Substituted imidazopyrazine compounds as ligand-targeted degraders of IRAK3

Abstract

Provided herein are compounds and compositions thereof for modulating IRAK3. In some embodiments, the compounds and compositions are provided for the treatment of cancer.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 391,969, filed July 25, 2022, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates generally to compounds and compositions, as well as methods for making and using said compounds and compositions (eg, for treating cancer). [Background technology]

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

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

[0005] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. Damaged, misfolded, or excess proteins are selectively identified and removed via the ubiquitin-proteasome pathway (UPP). The UPP plays a central role in regulating almost all intracellular processes. Protein ubiquitination is achieved by E3 ubiquitin ligases, which bind to proteins and attach ubiquitin molecules to them, leading to their proteasomal degradation.

[0006] The therapeutic use of UPP has attracted considerable interest (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising approach is the use of proteolysis-targeting chimeric molecules (PROTACs), which remove unwanted proteins through proteolysis (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTACS are ligand-targeted degraders that combine an E3 ligase with a target protein for degradation. These bivalent molecules typically consist of an E3 ligase ligand and a small linker that binds to the target protein. PROTACs position the E3 ligase at the appropriate distance and orientation relative to the target protein, allowing it to ubiquitinate the target protein. The ubiquitinated target protein is then recognized by the proteasome for degradation.

[0007] Thus, in one embodiment, provided herein are compounds that target IRAK3 for degradation.

[0008] (Summary of the Invention) In certain embodiments, the present disclosure provides compounds and compositions for degrading IRAK3.In various embodiments, compounds and compositions can be used for cancer treatment.In various embodiments, compounds and compositions can be used for enhancing immunity in the subject who receives vaccine.

[0009] The present embodiments may be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments.

[0010] Embodiment A1. Formula (I): [ka] [In the formula, Ring A is C6-C 10 aryl or 5-6 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; Ring B is C6-C 10 aryl or C3-C6 cycloalkyl, each of which is optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN; X is CH or N; L is -O(C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)-O-(C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)- or -C(O)(6- to 11-membered spiroheterocyclene)-; R 1 is H or C1-C6 alkyl; and R 2a and R 2bare each H or together form an oxo group. or a pharmaceutically acceptable salt thereof.

[0011] Embodiment A2. Ring A is C6-C 10 The compound of embodiment A1, or a pharmaceutically acceptable salt thereof, wherein: R is aryl.

[0012] Embodiment A3. A compound of Embodiment A1, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5-6 membered heteroaryl, said heteroaryl containing 1 to 3 nitrogen atoms.

[0013] Embodiment A4. Ring A is [ka] or a pharmaceutically acceptable salt thereof.

[0014] Embodiment A5. Ring A is [ka] or a pharmaceutically acceptable salt thereof.

[0015] Embodiment A6. Ring B is a C6-C6 alkyl optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl. 10 The compound of any one of embodiments A1 to A5, or a pharmaceutically acceptable salt thereof, wherein: R is aryl.

[0016] Embodiment A7. Ring B is a C6-C alkyl optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl. 10 The compound of embodiment A6, or a pharmaceutically acceptable salt thereof, wherein: R is aryl.

[0017] Embodiment A8. Ring B is [ka] or a pharmaceutically acceptable salt thereof.

[0018] Embodiment A9. A compound according to any one of Embodiments A1-A8, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0019] Embodiment A10. A compound according to any one of Embodiments A1-A8, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0020] Embodiment A11. L is -O(C1-C3 alkylene)C(O)-, -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)C(O)-, -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)-O-(C1-C3 alkylene)C(O)-, -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)- or -C(O)(10-11 membered spiroheterocyclene)-; and R 1 A compound according to any one of embodiments A1 to A10, or a pharmaceutically acceptable salt thereof, wherein is H.

[0021] Embodiment A12. L is [ka] or a pharmaceutically acceptable salt thereof.

[0022] Embodiment A13.R 2a and R 2b and R are each H; or a pharmaceutically acceptable salt thereof.

[0023] Embodiment A14.R 2a and R2b or a pharmaceutically acceptable salt thereof. The compound according to any one of embodiments A1 to A12, wherein: taken together form an oxo group.

[0024] Embodiment A15. The compound is represented by Formula (II), (IIIa), (IIIb) or (IV): [ka] or a pharmaceutically acceptable salt thereof.

[0025] Embodiment A16. A compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0026] Embodiment A17. A pharmaceutical composition comprising a compound according to any one of Embodiments A1-A16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0027] Embodiment A18. A method for modulating interleukin-1 receptor-associated kinase 3 (IRAK3), comprising contacting IRAK3 with an effective amount of a compound according to any one of Embodiments A1 to A16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment A17.

[0028] Embodiment A19. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound described in any one of Embodiments A1 to A16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment A17; optionally, the cancer is selected from bladder cancer, breast cancer, esophageal cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma, and gastric cancer.

[0029] Embodiment A20. A method for enhancing immunity in a subject receiving a vaccine, comprising administering to the subject an effective amount of a compound according to any one of Embodiments A1 to A16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment A17.

[0030] (definition) As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" are intended to specify the presence of the stated features or components as referred to, but do not exclude the presence or additional of one or more features, components, or groups thereof. Furthermore, the terms "comprising" and "including" are also intended to include examples encompassed by the term "consisting of." Consequently, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0031] The term "consisting of" means that an object has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components that make up the object. In other embodiments, the term "consisting of" excludes from the scope of the subsequent description other features or components, except those that are not essential to the technical effect being achieved.

[0032] As used herein, the term "or" is to be interpreted as an inclusive "or" meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C."

[0033] In the present description, any concentration range, percentage range, percentage range, or integer range is understood to include any integer within the stated range, and, where appropriate, fractions thereof (such as tenths and hundredths of integers), unless otherwise indicated. Also, any numerical ranges recited herein for any physical characteristic, such as polymer subunits, size, or thickness, are understood to include every integer within the recited range, unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the stated range, value, or structure, unless otherwise indicated.

[0034] An "alkyl" group is an alkyl group containing 1 to 10 carbon atoms (C1-C 10

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

[0035] An "alkylene" group refers to the same residues as alkyl, but which are divalent. Particular alkylene groups contain 1 to 10 carbon atoms (C-C 10 alkylene), typically having 1 to 8 carbon atoms (C1-C8 alkylene), or in some embodiments 1 to 6 carbon atoms (C1-C6 alkylene) or 1 to 3 carbon atoms (C1-C3 alkylene). Examples of alkylene include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), heptylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), and the like.

[0036] A "cycloalkyl" group refers to a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms (C3-C6) having a single ring or multiple fused or bridged rings, which may be optionally substituted.10 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. Examples of saturated cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, or multiple ring or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, and the like. The cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol.

[0037] "Heterocyclyl" refers to a non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are replaced with a heteroatom independently selected from O, S, and N. In some embodiments, heterocyclyl groups contain 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyl groups can also be attached to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). Heterocyclyl groups can be substituted or unsubstituted. Heterocyclyl groups encompass saturated and partially saturated ring systems. Furthermore, the term heterocyclyl is intended to encompass non-aromatic rings containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of attachment to the rest of the molecule. The term also includes bridged polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4 dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be mono- or di-substituted, including, but not limited to, pyridyl or morpholinyl groups that are di-, tri-, tetra-, pentad or hexa-substituted or di-substituted with various substituents such as those listed below.

[0038] A "heterocyclylene" group refers to a divalent "heterocyclyl" group.

[0039] An "aryl" group is an aromatic carbocyclic group (C6-C8) having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) and having 6 to 14 carbon atoms. 14 In certain embodiments, an aryl group has 6 to 14 carbon atoms (C6-C8) in the ring portion of the aryl group. 14 aryl), and in other embodiments, 6 to 12 carbon atoms (C-C 12 aryl) or 6 to 10 carbon atoms (C6-C 10 Also included are groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl). Particular aryls include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl).

[0040] A "heteroaryl" group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, with the remaining atoms being carbon atoms. In certain embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in other embodiments, 6 to 9, or even 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azaindolyl), Heteroaryl groups include, but are not limited to, benzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4 dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be substituted or unsubstituted.

[0041] "Halogen" or "halo" means fluorine, chlorine, bromine or iodine.

[0042] An "alkoxy" group is an --O-(alkyl), where alkyl is defined above.

[0043] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo groups, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms and is substituted with one or more halo groups (C-C haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halo groups (C-C haloalkyl). The halo groups may all be the same or different. Unless otherwise specified, the haloalkyl group is optionally substituted.

[0044] With the exception of alkyl groups, when groups described herein are said to be "substituted," they may be substituted with any suitable substituent. Exemplary substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH), O(alkyl)aminocarbonyl; monocyclic or fused or unfused rings. cycloalkyl, which may be monocyclic or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0045] Embodiments of the present disclosure are meant to include pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein (e.g., compounds of Formula (I)).

[0046] As used herein, the term " pharmaceutically acceptable salts " refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, metal salts derived from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts derived from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloride, isethionic acid, lactate, maleic acid, malate, mandelate, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Specific examples of salts include hydrochloride, formate, and mesylate. Others are well known in the art, see, e.g., Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).

[0047] As used herein, unless otherwise specified, the terms "stereoisomer" or "stereoisomerically pure" refer to one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound is one that contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound; one that contains more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound; one that contains more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound; or one that contains more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound. The compounds disclosed herein contain chiral centers and can exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

[0048] The use of stereoisomerically pure forms of the compounds disclosed herein, as well as mixtures of those forms, are encompassed within the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of the enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or separated using standard techniques, such as chiral columns or chiral resolving agents. For example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); See Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0049] It should also be noted that the compounds disclosed herein can include E isomers and Z isomers or mixtures thereof, and cis and trans isomers or mixtures thereof.In certain embodiments, the compound is isolated as either E isomers or Z isomers.In other embodiments, the compound is a mixture of E isomers and Z isomers.

[0050] "Tautomers" are isomers of a compound that exist in equilibrium with one another. The concentration of the isomers may vary depending on the environment in which the compound is found, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomers, which are referred to as tautomers of each other: [ka] .

[0051] As will be readily understood by one of ordinary skill in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the present disclosure.

[0052] It should also be noted that the compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), sulfur 35( 35 S) or carbon 14 ( 14 It can be radiolabeled with a radioisotope such as C) or deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15The compound may be isotopically enriched, such as with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 120, 121, 132, 143, 144, 150, 151, 162, 173, 184, 190, 191, 192, 193, 194, 195, 196, 197, As used herein, "deuterated" means that at least one hydrogen (H) is replaced with a deuterium (D or 2 H), i.e., compounds enriched with deuterium in at least one position.

[0053] Regardless of stereoisomeric or isotopic composition, it is understood that each compound disclosed herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein.Similarly, it is understood that the isotopic composition can vary independently from the stereoisomeric composition of each compound mentioned herein.Furthermore, the isotopic composition is limited to the elements present in each compound disclosed herein or its salt, or can vary independently from the selection of the pharmaceutically acceptable salt of each compound.

[0054] It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure shall take precedence.

[0055] As used herein, " treatment " refers to the total or partial alleviation of disorder, disease or condition, or one or more symptoms related to disorder, disease or condition, or the reduction or stop of the further progression or worsening of these symptoms, or the alleviation or eradication of the cause of disorder, disease or condition itself.In one embodiment, disorder is neurodegenerative disease as described herein or its symptoms.

[0056] As used herein, "prevention" refers to a method of delaying and / or preventing the onset, recurrence, or spread of a disorder, disease, or condition, in whole or in part, a method of preventing a subject from acquiring a disorder, disease, or condition, or a method of reducing the risk of a subject acquiring a disorder, disease, or condition. In one embodiment, the disorder is a neurodegenerative disease or symptom thereof as described herein.

[0057] The term "effective amount" in reference to a compound disclosed herein means an amount capable of treating or preventing a disorder, disease or condition disclosed herein, or a symptom thereof.

[0058] As used herein, the term "subject" or "patient" includes animals, including but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, which in one embodiment are mammals, and in another embodiment are humans. In one embodiment, the subject is a human having or at risk of having an IRAK3-mediated disease or symptom thereof.

[0059] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein for clarity in the context of separate embodiments, the invention may also be practiced in a single embodiment.

[0060] compound In one aspect, provided herein is a compound of formula (I): [ka] [In the formula, Ring A is C6-C 10 aryl or 5-6 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; Ring B is C6-C 10 aryl or C3-C6 cycloalkyl, each of which is optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN; X is CH or N; L is -O(C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)-O-(C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)- or -C(O)(6- to 11-membered spiroheterocyclene)-; R 1 is H or C1-C6 alkyl; and R 2a and R 2b are each H or together form an oxo group. or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, ring A is C6-C 10 In some embodiments, ring A is a C6-C6 aryl or a 5- to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. 10In some embodiments, ring A is aryl or 5- or 6-membered heteroaryl, wherein the heteroaryl contains 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is phenyl or 5-membered heteroaryl, wherein the heteroaryl contains 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is phenyl or 5-membered heteroaryl, wherein the heteroaryl contains 2 to 3 nitrogen atoms. In some embodiments, ring A is phenyl. In some embodiments, ring A is 5-membered heteroaryl containing 2 to 3 nitrogen atoms.

[0062] In some embodiments, ring A is C6-C 10 In some embodiments, ring A is C aryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is C 10 In some embodiments, ring A is C-C 10 In some embodiments, Ring A is [ka] is.

[0063] In some embodiments, ring A is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl containing 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl containing 2 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered heteroaryl containing 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered heteroaryl containing 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered heteroaryl containing 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, ring A is a 5-membered heteroaryl containing 3 nitrogen atoms. In some embodiments, ring A is a 5-membered heteroaryl containing one nitrogen atom and one sulfur atom. In some embodiments, ring A is a 5-membered heteroaryl containing one nitrogen atom and one oxygen atom. In some embodiments, ring A is pyrrolyl, pyrazolyl, triazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, or thiadiazolyl. In some embodiments, ring A is a 6-membered heteroaryl containing one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 6-membered heteroaryl containing two to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 6-membered heteroaryl containing two heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 6-membered heteroaryl containing three heteroatoms selected from nitrogen, oxygen, and sulfur.In some embodiments, ring A is a 6-membered heteroaryl containing two nitrogen atoms. In some embodiments, ring A is a 6-membered heteroaryl containing three nitrogen atoms. In some embodiments, ring A is a 6-membered heteroaryl containing one nitrogen atom and one sulfur atom. In some embodiments, ring A is a 6-membered heteroaryl containing one nitrogen atom and one oxygen atom. In some embodiments, ring A is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl. In some embodiments, ring A is. [ka] is.

[0064] In some embodiments, ring B is C6-C 10 In some embodiments, Ring B is a C6-C6 aryl or C3-C6 cycloalkyl, each of which is 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, Ring B is a C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, or -CN. 10 In some embodiments, Ring B is a C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, or -CN. 10 In some embodiments, Ring B is a C6-C6 aryl or C3-C6 cycloalkyl, each of which is 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, Ring B is a C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, or -CN. 10 In some embodiments, Ring B is a C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, or -CN. 10 aryl or C-C cycloalkyl, each of which is C-C 10 In some embodiments, ring B is optionally substituted with one substituent selected from alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 10aryl or C3-C6 cycloalkyl, each of which is optionally substituted with one substituent selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. In some embodiments, Ring B is phenyl or cyclohexyl, each of which is optionally substituted with one substituent selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, -OH, and -CN. In some embodiments, ring B is phenyl or cyclohexyl, each of which is 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, ring B is phenyl or cyclohexyl, each of which is optionally substituted with one substituent selected from methyl, -CF3, -CHF2, -CH2F, -OCH3, halo, -OH, and -CN. In some embodiments, ring B is phenyl or cyclohexyl, each of which is optionally substituted with methyl. In some embodiments, ring B is phenyl optionally substituted with methyl. In some embodiments, Ring B is cyclohexyl optionally substituted with methyl. In some embodiments, Ring B is phenyl substituted with methyl.

[0065] In some embodiments, Ring B is a C-C alkyl group optionally substituted with 1 to 5 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, —OH, and —CN. 10In some embodiments, Ring B is a C-C alkyl group optionally substituted with five substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 10 In some embodiments, Ring B is a C-C alkyl group optionally substituted with four substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 10 In some embodiments, Ring B is a C-C alkyl group optionally substituted with 1 to 3 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 10 In some embodiments, Ring B is a C-C alkyl group optionally substituted with three substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 10 In some embodiments, Ring B is a C-C alkyl group optionally substituted with two substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 10 In some embodiments, ring B is C-C 10 C-C optionally substituted with one substituent selected from alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 10 In some embodiments, Ring B is a C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN optionally substituted with one substituent selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. 10In some embodiments, ring B is aryl. In some embodiments, ring B is phenyl optionally substituted with one substituent selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, ring B is phenyl optionally substituted with one substituent selected from propyl, ethyl, methyl, CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, -CH2F, -OCH2CH2CH3, -OCH2CH3, -OCH3, halo, -OH, and -CN. In some embodiments, ring B is phenyl optionally substituted with one substituent selected from methyl, -CF3, -CHF2, -CH2F, -OCH3, halo, -OH, and -CN. In some embodiments, ring B is phenyl optionally substituted with one substituent selected from methyl, -CF3, -CHF2, -CH2F, -OCH3, halo, -OH, and -CN. In some embodiments, ring B is phenyl optionally substituted with methyl. In some embodiments, ring B is phenyl substituted with methyl.

[0066] In some embodiments, Ring B is C-C cycloalkyl optionally substituted with 1 to 5 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, Ring B is C-C cycloalkyl optionally substituted with 5 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, Ring B is C-C cycloalkyl optionally substituted with 4 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, Ring B is C-C cycloalkyl optionally substituted with 1 to 3 substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, ring B is C6-C 10

[0023] In some embodiments, Ring B is C-C cycloalkyl optionally substituted with one substituent selected from alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, Ring B is C-C cycloalkyl optionally substituted with three substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, Ring B is C-C cycloalkyl optionally substituted with two substituents selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, Ring B is C-C cycloalkyl optionally substituted with one substituent selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, Ring B is cyclohexyl optionally substituted with one substituent selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, halo, -OH, and -CN. In some embodiments, Ring B is cyclohexyl optionally substituted with one substituent selected from propyl, ethyl, methyl, CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CF3, -CHF2, -CH2F, -OCH2CH2CH3, -OCH2CH3, -OCH3, halo, -OH, and -CN. In some embodiments, Ring B is cyclohexyl optionally substituted with one substituent selected from methyl, -CF3, -CHF2, -CH2F, -OCH3, halo, -OH, and -CN. In some embodiments, Ring B is cyclohexyl optionally substituted with methyl.

[0067] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0068] In some embodiments, X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

[0069] In some embodiments, L is -O(C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)-C(O)NR 1 (C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)-O-(C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)- or -C(O)(6- to 11-membered spiroheterocyclene)-. In some embodiments, L is -O(C1-C3 alkylene)C(O)-, -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)C(O)-, -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)-O-(C1-C3 alkylene)C(O)-, -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)- or -C(O)(6- to 11-membered spiroheterocyclene)-.

[0070] In some embodiments, L is -O(C1-C6 alkylene)C(O)-. In some embodiments, L is -O(C1-C3 alkylene)C(O)-. In some embodiments, L is -OCH2C(O)-, -OCH2CH2C(O)-, or -OCH2CH2CH2C(O)-. In some embodiments, L is -OCH2C(O)-.

[0071] In some embodiments, L is —O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)C(O)-. In some embodiments, L is -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)C(O)-. In some embodiments, L is -O(C1 alkylene)C(O)NR 1 (C1-C3 alkylene)C(O)-. In some embodiments, R 1 is H. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C1-C3 alkyl. In some embodiments, R 1 is methyl, ethyl, or propyl. In some embodiments, L is -OCHC(O)NH(CH)C(O)-. In some embodiments, L is -OCHC(O)NH(CHCH)C(O)-. In some embodiments, L is -OCHC(O)NH(CHCHCH)C(O)-. In some embodiments, L is -OCHC(O)NH(CHCHCH)C(O)-.

[0072] In some embodiments, L is —O(C1-C6 alkylene)C(O)NR 1 In some embodiments, L is —O(C1-C3 alkylene)C(O)NR 1 In some embodiments, L is —O(Ci alkylene)C(O)NR 1 (C1-C3 alkylene)-O-(C1-C3 alkylene)C(O)-. In some embodiments, R 1 is H. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C1-C3 alkyl. In some embodiments, R 1is methyl, ethyl, or propyl. In some embodiments, L is -OCHC(O)NHCH-O-CHC(O)-. In some embodiments, L is -OCHC(O)NHCH-O-CHCHC(O)-. In some embodiments, L is -OCHC(O)NHCH-O-CHCHC(O)-. In some embodiments, L is -OCHC(O)NHCH-O-CHCHCHC(O)-. In some embodiments, L is -OCHC(O)NHCH-O-CHCHCHC(O)-. In some embodiments, L is -OCHC(O)NHCH-O-CHC(O)-. In some embodiments, L is -OCHC(O)NHCHCH-O-CHC(O)-. In some embodiments, L is -OCHC(O)NHCHCH-O-CHC(O)-. In some embodiments, L is -OCHC(O)NHCHCH-O-CHCHC(O)-. In some embodiments, L is -OCHC(O)NHCHCH-O-CHCHC(O)-. In some embodiments, L is -OCHC(O)NHCHCHCHCH-O-CHC(O)-. In some embodiments, L is -OCHC(O)NHCHCHCHCH-O-CHCHC(O)-. In some embodiments, L is -OCHC(O)NHCHCHCHCH-O-CHCHCHC(O)-. In some embodiments, L is -OCHC(O)NHCHCHCHCH-O-CHCHCHC(O)-.

[0073] In some embodiments, L is —O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)-. In some embodiments, L is -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)-. In some embodiments, L is -O(C1 alkylene)C(O)NR 1 (C1-C3 alkylene)-. In some embodiments, R 1 is H. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C1-C3 alkyl. In some embodiments, R 1is methyl, ethyl, or propyl. In some embodiments, L is -OCH2C(O)NHCH2-. In some embodiments, L is -OCH2C(O)NHCH2CH2-. In some embodiments, L is -OCH2C(O)NHCH2CH2CH2-. In some embodiments, L is -OCH2C(O)NHCH2CH2CH2-.

[0074] In some embodiments, L is -C(O)(6- to 11-membered spiroheterocyclene)-. In some embodiments, L is -C(O)(6-membered spiroheterocyclene)-. In some embodiments, L is -C(O)(7-membered spiroheterocyclene)-. In some embodiments, L is -C(O)(8-membered spiroheterocyclene)-. In some embodiments, L is -C(O)(9-membered spiroheterocyclene)-. In some embodiments, L is -C(O)(10-membered spiroheterocyclene)-. In some embodiments, L is -C(O)(11-membered spiroheterocyclene)-.

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

[0076] In some embodiments, R 2a and R 2b are each H or together form an oxo group. In some embodiments, R 2a and R 2b are each H. In some embodiments, R 2a and R 2b together form an oxo group.

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

[0078] In some embodiments, the group of formula (I): [ka] teeth, [ka] In some embodiments, the group of formula (I): [ka] teeth, [ka] In some embodiments, the group of formula (I): [ka] teeth, [ka] In some embodiments, the group of formula (I): [ka] teeth, [ka] is.

[0079] In some embodiments, the compound of Formula (I) has the formula (II): [ka] wherein L is as described for formula (I). is a compound of

[0080] In some embodiments, the compound of Formula (I) has Formula (II-A) or (II-B): [ka] wherein L is as described for formula (I). is a compound of

[0081] In some embodiments, the compound of Formula (I) has Formula (IIIa) or (IIIb): [ka] wherein L is as described for formula (I). is a compound of

[0082] In some embodiments, the compound of Formula (I) has Formula (III-A), (III-B), (III-C), or (III-D): [ka] wherein L is as described for formula (I). is a compound of

[0083] In some embodiments, the compound of Formula (I) has the formula (IV): [ka] wherein L is as described for formula (I). is a compound of

[0084] In some embodiments, the compound of Formula (I) has Formula (IV-A) or (IV-B): [ka] wherein L is as described for formula (I). is a compound of

[0085] In some embodiments, the compound of Formula (I) has the formula (VA), (VB), (VC), (VD), (VE) or (VF): [ka] [In the formula, ring A, ring B, R 2a , R 2b and X is as described for formula (I). is a compound of

[0086] In the description of this specification, any description, variation, embodiment or aspect of one site may be combined with any description, variation, embodiment or aspect of another site, and each combination of descriptions is understood to be the same as if it were specifically and individually described. For example, R 1 All descriptions, variations, embodiments or aspects provided herein regarding ring A, ring B, X, L, R 2a and R 2band may be combined with any and all descriptions, variations, embodiments or aspects of formula (I), and may be combined in the same manner as if each combination were specifically and individually listed. Also, all descriptions, variations, embodiments or aspects of formula (I) apply equally to other formulas detailed herein, where applicable, and for all formulas, it is understood that each and every description, variation, embodiment or aspect is described in the same manner as if described separately and individually. For example, all statements, variations, embodiments or aspects of formula (I), where applicable, apply equally to any of the formulas detailed herein, e.g., formulas (II), (II-A), (II-B), (IIIa), (IIIb), (III-A), (III-B), (III-C), (III-D), (IV), (IV-A), (IV-B), (VA), (VB), (VC), (VD), (VE) and (VF), and each and every statement, variation, embodiment or aspect is to be set forth in relation to all formulas as if set forth separately and individually.

[0087] In some embodiments, provided is a compound selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof. Although certain compounds described in this disclosure, including in Table 1, are depicted as particular stereoisomers and / or as non-stereochemical forms, it is understood that any and all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms of the compounds of this disclosure, including in Table 1, are described herein.

[0088] [Table 1-1] [Table 1-2] [Table 1-3] The above compound or a pharmaceutically acceptable salt thereof.

[0089] It is understood that combinations of substituents and / or variables of the depicted formulae herein are permissible only if such combinations result in stable compounds.

[0090] Furthermore, all compounds of formula (I) that exist in free base or acid form can be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of formula (I) can be converted into their free base or acid form by standard techniques.

[0091] Synthesis method The compounds described herein can be prepared using conventional organic synthesis methods and commercially available starting materials, or using the methods provided herein. By way of example and not limitation, compounds of formula (I) can be prepared as outlined in Schemes 1-3, as well as in the Examples described herein. It should be noted that one skilled in the art would know how to modify the methods described in the illustrative Schemes and Examples to obtain the desired products.

[0092] Scheme 1. [ka] [Wherein, L' is -(C1-C6 alkylene)-, -(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)- or -(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)-O-(C1-C6 alkylene)-; and ring A is as described for formula (I).

[0093] As outlined in Scheme 1, compounds of general formula A can be synthesized by reacting intermediate a and intermediate b with various amide coupling reagents to produce compounds of general formula A. Scheme 2. [ka] wherein PG is a protecting group; and X and ring A are as described for formula (I).

[0094] As outlined in Scheme 2, compounds of general formula B containing various substituted heteroaryl or aryl groups can be synthesized by coupling intermediates c and d to intermediate e. For example, bromoimidazopyrazine intermediate e can be prepared using a Buchwald-Hartwig amination reaction of intermediates c and d with an appropriate ligand, catalyzed by a palladium salt. Subsequent Suzuki cross-coupling with m-tolylboronic acid and standard Boc deprotection (e.g., with TFA) affords intermediate f. Intermediate g can be prepared by reductive amination of tert-butyl N-(2-oxoethyl)carbamate and intermediate f in the presence of a reducing agent such as STAB and a base such as DIPEA, followed by Boc deprotection with HCl (or TFA). Finally, intermediate g can be amide-coupled with intermediate h using an amide coupling reagent such as PyAOP and DIPEA to afford compounds of general formula B. Scheme 3. [ka]

[0095] Compounds of formula C containing spirocyclic linkers can be synthesized via a route similar to that shown in Scheme 2. As outlined in Scheme 3, this compound, shown as a representative example of compounds with spirocyclic linkers, can be synthesized by utilizing a spirocyclic ketone (intermediate j) rather than a linear aldehyde. Reductive amination of intermediate i using the ketone-bearing intermediate j, a reducing agent such as STAB, and a base, followed by Boc-deprotection, affords spirocyclic intermediate k. In the final step, coupling of the carboxylic acid of intermediate l with the secondary amine of intermediate k using an amide coupling reagent such as HATU affords compounds of formula C.

[0096] How to use An embodiment of the present disclosure provides a method for modulating IRAK3 in a subject, comprising administering to the subject in need thereof an effective amount of a compound of Formula (I). Modulation (e.g., inhibition or activation) of IRAK3 can be assessed and demonstrated by various methods known in the art. Kits and commercially available assays are available for determining whether and to what extent IRAK3 is modulated (e.g., inhibited or activated).

[0097] In one aspect, provided herein is a method for modulating IRAK3, comprising contacting IRAK3 with an effective amount of a compound of Formula (I) or any embodiment or variation thereof. In some embodiments, the compound of Formula (I) inhibits IRAK3. In some embodiments, the compound of Formula (I) causes degradation of IRAK3.

[0098] In some embodiments, provided herein is a method for targeted degradation of IRAK3, comprising contacting IRAK3 with an effective amount of a compound of Formula (I) or any embodiment or variation thereof.

[0099] In some embodiments, the compound of Formula (I) modulates the activity of IRAK3 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In some embodiments, the compound of formula (I) increases the activity of IRAK3 by about 1 to 100%, 5 to 100%, 10 to 100%, 15 to 100%, 20 to 100%, 25 to 100%, 30 to 100%, 35 to 100%, 40 to 100%, 45 to 100%, 50 to 100%, 55 to 100%, 60 to 100%, 65 to 100%, 70 to 100%, 75 to 100%, 80 to 100%, Adjust to 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70% or 40-60%.

[0100] Also provided in certain embodiments of the present disclosure is a method for degrading IRAK3 in a subject, comprising administering an effective amount of a compound of formula (I) to a subject in need thereof.The degradation of IRAK3 can be assessed and demonstrated by various methods known in the art.Kits and commercially available assays (for example, cell-based assays) can be used to determine whether and to what extent IRAK3 is degraded.

[0101] In one aspect, provided herein is a method for degrading IRAK3, comprising contacting IRAK3 with an effective amount of a compound of Formula (I) or any embodiment or variation thereof. In some embodiments, the compound of Formula (I) partially degrades IRAK3. In some embodiments, the compound of Formula (I) completely degrades IRAK3.

[0102] In some embodiments, the compound of Formula (I) degrades IRAK3 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In some embodiments, the compound of formula (I) inhibits IRAK3 by about 1 to 100%, 5 to 100%, 10 to 100%, 15 to 100%, 20 to 100%, 25 to 100%, 30 to 100%, 35 to 100%, 40 to 100%, 45 to 100%, 50 to 100%, 55 to 100%, 60 to 100%, 65 to 100%, 70 to 100%, 75 to 100%, 80 to 100%, Decomposes by 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70% or 40-60%.

[0103] In another aspect, provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I). In some embodiments, provided herein is a method for preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I). Non-limiting examples of cancer include bladder cancer, breast cancer, esophageal cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma and gastric cancer.

[0104] In some embodiments, administering a compound of Formula (I) to a subject predisposed to developing cancer prevents the subject from developing any symptoms of cancer (e.g., tumor growth or metastasis). In some embodiments, administering a compound of Formula (I) to a subject who does not yet exhibit symptoms of cancer prevents the subject from developing symptoms of cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof reduces the extent of cancer in the subject. In some embodiments, administering a compound of Formula (I) to a subject in need thereof stabilizes the cancer (prevents or slows the progression of the cancer). In some embodiments, administering a compound of Formula (I) to a subject in need thereof slows the onset or recurrence of cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof slows the progression of cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof provides partial remission of cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof provides complete remission of cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof reduces the dose of one or more other drugs required to treat cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof enhances the effectiveness of another drug used to treat cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof slows the progression of cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof improves the quality of life of a subject with cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof prolongs the survival time of a subject with cancer.

[0105] In one aspect, provided herein is a method for preventing a subject having a predisposition to cancer from developing cancer, the method comprising administering to the subject a compound of Formula (I).

[0106] In some embodiments, provided herein is a method for reducing the extent of cancer in a subject, the method comprising administering a compound of Formula (I) to the subject. In some embodiments, provided herein is a method for stabilizing cancer in a subject, the method comprising administering a compound of Formula (I) to the subject. In some embodiments, the method prevents the cancer from worsening.

[0107] In another aspect, provided herein is a method of delaying the onset or recurrence of cancer in a subject, the method comprising administering to the subject a compound of Formula (I).

[0108] In some embodiments, provided herein is a method for delaying the progression of cancer in a subject, the method comprising administering a compound of Formula (I) to the subject.In some embodiments, the method provides partial remission of cancer.In some embodiments, the method provides complete remission of cancer.

[0109] In a further aspect, provided herein is a method for reducing the dose of one or more other drugs required to treat cancer in a subject, the method comprising administering to the subject a compound of Formula (I). In some embodiments, provided herein is a method for enhancing the effect of another drug used to treat cancer in a subject, the method comprising administering to the subject a compound of Formula (I).

[0110] Also provided herein is a method for delaying the progression of cancer in a subject, the method comprising administering a compound of formula (I) to the subject.In some embodiments, the method improves the quality of life of the subject with cancer.In some embodiments, the method prolongs the survival time of the subject with cancer.

[0111] In some embodiments, the compounds of Formula (I) are useful for treating a cancer selected from bladder cancer, breast cancer, esophageal cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma, and gastric cancer.

[0112] In some embodiments, provided herein is a method for enhancing immunity in a subject receiving a vaccine, comprising administering an effective amount of a compound of Formula (I) to the subject. In some embodiments, the compound of Formula (I) is administered to the subject before administration of the vaccine. In some embodiments, the compound of Formula (I) is administered to the subject simultaneously with administration of the vaccine. In some embodiments, the compound of Formula (I) is administered to the subject after administration of the vaccine. In some embodiments, the compound of Formula (I) is formulated as a component of a vaccine. In some embodiments, the compound of Formula (I) is formulated separately from the vaccine.

[0113] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered orally, topically, or parenterally to a subject in conventional dosage forms such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0114] The compounds disclosed herein can be administered orally, topically, or parenterally to a subject in conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations may contain excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, light It can be prepared by conventional methods using conventional organic or inorganic additives such as silicic anhydride, talc, sodium lauryl sulfate), flavoring agents (for example, citric acid, menthol, glycine or orange powder), preservatives (for example, sodium benzoate, sodium hydrogen sulfate, methylparaben or propylparaben), stabilizers (for example, citric acid, sodium citrate or acetic acid), suspending agents (for example, methylcellulose, polyvinylpyrrolidone or aluminum stearate), dispersing agents (for example, hydroxypropylmethylcellulose), diluents (for example, water) and base wax (for example, cocoa butter, white petrolatum or polyethylene glycol).The effective amount of the compound of formula (I) in the pharmaceutical composition can be present at a level that exerts desired effects; for example, in both oral and parenteral administration unit doses, it is about 0.005 mg / kg of subject body weight to about 10 mg / kg of subject body weight.

[0115] The dose of a compound of Formula (I) administered to a subject can vary widely and be at the discretion of a medical professional. Generally, the compounds disclosed herein can be administered at a dose of about 0.001 mg / kg to about 10 mg / kg of subject body weight, 1 to 4 times daily, although this dosage can be appropriately modified depending on the subject's age, body weight, condition, and route of administration. In one embodiment, the dose is about 0.001 mg / kg to about 5 mg / kg of subject body weight, about 0.01 mg / kg to about 5 mg / kg of subject body weight, about 0.05 mg / kg to about 1 mg / kg of subject body weight, about 0.1 mg / kg to about 0.75 mg, or about 0.25 mg / kg to about 0.5 mg / kg of subject body weight. In one embodiment, the compound is administered once daily. In any case, the amount of a compound of Formula (I) administered will vary depending on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0116] In some embodiments, the compound of Formula (I) is administered to a subject at a dose of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0117] In another embodiment, provided herein is a unit dosage form comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of a compound of Formula (I).

[0118] In certain embodiments, provided herein is a unit dosage form comprising about 0.1 mg or 100 mg of a compound of Formula (I).

[0119] In another embodiment, provided herein is a unit dosage form comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of the compound of Formula (I).

[0120] The compound of formula (I) can be administered once, twice, three times, four or more times daily. In certain embodiments, doses of 100 mg or less are administered as a single dose daily, and doses of more than 100 mg are administered twice daily at half the total daily dose.

[0121] The compound of formula (I) can be conveniently administered orally.In one embodiment, when orally administered, the compound of formula (I) is administered with food and water.In another embodiment, the compound of formula (I) is dispersed in water or juice (for example, apple juice or orange juice) or any other liquid, and is orally administered as solution or suspension.

[0122] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, orally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, or by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is left to the discretion of the health care practitioner and may vary depending on the site of the medical condition.

[0123] In one embodiment, provided herein is a capsule containing a compound of Formula (I) without any additional carriers, excipients, or vehicles.

[0124] In another embodiment, provided herein is a composition comprising an effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle can comprise an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0125] The compositions can take the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, suspensions, etc. The compositions can be formulated to contain a daily dose or a suitable fraction of a daily dose in a dosage unit, which may be a single tablet or capsule, or a suitable amount of liquid. In one embodiment, the solution is prepared from a water-soluble salt such as a hydrochloride salt. Generally, all compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing the compound of formula (I) with a suitable carrier or diluent and filling the appropriate amount of the mixture into capsules. Typical carriers and diluents include, but are not limited to, inert powdered substances such as many different starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, grain flours, and similar edible powders.

[0126] Tablets can be prepared by direct compression, wet granulation, or dry granulation. The formulation typically includes not only the compound but also diluents, binders, lubricants, and disintegrants. Typical diluents include, for example, various starches, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include starch, gelatin, and sugars (e.g., lactose, fructose, glucose, etc.). Natural and synthetic gums, such as acacia, alginate, methylcellulose, and polyvinylpyrrolidine, are also useful. Polyethylene glycol, ethylcellulose, and waxes can also function as binders.

[0127] Tablets may require lubricants to prevent dyes from adhering to the tablet and tableting equipment. Lubricants can be selected from lubricating solids such as talc, magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when moistened, disintegrating the tablet and releasing the compound. These include starch, clay, cellulose, algins, gums, and the like. More specifically, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose, such as sodium lauryl sulfate, can also be used. Tablets can also be coated with sugars as flavor enhancers or with film-forming protective agents to modify the tablet's dissolution properties. Chewable tablets can also be formulated by using substances such as mannitol in the formulation.

[0128] When a compound of formula (I) is to be administered as a suppository, typical bases can be used. Cocoa butter is a conventional suppository base, which can be modified by adding waxes to slightly raise its melting point. In particular, water-miscible suppository bases containing polyethylene glycols of various molecular weights are widely used.

[0129] The effect of the compound of formula (I) can be delayed or prolonged by appropriate formulation.For example, the compound of formula (I) can be prepared into slowly dissolving pellets and incorporated into tablets or capsules, or as a sustained-release implantable device.This technique also includes preparing pellets with several different dissolution rates and filling a capsule with a mixture of pellets.The tablet or capsule can be coated with a film that is difficult to dissolve for a predictable period of time.Even in parenteral preparations, the compound of formula (I) can be made long-acting by dissolving or suspending it in an oil or emulsifying agent that will slowly disperse in serum.

[0130] Illustrative Examples The present disclosure is further illustrated by the following embodiments, the features of each embodiment may be combined with any of the other embodiments where appropriate and practical.

[0131] Embodiment 1. Formula (I): [ka] [In the formula, Ring A is C6-C 10 aryl or 5-6 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; Ring B is C6-C 10 aryl or C3-C6 cycloalkyl, each of which is optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halo, -OH, and -CN; X is CH or N; L is -O(C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)-O-(C1-C6 alkylene)C(O)-, -O(C1-C6 alkylene)C(O)NR 1 (C1-C6 alkylene)- or -C(O)(6- to 11-membered spiroheterocyclene)-; R 1 is H or C1-C6 alkyl; and R 2a and R 2b are each H or together form an oxo group. or a pharmaceutically acceptable salt thereof.

[0132] Embodiment 2. Ring A is C6-C 10 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein:

[0133] Embodiment 3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5-6 membered heteroaryl, said heteroaryl containing 1-3 nitrogen atoms.

[0134] Embodiment 4. Ring A is [ka] or a pharmaceutically acceptable salt thereof.

[0135] Embodiment 5. Ring A is [ka] or a pharmaceutically acceptable salt thereof.

[0136] Embodiment 6. Ring B is a C6-C alkyl optionally substituted with 1 to 5 substituents selected from C1-C6 alkyl. 10 6. The compound according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein:

[0137] Embodiment 7. Ring B is a C6-C alkyl group optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl. 10 7. The compound of embodiment 6, or a pharmaceutically acceptable salt thereof, wherein:

[0138] Embodiment 8. Ring B is [ka] or a pharmaceutically acceptable salt thereof.

[0139] Embodiment 9. A compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0140] Embodiment 10. A compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0141] Embodiment 11. L is -O(C1-C3 alkylene)C(O)-, -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)C(O)-, -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)-O-(C1-C3 alkylene)C(O)-, -O(C1-C3 alkylene)C(O)NR 1 (C1-C3 alkylene)- or -C(O)(10-11 membered spiroheterocyclene)-; and R 1 is H; or a pharmaceutically acceptable salt thereof.

[0142] Embodiment 12. L is [ka] or a pharmaceutically acceptable salt thereof.

[0143] Embodiment 13. R 2a and R 2b and R are each H; or a pharmaceutically acceptable salt thereof.

[0144] Embodiment 14. R 2a and R 2b or a pharmaceutically acceptable salt thereof.

[0145] Embodiment 15. The compound has the formula (II): [ka] 15. The compound of any one of embodiments 1, 2, 4, 6-8, 10, 12, or 14, wherein:

[0146] Embodiment 16. The compound has the formula (IIIa): [ka] 15. The compound of any one of embodiments 1, 2, 4, 6-9, 11, 12, or 14, or a pharmaceutically acceptable salt thereof, wherein:

[0147] Embodiment 17. The compound has the formula (IIIb): [ka] 15. The compound of any one of embodiments 1, 3, 5, 6-9, 11, 12, or 14, wherein:

[0148] Embodiment 18. The compound has the formula (IV): [ka] 16. The compound of any one of embodiments 1, 2, 4, 9, 10, or 13-15, wherein:

[0149] Embodiment 19. A compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0150] Embodiment 20. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0151] Embodiment 21. A method for modulating interleukin-1 receptor-associated kinase 3 (IRAK3), comprising contacting IRAK3 with an effective amount of a compound according to any one of embodiments 1 to 19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 20.

[0152] Embodiment 22. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 20.

[0153] Embodiment 23. The method of embodiment 22, wherein the cancer is selected from bladder cancer, breast cancer, esophageal cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma, and gastric cancer.

[0154] Embodiment 24. A method for enhancing immunity in a subject receiving a vaccine, comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 20.

[0155] Embodiment 25. The method of embodiment 24, wherein the subject is administered a vaccine before, simultaneously with, or after administration of a compound of any one of embodiments 1 to 19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 20. [Example]

[0156] The following examples are offered for illustrative purposes, not limitation. Compounds were named using the automated naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures while adhering to the Cahn-Ingold-Prelog rules of stereochemistry. Those skilled in the art can modify the procedures described in the illustrated examples to arrive at the desired products.

[0157] Salts of the compounds described herein can be prepared by standard methods, such as incorporating an acid (e.g., TFA, formic acid, or HCl) into the mobile phase during chromatographic purification, or stirring the product after chromatographic purification with an acid solution (e.g., aqueous HCl).

[0158] The following abbreviations may be relevant to this application: [Table 2-1] [Table 2-2]

[0159] Synthesis Examples Analysis method LC / MS Method 1. Column: Luna C18(2) 50 x 3 mm, 3 um. Temperature: 45 °C, Flow rate: 2 mL / min, Run time: 2 min. Mobile phase conditions: Starting with 95% H2O 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1 min, then hold at 95% CH3CN 0.1% FA for 1 min. LC / MS Method 2. Waters Acquity UPLC system. Column: ACQUIty UPLC BEH C18 1.7 mm (2.1 x 50 mm). Modifier: Formic acid. Mobile phase: Water-0.1% formic acid (A) and acetonitrile-0.1% formic acid (B). Flow rate: 0.8 mL / min. Gradient: 5% B to 95% B in 1.5 min, hold at 95% B for 0.5 min, hold at 95% B for 0.1 min, hold at 95% B to 5% B for 0.1 min. Detector: UV 214 nm and 254 nm. LC / MS Method 3. SunFire C18 75 x 4.6 mm, 3.5 μm. Temperature: 45°C, Flow rate: 1.5 mL / min, Run time: 6 min. Mobile phase conditions: Initial 95% HO + 0.1% FA / 5% MeCN + 0.1% FA, followed by a linear gradient to 95% MeCN over 4 min, then hold at 95% MeCN for 2 min. LC / MS Method 4. Luna C18(2) 50 x 3 mm, 3 μm. Temperature: 45°C, Flow Rate: 1.5 mL / min, Run Time: 2.5 min. Mobile Phase Conditions: Starting with 95% HO 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.3 min, then hold at 95% MeCN 0.1% FA for 1.2 min.

[0160] Example I-1. Preparation of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (I-1) [ka] Available from multiple suppliers.

[0161] Example I-2. Preparation of 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)butanoic acid (I-2) [ka] It is currently available from Astatech and Matrix Scientific.

[0162] Example I-3. Preparation of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)propanoic acid (I-3) [ka] Previously reported in Chessum et al., Journal of Medicinal Chemistry, 2018, 61 (3), 918-933.

[0163] Example I-4. Preparation of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetic acid (I-4) [ka] Previously reported in Bricelj et al., ACS Med. Chem. Lett., 2021, 12 (11), 1733-1738.

[0164] Example I-5. Preparation of 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamido)butanoic acid (I-5) [ka] Prepared similarly to I-6 (below). LC / MS Method 2: MS (ESI) [M+H] + 418, rt:1.37 minutes.

[0165] Example I-6. Preparation of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamido)ethoxy)propanoic acid (I-6) [ka] tert-Butyl 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamido)ethoxy)propanoate To a solution of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetic acid (1.8 g, 5.42 mmol) and HATU (2.472 g, 6.50 mmol) in DMF (20 mL) was added DIEA (2.365 mL, 13.54 mmol) followed by tert-butyl 3-(2-aminoethoxy)propanoate (1.025 g, 5.42 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated and then purified by normal phase column chromatography (0-100% EtOAc / hexanes, then 0-20% MeOH / DCM) to give the product tert-butyl 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamido)ethoxy)propanoate (1.4 g, 3.34 mmol, 62% yield).

[0166] 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamido)ethoxy)propanoic acid To a solution of tert-butyl 3-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamido)ethoxy)propanoate (200 mg, 0.40 mmol) in DCM (4 mL) was added TFA (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated and purified by preparative HPLC to give the product 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-5-yl)oxy)acetamido)ethoxy)propanoic acid (110 mg, 61% yield) as a white solid. LC / MS Method 2: MS (ESI) [M+H]+ 448, rt: 1.45 min.

[0167] Example I-7. Preparation of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (I-7) [ka] It is currently available commercially from Sigma Aldrich and Enamine.

[0168] Example I-8. Preparation of N-(4-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (I-8) [ka] tert-Butyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate tert-Butyl 4-(4-aminophenyl)piperazine-1-carboxylate (604.3 mg, 2.18 mmol) and DIPEA (0.38 mL, 2.18 mmol) were added to a solution of 5,8-dibromoimidazo[1,2-α]pyrazine (402.2 mg, 1.45 mmol) in ethanol (2.69 mL). The reaction solution was heated to 80 °C and stirred overnight. LCMS showed that the reaction had progressed to 94% conversion, so the reaction was stopped. The ethanol was removed in vacuo, and the product was taken up in DCM. The resulting solution was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by reverse-phase column chromatography (5% to 100% MeOH in water with 0.1% formic acid) to give the desired product, tert-butyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (443 mg, 0.935 mmol, 64% yield). LC / MS Method 1: MS (ESI) [M]+ 473.2, rt: 1.479 min.

[0169] tert-Butyl 4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate A mixture of 2M aqueous NaCO (1.01 mL, 2.03 mmol) and m-tolylboronic acid (91.91 mg, 0.680 mmol) in 1,4-dioxane (5 mL) and tert-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate (320 mg, 0.680 mmol) was placed in a microwave vial and flushed with N for 10 min. Pd(PhP) (78.12 mg, 0.070 mmol) was then added, and the suspension was flushed with N for another 10 min. The reaction mixture was heated to 100 °C and irradiated in a microwave reactor for 1 h. The reaction mixture was then partitioned between EtOAc and HO and extracted with EtOAc (2x). The organic layer was then washed with HO, brine, and dried over NaSO. The reaction mixture was concentrated directly onto silica gel and purified by normal phase chromatography (30% to 100% EtOAc in heptane) to give tert-butyl 4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (80% purity, 198 mg, 0.327 mmol, 48% yield) as an orange solid. LC / MS Method 1: MS (ESI) [M+H]+ 485.4, rt: 1.504 min.

[0170] N-(4-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine A solution of tert-butyl 4-[4-[[5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]phenyl]piperazine-1-carboxylate (580 mg, 1.2 mmol) in DCM (5 mL) at room temperature was treated with TFA (3.0 mL, 11.76 mmol). The reaction solution was stirred at room temperature for 4 h. The reaction mixture was concentrated to dryness, taken up in DCM, and washed with saturated aqueous NaHCO3 (1x). The aqueous layer was then back-extracted with DCM (2x), and the combined organic layers were concentrated. The resulting residue was purified by reverse-phase column chromatography (5% to 100% MeCN in water with 0.1% formic acid) to give the product, N-(4-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (256.6 mg, 0.666 mmol, 56% yield), as an orange solid after lyophilization. MS (ESI) [M+H] + = 385.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3 H), 3.23 (br s, 4 H), 3.31 - 3.59 (m, 4 H), 7.10 (d, J = 8.8 Hz, 2 H), 7.38 - 7.43 (m, 1 H), 7.44 - 7.60 (m, 4 H), 7.79 (br d, J = 7.6 Hz, 2H), 8.08 - 8.16 (m, 2 H), 9.34 (br s, 2 H), 10.93 (br s, 1 H).

[0171] Example I-9. N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (I-9) [ka] tert-Butyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate 5,8-Dibromoimidazo[1,2-α]pyrazine (500 mg, 1.8 mmol), tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (500 mg, 1.05 equiv.), and pivalic acid (1.8 g, 10 equiv.) were added to a 2.0-5.0 mL microwave-safe tube equipped with a stir bar. The tube was sealed with a septum and heated at 100 °C under microwave irradiation for 1 h. LCMS analysis of the reaction mixture confirmed complete conversion of the starting material to the desired product (~10% Boc cleavage had occurred). The reaction mixture was then diluted with EtOAc and transferred to a separatory funnel containing saturated aqueous NaHCO3. The organic layer was then removed, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The reaction mixture was purified by reverse-phase column chromatography (25% to 100% MeCN in water with 0.1% TFA) to give the product tert-butyl 4-(4-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (300 mg, 0.642 mmol, 35% yield) as a brown solid. LC / MS Method 2: MS (ESI) [M]+ 462.3, rt: 1.66 min.

[0172] N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine A 0.5-2 mL microwave-safe reaction tube equipped with a stir bar was charged with tert-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (200 mg, 0.43 mmol), m-tolylboronic acid (120 mg, 2.0 equiv), XPhos (15.5 mg, 7.5 mol%), and XPhos-Pd-G3 (27.5 mg, 7.5 mol%). The reaction vessel was sealed with a septum and purged with nitrogen. 1,4-Dioxane (2.2 mL, 0.2 M) and 2 M aqueous sodium carbonate (650 μL, 3 equiv) were then added to the reaction vessel via syringe. The reaction vessel was then sealed with a septum cap and vortexed. The vessel was then heated under microwave irradiation at 135°C for 45 minutes. The reaction mixture was then cooled to 22°C and filtered through a pad of Celite. The filter cake was washed with EtOAc. LCMS analysis of the crude reaction mixture indicated complete conversion of the starting material to the desired product. The reaction mixture was then purified by reverse-phase column chromatography (25% to 100% MeCN in water with 0.1% TFA). The fractions were then concentrated and immediately dissolved in 1:1 DCM / TFA and stirred at room temperature for 1 hour. LCMS analysis confirmed complete deprotection of the desired product. The reaction mixture was purified again by reverse-phase column chromatography (15% to 100% MeCN in water with 0.1% TFA) to give the product, N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (141 mg, 0.379 mmol, 88% yield), as a pale yellow solid after lyophilization. MS (ESI) [M+H] + 374.5. 1H NMR (400 MHz, methanol-d4) δ ppm 2.27 - 2.41 (m, 4 H), 2.45 (s, 3 H), 3.19 - 3.29 (m, 2 H), 3.59 (br d, J=13.2 Hz, 2 H), 4.60 (tt, J=10.1, 4.8 Hz, 1 H), 7.31 (s, 1 H), 7.39 - 7.51 (m, 4 H), 7.81 (s, 2 H), 7.94 (s, 1 H), 8.24 (s, 1 H).

[0173] Library procedures for Examples S1-6 Six 2-dram round-bottom vials were first filled with N,N-dimethylformamide (DMF) (0.5 mL). To each vial, a 0.25 M solution of the corresponding intermediate (I-1 to I-6, 100 μL, 25 μmol) was added, followed by a 0.25 M solution of HATU (100 μL, 50 μmol). Next, a 0.25 M solution of N-(4-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (120 μL, 30 μmol) was added, followed by DIPEA (50 μL). The vials were then sealed and shaken at 25 °C for 16 h. After removing the solvent using a Genevac EZ-2, the residue was redissolved in 1.0–2.0 mL of DMSO. The solution was then subjected to HPLC analysis using a single quadrupole mass detector (SQD2, Waters); a 19 x 100 mm XBridge TM Purification was performed by reverse-phase preparative HPLC on a Waters Automated Purification System using a C-18 preparative column. In all cases, the library compounds were separated using a focused gradient from 10% to 90% CHCN in HO (containing 0.1% formic acid v / v) at a flow rate of 20 mL / min. The resulting fractions were concentrated using a Genevac EZ-2 column to give the product as an off-white solid (as the formate salt).

[0174] Example S1. 2-(2,6-dioxopiperidin-3-yl)-4-(2-oxo-2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethoxy)isoindoline-1,3-dione (1) [ka] Compound (1) was prepared by the general library method described above. LC / MS Method 2: MS (ESI) [M+H] + 699.3, rt:1.54 minutes.

[0175] Example S2. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(4-oxo-4-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)butyl)acetamide (2) [ka] Compound (2) was prepared by the general library method described above. LC / MS Method 2: MS (ESI) [M+H] + 784.4, rt:1.48 minutes.

[0176] Example S3. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(3-oxo-3-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)propoxy)ethyl)acetamide (3) [ka] Compound (3) was prepared by the general library method described above. LC / MS Method 2: MS (ESI) [M+H] + 814.5, rt:1.47 minutes.

[0177] Example S4. 2-(2,6-dioxopiperidin-3-yl)-5-(2-oxo-2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethoxy)isoindoline-1,3-dione (4) [ka] Compound (4) was prepared by the general library method described above. LC / MS Method 2: MS (ESI) [M+H] + 699.3, rt:1.55 minutes.

[0178] Example S5. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(4-oxo-4-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)butyl)acetamide (5) [ka] Compound (5) was prepared by the general library method described above. LC / MS Method 2: MS (ESI) [M+H] + 784.3, rt:1.48 minutes.

[0179] Example S6. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(3-oxo-3-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)propoxy)ethyl)acetamide (6) [ka]

[0180] Compound (6) was prepared by the general library method described above. LC / MS Method 2: MS (ESI) [M+H] + 814.4, rt:1.47 minutes.

[0181] Example S7. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)acetamide (7) [ka]

[0182] tert-Butyl (2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)carbamate To a solution of N-(4-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (43.0 mg, 0.10 mmol) in DMF (510 μL) was added tert-butyl N-(2-bromoethyl)carbamate (23.0 mg, 0.10 mmol) and DIPEA (270 μL, 1.53 mmol) at room temperature. The reaction mixture was monitored by LCMS. After 72 h, LCMS indicated approximately 50% conversion to the desired product, so 0.5 equivalents of tert-butyl N-(2-bromoethyl)carbamate were added, and the mixture was stirred at room temperature. After 96 h, LCMS indicated approximately 75% conversion to the desired product, so 0.5 equivalents of tert-butyl N-(2-bromoethyl)carbamate were added, and the mixture was stirred at room temperature. After 128 h, LCMS indicated approximately 85% conversion to the desired product, so an additional 0.5 equivalents of tert-butyl N-(2-bromoethyl)carbamate was added and the mixture was stirred at 35 °C. After 152 h of stirring, the reaction was stopped and directly purified by reverse-phase flash chromatography (5% MeOH to 100% MeOH in water containing 0.1% FA) to give the product, tert-butyl (2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)carbamate (26 mg, 0.049 mmol, 48% yield) as a pale yellow oil. LC / MS Method 4: MS (ESI) [M+H]+ 528.3, rt: 1.443 min.

[0183] N-[4-[4-(2-aminoethyl)piperazin-1-yl]phenyl]-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine To a solution of tert-butyl N-[2-[4-[4-[[5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]phenyl]piperazin-1-yl]ethyl]carbamate (26.0 mg, 0.050 mmol) in methanol (570 μL) was added HCl / dioxane (0.2 mL, 0.790 mmol), and the solution was stirred at room temperature for 24 h. LCMS confirmed complete conversion to the desired product. The reaction solution was then concentrated and triturated with MeOH (3x) and MTBE (2x) to give the product, N-[4-[4-(2-aminoethyl)piperazin-1-yl]phenyl]-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (21 mg, 0.045 mmol, 92% yield), as the hydrochloride salt as a yellow solid. LC / MS Method 1: MS (ESI) [M+H] + 428.2, rt:1.244 minutes.

[0184] 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)acetamide To a solution of N-[4-[4-(2-aminoethyl)piperazin-1-yl]phenyl]-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (21.0 mg, 0.050 mmol), 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetic acid (16.32 mg, 0.050 mmol), and DIPEA (0.09 mL, 0.490 mmol) in DMF (0.24 mL) was added PyAOP (31 mg, 0.060 mmol). The mixture was then stirred at room temperature overnight. LCMS confirmed complete conversion to the desired product. The solution was then directly purified by reverse-phase flash chromatography (5% to 100% MeCN in water with 0.1% MeCN) to give the product, 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)acetamide (28.6 mg, 0.038 mmol, 78% yield) as a yellow solid. LC / MS Method 3: MS (ESI) [M+H] + 742.2, rt:2.565 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.96 - 2.04 (m, 1 H), 2.39 - 2.42 (m, 3 H), 2.42 - 2.47 (m, 2 H), 2.52 - 2.63 (m, 6 H), 2.81 - 2.94 (m, 1 H), 3.02 - 3.10 (m, 4 H), 4.75 (s, 2 H), 5.11 (dd, J = 12.6, 5.3 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 2 H), 7.33 (br d, J = 6.6 Hz, 1 H), 7.38 - 7.42 (m, 2 H), 7.43 - 7.49 (m, 3 1H), 7.49 - 7.52 (m, 1H), 7.66 (s, 1H), 7.87 (dd, J = 8.7, 3.8 Hz, 3H), 7.90 - 7.92 (m, 1H), 8.12 - 8.18 (m, 2H), 9.40 (s, 1H), 11.11 (s, 1H) (three protons not observed).

[0185] Example S8. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)ethyl)acetamide (8) [ka]

[0186] tert-Butyl N-[2-[4-[4-[[5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]pyrazol-1-yl]-1-piperidyl]ethyl]carbamate To a solution of N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (300.0 mg, 0.67 mmol) and tert-butyl N-(2-oxoethyl)carbamate (168.92 mg, 1.01 mmol) in DCM (7 mL) was added DIPEA (0.47 mL, 2.69 mmol). The resulting mixture was stirred at room temperature for 5 minutes. NaBH(OAc) (284.88 mg, 1.34 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. After 18 hours, LCMS indicated approximately 70% conversion, so an additional 0.5 equivalents of aldehyde and 1.0 equivalents of NaBH(OAc) were added at room temperature. After an additional 2 hours, LCMS indicated complete conversion to the desired product. The mixture was then quenched with water, extracted with DCM, dried over sodium sulfate, filtered, and concentrated. This material was then purified by reverse-phase column chromatography (5% to 100% MeOH in water containing 0.1% FA) to give the product, tert-butyl N-[2-[4-[[5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]pyrazol-1-yl]-1-piperidyl]ethyl]carbamate (336 mg, 0.52 mmol, 77% yield) as a colorless oil. LC / MS Method 4: MS (ESI) [M+H]+ 517.4, rt: 1.526 min.

[0187] N-(1-(1-(2-aminoethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine To a solution of tert-butyl N-[2-[4-[4-[[5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]pyrazol-1-yl]-1-piperidyl]ethyl]carbamate (340.0 mg, 0.66 mmol) in methanol (6 mL) was added 4 M hydrochloric acid (3.0 mL, 6.57 mmol) in dioxane at room temperature. The reaction mixture was stirred at room temperature overnight. LCMS showed 80% conversion, so an additional aliquot of 4 M hydrochloric acid / dioxane (1 mL) was added, and after an additional 3 h, LCMS showed complete conversion. The solvent was evaporated and co-evaporated with MTBE (3x) to give the desired product N-(1-(1-(2-aminoethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (280 mg, 0.57 mmol, 87% yield) as a pale yellow solid. LC / MS Method 4: MS (ESI) [M+H]+ 417.2, rt: 1.458 min.

[0188] 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)ethyl)acetamide To a solution of N-(1-(1-(2-aminoethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (200.0 mg, 0.41 mmol) in DMF (1.5 mL) was added DIPEA (0.43 mL, 2.45 mmol) and 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetic acid (136 mg, 0.410 mmol) at room temperature. The resulting solution was stirred at room temperature for 10 minutes. PyAOP (213.0 mg, 0.41 mmol) was then added in one portion. The reaction mixture was stirred at room temperature for 2 hours. LCMS confirmed complete conversion of the desired product. The mixture was directly purified by reverse-phase column chromatography (5% MeCN to 100% MeCN in water with 0.1% FA) to afford impure material. A second reverse-phase purification (5 to 100% MeCN in water) afforded the product, 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)ethyl)acetamide (35 mg, 0.48 mmol, 11% yield) as a yellow solid. LC / MS Method 3: MS (ESI) [M+H] + 731.3, rt:2.381 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83 - 2.04 (m, 5 H), 2.07 - 2.18 (m, 2 H), 2.39 - 2.46 (m, 5 H), 2.52- 2.62 (m, 2 H), 2.81 - 2.89 (m, 1 H), 2.95 (br d, J = 11.5 Hz, 2 H), 3.26 - 3.30 (m, 2 H), 4.05 - 4.20 (m, 1H), 4.75 (s, 2 H), 5.12 (dd, J = 12.7, 5.6 Hz, 1 H), 7.28 - 7.35 (m, 1 H), 7.38 - 7.52 (m, 6 H), 7.64 (d, J =1.0 Hz, 1 H), 7.80 (s, 1 H), 7.86 - 7.90 (m, 2 H), 8.14 (t, J = 5.6 Hz, 1 H), 8.22 (s, 1 H), 9.88 (s, 1 H), 11.12 (s, 1 H).

[0189] Example S9. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)acetamide (9) [ka] tert-Butyl 4-(3-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidine-1-carboxylate 5,8-Dibromoimidazo[1,2-α]pyrazine (165 mg, 0.6 mmol), tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate (198 mg, 0.72 mmol), and pivalic acid (0.67 mL, 5.96 mmol) were added to a vial and sealed with a septum cap. The mixture was stirred in an oil bath at 100 °C for 1 h. HPLC confirmed complete conversion to the desired product. The resulting residue was cooled to room temperature, added to 100 mL of 10% aqueous Na2CO3, and extracted with EtOAc (3 x 20 mL). The combined organic material was dried over MgSO4 and evaporated to give the product (303 mg, 0.574 mmol, 96% yield) as an orange oil, which was used directly in the next step. LC / MS Method 4: MS (ESI) [M]+ 472.2, rt:2.092 min.

[0190] tert-Butyl 4-[3-[[5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]phenyl]piperidine-1-carboxylate In a 30 mL microwave vial equipped with a stir bar, tert-butyl 4-(3-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidine-1-carboxylate (303.0 mg, 0.64 mmol) was dissolved in 1,4-dioxane (3.78 mL) and water (0.49 mL). m-Tolylboronic acid (174 mg, 1.28 mmol) was then added. The resulting solution was degassed with nitrogen for 10 minutes. After this time, NaHCO3 (0.04 mL, 1.92 mmol) and Xphos (24 mg, 0.05 mmol) were added, followed by Xphos Pd G3 (44 mg, 0.05 mmol). The system was degassed for 5 minutes and heated under microwave irradiation at 135 °C for 45 minutes. The resulting black suspension was filtered through Celite and the resulting solution was evaporated; the residue was purified by reverse-phase flash chromatography (5% to 100% MeOH in water with 0.1% FA) to give the product (217 mg, 0.448 mmol, 70% yield) as an orange semi-solid. LC / MS Method 4: MS (ESI) [M+H]+ 484.2, rt: 2.205 min.

[0191] N-(3-(piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine tert-Butyl 4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidine-1-carboxylate (217.0 mg, 0.45 mmol) was dissolved in methanol (4.49 mL). A solution of 4.0 M HCl / dioxane (2.24 mL, 8.97 mmol) was added and the resulting solution was stirred at room temperature. The reaction was monitored by HPLC. After 3 h, the reaction was complete. The solvent was evaporated in vacuo and the residue was removed with MeCN (2 x 5 mL) to form a colorless solid. The residue was purified by reverse-phase flash chromatography (5 to 100% MeOH in 0.1% FA) to give the product N-(3-(piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (152 mg, 0.354 mmol, 79%) as a white solid. LC / MS Method 4: MS (ESI) [M+H] + 384.2, rt:1.425 minutes.

[0192] tert-Butyl (2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)carbamate N-(3-(piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (152.0 mg, 0.35 mmol) and tert-butyl N-(2-oxoethyl)carbamate (84.5 mg, 0.53 mmol) were dissolved in DCE (3.53 mL). DIPEA (0.07 mL, 0.39 mmol) and NaBH(OAc) (90.0 mg, 0.42 mmol) were added to the reaction vessel. The resulting suspension was stirred at room temperature overnight. LCMS analysis indicated that the reaction had gone to 70% conversion, so additional aldehyde (20 mg) and NaBH(OAc) (20 mg) were added. After 3 hours, the solvent was removed in vacuo and the residue was purified by reverse-phase flash chromatography (5% to 100% MeOH in water with 0.1% FA) to give the product tert-butyl (2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)carbamate (176 mg, 0.297 mmol, 84%) as a colorless semi-solid. LC / MS Method 4: MS (ESI) [M+2H] 2+ 264.4, rt:1.531 minutes.

[0193] N-(3-(1-(2-aminoethyl)piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine tert-Butyl (2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)carbamate (175.0 mg, 0.33 mmol) was dissolved in methanol (3.3 mL). 4.0 M hydrochloric acid in dioxane (1.66 mL, 6.65 mmol) was added, and the resulting solution was stirred at room temperature. After 3 hours, LCMS analysis indicated the reaction was complete. The solvent was evaporated in vacuo, and the residue was removed with MeOH (2 x 5 mL) to give the product, N-(3-(1-(2-aminoethyl)piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (166 mg, 0.332 mmol, 100% yield), as a brown solid. LC / MS Method 4: MS (ESI) [M+H]+ 427.3, rt:1.330 min.

[0194] 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)acetamide N-(3-(1-(2-aminoethyl)piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (166.0 mg, 0.33 mmol) and 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetic acid (115.95 mg, 0.3500 mmol) were dissolved in DMF (2.2156 mL) and then DIPEA (0.29 mL, 1.66 mmol). The resulting solution was stirred for 5 minutes and then cooled using an ice bath. Solid PyAOP (191 mg, 0.37 mmol) was then added. The reaction solution was stirred in the ice bath for 15 minutes and then at room temperature for 1 hour. The reaction solution was directly purified by reverse-phase column chromatography (5% MeCN to 40% MeCN in water containing 0.1% FA). Because the recovered material was impure, a second reverse-phase purification (5 to 100% ACN in water) was performed. The desired product, 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)acetamide (27.3 mg, 0.036 mmol, 11% yield), was obtained as a pale yellow solid. LC / MS Method 3: MS (ESI) [M+H] + 741.2, rt:2.619 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64 (qd, J = 12.2, 2.9 Hz, 2 H), 1.72-1.80 (m, 2 H), 1.96 - 2.02 (m, 1 H), 2.07 (td, J = 11.5, 1.5 Hz, 2 H), 2.41 (s, 3 H), 2.42 - 2.48 (m, 3 H), 2.54 (s, 2 H), 2.81 - 2.96 (m, 1 H), 2.97 (br d, J = 11.2 Hz, 2 H), 4.75 (s, 2 H), 5.11 (dd, J = 13.0, 5.4, ​​1 H), 6.89 (d, J = 7.8 Hz, 1 H), 7.25 (t, J = 7.8 Hz, 1 H), 7.34 (d, J = 7.1 Hz, 1 H), 7.40 (dd, J = 8.3, 2.4 Hz, 1 H), 7.44 - 7.48 (m, 3 H), 7.51 (br d, J = 13.7 Hz, 2 H), 7.69 (d, J = 1.0 Hz, 1 H), 7.87 (dd, J = 8.3 Hz, 1 H), 7.91 - 7.94 (m, 1 H), 7.94 (d, J = 1.2 Hz, 2 H), 8.10 - 8.16 (m, 1 H), 9.47 (s, 1 H), 11.11 (s, 1 H), (Three protons were not observed).

[0195] Example S10. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)acetamide (10) [ka]

[0196] tert-Butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperidine-1-carboxylate 5,8-Dibromoimidazo[1,2-α]pyrazine (250 mg, 0.0 mmol), tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (299 mg, 1.08 mmol), and pivalic acid (1.02 mL, 9.03 mmol) were added to a vial and sealed with a septum. The resulting mixture was stirred in an oil bath at 100 °C for 1 h. HPLC analysis confirmed complete conversion to the desired product. The resulting residue was cooled to room temperature, and heptane (approximately 20 mL) was added. The suspension was stirred for 10 min. The suspension was filtered through a Buchner funnel, and the solid was washed twice with heptane. The resulting solid was dried under vacuum for 3 hours to give the desired product, tert-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperidine-1-carboxylate (415 mg, 0.8 mmol, 89% yield) as a pale yellow solid. LC / MS Method 4: MS (ESI) [M]+ 472.1, rt: 2.088 min.

[0197] tert-Butyl 4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidine-1-carboxylate In a 30 mL microwave vial equipped with a stir bar, tert-butyl 4-[4-[(5-bromoimidazo[1,2-α]pyrazin-8-yl)amino]phenyl]piperidine-1-carboxylate (250 mg, 0.53 mmol) was dissolved in 1,4-dioxane (2.8 mL). m-Tolylboronic acid (144 mg, 1.06 mmol) was then added. The resulting solution was degassed with nitrogen for 10 minutes. 2.0 M aqueous sodium bicarbonate (133 mg, 1.59 mmol) and Xphos Pd G3 (36 mg, 0.04 mmol) were then added, followed by Xphos (20 mg, 0.04 mmol). The system was degassed for 5 minutes and then heated at 135 °C under microwave irradiation for 45 minutes. The resulting black suspension was then filtered over Celite, and the resulting solution was concentrated. The residue was purified by reverse-phase column chromatography (5 to 100% MeOH in water containing 0.1% FA) to give the product tert-butyl 4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidine-1-carboxylate (179 mg, 0.37 mmol, 70% yield) as a white solid. LC / MS Method 4: MS (ESI) [M+H] + 484.4, rt:2.191 minutes.

[0198] N-(4-(piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine tert-Butyl 4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidine-1-carboxylate (179 mg, 0.37 mmol) was dissolved in methanol (3.7 mL) and 4.0 M HCl / dioxane (1.85 mL, 7.4 mmol), and the resulting solution was stirred at room temperature. After 3 h, HPLC analysis indicated the reaction was complete. The solvent was evaporated in vacuo, and the residue was removed with MeCN (2 x 5 mL) to give the product, N-(4-(piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (quantitative) as a yellow solid. LC / MS Method 4: MS (ESI) [M+H] + 384.5, rt:1.391 minutes.

[0199] tert-Butyl (2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)carbamate N-(4-(piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (209 mg, 0.46 mmol) was suspended in DCE (5.0 mL), followed by DIPEA (0.17 mL, 0.96 mmol), followed by tert-butyl N-(2-oxoethyl)carbamate (109 mg, 0.69 mmol). After 10 min, NaBH(OAc) (116 mg, 0.55 mmol) was added, and the reaction solution was stirred at room temperature. After 3 h, 20% conversion was observed; the reaction solution was then heated at 40 °C for 1 h and stirred at room temperature overnight. Silica gel was added to the resulting solution, and the solvent was removed in vacuo. The resulting residue was purified by normal phase column chromatography (0-10% MeOH in DCM) to give the product tert-butyl (2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)carbamate (76 mg 0.13 mmol, 29% yield) as a clear oil. LC / MS Method 4: MS (ESI) [M+H]+ 527.4, rt: 1.508 min.

[0200] N-(4-(1-(2-aminoethyl)piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine tert-Butyl (2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)carbamate (75.0 mg, 0.1400 mmol) was dissolved in methanol (1.9 mL). 4.0 M HCl / dioxane (0.71 mL, 2.85 mmol) was added, and the resulting solution was stirred at room temperature. After 3 h, HPLC analysis confirmed the reaction was complete. The solvent was evaporated in vacuo, and the residue was removed with MeCN (2 x 5 mL) to give the product, N-(4-(1-(2-aminoethyl)piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (76 mg, 0.144, 100% yield) as a pale yellow solid. LC / MS Method 4: MS (ESI) [M+2H] 2+ 214.4, rt:1.337 minutes.

[0201] 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)acetamide N-(4-(1-(2-aminoethyl)piperidin-4-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (74.0 mg, 0.15 mmol) and 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetic acid (51.69 mg, 0.16 mmol) were dissolved in DMF (1.0 mL), and DIPEA (0.13 mL, 0.74 mmol) was added. The resulting solution was stirred for 5 minutes and then cooled using an ice bath. PyAOP (85 mg, 0.16 mmol) was then added. The reaction solution was stirred in the ice bath for 15 minutes and then at room temperature for 1 hour. The product was then purified by reverse-phase flash chromatography (5% to 100% MeCN in water with 0.1% FA) to give the product, 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperidin-1-yl)ethyl)acetamide (2.7 mg, 0.0036 mmol, 2.4% yield) as a pale yellow solid. LC / MS Method 3: MS (ESI) [M+H] + 741.2, rt:2.598 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 - 1.67 (m, 2 H), 1.68 - 1.76 (m, 2 H), 1.94 - 2.08 (m, 3 H), 2.39 - 2.44 (m, 6 H), 2.53 - 2.62 (m, 2 H), 2.81 - 2.91 (m, 1 H), 2.92 - 3.00 (m, 2 H), 4.75 (s, 2 H), 5.12 (dd, J = 13.0, 5.4 Hz, 1 H), 7.18 (d, J = 8.8 Hz, 2 H), 7.32 - 7.38 (m, 1 H), 7.39 -7.42 (m, 1 H), 7.42 (s, 1 H), 7.44 - 7.49 (m, 3 H), 7.52 (s, 1 H), 7.68 (d, J = 1.2 Hz, 1 H), 7.88 (d, J = 8.3 Hz, 1 H), 7.91 - 7.95 (m, 2 H), 7.96 (s, 1 H), 8.13 (t, J = 5.7 Hz, 1 H), 9.53 (s, 1 H), 11.11 (s, 1 H), (two protons not observed).

[0202] Example S11. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)acetamide (11) [ka] tert-Butyl 4-(3-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (1 g, 3.61 mmol) and 5,8-dibromoimidazo[1,2-α]pyrazine (0.9 g, 3.24 mmol) in NMP (6 mL) was added DIPEA (1.3 mL, 7.45 mmol) at room temperature. The reaction flask was placed in an oil bath pre-equilibrated to 100 °C and stirred for 48 h. The reaction mixture was cooled to room temperature, and saturated aqueous NaHCO (100 mL) was added. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over NaSO, and evaporated to form a black oil (5.93 g). This was purified using reverse-phase column chromatography (5% to 100% MeOH in water containing 0.1% FA) to give the product, tert-butyl 4-(3-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (750 mg, 1.47 mmol, 41% yield) as a brown solid.

[0203] tert-Butyl 4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate A dried, sealed tube was charged with tert-butyl 4-(3-((5-bromoimidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (500 mg, 0.96 mmol) and m-tolylboronic acid (158 mg, 1.17 mmol) at room temperature. 1,4-Dioxane (10 mL) and saturated aqueous NaHCO3 (7.82 mL, 7.82 mmol) were then added, and the mixture was sparged with nitrogen for 10 minutes. Pd(PPh3)4 (58 mg, 0.05 mmol) was then added in one portion, and nitrogen sparging continued for 5 minutes. The tube was sealed and placed in an oil bath pre-equilibrated to 90 °C. The mixture was heated at that temperature overnight. LCMS analysis confirmed complete conversion to the desired product. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated to give a crude residue which was purified by normal phase chromatography (70% EtOAc / heptane) to give the desired product tert-butyl 4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (quantitative yield, 91% purity). LC / MS Method 4: MS (ESI) [M+H] 485.4, rt: 2.082 min.

[0204] N-(3-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine tert-Butyl 4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate (600 mg, 1.24 mmol) was dissolved in methanol (8 mL). A solution of 4 M HCl / dioxane (3.1 mL, 12.4 mmol) was then added at room temperature. The reaction mixture was stirred at room temperature overnight. LCMS analysis confirmed complete conversion to the desired product. The precipitate that formed overnight was filtered off and washed with MeOH to give the desired product, N-(3-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (285 mg, 0.73 mmol, 59% yield), as a yellow solid. LC / MS Method 3: MS (ESI) [M+H]+ 385.2, rt:2.558 min.

[0205] tert-Butyl (2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)carbamate tert-Butyl N-(2-oxoethyl)carbamate (41.6 mg, 0.26 mmol) was mixed with N-(3-(piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (75 mg, 0.17 mmol) in DCE (1.74 mL) and DIPEA (0.03 mL, 0.19 mmol). NaBH(OAc) (44 mg, 0.21 mmol) was added, and the suspension was stirred at room temperature overnight. HPLC analysis confirmed approximately 95% conversion to the desired product. The solvent was removed in vacuo and the residue was purified by normal phase column chromatography (0-10% MeOH in DCM) to give the product tert-butyl (2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)carbamate (76 mg, 0.144 mmol, 82% yield) as a colorless semi-solid. LC / MS Method 4: MS (ESI) [M+2H] 2+ 264.8, rt:1.519 minutes.

[0206] N-(3-(4-(2-aminoethyl)piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine tert-Butyl (2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)carbamate (76 mg, 0.14 mmol) was dissolved in methanol (1.4 mL), and 4.0 M HCl / dioxane (0.71 mL, 2.84 mmol) was added. The resulting solution was stirred at room temperature. After 3 h, HPLC analysis confirmed the reaction was complete. The solvent was evaporated in vacuo, and the residue was removed with MeCN (2 x 5 mL) to give the product, N-(3-(4-(2-aminoethyl)piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (quantitative) as a colorless semisolid. LC / MS Method 4: MS (ESI) [M+H]+ 428.2, rt:1.392 min.

[0207] 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)acetamide N-(3-(4-(2-aminoethyl)piperazin-1-yl)phenyl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (76 mg, 0.15 mmol) and 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetic acid (55.5 mg, 0.17 mmol) were dissolved in DMF (0.76 mL), followed by the addition of DIPEA (0.11 mL, 0.6100 mmol). The resulting solution was stirred for 5 minutes, and HATU (69 mg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The residue was purified by reverse-phase column chromatography (5% to 100% MeCN in water containing 0.1% FA). The resulting material was impure and was further purified by reverse phase column chromatography (5% to 100% MeCN in water) to give the product, 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(4-(3-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)phenyl)piperazin-1-yl)ethyl)acetamide (13.3 mg, 0.0179 mmol, 12% yield) as a yellow solid. LC / MS Method 3: MS (ESI) [M+H] + 742.2, rt:2.605 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.94 - 2.06 (m, 1 H), 2.41 (s, 3 H), 2.43 - 2.48 (m, 2H), 2.53 - 2.62 (m, 4 H), 2.81 - 2.95 (m, 1 H), 3.11 (br s, 4 H), 4.75 (s, 2 H), 5.11 (dd, J = 12.7, 5.4 Hz, 1 H), 6.60 (d, J = 7.8 Hz, 1 H), 7.15 (t, J = 8.1 Hz, 1 H), 7.34 (d, J = 7.3 Hz, 1 H), 7.40 (dd, J = 8.3, 2.4 Hz, 1H), 7.43 - 7.46 (m, 2H), 7.46 - 7.51 (m, 2H), 7.52 (s, 1H), 7.60 - 7.67 (m, 2H), 7.69 (d, J = 1.0 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 8.14 (t, J = 4.9 Hz, 1H), 9.33 (s, 1H), 11.13 (s, 1H), (four protons were obscured by the DMSO peak).

[0208] Example S12. 3-(1-oxo-5-(9-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carbonyl)isoindolin-2-yl)piperidine-2,6-dione (12) [ka] tert-Butyl 9-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate To a solution of N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (370 mg, 0.99 mmol) and tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (344 mg, 1.29 mmol) in DCE (10 mL) was added NaBH(OAc)3 (315 mg, 1.49 mmol). The reaction mixture was stirred at room temperature. After 1.5 h, LCMS indicated that ∼30% of the starting material remained. DIPEA (0.35 mL, 2 mmol) was added and the reaction mixture was stirred at room temperature overnight. LCMS indicated that ∼16% of the starting material remained. The ketone (0.3 equiv) and NaBH(OAc)3 (0.3 equiv) were added, and the reaction was stirred for an additional 2 h. The reaction was quenched with water and diluted with EtOH. The phases were separated and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by reverse-phase column chromatography (5% to 100% MeOH in water with 0.1% FA) to afford the product, tert-butyl 9-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate (420 mg, 0.62 mmol, 63% yield, formate salt) as a yellow semi-solid. LC / MS Method 4: MS (ESI) [M+H]+ 625.4, rt:1.529 min.

[0209] N-(1-(1-(3-Azaspiro[5.5]undecan-9-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine To a solution of tert-butyl 9-[4-[4-[[5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl]amino]pyrazol-1-yl]-1-piperidyl]-3-azaspiro[5.5]undecane-3-carboxylate (418.0 mg, 0.62 mmol) in methanol (6 mL) was added 4 M hydrochloric acid (1.6 mL, 6.4 mmol) in dioxane. The resulting solution was stirred at room temperature overnight. HPLC analysis confirmed complete conversion. The volatiles were removed in vacuo and the crude product was purified by reverse phase column chromatography (5% to 100% MeOH / water, pH 10 buffer) to give the product N-(1-(1-(3-azaspiro[5.5]undecan-9-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (300 mg, 0.57 mmol, 92% yield) as a pale yellow solid. LC / MS Method 4: MS (ESI) [M+H]+ 525.3, rt: 1.239 min.

[0210] 3-(1-oxo-5-(9-(4-(4-((5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carbonyl)isoindolin-2-yl)piperidine-2,6-dione To a solution of 2-(2,6-dioxopiperidin-3-yl)-1-oxoindoline-5-carboxylic acid (103 mg, 0.36 mmol) in DMF (3 mL) was added HATU (159 mg, 0.42 mmol), followed by a solution of N-(1-(1-(3-azaspiro[5.5]undecan-9-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(m-tolyl)imidazo[1,2-α]pyrazin-8-amine (208 mg, 0.35 mmol) and DIPEA (0.61 mL, 3.48 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 1 hour. LCMS analysis confirmed complete conversion. The mixture was purified by reverse-phase column chromatography (5% to 100% MeCN in water with 0.1% FA) to give the product, 3-(1-oxo-5-(9-(4-(4-(5-(m-tolyl)imidazo[1,2-α]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carbonyl)isoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.126 mmol, 36% yield) as a pale yellow solid. LC / MS Method 3: MS (ESI) [M+H] + 795.3, rt:2.391 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 - 1.20 (m, 2 H), 1.22 - 1.29 (m, 1 H), 1.33 - 1.50 (m, 4 H), 1.52 - 1.65 (m, 3 H), 1.75 - 1.82 (m, 2 H), 1.86 - 1.95 (m, 2 H), 1.98 - 2.06 (m, 3 H), 2.32 - 2.43 (m, 7 H), 2.61 (br d, J = 17.6 Hz, 1 H), 2.86 - 2.94 (m, 1 H), 2.95 - 3.03 (m, 2 H), 3.24 - 3.27 (m, 2 H), 3.58 - 3.65 (m, 2 H), 4.06 - 4.16 (m, 1 H), 4.38 (d, J = 17.7 Hz, 1 H), 4.50 (d, J = 17.7 Hz, 1 H), 5.13 (br dd, J = 13.4, 5.1 Hz, 1 H), 7.32 (br d, J = 6.4 Hz, 1 H), 7.40 - 7.51 (m, 5 H), 7.60 - 7.65 (m, 2 H), 7.76 - 7.81 (m, 2 H), 7.89 (s, 1 H), 8.16 (s, 1 H), 8.23 ​​(br s, 1 H), 9.88 (s, 1 H), 11.00 (s, 1 H), (one proton was not observed in the spectrum).

[0211] Biological Examples Example B1. IRAK3-ePL overexpression degradation assay Stable cell lines were generated using the following protocol: 3 × 10 5Lenti-X 293T cells (Clonetech) were seeded in 0.8 mL of medium in a 12-well plate and incubated overnight at 37°C / 5% CO2. The packaging plasmid (0.4 μg, pMD), envelope plasmid (0.4 μg, pSP), and lentiviral transduction IRAK3-ePL plasmid (0.8 μg, IRAK3 sequence NM_007199.3) were mixed in 0.1 mL of Opti-MEM and incubated for 5 minutes. Simultaneously, 2.4 μL of Lipofectamine 2000 (Invitrogen) was added to 0.1 mL of Opti-MEM (Gibco) and incubated for 5 minutes. The plasmid DNA and Lipofectamine were combined and the mixture was incubated for 20 minutes. The DNA:Lipofectamine Opti-MEM mixture was then added dropwise to the pre-seeded cells, and the cells were incubated for ~16 hours at 37°C / 5% CO2. After incubation, the medium was removed and 1.2 mL of fresh medium was added per well. Lenti-X 293T cells were incubated at 37°C / 5% CO2 for 30 hours. 0.5 × 10 6 293T CRBN OE / GSPT1 G575N KI Cells were seeded in 12-well plates with 0.5 mL of medium / well and incubated at 37°C / 5% CO2 for ~16 hours. After incubation, the medium was removed from the Lenti-X 293T wells and passed through a 0.45 μM filter. A portion of the viral supernatant was used for cell transduction, and the remainder was stored at -80°C. The virus was then transferred to the 293T wells. CRBN OE / GSPT1 G575N KIVirus was added individually to each well of cells (0.5 mL), followed by the addition of polybrene (10 mg / mL Millipore) to each well at a final concentration of 5.0 μg / mL. Cells were incubated for ~24 hours at 37°C / 5% CO2. After aspirating the medium from the plate, the cells were washed with DPBS, trypsinized, and seeded into 10 cm dishes containing 15 mL of medium and 1 μg / mL puromycin. After culturing the cells for ~72 hours at 37°C / 5% CO2, the medium was aspirated from the plate, washed with DPBS, and trypsinized. Cells were seeded into 15 cm dishes containing 1.0 μg / mL puromycin (Gibco) and 40 mL of medium and incubated for ~72 hours at 37°C / 5% CO2. After incubation, the medium was removed, and the cells were washed with DPBS and trypsinized. The majority of the cells were resuspended in Invitrogen freezing medium and stored (approximately 6–8 × 10 6 cells / vial).

[0212] The dose-response curve resolution assay for IRAK3-ePL cells was performed using the following protocol. Test compounds were dispensed into white 384-well tissue culture-treated plates using an acoustic liquid dispenser. Dilutions were prepared in duplicate based on a 25 μL assay volume, with 10-point, 3-fold serial dilutions starting from a 10 μM dose. Negative control wells containing 0.2% DMSO alone were included to calculate 100% signal. Positive control wells containing 30 μM Ataluren (luciferase inhibitor) were included to calculate background signal levels. To ensure uniform DMSO concentrations between wells, all wells were adjusted to a final DMSO concentration of 0.2%. IRAK3-ePL expressing cells (IRAK3-ePL Lenti-X 293T) were cultured in 10 wells of 100% DMSO. CRBN / GSPT1 G575N) were washed, trypsinized, counted, and resuspended in fresh DMEM (Gibco) to a cell concentration of 200,000 cells / mL. 25 μL of cells (5,000 cells / well) were dispensed into 384-well plate wells containing compounds and incubated overnight at 37°C / 5% CO2. After incubation, the 384-well plate was removed from the incubator and placed at room temperature for 30 minutes. InCELL hunter reagent was prepared according to the manufacturer's instructions (EA reagent, lysis buffer, and substrate reagent in a 1:1:4 ratio, Cat# 96-0002, DiscoverX) and added to the 384-well plate at 25 μL / well. The plate was incubated at room temperature for 1 hour, after which the luminescence signal was read using a ViewLux plate reader. Data were processed and analyzed using ActivityBase software. In other words, the mean luminescence value of the positive control wells was subtracted from the remaining wells to correct for background, and all luminescence values ​​were normalized to the DMSO control wells. The mean value of the DMSO control wells was set equal to 100% of the relative level of IRAK3-ePL protein. The normalized luminescence values ​​were plotted on a graph as a function of compound concentration. Compound concentration was plotted on the x-axis, and the corresponding relative level of IRAK3-ePL protein was plotted on the y-axis. The EC of the compounds on the degradation of IRAK3-ePL was calculated. 50 The median effective concentration (MEC) was calculated using a four-parameter logistic model (sigmoidal dose-response model) (FIT = (A + {(BA) / 1 + [(C / x) D ]})) (where C is the inflection point (EC 50 ), where D is the correlation coefficient, and A and B are the lower and upper bounds on the fit, respectively.

[0213] D max was calculated by determining the % maximum loss of target protein after compound treatment.

[0214] Example B2. IRAK endogenous HTRF degradation assay Cells (~50kJ) were seeded into a Cisbio 96-well low-volume white plate (Cisbio: cat# 66PL96005). Compounds were dissolved in DMSO and serially diluted 3-fold using a TECAN D300E. Cells were incubated with compounds overnight. For degradation analysis, a Cisbio Total-IRAK3 HTRF kit (Cisbio: 63ADK101PEH) was used. Cryptate and D2 antibodies were diluted in detection buffer according to the manufacturer's recommendations. 2 μL of each solution was then added to 16 μL of degradation mixture. Buffer controls (degradation buffer, detection buffer), cryptate controls (degradation buffer + cryptate antibody + detection buffer), and negative controls (degradation buffer + cryptate antibody + D2 antibody) were prepared according to the manufacturer's recommendations. After incubation with the antibody, the HTRF signal was measured on a Perkin Elmer Envision reader, and the HTRF signal was calculated using the formula: (emission at 665 nm / emission at 615 nm) * 10,000. All HTRF values ​​were normalized to the mean value of DMSO. The mean value of the DMSO control wells was set equal to 100% of the relative level of IRAK3 protein. The normalized luminescence values ​​were plotted on a graph as a function of compound concentration. Compound concentration was plotted on the x-axis, and the corresponding normalized IRAK3 protein level was plotted on the y-axis. The EC of compounds on the degradation of IRAK3 50 The median effective concentration (MEC) was calculated using a four-parameter logistic model (sigmoidal dose-response model) (FIT = (A + {(BA) / 1 + [(C / x) D ]})) (where C is the inflection point (EC 50 ), where D is the correlation coefficient, and A and B are the lower and upper bounds on the fit, respectively. min was calculated by determining the minimum percentage of target protein remaining after compound treatment. max is Y min Calculated from (% D max = 100-Y min ).

[0215] Example B3. IRAK3 Biochemical Binding Assay The LanthaScreen® Eu Kinase Binding Assay was performed as described by the supplier (ThermoFisher Scientific, Waltham, MA). Briefly, 100x solutions of compounds were prepared in DMSO and final concentrations were determined by serially diluting 10 mM stock solutions at 3-fold intervals in a 384-well reagent plate. Serially diluted compounds (1 μL) were added to corresponding wells of a 384-well reagent plate containing 32.3 μL of 1x buffer [50 mM HEPES (pH 7.4), 10 nM MgCl2, 1 mM EGTA, 0.01% Brij-35]. Buffer-diluted compounds (5 μL) were transferred to corresponding wells of a 384-well assay plate. 3x tracer (5 μL) was transferred to each well of the assay plate to achieve a final tracer concentration of 10 nM. Finally, 5 μL of 3×Eu-anti-GST and IRAK3 mix was transferred to each well to a final concentration of 2 nM and 10 nM, respectively. The reaction solution was incubated at room temperature for 1 hour. The TR-FRET signal (λex340 / λem665 / λem615) for the interaction was read using an Envision plate reader at room temperature with a delay time of 100 μs and an integration time of 200 μs. The background-corrected emission signal ratio at each compound concentration was used to calculate the inhibition rate (% inhibition). A plot of % inhibition versus inhibitor concentration was fitted to a dose-response equation (Equation 1) to calculate the IC using Dotmatics software (Dotmatics, Bishops Stortford, Hertfordshire, England). 50 and Hill slope values ​​were calculated.

number

[0216] Using these assays, the IC of the following compounds was determined: 50 , D max , E.C. 50 and D.C. 50 The value was determined. maxis defined as the maximum degradation achieved, and DC 50 is the concentration at which 50% degradation was achieved. The data are summarized in Table 2. [Table 3]

[0217] The present invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, but these descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein by reference in their entireties.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, Ring A is C 6 -C 10 The heteroaryl is an aryl or a 5-6 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; Ring B is C 6 -C 10 aryl or C 3 -C 6 cycloalkyl, each of which may optionally be substituted by 1 to 5 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, halo, -OH and -CN; X is either CH or N; L is -O(C 1 -C 6 Alkylene)C(O)-, -O(C 1 -C 6 Alkylene)C(O)NR 1 (C 1 -C 6 Alkylene)C(O)-, -O(C 1 -C 6 Alkylene)C(O)NR 1 (C 1 -C 6 Alkylene)-O-(C 1 -C 6 Alkylene)C(O)-, -O(C 1 -C 6 Alkylene)C(O)NR 1 (C 1 -C 6 It is alkylene)- or -C(O)(6-11 member spiroheterocyclylene)-; R 1 is H or C 1 -C 6 It is alkyl; and R 2a and R 2b Compounds of [each H, or together they form an oxo group] or pharmaceutically acceptable salts thereof.

2. Ring A is C 6 -C 10 A compound according to claim 1, wherein the compound is an aryl compound, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-6 membered heteroaryl, and the heteroaryl contains 1-3 nitrogen atoms.

4. Ring A is 【Chemistry 2】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. Ring A is 【Transformation 3】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. Ring B is C 1 -C 6 C may optionally be substituted with 1 to 5 substituents selected from alkyl groups. 6 -C 10 A compound according to claim 1, wherein the compound is an aryl compound, or a pharmaceutically acceptable salt thereof.

7. Ring B is C 1 -C 3 C may optionally be substituted with 1 to 3 substituents selected from alkyl groups. 6 -C 10 A compound according to claim 6, wherein the compound is an aryl compound, or a pharmaceutically acceptable salt thereof.

8. Ring B is 【Chemistry 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is CH.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is N.

11. L is -O(C 1 -C 3 Alkylene)C(O)-, -O(C 1 -C 3 Alkylene)C(O)NR 1 (C 1 -C 3 Alkylene)C(O)-, -O(C 1 -C 3 Alkylene)C(O)NR 1 (C 1 -C 3 Alkylene)-O-(C 1 -C 3 Alkylene)C(O)-, -O(C 1 -C 3 Alkylene)C(O)NR 1 (C 1 -C 3 Alkylene)- or -C(O)(10-11 member spiroheterocyclylene)-; and R 1 However, H is The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. L, 【Transformation 5】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. R 2a and R 2b The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each of the atoms is H.

14. R 2a and R 2b The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compounds together form an oxo group.

15. The compound is of formula (II), (IIIa), (IIIb), or (IV): 【Transformation 6】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the following characteristics.

16. Compounds listed in the following table: Table 1-1 Table 1-2 Table 1-3 A compound or a pharmaceutically acceptable salt thereof, selected from the above.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for modulating interleukin-1 receptor-related kinase 3 (IRAK3).

19. A pharmaceutical composition for treating cancer, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein the cancer is optionally selected from bladder cancer, breast cancer, esophageal cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma, and gastric cancer.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, for enhancing immunity in a person receiving a vaccine.

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