Substituted imidazopyrazine compounds as IRAK3 binding agents

Abstract

Provided herein are compounds and compositions thereof that bind to IRAK3.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 391,972, filed July 25, 2022, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE DISCLOSURE The present disclosure relates generally to compounds and compositions, and methods for their preparation and use to bind IRAK3. [Background technology]

[0003] The recruitment of immune cells to the site of injury involves the coordinated interaction of multiple soluble mediators. Several cytokines, including interleukin-1 (IL-1), appear to play important roles in these processes. IL-1 triggers proinflammatory responses and is involved in the tissue degeneration seen in chronic inflammatory states. IL-1 is also involved in the process of bone resorption and the regulation of adipose tissue. Thus, IL-1 plays an important role in many pathologies, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, cancer, and sepsis.

[0004] Treatment of cells with IL-1 induces the formation of a complex consisting of two IL-1 receptor chains, IL-1R1 and IL-1RAcP. The resulting heterodimer recruits an adaptor molecule called MyD88 and binds to IL-1 receptor-associated kinases (IRAKs) (Wesche et al., J. Biol. Chem. 1999, 274, 19403-19410; O'Neill et al., J. Leukoc. Biol. 1998, 63, 650-657; Auron, Cytokine Growth Factor Rev. 1998, 9:221-237; and O'Neill, Biochem. Soc. Trans. 2000, 28, 557-563). Four members of the IRAK family have been identified: IRAK1, IRAK2, IRAK3, and IRAK4. These proteins are characterized by a typical N-terminal death domain and a centrally located kinase domain that mediates interactions with adaptor proteins of the MyD88 family. Among the four members of the mammalian IRAK family, IRAK2 and IRAK3 are thought to be catalytically inactive pseudokinases (Wesche et al., J. Biol. Chem. 1999, 274, 19403-19410), but the detailed roles of these two kinases remain largely unknown (Lagne et al., Structure 2021, 29, 238-251). However, IRAK3 has been reported to be involved in the negative regulation of TLR (toll-like receptor) signaling, which is involved in microbial detection and infection prevention in multicellular organisms. Furthermore, recent studies have revealed that IRAK3 mutations and high expression levels are associated with various diseases, including asthma and cancer (Balaci et al., J. Hum. Genet. 2007, 80 (6), 1103-1114; Kesselring et al., Cancer Cell 2016, 29 (5), 685-696), suggesting the potential of IRAK3 as a drug target and the need for small molecule compounds that bind to IRAK3.

[0005] Thus, in one embodiment, provided herein are compounds that bind to IRAK3.

[0006] (Summary of the Invention) Described herein are compounds and compositions thereof that bind to IRAK3 in certain embodiments. In various embodiments, the compounds and compositions thereof can be used to treat inflammatory diseases, autoimmune diseases or cancer.

[0007] The present embodiments may be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments.

[0008] Embodiment A1. Formula (I): [ka] [In the formula, Ring A is C6-C 10 aryl or 5-6 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; R 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein said aryl and cycloalkyl are optionally substituted by 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN; W is NR 2 or CR 3a R 3b and; R 2 is H, C-C alkyl, C-C haloalkyl, or —C(O)(C-C alkyl); R 3a and R 3b are independently H, C-C alkyl, C-C haloalkyl, C-C alkoxy, or —C(O)(C-C alkyl); and X is CH or N. or a pharmaceutically acceptable salt thereof.

[0009] Embodiment A2. Ring A is C6-C 10 A compound according to embodiment A1, or a pharmaceutically acceptable salt thereof, wherein: R is aryl.

[0010] Embodiment A3. A compound according to embodiment A1, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 6-membered heteroaryl, said heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0011] Embodiment A4. Ring A is [ka] or a pharmaceutically acceptable salt thereof.

[0012] Embodiment A5.R 1 A compound according to any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof, wherein is H.

[0013] Embodiment A6.R 1 or a pharmaceutically acceptable salt thereof.

[0014] Embodiment A7.R 1 is C3-C6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0015] Embodiment A8.R 1 is optionally substituted by 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN;10 The compound of any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof, wherein: R is aryl.

[0016] Embodiment A9.R 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0017] Embodiment A10. R 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0018] Embodiment A11. W is NR 2 or CR 3a R 3b and; R 2 is H, C1-C6 alkyl, or —C(O)(C1-C3 alkyl); and R 3a and R 3b is independently H, C1-C3 alkyl, or —C(O)(C1-C6 alkyl); A compound according to any one of embodiments A1 to A10, or a pharmaceutically acceptable salt thereof.

[0019] Embodiment A12. W is NR 2 and R 2 The compound according to embodiment A11, wherein is H, C1-C6 alkyl, or -C(O)(C1-C3 alkyl), or a pharmaceutically acceptable salt thereof.

[0020] Embodiment A13. A compound according to any one of Embodiments A1-A10, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0021] Embodiment A14. A compound according to any one of Embodiments A1-A10, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0022] Embodiment A15. [ka] but [ka] or a pharmaceutically acceptable salt thereof.

[0023] Embodiment A16. [ka] but [ka] or a pharmaceutically acceptable salt thereof.

[0024] Embodiment A17. The compound has the formula (II): [ka] wherein ring A is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. or Formula (III): [ka] or a pharmaceutically acceptable salt thereof.

[0025] Embodiment A18. A compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0026] Embodiment A19. A pharmaceutical composition comprising a compound according to any one of Embodiments A1-A18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0027] A method for binding interleukin-1 receptor-associated kinase 3 (IRAK3), comprising contacting IRAK3 with an effective amount of a compound according to any one of Embodiments A1 to A18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment A19.

[0028] (definition) As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" are intended to specify the presence of the stated features or components as referred to, but do not exclude the presence or additional of one or more features, components, or groups thereof. Furthermore, the terms "comprising" and "including" are also intended to include examples encompassed by the term "consisting of." Consequently, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0029] The term "consisting of" means that an object has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components that make up the object. In other embodiments, the term "consisting of" excludes from the scope of the subsequent description other features or components, except those that are not essential to the technical effect being achieved.

[0030] As used herein, the term "or" is to be interpreted as an inclusive "or" meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C."

[0031] In the present description, any concentration range, percentage range, percentage range, or integer range is understood to include any integer within the stated range, and, where appropriate, fractions thereof (such as tenths and hundredths of integers), unless otherwise indicated. Also, any numerical ranges recited herein for any physical characteristic, such as polymer subunits, size, or thickness, are understood to include every integer within the recited range, unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the stated range, value, or structure, unless otherwise indicated.

[0032] An "alkyl" group is an alkyl group containing 1 to 10 carbon atoms (C1-C 10

[0023] An alkyl group is a saturated, partially saturated, or unsaturated, straight- or branched-chain acyclic hydrocarbon, typically having 1 to 8 carbon atoms (C-C alkyl), or in some embodiments, 1 to 6 carbon atoms (C-C alkyl), 1 to 4 carbon atoms (C-C alkyl), 1 to 3 carbon atoms (C-C alkyl), or 2 to 6 carbon atoms (C-C alkyl). In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also referred to as an alkenyl or alkynyl group. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH, -C(CH)=CH, -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH). Alkyl groups can be substituted or unsubstituted.When alkyl groups described herein are said to be "substituted," they are meant to include any substituents found in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkyl and optionally substituted with alkylamino, aralkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.In certain embodiments, when alkyl groups described herein are referred to as "substituted," they can be substituted with any of the substituents found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonic acid; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0033] A "cycloalkyl" group refers to a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms (C3-C6) having a single ring or multiple fused or bridged rings, which may be optionally substituted. 10In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), while in other embodiments, the number of ring carbon atoms ranges from 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl), or 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. Examples of saturated cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, or multiple ring or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, and the like. The cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol.

[0034] "Heterocyclyl" refers to a non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are replaced with a heteroatom independently selected from O, S, and N. In some embodiments, heterocyclyl groups contain 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyl groups can also be attached to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). Heterocycloalkyl groups can be substituted or unsubstituted. Heterocyclyl groups encompass saturated and partially saturated ring systems. Furthermore, the term heterocyclyl is intended to encompass non-aromatic rings containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of attachment to the rest of the molecule. The term also includes bridged polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4 dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be mono- or di-substituted, including, but not limited to, pyridyl or morpholinyl groups that are di-, tri-, tetra-, pentad or hexa-substituted or di-substituted with various substituents such as those listed below.

[0035] An "aryl" group is an aromatic carbocyclic group (C6-C8) having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) and having 6 to 14 carbon atoms. 14In certain embodiments, an aryl group has 6 to 14 carbon atoms (C6-C8) in the ring portion of the aryl group. 14 aryl), and in other embodiments, 6 to 12 carbon atoms (C-C 12 aryl) or 6 to 10 carbon atoms (C6-C 10 Also included are groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl). Particular aryls include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl).

[0036] A "heteroaryl" group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, with the remaining atoms being carbon atoms. In certain embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in other embodiments, 6 to 9, or even 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azaindolyl), Heteroaryl groups include, but are not limited to, benzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4 dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be substituted or unsubstituted.

[0037] "Halogen" or "halo" means fluorine, chlorine, bromine or iodine.

[0038] An "alkoxy" group is an --O-(alkyl), where alkyl is defined above.

[0039] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo groups, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms and is substituted with one or more halo groups (C-C haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halo groups (C-C haloalkyl). The halo groups may all be the same or different. Unless otherwise specified, the haloalkyl group is optionally substituted.

[0040] With the exception of alkyl groups, when groups described herein are said to be "substituted," they may be substituted with any suitable substituent. Exemplary substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH), O(alkyl)aminocarbonyl; monocyclic or fused or unfused rings. cycloalkyl, which may be monocyclic or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0041] Embodiments of the present disclosure are meant to include pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein (e.g., compounds of Formula (I)).

[0042] As used herein, the term " pharmaceutically acceptable salts " refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, metal salts derived from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts derived from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloride, isethionic acid, lactate, maleic acid, malate, mandelate, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Specific examples of salts include hydrochloride, formate, and mesylate. Others are well known in the art, see, e.g., Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).

[0043] As used herein, unless otherwise specified, the terms "stereoisomer" or "stereoisomerically pure" refer to one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound is one that contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound; one that contains more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound; one that contains more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound; or one that contains more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound. The compounds disclosed herein contain chiral centers and can exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

[0044] The use of stereoisomerically pure forms of the compounds disclosed herein, as well as mixtures of those forms, are encompassed within the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of the enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or separated using standard techniques, such as chiral columns or chiral resolving agents. For example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); See Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0045] It should also be noted that the compounds disclosed herein can include E isomers and Z isomers or mixtures thereof, and cis and trans isomers or mixtures thereof.In certain embodiments, the compound is isolated as either E isomers or Z isomers.In other embodiments, the compound is a mixture of E isomers and Z isomers.

[0046] "Tautomers" are isomers of a compound that exist in equilibrium with one another. The concentration of the isomers may vary depending on the environment in which the compound is found, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomers, which are referred to as tautomers of each other: [ka] .

[0047] As will be readily understood by one of ordinary skill in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the present disclosure.

[0048] It should also be noted that the compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), sulfur 35( 35 S) or carbon 14 ( 14 It can be radiolabeled with a radioisotope such as C) or deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15The compound may be isotopically enriched, such as with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 120, 121, 132, 143, 144, 150, 151, 162, 173, 184, 190, 191, 192, 193, 194, 195, 196, 197, As used herein, "deuterated" means that at least one hydrogen (H) is replaced with a deuterium (D or 2 H), i.e., compounds enriched with deuterium in at least one position.

[0049] Regardless of stereoisomeric or isotopic composition, it is understood that each compound disclosed herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein.Similarly, it is understood that the isotopic composition can vary independently from the stereoisomeric composition of each compound mentioned herein.Furthermore, the isotopic composition is limited to the elements present in each compound disclosed herein or its salt, or can vary independently from the selection of the pharmaceutically acceptable salt of each compound.

[0050] It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure shall take precedence.

[0051] As used herein, " treatment " refers to the total or partial alleviation of disorder, disease or condition, or one or more symptoms related to disorder, disease or condition, or the reduction or stop of the further progression or worsening of these symptoms, or the alleviation or eradication of the cause of disorder, disease or condition itself.In one embodiment, disorder is neurodegenerative disease as described herein or its symptoms.

[0052] As used herein, "prevention" refers to a method of delaying and / or preventing the onset, recurrence, or spread of a disorder, disease, or condition, in whole or in part, a method of preventing a subject from acquiring a disorder, disease, or condition, or a method of reducing the risk of a subject acquiring a disorder, disease, or condition. In one embodiment, the disorder is a neurodegenerative disease or symptom thereof as described herein.

[0053] The term "effective amount" in reference to a compound disclosed herein means an amount capable of treating or preventing a disorder, disease or condition disclosed herein, or a symptom thereof.

[0054] As used herein, the term "subject" or "patient" includes animals, including but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, which in one embodiment are mammals, and in another embodiment are humans. In one embodiment, the subject is a human having or at risk of having an IRAK3-mediated disease or symptom thereof.

[0055] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein for clarity in the context of separate embodiments, the invention may also be practiced in a single embodiment.

[0056] compound In one aspect, provided herein is a compound of formula (I): [ka] [In the formula, Ring A is C6-C 10 aryl or 5-6 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; R 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein said aryl and cycloalkyl are optionally substituted by 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN; W is NR 2 or CR 3a R 3b and; R 2 is H, C-C alkyl, C-C haloalkyl, or —C(O)(C-C alkyl); R 3a and R 3b are independently H, C-C alkyl, C-C haloalkyl, C-C alkoxy, or —C(O)(C-C alkyl); and X is CH or N. or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, ring A is C6-C 10 In some embodiments, ring A is a C6-C6 aryl or a 5- to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. 10In some embodiments, ring A is aryl or 5- or 6-membered heteroaryl, wherein the heteroaryl contains 2-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is phenyl or 5-membered heteroaryl, wherein the heteroaryl contains 2-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is phenyl. In some embodiments, ring A is 5-membered heteroaryl containing 2-3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0058] In some embodiments, ring A is C6-C 10 In some embodiments, ring A is C aryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is C 10 In some embodiments, Ring A is aryl. In some embodiments, Ring A is naphthyl. In some embodiments, Ring A is [ka] In some embodiments, ring A is [ka] is.

[0059] In some embodiments, ring A is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl containing 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl containing 2 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl containing 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered heteroaryl containing 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered heteroaryl containing 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, ring A is a 5-membered heteroaryl containing 3 nitrogen atoms. In some embodiments, ring A is a 5-membered heteroaryl containing one nitrogen atom and one sulfur atom. In some embodiments, ring A is a 5-membered heteroaryl containing one nitrogen atom and one oxygen atom. In some embodiments, ring A is pyrrolyl, pyrazolyl, triazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, or thiadiazolyl. In some embodiments, ring A is a 6-membered heteroaryl containing one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 6-membered heteroaryl containing two to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 6-membered heteroaryl containing two heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 6-membered heteroaryl containing three heteroatoms selected from nitrogen, oxygen, and sulfur.In some embodiments, ring A is a 6-membered heteroaryl containing two nitrogen atoms. In some embodiments, ring A is a 6-membered heteroaryl containing three nitrogen atoms. In some embodiments, ring A is a 6-membered heteroaryl containing one nitrogen atom and one sulfur atom. In some embodiments, ring A is a 6-membered heteroaryl containing one nitrogen atom and one oxygen atom. In some embodiments, ring A is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl. In some embodiments, ring A is. [ka] is.

[0060] In some embodiments, R 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN. 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein said aryl and cycloalkyl are optionally substituted with five substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein said aryl and cycloalkyl are optionally substituted with four substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 H, C6-C 10aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein said aryl and cycloalkyl are optionally substituted with three substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein said aryl and cycloalkyl are optionally substituted with two substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with one substituent selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein said aryl and cycloalkyl are optionally substituted with three substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. 1 H, C6-C10 aryl or C3-C6 cycloalkyl, wherein said aryl and cycloalkyl are optionally substituted with two substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein said aryl and cycloalkyl are optionally substituted with one substituent selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is H, phenyl, or cyclohexyl, wherein said phenyl and cyclohexyl are optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is H, phenyl, or cyclohexyl, wherein said phenyl and cyclohexyl are optionally substituted with three substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 1 is H, phenyl, or cyclohexyl, wherein said phenyl and cyclohexyl are optionally substituted with two substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 1 is H, phenyl, or cyclohexyl, wherein said phenyl and cyclohexyl are optionally substituted with one substituent selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. In some embodiments, R 1is H, phenyl, or cyclohexyl, wherein said phenyl and cyclohexyl are optionally substituted with one substituent selected from propyl, ethyl, methyl, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, -CH2F, -OCH2CH2CH3, -OCH2CH3, -OCH3, halo, -OH, and -CN. 1 is H, phenyl, or cyclohexyl, wherein said phenyl and cyclohexyl are optionally substituted with one substituent selected from methyl, —CF, —CHF, —CHF, —OCH, halo, —OH, and —CN. In some embodiments, R 1 is H, phenyl, or cyclohexyl, wherein said phenyl and cyclohexyl are optionally substituted with methyl. In some embodiments, R 1 is H. In some embodiments, R 1 is phenyl optionally substituted with methyl. In some embodiments, R 1 is cyclohexyl optionally substituted with methyl. In some embodiments, R 1 is cyclohexyl.

[0061] In some embodiments, R 1 is H.

[0062] In some embodiments, R 1 is a C6-C alkyl group optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN; 10 In some embodiments, R 1 is a C-C alkyl group optionally substituted by five substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN; 10In some embodiments, R 1 is a C-C alkyl group optionally substituted by four substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN; 10 In some embodiments, R 1 is a C6-C alkyl group optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN; 10 In some embodiments, R 1 is a C-C alkyl group optionally substituted by three substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN; 10 In some embodiments, R 1 is a C-C alkyl group optionally substituted by two substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN; 10 In some embodiments, R 1 is a C-C alkyl group optionally substituted by one substituent selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN; 10 In some embodiments, R 1 is a C6-C alkyl group optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN; 10 In some embodiments, R 1 is a C-C alkyl group optionally substituted by three substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN; 10 In some embodiments, R 1is a C6-C alkyl group optionally substituted by two substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN; 10 In some embodiments, R 1 is a C-C alkyl group optionally substituted by one substituent selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN; 10 In some embodiments, R 1 is phenyl optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is phenyl optionally substituted with two substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. 1 is phenyl optionally substituted with one substituent selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. 1 is phenyl optionally substituted with one substituent selected from propyl, ethyl, methyl, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, -CH2F, -OCH2CH2CH3, -OCH2CH3, -OCH3, halo, -OH, and -CN. 1 is phenyl optionally substituted with one substituent selected from methyl, —CF, —CHF, —CHF, —OCH, halo, —OH, and —CN. In some embodiments, R 1 is phenyl optionally substituted with methyl. In some embodiments, R 1 teeth, [ka] is.

[0063] In some embodiments, R 1 is C3-C6 cycloalkyl optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is cyclopropyl optionally substituted with 1 to 5 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, —OH, and —CN. In some embodiments, R 1 is cyclobutyl optionally substituted with 1 to 5 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, —OH, and —CN. In some embodiments, R 1 is cyclopentyl optionally substituted with 1 to 5 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, —OH, and —CN. In some embodiments, R 1 is cyclohexyl optionally substituted with 1 to 5 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, —OH, and —CN. In some embodiments, R 1 is C-C cycloalkyl optionally substituted with 5 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, —OH, and —CN. In some embodiments, R 1 is C-C cycloalkyl optionally substituted with four substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, —OH, and —CN. In some embodiments, R 1is C3-C6 cycloalkyl optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is C-C cycloalkyl optionally substituted with three substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is C-C cycloalkyl optionally substituted with two substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, —OH, and —CN. In some embodiments, R 1 is C-C cycloalkyl optionally substituted with one substituent selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is C3-C6 cycloalkyl optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is C-C cycloalkyl optionally substituted with three substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 1 is C-C cycloalkyl optionally substituted with two substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is C-C cycloalkyl optionally substituted with one substituent selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, R 1is cyclohexyl optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is cyclohexyl optionally substituted with three substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is cyclohexyl optionally substituted with two substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is cyclohexyl optionally substituted with one substituent selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, R 1 is cyclohexyl optionally substituted with one substituent selected from propyl, ethyl, methyl, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, -CH2F, -OCH2CH2CH3, -OCH2CH3, -OCH3, halo, -OH, and -CN. 1 is cyclohexyl optionally substituted with one substituent selected from methyl, —CF, —CHF, —CHF, —OCH, halo, —OH, and —CN. In some embodiments, R 1 is cyclohexyl optionally substituted with methyl. In some embodiments, R 1 is unsubstituted cyclohexyl. In some embodiments, R 1 teeth, [ka] is.

[0064] In some embodiments, W is NR 2 or CR 3a R 3b In some embodiments, W is NR 2 In some embodiments, W is CR 3a R 3b is.

[0065] In some embodiments, R 2 is H, C-C alkyl, C-C haloalkyl, C-C alkoxy, or —C(O)(C-C alkyl). In some embodiments, R 2 is H, C-C alkyl, C-C haloalkyl, C-C alkoxy, or —C(O)(C-C alkyl). 2 is H, methyl, ethyl, propyl, butyl, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, -CH2F, -OCH2CH2CH3, -OCH2CH3, -OCH3, -C(O)(CH3), -C(O)(CH2CH3), or -C(O)(CH2CH2CH3). In some embodiments, R 2 is , H, butyl, or —C(O)(CHCHCH). In some embodiments, R 2 is H. In some embodiments, R 2 is butyl. In some embodiments, R 2 is -C(O)(CH2CH2CH3).

[0066] In some embodiments, R 2 is H.

[0067] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C4 alkyl. In some embodiments, R 2is methyl, ethyl, propyl, or butyl. In some embodiments, R 2 is butyl.

[0068] In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is C1-C3 haloalkyl. In some embodiments, R 2 is -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, or -CH2F. In some embodiments, R 2 is -CF3, -CHF2 or -CH2F.

[0069] In some embodiments, R 2 is C1-C6 alkoxy. In some embodiments, R 2 is C1-C3 alkoxy. In some embodiments, R 2 is —OCH2CH2CH3, —OCH2CH3, or —OCH3. In some embodiments, R 2 is -OCH3.

[0070] In some embodiments, R 2 is C(O)(C1-C6 alkyl). In some embodiments, R 2 is —C(O)(C1-C3 alkyl). In some embodiments, R 2 is —C(O)(CH), —C(O)(CHCH), or —C(O)(CHCHCH). In some embodiments, R 2 is -C(O)(CH2CH2CH3).

[0071] In some embodiments, R 3a is H, C-C alkyl, C-C haloalkyl, C-C alkoxy, or —C(O)(C-C alkyl). In some embodiments, R 3ais H, C-C alkyl, C-C haloalkyl, C-C alkoxy, or —C(O)(C-C alkyl). In some embodiments, R 3a is H. In some embodiments, R 3a is butyl, propyl, ethyl, or methyl. In some embodiments, R 3a is -CH2CH2CH2CF3, -CH2CH2CH2CHF2, -CH2CH2CH2CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, or -CH2F. In some embodiments, R 3a is —OCH2CH2CH2CH3, —OCH2CH2CH3, —OCH2CH3 or —OCH3. In some embodiments, R 3a is —C(O)(CH), —C(O)(CHCH), —C(O)(CHCHCH) or —C(O)(CHCHCHCH). In some embodiments, R 3a is H, butyl, -CF3, -CHF2, -CH2F, OCH3 or -C(O)(CH2CH2CH3).

[0072] In some embodiments, R 3b is H, C-C alkyl, C-C haloalkyl, C-C alkoxy, or —C(O)(C-C alkyl). In some embodiments, R 3b is H, C-C alkyl, C-C haloalkyl, C-C alkoxy, or —C(O)(C-C alkyl). In some embodiments, R 3b is H. In some embodiments, R 3b is butyl, propyl, ethyl, or methyl. In some embodiments, R 3bis -CH2CH2CH2CF3, -CH2CH2CH2CHF2, -CH2CH2CH2CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, or -CH2F. In some embodiments, R 3b is -OCH2CH2CH2CH3, -OCH2CH2CH3, -OCH2CH3 or -OCH3 。 In some embodiments, R 3b is —C(O)(CH), —C(O)(CHCH), —C(O)(CHCHCH) or —C(O)(CHCHCHCH). In some embodiments, R 3b is H, butyl, -CF3, -CHF2, -CH2F, OCH3 or -C(O)(CH2CH2CH3).

[0073] In some embodiments, R 3a and R 3b and R are both H. In some embodiments, R 3a is C1-C4 alkyl, and R 3b is H. In some embodiments, R 3a is butyl, propyl, ethyl or methyl, and R 3b is H. In some embodiments, R 3a is butyl, and R 3b is H.

[0074] In some embodiments, X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

[0075] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0076] In some embodiments, the group of formula (I) [ka] teeth, [ka] is.

[0077] In some embodiments, the group of formula (I) [ka] teeth, [ka] is.

[0078] In some embodiments, the compound of Formula (I) is Formula (IA): [ka] [Wherein, rings A, W and R 1 is as described for formula (I). In some variations, ring A is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0079] In some embodiments, the compound of Formula (I) has Formula (IB) or Formula (IC): [ka] [In the formula, rings A, R 1 , R 2 , R 3a and R 3b is as described in formula (I). In some variations, ring A is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0080] In some embodiments, the compound of Formula (I) has the formula (II): [ka] wherein ring A is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. is a compound of

[0081] In some embodiments, the compound of Formula (I) has the formula (III): [ka] (In the formula, R 1 and R 2 is as described for formula (I) is a compound of

[0082] In some embodiments, the compound of Formula (I) has Formula (III-A) or Formula (III-B): [ka] [In the formula, R 1 and R 2 is as described for formula (I). is a compound of

[0083] In the description herein, any description, variation, embodiment or aspect of one site may be combined with any description, variation, embodiment or aspect of another site, and each combination of descriptions is understood to be the same as if it were specifically and individually set forth. For example, R 1 All descriptions, variations, embodiments or aspects provided herein relate to rings A, W, R 2 , R 3a , R 3b and X may be combined in the same manner as if each combination were specifically and individually listed. It will also be understood that all descriptions, variations, embodiments, or aspects of formula (I) apply equally, where applicable, to other formulas detailed herein, with each and every description, variation, embodiment, or aspect being equally described for all formulas as if they were separately and individually listed. For example, all descriptions, variations, embodiments, or aspects of formula (I) apply equally, where applicable, to any of the formulas detailed herein, for example, formulas (IA), (IB), (IC), (II), (III), (III-A), and (III-B), with each description and every description, variation, embodiment, or aspect being the same for all formulas as if they were separately and individually listed.

[0084] In some embodiments, provided is a compound selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof. While certain compounds described in this disclosure, including in Table 1, are depicted as particular stereoisomers and / or non-stereochemical forms, it is understood that any and all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms of the compounds of this disclosure, including in Table 1, are described herein.

[0085] [Table 1-1] [Table 1-2] The compound is a compound of Table 1 above or a pharmaceutically acceptable salt thereof.

[0086] It is understood that combinations of substituents and / or variables of the depicted formulae herein are permissible only if such combinations result in stable compounds.

[0087] Furthermore, all compounds of formula (I) that exist in free base or acid form can be converted into 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 formula (I) can be converted into their free base or acid form by standard techniques.

[0088] Synthesis method The compounds described herein can be prepared using conventional organic synthesis methods and commercially available starting materials, or using the methods provided herein. By way of example and not limitation, compounds of formula (I) can be prepared as outlined in Schemes 1-4, as well as in the Examples described herein. It should be noted that one skilled in the art would know how to modify the methods described in the illustrative Schemes and Examples to obtain the desired products.

[0089] Scheme 1 [ka] wherein Pg is a protecting group; X and ring A are as described for formula (I); and R is 0 to 5 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN.

[0090] As outlined in Scheme 1, compounds of general formula A can be synthesized by coupling intermediate a and intermediate b to generate intermediate C. In some instances, intermediate a and intermediate b can be coupled to form intermediate c using acid- or base-promoted aromatic nucleophilic substitution. Alternatively, intermediate c can be synthesized using a Buchwald-Hartwig cross-coupling (Ruiz-Castillo, P. and Buchwald, SL Chemical Reviews, 116:12564-12649, 2016). Intermediate c can then undergo a Pd-catalyzed Suzuki cross-coupling (Miyaura, N. and Suzuki, A. Chemical Reviews, 95:2457-2483, 1995) with an appropriate boronic acid or ester, followed by acid-promoted deprotection to provide compounds of general formula A. In some cases, preparation of compound A also includes removal of a protecting group (e.g., CBz) using, for example, reductive conditions.

[0091] Scheme 2 [ka] wherein Pg is a protecting group; X and ring A are as described for formula (I); and n is an integer of 1, 2, 3, or 4.

[0092] As outlined in Scheme 2, compounds of general formula B containing cycloalkyl substituents on the imidazopyrazine scaffold can be synthesized by Suzuki cross-coupling of intermediate c and the corresponding alkenylboronic acid pinacol ester (intermediate d) to produce the styrenyl intermediate (e), which can then be subjected to palladium-catalyzed hydrogenation followed by removal of the protecting group to afford compounds of general formula B.

[0093] Scheme 3 [ka] wherein X and ring A are as described for formula (I).

[0094] Compounds of general formula C containing unsubstituted imidazopyrazines can be synthesized from the reduction of the corresponding aryl bromides as outlined in Scheme 3. Treatment of the benzyl carbamate-protected intermediate e with palladium on carbon under a hydrogen gas atmosphere provides the unsubstituted imidazopyrazines exemplified by compounds of general formula C. Scheme 4 [ka] wherein R is 0 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN; R' is C1-C6 alkyl; R'' is C1-C5 alkyl; and X and ring A are as described for formula (I).

[0095] Compounds of general formula A can be further functionalized via amide bond formation or reductive amination to produce compounds of general formula D or E, as outlined in Scheme 4. Treatment of compounds of general formula A with a carboxylic acid, HATU, and DIPEA provides amide-protected derivatives of general formula D. Alkyl-protected compounds of general formula E can be prepared by reacting compounds of general formula A with a suitable reducing agent (e.g., an aldehyde and STAB).

[0096] How to use In some embodiments, provided herein are methods for binding IRAK3 in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound of Formula (I). IRAK3 binding can be assessed and demonstrated by various methods known in the art. Kits and commercially available assays are available for determining whether and to what extent IRAK3 is bound. In some embodiments, the compound of Formula (I) binds to IRAK3 with an IC of at least about 5 nM (IC 50 In some embodiments, a compound of Formula (I) binds to IRAK3 with an affinity of about 0.5 nM, 1 nM, 1.5 nM, 2 nM, 2.5 nM, 3 nM, 3.5 nM, 4 nM, 4.5 nM, or 5 nM. In some embodiments, a compound of Formula (I) binds to IRAK3 with an affinity of about 5 to 10,000 nM, about 10 to 9,000 nM, about 50 to 8,000 nM, about 100 to 7,000 nM, about 200 to 6,000 nM, about 300 to 5,000 nM, about 400 to 4,000 nM, about 500 to 3,000 nM, about 600 to 2,000 nM, about 700 to 1,000 nM, or about 800 to 900 nM. In some embodiments, a compound of Formula (I) binds to IRAK3 with an affinity of about 5-500 nM, 5-400 nM, 5-300 nM, 5-200 nM, or 5-100 nM. In some embodiments, a compound of Formula (I) binds to IRAK3 with an affinity of about 5 nM, 10 nM, 15 nM, 20 nM, 25 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 1000 nM, 1500 nM, 2000 nM, 3000 nM, 4000 nM, 5000 nM, 6000 nM, 7000 nM, 8000 nM, 9000 nM, or 10,000 nM. In any of these embodiments, binding affinity can be determined using the TR-FRET biochemical assay described in Example B1.

[0097] In another aspect, provided herein is a method of binding IRAK3, comprising contacting IRAK3 with an effective amount of a compound of Formula (I) or any embodiment or variation thereof.

[0098] In some embodiments, the compound of formula (I) can be used as the ligand of heterobifunctional degradant.In some embodiments, the compound of formula (I) is used as the ligand for heterobifunctional degradant that targets IRAK3 for degradation.Such heterobifunctional degradant is useful for treating cancer such as bladder cancer, breast cancer, esophageal cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma and gastric cancer.In some embodiments, the heterobifunctional degradant enhances immunity in the subject who receives the vaccine.

[0099] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered orally, topically, or parenterally to a subject in conventional dosage forms such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0100] The compounds disclosed herein can be administered orally, topically, or parenterally to a subject in conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations may contain excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, light The pharmaceutical compositions can be prepared by conventional methods using conventional organic or inorganic additives such as silicic anhydride, talc, sodium lauryl sulfate, flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium hydrogen sulfate, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound of formula (I) in the pharmaceutical composition can be present at a level that exerts the desired effect; for example, in a unit dose for both oral and parenteral administration, it is about 0.005 mg per kg of subject's body weight to about 10 mg per kg of subject's body weight.

[0101] The dose of a compound of Formula (I) administered to a subject can vary widely and be at the discretion of a medical professional. Generally, the compounds disclosed herein can be administered at a dose of about 0.001 mg / kg to about 10 mg / kg of subject body weight, 1 to 4 times daily, although this dosage can be appropriately modified depending on the subject's age, body weight, condition, and route of administration. In one embodiment, the dose is about 0.001 mg / kg to about 5 mg / kg of subject body weight, about 0.01 mg / kg to about 5 mg / kg of subject body weight, about 0.05 mg / kg to about 1 mg / kg of subject body weight, about 0.1 mg / kg to about 0.75 mg, or about 0.25 mg / kg to about 0.5 mg / kg of subject body weight. In one embodiment, the compound is administered once daily. In any case, the amount of a compound of Formula (I) administered will vary depending on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0102] In some embodiments, the compound of Formula (I) is administered to a subject at a dose of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0103] In another embodiment, provided herein is a unit dosage form comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of a compound of Formula (I).

[0104] In certain embodiments, provided herein is a unit dosage form comprising about 0.1 mg or 100 mg of a compound of Formula (I).

[0105] In another embodiment, provided herein is a unit dosage form comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of the compound of Formula (I).

[0106] The compound of formula (I) can be administered once, twice, three times, four or more times daily. In certain embodiments, doses of 100 mg or less are administered as a single dose daily, and doses of more than 100 mg are administered twice daily at half the total daily dose.

[0107] The compound of formula (I) can be conveniently administered orally.In one embodiment, when orally administered, the compound of formula (I) is administered with food and water.In another embodiment, the compound of formula (I) is dispersed in water or juice (for example, apple juice or orange juice) or any other liquid, and is orally administered as solution or suspension.

[0108] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, orally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, or by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is left to the discretion of the health care practitioner and may vary depending on the site of the medical condition.

[0109] In one embodiment, provided herein is a capsule containing a compound of Formula (I) without any additional carriers, excipients, or vehicles.

[0110] In another embodiment, provided herein is a composition comprising an effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle can comprise an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0111] The compositions can take the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, suspensions, etc. The compositions can be formulated to contain a daily dose or an appropriate fraction of a daily dose in a dosage unit, which may be a single tablet or capsule, or a suitable amount of liquid. In one embodiment, the solution is prepared from a water-soluble salt such as a hydrochloride salt. Generally, all compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing the compound of formula (I) with a suitable carrier or diluent and filling the appropriate amount of the mixture into capsules. Typical carriers and diluents include, but are not limited to, inert powdered substances such as many different starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, grain flours, and similar edible powders.

[0112] Tablets can be prepared by direct compression, wet granulation, or dry granulation. The formulation typically includes not only the compound but also diluents, binders, lubricants, and disintegrants. Typical diluents include, for example, various starches, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include starch, gelatin, and sugars (e.g., lactose, fructose, glucose, etc.). Natural and synthetic gums, such as acacia, alginate, methylcellulose, and polyvinylpyrrolidine, are also useful. Polyethylene glycol, ethylcellulose, and waxes can also function as binders.

[0113] Tablets may require lubricants to prevent dyes from adhering to the tablet and tableting equipment. Lubricants can be selected from lubricating solids such as talc, magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when moistened, disintegrating the tablet and releasing the compound. These include starch, clay, cellulose, algins, gums, and the like. More specifically, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose, such as sodium lauryl sulfate, can also be used. Tablets can also be coated with sugars as flavor enhancers or with film-forming protective agents to modify the tablet's dissolution properties. Chewable tablets can also be formulated by using substances such as mannitol in the formulation.

[0114] When a compound of formula (I) is to be administered as a suppository, typical bases can be used. Cocoa butter is a conventional suppository base, which can be modified by adding waxes to slightly raise its melting point. In particular, water-miscible suppository bases containing polyethylene glycols of various molecular weights are widely used.

[0115] The effect of the compound of formula (I) can be delayed or prolonged by appropriate formulation.For example, the compound of formula (I) can be prepared into slowly dissolving pellets and incorporated into tablets or capsules, or as a sustained-release implantable device.This technique also includes preparing pellets with several different dissolution rates and filling a capsule with a mixture of pellets.The tablet or capsule can be coated with a film that is difficult to dissolve for a predictable period of time.Even in parenteral preparations, the compound of formula (I) can be made long-acting by dissolving or suspending it in an oil or emulsifying agent that will slowly disperse in serum.

[0116] Illustrative Examples The present disclosure is further illustrated by the following embodiments, the features of each embodiment may be combined with any of the other embodiments where appropriate and practical.

[0117] Embodiment 1. Formula (I): [ka] [In the formula, Ring A is C6-C 10 aryl or 5-6 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; R 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein said aryl and cycloalkyl are optionally substituted by 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN; W is NR 2 or CR 3a R 3b and; R 2 is H, C-C alkyl, C-C haloalkyl, or —C(O)(C-C alkyl); R 3a and R 3b are independently H, C-C alkyl, C-C haloalkyl, C-C alkoxy, or —C(O)(C-C alkyl); and X is CH or N. or a pharmaceutically acceptable salt thereof.

[0118] Embodiment 2. Ring A is C6-C 10 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein:

[0119] Embodiment 3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- to 6-membered heteroaryl, said heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0120] Embodiment 4. Ring A is [ka] or a pharmaceutically acceptable salt thereof.

[0121] Embodiment 5. Ring A is [ka] or a pharmaceutically acceptable salt thereof.

[0122] Embodiment 6. R 1 or a pharmaceutically acceptable salt thereof.

[0123] Embodiment 7. R 1 is C3-C6 cycloalkyl optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, —OH, and —CN; or a pharmaceutically acceptable salt thereof.

[0124] Embodiment 8. R 1 is C3-C6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0125] Embodiment 9. R 1 is optionally substituted by 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN; 106. The compound according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein:

[0126] Embodiment 10. R 1 C6-C optionally substituted by 1 to 5 substituents selected from C1-C6 alkyl 10 10. The compound of embodiment 9, or a pharmaceutically acceptable salt thereof, wherein:

[0127] Embodiment 11. R 1 C6-C optionally substituted by 1 to 3 substituents selected from C1-C3 alkyl 10 10. The compound of embodiment 9, or a pharmaceutically acceptable salt thereof, wherein:

[0128] Embodiment 12. R 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0129] Embodiment 13. R 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0130] Embodiment 14. W is NR 2 or CR 3a R 3b and; R 2 is H, C1-C6 alkyl, or —C(O)(C1-C3 alkyl); and R 3a and R 3b is independently H, C1-C3 alkyl, or —C(O)(C1-C6 alkyl); 14. A compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof.

[0131] Embodiment 15. W is NR 2 and R 2 is H, C1-C6 alkyl, or —C(O)(C1-C3 alkyl), or a pharmaceutically acceptable salt thereof.

[0132] Embodiment 16. A compound according to any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0133] Embodiment 17. A compound according to any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0134] Embodiment 18. [ka] but [ka] 17. The compound of any one of embodiments 1 to 15 and 16, wherein:

[0135] Embodiment 19. [ka] but [ka] 18. The compound of any one of embodiments 1 to 15 and 17, wherein:

[0136] Embodiment 20. The compound has the formula (II): [ka] and Ring A is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; or a pharmaceutically acceptable salt thereof.

[0137] Embodiment 21. The compound has the formula (III): [ka] 20. The compound of any one of embodiments 1, 2, 4, 6-15, 17, or 19, wherein:

[0138] Embodiment 22. A compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0139] Embodiment 23. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0140] Embodiment 24. A method for binding interleukin-1 receptor-associated kinase 3 (IRAK3), comprising contacting IRAK3 with an effective amount of a compound according to any one of embodiments 1 to 22 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 23. [Example]

[0141] The following examples are offered for illustrative purposes, not limitation. Compounds were named using the automated naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures while adhering to the Cahn-Ingold-Prelog rules of stereochemistry. Those skilled in the art can modify the procedures described in the illustrated examples to arrive at the desired products.

[0142] Salts of the compounds described herein can be prepared by standard methods, such as incorporating an acid (e.g., TFA, formic acid, or HCl) into the mobile phase during chromatographic purification, or stirring the product after chromatographic purification with an acid solution (e.g., aqueous HCl).

[0143] The following abbreviations may be relevant to this application:

[0144] [Table 2-1] [Table 2-2]

[0145] Synthesis Examples Example S1. Synthesis of N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-α]pyrazin-8-amine (1) [ka]

[0146] Synthesis of benzyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate A 40 mL vial containing a stir bar was charged with 6,8-dibromoimidazo[1,2-α]pyrazine (0.89 g, 3.2 mmol) and benzyl 4-(4-aminophenyl)piperazine-1-carboxylate (1.1 equiv., 1.1 g, 3.5 mmol). Next, isopropanol (10.7 mL, 0.3 M) and N,N-diisopropylethylamine (2.0 equiv., 1.1 mL, 6.4 mmol) were added to the vial. The vial was then sealed with a septum and vortexed. The reaction vessel was heated to 65°C and stirred for 72 hours. The reaction vessel was cooled to room temperature. The reaction mixture was poured into water (20 mL) and vortexed. The crude reaction mixture initially contained a brown sludge, which solidified upon thorough mixing with water. The mixture was filtered and the filter cake was washed with water (20 mL) and diethyl ether (20 mL). The resulting solid was collected and dried under high vacuum to give the product, benzyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (1.37 g, 2.7 mmol, 84% yield) as a light brown solid. LC / MS Method 2: MS (ESI) [M+H]+ 508.4, rt: 1.71 min

[0147] Synthesis of N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-α]pyrazin-8-amine To a 20 mL vial containing benzyl 4-[4-[(6-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (50.0 mg, 0.099 mmol) was added 10% Pd / C (10.5 mg, 10 mol%). A stir bar was then added, and the vial was sealed with a septa cap. The solid was suspended in methanol (1.0 mL, 0.1 M). The vial was then evacuated and refilled with a balloon containing H. This process was repeated five times. The reaction mixture was then stirred at 22 °C for 72 h. The vial was purged with N to remove traces of H. The crude reaction mixture was filtered through a plug of Celite and carefully washed with excess methanol. LCMS analysis of the crude reaction mixture confirmed partial conversion of the starting material to the desired product. The filtrate was then concentrated and purified by reverse-phase column chromatography (5% to 100% water in MeCN containing 0.1% TFA) to give the product N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-α]pyrazin-8-amine (40 mg, 0.0985 mmol, 98% yield) as a yellow solid after lyophilization. LC / MS Method 2: MS (ESI) [M+H] + 295.4, rt: 0.18 min. 1 H NMR (400 MHz, methanol-d4) δ ppm 3.32 - 3.43 (m, 4 H) 3.45 - 3.54 (m, 4 H) 7.15 (d, J = 5.5 Hz, 1 H) 7.17 - 7.23 (m, 2 H) 7.50 (d, J = 8.1 Hz, 2 H) 7.83 (s, 1 H) 7.99 (d, J=5.4 Hz, 1 H) 8.07 (d, J=1.0 Hz, 1 H).

[0148] Example S2. Synthesis of 5-phenyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-α]pyrazin-8-amine (2) [ka] Synthesis of tert-butyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate tert-Butyl 4-(4-aminophenyl)piperazine-1-carboxylate (604.3 mg, 2.18 mmol) and DIPEA (0.38 mL, 2.18 mmol) were added to a solution of 5,8-dibromoimidazo[1,2-α]pyrazine (402.2 mg, 1.45 mmol) in ethanol (2.69 mL). The reaction mixture was heated to 80 °C and stirred overnight. LCMS showed 94% conversion, so the reaction was stopped. The ethanol was removed in vacuo, and the product was taken up in DCM. The resulting solution was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by reverse-phase column chromatography (5% to 100% MeOH in water with 0.1% formic acid) to give the desired product, tert-butyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (443 mg, 0.935 mmol, 64% yield). LC / MS Method 1: MS (ESI) [M]+ 473.2, rt: 1.479 min.

[0149] Synthesis of tert-butyl 4-(4-((5-phenylimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate tert-Butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (80.0 mg, 0.1700 mmol), phenylboronic acid (24.73 mg, 0.20 mmol), 1,4-dioxane (3.5 mL), and saturated aqueous NaHCO3 (1.0 mL, 0.170 mmol) were placed in a sealed vial. The solution was sparged with nitrogen for 5 minutes, after which Pd(PPh3)4 (9.76 mg, 0.010 mmol) was added, and the mixture was sparged with nitrogen for 5 minutes. The solution was heated at 95 °C for 16 hours. The next day, the solution turned orange. TLC analysis (eluting with 40% EtOAc / heptane three times) indicated the reaction was not complete, so an additional 0.05 eq of Pd(PPh3)4 was added and the reaction mixture was stirred at 95 °C for an additional 4 h. The reaction was stopped, quenched with water, and extracted with EtOAc (2x). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by reverse-phase column chromatography (0% to 100% MeOH in water with 0.1% formic acid) to give the desired product, tert-butyl 4-(4-((5-phenylimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (58.7 mg, 0.124 mmol, 73% yield) as a brown solid. LC / MS Method 1: MS (ESI) [M+H]+ 471.4, rt: 1.454 min

[0150] Synthesis of 5-phenyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-α]pyrazin-8-amine To a solution of tert-butyl 4-[4-[(5-phenylimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (58.7 mg, 0.120 mmol) in methanol (1.2474 mL) was added HCl / dioxane (477.23 μL, 1.91 mmol) at room temperature. The resulting solution was stirred at room temperature for 3 hours and 30 minutes. The mixture was concentrated on a rotovap, and the residue was purified by reverse-phase column chromatography (5% to 100% MeOH in water with 0.1% formic acid) to give the product as an impure yellow oil. This oil was purified again by reverse-phase column chromatography (5% to 100% MeOH in water at pH 10) to give the product, 5-phenyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-α]pyrazin-8-amine (17.2 mg, 0.046 mmol, 37% yield) as a yellow solid after lyophilization. MS (ESI) [M+H] + 371.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.78 - 2.89 (m, 4 H), 2.93 - 3.06 (m, 4 H), 3.30 - 3.32 (m, 1 H), 6.91 (br d, J = 8.9 Hz, 2 H), 7.41 (s, 1 H), 7.49 - 7.62 (m, 3 H), 7.64 - 7.72 (m, 3 H), 7.83 - 7.92 (m, 3 H), 9.41 (s, 1 H).

[0151] Example S3. Synthesis of 5-cyclohexyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-α]pyrazin-8-amine (3) [ka] Synthesis of tert-butyl 4-(4-((5-(cyclohexyl-1-en-1-yl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate A 0.5-2 mL microwave reaction tube equipped with a stir bar was charged with tert-8-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (75 mg, 0.16 mmol), cyclohexen-1-ylboron (39.9 mg, 0.32 mmol), XPhos-Pd-G3 (10.0 mg, 0.012 mmol), and Xphos (5.7 mg, 0.012 mmol). The reaction vessel was sealed with a septum and purged with nitrogen. 1,4-Dioxane (0.8 mL, 0.2 M) and 2 M aqueous sodium carbonate (240 μL, 0.295 mmol) were then added to the reaction vessel via syringe. The reaction vessel was then sealed with a microwave cap and vortexed. The vessel was heated under microwave irradiation at 135°C for 45 minutes. After this time, the reaction mixture was cooled to 22°C and filtered through Celite. The filter cake was washed with methanol. LCMS analysis of the crude reaction mixture confirmed the formation of the desired product. The reaction mixture was then concentrated and purified by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA). The fractions were then concentrated and dried in vacuo to afford the product, tert-butyl 4-(4-((5-(cyclohexyl-1-en-1-yl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (60.7 mg, 0.128 mmol, 80% yield) as an off-white solid. LC / MS Method 2: MS (ESI) [M+H] + 475.4, rt:1.76 minutes

[0152] Synthesis of 5-cyclohexyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-α]pyrazin-8-amine tert-Butyl 4-[4-[[5-(cyclohexen-1-yl)imidazo[1,2-α]pyrazin-8-yl]amino]phenyl]piperazine-1-carboxylate (39.7 mg, 0.084 mmol) and palladium hydroxide powder on carbon (6.0 mg, 10 mol%) were added to a 20 mL vial containing a stir bar. Methanol (0.03 M, 2.8 mL) was then added, and the vial was sealed with a septa cap. The reaction vessel was then evacuated and refilled with hydrogen (3x). The reaction mixture was stirred under a hydrogen atmosphere overnight. The next morning, the reaction mixture was filtered through a pad of Celite and washed with methanol. LCMS analysis of the crude reaction mixture confirmed the formation of the desired product, with a trace of the unsaturated isomer remaining. The reaction mixture was purified by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA). The collected fractions were concentrated and immediately treated with 1:1 TFA / DCM. LCMS analysis of the crude reaction mixture confirmed complete deprotection of the piperazine. The crude residue was subjected to MS-HPLC (5% to 100% MeCN in water with 0.1% formic acid) to give the product, 5-cyclohexyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-α]pyrazin-8-amine (15.4 mg, 0.041 mmol, 48% yield), as a pale yellow solid after lyophilization. MS (ESI) [M+H] + 371.1. 1 H NMR (400 MHz, methanol-d4) δ ppm 1.45 - 1.63 (m, 4 H) 1.92 (br d, J=12.8 Hz, 2 H) 2.14 (br d, J = 12.1 Hz, 2 H) 2.95 (br t, J = 11.2 Hz, 1 H) 3.37 - 3.48 (m, 8 H) 6.97 (s, 1 H) 7.15 (m, 2 H) 7.57 (m, 2 H) 7.79 (s, 1 H) 8.13 (s, 1 H).

[0153] Example S4. Synthesis of N-(4-(piperazin-1-yl)phenyl)-5-(o-tolyl)imidazo[1,2-α]pyrazin-8-amine (4) [ka] Synthesis of tert-butyl 4-(4-((5-(o-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate A dry, sealed tube was charged with tert-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (110 mg, 0.230 mmol) and o-tolylboronic acid (38.78 mg, 0.290 mmol) at room temperature. 1,4-Dioxane (2.7463 mL) and saturated aqueous NaHCO3 (1.2 mL) were then added, and the mixture was sparged with nitrogen for 20 minutes. Pd(PPh3)4 (13.94 mg, 0.010 mmol) was added in one portion, and nitrogen sparging continued for 10 minutes. The tube was sealed and placed in an oil bath pre-equilibrated to 95 °C for 2 hours. The reaction mixture was then diluted with saturated NaHCO3 (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by reverse-phase column chromatography (5% to 100% MeOH in water with 0.1% formic acid) to give the desired product, tert-butyl 4-(4-((5-(o-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (97 mg, 0.184 mmol, 79% yield) as a brown solid. LC / MS Method 1: MS (ESI) [M+H] 485.4, rt: 1.464 min.

[0154] Synthesis of N-(4-(piperazin-1-yl)phenyl)-5-(o-tolyl)imidazo[1,2-α]pyrazin-8-amine To a solution of tert-butyl 4-[4-[[5-(o-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]phenyl]piperazine-1-carboxylate (97 mg, 0.20 mmol) in methanol (1.2535 mL) was added HCl / dioxane (765.79 μL, 3.06 mmol) at room temperature. The resulting solution was stirred at room temperature. After 4 h, HPLC analysis confirmed approximately 95% conversion. After stirring the solution for an additional 1 h, the resulting suspension was concentrated on a rotovap, and the residue was purified by reverse-phase column chromatography (5% to 100% MeOH in water with 0.1% formic acid) to give the product as a pale yellow solid containing some impurities. This material was purified again by reverse-phase column chromatography (5% to 100% MeOH / water, pH 10) to give the product, N-(4-(piperazin-1-yl)phenyl)-5-(o-tolyl)imidazo[1,2-α]pyrazin-8-amine (19.6 mg, 0.05 mmol, 25% yield) as an off-white solid after lyophilization. [M+H] + 385.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.13 (s, 3 H), 2.52 - 2.55 (m, 1 H), 2.80 - 2.88 (m, 4 H), 2.96 - 3.04 (m, 4 H), 6.91 (d, J = 9.0 Hz, 2 H),7.29 (s, 2 H), 7.34 - 7.50 (m, 4 H), 7.60 (s, 1 H), 7.87 (d, J = 9.0 Hz, 2 H), 9.38 (s, 1 H).

[0155] Example S5. Synthesis of N-(4-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (5) [ka] Synthesis of tert-butyl 4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate A mixture of 2M aqueous Na2CO3 (1.01 mL, 2.03 mmol) and m-tolylboronic acid (91.91 mg, 0.680 mmol) in 1,4-dioxane (5 mL) and tert-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (320 mg, 0.680 mmol) was flushed with N2 in a microwave vial for 10 min. Pd(Ph3P)4 (78.12 mg, 0.070 mmol) was then added, and the suspension was flushed with nitrogen for another 10 min. The reaction mixture was heated to 100 °C and irradiated in a microwave reactor for 1 h. The reaction mixture was then partitioned between EtOAc / HO and extracted with EtOAc (2x). The organic layer was washed with HO, brine, and dried over Na2SO4. The reaction mixture was concentrated directly onto silica gel and purified by normal phase chromatography (30% to 100% EtOAc in heptane) to afford tert-butyl 4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (80% purity, 198 mg, 0.327 mmol, 48% yield) as an orange solid. LC / MS Method 1: MS (ESI) [M+H]+ 485.4, rt: 1.504 min

[0156] Synthesis of N-(4-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine A rt solution of tert-butyl 4-[4-[[5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]phenyl]piperazine-1-carboxylate (580 mg, 1.2 mmol) in DCM (5 mL) was treated with TFA (3.0 mL, 11.76 mmol). The reaction mixture was stirred for 4 h. The reaction mixture was concentrated to dryness, taken up in DCM, and washed with saturated aqueous NaHCO3 (1x). The aqueous layer was then back-extracted with DCM (2x), and the combined organic layers were concentrated. The resulting residue was purified by reverse-phase column chromatography (5% to 100% MeCN in water with 0.1% formic acid) to give the product, N-(4-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (256.6 mg, 0.666 mmol, 56% yield), as an orange solid after lyophilization. MS (ESI) [M+H] + = 385.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3 H), 3.23 (br s, 4 H), 3.31 - 3.59 (m, 4 H), 7.10 (d, J = 8.8 Hz, 2 H), 7.38 - 7.43 (m, 1 H), 7.44 - 7.60 (m, 4 H), 7.79 (br d, J = 7.6 Hz, 2H), 8.08 - 8.16 (m, 2 H), 9.34 (br s, 2 H), 10.93 (br s, 1 H).

[0157] Example S6. Synthesis of N-(4-(piperazin-1-yl)phenyl)-5-(p-tolyl)imidazo[1,2-α]pyrazin-8-amine (6) [ka] Synthesis of tert-butyl 4-(4-((5-(p-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate A dried sealed tube was charged with tert-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (64.8 mg, 0.140 mmol) and p-tolylboronic acid (22.6 mg, 0.170 mmol) at room temperature. 1,4-Dioxane (3 mL) and saturated aqueous NaHCO3 (1 mL) were then added, and the mixture was sparged with nitrogen for 8 minutes. Pd(PPh3)4 (8.4 mg, 0.010 mmol) was added in one portion, and nitrogen sparging continued for 10 minutes. The tube was sealed and placed in an oil bath equilibrated to 95 °C. The mixture was heated at that temperature overnight. LCMS analysis confirmed the reaction was complete. The reaction flask was removed from the oil bath, and the mixture was cooled to room temperature. The reaction mixture was diluted with water (5 mL), and the mixture was extracted with EtOAc (10 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by reverse-phase column chromatography (5% to 100% MeOH in water with 0.1% formic acid) to give the product tert-butyl 4-(4-((5-(p-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (57 mg, 0.117 mmol, 86% yield) as an orange solid. LC / MS Method 1: MS (ESI) [M+H]+ 485.4, rt: 1.507 min

[0158] Synthesis of N-(4-(piperazin-1-yl)phenyl)-5-(p-tolyl)imidazo[1,2-α]pyrazin-8-amine To a solution of tert-butyl 4-[4-[[5-(p-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]phenyl]piperazine-1-carboxylate (57.0 mg, 0.120 mmol) in methanol (1 mL) was added HCl / dioxane (450.0 μL, 1.8 mmol) at room temperature. The resulting solution was stirred at room temperature overnight. The next morning, HPLC analysis confirmed the reaction was complete. The reaction mixture was concentrated and purified by reverse-phase column chromatography (5% to 100% MeOH in water with 0.1% formic acid) to give the product as a pale yellow solid containing some impurities. This solid was purified again by reverse-phase column chromatography (5% to 100% MeOH / water with buffer (pH 10)) to give the product, N-(4-(piperazin-1-yl)phenyl)-5-(p-tolyl)imidazo[1,2-α]pyrazin-8-amine (28 mg, 0.074 mmol, 62% yield), as a yellow solid after lyophilization. MS (ESI) [M+H] + = 385.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3 H), 2.52 - 2.53 (m, 1 H), 2.81 - 2.86 (m, 4H), 2.97 - 3.02 (m, 4 H), 6.90 (d, J = 9.3 Hz, 2 H), 7.35 - 7.41 (m, 3 H), 7.57 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 1.0 Hz, 1 H), 7.83 - 7.89 (m, 3 H), 9.37 (s, 1 H).

[0159] Example S7. Synthesis of N-(4-(piperazin-1-yl)phenyl)-6-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (7) [ka] Synthesis of tert-butyl 4-(4-((6-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate 6,8-Dibromoimidazo[1,2-α]pyrazine (1.0 g, 3.6 mmol) and 1-boc-4-(4-aminophenyl)piperazine (1.5 g, 1.5 equiv, 5.4 mmol) were added to a 20 mL vial containing a stir bar. The solid was then dissolved in ethanol (7 mL, 0.5 M) and the vial was sealed with a septa cap. The reaction mixture was stirred for 5 min, after which N,N-diisopropylethylamine (1.3 mL, 2.0 equiv, 7.2 mmol) was added. The reaction mixture was warmed to 80 °C and stirred over the weekend. LCMS analysis of the crude reaction mixture confirmed complete conversion to the desired product. The reaction mixture was concentrated onto silica gel and purified by normal phase column chromatography (0% to 10% MeOH in DCM) to give the product (0.9 g, 1.91 mmol, 53% yield) as a dark yellow solid. LC / MS Method 2: MS (ESI) [M]+ 473.4, rt: 1.68 min

[0160] Synthesis of tert-butyl 4-(4-((6-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate A microwave-safe reaction vessel was charged with tert-butyl 4-[4-[(6-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (80.0 mg, 0.170 mmol) and m-tolylboronic acid (27.66 mg, 0.200 mmol) at room temperature. 1,4-Dioxane (3 mL) and saturated aqueous NaHCO3 (1 mL) were then added, and the mixture was sparged with nitrogen for 5 minutes. Pd(PPh3)4 (11.54 mg, 0.010 mmol) was added in one portion, and nitrogen sparging continued for 5 minutes. The reaction mixture was heated to 100 °C and microwaved for 1 hour. After cooling to room temperature, LCMS confirmed complete conversion to the desired product. The reaction mixture was diluted with water (5 mL), and the mixture was extracted with EtOAc. The phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organics were washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by reverse-phase column chromatography (5% to 100% MeOH in water with 0.1% formic acid) to give the product tert-butyl 4-(4-((6-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (59 mg, mmol, 72% yield) as a pale yellow color. LC / MS Method 1: MS (ESI) [M+H] 485.4, rt: 1.536 min.

[0161] Synthesis of N-(4-(piperazin-1-yl)phenyl)-6-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine To a solution of tert-butyl 4-[4-[[6-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]phenyl]piperazine-1-carboxylate (59.0 mg, 0.120 mmol) in DCM was added 4 M hydrochloric acid / dioxane (0.49 mL, 1.95 mmol) at room temperature. The resulting solution was stirred at room temperature overnight. LCMS confirmed complete conversion. The mixture was concentrated to dryness and dissolved in 25 mL of 1:1 MeOH / DCM. The solution was filtered through a pad of NaHCO3, concentrated, and dried. The crude residue was purified by reverse-phase column chromatography (5% to 100% MeOH in water with 0.1% formic acid) to give the product, N-(4-(piperazin-1-yl)phenyl)-6-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (20.6 mg, 0.054 mmol, 44% yield), as a yellow solid after lyophilization. MS (ESI) [M+H] + 385.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.37 - 2.43 (m, 3 H), 2.51 - 2.54 (m, 1 H), 2.78 - 2.90 (m, 4 H), 2.96 - 3.08 (m, 4 H), 6.95 (d, J = 9.0 Hz, 2 H), 7.19 (d, J = 7.6 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.62 (d, J = 1.0 Hz, 1 H), 7.73 - 7.86 (m, 2 H), 7.91 - 8.04 (m, 3 H), 8.55 (s, 1 H), 9.44 (s, 1 H).

[0162] Example S8. Synthesis of 1-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)butan-1-one (8) [ka] HATU (13.6 mg, 1.0 equiv) was added to a 2 mL vial containing a stir bar. DMF (120 μL, 0.3 M) was then added, followed by butyric acid (3.3 μL, 1.0 equiv). DIPEA (13.2 μL, 4.0 equiv) was then added. The resulting reaction mixture was stirred for approximately 5 minutes, after which N-(4-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine hydrochloride (15 mg, 0.037 mmol) was added. The vial was then capped and stirred overnight at room temperature. LCMS analysis confirmed 66% conversion to the desired product. The reaction mixture was purified by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA) to give the product, 1-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)butan-1-one (8.2 mg, 0.0179 mmol, 50% yield), as a yellow solid after lyophilization. MS (ESI) [M+H] + 455.6. 1 H NMR (400 MHz, methanol-d4) δ ppm 1.00 (t, J=7.4 Hz, 3 H), 1.67 (sxt, J=7.5 Hz, 2 H), 2.42 - 2.48 (m, 5 H), 3.23 - 3.35 (m, 4 H) (overlaps with d4-MeOH), 3.76 (dt, J=10.6, 5.2 Hz, 4 H), 7.07 (s, 1 H), 7.20 (d, J=8.9 Hz, 2 H), 7.41 - 7.52 (m, 6 H), 7.83 (s, 1 H), 7.96 (s, 1 H).

[0163] Example S9. Synthesis of N-(4-(4-butylpiperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (9) [ka] N-(4-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine hydrochloride (15 mg, 0.036 mmol) was added to a 1-dram vial containing a stir bar. DCE (42 μL) was then added, followed by triethylamine (8 μL, 1.5 equiv.). The resulting solution was stirred for approximately 15 minutes. At this point, sodium triacetoxyborohydride (11.3 mg, 1.5 equiv.) was added, followed by 100 μL of a DCE solution containing butyraldehyde (3.2 μL, 1.0 equiv.) and acetic acid (6.2 μL, 3.0 equiv.). The resulting mixture was stirred at room temperature overnight. LCMS analysis of the reaction mixture confirmed approximately 88% conversion to the desired product. The reaction mixture was purified by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA) to give the product, N-(4-(4-butylpiperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (8.1 mg, 0.018 mmol, 51% yield), as a yellow solid after lyophilization. MS (ESI) [M+H] + 441.6. 1 H NMR (400 MHz, methanol-d4) δ ppm 1.03 (t, J=7.4 Hz, 3 H), 1.47 (sxt, J=7.5 Hz, 2 H), 1.73 - 1.83 (m, 2 H), 2.45 (s, 3 H), 3.11 (br d, J=11.5 Hz, 2 H), 3.18 - 3.28 (m, 4 H), 3.70 (br d, J=11.0 Hz, 2 H), 3.90 (br d, J=11.4 Hz, 2 H), 7.17 (d, J=8.9 Hz, 2 H), 7.21 (s, 1 H), 7.38 - 7.50 (m, 4 H), 7.66 (d, J=8.9 Hz, 2 H), 7.76 (s, 1 H), 7.92 (s, 1 H).

[0164] Example S10. Synthesis of N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (10) [ka]

[0165] Synthesis of tert-butyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate 5,8-Dibromoimidazo[1,2-α]pyrazine (500 mg, 1.8 mmol), tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (500 mg, 1.05 equiv.), and pivalic acid (1.8 g, 10 equiv.) were added to a 2.0-5.0 mL microwave-safe reaction tube equipped with a stir bar. The tube was then sealed with a septum and heated at 100 °C under microwave irradiation for 1 h. LCMS analysis of the reaction mixture confirmed complete conversion of the starting material to the desired product (~10% Boc cleavage had occurred). The reaction mixture was then diluted with EtOAc and transferred to a separatory funnel containing saturated aqueous NaHCO3. The organic layer was then removed, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The reaction mixture was then purified by reverse-phase column chromatography (25% to 100% MeCN in water with 0.1% TFA) to give the product tert-butyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (300 mg, 0.642 mmol, 35% yield) as a brown solid. LC / MS Method 2: MS (ESI) [M] 462.3, rt: 1.66 min

[0166] Synthesis of N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine A 0.5-2 mL microwave-safe reaction tube containing a stir bar was charged with tert-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (200 mg, 0.43 mmol), m-tolylboronic acid (120 mg, 2.0 equiv), Xphos (15.5 mg, 7.5 mol%), and XPhos-Pd-G3 (27.5 mg, 7.5 mol%). The reaction vessel was then sealed with a septum and purged with nitrogen. 1,4-Dioxane (2.2 mL, 0.2 M) and 2 M aqueous sodium carbonate (650 μL, 3 equiv) were then added to the reaction vessel via syringe. The reaction vessel was then sealed with a septum cap and vortexed. The vessel was then heated under microwave irradiation at 135°C for 45 minutes. After this time, the reaction mixture was cooled to 22°C and filtered through a pad of Celite. The filter cake was washed with EtOAc. LCMS analysis of the crude reaction mixture confirmed complete conversion of the starting material to the desired product. The reaction mixture was purified by reverse-phase column chromatography (25% to 100% MeCN in water with 0.1% TFA). The fractions were then concentrated and immediately dissolved in 1:1 DCM / TFA and stirred at room temperature for 1 hour. LCMS analysis confirmed complete deprotection to the desired product. The reaction mixture was purified again by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA) to give the product, N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (141 mg, 0.379 mmol, 88% yield), as a pale yellow solid after lyophilization. MS (ESI) [M+H] + 374.5. 1H NMR (400 MHz, methanol-d4) δ ppm 2.27 - 2.41 (m, 4 H), 2.45 (s, 3 H), 3.19 - 3.29 (m, 2 H), 3.59 (br d, J=13.2 Hz, 2 H), 4.60 (tt, J=10.1, 4.8 Hz, 1 H), 7.31 (s, 1 H), 7.39 - 7.51 (m, 4 H), 7.81 (s, 2 H), 7.94 (s, 1 H), 8.24 (s, 1 H).

[0167] Example S11. Synthesis of 4-(piperidin-4-yl)-N-(5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)thiazol-2-amine (11) [ka] Synthesis of tert-butyl 4-(2-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)thiazol-4-yl)piperidine-1-carboxylate 5,8-Dibromoimidazo[1,2-α]pyrazine (200 mg, 0.7200 mmol), tert-butyl 4-(2-aminothiazol-4-yl)piperidine-1-carboxylate (245.61 mg, 0.8700 mmol), sodium tert-butoxide (104.11 mg, 1.08 mmol), Pd2(dba)3 (33.07 mg, 0.0400 mmol), and Xantphos (41.79 mg, 0.070 mmol) were added to a 20 mL vial containing a stir bar. The vial was then sealed with a septum and purged with nitrogen. Toluene (7.2 mL) was then added, and the reaction mixture was sparged with a nitrogen balloon for 2 minutes while sonicating. The reaction vessel was then heated to 100 °C and stirred for 16 hours. The next morning, LCMS analysis confirmed the formation of the desired product. The reaction mixture was filtered, concentrated, and purified by reverse-phase column chromatography. The collected fractions were basified with saturated aqueous sodium bicarbonate and then concentrated. The remaining aqueous mixture was then extracted with EtOAc. The collected organic layers were dried over sodium sulfate and concentrated to give the product, tert-butyl 4-[2-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]thiazol-4-yl]piperidine-1-carboxylate (230 mg, 0.45 mmol, 63.1% yield), as a brown oil. LC / MS Method 2: MS (ESI) [M] 479.3, rt: 1.82 min

[0168] Synthesis of 4-(piperidin-4-yl)-N-(5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)thiazol-2-amine To a 1-dram vial containing a stir bar was added tert-butyl 4-[2-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]thiazol-4-yl]piperidine-1-carboxylate (24.0 mg, 0.050 mmol), m-tolylboronic acid (13.6 mg, 0.10 mmol), potassium phosphate (48.94 mg, 0.1500 mmol), and Pd(dppf)Cl2 (4.24 mg, 0.010 mmol). The reaction vessel was sealed with a septum and purged with nitrogen. 1,4-Dioxane (0.7614 mL) and water (0.0730 mL) were added to the reaction vessel via syringe. The reaction vessel was then sealed with a septum cap and vortexed. The vessel was then heated at 100 °C for 16 h. After this time, the reaction mixture was cooled to 22 °C and filtered through a pad of Celite. The filter cake was washed with EtOAc. LCMS analysis of the crude reaction mixture confirmed complete conversion of the starting material to the desired product. The reaction mixture was then purified by reverse-phase column chromatography (25% to 100% MeCN in water with 0.1% TFA). The fractions were then concentrated and immediately dissolved in 1:1 DCM / TFA and stirred at room temperature for 1 hour. LCMS analysis confirmed complete deprotection to the desired product. The reaction mixture was purified again by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA) to give the product, 4-(piperidin-4-yl)-N-(5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)thiazol-2-amine (8.9 mg, 0.022 mmol, 45% yield), as a pale yellow solid after lyophilization. MS (ESI) [(M+2H) / 2] + 196.5. 1H NMR (400 MHz, methanol-d4) δ ppm 1.90 - 2.03 (m, 2 H), 2.30 (br d, J=12.5 Hz, 2 H), 2.46 (s, 3 H), 3.01 - 3.11 (m, 1 H), 3.11 - 3.21 (m, 2 H), 3.51 (br d, J=12.8 Hz, 2 H), 6.79 (s, 1 H), 7.37 - 7.44 (m, 1 H), 7.47 - 7.54 (m, 3 H), 7.70 (s, 1 H), 7.82 (s, 1 H), 7.97 (s, 1 H).

[0169] Example S12. Synthesis of N-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (12) [ka] Synthesis of tert-butyl 4-(4-amino-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate 4-Nitro-2H-triazole (489.97 mg, 4.3 mmol), t-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1200 mg, 4.3 mmol), and cesium carbonate (2799 mg, 8.59 mmol) were weighed into a 40 mL vial equipped with a stir bar. The reaction vessel was then sealed with a septum, and the solid was suspended in DMF (7.2 mL). The reaction mixture was warmed to 95 °C and stirred overnight. The next morning, cold water (~25 mL) was added to the reaction vessel. The precipitate was filtered, washed with cold water, and then transferred to a 250 mL RBF equipped with a stir bar. 10% palladium on carbon (200 mg, 1.88 mmol) was then added, the flask was capped with a septum, and ethanol (18.8 mL) was added. The vessel was then evacuated and refilled with hydrogen gas three times. The reaction mixture was stirred at room temperature for 4 hours. The vessel was then removed and the flask was purged with nitrogen gas. The mixture was filtered through a pad of Celite, and the filtrate was concentrated. Purification by reverse-phase silica gel chromatography (5% to 100% MeCN in water containing 0.1% ammonium hydroxide) afforded the product, tert-butyl 4-(4-amino-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (220 mg, 0.823 mmol, 19% yield) as a yellow solid. LC / MS Method 2: MS (ESI) [M+Ht-Bu]+ 212.5, rt: 1.29 min

[0170] Synthesis of tert-butyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate 5,8-Dibromoimidazo[1,2-α]pyrazine (200.0 mg, 0.720 mmol), tert-butyl 4-(4-aminotriazol-2-yl)piperidine-1-carboxylate (231.7 mg, 0.870 mmol), sodium tert-butoxide (104.1 mg, 1.08 mmol), Pd(dba) (33.1 mg, 0.040 mmol), and Xantphos (41.8 mg, 0.070 mmol) were added to a 20 mL vial containing a stir bar. The vial was then sealed with a septum and purged with nitrogen. Toluene (7.2 mL) was then added, and the reaction mixture was sparged with a nitrogen balloon for 2 minutes while sonicating. The reaction vessel was then heated to 100 °C and stirred for 16 hours. The next morning, LCMS analysis confirmed the formation of the desired product. The reaction mixture was then filtered, concentrated, and purified by reverse-phase column chromatography (5% to 100% MeCN in water with 0.1% TFA). The collected fractions were basified with saturated sodium bicarbonate and then concentrated. The remaining aqueous mixture was extracted with EtOAc. The collected organic layers were dried over sodium sulfate and concentrated to give the product, tert-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]triazol-2-yl]piperidine-1-carboxylate (158 mg, 0.3069 mmol, 42.5% yield) as a brown oil. LC / MS Method 2: MS (ESI) [M]+ 463.4, rt: 1.75 min

[0171] Synthesis of N-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine A 1-dram vial containing a stir bar was charged with tert-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]triazol-2-yl]piperidine-1-carboxylate (158.0 mg, 0.340 mmol), m-tolylboronic acid (92.7 mg, 0.680 mmol), potassium phosphate (333.3 mg, 1.02 mmol), and Pd(dppf)Cl2 (28.9 mg, 0.030 mmol). The reaction vessel was then sealed with a septum and purged with nitrogen. 1,4-Dioxane (3.1 mL) and water (0.3 mL) were then added to the reaction vessel via syringe. The reaction vessel was then sealed with a septum cap and vortexed. The vessel was then heated to 100 °C for 16 h. After this time, the reaction mixture was cooled to 22°C and filtered through a pad of Celite. The filter cake was then washed with EtOAc. LCMS analysis of the crude reaction mixture confirmed complete conversion of the starting material to the desired product. The reaction mixture was purified by reverse-phase column chromatography (25% to 100% MeCN in water with 0.1% TFA). The fractions were then concentrated and immediately dissolved in 1:1 DCM / TFA and stirred at room temperature for 1 hour. LCMS analysis confirmed complete deprotection to the desired product. The reaction mixture was purified again by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA) to give the product, N-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (104 mg, 0.272 mmol, 80% yield), as a white solid after lyophilization. MS (ESI) [M+H] + 375.5. 1H NMR (400 MHz, methanol-d4) δ ppm 2.39 - 2.52 (m, 7 H), 3.25 - 3.3.28 (m, 2 H), 3.53 - 3.57 (m, 2 H), 4.82 - 4.87 (m, 1 H), 7.38 - 7.39 (m, 1 H) 7.46 - 7.56 (m, 4 H) 7.75 (s, 1 H) 7.93 (s, 1 H), 8.25 (s, 1 H).

[0172] Example S13. Synthesis of 5-(piperidin-4-yl)-N-(5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)thiazol-2-amine (13) [ka] Synthesis of tert-butyl 4-(2-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)thiazol-5-yl)piperidine-1-carboxylate 5,8-Dibromoimidazo[1,2-α]pyrazine (200.0 mg, 0.720 mmol), tert-butyl 4-(2-aminothiazol-5-yl)piperidine-1-carboxylate (245.6 mg, 0.87 mmol), sodium tert-butoxide (104.1 mg, 1.08 mmol), Pd(dba) (33.07 mg, 0.040 mmol), and Xantphos (41.79 mg, 0.0700 mmol) were added to a 20 mL vial containing a stir bar. The vial was then sealed with a septum and purged with nitrogen. Toluene (7.2 mL) was then added, and the reaction mixture was sparged with a nitrogen balloon for 2 minutes while sonicating. The reaction vessel was then heated to 100 °C and stirred for 16 hours. LCMS analysis the next morning confirmed the formation of the desired product. The reaction mixture was then filtered, concentrated, and purified by reverse-phase column chromatography. The collected fractions were basified with saturated aqueous sodium bicarbonate and then concentrated. The remaining aqueous mixture was extracted with EtOAc. The collected organic layers were dried over sodium sulfate and concentrated to give the product, tert-butyl 4-[2-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]thiazol-5-yl]piperidine-1-carboxylate (140 mg, 0.27 mmol, 38% yield) as a yellow powder. LC / MS Method 2: MS (ESI) [M]+ 479.4, rt: 1.77 min

[0173] Synthesis of 5-(piperidin-4-yl)-N-(5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)thiazol-2-amine To a 1-dram vial containing a stir bar was added tert-butyl 4-[2-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]thiazol-5-yl]piperidine-1-carboxylate (140.0 mg, 0.2900 mmol), m-tolylboronic acid (79.4 mg, 0.580 mmol), potassium phosphate (285.5 mg, 0.880 mmol), and Pd(dppf)Cl2 (24.75 mg, 0.0300 mmol). The reaction vessel was sealed with a septum and purged with nitrogen. 1,4-Dioxane (2.6 mL) and water (0.25 mL) were added to the reaction vessel via syringe. The reaction vessel was sealed with a septum cap and vortexed. The vessel was then heated at 100 °C for 16 h. After this time, the reaction mixture was cooled to 22 °C and filtered through a pad of Celite. The filter cake was then washed with EtOAc. LCMS analysis of the crude reaction mixture confirmed complete conversion of the starting material to the desired product. The reaction mixture was purified by reverse-phase column chromatography (25% to 100% MeCN in water with 0.1% TFA). The fractions were then concentrated and immediately dissolved in 1:1 DCM / TFA and stirred at room temperature for 1 hour. LCMS analysis confirmed complete deprotection to the desired product. The reaction mixture was purified again by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA) to give the product, 5-(piperidin-4-yl)-N-(5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)thiazol-2-amine (34.4 mg, 0.086 mmol, 29% yield), as a yellow solid after lyophilization. MS (ESI) [M+H] + 391.5. 1H NMR (400 MHz, methanol-d4) δ ppm 1.86 - 2.01 (m, 2 H), 2.23 - 2.35 (m, 2 H), 2.47 (s, 3 H), 3.11 - 3.24 (m, 3 H), 3.45 - 3.56 (m, 2 H), 7.24 (s, 1 H), 7.39 - 7.47 (m, 1 H) 7.47 - 7.56 (m, 3 H) 7.86 (s, 1 H), 7.96 (s, 1 H), 8.05 (s, 1 H).

[0174] Example S14. Synthesis of N-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (14) [ka] Synthesis of tert-butyl 4-(3-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate 5,8-Dibromoimidazo[1,2-α]pyrazine (200.0 mg, 0.720 mmol), tert-butyl 4-(3-aminopyrazol-1-yl)piperidine-1-carboxylate (230.8 mg, 0.870 mmol), sodium tert-butoxide (104.1 mg, 1.08 mmol), Pd(dba) (33.1 mg, 0.040 mmol), and Xantphos (41.8 mg, 0.070 mmol) were added to a 20 mL vial containing a stir bar. The vial was then sealed with a septum and purged with nitrogen. Toluene (7.2 mL) was then added, and the reaction mixture was sparged with a nitrogen balloon for 2 minutes while sonicating. The reaction vessel was then heated to 100 °C and stirred for 16 hours. The next morning, LCMS analysis confirmed the formation of the desired product. The reaction mixture was filtered, concentrated, and purified by reverse-phase column chromatography. The collected fractions were basified with saturated aqueous sodium bicarbonate and then concentrated. The remaining aqueous mixture was then extracted with EtOAc. The collected organic layers were dried over sodium sulfate and concentrated to give the product, tert-butyl 4-[3-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (240 mg, 0.4153 mmol, 57.5% yield), as a brown powder. LC / MS Method 2: MS (ESI) [M]+ 462.3, rt: 1.59 min

[0175] Synthesis of N-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine To a 1-dram vial containing a stir bar was added tert-butyl 4-[3-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (240.0 mg, 0.520 mmol), m-tolylboronic acid (141.2 mg, 1.04 mmol), potassium phosphate (507.4 mg, 1.56 mmol), and Pd(dppf)Cl2 (44.0 mg, 0.050 mmol). The reaction vessel was sealed with a septum and purged with nitrogen. 1,4-Dioxane (4.7 mL) and water (0.46 mL) were added to the reaction vessel via syringe. The reaction vessel was sealed with a septum cap and vortexed. The vessel was then heated to 100 °C for 16 h. After this time, the reaction mixture was cooled to 22 °C and filtered through a pad of Celite. The filter cake was washed with EtOAc. LCMS analysis of the crude reaction mixture confirmed complete conversion of the starting material to the desired product. The reaction mixture was then purified by reverse-phase column chromatography (25% to 100% MeCN in water with 0.1% TFA). The concentrated fractions were then immediately dissolved in 1:1 DCM / TFA and stirred at room temperature for 1 hour. LCMS analysis confirmed complete deprotection to the desired product. The reaction mixture was then purified again by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA) to give the product, N-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (162 mg, 0.41 mmol, 79% yield), as a pale yellow solid after lyophilization. LC / MS Method 2: MS (ESI) [M+H] + 374.5, rt: 1.11 min. 1H NMR (400 MHz, methanol-d4) δ ppm 2.25 - 2.42 (m, 4 H), 2.45 (s, 3 H), 3.08 - 3.22 (m, 2 H), 3.51 - 3.61 (m, 2 H), 4.62 - 4.73 (m, 1 H), 6.39 - 6.48 (m, 1 H), 7.33 (s, 1 H), 7.35 - 7.41 (m, 1 H), 7.41 - 7.51 (m, 3 H), 7.60 - 7.66 (m, 1 H), 7.73 - 7.80 (m, 1 H), 7.90 - 7.96 (m, 1 H).

[0176] Example S15. Synthesis of 3-(piperidin-4-yl)-N-(5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)isoxazol-5-amine (15) [ka] Synthesis of tert-butyl 4-(5-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)isoxazol-3-yl)piperidine-1-carboxylate 5,8-Dibromoimidazo[1,2-α]pyrazine (200.0 mg, 0.720 mmol), tert-butyl 4-(5-aminoisoxazol-3-yl)piperidine-1-carboxylate (231.7 mg, 0.870 mmol), sodium tert-butoxide (104.1 mg, 1.08 mmol), Pd(dba) (33.1 mg, 0.040 mmol), and Xantphos (41.8 mg, 0.070 mmol) were added to a 20 mL vial containing a stir bar. The vial was then sealed with a septum and purged with nitrogen. Toluene (7.2 mL) was then added, and the reaction mixture was sparged with a nitrogen balloon for 2 minutes while sonicating. The reaction vessel was then heated to 100 °C and stirred for 16 hours. The next morning, LCMS analysis confirmed the formation of the desired product. The reaction mixture was filtered, concentrated, and purified by reverse-phase column chromatography (5% to 100% MeCN in water with 0.1% TFA). The collected fractions were made basic with saturated aqueous sodium bicarbonate and then concentrated. The remaining aqueous mixture was extracted with EtOAc. The collected organic layers were dried over sodium sulfate and concentrated to give the product, tert-butyl 4-[5-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]isoxazol-3-yl]piperidine-1-carboxylate (145 mg, 0.3067 mmol, 42.465% yield) as an off-white solid. LC / MS Method 2: MS (ESI) [M+Na]+ 485.3, rt: 1.75 min

[0177] Synthesis of 3-(piperidin-4-yl)-N-(5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)isoxazol-5-amine To a 1-dram vial containing a stir bar was added tert-butyl 4-[5-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]isoxazol-3-yl]piperidine-1-carboxylate (145.0 mg, 0.310 mmol), m-tolylboronic acid (85.1 mg, 0.630 mmol), potassium phosphate (306 mg, 0.940 mmol), and Pd(dppf)Cl2 (26.5 mg, 0.030 mmol). The reaction vessel was sealed with a septum and purged with nitrogen. 1,4-Dioxane (2.8 mL) and water (0.28 mL) were added to the reaction vessel via syringe. The reaction vessel was sealed with a septum cap and vortexed. The vessel was then heated at 100 °C for 16 h. After this time, the reaction mixture was cooled to 22 °C and filtered through a pad of Celite. The filter cake was washed with EtOAc. LCMS analysis of the crude reaction mixture confirmed complete conversion of the starting material to the desired product. The reaction mixture was purified by reverse-phase column chromatography (25% to 100% MeCN in water with 0.1% TFA). The concentrated fractions were then immediately dissolved in 1:1 DCM / TFA and stirred at room temperature for 1 hour. LCMS analysis confirmed complete deprotection to the desired product. The reaction mixture was purified again by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA) to give the product, 3-(piperidin-4-yl)-N-(5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)isoxazol-5-amine (23.6 mg, 0.061 mmol, 19% yield), as a brown solid after lyophilization. LC / MS Method 2: MS (ESI) [M+H] + 375.5, rt: 1.14 min. 1H NMR (400 MHz, methanol-d4) δ ppm 2.01 - 2.14 (m, 2 H), 2.26 - 2.36 (m, 2 H), 2.48 (s, 3 H), 3.10 - 3.21 (m, 3 H), 3.44 - 3.53 (m, 2 H), 6.65 (s, 1 H), 7.36 - 7.41 (m, 1 H), 7.42 - 7.52 (m, 3 H), 7.52 - 7.56 (m, 1 H), 7.66 - 7.72 (s, 1 H), 7.82 - 7.88 (s, 1 H).

[0178] Biological Examples Example B1. IRAK3 Biochemical Binding Assay The LanthaScreen® Eu Kinase Binding Assay was performed as described by the supplier (ThermoFisher Scientific, Waltham, MA). Briefly, 100x solutions of compounds were prepared in DMSO and final concentrations were determined by serially diluting 10 mM stock solutions at 3-fold intervals in a 384-well reagent plate. 1 μL of serially diluted compound solutions was added to corresponding wells of a 384-well reagent plate containing 32.3 μL of 1x buffer [50 mM HEPES (pH 7.4), 10 nM MgCl2, 1 mM EGTA, 0.01% Brij-35]. 5 μL of buffer-diluted compound was transferred to the corresponding wells of a 384-well assay plate. 5 μL of 3x tracer was transferred to each well of the assay plate, resulting in a final tracer concentration of 10 nM. Finally, 5 μL of 3×Eu-anti-GST and IRAK3 mix was transferred to each well to a final concentration of 2 nM and 10 nM, respectively. The reaction solution was incubated at room temperature for 1 hour. The TR-FRET signal (λex340 / λem665 / λem615) for the interaction was read using an Envision plate reader at room temperature with a delay time of 100 μs and an integration time of 200 μs. Using this assay, the IC of the following compounds was determined: 50 The values ​​were determined, and the results are shown in Table 2. [Table 3]

[0179] The present invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, but these descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein by reference in their entireties.

Claims

1. Formula (I): 【Chemical 1】 [In the formula, Ring A is C 6 -C 10 aryl or 5-6 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; R 1 is H, C 6 -C 10 Aryl or C 3 -C 6 and cycloalkyl, wherein said aryl and cycloalkyl are C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 optionally substituted with 1 to 5 substituents selected from alkoxy, halo, —OH and —CN; W is NR 2 or CR 3a R 3b and R 2 is H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or -C(O)(C 1 -C 6 alkyl); R 3a and R 3b are independently H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy or -C(O)(C 1 -C 6 alkyl); and X is CH or N. or a pharmaceutically acceptable salt thereof.

2. Ring A is C 6 -C 10 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

4. Ring A is 【Chemistry 2】 4. The compound according to any one of claims 1 to 3, wherein:

5. R 1 or a pharmaceutically acceptable salt thereof.

6. R 1 But C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 C optionally substituted with 1 to 5 substituents selected from alkoxy, halo, —OH and —CN 3 -C 6 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

7. R 1 But C 3 -C 6 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein:

8. R 1 But C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 C optionally substituted with 1 to 5 substituents selected from alkoxy, halo, —OH and —CN 6 -C 10 5. The compound of claim 1, wherein R is aryl, or a pharmaceutically acceptable salt thereof.

9. R 1 but, 【Chemistry 3】 8. The compound according to any one of claims 1 to 4, 6 and 7, wherein:

10. R 1 but, 【Chemistry 4】 9. The compound according to any one of claims 1 to 4 and 8, wherein:

11. W is NR 2 or CR 3a R 3b and R 2 But H, C 1 -C 6 Alkyl or -C(O)(C 1 -C 3 alkyl); and R 3a and R 3b However, independently, H, C 1 -C 3 Alkyl or -C(O)(C 1 -C 6 alkyl), 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. W is NR 2 and R 2 But H, C 1 -C 6 Alkyl or -C(O)(C 1 -C 3 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2;

13. 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X is CH.

14. 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X is N.

15. 【Chemical 5】 but 【Chemistry 6】 14. The compound according to any one of claims 1 to 13, wherein:

16. 【Chemical 7】 but 【Chemistry 8】 15. The compound of any one of claims 1 to 12 and 14, wherein:

17. The compound is of formula (II) or (III): 【Chemistry 9】 wherein ring A is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. 【Chemistry 10】 17. The compound of any one of claims 1 to 16, wherein:

18. A compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

19. 19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. A method for binding interleukin-1 receptor-associated kinase 3 (IRAK3), comprising contacting IRAK3 with an effective amount of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19.

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