35 mg, 0.06 mmol), and Pd(OAc) (6.8 mg, 0.03 mmol), and 1,4-dioxane (3.2 mL). 1 H NMR(400MHz,DMSO-d6) δ 10.87(s,1H),10.01(s,1H),9.12(s,1H),8.53(s,1H),8.47(s,1H),7.85(s,1H),4.62(br,1H),3.48(m,1H),2.44(s,3H) ,2.02(pent,J=6.0Hz,1H),1.87-1.57(m,4H),1.42(m,2H),1.17(m,2H),0.84(d,J=6.0Hz,4H);UHPLC-MS(HESI / APCI):Rt 0.81 min, m / z 425.3[M+H].

[0678] Example 24 Synthesis of N-(6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-017) [ka] Compound 4ET-03-017 was synthesized according to general procedure E. Compound 4ET-03-017 (33 mg, 0.084 mmol, 25%) was produced from compound 7b (100 mg, 0.34 mmol), N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide (8b) (72 mg, 0.4 mmol), CsCO (329 mg, 1.0 mmol), Xantphos (39 mg, 0.07 mmol), and Pd(OAc) (8 mg, 0.034 mmol) in 1,4-dioxane (3.5 mL). 1 H NMR(400MHz,DMSO-d6) δ 10.83(s,1H),9.84(s,1H),9.16(s,1H),8.50(s,1H),8.46(s,1H),7.83(s,1H),2.80-2.74(comp,3H),2.40(s, 3H),2.01-1.94(m,2H),1,82-1.79(m,2H),1.67-1.63(m,2H),0.81(d,J=4.0Hz,4H);UHPLC-MS(HESI / APCI):Rt 1.3 minutes, m / z 395.3[M+H].

[0679] Example 25 Synthesis of N-(5-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyridazin-3-yl)cyclopropanecarboxamide (4ET-04-003) [ka] Compound 4ET-04-003 was synthesized according to General Procedure E. In General Procedure E, compound 4ET-04-003 (114 mg, 0.29 mmol, 88%) was produced from compound 7b (100 mg, 0.33 mmol), N-(5-aminopyridazin-3-yl)cyclopropanecarboxamide (8c) (90 mg, 0.50 mmol), CsCO (328 mg, 1.01 mmol), Xantphos (39 mg, 0.06 mmol), and Pd(OAc) (7.5 mg, 0.03 mmol) in 1,4-dioxane (3.2 mL). 1H NMR(500MHz,DMSO-d6) δ 11.15(s,1H),9.93(s,1H),9.04(s,1H),8.88(s,1H),8.12(s,1H),7.33(s,1H),2.79(m,2H),2.40(s,3H),2.0 4(pent,J=6.0Hz,1H),1.96(m,2H),1.83(m,2H),1.69(m,2H),0.83(d,J=6.0Hz,4H);UHPLC-MS(HESI / APCI):Rt 1.17 minutes, m / z 395.3[M+H].

[0680] General Procedures F1 and F2 Synthesis of aminopyrimidinyl and aminopyridazinyl pyridones from cyclopropyl amides. [ka] General Procedure F1: Aqueous potassium hydroxide (12 equiv.) and ethylenediamine (12 equiv.) were added sequentially to a solution of cyclopropylamide 12 (1 equiv.) in tetrahydrofuran and ethanol (1:1, v / v). After stirring at room temperature for 24 h, the mixture was concentrated under reduced pressure, and the residue was diluted with dichloromethane and then washed with water. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (silica gel column) eluting with a gradient of 0 to 10% methanol in dichloromethane to give the aminopyrimidine or aminopyridazine.

[0681] General Procedure F2: To a mixture of cyclopropylamide (1 equivalent) in EtOH / THF / water (v:v:v / 2:1:1) was added KOH (6 M in HO, 4.8 equivalents). The resulting mixture was stirred at ambient temperature for 16 hours, after which the mixture was concentrated under reduced pressure and azeotropically washed with toluene. The crude material was purified by Biotage flash chromatography (gradient elution, 0% to 25% MeOH in CHCl) to afford the aminopyrimidine or aminopyridazine.

[0682] Example 26 Synthesis of 6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (4ET-01-001) [ka]

[0683] Compound 4ET-01-001 was synthesized according to general procedure F1. Potassium hydroxide (214 mg, 3.82 mmol, 12.0 equiv.) in water (1 mL), ethylenediamine (230 mg, 3.82 mmol, 12.0 equiv.), and compound 4ET-03-017 (125 mg, 0.318 mmol, 1.0 equiv.) in tetrahydrofuran (2 mL) and ethanol (2 mL) gave compound 4ET-01-001 (12 mg, 12% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 9.78(s,1H),8.62(s,1H),8.40(s,1H),8.17(s,1H),6.49(s,2H),6.16(d,J=0.9Hz,1H),2.84- 2.75(m,2H),2.41(s,3H),2.02-1.93(m,2H),1.88-1.78(m,2H),1.68(td,J=5.8,11.9Hz,2H); 13 C NMR(100MHz,DMSO-d6) δ 164.4,161.6,159.9,158.1,153.8,134.0,122.3,121.3,117.0,88.2,36.0,25.3,14.2;LCMS(ES-API):Rt 3.0 min, m / z 327.1[M+H].

[0684] Example 27 Synthesis of 6-((6-aminopyrimidin-4-yl)amino)-8-methyl-2',3',5',6'-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-pyran]-1,5-dione (4ET-01-002) [ka]

[0685] Compound 4ET-01-002 was synthesized according to general procedure F1. Compound 4ET-01-002 (23 mg, 89% yield) was obtained as a white solid from potassium hydroxide (51 mg, 0.91 mmol, 12.0 equiv.) in water (0.5 mL), ethylenediamine (54 mg, 0.91 mmol, 12.0 equiv.) in tetrahydrofuran (0.7 mL) and ethanol (0.7 mL) and compound 4ET-03-009 (31 mg, 0.076 mmol, 1.0 equiv.). 1 H NMR(400MHz,DMSO-d6) δ 10.2(br s,1H),8.60(s,1H),8.41(s,1H),8.17(s,1H),6.50(s,2H),6.19(d,J=0.7Hz,1H),3.9 5-3.90(m,2H),3.73-3.66(m,2H),3.26(dt,J=5.5,13.0Hz,2H),2.43(s,3H),1.42(br d,J=12.5Hz,2H); 13 C NMR(100MHz,DMSO-d6) δ 164.4,162.3,159.8,158.1,154.1,134.3,121.9,121.8,117.5,88.3,77.0,63.8,33.3,14.3;LCMS(ES-API):Rt 2.6 min, m / z 343.1[M+H].

[0686] Example 28 Synthesis of 6-((6-aminopyrimidin-4-yl)amino)-3,3,8-trimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (4ET-01-003) [ka] Compound 4ET-01-003 was synthesized according to general procedure F1. Potassium hydroxide (84 mg, 1.5 mmol, 12.0 equiv.) in water (0.5 mL), ethylenediamine (90 mg, 1.5 mmol, 12.0 equiv.), and compound 4ET-03-002 (46 mg, 0.12 mmol, 1.0 equiv.) in tetrahydrofuran (1.0 mL) and ethanol (1.0 mL) gave compound 4ET-01-003 (33 mg, 88% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 9.44(s,1H),8.58(s,1H),8.38(s,1H),8.17(s,1H),6.49(s,2H),6.17(d,J=0.9Hz,1H),2.41(s,3H),1.78(s,6H); 13 C NMR(100MHz,DMSO-d6) δ 164.4,161.5,159.9,158.1,153.9,134.0,122.0,121.9,117.1,88.2,76.3,25.3,14.3;LCMS(ES-API):Rt 2.6 min, m / z 301.1[M+H].

[0687] Example 29 Synthesis of N-(6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-1',5'-dioxo-1',5'-dihydro2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-4-yl)methanesulfonamide (4ET-01-004) [ka] Compound 4ET-01-004 was synthesized according to general procedure F1. Potassium hydroxide (48 mg, 0.86 mmol, 12.0 equiv.) in water (0.35 mL), ethylenediamine (52 mg, 0.86 mmol, 12.0 equiv.) and compound 4ET-03-033 (see below) (36 mg, 0.07 mmol, 1.0 equiv.) in tetrahydrofuran (0.7 mL) and ethanol (0.7 mL) gave 20 mg, which was repurified to give 6 mg of compound 4ET-01-004 as an off-white solid (19%). 1H NMR(400MHz,DMSO-d6) δ 8.47(s,1H),8.33(s,1H),8.13(s,1H),7.30(br s,2H),6.49(s,2H),6.13(s,1H),3.14-3.10(m,1H),2.93(s,3H),2.39(s,3H),1.96-1.91(m,2H),1.73-1.64(m,2H),1.45(br d,J=16.0Hz,2H),1.26-1.14(m,2H);UHPLC-MS(HESI / APCI):Rt 0.78min,m / z 434.2[M+H].

[0688] Example 30 Synthesis of 6'-((6-aminopyrimidin-4-yl)amino)-4-hydroxy-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (4ET-01-005) [ka] Compound 4ET-01-005 was synthesized according to general procedure F2: cyclopropylamide 11f (4ET-03-015) (50 mg, 0.12 mmol) and KOH (6 M in HO, 0.1 mL, 0.58 mmol) in EtOH / THF / water (v:v:v / 2:1:1, 2.0 mL) to give compound 4ET-01-005 (25 mg, 0.07 mmol, 63%). 1 H NMR(400MHz,DMSO-d6) δ 10.00(s,1H),8.56(s,1H),8.37(s,1H),8.17(s,1H),6.51(br,2H),6.15(s,1H),4.62(br.1H),3.5 7-3.40(m,2H),3.10(m,1H),2.42(s,3H),1.87-1.56(m,4H),1.30(m,2H);UHPLC-MS(HESI / APCI):Rt 0.47 min, m / z 357.3[M+H].

[0689] The synthesis of other compounds not specifically described in these examples, 4ET-01-001-005, 4ET-02-001-023, 4ET-03-001-034, 4ET-04-003, can be readily achieved by applying general principles known to those skilled in the art to the synthetic methods described herein.

[0690] Example 31 Synthesis of 6'-bromo-3,8'-dimethyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-2-ene-1',5'-dione [ka]

[0691] In general procedure A, the title compound (60 mg, 0.186 mmol, 43%) was produced from compound 5 (100 mg, 0.433 mmol), 3-methylcyclohex-2-en-1-one (6s, 477 mg, 4.328 mmol), HSO (0.012 mL, 0.216 mmol), and 1,4-dioxane (4.0 mL). 1 H NMR(400MHz,CDCl3) δ 7.75(s,1H),6.70(s,1H),5.51(s,1H),3.89(d,J=16.9Hz,1H),3.21(td,J=12.5,6.9Hz,1H),2.48( s,3H),2.24(m,2H),1.78(d,J=16.6Hz,1H),1.70(s,3H),1.59(d,J=6.6Hz,1H).UHPLC-MS(ESI):Rt 1.05 min, m / z 323.2[M] + .

[0692] Example 32 Synthesis of N-(6-((3,8'-dimethyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-2-en-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide [ka] Following general procedure E, the title compound (15 mg, 0.035 mmol, 19%) was produced from 6'-bromo-3,8'-dimethyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-2-ene-1',5'-dione (60 mg, 0.186 mmol), N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide (40 mg, 0.223 mmol), CsCO (181 mg, 0.557 mmol), Xantphos (21 mg, 0.037 mmol), Pd(OAc) (4.0 mg, 0.019 mmol), and 1,4-dioxane (4.0 mL). 1 H NMR(400MHz,CDCl3) δ 8.54(d,J=3.2Hz,2H),8.30(s,1H),7.67(s,1H),6.89(s,1H),5.60-5.55( m,1H),3.84(d,J=16.9Hz,1H),3.18(td,J=12.4,6.8Hz,1H),2.57(s,3H), 2.42(d,J=18.2Hz,1H),1.90-1.76(comp,3H),1.72(s,3H),1.66-1.60(m,1H),1.12(q,J=3.8Hz,2H),0.95(dq,J=7.4,4.0Hz,2H).UHPLC-MS(ESI):Rt 1.15 min, m / z 421.4[M] + .

[0693] Example 33 Synthesis of 6'-((6-aminopyrimidin-4-yl)amino)-3,8'-dimethyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-2-ene-1',5'-dione (4ET-01-058) [ka] Following general procedure F2, the title compound (4ET-01-058) (7 mg, 0.020 mmol, 88%) was produced from N-(6-((3,8'-dimethyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-2-en-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (10 mg, 0.024 mmol), 6 N aqueous KOH (0.079 mL, 0.476 mmol) in EtOH / THF / HO (2 mL, v:v:v / 2:1:1). 1H NMR(400MHz,DMSO-d6) δ 9.65(s,1H),8.54(s,1H),8.38(s,1H),8.15(s,1H),6.48(s,2H),6.14(d,J=1.0Hz,1H),5.46(s,1H),3.65(d,J=17.0Hz,1H),2.98(td ,J=12.2,6.8Hz,1H),2.41(s,3H),2.27-2.17(m,2H),1.77(d,J=16.3Hz,1H),1.64(s,3H),1.47(d,J=13.7Hz,1H);UHPLC-MS(ESI):Rt 0.95 min, m / z 353.3[M+H]+.

[0694] Example 34 Synthesis of 6'-bromo-3-ethyl-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-2-ene-1',5'-dione [ka]

[0695] In general procedure A, the title compound (65 mg, 0.19 mmol, 22%) was produced from compound 5 (200 mg, 0.86 mmol), 3-ethylcyclohex-2-en-1-one (6t, 322 mg, 2.60 mmol), H2SO4 (0.023 mL, 0.43 mmol), and 1,4-dioxane (8.0 mL). 1H NMR(400MHz,DMSO-d6) δ 10.04(s,1H),8.04(s,1H),5.46(s,1H),3.61(m,1H),2.95(m,1H),2.39(s,3H),2.25(m ,2H),1.97(m,2H),1.81(m,1H),1.55(m,1H),0.96(t,J=7.4Hz,3H).UHPLC-MS(ESI):Rt 0.78 min, m / z 337.1[M] + .

[0696] Example 35 Synthesis of N-(6-((3-ethyl-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-2-en-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-039) [ka] In general procedure E, the title compound (4ET-03-039) (42 mg, 0.096 mmol, 53%) was produced from compound 7h (63 mg, 0.18 mmol), N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide (50 mg, 0.28 mmol), CsCO (183 mg, 0.56 mmol), Xantphos (21.6 mg, 0.037 mmol), Pd(OAc) (4.2 mg, 0.019 mmol), and 1,4-dioxane (2.0 mL). 1 H NMR(400MHz,DMSO-d6) δ 10.85(s,1H),9.72(br s,1H),9.12(s,1H),8.53(s,1H),8.49(s,1H),7.85(s,1H),5.48(br s,1H),3.67(m,1H),3.03(m,1H),2.45(s,3H),2.27(m,2H),2.00(m,3H),1.82(m, 1H),1.52(m,1H),0.97(t,J=7.4Hz,3H),0.84(d,J=6.2Hz,4H).UHPLC-MS(ESI):Rt 0.78 min, m / z 435.3[M+H] + .

[0697] Example 36 Synthesis of 6'-((6-aminopyrimidin-4-yl)amino)-3-ethyl-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-2-ene-1',5'-dione (4ET-01-021) [ka] In general procedure F2, compound 4ET-03-039 (30 mg, 0.069 mmol), 6N aqueous KOH (0.060 mL, 0.35 mmol) in EtOH / THF / HO (2 mL, v:v:v / 2:1:1) gave the title compound 12g (4ET-01-021) (18 mg, 0.049 mmol, 72%). 1 H NMR(400MHz,DMSO-d6) δ 9.66(br,1H),8.57(s,1H),8.41(s,1H),8.17(s,1H),6.50(br,2H),6.16(s,1H),5.48(s,1H),3.70(m,1H),3 .03(m,1H),2.43(s,3H),2.27(m,2H),1.97(m,2H),1.82(m,1H),1.50(m,1H),0.97(m,3H).UHPLC-MS(ESI):Rt 0.65 min, m / z 367.3[M+H] + .

[0698] Example 37 Synthesis of N-(6-((8'-methyl-1',5'-dioxo-1',2,3,3a,4,5',6,6a-octahydro-1H,2'H-spiro[cyclopenta[c]pyrrole-5,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-050A) [ka] Second eluting isomer on reverse phase HPLC: 1H NMR(400MHz,DMSO-d6) δ 10.85(s,1H),9.18(s,1H),8.55(s,1H),8.50(s,1H),7.85(s,1H),3.15-2.98(m,8H),2.4 2(s,3H),2.05-1.99(m,1H),1.95-1.80(m,2H),0.82(d,J=6.2Hz,4H);UHPLC-MS(ESI):Rt 0.61 min, m / z 436.3[M+H] + .

[0699] Example 38 Synthesis of N-(6-((8'-methyl-1',5'-dioxo-1',2,3,3a,4,5',6,6a-octahydro-1H,2'H-spiro[cyclopenta[c]pyrrole-5,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-050B) [ka] First eluting isomer on reverse phase HPLC): 1 H NMR(400MHz,DMSO-d6) δ 10.85(s,1H),9.18(s,1H),8.55(s,1H),8.51(s,1H),7.86(s,1H),3.55-3.40(m,4H),3.10-3.04(m,2H),3 .10-2.95(m,2H),2.42(s,3H),2.04-1.98(m,1H),1.95-1.81(m,2H),0.84-0.78(m,4H).UHPLC-MS(ESI):Rt 0.60min, m / z 436.3[M+H] + .

[0700] Example 39 Synthesis of 6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-3a,4,6,6a-tetrahydro-1H,2'H,3H-spiro[cyclopenta[c]furan-5,3'-imidazo[1,5-a]pyridine]-1',5'-dione (4ET-01-014A) [ka] Second eluting isomer on reverse phase HPLC): 1 H NMR(400MHz,CDCl3) δ 8.48(s,1H),8.38(s,1H),7.98(s,1H),7.83(s,1H),5.80(s,1H),4.69(br s,2H),3.93(d,J=10.0Hz,2H),3.75-3.65(m,4H),3.48(s,2H),3.15-3.02(m,2H),2.55(s,3H);UHPLC-MS(ESI):Rt 0.61min,m / z 369.3[M+H] + .

[0701] Example 40 Synthesis of 6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-3a,4,6,6a-tetrahydro-1H,2'H,3H-spiro[cyclopenta[c]furan-5,3'-imidazo[1,5-a]pyridine]-1',5'-dione (4ET-01-014B) [ka] First eluting isomer on reverse phase HPLC): 1 H NMR(400MHz,CDCl3) δ 8.48(s,1H),8.38(s,1H),7.98(br s,1H),7.83(br s,1H),5.80(s,1H),4.69(br s,2H),3.93(d,J=10.0Hz,2H),3.75-3.66(m,4H),3.48(s,2H),3.12-3.05(m,2H),2.55(s,3H);UHPLC-MS(ESI):Rt 0.58 min,m / z 369.3[M+H] + .

[0702] Example 41 Synthesis of N-(6-((1'-fluoro-8-methyl-1,5-dioxo-1,1',3',5-tetrahydro-2H-spiro[imidazo[1,5-a]pyridin-3,2'-inden]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-052A) [ka] First eluting atropisomer on reverse phase HPLC): 1 H NMR(400MHz,DMSO-d6) δ 10.76(s,1H),9.78(br s,1H),9.22(s,1H),8.49(s,1H),7.79(s,1H),7.42-7.38(m,2H),7.30-7.26(m,2H),6.00(d,J=55.2Hz,1H),4.02(d,J=17.6Hz,1H) ,3.36-3.30(m,1H),2.65(s,0.5H),2.48(s,3H),2.30(s,0.5H),1.99-1.94(m,1H),0.80-0.77(d,J=5.6Hz,4H);UHPLC-MS(ESI):Rt 0.73 min, m / z 461.3[M+H] + .

[0703] Example 42 Synthesis of N-(6-((1'-fluoro-8-methyl-1,5-dioxo-1,1',3',5-tetrahydro-2H-spiro[imidazo[1,5-a]pyridin-3,2'-inden]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-052B) [ka] Second eluting atropisomer on reverse phase HPLC): 1 H NMR(400MHz,DMSO-d6) δ 10.82(s,1H),9.98(br s,1H) 9.16(s,1H),8.52(s,1H),7.81(s,1H),7.47-7.33(m,4H),6.58(d,J=20.8Hz,1H),4.19(d,J=16.4Hz,1H),3. 30-3.12(m,1H),2.56-2.45(m,1H),2.47(s,3H),2.01-1.96(m,1H),0.80(d,J=6.0Hz,4H);UHPLC-MS(ESI):Rt 3.3 minutes, m / z 461.3.[M+H] + .

[0704] Example 43 Synthesis of 6-((6-aminopyrimidin-4-yl)amino)-1'-fluoro-8-methyl-1',3'-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,2'-indene]-1,5-dione (4ET-01-010A) [ka] Second eluting atropisomer on reverse phase HPLC): 1 H NMR(400MHz,DMSO-d6) δ 9.90(br s,1H),8.61(s,1H),8.48(s,1H),8.17(s,1H),7.50-7.17(m,4H),6.49(s,2H),6. 12(s,1H),4.20-4.12(m,1H),3.24-3.19(m,2H),2.42(s,3H);UHPLC-MS(ESI):Rt 0.64 min, m / z 393.2[M+H] + .

[0705] Example 44 Synthesis of 6-((6-aminopyrimidin-4-yl)amino)-1'-fluoro-8-methyl-1',3'-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,2'-indene]-1,5-dione (4ET-01-010B) [ka] First eluting atropisomer on reverse phase HPLC): 1 H NMR(400MHz,DMSO-d6) δ 8.60(br s,1H),8.40(s,1H),8.12(s,1H),7.42-7.37(m,2H),7.35-7.23(m,2H),6.41(s,2H),6.08(s,1H),6.02(br s,0.5H),5.88(br s,0.5H),4.00(d,J=16.0Hz,1H),3.18-3.16(m,1H),2.64-2.62(m,1H),2.41(s,3H);UHPLC-MS(ESI):Rt 0.62 min,m / z 393.3[M+H] + .

[0706] Example 45 Synthesis of N-(6-((1'-hydroxy-8-methyl-1,5-dioxo-1,1',3',5-tetrahydro-2H-spiro[imidazo[1,5-a]pyridin-3,2'-inden]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-063) [ka] 1 H NMR (400 MHz, DMSO-d6, one NH proton not detected) δ 10.81 (s, 1H), 8.18 (s, 1H), 8.56-8.50 (m, 2H), 7.88-7.72 (m, 2H), 7.72 (s, 1H), 7.68-7.62 (m, 1H), 7.56-7.49 (m, 1H), 4.08 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 12.0 Hz, 1H), 2.42 (s, 3H), 2.01-1.91 (m, 2H), 1.80-1.78 (m, 1H), 0.85-0.72 (m, 4H); UHPLC-MS (ESI): Rt 0.76 min, m / z 457.3 [M+H] + .

[0707] Example 46 Synthesis of 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide [ka] Step 1: Synthesis of ethyl 5-bromo-3-methylpicolinate. To a solution of 5-bromo-3-methylpicolinic acid (10 g, 42.3 mmol) in ethanol (37 mL) was added H2SO4 (2.3 mL, 18.4 M, 42.3 mmol) at 23 °C. The reaction mixture was heated at 80 °C for 16 h. The solvent was removed under reduced pressure, and ethyl acetate (250 mL) was added. After washing with NaHCO3 (200 mL × 2) and water (200 mL × 2), the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give ethyl 5-bromo-3-methylpicolinate (9.6 g, 39 mmol, 93%) as a colorless liquid. 1H NMR(400MHz,CDCl3) δ 8.58(s,1H),7.76(s,1H),4.43(q,J=7.1Hz,2H),2.56(s,3H),1.41(t,J=7.1Hz,3H).

[0708] [ka] Step 2: Synthesis of 5-bromo-2-(ethoxycarbonyl)-3-methylpyridine 1-oxide. To a solution of ethyl 5-bromo-3-methylpicolinate (9.6 g, 39 mmol) in CHCl (111 mL) was added urea hydrogen peroxide (6.4 g, 68.3 mmol), followed by trifluoroacetic anhydride (9.6 mL, 68.3 mmol) at 0 °C. The reaction mixture was stirred at 23 °C for 4 h and poured into an ice / water mixture (100 mL). After extraction with CHCl (50 mL × 3), the combined organic phase was washed with NaHCO (50 mL × 3) and water (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give 5-bromo-2-(ethoxycarbonyl)-3-methylpyridine 1-oxide (10.1 g, 39 mmol, 99%) as a colorless liquid. 1 H NMR(400MHz,CDCl3) δ 8.20(s,1H),7.26(s,1H),4.47(q,J=7.1Hz,2H),2.27(s,3H),1.39(t,J=7.1Hz,3H).

[0709] [ka] Step 3: Synthesis of ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate. To a solution of compound 3 (10.1 g, 39 mmol) in N,N-dimethylformamide (30.5 mL) was added trifluoroacetic anhydride (9.6 mL, 68.3 mmol) at 0 °C. The mixture was stirred at 40 °C for 8 h and diluted with water (100 mL). After extraction with ethyl acetate (100 mL × 3), the combined organic phase was washed with brine (100 mL × 5), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Biotage flash chromatography (silica gel, 0% to 30% ethyl acetate in hexane) to give ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (6.8 g, 26.1 mmol, 67%) as a white solid. 1 H NMR(400MHz,CDCl3) δ 7.83(s,1H),4.42(q,J=7.1Hz,2H),2.45(s,3H),1.41(t,J=7.1Hz,3H).

[0710] [ka] Step 4: Synthesis of 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide. Ammonium hydroxide (130.5 mL, 28% in water) was added to ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (6.8 g, 26.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 6 hours and concentrated under reduced pressure to give 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (5, 6.0 g, 26 mmol, 99%) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 7.87(s,1H),7.84(s,1H),7.71(s,1H),2.12(s,3H).

[0711] General Procedure G Synthesis of spirocycloalkylpyridones (7a-7w) [ka] To a solution of compounds 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1 equivalent) in 1,4-dioxane (0.2 M) was added ketones 6a–6w (4 equivalents), followed by HSO (0.5 equivalents). The reaction mixture was sealed in a pressure vessel and heated at 100° C. for 16 hours. The reaction mixture was cooled to 23° C. and concentrated under reduced pressure. The resulting crude material was purified by Biotage flash chromatography (gradient elution, 30–85% ethyl acetate in hexanes or 0–10% MeOH in CHCl) to give compounds 7a–7w.

[0712] Example 47 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-2'-ene-1'',5''-dione (7f3) [ka] The title compound (7f3) was prepared using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide and spiro[2.5]oct-4-en-6-one (6u) according to general procedure G, except that 4 angstrom molecular sieves were added to the reaction, to give 6″-bromo-8″-methyl-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridine]-2′-ene-1′,5″-dione (7f3) in 43% yield: 1 H NMR(400MHz,DMSO-d6) δ 10.15(s,1H),8.01(s,1H),5.43(d,J=9.6Hz,1H),5.36(d,J=9.3Hz,1H),3.16-3.10(m,1H),2.38( s,3H),2.28(t,J=14.2Hz,1H),1.58(d,J=12.5Hz,1H),1.23(d,J=12.9Hz,1H),0.78-0.53(m,4H).

[0713] Example 48 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7g) [ka] The title compound (7 g) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (144 mg, 0.63 mmol), spiro[2.5]octan-6-one (6 g, 232 mg, 1.87 mmol), HSO (0.017 mL, 0.31 mmol), and 1,4-dioxane (6.3 mL). Yield: 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7 g) (105 mg, 0.31 mmol, 50%). 1 H NMR(400MHz,DMSO-d6) δ 10.42(s,1H),8.02(s,1H),3.11(dt,J=13.3,4.5Hz,2H),2.39(s,3H),2.12(dt,J=14.6,3.8Hz,2 H),1.41(d,J=12.4Hz,2H),0.88(d,J=12.8Hz,2H),0.38(m,2H),0.29(m,2H).UHPLC-MS(ESI):Rt 0.79 min, m / z 337.1[M] + .

[0714] Example 49 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione(7H) [ka] The title compound (7h) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (150 mg, 0.65 mmol), spiro[2.5]octan-5-one (6h, 121 mg, 0.97 mmol), HSO (0.018 mL, 0.33 mmol), and 1,4-dioxane (6.0 mL). 6''-Bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7h) yield: (114 mg, 0.34 mmol, 52%). 1 H NMR(400MHz,chloroform-d) δ 8.00(br,1H),7.73(s,1H),3.73(m,1H),3.20(dt,J=4.0,13.6Hz,1H),2.48(s,3H),2.00-1.90(m,2H),1.65(m,1H),1 .58(m,1H),0.93(d,J=13.6Hz,1H),0.76(dt,J=13.0,2.0Hz,1H),0.46-0.40(m,3H),0.32(m,1H);UHPLC-MS(ESI):m / z 339.1[M] + .

[0715] Example 50 Synthesis of ethyl 6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-2-carboxylate (7R) [ka] The title compound (7r) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (141 mg, 0.61 mmol), ethyl 6-oxospiro[2.5]octane-1-carboxylate (6r, 240 mg, 1.22 mmol), HSO (0.016 mL, 0.31 mmol), and 1,4-dioxane (1.22 mL). Yield: 123 mg (50%) of ethyl 6"-bromo-8"-methyl-1",5"-dioxo-1",5"-dihydro-2"H-dispiro[cyclopropane-1,1'-cyclohexane-4',3"-imidazo[1,5-a]pyridine]-2-carboxylate (7r). 1 H NMR(400MHz,CDCl3) δ 7.73(s,1H),4.17(q,J=7.1Hz,2H),3.37(m,2H),2.46(s,3H),2.25-1.34(m,7H),1.25(t,J=7.1Hz,3H),1.11-0.90(m,2H).UHPLC-MS(ESI):Rt 0.77 min, m / z 409.0[M] + .

[0716] Example 51 Synthesis of benzyl 6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1-carboxylate (7J) [ka] The title compound (7j) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (205 mg, 0.89 mmol), benzyl 6-oxo-1-azaspiro[2.5]octane-1-carboxylate (6j, 345 mg, 1.33 mmol), HSO (0.024 mL, 0.44 mmol), and 1,4-dioxane (9.0 mL). Benzyl 6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1-carboxylate (7j) yield: (187 mg, 0.40 mmol, 46%). 1 H NMR(400MHz,DMSO-d6) δ 10.02(s,1H),8.04(s,1H),7.41-7.23(m,5H),5.04(s,2H),3.62(m,2H),3.01(m,2H),2.39( s,3H),2.21(m,2H),1.93(m,1H),1.58(m,1H),1.26(m,1H),0.86(m,1H).UHPLC-MS(ESI):Rt 0.76 min, m / z 337.1[M] + .

[0717] Example 52 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[azetidine-3,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7k). [ka] The title compound (7k) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.43 mmol), tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (6k, 414 mg, 1.73 mmol), HSO (0.012 mL, 0.22 mmol), and 1,4-dioxane (4.0 mL). Yield: 6''-bromo-8''-methyl-2''H-dispiro[azetidine-3,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7k) (101 mg, 0.29 mmol, 66%). 1 H NMR(400MHz,DMSO-d6) δ 8.02(s,1H),7.78(s,1H),3.05-2.80(m,4H),2.37(s,3H),2.00-1.92(m,4H),1.41(dd,J=25.2,12.9Hz,4H).UHPLC-MS(ESI):Rt 0.59 min, m / z 352.2[M] + .

[0718] Example 53 Synthesis of 6''-bromo-2,2-difluoro-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7f) [ka] The title compound (7f) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (125 mg, 0.54 mmol), 1,1-difluorospiro[2.5]octan-6-one (6f, 86 mg, 0.54 mmol), HSO (0.01 mL, 0.27 mmol), and 1,4-dioxane (1.1 mL). Yield: 6"-bromo-2,2-difluoro-8"-methyl-2"H-dispiro[cyclopropane-1,1'-cyclohexane-4',3"-imidazo[1,5-a]pyridine]-1",5"-dione (7f) (39 mg, 0.10 mmol, 19%). UHPLC-MS(ESI):Rt 0.80min, m / z 373.0[M] + .

[0719] Example 54 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7i) [ka] The title compound (7i) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.43 mmol), spiro[3.3]heptan-2-one (6i, 191 mg, 1.73 mmol), HSO (0.012 mL, 0.22 mmol), and 1,4-dioxane (4.0 mL). Yield: 6''-bromo-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7i) (101 mg, 0.31 mmol, 72%). 1H NMR(400MHz,DMSO-d6) δ 10.26(s,1H),8.02(s,1H),3.56(d,J=14.2Hz,2H),2.38(s,3H),2.35-2.29 (m,2H),2.23-2.12(m,4H),1.80(dt,J=14.7,7.2Hz,2H).UHPLC-MS(ESI):Rt 0.76 min, m / z 323.1[M] + .

[0720] Example 55 Synthesis of 6''-bromo-3,3-difluoro-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7n) [ka] The title compound (7n) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.43 mmol), 6,6-difluorospiro[3.3]heptan-2-one (6n, 108 mg, 0.74 mmol), HSO (0.012 mL, 0.22 mmol), and 1,4-dioxane (4.0 mL). Yield: 6"-bromo-3,3-difluoro-8"-methyl-2"H-dispiro[cyclobutane-1,1'-cyclobutane-3',3"-imidazo[1,5-a]pyridine]-1",5"-dione (7n) (93 mg, 0.26 mmol, 60%). 1 H NMR(400MHz,DMSO-d6) δ 10.26(s,1H),8.02(s,1H),3.53(d,J=14.7Hz,2H),2.78(dt,J=33.0,12.7Hz,4H),2.52(s,1H),2.49(s,1H),2.34(s,3H).UHPLC-MS(ESI):Rt 0.77 min, m / z 358.8[M] + .

[0721] Example 56 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclopentane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7l) [ka] The title compound (7l) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.43 mmol), spiro[3.4]octan-6-one (6l, 107 mg, 0.866 mmol), HSO (0.012 mL, 0.22 mmol), and 1,4-dioxane (3.0 mL). 6''-Bromo-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclopentane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7l) yield: (101 mg, 69%). 1 H NMR(400MHz,DMSO-d6) δ 10.05(s,1H),7.99(s,1H),2.82(d,J=13.8Hz,1H),2.70(dt,J=13.1,8.1Hz,1H),2.34(s,3H),2.16-1.61(m,9H).UHPLC-MS(ESI):Rt 0.82min,m / z 339.2[M] + .

[0722] Example 57 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclopentane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7m) [ka] The title compound (7m) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.43 mmol), spiro[4.4]nonan-2-one (6m, 120 mg, 0.866 mmol), HSO (0.012 mL, 0.22 mmol), and 1,4-dioxane (3.0 mL). Yield: 6''-bromo-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclopentane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7m) (91 mg, 59 mg). 1 H NMR(400MHz,DMSO-d6) δ 10.15(s,1H),7.99(s,1H),2.88-2.76(m,2H),2.35(s,3H),1.95-1.86(m,1H) ,1.81-1.74(m,1H),1.74-1.66(m,3H),1.64-1.52(m,8H).UHPLC-MS(ESI):Rt 0.86 min, m / z 351.1[M] + .

[0723] Example 58 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7o) [ka] The title compound (7o) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.43 mmol), spiro[3.4]octan-2-one (6o, 215 mg, 1.73 mmol), HSO (0.012 mL, 0.22 mmol), and 1,4-dioxane (4.0 mL). Yield: 6''-bromo-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7o) (100 mg, 0.3 mmol, 69%). 1H NMR(400MHz,DMSO-d6) δ 10.38(s,1H),8.00(s,1H),3.42(d,J=13.5Hz,2H),2.35(s,3H),2.07(d,J=13.6Hz ,2H),1.91-1.82(m,2H),1.82-1.73(m,2H),1.63-1.41(m,4H).UHPLC-MS(ESI):Rt 0.85 min, m / z 337.1[M] + .

[0724] Example 59 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7p) [ka] The title compound (7p) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.43 mmol), spiro[3.5]nonan-7-one (6p, 120 mg, 0.87 mmol), HSO (0.012 mL, 0.22 mmol), and 1,4-dioxane (4.0 mL). 6''-Bromo-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7p) yield: (73 mg, 0.21 mmol, 48%). 1 H NMR(400MHz,DMSO-d6) δ 10.32(s,1H),7.99(s,1H),2.97(t,J=11.7Hz,2H),2.36(s,3H),1.82(s,4H),1.78-1.56(m,6H),1.26(d,J=12.3Hz,2H).UHPLC-MS(ESI):Rt 0.86 min, m / z 351.2[M] + .

[0725] Example 60 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[cyclohexane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7q) [ka] The title compound (7q) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.43 mmol), spiro[3.5]nonan-2-one (6q, 120 mg, 0.87 mmol), HSO (0.012 mL, 0.22 mmol), and 1,4-dioxane (4.0 mL). Yield: 6''-bromo-8''-methyl-2''H-dispiro[cyclohexane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7q) (95 mg, 0.27 mmol, 63%). 1 H NMR(400MHz,DMSO-d6) δ 10.27(s,1H),8.00(s,1H),3.23(d,J=13.6Hz,2H),2.35(s,3H),1.95(d,J=13.7Hz ,2H),1.86-1.75(m,2H),1.73-1.60(m,2H),1.43-1.31(m,6H).UHPLC-MS(ESI):Rt 0.89 min, m / z 351.1[M] + .

[0726] Example 61 Synthesis of 6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-2-carboxylic acid (7n) [ka] The title compound (7n) was prepared according to general procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (460 mg, 1.99 mmol), 6-oxospiro[2.5]octane-1-carboxylic acid (6n, 668 mg, 3.97 mmol), HSO (0.05 mL, 0.1 mmol), and 1,4-dioxane (4.0 mL). 6"-Bromo-8"-methyl-1",5"-dioxo-1",5"-dihydro-2"H-dispiro[cyclopropane-1,1'-cyclohexane-4',3"-imidazo[1,5-a]pyridine]-2-carboxylic acid (7n) yield: (210 mg, 0.55 mmol, 28%). 1 H NMR(400MHz,CDCl3) δ 7.77(s,1H),3.49-3.25(m,2H),2.46(s,3H),2.24-1.44(m,7H),1.30-1.04(m,2H).UHPLC-MS(ESI):Rt 0.67min,m / z 381.0[M] + .

[0727] Example 62 Synthesis of 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cycloheptane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7w) [ka] To a stirred solution of 5 (25 mg, 0.108 mmol) in dry isopropanol was added ketone 6w (18 mg, 0.130 mmol), followed by Ti(iOPr) (46 mg, 0.162 mmol). The mixture was sealed and heated at 100 °C for 12 h. Purification via flash column chromatography (gradient elution, 5% to 50% hexanes / ethyl acetate) afforded 8 mg of 7w (28%): 1H NMR(400MHz,DMSO-d6) δ 10.29(s,1H),8.00(s,1H),2.99-2.69(m,2H),2.37(s,3H),1.89(s,1H),1.81(dd,J=14.8,10.8Hz,1H),1.6 8(dd,J=14.4,9.2Hz,2H),1.59(dd,J=14.0,8.0Hz,2H),1.36(dd,J=14.4,8.0Hz,2H),0.31(d,J=7.6Hz,4H).

[0728] Example 63 Synthesis of N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-084) [ka] A mixture of 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7h) (60 mg, 0.18 mmol), N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide (38.0 mg, 0.21 mmol), CsCO (174.0 mg, 0.53 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (21.2 mg, 0.04 mmol), and Pd(OAc) (4.0 mg, 0.02 mmol) in 1,4-dioxane (4.0 mL) was purged with inert gas (nitrogen or argon) for 20 min. The reaction vessel was sealed and heated at 95 °C for 12 h, then cooled to 23 °C and concentrated under reduced pressure. The resulting crude material was purified by Biotage flash chromatography (gradient elution, 0% to 10% MeOH in CH2Cl2) to afford 4ET-03-084 (48.0 mg, 0.11 mmol, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86(s,1H),9.92(s,1H),9.11(s,1H),8.53(s,1H).8.47(s,1H),7.85(s,1H),3 .49(d,J=12.8Hz,1H),3.03(dt,J=4.2,13.3Hz,1H),2.44(s,3H),2.02(pent,J=6. 2Hz,1H),1.90(m,1H),1.79-1.70(m,2H),1.52(m,1H),0.89(m,1H),0.84(m,4H),0 .75(d,J=12.2Hz,1H),0.43(m,2H),0.28(m,1H),0.19(m,1H);UHPLC-MS(ESI):m / z 435.3[M+H] +

[0729] Example 64 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-01-042) [ka] To a suspension of 4ET-03-084 (30 mg, 0.07 mmol) in EtOH / THF / HO (1 mL, v:v:v / 2:1:1) was added 6N aqueous KOH (0.23 mL, 1.38 mmol). The mixture was stirred at 23 °C for 16 h, then additional 6N aqueous KOH (0.23 mL, 1.38 mmol) was added and stirred for an additional 6 h until HPLC / MS indicated complete consumption of the starting material. The reaction was concentrated under reduced pressure, and the resulting crude material was purified by Biotage flash chromatography (gradient elution, 0% to 15% 3M NH / MeOH in CHCl) to afford 4ET-01-042 (19 mg, 0.05 mmol, 75%) as a white solid. 1H NMR(400MHz,DMSO-d6) δ 9.86(s,1H),8.62(s,1H),8.37(s,1H),8.18(s,1H).6.57(br,2H),6.16 (s,1H),3.49(d,J=12.8Hz,1H),3.04(dt,J=4.2,13.3Hz,1H),2.42(s,3H ),1.89(m,1H),1.78-1.70(m,2H),1.51(m,1H),0.89(m,1H),0.74(d,J=1 3.0Hz,1H),0.43(m,2H),0.27(m,1H),0.18(m,1H);UHPLC-MS(ESI / ):m / z 367.2[M+H] + .

[0730] Example 65 Synthesis of N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-029) [ka] The title compound was prepared according to the procedure for N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione to provide the title compound 4ET-03-029. 1H NMR(400MHz,DMSO-d6) δ 10.86(s,1H),10.12(s,1H),9.17(s,1H),8.54(s,1H),8.48(s,1H),7 .84(s,1H),3.22(dt,J=13.4,4.4Hz,2H),2.45(s,3H),2.15(t,J=13.6 Hz,2H),2.02(pent,J=6.4Hz,1H),1.42(d,J=12.4Hz,2H),0.90(d,J=13.4Hz,2H),0.83(m,4H),0.39(m,2H),0.30(m,2H).UHPLC-MS(ESI):Rt 0.77 min, m / z 435.3[M+H] + .

[0731] Example 66 Synthesis of N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-040) [ka] To a solution of N-(6-((8″-methyl-1″,5″-dioxo-1-(2-oxo-2-phenyl-112-ethyl)-1″,5″-dihydro-2″H-dispiro[aziridine-2,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-046) (50 mg, 0.087 mmol) in ethanol (1 mL) was added Pd / C (10% activated on charcoal, 10 mg, 0.0087 mmol). The suspension was degassed and repurged with hydrogen gas (this process was repeated three times). The reaction was stirred under a hydrogen atmosphere at 23 °C for 16 h. The reaction was filtered through Celite and washed with 1M NH3 / MeOH solution until complete recovery of the desired product (TLC analysis 10% 1M NH3 / MeOH in CHCl2). The filtrate was concentrated and purified by Biotage flash chromatography (gradient elution, 0-25% 3M NH3 / MeOH in CHCl2) to give the desired compound 4ET-03-040 (11 mg, 0.025 mmol, 30%) as a white powder. 1 H NMR(400MHz,DMSO-d6) δ 10.85(br,1H),9.14(br,1H),8.53(s,1H),8.49(s,1H),7.87(s,1H),5.53(m,1H),3.70(m,1H),3.10(m,4H),2. 35-2.19(m,3H),2.02(pent,J=6.2Hz,1H),1.93(m,1H),1.57(m,1H),0.85(d,J=6.2Hz,4H).UHPLC-MS(ESI):Rt 0.61 min, m / z 436.3[M+H] + .

[0732] Example 67 Synthesis of N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-043) [ka] The title compound was prepared according to the procedure for N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione to provide the title compound 4ET-03-043. 1 H NMR(400MHz,DMSO-d6) δ 10.82(s,1H),9.96(s,1H),9.27(s,1H),8.50(d,J=16.6Hz,2H),7.89(s,1H),3.55(d,J=13.8Hz,2H),2.40(s,3H),2.32(d,J =13.6Hz,2H),2.24-2.11(m,4H),2.07-1.96(m,1H),1.79(dt,J=14.9,7.6Hz,2H),0.83(d,J=6.1Hz,4H).UHPLC-MS(ESI):Rt 0.77 min, m / z 421.3[M+H] + .

[0733] Example 68 Synthesis of N-(6-((8''-methyl-1'',5''-dioxo-1-(2-oxo-2-phenyl-112-ethyl)-1'',5''-dihydro-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-046) [ka] The title compound was synthesized by the reaction of 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with benzyl 6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide except replacing 4ET-03-046 with 4ET-03-046-1-carboxylate to give the title compound 4ET-03-046. 1 H NMR(400MHz,DMSO-d6) δ 10.85(s,1H),9.70(br,1H),9.14(s,1H),8.53(s,1H),8.49(s,1H),7.87(s,1H),7.40-7.21(m,5H),5.04(s,2H),3.73-3.59(m,3H), 3.07(m,2H),2.45(s,3H),2.25(m,2H),2.02(pent,J=6.2Hz,1H),1.94(m,1H),1.58(m,2),0.84(d,J=6.2Hz,4H).UHPLC-MS(ESI):Rt 0.78 min, m / z 570.4[M+H] + .

[0734] Example 69 Synthesis of tert-butyl 6''-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[azetidine-3,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1-carboxylate (4ET-03-048) [ka] The title compound was synthesized by the reaction of 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with tert-butyl 6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[azetidine-3,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine ]-1-carboxylate (7k) was replaced by N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide to give the title compound 4ET-03-048. 1 H NMR(400MHz,DMSO-d6) δ 10.81(s,1H),10.06(s,1H),9.20(s,1H),8.49(d,J=13.1Hz,2H),7.84(s,1H),3.73-3.57(m,2H),3.57-3.41(m,2H),3.09- 2.97(m,2H),2.41(s,3H),1.93-1.73(m,4H),1.45-1.31(m,10H),1.19-1.08(m,2H),0.87-0.77(m,4H).UHPLC-MS(ESI):Rt 0.78 min, m / z 550.4[M+H] + .

[0735] Example 70 Synthesis of N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[azetidine-3,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-049) [ka] A solution of tert-butyl 6″-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[azetidine-3,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridine]-1-carboxylate (4ET-03-048) (12.5 mg, 0.023 mmol) in trifluoroacetic acid / CHCl [70:30] (1 mL) was stirred at 23° C. for 1 h. The reaction was concentrated and purified via strong cation exchange (SCX) flash column, eluting with CHCl, MeOH, and finally 1 M NH in MeOH to afford the title compound 4ET-03-049 (8 mg, 0.018 mmol, 78%). 1 H NMR(400MHz,DMSO-d6) δ 10.82(s,1H),9.21(s,1H),8.50(d,J=15.6Hz,2H),7.85(s,1H),3.48-3.39(m,2H),3.12-2.95(m,2H),2.43(s,3H),2 .08-1.95(m,J=6.7Hz,4H),1.84-1.71(m,2H),1.45-1.31(m,J=12.7Hz,2H),0.83(d,J=5.8Hz,4H).UHPLC-MS(ESI):Rt 0.61 min, m / z 450.3[M+H] + .

[0736] Example 71 Synthesis of 6''-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-03-074) [ka] The title compound can be prepared by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione and by cleaving N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide. Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing amide with 2-(6-aminopyrimidin-4-yl)amino)ethan-1-ol (8d) to give the title compound 4ET-03-074. 1 H NMR(400MHz,DMSO-d6) δ 10.03(s,1H),8.61(s,1H),8.37(s,1H),8.19(s,1H),6.97(s,1H),6.2 4(s,1H),4.68(t,J=5.6Hz,1H),3.53-3.43(m,2H),3.24-3.11(m,4H),2 .41(s,3H),2.18-2.05(m,2H),1.39(d,J=11.7Hz,2H),0.87(d,J=13.9Hz,2H),0.37(d,J=7.9Hz,2H),0.28(d,J=7.7Hz,2H).UHPLC-MS(ESI):Rt 0.66 min, m / z 411.3[M+H] + .

[0737] Example 72 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-03-053) [ka] The title compound was synthesized by the reaction of N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide with N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[ Prepared according to the procedure except substituting 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, except substituting 1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-029) to provide the title compound 4ET-03-053 (12 mg, 0.033 mmol, 75%). 1 H NMR(400MHz,DMSO-d6) δ 10.04(s,1H),8.62(s,1H),8.40(s,1H),8.17(s,1H),6.50(br,2H),6.15(s,1H),3.23(td,J=13.4,4.4Hz,2H) ,2.43(s,3H),2.15(t,J=13.4Hz,2H),1.41(m,2H),0.89(m,2H),0.40(m,2H),0.29(m,2H).UHPLC-MS(ESI):Rt 0.61 min, m / z 367.3[M+H] + .

[0738] Example 73 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-1-(2-oxo-2-phenyl-1L2-ethyl)-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-03-080) [ka] The title compound was obtained by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with benzyl 6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1-carboxylate (7j) and N-(6-amino)- N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide was prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing pyrimidine-4,6-diamine (8e) to give the title compound 4ET-03-080. 1 H NMR(400MHz,DMSO-d6) δ 8.59(s,1H),8.41(s,1H),8.16(s,1H),7.44-7.23(m,5H),6.50(br,2H),6.18(s,1H),5.55(s,1H),5.04(s,2H),3.73-3.55( m,2H),3.14-2.90(m,2H),2.43(s,3H),2.30(m,1H),2.18(m,1H),1.93(m,1H),1.58(m,1H),1.42(m,2H).UHPLC-MS(ESI):Rt 0.66 min, m / z 502.3[M+H] + .

[0739] Example 74 Synthesis of 1-(aminomethyl)-N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropane-1-carboxamide (4ET-03-055-HCl) [ka] tert-Butyl ((1-((6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)carbamoyl)cyclopropyl)methyl)carbamate with 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'' ,5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7g) (70 mg, 0.21 mmol), and N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide with tert-butyl((1-((6-aminopyrimidin-4-yl)carbamoyl)cyclopropyl)methyl)carbamate (8f) (83 mg, 0.27 mmol), N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridin]-6''-yl)amine was prepared, except that Cs2CO3 (203 mg, 0.62 mmol), bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.041 mmol), Pd(OAc)2 (4.7 mg, 0.027 mmol), and 1,4-dioxane (2.0 mL) were substituted. The Boc-protected intermediate tert-butyl ((1-((6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)carbamoyl)cyclopropyl)methyl)carbamate (110 mg, 0.19 mmol, 95%) was prepared according to the procedure for (1,4-dioxane)-2-pyrimidin-4-yl)cyclopropanecarboxamide to yield the Boc-protected intermediate tert-butyl ((1-((6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)carbamoyl)cyclopropyl)methyl)carbamate (110 mg, 0.19 mmol, 95%). The Boc-protected intermediate was dissolved in CHCl / methanol (v:v / 1:1, 2 mL) and HCl (0.15 mL, 4 M solution in 1,4-dioxane) was added.Upon completion of the reaction, as determined by HPLC / MS monitoring, the reaction was diluted with diethyl ether (30 mL), and the resulting precipitate was collected by filtration and washed with diethyl ether to give the title compound 4ET-03-055 as the hydrochloride salt (98 mg, 0.19 mmol, 93%). 1 H NMR(400MHz,DMSO-d6) δ 10.15(s,1H),10.02(m,1H),9.36(m,1H),8.58(s,1H),8.49(s,1H),7.96(br s,2H),7.87(s,1H),3.26-3.15(m,4H),2.45(s,3H),2.15(m,2H),1.43(m,4 H),1.11(m,2H),0.90(m,2H),0.40(m,2H),0.29(m,2H).UHPLC-MS(ESI):Rt 0.63 min, m / z 464.3[M+H] + .

[0740] Example 75 Synthesis of (1R,5S,6R)-N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (4ET-03-056-HCl) [ka] tert-Butyl (1R,5S,6r)-6-((6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin)-6''-yl)amino)pyrimidin-4-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was reacted with 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridin 6''-Bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7g) (70 mg, 0.21 mmol), tert-butyl-(1R,5S,6r)-6-((6-aminopyrimidin-4-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (8g) (86 mg, 0. 27 mmol), Cs2CO3 (203 mg, 0.62 mmol), bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.041 mmol), Pd(OAc)2 (4.7 mg, 0.027 mmol), and 1,4-dioxane (2.0 mL) were substituted for N-(6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3′′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidine. The Boc-protected intermediate tert-butyl (1R,5S,6r)-6-((6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1.1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (115 mg, 0.20 mmol, 96%) was prepared according to the procedure for (1R,5S,6r)-6-((6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1.1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (115 mg, 0.20 mmol, 96%).The Boc-protected intermediate was dissolved in CHCl / methanol (v:v / 1:1, 2 mL) and HCl (0.15 mL, 4 M solution in 1,4-dioxane) was added. Upon completion of the reaction, as determined by HPLC / MS monitoring, the reaction was diluted with diethyl ether (30 mL) and the resulting precipitate was collected by filtration and washed with diethyl ether to afford the title compound 4ET-03-056 as the hydrochloride salt (95 mg, 0.19 mmol, 88%). 1 H NMR (400 MHz, DMSO-d6) δ 11.09(s,1H),10.14(s,1H),9.67(br,1H),9.31(s,1H),9.10(br,1H),8.56(s, 1H),8.46(s,1H),7.80(s,1H),3.37(m,4H),3.21(dt,J=14.0,4.4Hz,2H),2.45( s,3H),2.22(m,2H),2.15(t,J=14.0Hz,2H),2.09(t,J=3.2Hz,1H),1.42(d,J=12 .0Hz,2H),0.89(d,J=13.2Hz,2H),0.40(m,2H),0.29(m,2H).UHPLC-MS(ESI):Rt 0.64 min, m / z 476.4[M+H] + .

[0741] Example 76 Synthesis of N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)-2-azaspiro[3.3]heptane-6-carboxamide (4ET-03-057-HCl) [ka] tert-Butyl 6-((6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine)-6''-yl)amino)pyrimidin-4-yl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate was reacted with 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]- Substituting 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7g) (70 mg, 0.21 mmol) for 1'',5''-dione and N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide with tert-butyl 6-((6-aminopyrimidin-4-yl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate 8h (90 mg, 0.27 mmol) l), Cs2CO3 (203 mg, 0.62 mmol), bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.041 mmol), Pd(OAc)2 (4.7 mg, 0.027 mmol), and 1,4-dioxane (2.0 mL) were substituted with N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridin)-6''-yl)amino). Prepared according to the procedure for pyrimidin-4-yl)cyclopropanecarboxamide to yield the Boc-protected intermediate tert-butyl 6-((6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin)-6″-yl)amino)pyrimidin-4-yl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (92 mg, 0.15 mmol, 75%).The Boc-protected intermediate was dissolved in CHCl / methanol (v:v / 1:1, 2 mL) and HCl (0.15 mL, 4 M solution in 1,4-dioxane) was added. Upon completion of the reaction, as determined by HPLC / MS monitoring, the reaction was diluted with diethyl ether (30 mL) and the resulting precipitate was collected by filtration and washed with diethyl ether to afford the title compound 4ET-03-057 as the hydrochloride salt (77 mg, 0.14 mmol, 94%). 1 H NMR(400MHz,DMSO-d6) δ 10.59(br,1H),10.14(s,1H),9.33(br,1H),8.92(br,1H),8.54(s,1H),8.46(s,1H),8.12(m,1H),7.86(s,1H),3.93(m,4H),3.21(m,3H),2.4 5(s,3H),2.41(m,2H),2.21(m,2H),2.15(m,2H),1.42(d,J=12.0Hz,2H),0.90(d,J=13.6Hz,2H),0.40(m,2H),0.30(m,2H).UHPLC-MS(ESI):Rt 0.65 min, m / z 490.4[M+H] + .

[0742] Example 77 Synthesis of 2-methyl-N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)-2-azaspiro[3.3]heptane-6-carboxamide (4ET-03-060) [ka] The title compound was prepared by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7g) (48 mg, 0.19 mmol), and N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide with N-(6-aminopyrimidin-4-yl)-2-methyl-2-azaspiro[3.3]heptane-6-carboxamide (8i) (50 mg, 0.14 mmol), C Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide except substituting s2CO3 (145 mg, 0.44 mmol), bis(diphenylphosphino)-9,9-dimethylxanthene (17.1 mg, 0.029 mmol), Pd(OAc)2 (3.3 mg, 0.014 mmol), and 1,4-dioxane (1.5 mL) to yield the title compound 4ET-03-060 (18 mg, 0.035 mmol, 24%). 1 H NMR(400MHz,DMSO-d6) δ 10.39(s,1H),10.12(s,1H),9.18(s,1H),8.51(s,1H,8.48(s,1H),7.90(s,1H),3.22(m,4H),3.13(m,3H),2.45(s,3H),2.26( m,4H),2.21(s,3H),2.15(m,2H),1.42(d,J=12.0Hz,2H),0.91(d,J=13.2Hz,2H),0.40(m,2H),0.30(m,2H).UHPLC-MS(ESI):Rt 0.65 min, m / z 504.4[M+H] + .

[0743] Example 78 Synthesis of (1R,5S,6R)-3-methyl-N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (4ET-03-061) [ka] To a solution of (1R,5S,6r)-N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide HCl (4ET-03-056-HCl) (50 mg, 0.10 mmol) in CHCl / methanol (v:v / 2:1, 1.5 mL) was added formaldehyde (40% aqueous solution, 0.10 mL, 1.57 mmol) and acetic acid (3.15 mg, 0.052 mmol). The reaction was cooled to 0 °C before the addition of NaCNBH (13.2 mg, 0.21 mmol). The reaction was stirred at 0° C. for 2 h, concentrated under reduced pressure, and the resulting material was purified by Biotage flash chromatography (silica gel, 0% to 20% 3M NH / MeOH in CH2Cl2) to afford the title compound 4ET-03-061 (32 mg, 0.065 mmol, 63%). 1H NMR(400MHz,DMSO-d6) δ 10.69(br,1H),10.12(s,1H),9.15(s,1H),8.52(s,1H),8.48(s,1H),7 .82(s,1H),3.22(dt,J=13.2,4.2Hz,2H),2.98(m,3H),2.45(s,3H),2.3 6(m,2H),2.28(m,3H),2.15(m,2H),1.90(m,2H),1.42(d,J=12.0Hz,2H),0.90(d,J=13.2Hz,2H),0.40(m,2H),0.30(m,2H).UHPLC-MS(ESI):Rt 0.65 min, m / z 504.4[M+H] + .

[0744] Example 79 Synthesis of N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)-1-(methylsulfonamidomethyl)cyclopropane-1-carboxamide (4ET-03-076) [ka] To a stirred solution of 1-(aminomethyl)-N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropane-1-carboxamide HCl (4ET-03-055-HCl) (20 mg, 0.037 mmol) in anhydrous acetonitrile (2.0 mL) under an inert atmosphere at 23° C., trimethylamine (0.026 mL, 0.187 mmol) and methanesulfonyl chloride (0.009 mL, 0.112 mmol) were added. After 3 h, pyridine (0.5 mL) and additional methanesulfonyl chloride (0.010 mL) were added. After stirring for 16 h, the mixture was diluted with methylene chloride (3 mL) and loaded onto a strong cation exchange (SCX) SPE cartridge (2 g SCX, CHCl / MeOH, then 1 M NH in MeOH). The product was the CHCl and MeOH fraction along with pyridine. These fractions were combined, pre-absorbed onto silica, and purified by flash chromatography (4 g SiO, CHCl:ethyl acetate 10-100% gradient) to give the title compound 4ET-03-076 (1.1 mg, 6%). 1 H NMR(400MHz,DMSO-d6) δ 10.10(s,1H),9.70(s,1H),9.24(s,1H),8.53(s,1H),8.49(s,1H),7.84(d ,J=1.1Hz,1H),7.34(t,J=6.3Hz,1H),3.27(s,2H),3.26-3.13(m,2H),2.92 (s,3H),2.43(s,4H),2.13(t,J=13.4Hz,2H),1.40(d,J=12.1Hz,2H),1.16 (d,J=2.9Hz,3H),0.93-0.81(m,3H),0.45-0.22(m,4H).UHPLC-MS(ESI):Rt 0.770min, m / z 542.3[M+H] + .

[0745] Example 80 Synthesis of 1-((dimethylamino)methyl)-N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropane-1-carboxamide (4ET-03-081) [ka] To a stirred solution of 1-(aminomethyl)-N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropane-1-carboxamide (4ET-03-055) (15 mg, 0.034 mmol) in CHCl (2.0 mL) cooled to 0 °C was added acetic acid (0.010 mL, 0.172 mmol) and 40% formaldehyde (0.039 mL, 0.517 mmol). The mixture was treated with sodium triacetoxyborohydride (9 mg, 0.138 mmol) and slowly warmed to 23 °C. After stirring for 16 h, the solvent was removed and the residue was taken up in trifluoroethanol (2.0 mL) and treated with sodium borohydride (6.4 mg, 0.170 mmol) in one portion at 23° C. After 1 h, the mixture was diluted with MeOH (3.0 mL) and applied to a strong cation exchange (SCX) SPE cartridge (2 g SCX) and eluted with methanol, then dichloromethane, then 1 M NH in methanol to give the title compound 4ET-03-081 (4.3 mg, 27%). 1H NMR(400MHz,chloroform-d) δ 8.58(s,1H),8.55(s,1H),8.22(s,1H),8.02(s,1H),7.64(s,1H),3.34(td, J=14.0,12.8,4.5Hz,2H),2.57(s,3H),2.51(s,2H),2.41(s,6H),2.02(td, J=13.3,12.0,3.7Hz,2H),1.55(d,J=11.3Hz,2H),1.39(q,J=4.0Hz,2H),1. 07(d,J=13.9Hz,2H),0.67(q,J=4.0Hz,2H),0.45(s,4H).UHPLC-MS(ESI):Rt 0.65 min, m / z 492.3[M+H] + .

[0746] Example 81 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-01-009) [ka] The title compound was synthesized by the reaction of N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide with N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1 Prepared according to the procedure except substituting 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, except substituting 6''-((6-aminopyrimidin-4-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-043) to give the title compound 4ET-01-009 (8 mg, 0.023 mmol, 87%).1 H NMR(400MHz,DMSO-d6) δ 9.89(s,1H),8.71(s,1H),8.42(s,1H),8.16(s,1H),6.49(s,2H),6.21(s,1H),3.56(d,J=14.2Hz,2H) ,2.38(s,3H),2.35-2.29(m,2H),2.24-2.12(m,4H),1.80(dt,J=14.7,7.2Hz,2H).UHPLC-MS(ESI / ):Rt 0.63 min, m / z 353.3[M+H] + .

[0747] Example 82 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-01-012) [ka] The title compound was synthesized by the reaction of N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide with N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1 Prepared according to the procedure except substituting 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, except substituting 6''-((6-aminopyrimidin-4-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (4ET-03-040) to give the title compound 4ET-01-012 (7 mg, 0.019 mmol, 38%). 1H NMR(400MHz,DMSO-d6) δ 8.58(s,1H),8.41(s,1H),8.16(s,1H),6.51(br,2H),6.17(s,1H),5.62(m,1H),3.72(m,1H),3.2 1(br,1H),3.10(m,2H),2.43(s,3H),2.29(m,2H),1.96(m,2H),1.60(m,2H).UHPLC-MS(ESI / ):Rt 0.55 min, m / z 368.3[M+H] + .

[0748] Example 83 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclopentane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-01-015) [ka] The title compound was obtained by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclopenten-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7l) and N-(6-aminopyrimidin-4-yl)cyclopropane. Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing cyclopropanecarboxamide with 4,6-diaminopyrimide (8e) to give the title compound 4ET-01-015 (16 mg, 37%). 1H NMR(400MHz,DMSO-d6) δ 9.68(s,1H),8.64(s,1H),8.39(s,1H),8.14(s,1H),6.47(s,2H),6.16(d,J=1.0Hz,1H),2.90(d,J=13.7Hz ,1H),2.75(dt,J=13.1,7.9Hz,1H),2.38(s,3H),2.22-2.01(m,2H),1.99-1.64(m,5H).UHPLC-MS(ESI):Rt 0.64 min, m / z 367.3[M+H] + .

[0749] Example 84 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclopentane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-01-016) [ka] The title compound can be prepared by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine-1'',5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclopentane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, and by N-(6-aminopyrimidin-4-yl)cyclo Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing propanecarboxamide with 4,6-diamopyrimidine (8e) to give the title compound 4ET-01-016. 1H NMR(400MHz,DMSO-d6) δ 9.77(s,1H),8.68(s,1H),8.41(s,1H),8.14(d,J=0.9Hz,1H),6.46(s,2H),6.18(d,J=1.0Hz,1H),2.91(d,J=14.0Hz, 1H),2.88-2.80(m,0H),2.39(s,3H),2.03-1.91(m,1H),1.86-1.68(m,2H),1.60(t,J=10.1Hz,9H).UHPLC-MS(ESI):Rt 0.66 min, m / z 381.3[M+H] + .

[0750] Example 85 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-3,3-difluoro-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-01-017) [ka] The title compound was obtained by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine-1'',5''-dione with 6''-bromo-3,3-difluoro-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7n) and N-(6-aminopyrimidine-4 Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide with 4,6-diamopyrimidine 8e to give the title compound 4ET-01-017. 1H NMR(400MHz,DMSO-d6) δ 9.91(s,1H),8.71(s,1H),8.41(s,1H),8.14(s,1H),6.48(s,2H),6.20(s,1H),3.61(d ,J=14.4Hz,2H),2.88-2.69(m,4H),2.36(s,3H),2.02-1.92(m,2H).UHPLC-MS(ESI):Rt 0.63 min, m / z 381.3[M+H] + .

[0751] Example 86 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-01-018) [ka] The title compound was obtained by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7o) and N-(6-aminopyrimidin-4-yl)silyl Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing cyclopropanecarboxamide with 4,6-diaminopyrimidine (8e) to give the title compound 4ET-01-018. 1H NMR(400MHz,DMSO-d6) δ 10.00(s,1H),8.72(s,1H),8.43(s,1H),8.17(s,1H),6.50(s,2H),6.21(s,1H),3.51(d,J=13.7Hz,2H),2.40 (s,3H),2.11(d,J=13.6Hz,2H),1.97-1.87(m,2H),1.86-1.77(m,2H),1.61-1.53(m,4H).UHPLC-MS(ESI):Rt 0.73 min, m / z 367.3[M+H] + .

[0752] Example 87 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-01-019) [ka] The title compound was obtained by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine-1'',5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclopentane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7p) and N-(6-aminopyrimidin-4-yl)silyl Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing cyclopropanecarboxamide with 4,6-diamopyrimidine (8e) to give the title compound 4ET-01-019. 1H NMR(400MHz,DMSO-d6) δ 9.95(s,1H),8.68(s,1H),8.40(s,1H),8.14(s,1H),6.47(s,2H),6.15(s,1H),3.14-3.00(m,2H),2 .39(s,3H),1.88-1.81(m,3H),1.80-1.60(m,J=12.9Hz,5H),1.32-1.19(m,4H).UHPLC-MS(ESI):Rt 0.66 min, m / z 381.3[M+H] + .

[0753] Example 88 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclohexane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-01-020): [ka] The title compound was obtained by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine-1'',5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclopentane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7q) and N-(6-aminopyrimidin-4-yl)cyclopropanecarbohydrate. Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing oxamide with 4,6-diamopyrimidine (8e) to give the title compound 4ET-01-020 (18 mg, 0.05 mmol, 33%). 1H NMR(400MHz,DMSO-d6) δ 9.94-9.87(m,1H),8.69(s,1H),8.43(s,1H),8.17(s,1H),6.50(s,2H),6.20(s,1H),3.30-3.25(m,2H),2.40 (s,3H),2.00(d,J=13.7Hz,2H),1.94-1.84(m,2H),1.75-1.65(m,2H),1.47-1.30(m,6H).UHPLC-MS(ESI):Rt 0.67min, m / z 381.2[M+H] + .

[0754] Example 89 Synthesis of ethyl 6''-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-2-carboxylate (4ET-03-045) [ka] The title compound was synthesized by the reaction of 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with ethyl 6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-2-carboxylate Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except replacing with (7r) to give the title compound 4ET-03-045 (38 mg, 0.075 mmol, 25%). 1H NMR(400MHz,DMSO-d6) δ 10.83(s,1H),10.09(bs,1H),9.12(s,1H),8.50(s,1H),8.44(s,1H),7.82(s,1H),4.07(q,J=7.0Hz,2H),3.24-3.12(m,2H),2.42 (s,3H),2.30-2.12(m,2H),1.90-1.29(m,6H),1.20(t,J=7.1Hz,3H),1.08-0.92(m,2H),0.82(d,J=6.1Hz,4H).UHPLC-MS(ESI):Rt 0.77 min, m / z 507.3[M+H] + .

[0755] Example 90 Synthesis of tert-butyl (6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-2-yl)carbamate [ka] To a solution of 6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-2-carboxylic acid (7s) (210 mg, 0.55 mmol) in toluene (1.8 mL) was added triethylamine (0.12 mL, 0.83 mmol) and diphenylphosphoryl azide (0.18 mL, 0.83 mmol). The reaction mixture was heated to reflux for 2 h. Then, t-BuOH (0.06 mL, 0.605 mmol) was added, and the reaction mixture was refluxed for 16 h. The solvent was removed under reduced pressure, and NaHCO3 (50 mL) was added. After washing with ethyl acetate (50 mL × 3), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was purified by Biotage flash chromatography (gradient elution, 0–10% MeOH in CHCl) to give tert-butyl (6″-bromo-8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-2-yl)carbamate (7t) (14 mg, 0.031 mmol). 1 H NMR(400MHz,CDCl3) δ 7.73(s,1H),3.23(m,2H),2.51(m,1H),2.48(s,3H),2.10(m,2H),1.53(m,2 H),1.30(m,2H),1.11(m,9H),0.81(m,1H),0.42(m,1H).UHPLC-MS(ESI):Rt 0.74 min, m / z 451.1[M+H] + .

[0756] Example 91 Synthesis of tert-butyl (6''-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-2-yl)carbamate (4ET-03-047) [ka] The title compound was synthesized by the reaction of 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with tert-butyl(6''-bromo-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-2-yl)carbamate. Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except substituting bamate (7t) to give the title compound 4ET-03-047 (2 mg, 0.004 mmol, 12%). 1 H NMR(400MHz,DMSO-d6) δ 10.83(s,1H),10.06(bs,1H),9.16(s,1H),8.51(s,1H),8.46(s,1H),7.82(s,1H),3.23-3.09(m,2H),2.59(m,1H),2 .42(s,3H),2.04-1.93(m,2H),1.57(m,1.0),1.50-1.31(m,4H),0.98-0.82(m,11H),0.53(m,2H).UHPLC-MS(ESI):Rt 0.75 min, m / z 549.4[M+H] + .

[0757] Example 92 Synthesis of N-(6-((2,2-difluoro-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (7F1) [ka] The title compound was prepared by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with 6''-bromo-2,2-difluoro-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7f). Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide except for substituting to give the title compound (7f1) (21 mg, 0.045 mmol, 43%).

[0758] Example 93 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-2,2-difluoro-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-03-068) [ka] The title compound was synthesized by the reaction of 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with N-(6-((2,2-difluoro-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-6''-yl)amino)pyrimidin-4-yl Prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide except substituting N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (7f1) to give the title compound 4ET-03-068 (15 mg, 0.037 mmol, 83%). 1 H NMR(400MHz,DMSO-d6) δ 8.68(s,1H),8.60(s,1H),8.38(s,1H),8.15(s,1H),6.49(s,2H),6.13(s,1H),3.23-3.04(m,2H),2.41(s,3H) ,2.18-1.97(m,2H),1.50(d,J=11.5Hz,2H),1.39(d,J=12.9Hz,2H),1.31(t,J=8.3Hz,2H).UHPLC-MS(ESI):Rt 0.65 min, m / z 403.3[M+H] + .

[0759] Example 94 Synthesis of 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cycloheptane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (4ET-01-027) [ka] The title compound was prepared by replacing 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione with 6''-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cycloheptane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, and by N-(6-aminopyridine)-2-bromo-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cycloheptane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione. N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide was prepared according to the procedure for N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, except for replacing N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-3′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide with 4,6-diaminopyrimidine: 1 H NMR(400MHz,DMSO-d6) δ 9.91(s,1H),8.69(s,1H),8.40(s,1H),8.17(s,1H),6.50(br s,2H),6.18(d,J=1.1Hz,1H),3.04-2.94(m,1H),2.88(dd,J=14.2,10.1Hz,1H),2.41(s,3H),2.0-1.97(m,1H),1.90-1.80(m,1H),1.71( dd,J=14.4,9.3Hz,2H),1.59(dd,J=14.0,7.7Hz,2H),1.35(dt,J=15.5,8.5Hz,2H),0.32(d,J=6.2Hz,4H);UHPLC-MS(ESI):Rt:0.98min,m / z 381.4[M+H] + .

[0760] The enantiomers of rac-4ET-01-027 ("4ET-01-027 enantiomer 1" and "4ET-01-027 enantiomer 2") were obtained by separation using chiral analytical and preparativ...

Claims

1. 1. A composition for treating, preventing, or alleviating the effects of migraine or symptoms associated with migraine, said composition comprising a compound having the following structure (II): 【Chemical 242】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, wherein: R １ａ But C １ -C ６ is alkyl or aryl, R １ｂ But C １ -C ６ alkyl or aryl; Or, R １ａ and R １ｂ are joined together with the carbon to which they are both attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; R ２ But, -NHR ３ａ , -NHC(=O)R ３ｂ , -NHC(=S)R ３ｂ , or -C(=O)R ３ｃ and R ３ａ But hydrogen, C １ -C ６ Alkyl, or C ３ -C ６ cycloalkyl, each of which optionally includes hydroxyl, C ３ -C ６ Cycloalkyl, —NHS(O) ２ CH ３ , heterocyclyl, —C(═O)OH, —C(═O)N(R ３ｄ ) R ３ｄ , or -N(R ３ｄ ) R ３ｄ and is substituted with one or more substituents selected from the group consisting of R ３ｂ But C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, or heterocyclyl, each of which is optionally selected from hydroxyl, halo, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, —NHS(O) ２ CH ３ , -N(R ３ｄ ) R ３ｄ , heterocyclyl, —C(═O)OH, —C(═O)N(R ３ｄ ) R ３ｄ , -NHC(=O)CH ３ , -CH ２ C(═O)OH; R ３ｃ But -N(R ３ｄ ) R ３ｄ or heterocyclyl, R ３ｄ may, at each occurrence, independently represent hydrogen, C １ -C ６ Alkyl, or C ３ -C ６ is cycloalkyl, L is —NH— or —CH ２ NH-, A composition wherein X is N and Y is CH or X is CH and Y is N.

2. R １ａ But C １ -C ６ The composition of claim 1 wherein the alkyl is alkyl.

3. R １ａ The composition of claim 1 or 2, wherein is methyl.

4. R １ａ The composition of claim 1 , wherein is aryl.

5. R １ａ The composition of claim 1 , wherein is phenyl.

6. R １ｂ But C １ -C ６ 6. The composition of any one of claims 1, 2, 4 and 5, wherein the alkyl is alkyl.

7. R １ｂ The composition of any one of claims 1, 2, 4 and 5, wherein is methyl.

8. R １ａ and R １ｂ The composition of claim 1 , wherein:

9. 9. The composition of claim 8, wherein the cycloalkyl is cyclopentyl or cyclohexyl.

10. R １ａ and R １ｂ The composition of claim 1 , wherein: is joined together with the carbon to which they are both attached to form a cycloalkenyl.

11. The composition of claim 10, wherein the cycloalkenyl is cyclopentenyl, cyclohexenyl, or cycloheptenyl.

12. R １ａ and R １ｂ The composition of claim 1 , wherein: is joined together with the carbon to which they are both attached to form a heterocyclyl.

13. R １ａ and R １ｂ The composition of claim 12 , wherein: is joined together with the carbon to which they are both attached to form an aryl.

14. R １ａ and R １ｂ The composition of claim 1 , wherein:

15. The compound has the following structure: 【Chemical 243】 【Chemical 244】 One of the or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, wherein: 【Chemistry 245】 represents a double bond or a single bond, R ４ However, each occurrence independently, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, halo, haloalkyl, hydroxyl, -NHS(O) ２ CH ３ or —C(O)OH, or two R ４ are bonded together with the carbon to which they are both attached to form a cycloalkyl, W is N or O; Z is C or O, The composition of any one of claims 1, 2, 4, 5 and 8 to 14, wherein n is 0, 1, 2, 3, or 4.

16. 16. The composition of claim 15, wherein n is 0, 1, or 2.

17. R ２ But, -NHR ３ａ The composition according to any one of claims 1, 2, 4, 5 and 8 to 14,

18. R ２ but has the following structure: -NH ２ 、 【Chemical 246】 The composition of any one of claims 1, 2, 4, 5 and 8 to 14, wherein the composition has one of the following:

19. R ２ is -NHC(=O)R ３ｂ The composition according to any one of claims 1, 2, 4, 5 and 8 to 14,

20. R ２ but has the following structure: 【Chemical 247】 20. The composition of claim 19, wherein

21. R ２ But -NHC(=S)R ３ｂ The composition according to any one of claims 1, 2, 4, 5 and 8 to 14,

22. R ２ but has the following structure: 【Chemical 248】 22. The composition of claim 21 having:

23. R ２ But -C(=O)R ３ｃ The composition according to any one of claims 1, 2, 4, 5 and 8 to 14,

24. R ２ but has the following structure: 【Chemical 249】 24. The composition of claim 23, wherein

25. R ２ but has the following structure: -NH ２ 、 【Chemistry 250】 The composition of any one of claims 1, 2, 4, 5 and 8 to 14, wherein the composition has one of the following:

26. R ２ but has the following structure: -NH ２ or 【Chemistry 251】 The composition of any one of claims 1, 2, 4, 5 and 8 to 14, wherein the composition has one of the following:

27. 15. The composition of any one of claims 1, 2, 4, 5 and 8-14, wherein X is CH and Y is N.

28. 15. The composition of any one of claims 1, 2, 4, 5 and 8-14, wherein X is N and Y is CH.

29. The composition of any one of claims 1, 2, 4, 5 and 8 to 14, wherein L is -NH-.

30. L is -CH ２ NH-.

31. 15. The composition of any one of claims 1, 2, 4, 5 and 8-14, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

32. 1. A composition for treating, preventing, or alleviating the effects of migraine or symptoms associated with migraine, said composition comprising a compound having the following structure (IV): 【Chemical 252】 or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: Z １ but, 【Chemical 253】 is selected from the group consisting of R １ But hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, cyano, C １－６ Alkoxyl, C ３－７ Branched alkoxy, hydroxy, and halogen, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyalkyl ３－６ cycloalkyl; R ２ is selected from the group consisting of: 【Chemical 254】 R ３ But hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, cyano, C １－６ Alkoxyl, C ３－７ Branched alkoxy, hydroxy, and halogen, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyalkyl ３－６ cycloalkyl; R ４ａ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHCO(C ３－７ Cycloalkyl), NHSO ２ (C １－６ alkyl), NHSO ２ (C ３－７ branched alkyl), and NHSO ２ (C ３－７ cycloalkyl); R ４ｂ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHCO(C ３－７ Cycloalkyl), NHSO ２ (C １－６ alkyl), NHSO ２ (C ３－７ branched alkyl), and NHSO ２ (C ３－７ cycloalkyl); R ４ｃ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHCO(C ３－７ Cycloalkyl), NHSO ２ (C １－６ alkyl), NHSO ２ (C ３－７ branched alkyl), and NHSO ２ (C ３－７ cycloalkyl); R ４ｄ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHCO(C ３－７ Cycloalkyl), NHSO ２ (C １－６ alkyl), NHSO ２ (C ３－７ branched alkyl), and NHSO ２ (C ３－７ cycloalkyl); R ４ｅ But hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, and C ３－７ is a branched haloalkyl; R ４ｆ But hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, and C ３－７ is a branched haloalkyl; R １ａ and R １ｂ together, and optionally X １ forming an optionally substituted 3- to 7-membered ring containing a group, X １ But CF ２ , CHCO ２ R １２ , O, N.H., N.R. ８ , and SO ２ is selected from the group consisting of m is 0, 1, or 2; n is 1, 2, or 3; R ５ But hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Alkoxyl, C ３－７ selected from the group consisting of branched alkoxy and hydroxy; R ６ But hydrogen, NH ２ , N.H.R. ６ａ , NHCH ２ CH ２ OH,NHCH ２ CH ２ NHSO ２ Me, C １－６ Alkoxyl, C ３－７ selected from the group consisting of branched alkoxy and hydroxy; R ６ａ But -(CO)C １－６ Alkyl, —(CO)C ３－７ Branched alkyl, —(CO)C １－６ hydroxyalkyl, 【Chemistry 255】 is selected from the group consisting of q is 1, 2, 3, 4, 5, or 6; e is 1, 2, 3, 4, 5, or 6; X ２ But hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, hydroxy, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, C １－６ Alkoxy, C ３－７ Branched alkoxy, C １－６ Haloalkoxy, C ３－７ Branched haloalkoxy, NH ２ , NH(C １－６ alkyl), N(C １－６ alkyl) 2, C １－５ (COOH), C １－６ (NHSO ２ Me), X ３ But hydrogen, halogen, C １－５ Alkyl, C ３－７ Branched alkyl, C １－５ Haloalkyl, C ３－７ Branched haloalkyl, hydroxy, C １－５ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, C １－５ Alkoxy, C ３－７ Branched alkoxy, C １－５ Haloalkoxy, C ３－７ Branched haloalkoxy, NH ２ , NH(C １－６ alkyl), N(C １－６ alkyl) ２ , COOH, C １－５ (COOH), NHSO ２ Me, C １－５ (NHSO ２ Me), R ７ But hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Alkoxyl, C ３－７ selected from the group consisting of branched alkoxy and hydroxy; R ８ But C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, C １－６ Alkoxyl, C ３－７ Branched alkoxy, CO(C １－６ alkyl), CO(C ３－７ branched alkyl), SO ２ (C １－６ alkyl), and SO ２ (C ３－７ branched alkyl), R １０ But hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxyl, C ３－７ Branched alkoxy, CO(C １－６ alkyl), CO(C ３－７ branched alkyl), SO ２ (C １－６ alkyl), and SO ２ (C ３－７ branched alkyl), R １１ is hydrogen and C １－６ is selected from the group consisting of alkyl, R １２ is hydrogen and C １－６ The composition of matter, wherein the alkyl is selected from the group consisting of:

33. The compound has the following structure (V): 【256】 or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof.

34. The compound has the following structure (VI): 【Chemistry 257】 or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof.

35. The compound has the following structure (VII): 【Chemical 258】 or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof.

36. The compound has the following structure (VIII): 【Chemical 259】 or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof.

37. The compound has the following structure (IX): 【Chemistry 260】 or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R ８ａ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHSO ２ (C １－６ alkyl), and NHSO ２ (C ３－７ branched alkyl), R ８ｂ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHSO ２ (C １－６ alkyl), and NHSO ２ (C ３－７ branched alkyl), R ８ｃ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHSO ２ (C １－６ alkyl), and NHSO ２ (C ３－７ branched alkyl), R ８ｄ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHSO ２ (C １－６ alkyl), and NHSO ２ (C ３－７ branched alkyl), R ９ａ But hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl and C ３－７ branched alkoxy; R ９ｂ But hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl and C ３－７ branched alkoxy; R ９ａ and R ９ｂ together form an optionally substituted 3- to 7-membered ring, q is 1, 2, or 3; 33. The composition of claim 32, wherein z is 0, 1, or 2.

38. The compound has the following structure (X): 【Chemical 261】 or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R ８ａ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHSO ２ (C １－６ alkyl), and NHSO ２ (C ３－７ branched alkyl), R ８ｂ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHSO ２ (C １－６ alkyl), and NHSO ２ (C ３－７ branched alkyl), R ８ｃ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHSO ２ (C １－６ alkyl), and NHSO ２ (C ３－７ branched alkyl), R ８ｄ may, at each occurrence, independently represent hydrogen, halogen, C １－６ Alkyl, C ３－７ Branched alkyl, C １－６ Haloalkyl, C ３－７ Branched haloalkyl, C １－６ Hydroxyalkyl, C ３－７ Branched hydroxyalkyl, hydroxy, C １－６ Alkoxyl, C ３－７ Branched alkoxy, NHCO(C １－６ alkyl), NHCO(C ３－７ Branched alkyl), NHSO ２ (C １－６ alkyl), and NHSO ２ (C ３－７ branched alkyl), q is 1, 2, or 3; 33. The composition of claim 32, wherein z is 0, 1, or 2.

39. The compound is N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, N-(6-((8''-methyl-1'',5''-dioxo-1-(2-oxo-2-phenyl-112-ethyl)-1'',5''-dihydro-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, tert-butyl 6''-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[azetidine-3,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1-carboxylate, N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[azetidine-3,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, 6''-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-1-(2-oxo-2-phenyl-112-ethyl)-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 1-(aminomethyl)-N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropane-1-carboxamide, (1R,5S,6R)-N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide, N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)-2-azaspiro[3.3]heptane-6-carboxamide, 2-methyl-N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)-2-azaspiro[3.3]heptane-6-carboxamide, (1R,5S,6R)-3-methyl-N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide, N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)-1-(methylsulfonamidomethyl)cyclopropane-1-carboxamide, 1-((dimethylamino)methyl)-N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-a]pyridin]-6″-yl)amino)pyrimidin-4-yl)cyclopropane-1-carboxamide, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[aziridine-2,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclopentane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclopentane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-3,3-difluoro-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopentane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclobutane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclohexane-1,1'-cyclobutane-3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, ethyl 6''-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-2-carboxylate, tert-butyl (6''-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-2-yl)carbamate, N-(6-((2,2-difluoro-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide, 6''-((6-aminopyrimidin-4-yl)amino)-2,2-difluoro-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cycloheptane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione, 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-2'-ene-1'',5''-dione, or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof.

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