Substituted imidazopyrazine compounds as IRAK3 binders

Abstract

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

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 391,972, filed on July 25, 2022, which is incorporated herein in its entirety. Technical Field

[0002] The present disclosure generally relates to compounds, compositions and methods for their preparation for binding IRAK3, and uses of the compounds and compositions. Background Art

[0003] The recruitment of immune cells to the site of injury involves a coordinated interaction of a large number of soluble mediators. Several cytokines appear to play a key role in these processes, such as interleukin-1 (IL-1). IL-1 produces a proinflammatory response and contributes to the tissue degeneration observed in chronic inflammatory conditions. IL-1 is also involved in the processes of bone resorption and adipose tissue regulation. Therefore, IL-1 plays a key role in a large number of pathological conditions including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, cancer and sepsis.

[0004] IL-1 treatment of cells mediates the formation of a complex consisting of two IL-1 receptor chains (IL-1R1 and IL-1RAcP), and the resulting heterodimer recruits an adaptor molecule named MyD88, which binds to IL-1 receptor-associated kinase (IRAK) (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 that mediates interaction with the MyD88-family adaptor protein and a central kinase domain. Of the four members of the mammalian IRAK family, IRAK2 and IRAK3 are considered to be catalytically inactive pseudokinases (Wesche et al., J. Biol. Chem. 1999, 274, 19403-19410), but the specific roles of these two kinases are still largely unknown (Lagne et al., Structure 2021, 29, 238-251). Nevertheless, reports indicate that IRAK3 is associated with negative regulation of TLR (toll-like receptor) signaling, which is involved in detecting microorganisms and protecting multicellular organisms from infection (Kobayashi et al., Cell 2002, 110, 191-202). Many recent studies have revealed the link between IRAK3 mutations or high expression levels and various diseases such as asthma and cancer (Balaci et al., Am. J. Hum. Genet. 2007, 80(6), 1103-1114; Kesselring et al., Cancer Cell 2016, 29(5), 685-696), indicating the potential of IRAK3 as a drug target and the need for IRAK3-binding small molecules.

[0005] Accordingly, in one aspect, provided herein are compounds that bind IRAK3. Summary of the invention

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

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

[0008] Embodiment A1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is C6-C 10 Aryl or 5- to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; R 1 H, C6-C 10 Aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 1-5 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 ; R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl or -C(O)(C1-C6 alkyl); R 3a and R 3b are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -C(O)(C1-C6 alkyl); and X is CH or N.

[0009] Embodiment A2. A compound according to Embodiment A1 or a pharmaceutically acceptable salt thereof, wherein: Ring A is C6-C 10 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 group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.

[0011] Embodiment A4. A compound according to any one of Embodiments A1-A3 or a pharmaceutically acceptable salt thereof, wherein: Ring A is

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

[0013] Embodiment A6. A compound according to any one of Embodiments A1-A4 or a pharmaceutically acceptable salt thereof, wherein R 1 is a C3-C6 cycloalkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, -OH and -CN.

[0014] Embodiment A7. A compound according to Embodiment A6 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a C3-C6 cycloalkyl group.

[0015] Embodiment A8. A compound according to any one of Embodiments A1-A4 or a pharmaceutically acceptable salt thereof, wherein R 1 is a C6-C6 alkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, -OH and -CN. 10 Aryl.

[0016] Embodiment A9. A compound according to any one of Embodiments A1-A4, A6 and A7, or a pharmaceutically acceptable salt thereof, wherein: R 1 for

[0017] Embodiment A10. A compound according to any one of Embodiments A1-A4 and A8, or a pharmaceutically acceptable salt thereof, wherein: R 1 for

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

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

[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. A compound according to any one of Embodiments A1-A13, or a pharmaceutically acceptable salt thereof, wherein: for

[0023] Embodiment A16. A compound according to any one of Embodiments A1-A12 and A14, or a pharmaceutically acceptable salt thereof, wherein: for

[0024] Embodiment A17. A compound according to any one of Embodiments A1-A16, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (II) or (III): wherein Ring A is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

[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] Embodiment A20. A method of 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-A18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment A19. DETAILED DESCRIPTION definition

[0028] As used herein, the terms "include" and "comprising" can be used interchangeably. The terms "include" and "comprising" can be interpreted as specifying the presence of the features or components, but not excluding the presence or addition of one or more features or components or groups thereof. Additionally, the terms "include" and "comprising" are intended to include examples covered by the term "consisting of". Therefore, the term "consisting of" can be used to replace the terms "include" and "comprising" to provide more specific embodiments of the present invention.

[0029] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98% or 99% of the features or components it consists of. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any subsequent statement, except those features or components that are not necessary for the technical effect to be achieved.

[0030] As used herein, the term "or" is 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". Exceptions to this definition will only occur if a combination of elements, functions, steps or acts are inherently mutually exclusive to some extent.

[0031] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the range, and where appropriate, include its fractions (such as one tenth and one hundredth of an integer). In addition, unless otherwise indicated, any numerical range related to any physical feature (such as polymer subunits, size or thickness) described herein should be understood to include any integer within the range. As used herein, unless otherwise indicated, the terms "about" and "approximately" mean ±20%, ±10%, ±5% or ±1% of the indicated range, value or structure.

[0032] An "alkyl" group is a saturated, partially saturated or unsaturated straight or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms (C1-C 10In some embodiments, the alkyl group is an unsaturated alkyl group, also known 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(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3), etc. The alkyl group may be substituted or unsubstituted. When an alkyl group described herein is referred to as "substituted," it may be substituted with any one or more of the substituents in the exemplary compounds and embodiments disclosed herein as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocyclylalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocyclylalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocyclylalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino alkylamino; heteroarylalkylamino; heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; amide; sulfonylamino; urea; nitrourea; oxime; hydroxyamino; alkoxyamino; aralkyloxyamino; hydrazine; hydrazido; hydrazo; azido; nitro; sulfhydryl (-SH), alkylthiol; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acetyl; formyl; carboxyl; ester; carbamate; amino; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.In certain embodiments, when an alkyl group described herein is referred to as "substituted," it may be substituted with any one or more of the substituents in the exemplary compounds and embodiments disclosed herein as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acetylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyamino; alkoxyamine; aryloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0033] A "cycloalkyl" group is a saturated or partially saturated cycloalkyl group (C3-C 10 Cycloalkyl) with a single ring or multiple fused or bridged rings that are optionally substituted. In 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. The saturated cycloalkyl group includes, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or polycyclic 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, etc. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, etc. The cycloalkyl group may be substituted or unsubstituted. The substituted cycloalkyl group includes, for example, cyclohexanol, etc.

[0034] "Heterocyclyl" is a non-aromatic cycloalkyl group in which 1 to 4 ring carbon atoms are independently replaced by heteroatoms selected from O, S and N. In some embodiments, the heterocyclyl group includes 3 to 10 ring members, while other groups have 3 to 5, 3 to 6 or 3 to 8 ring members. The heterocyclyl group can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). The heterocyclyl group may be substituted or unsubstituted. The heterocyclyl group encompasses saturated and partially unsaturated ring systems. In addition, the term heterocyclyl is intended to encompass any non-aromatic ring having at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, whether or not attached to the rest of the molecule. The phrase also includes bridged polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl groups include, but are not limited to, aziridine, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyran), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclyl, or tetrahydropyridin-2(1H)-one. Representative substituted heterocyclyl groups may be monosubstituted or polysubstituted, such as, but not limited to, pyridinyl or morpholinyl, 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below.

[0035] An "aryl" group is an aromatic carbocyclic group (C6-C14) of 6 to 14 carbon atoms having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthracenyl). 14 In some embodiments, aryl groups contain 6-14 carbon atoms (C6-C 14 aryl), and in other embodiments contains 6 to 12 (C6-C 12 aryl) or even 6 to 10 carbon atoms (C6-C 10 Typical aryl groups include phenyl, biphenyl, naphthyl, etc. The aryl group may be substituted or unsubstituted. The phrase "aryl group" also includes fused rings, such as fused aromatic-aliphatic ring systems (e.g., dihydroindenyl, tetrahydronaphthyl, etc.).

[0036] "Heteroaryl" groups are aromatic ring systems having one to four heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms in the ring portion of the group, and in other embodiments contains 6 to 9 or even 6 to 10 atoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl (e.g., indol-2-one or indolin-1-one), azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazoles), The heteroaryl groups may be substituted or unsubstituted.

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

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

[0039] "Haloalkyl" refers to an alkyl group as defined above, which is substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms and is substituted with one or more halo groups (C1-C6 haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halo groups (C1-C3 haloalkyl). The halo groups may be all the same or the halo groups may be different. Unless otherwise specifically stated, the haloalkyl group is optionally substituted.

[0040] When groups described herein (except alkyl) are referred to as "substituted", they may be substituted with any suitable substituent or substituents. Illustrative examples of substituents are those in the embodiments and exemplary compounds disclosed herein, as well as halogen (chlorine, iodine, bromine or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; mercapto; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; amide; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or heterocyclic, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy substitution.

[0041] Embodiments of the present disclosure are intended to encompass pharmaceutically acceptable salts, tautomers, isotopic conformers, and stereoisomers of the compounds provided herein, such as compounds of Formula (I).

[0042] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base 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 prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts prepared 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, aminobenzoic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, 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. Examples of specific salts therefore include hydrochloride, formate and mesylate. Others are well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0043] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" means one stereoisomer of a particular compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds include greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compounds disclosed herein may have chiral centers and may occur as racemates, individual enantiomers or diastereomers, or mixtures thereof. All such isomeric forms are included in the embodiments disclosed herein, including mixtures thereof.

[0044] The use of stereoisomerically pure forms of the compounds disclosed herein and the use of mixtures of those forms are encompassed in the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular compound can 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. See, 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., SeparationOf 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); 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 may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the compounds are isolated as E or Z isomers. In other embodiments, the compounds are mixtures of E and Z isomers.

[0046] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is located and may differ, for example, depending on whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0047] As will be readily appreciated by those skilled in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of 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 be radiolabeled with a radioactive isotope, such as, for example, tritium ( 3 H), iodine-125 ( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 C), or may be isotopically enriched, such as with deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15 N) enrichment. As used herein, an "isotope configuration" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of the atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope in a given atom. Isotopically labeled and isotopically enriched compounds can be used as therapeutic agents, for example, cancer therapeutic agents, research reagents, for example, combined with assay reagents and diagnostic reagents, for example, in vivo imaging agents. All isotopic variations of the compound are as described herein, whether or not radioactive, and are intended to be covered within the scope of the embodiments provided herein. In some embodiments, an isotopic configuration of a compound disclosed herein is provided, for example, the isotopic configuration is a deuterium, carbon-13 and / or nitrogen-15 enriched compound. As used herein, "deuterated" means that at least one hydrogen (H) in a compound has been replaced by deuterium (referring to D or 2 H) substitution, i.e., the compound is enriched in deuterium at at least one position.

[0049] It is understood that, independent of stereoisomer or isotopic composition, each compound disclosed herein may be provided in the form of any pharmaceutically acceptable salt discussed herein. Likewise, it is understood that the isotopic composition may vary independently of the stereoisomer composition of each compound described herein. In addition, the isotopic composition, while limited to those elements present in each compound disclosed herein or a salt thereof, may vary independently of the choice of a pharmaceutically acceptable salt of each compound.

[0050] It should be noted that if there is a discrepancy between the structure being described and the name of that structure, the structure being described will be given more weight.

[0051] As used herein, "treating" means alleviating one or more of the symptoms associated with a disorder, disease or condition, or slowing or preventing further progression or worsening of the symptoms, or alleviating or eradicating the cause of the disorder, disease or condition itself. In one embodiment, the disorder is a neurodegenerative disease or a symptom thereof as described herein.

[0052] As used herein, "prevention" means a method for delaying and / or preventing the onset, recurrence, or spread of all or part of a disorder, disease, or condition; preventing a subject from suffering from a disorder, disease, or condition; or reducing the risk of a subject suffering from a disorder, disease, or condition. In one embodiment, the disorder is a neurological disease or a symptom thereof as described herein.

[0053] The term "effective amount" in connection with 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, in one embodiment mammals, in another embodiment humans. In one embodiment, the subject is a human who suffers from an IRAK3-mediated disease or a symptom thereof or is at risk of suffering from an IRAK3-mediated disease or a symptom thereof.

[0055] Although various features of the present 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 for clarity, the present invention may be described herein in the context of separate embodiments, the present invention may also be implemented in a single embodiment. Compound

[0056] In one aspect, there is provided a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is C6-C 10 Aryl or 5- to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; R 1 H, C6-C 10 Aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 1-5 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 ; R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -C(O)(C1-C6 alkyl); R 3a and R 3b are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -C(O)(C1-C6 alkyl); and X is CH or N.

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

[0059] In some embodiments, ring A is a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl group containing 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl group containing 2-3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl group containing 2 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl group containing 3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl group containing 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 5-membered heteroaryl group containing 2-3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 5-membered heteroaryl group 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 1 nitrogen atom and 1 sulfur atom. In some embodiments, ring A is a 5-membered heteroaryl containing 1 nitrogen atom and 1 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 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 6-membered heteroaryl containing 2-3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 6-membered heteroaryl containing 2 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 6-membered heteroaryl containing 3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, ring A is a 6-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, Ring A is a 6-membered heteroaryl group containing 3 nitrogen atoms. In some embodiments, Ring A is a 6-membered heteroaryl group containing 1 nitrogen atom and 1 sulfur atom. In some embodiments, Ring A is a 6-membered heteroaryl group containing 1 nitrogen atom and 1 oxygen atom. In some embodiments, Ring A is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl. In some embodiments, Ring A 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 1-5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, -OH and -CN. 1 H, C6-C 10aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 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 the aryl and cycloalkyl are optionally substituted with 4 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 the aryl and cycloalkyl are optionally substituted with 1-3 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 the aryl and cycloalkyl are optionally substituted with 3 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 the aryl and cycloalkyl are optionally substituted with 2 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 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. 1 H, C6-C 10 aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 1-3 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 the aryl and cycloalkyl are optionally substituted with 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 H, C6-C 10aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 2 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 the aryl and cycloalkyl are optionally substituted with one substituent selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is H, phenyl or cyclohexyl, wherein the phenyl and cyclohexyl are optionally substituted with 1-3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is H, phenyl or cyclohexyl, wherein the phenyl and cyclohexyl are optionally substituted with 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is H, phenyl or cyclohexyl, wherein the phenyl and cyclohexyl are optionally substituted with 2 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is H, phenyl or cyclohexyl, wherein the phenyl and cyclohexyl are optionally substituted with one substituent selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 R is H, phenyl or cyclohexyl, wherein the 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. In some embodiments, R 1 is H, phenyl or cyclohexyl, wherein the phenyl and cyclohexyl are optionally substituted with one substituent selected from methyl, -CF3, -CHF2, -CH2F, -OCH3, halo, -OH and -CN. In some embodiments, R 1 is H, phenyl or cyclohexyl, wherein the phenyl and cyclohexyl are optionally substituted with methyl. 1 is H. In some embodiments, R 1 is phenyl optionally substituted with methyl. 1 is a cyclohexyl group optionally substituted with methyl.1 It is cyclohexyl.

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

[0062] In some embodiments, R 1 is a C6-C6 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 C6-C6 alkyl group optionally substituted with 5 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 10 In some embodiments, R 1 is a C6-C6 alkyl group optionally substituted with 4 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 10 In some embodiments, R 1 is a C6-C6 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 C6-C6 alkyl group optionally substituted with 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 C6-C6 alkyl group optionally substituted with 2 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, -OH and -CN. 10 In some embodiments, R 1 is a C6-C6 alkyl group optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 10 In some embodiments, R 1 is a C6-C3 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 C6-C3 alkyl group optionally substituted with 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN 10 In some embodiments, R 1is a C6-C3 alkyl group optionally substituted with 2 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN 10 In some embodiments, R 1 is a C6-C3 alkyl group optionally substituted with one substituent selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 10 In some embodiments, R 1 is phenyl optionally substituted with 1-3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is phenyl optionally substituted with 2 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 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 the group consisting of propyl, ethyl, methyl, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, -CH2F, -OCH2CH2CH3, -OCH2CH3, -OCH3, halo, -OH and -CN. In some embodiments, R 1 is phenyl optionally substituted with one substituent selected from methyl, -CF3, -CHF2, -CH2F, -OCH3, halo, -OH and -CN. In some embodiments, R 1 is phenyl optionally substituted with methyl. 1 for

[0063] In some embodiments, R 1 is a C3-C6 cycloalkyl group optionally substituted with 1-5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 1 is a cyclopropyl group optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 1 is a cyclobutyl group optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN.1 is a cyclopentyl group optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 1 is a cyclohexyl group optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 1 is a C3-C6 cycloalkyl group optionally substituted with 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 1 is a C3-C6 cycloalkyl group optionally substituted with 4 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 1 is a C3-C6 cycloalkyl group optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 1 is a C3-C6 cycloalkyl group optionally substituted with 3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 1 is a C3-C6 cycloalkyl group optionally substituted with 2 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 1 is a C3-C6 cycloalkyl group optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN. 1 is a C3-C6 cycloalkyl group optionally substituted with 1-3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is a C3-C6 cycloalkyl group optionally substituted with 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is a C3-C6 cycloalkyl group optionally substituted with 2 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is a C3-C6 cycloalkyl group optionally substituted with one substituent selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN.1 is a cyclohexyl group optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is a cyclohexyl group optionally substituted with 3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is a cyclohexyl group optionally substituted with 2 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is a cyclohexyl group optionally substituted with one substituent selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH and -CN. 1 is a cyclohexyl group optionally substituted with one substituent selected from the group consisting of propyl, ethyl, methyl, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, -CH2F, -OCH2CH2CH3, -OCH2CH3, -OCH3, halo, -OH and -CN. In some embodiments, R 1 is a cyclohexyl group optionally substituted with one group selected from methyl, -CF3, -CHF2, -CH2F, -OCH3, halo, -OH and -CN. In some embodiments, R 1 is a cyclohexyl group optionally substituted with methyl. 1 is an unsubstituted cyclohexyl group. In some embodiments, R 1 for

[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 .

[0065] In some embodiments, R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -C(O)(C1-C6 alkyl). 2 is H, C1-C4 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or -C(O)(C1-C3 alkyl). 2is 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)(CH2CH2CH3). 2 is H. In some embodiments, R 2 In some embodiments, R 2 It is -C(O)(CH2CH2CH3).

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

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

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

[0069] In some embodiments, R 2 is C1-C6 alkoxy. 2 is C1-C3 alkoxy. 2 In some embodiments, R 2 It is -OCH3.

[0070] In some embodiments, R 2 is C(O)(C1-C6 alkyl). 2is -C(O)(C1-C3 alkyl). 2 is -C(O)(CH3), -C(O)(CH2CH3) or -C(O)(CH2CH2CH3). In some embodiments, R 2 It is -C(O)(CH2CH2CH3).

[0071] In some embodiments, R 3a is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -C(O)(C1-C6 alkyl). 3a is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or -C(O)(C1-C4 alkyl). 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, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, or -CH2F. In some embodiments, R 3a In some embodiments, R 3a is -C(O)(CH3), -C(O)(CH2CH3), -C(O)(CH2CH2CH3) or -C(O)(CH2CH2CH2CH3). In some embodiments, R 3a It is H, butyl, -CF3, -CHF2, -CH2F, OCH3 or -C(O)(CH2CH2CH3).

[0072] In some embodiments, R 3b is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -C(O)(C1-C6 alkyl). 3b is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or -C(O)(C1-C4 alkyl). 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, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, or -CH2F. In some embodiments, R 3b In some embodiments, R 3b is -C(O)(CH3), -C(O)(CH2CH3), -C(O)(CH2CH2CH3) or -C(O)(CH2CH2CH2CH3). In some embodiments, R 3b It is H, butyl, -CF3, -CHF2, -CH2F, OCH3 or -C(O)(CH2CH2CH3).

[0073] In some embodiments, R 3a and R 3b are all H. In some embodiments, R 3a is a C1-C4 alkyl group 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 For 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, for In some embodiments, for:

[0076] In some embodiments, the Part of In some embodiments, the Part of

[0077] In some embodiments, the compound of formula (I) is a compound of formula (IA): Among them, rings A, W and R 1 As described for Formula (I). In some variations, Ring A is a 5-membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0078] In some embodiments, the compound of formula (I) is a compound of formula (IB) or a compound of formula (IC): Among them, ring A, R 1 , R 2 , R 3a and R 3b As described for Formula (I). In some variations, Ring A is a 5-membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0079] In some embodiments, the compound of formula (I) is a compound of formula (II): wherein Ring A is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.

[0080] In some embodiments, Formula (I) is a compound of Formula (III): Where R 1 and R 2 As described for formula (I).

[0081] In some embodiments, the compound of formula (I) is a compound of formula (III-A) or formula (III-B): Where R 1 and R 2 As described for formula (I).

[0082] In the description herein, it should be understood that each description, variation, embodiment or aspect of a part can be combined with each description, variation, embodiment or aspect of other parts, just as if each and each combination of descriptions were specifically and individually listed. For example, the R of formula (I) provided herein 1 The various descriptions, variations, embodiments or aspects of the rings A, W, R 2 , R 3a , R 3bWith each description, variation, embodiment or aspect of X, as each and each combination is specifically and individually listed. It should also be understood that all descriptions, variations, embodiments or aspects of formula (I), when applicable, are equally applicable to other formulas described in detail herein, and are described equally, as each and each description, variation, embodiment or aspect of all formulas are listed separately and individually. For example, all descriptions, variations, embodiments or aspects of formula (I), when applicable, are equally applicable to any one of the formulas described in detail herein, such as formula (IA), (IB), (IC), (II), (III), (III-A) and (III-B), and are described equally, as each and each description, variation, embodiment or aspect of all formulas are listed separately and individually.

[0083] In some embodiments, a compound or a pharmaceutically acceptable salt thereof is provided that is selected from the compounds in Table 1. Although the present disclosure includes certain compounds described in Table 1 as specific stereoisomers and / or in non-stereoisomeric forms, it is understood that any or all stereochemical forms of any compound of Table 1 described herein, including any enantiomeric or diastereomeric form and any tautomeric or other form, are included in the present disclosure. Table 1 or a pharmaceutically acceptable salt thereof.

[0084] It is understood that in this specification, combinations of substituents and / or variables of the described formulae are permissible only if such combinations result in stable compounds.

[0085] In addition, all compounds of formula (I) in free base or free acid form can be converted into their pharmaceutically acceptable salts by methods known to those skilled in the art with appropriate inorganic or organic bases or acids. The salts of compounds of formula (I) can be converted into free base or acid form by standard techniques. Synthesis method

[0086] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or methods provided herein. As an example and not limitation, compounds of formula (I) can be prepared according to the examples listed in Schemes 1-4 and listed herein. It should be noted that those skilled in the art will know how to modify the methods shown in the illustrative schemes and examples to obtain the desired products. Solution 1. wherein Pg is a protecting group; X and ring A are as described for formula (I); and R is 0-5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH and -CN.

[0087] As shown in Scheme 1, compounds of Formula A can be synthesized by coupling intermediate a and intermediate b to generate intermediate C. In some examples, intermediate a and intermediate b can be coupled using acid or base-promoted aromatic nucleophilic substitution to form intermediate c. Alternatively, intermediate c can be synthesized using Buchwald-Hartwig cross-coupling (Ruiz-Castillo, P. and Buchwald, SL Chemical Reviews, 116: 12564-12649, 2016). Later, intermediate c is cross-coupled with palladium catalysis of a suitable boronic acid or boronic ester (Miyaura, N. and Suzuki, A. Chemical Reviews, 95: 2457-2483, 1995), followed by acid-promoted deprotection to produce compounds of Formula A. In some examples, the preparation of compound A also involves removing a protecting group (such as CBz) using, for example, reducing conditions. Solution 2. 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.

[0088] As shown in Scheme 2, compounds of Formula B containing cycloalkyl substituents on the imidazopyrazine backbone can be synthesized by Suzuki cross coupling of intermediate c with the corresponding alkenylboronic acid pinacol ester (intermediate d) to generate styrenyl intermediate (e). Subsequently, palladium catalyzed hydrogenation followed by removal of the protecting group provides compounds of Formula B. Solution 3. wherein X and Ring A are as described for Formula (I).

[0089] As shown in Scheme 3, the compounds of Formula C containing unsubstituted imidazopyrazine can be synthesized by reduction of the corresponding aryl bromide. Treating the benzyl carbamate-protected intermediate e with palladium on carbon under a hydrogen atmosphere can provide unsubstituted imidazopyrazine compounds exemplified by the compounds of Formula C. Solution 4. wherein R is 0-5 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).

[0090] As depicted in Scheme 4, compounds of formula A can be further functionalized via amide bond formation or reductive amination to generate compounds of formula D or E. Treatment of compounds of formula A with carboxylic acids, HATU and DIPEA provides amide-terminated derivatives of formula D. Alkyl-terminated compounds of formula E can be prepared by reacting compounds of formula A with an aldehyde and an appropriate reducing agent such as STAB. How to use

[0091] In some embodiments, provided herein are methods for binding IRAK3 in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound of formula (I). Binding of IRAK3 can be assessed and demonstrated via a variety of methods known in the art. Kits and commercially available assays can be used to determine whether and to what extent IRAK3 is bound. In some embodiments, a compound of formula (I) binds to IRAK3 with an affinity (IC) of at least about 5 nM. 50 ) binds to IRAK3. In some embodiments, the 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, the compound of formula (I) binds to IRAK3 with an affinity of about 5 to 10,000 nM, about 10 to 9000 nM, about 50 to 8000 nM, about 100 to 7000 nM, about 200 to 6000 nM, about 300 to 5000 nM, about 400 to 4000 nM, about 500 to 3000 nM, about 600 to 2000 nM, about 700 to 1000 nM, or about 800 to 900 nM. In some embodiments, the compound of formula (I) binds to IRAK3 with an affinity of about 5 to 500 nM, 5 to 400 nM, 5 to 300 nM, 5 to 200 nM, or 5 to 100 nM. In some embodiments, the 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, the binding affinity can be determined using the TR-FRET biochemical assay described in Example B1.

[0092] 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.

[0093] In some embodiments, the compound of formula (I) can be used as a ligand of a heterobifunctional degrader. In some embodiments, the compound of formula (I) is used as a ligand of a heterobifunctional degrader that targets IRAK3 for degradation. Such heterobifunctional degraders can be used, for example, to treat cancers 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, heterobifunctional degraders enhance the immunity of vaccinated subjects. Pharmaceutical compositions and routes of administration

[0094] The compounds provided herein can be administered to a subject orally, topically or parenterally in conventional forms of preparations such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.

[0095] The compounds disclosed herein can be administered orally, topically or parenterally to a subject in conventional forms of preparations (such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions). Suitable preparations can be prepared by conventional methods using conventional, organic or inorganic additives, such as 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 hydroxypropyl cellulose, sodium bicarbonate). , calcium phosphate or calcium citrate), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine or sweet orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben or propylparaben), stabilizers (e.g., citric acid, sodium citrate or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone or aluminum stearate), dispersants (e.g., hydroxypropylmethylcellulose), diluents (e.g., water) and matrix waxes (e.g., cocoa butter, white vaseline or polyethylene glycol). The effective amount of the compound of formula (I) in the pharmaceutical composition can be a level that achieves the desired effect; the unit dose for oral and parenteral administration is, for example, about 0.005 mg / kg of the subject's body weight to about 10 mg / kg of the subject's body weight.

[0096] The dosage of the compound of formula (I) applied to the subject varies greatly and can be judged by health care practitioners. In general, the compound disclosed herein can be applied 1 to 4 times a day at a dosage of about 0.001 mg / kg subject weight to about 10 mg / kg subject weight, but the above dosage can be appropriately changed according to the age, weight and medical condition of the subject and the type of application. In one embodiment, the dosage is about 0.001 mg / kg subject weight to about 5 mg / kg subject weight, about 0.01 mg / kg subject weight to about 5 mg / kg subject weight, about 0.05 mg / kg subject weight to about 1 mg / kg subject weight, about 0.1 mg / kg subject weight to about 0.75 mg / kg subject weight or about 0.25 mg / kg subject weight to about 0.5 mg / kg subject weight. In one embodiment, a dose is given every day. In any given case, the amount of the compound of formula (I) applied will depend on factors such as the solubility of the active ingredient, the preparation used and the route of administration.

[0097] In some embodiments, the compound of Formula (I) is administered to a subject at a dosage 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.

[0098] In another embodiment, provided herein is a unit dosage formulation comprising between about 0.1 mg and 500 mg, between about 1 mg and 250 mg, between about 1 mg and about 100 mg, between about 1 mg and about 50 mg, between about 1 mg and about 25 mg, or between about 1 mg and about 10 mg of a compound of Formula (I).

[0099] In a specific embodiment, provided herein is a unit dosage formulation comprising about 0.1 mg or 100 mg of a compound of Formula (I).

[0100] In another embodiment, provided herein are unit dosage formulations 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 a compound of formula (I).

[0101] The compound of formula (I) may be administered once, twice, three times, four times or more daily. In a particular embodiment, a dose of 100 mg or less is administered once daily and a dose of 100 mg or more is administered twice daily in an amount equal to half of the total daily dose.

[0102] For reasons of convenience, the compounds of formula (I) can be administered orally. In one embodiment, when used orally, the compounds of formula (I) are administered with a meal and water. In another embodiment, the compounds of formula (I) are dispersed in water or fruit juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0103] The compounds disclosed herein can also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is at the discretion of the health care practitioner and may depend in part on the location of the medical condition.

[0104] In one embodiment, provided herein are capsules containing a compound of Formula (I) without additional carriers, excipients or vehicles.

[0105] 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 may include an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0106] The composition can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories and suspensions, etc. The composition can be formulated to contain a daily dose or a convenient portion of a daily dose in a dosage unit, which can be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solution is prepared by a water-soluble salt, such as a hydrochloride. In general, 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 a suitable amount of the mixture in the capsule. Common carriers and diluents include, but are not limited to, inert powdered substances, such as many different types of starch, cellulose powder, particularly crystalline and microcrystalline cellulose, sugars, such as fructose, mannitol and sucrose, cereal flour and similar edible powders.

[0107] Tablets can be prepared by direct compression, wet granulation or dry granulation. Their formulations generally include diluents, binders, lubricants and disintegrants and compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts such as sodium chloride and icing sugar. Cellulose powder derivatives can also be used. Typical tablet binders are materials such as starch, gelatin and sugars such as lactose, fructose, glucose, etc. Natural and synthetic gums are also very convenient, including gum arabic, alginate, methylcellulose, polyvinyl pyrrolidone, etc. Polyethylene glycol, ethyl cellulose and wax can also be used as binders.

[0108] In tablet formulations, lubricants may be necessary to prevent tablets from sticking to the punch. Lubricants can be selected from smooth solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are substances that expand when wet to break the tablet and release the compound. They include starch, clay, cellulose, algin and gum. More specifically, corn and potato starch, methylcellulose, agar, bentonite, lignocellulose, powdered natural sponges, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used simultaneously with sodium lauryl sulfate. Tablets can be coated with sugar as a flavoring agent and sealant, or coated with a film-forming protective agent to change the dissolution characteristics of the tablet. The composition can also be formulated as a chewable tablet, for example, by using a substance such as mannitol in the formulation.

[0109] When it is desired to administer the compound of formula (I) as a suppository, typical bases may be used. Cocoa butter is a traditional suppository base, the melting point of which may be slightly increased by the addition of waxes. Water-soluble bases including, inter alia, polyethylene glycols of various molecular weights are widely used.

[0110] The effect of the compound of formula (I) can be delayed or prolonged by a suitable formulation. For example, slowly dissolving pellets of the compound of formula (I) can be prepared and included in tablets or capsules, or as a sustained-release implant. The technology also includes making pellets with several different dissolution rates and filling capsules with a mixture of these pellets. Tablets or capsules can be coated with a film to delay dissolution over a predictable period of time. By dissolving or suspending the compound of formula (I) in an oily or emulsified carrier so that it is slowly dispersed in the serum, even parenteral preparations can be made into long-acting preparations. Exemplary Implementation

[0111] The present disclosure is further described by the following embodiments. The features of each embodiment may be combined with any other embodiment where appropriate and practical.

[0112] Embodiment 1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is C6-C 10 Aryl or 5- to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; R 1 H, C6-C 10 Aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 1-5 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 ; R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl or -C(O)(C1-C6 alkyl); R 3a and R 3b are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -C(O)(C1-C6 alkyl); and X is CH or N.

[0113] Embodiment 2. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein: Ring A is C6-C 10 Aryl.

[0114] Embodiment 3. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.

[0115] Embodiment 4. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: Ring A is

[0116] Embodiment 5. The compound according to Embodiment 1 or 3 or a pharmaceutically acceptable salt thereof, wherein: Ring A is

[0117] Embodiment 6. A compound according to any one of Embodiments 1-5 or a pharmaceutically acceptable salt thereof, wherein R 1 For H.

[0118] Embodiment 7. A compound according to any one of Embodiments 1-5 or a pharmaceutically acceptable salt thereof, wherein R 1is a C3-C6 cycloalkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, -OH and -CN.

[0119] Embodiment 8. The compound according to Embodiment 7 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a C3-C6 cycloalkyl group.

[0120] Embodiment 9. A compound according to any one of Embodiments 1-5 or a pharmaceutically acceptable salt thereof, wherein R 1 is a C6-C6 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 Aryl.

[0121] Embodiment 10. The compound according to Embodiment 9 or a pharmaceutically acceptable salt thereof, wherein R 1 is a C6-C6 alkyl group optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl 10 Aryl.

[0122] Embodiment 11. The compound according to Embodiment 9 or a pharmaceutically acceptable salt thereof, wherein R 1 is a C6-C3 alkyl group optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl 10 Aryl.

[0123] Embodiment 12. A compound according to any one of Embodiments 1-5 and 7-8, or a pharmaceutically acceptable salt thereof, wherein: R 1 for

[0124] Embodiment 13. A compound according to any one of Embodiments 1-5 and 9-11, or a pharmaceutically acceptable salt thereof, wherein: R 1 for

[0125] Embodiment 14. A compound according to any one of Embodiments 1-13 or a pharmaceutically acceptable salt thereof, wherein: W is NR 2 or CR 3a R 3b ; R 2 is H, C1-C6 alkyl or -C(O)(C1-C3 alkyl); and R 3a and R 3bare independently H, C1-C3 alkyl or -C(O)(C1-C6 alkyl).

[0126] Embodiment 15. The compound according to Embodiment 14 or a pharmaceutically acceptable salt thereof, wherein: W is NR 2 ;as well as R 2 It is H, C1-C6 alkyl or -C(O)(C1-C3 alkyl).

[0127] Embodiment 16. A compound according to any one of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0128] Embodiment 17. The compound according to any one of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0129] Embodiment 18. A compound according to any one of Embodiments 1-15 and 16, or a pharmaceutically acceptable salt thereof, wherein: for

[0130] Embodiment 19. A compound according to any one of Embodiments 1-15 and 17, or a pharmaceutically acceptable salt thereof, wherein: for

[0131] Embodiment 20. A compound according to any one of Embodiments 1-5, 9-11, 13-16 or 18, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (II): And Ring A is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.

[0132] Embodiment 21. A compound according to any one of Embodiments 1, 2, 4, 6-15, 17 or 19, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (III):

[0133] Embodiment 22. A compound selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

[0134] Embodiment 23. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0135] Embodiment 24. A method of binding interleukin-1 receptor associated kinase 3 (IRAK3), comprising contacting IRAK3 with an effective amount of a compound according to any one of embodiments 1-22 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment 23. Example

[0136] The following examples are for illustration and not limitation. Compounds were named using the automatic name generation tool provided by ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures and supports the Cahn-Ingold-Prelog rule for stereochemistry. Those skilled in the art may modify the methods shown in the illustrative examples to obtain the desired products.

[0137] Salts of compounds described herein can be prepared by standard methods, such as including an acid (eg, TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or stirring the product with an acid solution (eg, aqueous HCl) after chromatographic purification.

[0138] The following abbreviations may be relevant to this application. abbreviation Synthesis Example Example S1. Synthesis of N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine (1)

[0139] Synthesis of Benzyl 4-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate. To a 40 mL vial equipped with a stir bar was added 6,8-dibromoimidazo[1,2-a]pyrazine (0.89 g, 3.2 mmol) and Benzyl 4-(4-aminophenyl)piperazine-1-carboxylate (1.1 equiv, 1.1 g, 3.5 mmol). Isopropyl alcohol (10.7 mL, 0.3 M) and N,N-diisopropylethylamine (2.0 equiv., 1.1 mL, 6.4 mmol) were then added to the vial. The vial was then sealed with a septum and mixed by vortexing. The reaction vessel was heated to 65 °C and stirred for 72 h. The reaction was cooled to room temperature. The reaction mixture was poured into water (20 mL) and mixed by vortexing. Initially, the crude reaction mixture contained a brown sludge, which solidified after thorough mixing with water. The mixture was then 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 provide the product 4-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylic acid benzyl ester (1.37 g, 2.7 mmol, 84% yield) as a light brown solid. LC / MS Method 2: MS (ESI) [M+H] + 508.4,rt:1.71min.

[0140] Synthesis of N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine. To a 20 mL vial containing 4-[4-[(6-bromoimidazo[1,2-a]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylic acid benzyl ester (50.0 mg, 0.099 mmol) was added 10% Pd / C (10.5 mg, 10 mol%). A stirring bar was then added and the vial was sealed with a septum cap. The solid was suspended in methanol (1.0 mL, 0.1 M). The vial was then evacuated and refilled with a balloon containing H2. This process was repeated 5 times. The reaction was then stirred at 22 °C for 72 h. The vial was bubbled with N2 gas to remove traces of H2 gas. The crude reaction mixture was then filtered through a celite pad and carefully rinsed with excess methanol. LCMS analysis of the crude reaction mixture showed 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 / MeCN, containing 0.1% TFA) to provide the product, N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]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:0.18min. 1HNMR (400 MHz, methanol-d4) δ ppm 3.32-3.43 (m, 4H) 3.45-3.54 (m, 4H) 7.15 (d, J = 5.5 Hz, 1H) 7.17-7.23 (m, 2H) 7.50 (d, J = 8.1 Hz, 2H) 7.83 (s, 1H) 7.99 (d, J = 5.4 Hz, 1H) 8.07 (d, J = 1.0 Hz, 1H). Example S2. Synthesis of 5-phenyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine (2)

[0141] Synthesis of tert-butyl 4-(4-((5-bromoimidazo[1,2-a]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-a]pyrazine (402.2 mg, 1.45 mmol) in ethanol (2.69 mL). The reaction was heated to 80 °C and stirred overnight. LCMS indicated that the reaction conversion reached 94% and the reaction was stopped. The ethanol was removed in vacuo and the product was collected 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 / water with 0.1% formic acid) to give the desired product tert-butyl 4-(4-((5-bromoimidazo[1,2-a]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:1.479min.

[0142] Synthesis of tert-butyl 4-(4-((5-phenylimidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate. tert-Butyl 4-[4-[(5-bromoimidazo[1,2-a]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 bubbled with nitrogen for 5 min, then Pd(PPh3)4 (9.76 mg, 0.010 mmol) was added and the mixture was bubbled with nitrogen for 5 min. The solution was heated to 95°C for 16 h. The next day, the solution turned orange. TLC analysis (eluted 3 times with 40% EtOAc / heptane) indicated that the reaction had not reached completion, 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 / water, containing 0.1% formic acid) to obtain the desired product tert-butyl 4-(4-((5-phenylimidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (58.7 mg, 0.124 mmol, 73% yield) as a tan solid. LC / MS Method 1: MS (ESI) [M+H] + 471.4,rt:1.454min.

[0143] Synthesis of 5-phenyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine. To a solution of tert-butyl 4-[4-[(5-phenylimidazo[1,2-a]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (58.7 mg, 0.120 mmol) in methanol (1.2474 mL) was added HCl in dioxane (477.23 μL, 1.91 mmol) at room temperature. The resulting solution was stirred at room temperature for 3 h and 30 min. The mixture was concentrated on a rotary evaporator and the residue was purified by reverse column chromatography (5% to 100% MeOH / water with 0.1% formic acid) to obtain the compound as an impure yellow oil. The oil was re-purified by reverse phase column chromatography (5% to 100% MeOH / water, pH 10) to give the product 5-phenyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine (17.2 mg, 0.046 mmol, 37% yield) as a yellow solid after lyophilization. MS (ESI) [M+H] + 371.1. 1H NMR(400MHz,DMSO-d6)δppm 2.78-2.89(m,4H),2.93-3.06(m,4H),3.30-3.32(m,1H),6.91(br d,J=8.9Hz,2H),7.41(s,1H),7.49-7.62(m,3H),7.64-7.72(m,3H),7.83-7.92(m,3H),9.41(s,1H). Example S3. Synthesis of 5-cyclohexyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine (3)

[0144] Synthesis of tert-butyl 4-(4-((5-(cyclohex-1-en-1-yl)imidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate. To a 0.5-2 mL microwave reaction tube equipped with a stir bar was added tert-butyl 4-[4-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (75 mg, 0.16 mmol), cyclohexen-1-ylboronic acid (39.9 mg, 0.32 mmol) and XPhos-Pd-G3 (10.0 mg, 0.012 mmol) and Xphos (5.7 mg, 0.012 mmol). The reaction vessel was then sealed with a septum and sparged with nitrogen. Then 1,4-dioxane (0.8mL, 0.2M) and 2M sodium carbonate aqueous solution (240μL, 0.295mmol) were added to the reaction vessel via a syringe. The reaction vessel was then sealed with a microwave cap and then mixed by vortexing. The container was then heated to 135°C for 45min under microwave irradiation. After this period of time, the reaction was then cooled to 22°C and filtered through a diatomaceous earth pad. The filter cake was then washed with methanol. The LCMS analysis of the crude reaction mixture revealed the formation of the desired product. The reaction mixture was then concentrated and purified by reverse phase column chromatography (15% to 100% MeCN / water, containing 0.1% TFA). The fractions were then concentrated and dried in vacuo to obtain the product 4-(4-((5-(cyclohex-1-ene-1-yl)imidazo[1,2-a]pyrazine-8-yl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester (60.7mg, 0.128mmol, 80% yield) as an off-white solid. LC / MS method 2: MS (ESI) [M+H] + 475.4,rt:1.76min.

[0145] Synthesis of 5-cyclohexyl-N-(4-(piperazine-1-yl)phenyl)imidazo[1,2-a]pyrazine-8-amine. 4-[4-[[5-(cyclohexene-1-yl)imidazo[1,2-a]pyrazine-8-yl]amino]phenyl]piperazine-1-carboxylic acid tert-butyl ester (39.7 mg, 0.084 mmol) and palladium hydroxide on carbon powder (6.0 mg, 10 mol%) were added to a 20 mL vial equipped with a stirring bar. Methanol (0.03 M, 2.8 mL) was then added and the vial was sealed with a septum cap. The reaction vessel was then evacuated and backfilled with hydrogen (3x). The reaction was then stirred overnight under a hydrogen atmosphere. The next morning, the reaction was filtered through a celite pad and washed with methanol. LCMS analysis of the crude reaction mixture revealed the formation of the desired product with trace amounts of unsaturated isomers remaining. The reaction mixture was purified by reverse phase column chromatography (15% to 100% MeCN / water containing 0.1% TFA). The collected fractions were concentrated and immediately treated with 1:1 TFA / DCM. LCMS analysis of the crude reaction mixture revealed complete deprotection of piperazine. The unpurified residue was subjected to mass-directed HPLC (5% to 100% MeCN / water containing 0.1% formic acid) to provide the product 5-cyclohexyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazine-8-amine (15.4 mg, 0.041 mmol, 48% yield) as a light yellow solid after lyophilization. MS (ESI) [M+H] + 371.1. 1 H NMR (400MHz, methanol-d4) δppm1.45-1.63(m,4H)1.92(br d,J=12.8Hz,2H)2.14(br d,J=12.1Hz,2H)2.95(br t,J=11.2Hz,1H)3.37-3.48(m,8H)6.97(s,1H)7.15(m,2H)7.57(m,2H)7.79(s,1H)8.13(s,1H). Example S4. Synthesis of N-(4-(piperazin-1-yl)phenyl)-5-(o-phenylmethyl)imidazo[1,2-a]pyrazin-8-amine (4)

[0146] Synthesis of tert-butyl 4-(4-((5-(o-phenylmethyl)imidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate. To a dry sealed tube was added tert-butyl 4-[4-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (110.mg, 0.230mmol) and o-phenylmethylboronic acid (38.78mg, 0.290mmol) at room temperature. 1,4-dioxane (2.7463mL) and saturated aqueous NaHCO3 (1.2mL) were then added and the mixture was bubbled with nitrogen for 20 minutes. Pd(PPh3)4 (13.94mg, 0.010mmol) was added in one portion and bubbling with nitrogen 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 20 mL of saturated NaHCO and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered and concentrated. The residue was purified by reverse phase column chromatography (5% to 100% MeOH / water, containing 0.1% formic acid) to obtain the desired product tert-butyl 4-(4-((5-(o-benzyl)imidazo[1,2-a]pyrazine-8-yl)amino)phenyl)piperazine-1-carboxylate (97 mg, 0.184 mmol, 79% yield) as a tan solid. LC / MS Method 1: MS (ESI) [M+H] + 485.4,rt:1.464min.

[0147] Synthesis of N-(4-(piperazin-1-yl)phenyl)-5-(o-phenylmethyl)imidazo[1,2-a]pyrazin-8-amine. To a solution of tert-butyl 4-[4-[[5-(o-phenylmethyl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]piperazine-1-carboxylate (97.mg, 0.20mmol) in methanol (1.2535mL) was added HCl in dioxane (765.79μL, 3.06mmol) at room temperature. The resulting solution was stirred at room temperature. After 4 hours, HPLC analysis indicated approximately 95% conversion. The solution was stirred for another hour and the resulting suspension was then concentrated on a rotary evaporator and the residue was purified by reverse phase column chromatography (5% to 100% MeOH / water, containing 0.1% formic acid) to obtain the product as an impure light yellow solid. The material was re-purified by reverse phase column chromatography (5% to 100% MeOH / water, pH 10) to afford the product N-(4-(piperazin-1-yl)phenyl)-5-(o-phenylmethyl)imidazo[1,2-a]pyrazin-8-amine (19.6 mg, 0.05 mmol, 25% yield) as an off-white solid after lyophilization. [M+H] + 385.2. 1H NMR(400MHz,DMSO-d6)δppm 2.13(s,3H),2.52–2.55(m,1H),2.80–2.88(m,4H),2.96–3.04(m,4H),6.91(d,J=9.0Hz ,2H),7.29(s,2H),7.34–7.50(m,4H),7.60(s,1H),7.87(d,J=9.0Hz,2H),9.38(s,1H). Example S5. Synthesis of N-(4-(piperazin-1-yl)phenyl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine (5)

[0148] Synthesis of tert-butyl 4-(4-((5-(m-benzyl)imidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate. In a microwave vial, a mixture of 2M aqueous Na2CO3 (1.01 mL, 2.03 mmol) and m-benzylboronic acid (91.91 mg, 0.680 mmol) in 1,4-dioxane (5 mL) and tert-butyl 4-[4-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (320 mg, 0.680 mmol) was flushed with N2 for 10 min, then Pd(Ph3P)4 (78.12 mg, 0.070 mmol) was added and the suspension was flushed with nitrogen for another 10 min. The reaction was heated to 100 °C and irradiated in a microwave reactor for 1 h. The reaction was then partitioned between EtOAc / H2O and extracted with EtOAc (2x). The organic layer was then washed with H2O, brine and dried over Na2SO4. The reaction was then concentrated directly onto silica gel and purified by normal chromatography (30% to 100% EtOAc / hexanes) to afford tert-butyl 4-(4-((5-(m-benzyl)imidazo[1,2-a]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:1.504min.

[0149] Synthesis of N-(4-(piperazine-1-yl)phenyl)-5-(o-phenylmethyl)imidazo[1,2-a]pyrazine-8-amine. A solution of tert-butyl 4-[4-[[5-(o-phenylmethyl)imidazo[1,2-a]pyrazine-8-yl]amino]phenyl]piperazine-1-carboxylate (580 mg, 1.2 mmol) in DCM (5 mL) at room temperature was treated with TFA (3.0 mL, 11.76 mmol). The reaction was stirred at room temperature for 4 h. The reaction mixture was concentrated to dryness, collected in DCM and washed with saturated NaHCO3 aqueous solution (1x). The aqueous layer was then stripped with DCM (2x) and the organic layers were combined and concentrated. The resulting residue was purified by reverse phase column chromatography (5% to 100% MeCN / water, containing 0.1% formic acid) to obtain the product N-(4-(piperazin-1-yl)phenyl)-5-(o-phenylmethyl)imidazo[1,2-a]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 (400MHz, DMSO-d6) δppm 2.42 (s, 3H), 3.23 (br s, 4H), 3.31-3.59 (m, 4H), 7.10 (d, J = 8.8Hz, 2H), 7.38-7.43 (m, 1H), 7.44-7.60 (m, 4H), 7.79 (br d,J=7.6Hz,2H),8.08-8.16(m,2H),9.34(br s,2H),10.93(br s,1H). Example S6. Synthesis of N-(4-(piperazin-1-yl)phenyl)-5-(p-phenylmethyl)imidazo[1,2-a]pyrazin-8-amine (6)

[0150] Synthesis of tert-butyl 4-(4-((5-(p-phenylmethyl)imidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate. To a dry sealed tube was added tert-butyl 4-[4-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (64.8 mg, 0.140 mmol) and p-phenylboronic acid (22.6 mg, 0.170 mmol) at room temperature. 1,4-dioxane (3 mL) and saturated aqueous NaHCO3 solution (1 mL) were then added, and the mixture was bubbled with nitrogen for 8 minutes. Pd(PPh3)4 (8.4 mg, 0.010 mmol) was added in one go, and bubbling with nitrogen continued for 10 minutes. The tube was sealed and placed in an oil bath pre-equilibrated to 95°C. The mixture was heated at this temperature overnight. LCMS analysis revealed that the reaction was completely complete. The reaction flask was taken out from the oil bath, and the mixture was cooled to room temperature. The reaction mixture was diluted with 5mL water, and the mixture was extracted with EtOAc (10mL). The phases were separated, and the aqueous layer was extracted with EtOAc (2x 10mL). The combined organic matter was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase column chromatography (5% to 100% MeOH / water, containing 0.1% formic acid) to obtain the product 4-(4-((5-(p-phenylmethyl)imidazo[1,2-a]pyrazine-8-yl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester (57mg, 0.117mmol, 86% yield) as an orange solid. LC / MS method 1: MS (ESI) [M+H] + 485.4,rt:1.507min.

[0151] Synthesis of N-(4-(piperazine-1-yl)phenyl)-5-(p-phenylmethyl)imidazo[1,2-a]pyrazine-8-amine. To a solution of tert-butyl 4-[4-[[5-(p-phenylmethyl)imidazo[1,2-a]pyrazine-8-yl]amino]phenyl]piperazine-1-carboxylate (57.0 mg, 0.120 mmol) in methanol (1 mL) was added HCl in dioxane (450.0 μL, 1.8 mmol) at room temperature. The resulting solution was stirred at room temperature overnight. The next morning, HPLC analysis showed that the reaction was completely complete. The reaction mixture was concentrated and purified by reverse phase column chromatography (5% to 100% MeOH / water, containing 0.1% formic acid) to obtain the product as an impure light yellow solid. The solid was re-purified by reverse phase column chromatography (5% to 100% MeOH / water with pH 10 buffer) to give the product N-(4-(piperazin-1-yl)phenyl)-5-(p-phenylmethyl)imidazo[1,2-a]pyrazin-8-amine (28 mg, 0.074 mmol, 62% product) as a yellow solid after lyophilization. MS (ESI) [M+H] +=385.2. 1 H NMR(400MHz,DMSO-d6)δppm 2.40(s,3H),2.52-2.53(m,1H),2.81-2.86(m,4H),2.97-3.02(m,4H),6.90(d,J=9.3Hz,2H),7 .35-7.41(m,3H),7.57(d,J=8.1Hz,2H),7.65(d,J=1.0Hz,1H),7.83-7.89(m,3H),9.37(s,1H). Example S7. Synthesis of N-(4-(piperazin-1-yl)phenyl)-6-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine (7)

[0152] Synthesis of tert-butyl 4-(4-((6-bromoimidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate. 6,8-Dibromoimidazo[1,2-a]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 equipped with a stir bar. The solids were then dissolved in ethanol (7 mL, 0.5 M) and the vial was then sealed with a septum. The reaction mixture was then stirred for ~5 min before N,N-diisopropylethylamine (1.3 mL, 2.0 equiv., 7.2 mmol) was added. The reaction was then heated to 80 °C and allowed to stir over the weekend. LCMS analysis of the crude reaction mixture revealed complete conversion to the desired product. The reaction mixture was concentrated on silica gel and purified by normal column chromatography (0% to 10% MeOH / DCM) to afford the product as a dark yellow solid (0.9 g, 1.91 mmol, 53% yield). LC / MS Method 2: MS (ESI) [M] + 473.4,rt:1.68min.

[0153] Synthesis of tert-butyl 4-(4-((6-(m-benzyl)imidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate. tert-butyl 4-[4-[(6-bromoimidazo[1,2-a]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (80.mg, 0.170mmol) and m-benzylboronic acid (27.66mg, 0.200mmol) were added to a microwave tube at room temperature. 1,4-dioxane (3mL) and saturated aqueous NaHCO3 solution (1mL) were then added, and the mixture was bubbled with nitrogen for 5min. Pd(PPh3)4 (11.54mg, 0.010mmol) was added in one portion, and bubbling with nitrogen continued for 5min. The reaction mixture was heated to 100°C and irradiated with microwaves for 1h. After cooling to room temperature, LCMS indicated complete conversion to the desired product. The reaction mixture was diluted with 5 mL of water, and the mixture was extracted with EtOAc. The phases were separated, and the aqueous phase was washed with EtOAc (2x). 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 / water, containing 0.1% formic acid) to obtain the product 4-(4-((6-(m-benzyl)imidazo[1,2-a]pyrazine-8-yl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester (59 mg, mmol, 72% yield) as a light yellow color. LC / MS method 1: MS (ESI) [M+H] + 485.4,rt:1.536min.

[0154] Synthesis of N-(4-(piperazine-1-yl)phenyl)-6-(m-benzyl)imidazo[1,2-a]pyrazine-8-amine. To a solution of tert-butyl 4-[4-[[6-(m-benzyl)imidazo[1,2-a]pyrazine-8-yl]amino]phenyl]piperazine-1-carbamate (59.0 mg, 0.120 mmol) in DCM was added 4M HCl in dioxane (0.49 mL, 1.95 mmol) at room temperature. The resulting solution was stirred at room temperature overnight. LCMS showed complete conversion. The mixture was concentrated to dryness and dissolved in 25 mL 1:1 MeOH / DCM. The solution was filtered through a NaHCO pad and concentrated to dryness. The crude residue was purified by reverse column chromatography (5% to 100% MeOH / water with 0.1% formic acid) to afford the product N-(4-(piperazin-1-yl)phenyl)-6-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine (20.6 mg, 0.054 mmol, 44% yield) as a yellow solid after lyophilization. MS (ESI) [M+H] + 385.2. 1H NMR(400MHz,DMSO-d6)δppm 2.37–2.43(m,3H),2.51–2.54(m,1H),2.78–2.90(m,4H),2.96–3.08(m,4H),6.95(d,J=9.0Hz,2H),7.19(d,J=7.6Hz ,1H),7.37(t,J=7.6Hz,1H),7.62(d,J=1.0Hz,1H),7.73–7.86(m,2H),7.91–8.04(m,3H),8.55(s,1H),9.44(s,1H). Example S8. Synthesis of 1-(4-(4-((5-(m-phenylmethyl)imidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)butan-1-one (8)

[0155] HATU (13.6 mg, 1.0 equiv) was added to a 2 mL vial equipped with 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 ~5 min before the addition of N-(4-(piperazin-1-yl)phenyl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine; hydrochloride (15 mg, 0.037 mmol). The vial was then sealed with a cap and stirred overnight at room temperature. LCMS analysis revealed ~66% conversion to the desired product. The reaction mixture was then purified by reverse phase column chromatography (15% to 100% MeCN / water with 0.1% TFA) to afford the product 1-(4-(4-((5-(m-benzyl)imidazo[1,2-a]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, 3H), 1.67 (sxt, J = 7.5 Hz, 2H), 2.42-2.48 (m, 5H), 3.23-3.35 (m, 4H) (overlapping with d4-MeOH), 3.76 (dt, J = 10.6, 5.2 Hz, 4H), 7.07 (s, 1H), 7.20 (d, J = 8.9 Hz, 2H), 7.41-7.52 (m, 6H), 7.83 (s, 1H), 7.96 (s, 1H). Example S9. Synthesis of N-(4-(4-butylpiperazin-1-yl)phenyl)-5-(m-phenylmethyl)imidazo[1,2-a]pyrazin-8-amine (9)

[0156] N-(4-(Piperazin-1-yl)phenyl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine; hydrochloride (15 mg, 0.036 mmol) was added to a 1-dram vial equipped with a stir bar. DCE (42 μL) was then added followed by triethylamine (8 μL, 1.5 equiv.). The resulting solution was stirred for ~15 min. At this time, 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 revealed ~88% conversion to the desired product. The reaction mixture was then purified by reverse phase column chromatography (15% to 100% MeCN / water, containing 0.1% TFA) to obtain the product N-(4-(4-butylpiperazin-1-yl)phenyl)-5-(m-benzyl)imidazo[1,2-a]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 (400MHz, methanol-d4) δppm 1.03 (t, J = 7.4Hz, 3H), 1.47 (sxt, J = 7.5Hz, 2H), 1.73-1.83 (m, 2H), 2.45 (s, 3H), 3.11 (br d,J=11.5Hz,2H),3.18-3.28(m,4H),3.70(br d,J=11.0Hz,2H),3.90(br d,J=11.4Hz,2H),7.17(d,J=8.9Hz,2H),7.21(s,1H),7.38-7.50(m,4H),7.66(d,J=8.9Hz,2H),7.76(s,1H),7.92(s,1H). Example S10. Synthesis of N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine (10)

[0157] Synthesis of tert-butyl 4-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate. 5,8-Dibromoimidazo[1,2-a]pyrazine (500 mg, 1.8 mmol), tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (500 mg, 1.05 equiv.) and vitanoic acid (1.8 g, 10 equiv.) were added to a 2.0-5.0 mL microwave tube equipped with a stir bar. The tube was then sealed with a septum and heated to 100 °C for 1 h under microwave irradiation. LCMS analysis of the reaction mixture revealed complete conversion of the starting material to the desired product (~10% boc cleavage 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 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 / water, containing 0.1% TFA) to obtain the product tert-butyl 4-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (300 mg, 0.642 mmol, 35% yield) as a tan solid. LC / MS method 2: MS (ESI) [M] 462.3, rt: 1.66 min.

[0158] Synthesis of N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine. To a 0.5-2 mL microwave reaction tube equipped with a stir bar was added tert-butyl 4-[4-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (200 mg, 0.43 mmol), m-benzylboronic 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 sparged with nitrogen. 1,4-dioxane (2.2 mL, 0.2 M) and 2 M aqueous sodium carbonate solution (650 μL, 3 equiv.) were then added to the reaction vessel via syringe. The reaction vessel is then sealed with a septum cap and then mixed by vortex. The container is then heated at 135 ° C for 45 min under microwave irradiation. After this period of time, the reaction is cooled to 22 ° C and filtered through a diatomaceous earth pad. The filter cake is then washed with EtOAc. The LCMS analysis of the crude reaction mixture reveals that the starting material is completely converted into the desired product. The reaction mixture is then purified by reverse phase column chromatography (25% to 100% MeCN / water, containing 0.1% TFA). The fraction is then concentrated and immediately dissolved in 1: 1DCM / TFA and stirred at room temperature for 1h, and LCMS analysis reveals that the desired product is completely deprotected. The reaction mixture was purified again by reverse phase column chromatography (15% to 100% MeCN / water, containing 0.1% TFA) to obtain N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine (141 mg, 0.379 mmol, 88% yield) as a light yellow solid after lyophilization. MS (ESI) [M+H] + 374.5. 1 H NMR (400MHz, methanol-d4) δppm 2.27-2.41(m,4H),2.45(s,3H),3.19-3.29(m,2H),3.59(br d,J=13.2Hz,2H),4.60(tt,J=10.1,4.8Hz,1H),7.31(s,1H),7.39-7.51(m,4H),7.81(s,2H),7.94(s,1H),8.24(s,1H). Example S11. Synthesis of 4-(piperidin-4-yl)-N-(5-(m-phenylmethyl)imidazo[1,2-a]pyrazin-8-yl)thiazol-2-amine (11)

[0159] Synthesis of tert-butyl 4-(2-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)thiazol-4-yl)piperidine-1-carboxylate. 5,8-Dibromoimidazo[1,2-a]pyrazine (200.mg, 0.7200mmol), tert-butyl 4-(2-aminothiazol-4-yl)piperidine-1-carboxylate (245.61mg, 0.8700mmol), sodium tert-butoxide (104.11mg, 1.08mmol), Pd2(dba)3 (33.07mg, 0.0400mmol) and Xantphos (41.79mg, 0.070mmol) were added to a 20mL bottle equipped with a stir bar. The bottle was then sealed with a septum and bubbled with nitrogen. Toluene (7.2 mL) was then added, and the reaction mixture was bubbled with a nitrogen balloon while ultrasonicating for 2 minutes, then the reaction vessel was heated to 100 ° C, and stirred for 16 hours. The formation of the desired product was revealed by LCMS analysis the next morning. The reaction mixture was then filtered, concentrated and purified by reverse column chromatography. The fractions were collected and alkalized with aqueous sodium carbonate solution before concentration. The residual aqueous mixture was then extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated to obtain the product 4-(2-((5-bromoimidazo[1,2-a]pyrazine-8-yl)amino)thiazole-4-yl)piperidine-1-carboxylic acid tert-butyl ester (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.

[0160] Synthesis of 4-(piperidin-4-yl)-N-(5-(m-benzyl)imidazo[1,2-a]pyrazin-8-yl)thiazol-2-amine. To a dram bottle equipped with a stir bar was added tert-butyl 4-[2-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]thiazol-4-yl]piperidine-1-carboxylate (24.0 mg, 0.050 mmol), m-benzylboronic 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 then sealed with a septum and sparged with nitrogen. 1,4-dioxane (0.7614 mL) and water (0.0730 mL) were then added to the reaction vessel via syringe. The reaction vessel was then sealed with a septum cap and then mixed by vortexing. The container was then heated at 100 ° C for 16 hours. After this period of time, the reaction was cooled to 22 ° C and filtered through a diatomaceous earth pad. The filter cake was then washed with EtOAc. LCMS analysis of the crude reaction mixture revealed that the starting material was completely converted into the desired product. The reaction mixture was then purified by reverse column chromatography (25% to 100% MeCN / water, containing 0.1% TFA). The fractions were then concentrated and then dissolved in 1:1DCM / TFA and stirred at room temperature for 1h, and LCMS analysis revealed that the desired product was completely deprotected. The reaction mixture was purified again by reverse column chromatography (15% to 100% MeCN / water, containing 0.1% TFA) to obtain the synthesis of the product 4-(piperidin-4-yl)-N-(5-(m-benzyl)imidazo[1,2-a]pyrazine-8-yl)thiazole-2-amine as a light yellow solid after freeze-drying (8.9 mg, 0.022 mmol, 45% yield). MS (ESI) [(M+2H) / 2] + 196.5. 1 H NMR (400MHz, methanol-d4) δppm 1.90-2.03(m,2H),2.30(br d,J=12.5Hz,2H),2.46(s,3H),3.01-3.11(m,1H),3.11-3.21(m,2H),3.51(br d,J=12.8Hz,2H),6.79(s,1H),7.37-7.44(m,1H),7.47-7.54(m,3H),7.70(s,1H),7.82(s,1H),7.97(s,1H). Example S12. Synthesis of N-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine (12)

[0161] 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), tert-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 bottle equipped with a stirring bar. The reaction vessel was then sealed with a septum and the solid was suspended in DMF (7.2 mL). The reaction was then heated to 95 °C and stirred overnight. The next morning, cold water (~25 mL) was added to the reaction vessel. The precipitate was filtered and washed with cold water and transferred to a 250 mL RBF equipped with a stirring bar. 10% palladium on carbon (200 mg, 1.88 mmol) was then added and the flask was then capped with a septum and ethanol (18.8 mL) was added. The container was then evacuated and backfilled with hydrogen 3 times. The reaction was stirred at room temperature for 4 h. The container was then removed and the flask was purged with nitrogen. The mixture was then filtered through a pad of celite and the filtrate was concentrated. The product 4-(4-amino-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.823 mmol, 19% yield) was obtained as a yellow solid by reverse phase silica gel column chromatography (5% to 100% MeCN / water, containing 0.1% ammonium hydroxide). LC / MS method 2: MS (ESI) [M+Ht-Bu] + 212.5,rt:1.29min.

[0162] Synthesis of tert-butyl 4-(4-((5-bromoimidazo[1,2-a]pyrazine-8-yl)amino)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate. 5,8-Dibromoimidazo[1,2-a]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), Pd2(dba)3 (33.1 mg, 0.040 mmol) and Xantphos (41.8 mg, 0.070 mmol) were added to a 20 mL bottle equipped with a stirring bar. The bottle was then sealed with an isolation film and purged with nitrogen. Toluene (7.2 mL) was then added, and the reaction mixture was bubbled with a nitrogen balloon while sonicating for 2 minutes. The reaction vessel was then heated to 100 ° C and stirred for 16 hours. LCMS analysis revealed the formation of the desired product the next morning. The reaction mixture was then filtered, concentrated and purified by reverse column chromatography (5% to 100% MeCN / water, containing 0.1% TFA). The fractions were collected and alkalized with saturated aqueous sodium bicarbonate before concentration. The residual aqueous mixture was then extracted with EtOAc. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated to obtain the product 4-[4-[(5-bromoimidazo[1,2-a]pyrazine-8-yl)amino]triazole-2-yl]piperidine-1-carboxylic acid tert-butyl ester (158 mg, 0.3069 mmol, 42.5% yield) as a brown oil. LC / MS method 2: MS (ESI) [M] + 463.4,rt:1.75min.

[0163] Synthesis of N-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine. To a 1 dram bottle equipped with a stir bar was added tert-butyl 4-[4-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]triazol-2-yl]piperidine-1-carboxylate (158.0 mg, 0.340 mmol), m-benzylboronic 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 is then sealed with a septum cap and then mixed by vortex. The container is then heated at 100 ° C for 16 hours. After this period of time, the reaction is cooled to 22 ° C and filtered through a diatomaceous earth pad. The filter cake is then washed with EtOAc. The LCMS analysis of the crude reaction mixture explains that the starting material is completely converted into the desired product. The reaction mixture is then purified by reverse phase column chromatography (25% to 100% MeCN / water, containing 0.1% TFA). The fraction is then concentrated and immediately dissolved in 1: 1DCM / TFA and stirred at room temperature for 1h, and LCMS analysis reveals that the desired product is completely deprotected. The reaction mixture was purified again by reverse phase column chromatography (15% to 100% MeCN in water with 0.1% TFA) to obtain the product N-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine (104 mg, 0.272 mmol, 80% yield) as a white solid after lyophilization. MS (ESI) [M+H] + 375.5. 1 H NMR (400 MHz, methanol-d4) δ ppm 2.39-2.52 (m, 7H), 3.25-3.3.28 (m, 2H), 3.53-3.57 (m, 2H), 4.82-4.87 (m, 1H), 7.38-7.39 (m, 1H) 7.46-7.56 (m, 4H) 7.75 (s, 1H) 7.93 (s, 1H), 8.25 (s, 1H). Example S13. Synthesis of 5-(piperidin-4-yl)-N-(5-(m-phenylmethyl)imidazo[1,2-a]pyrazin-8-yl)thiazol-2-amine (13)

[0164] Synthesis of tert-butyl 4-(2-((5-bromoimidazo[1,2-a]pyrazine-8-yl)amino)thiazol-5-yl)piperidine-1-carboxylate. 5,8-Dibromoimidazo[1,2-a]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), Pd2(dba)3 (33.07 mg, 0.040 mmol) and Xantphos (41.79 mg, 0.0700 mmol) were added to a 20 mL bottle equipped with a stirring bar. The bottle was then sealed with an septum and purged with nitrogen. Toluene (7.2 mL) was then added, and the reaction mixture was bubbled with nitrogen while sonicating for 2 minutes. The reaction vessel was then heated to 100 °C and stirred for 16 hours. The next morning, LCMS analysis revealed the formation of the desired product. The reaction mixture was then filtered, concentrated and purified by reverse phase column chromatography. The fractions were collected and basified with saturated aqueous sodium bicarbonate before concentration. The residual aqueous mixture was then extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated to obtain the product tert-butyl 4-[2-[(5-bromoimidazo[1,2-a]pyrazine-8-yl)amino]thiazole-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:1.77min.

[0165] Synthesis of 5-(piperidin-4-yl)-N-(5-(m-benzyl)imidazo[1,2-a]pyrazin-8-yl)thiazol-2-amine. To a 1 dram bottle equipped with a stir bar was added tert-butyl 4-[2-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]thiazol-5-yl]piperidine-1-carboxylate (140.0 mg, 0.2900 mmol), m-benzylboronic 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 then sealed with a septum and purged with nitrogen. 1,4-dioxane (2.6 mL) and water (0.25 mL) were then added to the reaction vessel via syringe. The reaction vessel was then sealed with a septum cap and then mixed by vortexing. The container is then heated to 100 ° C for 16 hours. After this period of time, the reaction is cooled to 22 ° C and filtered through a diatomaceous earth pad. The filter cake is then washed with EtOAc. LCMS analysis of the crude reaction mixture reveals that the starting material is completely converted into the desired product. The reaction mixture is then purified by reverse column chromatography (25% to 100% MeCN / water, containing 0.1% TFA). The fraction is then concentrated and then dissolved in 1:1DCM / TFA and stirred at room temperature for 1h, and LCMS analysis reveals that the desired product is completely deprotected. The reaction mixture is purified again by reverse column chromatography (15% to 100% MeCN / water, containing 0.1% TFA) to obtain the product 5-(piperidin-4-yl)-N-(5-(m-benzyl)imidazo[1,2-a]pyrazine-8-yl)thiazole-2-amine (34.4mg, 0.086mmol, 29% yield) as a yellow solid after freeze-drying. MS (ESI) [M+H] + 391.5. 1 H NMR (400 MHz, methanol-d4) δ ppm 1.86-2.01 (m, 2H), 2.23-2.35 (m, 2H), 2.47 (s, 3H), 3.11-3.24 (m, 3H), 3.45-3.56 (m, 2H), 7.24 (s, 1H), 7.39-7.47 (m, 1H) 7.47-7.56 (m, 3H) 7.86 (s, 1H), 7.96 (s, 1H), 8.05 (s, 1H). Example S14. Synthesis of N-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine (14)

[0166] Synthesis of tert-butyl 4-(3-((5-bromoimidazo[1,2-a]pyrazine-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate. 5,8-Dibromoimidazo[1,2-a]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), Pd2(dba)3 (33.1 mg, 0.040 mmol) and Xantphos (41.8 mg, 0.070 mmol) were added to a 20 mL bottle equipped with a stirring bar. The bottle was then sealed with an isolation film and purged with nitrogen. Toluene (7.2 mL) was then added, and the reaction mixture was bubbled with a nitrogen balloon while sonicating for 2 minutes. The reaction vessel was then heated to 100 °C and stirred for 16 hours. LCMS analysis the next morning revealed the formation of the desired product. The reaction mixture was then filtered, concentrated and purified by reverse phase column chromatography. The fractions were collected and basified with saturated aqueous sodium bicarbonate solution before concentration. The residual aqueous mixture was then extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated to obtain the product tert-butyl 4-[3-[(5-bromoimidazo[1,2-a]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:1.59min.

[0167] Synthesis of N-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-5-(m-benzyl)imidazo[1,2-a]pyrazin-8-amine. To a 1 dram bottle equipped with a stir bar was added tert-butyl 4-[3-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (240.0 mg, 0.520 mmol), m-benzylboronic 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 then sealed with a septum and purged with nitrogen. 1,4-Dioxane (4.7 mL) and water (0.46 mL) were then added to the reaction vessel via syringe. The reaction vessel was then sealed with a septum cap and mixed by vortexing. The container was then heated at 100 ° C for 16 hours. After this period of time, the reaction was cooled to 22 ° C and filtered through a diatomaceous earth pad. The filter cake was then washed with EtOAc. The LCMS analysis of the crude reaction mixture revealed that the starting material was completely converted into the desired product. The reaction mixture was then purified by reverse column chromatography (25% to 100% MeCN / water, containing 0.1% TFA). The fraction was then concentrated and then dissolved in 1:1DCM / TFA and stirred at room temperature for 1h, and LCMS analysis revealed that the desired product was completely deprotected. The reaction mixture was purified by reverse column chromatography (15% to 100% MeCN / water, containing 0.1% TFA) again, providing the product N-(1-(piperidin-4-yl)-1H-pyrazole-3-yl)-5-(m-benzyl)imidazo[1,2-a]pyrazine-8-amine (162mg, 0.41mmol, 79% yield) as a light yellow solid after freeze-drying. LC / MS method 2: MS (ESI) [M+H] + 374.5,rt:1.11min. 1 H NMR (400MHz, methanol-d4) δppm 2.25-2.42(m,4H),2.45(s,3H),3.08-3.22(m,2H),3.51-3.61(m,2H),4.62-4.73(m,1H),6.39-6.48(m,1H), 7.33(s,1H),7.35-7.41(m,1H),7.41-7.51(m,3H),7.60-7.66(m,1H),7.73-7.80(m,1H),7.90-7.96(m,1H). Example S15. Synthesis of 3-(piperidin-4-yl)-N-(5-(m-phenylmethyl)imidazo[1,2-a]pyrazin-8-yl)isoxazol-5-amine (15)

[0168] Synthesis of tert-butyl 4-(5-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)isoxazol-3-yl)piperidine-1-carboxylate. 5,8-Dibromoimidazo[1,2-a]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), Pd2(dba)3 (33.1 mg, 0.040 mmol) and Xantphos (41.8 mg, 0.070 mmol) were added to a 20 mL bottle equipped with a stirring bar. The bottle was then sealed with an isolation septum and purged with nitrogen. Toluene (7.2 mL) was then added, and the reaction mixture was bubbled with a nitrogen balloon while sonicating for 2 minutes. The reaction vessel was then heated to 100°C and stirred for 16 hours. The next morning, LCMS analysis revealed the formation of the desired product. The reaction mixture was then filtered, concentrated and purified by reverse phase column chromatography (5% to 100% MeCN / water, containing 0.1% TFA). The fractions were collected and alkalized with saturated aqueous sodium bicarbonate solution before concentration. The residual aqueous mixture was extracted with EtOAc. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated to obtain the product 4-[5-[(5-bromoimidazo[1,2-a]pyrazine-8-yl)amino]isoxazole-3-yl]piperidine-1-carboxylic acid tert-butyl ester (145 mg, 0.3067 mmol, 42.465% yield) as an off-white solid. LC / MS method 2: MS (ESI) [M+Na] + 485.3,rt:1.75min.

[0169] Synthesis of 3-(piperidin-4-yl)-N-(5-(m-benzyl)imidazo[1,2-a]pyrazin-8-yl)isoxazol-5-amine. To a 1 dram bottle equipped with a stir bar was added tert-butyl 4-[5-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]isoxazol-3-yl]piperidine-1-carboxylate (145.0 mg, 0.310 mmol), m-benzylboronic 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 then sealed with a septum and purged with nitrogen. 1,4-dioxane (2.8 mL) and water (0.28 mL) were then added to the reaction vessel via syringe. The reaction vessel was then sealed with a septum cap and then mixed by vortexing. The container is then heated at 100 ° C for 16 hours. After this period of time, the reaction is cooled to 22 ° C and filtered through a diatomaceous earth pad. The filter cake is then washed with EtOAc. The LCMS analysis of the crude reaction mixture reveals that the starting material is completely converted into the desired product. The reaction mixture is then purified by reverse phase column chromatography (25% to 100% MeCN / water, containing 0.1% TFA). The fraction is then concentrated and immediately dissolved in 1:1DCM / TFA and stirred at room temperature for 1h, and LCMS analysis reveals that the desired product is completely deprotected. The reaction mixture is again purified by reverse column chromatography (15% to 100% MeCN / water, containing 0.1% TFA) to obtain the product 3-(piperidin-4-yl)-N-(5-(m-benzyl)imidazo[1,2-a]pyrazine-8-yl)isoxazole-5-amine (23.6mg, 0.061mmol, 19% yield) as a tan solid after freeze-drying. LC / MS method 2: MS (ESI) [M+H] + 375.5,rt:1.14min. 1 H NMR (400 MHz, methanol-d4) δ ppm 2.01-2.14 (m, 2H), 2.26-2.36 (m, 2H), 2.48 (s, 3H), 3.10-3.21 (m, 3H), 3.44-3.53 (m, 2H), 6.65 (s, 1H), 7.36-7.41 (m, 1H), 7.42-7.52 (m, 3H), 7.52-7.56 (m, 1H), 7.66-7.72 (s, 1H), 7.82-7.88 (s, 1H). Biological Examples Example B1. IRAK3 biological binding assay

[0170] Eu kinase binding assays were performed as described by the supplier (ThermoFisher Scientific Waltham, MA). In brief, 100X compound solutions were prepared in DMSO by serially diluting 10mM stock solutions in 384-well plates using 3-fold intervals to reach final concentrations. 1 μL of compound serial dilutions were added to the corresponding wells of a 384-well plate containing 32.3uL 1x buffer (50mM HEPES pH7.4, 10nM MgCl2, 1mM EGTA, 0.01% Brij-35). 5 μL of buffer-diluted compounds were transferred to the wells of the corresponding 384-well assay plates. 5uL 3X tracers were transferred to each well of the assay plate to a final tracer concentration of 10nM. Finally, 5uL 3X Eu-Anti-GST and IRAK3 mixtures were transferred to each well to a final concentration of 2nM and 10nM, respectively. The reaction was incubated for 1 hour at room temperature. The TR-FRET signal of the interaction was read using an Envision plate reader at room temperature (λex 340 / λem 665 / λem 615) with a delay time of 100 μs and an integration time of 200 μs. The IC of the following compounds was determined using this assay 50 The results are shown in Table 2. Table 2. IRAK3 biological binding assay. Compound No. <![CDATA[IRAK3 TR-FRET IC 50 (nM)]]> 1 4680 2 60 3 109 4 393 5 22 6 448 7 88 8 32 9 24 10 5 11 2499 12 59 13 1093 14 >10000 15 100

[0171] Although the present invention has been described in some detail by way of illustration and example for the purpose of clear understanding, these descriptions and examples should not be construed as limiting the scope of the present invention. The disclosures of all patents and scientific literature cited herein are expressly incorporated herein in their entirety by reference.

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is C6-C 10 Aryl or 5- to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; R 1 H, C6-C 10 Aryl or C3-C6 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 1-5 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 ; R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl or -C(O)(C1-C6 alkyl); R 3a and R 3b are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -C(O)(C1-C6 alkyl); and X is CH or N.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Ring A is C6-C 10 Aryl.

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

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: Ring A is 5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 1 For H.

6. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 1 is a C3-C6 cycloalkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, -OH and -CN.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a C3-C6 cycloalkyl group.

8. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 1 is a C6-C6 alkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, -OH and -CN. 10 Aryl.

9. A compound according to any one of claims 1 to 4, 6 and 7 or a pharmaceutically acceptable salt thereof, wherein: R 1 for 10. The compound according to any one of claims 1 to 4 and 8 or a pharmaceutically acceptable salt thereof, wherein: R 1 for 11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein: W is NR 2 or CR 3a R 3b ; R 2 is H, C1-C6 alkyl or -C(O)(C1-C3 alkyl); and R 3a and R 3b are independently H, C1-C3 alkyl or -C(O)(C1-C6 alkyl).

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein: W is NR 2 ;as well as R 2 It is H, C1-C6 alkyl or -C(O)(C1-C3 alkyl).

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

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

15. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein: for 16. A compound according to any one of claims 1 to 12 and 14 or a pharmaceutically acceptable salt thereof, wherein: for 17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein the compound is of formula (II) or (III): wherein Ring A is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; 18. A compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the 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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