Substituted imidazo compounds as ligand-targeted IRAK3 degraders

Abstract

The present application provides 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 priority to U.S. Provisional Application No. 63 / 434,197, filed December 21, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] The present disclosure relates generally to compounds, compositions, and methods for their preparation and use of such compounds and compositions for the treatment of cancer. [Background technology]

[0003] The recruitment of immune cells to the site of injury involves the coordinated interaction of multiple lytic mediators. Several cytokines, including interleukin-1 (IL-1), appear to play important roles in these processes. IL-1 triggers the inflammatory response and contributes to the tissue degeneration observed under chronic inflammatory conditions. IL-1 is also involved in processes of bone resorption and adipose tissue regulation. Therefore, IL-1 plays an important role in numerous 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, and the resulting heterodimer recruits an adaptor molecule, designated MyD88, which then 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, which mediates interactions with MyD88-family adaptor proteins, and a centrally located kinase domain. Among the four members of the mammalian IRAK family, IRAK2 and IRAK3 are considered catalytically inactive pseudokinases (Wesche et al., J. Biol. Chem. 1999, 274, 19403-19410), although the precise roles of these two kinases remain largely unclear (Lagne et al., Structure 2021, 29, 238-251). Nevertheless, a report has implicated IRAK3 in the negative regulation of TLR (toll-like receptor) signaling, which is involved in microbial detection and protection of multicellular organisms from infection (Kobayashi et al., Cell 2002, 110, 191-202). More recent studies have linked mutations or high expression levels of IRAK3 to various diseases such as asthma and cancer (Balaci et al., Am. 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 requirement for IRAK3 binding.

[0005] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is central to almost all cellular processes. Protein ubiquitination is achieved by E3 ubiquitin ligases, which bind to proteins and attach ubiquitin molecules to them, thereby marking them for proteasomal degradation.

[0006] The therapeutic use of UPPs has attracted considerable interest (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising treatment uses proteolysis-guiding chimeric molecules, commonly referred to as PROTACs, to achieve the removal of unwanted proteins by proteolysis (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTACs are ligand-targeted degraders that link E3 ligases to target proteins for degradation. These bifunctional molecules typically consist of an E3 ligase ligand connected via a linker moiety to a small molecule 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 ubiquitinated target protein is then recognized by the proteasome for degradation. Thus, in certain embodiments, provided herein are compounds that target IRAK3 for degradation. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Wesche et al., J. Biol. Chem.1999, 274, 19403-19410 [Non-patent document 2] O'Neill et al., J. Leukoc. Biol.1998, 63, 650-657 [Non-patent document 3] Auron, Cytokine Growth Factor Rev.1998, 9:221-237 [Non-patent document 4] O'Neill, Biochem. Soc. Trans.2000, 28, 557-563 [Non-Patent Document 5] Wesche et al., J. Biol. Chem.1999, 274, 19403-19410 [Non-patent document 6] Lagne et al., Structure 2021, 29, 238-251 [Non-Patent Document 7] Kobayashi et al., Cell 2002, 110, 191-202 [Non-patent document 8] Balaci et al., Am. J. Hum. Genet.2007, 80 (6), 1103-1114 [Non-Patent Document 9] Kesselring, R. Cancer Cell 2016, 29 (5), 685-696 [Non-Patent Document 10] Zhou et al., Mol. Cell 2000, 6, 751-756 [Non-Patent Document 11] Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176 Summary of the Invention

[0008] In certain embodiments, compounds and compositions thereof for IRAK3 degradation are described herein. In various embodiments, the compounds and compositions thereof may be used for the treatment of cancer.

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

[0010] Embodiment A1 is a compound of formula (I): [ka] [In the formula, A is C1-C6 alkyl, phenyl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl, or 6- to 10-membered heterocyclyl, and the phenyl, cycloalkyl, heteroaryl, and heterocyclyl are each independently selected from the group consisting of x R 1 substituted with a group, wherein the heteroaryl and heterocyclyl contain 1 to 3 heteroatoms selected from N and O; Each R 1 is independently halo, C-C alkyl, C-C cycloalkyl, C-C alkoxy, C-C haloalkyl, or —SO(C-C alkyl); or two R on adjacent carbon atoms 1 The groups taken together form a fused C3-C6 cycloalkyl or fused [ka] Forming a base; R a and R b are each H or together form an oxo group; R c is H or C1-C6 alkyl; x is 0 to 5; R 2 is H or C1-C6 alkyl; R 3 is H or C1-C6 alkyl; R 4 is H or C1-C6 alkyl; X 1 is CH or N; X 2 is N or CH2; Ring B is a C3-C6 cycloalkylene or a 5- to 7-membered heterocyclylene containing 1 or 2 nitrogen atoms; Each R 5 is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; w is 0 to 5; L 1 is -C(O)(CH2) n -, -(CH2) n - or -(CH2) n C(O)-; n is 1 to 6; Ring C is a 5- to 10-membered heterocyclylene ring containing 1 or 2 nitrogen atoms; Each R 6 is independently halo, C1-C6 haloalkyl, or C1-C6 alkyl; y is 0 to 5, Ring D is [ka] and; R 7a and R 7b are each H or together form an oxo group; Each R 8 is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; z is 0 to 4; X 3 is N or CR 9 and; R 9 is H or C1-C6 alkyl; R 10 is H or C1-C6 alkyl; Each R 11 is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; v is 0 to 4; and each [ka] are independently a single bond or a double bond. or a pharmaceutically acceptable salt thereof.

[0011] Embodiment A2 is A is C1-C3 alkyl, phenyl, C3-C5 cycloalkyl, 5- to 6-membered heteroaryl, or 8- to 10-membered heterocyclyl, and the phenyl, cycloalkyl, heteroaryl, and heterocyclyl are each independently selected from x R 1 substituted with a group; x is 0 to 3; and Each R 1 is independently halo, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or -SO2(C1-C3 alkyl); Or, two R on adjacent carbon atoms 1 The groups taken together form a fused C3-C5 cycloalkyl or fused [ka] Forming a base; R a and R b are each H or taken together to form an oxo group; and R c is H or C1-C3 alkyl; A compound according to embodiment A1 or a pharmaceutically acceptable salt thereof.

[0012] Embodiment A3 is A, [ka] That is, A compound according to embodiment A1 or A2 or a pharmaceutically acceptable salt thereof.

[0013] Embodiment A4 is R 2 is H or C1-C3 alkyl; R 3is H or C1-C3 alkyl; and R 4 is H or C1-C3 alkyl; A compound according to any one of embodiments A1 to A3 or a pharmaceutically acceptable salt thereof.

[0014] Embodiment A5 is X 1 is N, A compound according to any one of embodiments A1 to A4 or a pharmaceutically acceptable salt thereof.

[0015] Embodiment A6 is formula: [ka] but, [ka] That is, A compound according to any one of embodiments A1 to A5 or a pharmaceutically acceptable salt thereof.

[0016] Embodiment A7 is Ring B is a C4-C6 cycloalkylene or a 6- to 7-membered heterocyclylene containing one nitrogen atom; w is 0 to 2; and Each R 5 is independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; A compound according to any one of embodiments A1 to A6 or a pharmaceutically acceptable salt thereof.

[0017] Embodiment A8 is formula: [ka] but, [ka] That is, A compound according to any one of embodiments A1 to A7, or a pharmaceutically acceptable salt thereof.

[0018] Embodiment A9 is L 1 -C(O)CH2-, -(CH2) n - or -CH2C(O)-; and n is 1 to 5; A compound according to any one of embodiments A1 to A8, or a pharmaceutically acceptable salt thereof.

[0019] Embodiment A10 is Ring C is a 6- to 8-membered heterocyclylene ring containing 1 or 2 nitrogen atoms; y is 0 to 3; and Each R 6 is independently halo, C1-C3 haloalkyl, or C1-C3 alkyl; A compound according to any one of embodiments A1 to A9 or a pharmaceutically acceptable salt thereof.

[0020] Embodiment A11 is formula: [ka] but, [ka] That is, A compound according to any one of embodiments A1 to A10, or a pharmaceutically acceptable salt thereof.

[0021] Embodiment A12 is Ring D is [ka] That is, A compound according to any one of embodiments A1 to A11, or a pharmaceutically acceptable salt thereof.

[0022] Embodiment A13 is X 3 is CR 9 and; R 9 is H or C1-C3 alkyl; R 10 is H or C1-C3 alkyl; v is 0 to 2; and Each R 11 is independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; A compound according to any one of embodiments A1 to A12, or a pharmaceutically acceptable salt thereof.

[0023] Embodiment A14 is formula: [ka] but, [ka] That is, A compound according to any one of embodiments A1 to A13 or a pharmaceutically acceptable salt thereof.

[0024] Embodiment A15 is The compound has formula (IIIa), (IIIb), or (IIIc): [ka] or a pharmaceutically acceptable salt thereof.

[0025] Embodiment A16 is The compound has formula (IVa) or (IVb): [ka] or a pharmaceutically acceptable salt thereof.

[0026] Embodiment A17 is a compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0027] Embodiment A18 is a pharmaceutical composition comprising a compound according to any one of embodiments A1 through A17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0028] Embodiment A19 is a method for modulating interleukin-1 receptor-associated kinase 3 (IRAK3), characterized in that IRAK3 is contacted with an effective amount of a compound described in any one of embodiments A1 to A17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment A18.

[0029] Embodiment A20 is (I) a method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound described in any one of Embodiments A1 to A17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment A18, wherein the cancer may be 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; or (II) a method for enhancing the immunity of a vaccinated patient, comprising administering to the patient an effective amount of a compound described in any one of Embodiments A1 to A17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment A18. DETAILED DESCRIPTION OF THE INVENTION

[0030] definition As used herein, the terms "comprising" and "including" may be used interchangeably. The terms "comprising" and "including" are interpreted as stating the presence of a stated feature or component, but do not exclude the presence or addition of one or more features, components, or groups thereof. Furthermore, the terms "comprising" and "including" are intended to encompass examples encompassed by the term "consisting of." Thus, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide more specific embodiments of the invention.

[0031] The term "consisting of" means that the subject matter comprises at least 90%, 95%, 97%, 98%, or 99% of the stated features or components that make it up. In other embodiments, the term "consisting of" excludes from the scope of the succeeding description all other features or components, except those that are not essential to the technical effect to be achieved.

[0032] The term "or" as used herein should be interpreted as an inclusive "or" meaning any singular or in any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition occur only where combinations of elements, features, steps, or acts are inherently mutually exclusive in some way.

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

[0034] An "alkyl" group is a saturated, partially saturated, or unsaturated, straight- or branched-chain acyclic hydrocarbon having from 1 to 10 carbon atoms (C1-C 10alkyl), typically having 1 to 8 carbon atoms (C1-C8 alkyl), or in certain embodiments, 1 to 6 (C1-C6 alkyl), 1 to 4 (C1-C4 alkyl), 1 to 3 (C1-C3 alkyl), or 2 to 6 (C2-C6 alkyl) carbon atoms. In certain 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; while 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(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH), among others. Alkyl groups can be substituted or unsubstituted.When alkyl groups described herein are described as "substituted," they may be substituted with any one or more of the following substituents as found in the exemplary compounds and embodiments disclosed herein, as well as the following substituents: halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, ... and optionally substituted with chloroalkylalkylamino, aralkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkylalkylamino; imino; imide; 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 described as "substituted," they can be substituted with any one or more of the following substituents as found in the exemplary compounds and embodiments disclosed herein: 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; B(OH)2, or O(alkyl)aminocarbonyl.

[0035] A "cycloalkyl" group is an alkyl group having 3 to 10 carbon atoms (C-C) having a single ring or multiple fused or bridged rings, which may be optionally substituted. 10In some embodiments, the cycloalkyl group is a saturated or partially saturated cyclic alkyl group consisting of a cycloalkyl group (C3-C8 cycloalkyl). 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. Such 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, and the like, 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, among others, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl groups may be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and the like.

[0036] A "cycloalkylene" group refers to a divalent "cycloalkyl" group.

[0037] A "heterocyclyl" is a non-aromatic cycloalkyl in which 1 to 4 ring carbons are independently replaced by heteroatoms 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. A heterocyclyl can be attached to another group at any ring atom (i.e., any carbon atom or heteroatom on the heterocycle). A heterocyclyl group can be substituted or unsubstituted. A heterocyclyl group encompasses saturated and partially saturated ring systems. Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be fused to an aryl or heteroaryl ring regardless of attachment to the rest of the molecule. The phrase also includes bridged polycyclic ring systems containing at least one heteroatom. The phrase further includes spiro polycyclic ring systems containing at least one heteroatom. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidine-2,4-dioneyl), 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-, di-, or higher substituted, including, but not limited to, pyridyl or morpholinyl, which may be 2-, 3-, 4-, 5-, or 6-substituted or unsubstituted with a number of substituents, such as those listed below.

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

[0039] An "aryl" group is an alkyl group having 6 to 14 carbon atoms (C6-C8) having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). 14 In some embodiments, an aryl group contains 6 to 14 carbons (C6-C 14 aryl), in other embodiments, 6 to 12 (C-C 12 aryl), or further containing 6 to 10 carbon atoms (C6-C 10 aryl). Particular aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups may be substituted or unsubstituted. The phrase "aryl group" also includes fused rings, for example, fused aromatic-cycloaliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0040] A "heteroaryl" group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms, with the remainder of the atoms being carbon atoms. In some 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, but are not limited to, 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), imidazolyl, Examples of heteroaryl groups include pyridyl (e.g., azabenzimidazolyl 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 may 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 (as defined above), 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 can all be the same, or the halo groups can be different. Unless otherwise specified, haloalkyl groups are optionally substituted.

[0044] When groups described herein are described as "substituted," with the exception of alkyl groups, they may be substituted with any suitable one or more substituents. Illustrative examples of 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 polycyclic rings. cycloalkyl, which may be a single ring or a non-fused polycyclic ring system (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl, which may be a single ring or a fused polycyclic ring system or a non-fused polycyclic ring system (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); aryl or heteroaryl, which may be a single ring or a fused polycyclic ring system or a non-fused polycyclic ring system (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 intended to include pharmaceutically acceptable salts, tautomers, isotopic species, 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 and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of Formula (I) include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made 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 (e.g., acetic acid, arginic 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, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid). Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Examples of specific salts, therefore, include hydrochloride, formate, and mesylate salts. Other salts 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, the terms "stereoisomer" or "stereoisomerically pure," unless otherwise specified, 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. Typical stereoisomerically pure compounds will contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compounds disclosed herein may contain chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomers, including mixtures thereof, are included within the scope of the embodiments disclosed herein.

[0048] The use of stereomerically pure forms of the compounds disclosed herein, as well as mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be synthesized asymmetrically or resolved 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);Subramanian, G. See 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 be noted that the compounds disclosed herein also include E and Z isomers or mixtures thereof, and cis and trans isomers or mixtures thereof.In certain embodiments, the compound is isolated as either E or Z isomer.In other embodiments, the compound is a mixture of E and Z isomers.

[0050] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The concentration of isomers depends on the environment in which the compound is present, and can vary depending on, for example, whether the compound is a solid, whether the compound is in an organic solution, or whether the compound is in an aqueous solution. For example, in aqueous solution, pyrazole can exist in the following isomers: [ka] which are called tautomers of each other.

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

[0052] It should be noted that the compounds disclosed herein may also 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 may be radiolabeled with a radioisotope such as deuterium ( 2 H), carbon-13( 13 C), or nitrogen-15( 15The compound may be isotopically enriched with an isotope such as N). As used herein, an "isotopically enriched species" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled compounds and isotopically enriched compounds are useful as therapeutic agents (e.g., cancer therapeutic agents, research reagents (e.g., binding assays), and diagnostic agents (e.g., in vivo imaging agents)). All isotopic variations of the compounds described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, isotopically enriched species of the compounds disclosed herein are provided, for example, the isotopically enriched species are deuterium, carbon-13, and / or nitrogen-15 enriched compounds. As used herein, "deuterated" means that at least one hydrogen (H) is replaced with a deuterium (D or 2 H), meaning that the compound is enriched with deuterium at at least one position.

[0053] It is understood that each compound disclosed herein can be provided in any pharmaceutically acceptable salt form discussed herein, regardless of its stereoisomeric or isotopic composition.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 those elements present in each compound disclosed herein or its salt, but can also vary independently from the selection of a pharmaceutically acceptable salt of each compound.

[0054] It should be noted that if there is a discrepancy between the depicted structure and the nomenclature of that structure, the depicted structure shall bear more weight.

[0055] As used herein, "treatment" means to alleviate, in whole or in part, a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or to slow or stop the further progression or worsening of those symptoms, or to alleviate or eliminate the cause of the disorder, disease, or condition itself. In certain embodiments, the disorder is a neurodegenerative disease or symptom thereof described herein.

[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; preventing a subject from acquiring a disorder, disease, or condition; or reducing the likelihood of a subject acquiring a disorder, disease, or condition. In certain embodiments, the disorder is a neurodegenerative disease or symptom thereof described herein.

[0057] The term "effective amount" with respect 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, and in some embodiments, mammals, and in other embodiments, humans. In some embodiments, the subject is a human who has or is likely to have 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 for clarity be described herein in the context of separate embodiments, the invention may also be practiced in a single embodiment.

[0060] compound In some embodiments, a compound of formula (I): [ka] [In the formula, A is C1-C6 alkyl, phenyl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl, or 6- to 10-membered heterocyclyl, and the phenyl, cycloalkyl, heteroaryl, and heterocyclyl are each independently selected from the group consisting of x R 1 substituted with a group, wherein the heteroaryl and heterocyclyl contain 1 to 3 heteroatoms selected from N and O; Each R 1 is independently halo, C-C alkyl, C-C cycloalkyl, C-C alkoxy, C-C haloalkyl, or —SO(C-C alkyl); or two R on adjacent carbon atoms 1 The groups taken together form a fused C3-C6 cycloalkyl or fused [ka] Forming a base; R a and R b are each H or together form an oxo group; R c is H or C1-C6 alkyl; x is 0 to 5; R 2 is H or C1-C6 alkyl; R 3 is H or C1-C6 alkyl; R 4 is H or C1-C6 alkyl; X 1 is CH or N; X 2 is N or CH2; Ring B is a C3-C6 cycloalkylene or a 5- to 7-membered heterocyclylene ring containing 1 or 2 nitrogen atoms; Each R 5is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; w is 0 to 5; L 1 is -C(O)(CH2) n -, -(CH2) n - or -(CH2) n C(O)-; n is 1 to 6; Ring C is a 5- to 10-membered heterocyclylene ring containing 1 or 2 nitrogen atoms; Each R 6 is independently halo, C1-C6 haloalkyl, or C1-C6 alkyl; y is 0 to 5, Ring D is [ka] and; R 7a and R 7b are each H or together form an oxo group; Each R 8 is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; z is 0 to 4; X 3 is N or CR 9 and; R 9 is H or C1-C6 alkyl; R 10 is H or C1-C6 alkyl; Each R 11 is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; v is 0 to 4; and each [ka] are independently a single bond or a double bond. Provided herein is a compound of the formula: or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, A is C1-C6 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl, or 6-10 membered heterocyclyl, and the phenyl, cycloalkyl, heteroaryl, and heterocyclyl are each independently selected from x R 1 groups, and the heteroaryl and heterocyclyl contain 1 to 3 heteroatoms selected from N and O. In some embodiments, A is C1-C3 alkyl, phenyl, C3-C5 cycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heterocyclyl, and the phenyl, cycloalkyl, heteroaryl, and heterocyclyl are substituted with x R 1 The group is substituted.

[0062] In some embodiments, A is C1-C6 alkyl. In some embodiments, A is C1-C3 alkyl. In some embodiments, A is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, A is methyl. In some embodiments, A is ethyl. In some embodiments, A is n-propyl. In some embodiments, A is isopropyl. In some embodiments, A is methyl or ethyl.

[0063] In some embodiments, A is x R 1 The phenyl is substituted with a group.

[0064] In some embodiments, A is x R 1 In some embodiments, A is a C3-C6 cycloalkyl substituted with a group. In some embodiments, A is a C3-C5 cycloalkyl. In some embodiments, A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 0is cyclopropyl. In some embodiments, A is a saturated C3-C6 cycloalkyl. In some embodiments, A is a partially unsaturated C3-C6 cycloalkyl. In some embodiments, A is cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene. In some embodiments, A is cyclopentylene or cyclohexylene. In some embodiments, A is cyclopentylene. In some embodiments, A is a fused bicyclic C4-C6 cycloalkyl. In some embodiments, A is a fused bicyclic C4 cycloalkyl. In some embodiments, A is a fused bicyclic C5 cycloalkyl. In some embodiments, A is a fused bicyclic C6 cycloalkyl. In some embodiments, A is a cyclopropyl fused to a cyclobutyl or cyclopentyl ring. In some embodiments, A is a cyclopropyl fused to a cyclopentyl ring. In any of these variations, the cycloalkyl is selected from the group consisting of x R 1 The group is substituted.

[0065] In some embodiments, A contains 1 to 3 heteroatoms selected from N and O, and x R 1A is a 5- to 6-membered heteroaryl substituted with a group. In some embodiments, A is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O. In some embodiments, A is a 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O. In some embodiments, the heteroaryl contains 1 to 2 heteroatoms selected from N and O. In some embodiments, the heteroaryl contains 1 heteroatom selected from N and O. In some embodiments, the heteroaryl contains 1 oxygen atom. In some embodiments, the heteroaryl contains 1 nitrogen atom. In some embodiments, the heteroaryl contains 2 heteroatoms selected from N and O. In some embodiments, the heteroaryl contains 1 nitrogen atom and 1 oxygen atom. In some embodiments, the heteroaryl contains 2 nitrogen atoms. In some embodiments, A is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, or isoxazolyl. In some embodiments, A is pyrazolyl. In any of these variations, the heteroaryl is 1 The group is substituted.

[0066] In some embodiments, A contains 1 to 3 heteroatoms selected from N and O, and x R 1 In some embodiments, A is a 6- to 10-membered heterocyclyl substituted with a group. In some embodiments, A contains 1 to 3 heteroatoms selected from N and O, and x R 1 In some embodiments, A is an 8- to 10-membered heterocyclyl substituted with a group. In some embodiments, A contains 1 to 3 heteroatoms selected from N and O, and x R 1 In some embodiments, A is an 8- to 9-membered heterocyclyl substituted with a group. In some embodiments, A contains 1 to 3 heteroatoms selected from N and O, and x R 1 In some embodiments, A is a 9- to 10-membered heterocyclyl substituted with a group. ... 1In some embodiments, A is an 8-membered heterocyclyl substituted with a group. In some embodiments, A contains 1 to 3 heteroatoms selected from N and O, and x R 1 In some embodiments, A is a 9-membered heterocyclyl substituted with a group. In some embodiments, A contains 1 to 3 heteroatoms selected from N and O, and x R 1 In some embodiments, the heterocyclyl is a 10-membered heterocyclyl substituted with a group. In some embodiments, the heterocyclyl is a monocyclic heterocyclyl. In some embodiments, the heterocyclyl is a fused bicyclic heterocyclyl. In some embodiments, the fused bicyclic heterocyclyl comprises a heterocyclyl fused with an aryl group. In some embodiments, the fused bicyclic heterocyclyl comprises a heterocyclyl fused with a heteroaryl group. In any of these variations, the heterocyclyl comprises x R 1 The group is substituted.

[0067] In some embodiments, x is 0 to 5. In some embodiments, x is 0 to 3. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5.

[0068] In some embodiments, each R 1 is independently halo, C-C alkyl, C-C cycloalkyl, C-C alkoxy, C-C haloalkyl, or -SO(C-C alkyl). 1 is independently halo, C-C alkyl, C-C cycloalkyl, C-C alkoxy, C-C haloalkyl, or -SO(C-C alkyl). 1 are independently F, -CH3, cyclopropyl, -OCH3, or -SO2(CH3).

[0069] In some embodiments, R 1 is halo. In some embodiments, R 1is Cl, F, or Br. In some embodiments, R 1 is Cl. In some embodiments, R 1 is F. In some embodiments, R 1 is Br.

[0070] 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, n-propyl, or isopropyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is n-propyl. In some embodiments, R 1 is isopropyl.

[0071] In some embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1 is cyclopropyl.

[0072] In some embodiments, R 1 is C1-C6 alkoxy. In some embodiments, R 1 is C1-C3 alkoxy. In some embodiments, R 1 is —OCH3, —OCH2CH3, —OCH2CH2CH3, or —OCH(CH3)2. In some embodiments, R 1 is —OCH. In some embodiments, R 1 is -OCH2CH3.

[0073] In some embodiments, R 1is C1-C6 haloalkyl. In some embodiments, R 1 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 1 is C1-C3 haloalkyl. In some embodiments, R 1 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 1 is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. 1 is —CF. In some embodiments, R 1 is -CHF2.

[0074] In some embodiments, R 1 is —SO2(C1-C6 alkyl). In some embodiments, R 1 is —SO2(C1-C3 alkyl). In some embodiments, R 1 is —SO2(CH3), —SO2(CH2CH3), or —SO2(CH2CH2CH3). In some embodiments, R 1 is -SO2(CH3).

[0075] In some embodiments, two R on adjacent carbon atoms 1 The groups taken together form a fused C3-C6 cycloalkyl or fused [ka] group, and the R a and R b are each H or together form an oxo group, and R c is H or C1-C6 alkyl. In some embodiments, two R on adjacent carbon atoms 1 The groups taken together form a fused C3-C5 cycloalkyl or fused [ka] group, and the R a and R b are each H or together form an oxo group, and R c is H or C1-C3 alkyl. In some embodiments, two R on adjacent carbon atoms 1 The groups taken together form a fused cyclopropyl, cyclobutyl, [ka] Form.

[0076] In some embodiments, two R on adjacent carbon atoms 1 The groups taken together form a fused C-C cycloalkyl. In some embodiments, two R on adjacent carbon atoms 1 In some embodiments, two R groups on adjacent carbon atoms are joined together to form a fused C-C cycloalkyl. 1 The groups taken together form a fused cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, two R on adjacent carbon atoms 1 The groups taken together form a fused cyclopropyl or cyclobutyl. In some embodiments, two R groups on adjacent carbon atoms 1 In some embodiments, two R groups on adjacent carbon atoms are taken together to form a fused cyclopropyl. 1 The groups taken together form a fused cyclobutyl.

[0077] In some embodiments, two R on adjacent carbon atoms 1 The groups are condensed together [ka] group, and the R a and R b are each H or together form an oxo group, and R c is H or C1-C6 alkyl. In some embodiments, two R on adjacent carbon atoms1 The groups are condensed together [ka] group, and the R a and R b are each H or together form an oxo group, and R c is H or C1-C3 alkyl. In some embodiments, R a and R b are each H. In some embodiments, R a and R b taken together form an oxo group. In some embodiments, R c is H. In some embodiments, R c is C1-C6 alkyl (e.g., C1-C3 alkyl). In some embodiments, R c is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R c is methyl or ethyl. In some embodiments, two R on adjacent carbon atoms 1 The groups are condensed together [ka] Form.

[0078] In some embodiments, A is: [ka] is.

[0079] In some embodiments, R 2 is H or C1-C6 alkyl. In some embodiments, R 2 is H or C1-C3 alkyl. In some embodiments, R 2 is H or -CH3.

[0080] In some embodiments, R 2 is H.

[0081] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is methyl or ethyl.

[0082] In some embodiments, R 3 is H or C1-C6 alkyl. In some embodiments, R 3 is H or C1-C3 alkyl. In some embodiments, R 3 is H or -CH3.

[0083] In some embodiments, R 3 is H.

[0084] In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is C1-C3 alkyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is n-propyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is methyl or ethyl.

[0085] In some embodiments, R 4is H or C1-C6 alkyl. In some embodiments, R 4 is H or C1-C3 alkyl. In some embodiments, R 4 is H or -CH3.

[0086] In some embodiments, R 4 is H.

[0087] In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is C1-C3 alkyl. In some embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is methyl or ethyl.

[0088] In some embodiments, X 1 is CH or N. In some embodiments, X 1 is CH. In some embodiments, X 1 is N.

[0089] In some embodiments, X 2 is CH or N. In some embodiments, X 2 is CH. In some embodiments, X 2 is N.

[0090] In some embodiments, each [ka] is independently a single bond or a double bond. [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0091] In some embodiments, [ka] teeth [ka] is.

[0092] In some embodiments, ring B is C3-C6 cycloalkylene or a 5-7 membered heterocyclylene containing 1 or 2 nitrogen atoms, In some embodiments, ring B is C4-C6 cycloalkylene or a 6-7 membered heterocyclylene containing 1 nitrogen atom.

[0093] In some embodiments, ring B is C3-C6 cycloalkylene. In some embodiments, ring B is C4 cycloalkylene. In some embodiments, ring B is C5 cycloalkylene. In some embodiments, ring B is C6 cycloalkylene. In some embodiments, ring B is cyclobutylene, cyclopentylene, or cyclohexylene. In some embodiments, ring B is [ka] is.

[0094] In some embodiments, ring B is a 5- to 7-membered heterocyclylene containing 1 or 2 nitrogen atoms. In some embodiments, ring B is a 5-membered heterocyclylene containing 1 or 2 nitrogen atoms. In some embodiments, ring B is a 6-membered heterocyclylene containing 1 or 2 nitrogen atoms. In some embodiments, ring B is a 7-membered heterocyclylene containing 1 or 2 nitrogen atoms. In some embodiments, ring B is a 6- to 7-membered heterocyclylene containing 1 nitrogen atom. In some embodiments, ring B is a 6- to 7-membered heterocyclylene containing 2 nitrogen atoms. In some embodiments, ring B is [ka] is.

[0095] In some embodiments, ring B is: [ka] is.

[0096] In some embodiments, w is 0 to 5. In some embodiments, w is 0 to 2. In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5.

[0097] In some embodiments, each R 5 is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl. 5 is independently halo, C1-C3 alkyl, or C1-C3 haloalkyl. 5 are independently F, —CF3, or —CH3.

[0098] In some embodiments, R 5 is halo. In some embodiments, R 5is Cl, F, or Br. In some embodiments, R 5 is Cl. In some embodiments, R 5 is F. In some embodiments, R 5 is Br.

[0099] In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is n-propyl. In some embodiments, R 5 is isopropyl.

[0100] In some embodiments, R 5 is C1-C6 haloalkyl. In some embodiments, R 5 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 5 is C1-C3 haloalkyl. In some embodiments, R 5 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 5 is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. 5 is —CF. In some embodiments, R 5 is -CHF2.

[0101] In some embodiments, [ka] teeth: [ka] It comes out.

[0102] In some embodiments, L 1 is -C(O)(CH2) n -, -(CH2) n - or -(CH2) n C(O)-. In some embodiments, L 1 is -C(O)CH2-, -(CH2) n - or -CH2C(O)-, where n is 1 to 5. 1 is -C(O)CH2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, or -CH2C(O)-.

[0103] In some embodiments, L 1 is -C(O)(CH2) n -, wherein n is 1 to 6. In some embodiments, L 1 is —C(O)(CH)—. In some embodiments, L 1 is —C(O)(CH)—. In some embodiments, L 1 is —C(O)(CH)—. In some embodiments, L 1 is —C(O)(CH)—. In some embodiments, L 1 is —C(O)(CH)—. In some embodiments, L 1 is -C(O)(CH2)6-.

[0104] In some embodiments, L 1 Ha-(CH2) n -, where n is 1 to 6. In some embodiments, L 1 is —(CH)—. In some embodiments, L 1 is —(CH)—. In some embodiments, L 1 is —(CH)—. In some embodiments, L 1 is —(CH)—. In some embodiments, L1 is —(CH)—. In some embodiments, L 1 is -(CH2)6-.

[0105] In some embodiments, L 1 Ha-(CH2) n C(O)—, where n is 1 to 6. 1 is —(CH)C(O)—. In some embodiments, L 1 is —(CH)C(O)—. In some embodiments, L 1 is —(CH 2 ) 3 C(O)—. In some embodiments, L 1 is —(CH 2 ) 4 C(O)—. In some embodiments, L 1 is —(CH)C(O)—. In some embodiments, L 1 is -(CH2)6C(O)-.

[0106] In some embodiments, Ring C is a 5- to 10-membered heterocyclylene ring containing 1 or 2 nitrogen atoms. In some embodiments, Ring C is a 6- to 8-membered heterocyclylene ring containing 1 or 2 nitrogen atoms. In some embodiments, the heterocyclylene contains 1 nitrogen atom. In some embodiments, the heterocyclylene contains 2 nitrogen atoms. In some embodiments, the heterocyclylene is a monocyclic ring. In some embodiments, the heterocyclylene is piperazinylene, piperidinylene, or pyrrolidinylene. In some embodiments, the heterocyclylene is a polycyclic ring. In some embodiments, the heterocyclylene is spiro.

[0107] In some embodiments, ring C is: [ka] is.

[0108] In some embodiments, y is 0 to 5. In some embodiments, y is 0 to 3. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5.

[0109] In some embodiments, each R 6 is independently halo, C1-C6 haloalkyl, or C1-C6 alkyl. In some embodiments, each R 6 is independently halo, C1-C3 haloalkyl, or C1-C3 alkyl. 6 are independently Cl, —CF3, or —CH3.

[0110] In some embodiments, R 6 is halo. In some embodiments, R 6 is Cl, F, or Br. In some embodiments, R 6 is Cl. In some embodiments, R 6 is F. In some embodiments, R 6 is Br.

[0111] In some embodiments, R 6 is C1-C6 haloalkyl. In some embodiments, R 6 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 6 is C1-C3 haloalkyl. In some embodiments, R 6 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 6 is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. 6 is —CF. In some embodiments, R 6is -CHF2.

[0112] In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is C1-C3 alkyl. In some embodiments, R 6 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is n-propyl. In some embodiments, R 6 is isopropyl.

[0113] In some embodiments, [ka] teeth: [ka] is.

[0114] In some embodiments, ring D is: [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] is.

[0115] In some embodiments, ring D is [ka] and the R 7a and R 7b are each H or taken together form an oxo group. In some embodiments, ring D is [ka] and the R 7a and R 7b are each H. In some embodiments, ring D is [ka] and the R 7a and R 7b taken together form an oxo group. In some embodiments, Ring D is [ka] In some embodiments, ring D is [ka] is.

[0116] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] is.

[0117] In some embodiments, ring D is [ka] is.

[0118] In some embodiments, z is 0 to 4. In some embodiments, z is 0 to 2. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4.

[0119] In some embodiments, each R 8 is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy. 8 is independently halo, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy. 8 are independently F, Cl, —CH3, —OCH3, or —CF3.

[0120] In some embodiments, R 8 is halo. In some embodiments, R 8 is Cl, F, or Br. In some embodiments, R 8 is Cl. In some embodiments, R 8 is F. In some embodiments, R 8 is Br.

[0121] In some embodiments, R 8 is C1-C6 alkyl. In some embodiments, R 8 is C1-C3 alkyl. In some embodiments, R 8 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is n-propyl. In some embodiments, R 8 is isopropyl.

[0122] In some embodiments, R 8is C1-C6 haloalkyl. In some embodiments, R 8 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 8 is C1-C3 haloalkyl. In some embodiments, R 8 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 8 is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. 8 is —CF. In some embodiments, R 8 is -CHF2.

[0123] In some embodiments, R 8 is C1-C6 alkoxy. In some embodiments, R 8 is C1-C3 alkoxy. In some embodiments, R 8 is —OCH3, —OCH2CH3, —OCH2CH2CH3, or —OCH(CH3)2. In some embodiments, R 8 is —OCH. In some embodiments, R 8 is -OCH2CH3.

[0124] In some embodiments, ring D is: [ka] is.

[0125] In some embodiments, X 3 is N or CR 9 In some embodiments, X 3 is N. In some embodiments, X 3 is CR 9 is.

[0126] In some embodiments, R 9is H or C1-C6 alkyl. In some embodiments, R 9 is H or C1-C3 alkyl. In some embodiments, R 9 is H or -CH3.

[0127] In some embodiments, R 9 is H.

[0128] In some embodiments, R 9 is C1-C6 alkyl. In some embodiments, R 9 is C1-C3 alkyl. In some embodiments, R 9 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 9 is methyl. In some embodiments, R 9 is ethyl. In some embodiments, R 9 is n-propyl. In some embodiments, R 9 is isopropyl.

[0129] In some embodiments, R 10 is H or C1-C6 alkyl. In some embodiments, R 10 is H or C1-C3 alkyl. In some embodiments, R 10 is H or -CH3.

[0130] In some embodiments, R 10 is H.

[0131] In some embodiments, R 10 is C1-C6 alkyl. In some embodiments, R 10 is C1-C3 alkyl. In some embodiments, R 10 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 10 is methyl. In some embodiments, R 10 is ethyl. In some embodiments, R 10is n-propyl. In some embodiments, R 10 is isopropyl.

[0132] In some embodiments, v is 0 to 4. In some embodiments, v is 0 to 2. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4.

[0133] In some embodiments, each R 11 is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl. 11 is independently halo, C1-C3 alkyl, or C1-C3 haloalkyl. 11 are independently F, —CH3, or —CF3.

[0134] In some embodiments, R 11 is halo. In some embodiments, R 11 is Cl, F, or Br. In some embodiments, R 11 is Cl. In some embodiments, R 11 is F. In some embodiments, R 11 is Br.

[0135] In some embodiments, R 11 is C1-C6 alkyl. In some embodiments, R 11 is C1-C3 alkyl. In some embodiments, R 11 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 11 is methyl. In some embodiments, R 11 is ethyl. In some embodiments, R 11 is n-propyl. In some embodiments, R 11 is isopropyl.

[0136] In some embodiments, R 11 is C1-C6 haloalkyl. In some embodiments, R 11 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 11 is C1-C3 haloalkyl. In some embodiments, R 11 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 11 is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. 11 is —CF. In some embodiments, R 11 is -CHF2.

[0137] In some embodiments, [ka] teeth: [ka] is.

[0138] In some embodiments, the compound of Formula (I) has the formula (II): [ka] A compound represented by the formula: 5 , R 6 , w, y, L 1 , ring B, ring C, and ring D are as described in formula (I).

[0139] In some embodiments, the compound of Formula (I) has the formula (IIIa), (IIIb), or (IIIc): [ka] A compound represented by the formula:5 , R 6 , R 8 , w, y, z, L 1 is as described in formula (I).

[0140] In some embodiments, the compound of Formula (I) has Formula (IVa) or (IVb): [ka] and the compound represented by R 1 , R 5 , R 6 , R 8 , x, w, y, z, and L 1 is as described in formula (I).

[0141] It is understood that in the description herein, any description, variant, embodiment, or aspect of a moiety may be combined with any description, variant, embodiment, or aspect of any other moiety, as if each and every combination of descriptions were specifically and individually recited. For example, any description, variant, embodiment, or aspect provided herein for A as shown in formula (I) may be combined with R 1 , R a , R b , R c , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b , R 8 , R 9 , R 10 , R 11 , X 1 , X 2 , X 3 , L 1, ring B, ring C, ring D, n, v, w, x, y, and z may be combined with any and all descriptions, variants, embodiments, or aspects of formula (I). It is also understood that all descriptions, variants, embodiments, or aspects of formula (I) apply, where applicable, to other formulas described herein as if each and every description, variant, embodiment, or aspect were listed separately and individually for all formulas. For example, all descriptions, variants, embodiments, or aspects of formula (I) apply, where applicable, to any and all other formulas described herein (e.g., formulas (Ia), (II), (IIIa), (IIIb), (IIIc), (IVa), and (IVb)), as if each and every description, variant, embodiment, or aspect were listed separately and individually for all formulas.

[0142] In some embodiments, provided is a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof. While certain compounds described in this disclosure, including in Table 1, exist as particular stereoisomeric and / or non-stereoisomeric forms, it is understood that any and all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms, of any compound of this disclosure are described herein. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 [Table 26] [Table 27] [Table 28] [Table 29] [Table 30]

[0143] It is understood that, in the present description, combinations of substituents and / or variables of the depicted formulae are permissible only if such combinations result in stable compounds.

[0144] Additionally, all compounds of formula (I) that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of formula (I) can be converted to their free base or acid form by standard techniques.

[0145] Synthesis method The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials, or the methods provided herein. By way of example and not limitation, compounds of formula (I) can be prepared as described in Schemes 1-14, as well as in the Examples described herein. It should be noted that one skilled in the art would know how to modify the procedures described in the Schemes and Examples to obtain the desired products.

[0146] Compounds of formula (I) can be prepared from two main components: a target binding moiety (TBM) and a cereblon binding moiety (CBM). General synthetic routes for the preparation of TBMs and CBMs are described in Schemes 1-8. General synthetic routes for the reaction of TBMs and CBMs to form heterobifunctional molecules (i.e., ligand-targeted degraders, LDDs), compounds of formula (I), are provided in Schemes 9-14.

[0147] intermediate compound Scheme 1 [ka] wherein ring D is phenyl or pyrazole; G is N or CH; X is halo (e.g., Br); and Bn is benzyl. Scheme 1 illustrates a synthetic approach to intermediate compound CBM-A. Intermediate Aa and intermediate Ab can be coupled in the presence of a palladium catalyst to give intermediate Ac. Conversion of intermediate Ac to intermediate Ad, followed by deprotection, gives intermediate compound CBM-A.

[0148] Scheme 2 [ka] wherein X is halo (e.g., Br); and R 6 , R 8 , y, and z are as described for formula (I). Scheme 2 illustrates a synthetic approach to intermediate compound CBM-B. Intermediate Ba and tert-butyl acrylate can be coupled in the presence of a base (e.g., CsCO or KCO) to give intermediate Bb, which can then be coupled with intermediate Bc in the presence of a palladium catalyst to give intermediate Bd. Intermediate Bd undergoes intramolecular cyclization under acidic conditions to give intermediate compound CBM-B.

[0149] Scheme 3 [ka] wherein ring D is phenyl or indazole, and G is N or C(CH3). Scheme 3 illustrates a synthetic method for intermediate compound CBM-C. Intermediate Cb can be obtained by coupling intermediate Ca and tert-butyl bis(2-oxoethyl)carbamate in the presence of a reducing agent. Deprotection of intermediate Cb under acidic conditions gives intermediate compound CBM-C.

[0150] Scheme 4 [ka] wherein Z is CH, Cl, or Br; X is halo (e.g., Cl, Br, or I); R is H; and A, R 2 , R 3 , R 5 , X 1 , ring B, and w are as described for formula (I). Scheme 4 illustrates a synthetic method for intermediate compound TBM-D. Intermediate Da and intermediate Db can be coupled under acidic conditions to give intermediate Dc. Intermediate Dc and intermediate Dd are then coupled by palladium catalyst to give intermediate De, which is then deprotected under acidic conditions to give intermediate compound TBM-D.

[0151] Scheme 5 [ka] wherein X is halo (e.g., Br); and A is as described in formula (I). Scheme 5 illustrates a synthetic approach to intermediate compound TBM-E. Intermediate Ea and intermediate Eb can be coupled in the presence of a palladium catalyst to give intermediate compound TBM-E.

[0152] Scheme 6 [ka] wherein each X is independently halo (e.g., Br or Cl); and A and ring B are as described in formula (I). Scheme 6 illustrates a synthetic approach to intermediate compound TBM-F. Intermediate Fa and intermediate Fb can be coupled under acidic conditions to give intermediate Fc. Intermediate Fc and intermediate Fd are coupled by palladium catalysis to give intermediate Fe, which is then deprotected under acidic conditions to give intermediate compound TBM-F.

[0153] Scheme 7 [ka] wherein each X is independently halo (e.g., Br or Cl); R is alkyl; m is 0 or 1; ring B is cycloalkylene; and A and ring B are as described in formula (I). Scheme 7 illustrates a synthetic method for intermediate compound TBM-G. Intermediate Ga can be reduced in the presence of a palladium catalyst to obtain intermediate Gb. Intermediate Gb and intermediate Gc are coupled under acidic conditions to obtain intermediate Gd, which is then coupled with intermediate Ge to obtain intermediate Gf by a palladium-catalyzed coupling reaction. The acid group of intermediate Gf is converted to an alcohol group to obtain intermediate compound TBM-G.

[0154] Scheme 8 [ka] wherein X is halo (e.g., Br); and A and ring B are as described in formula (I). Scheme 8 illustrates a synthetic approach to intermediate compound TBM-H. Intermediate Ha and intermediate Hb can be coupled under basic conditions using a palladium catalyst to give intermediate compound TBM-H.

[0155] final compound Scheme 9 [ka] wherein A and ring D are as described in formula (I). Scheme 9 illustrates a synthetic method for compound LDD-a. TBM-D' (a derivative of intermediate TBM-D in Scheme 4) and 2-bromoacetic acid can be coupled under basic conditions to give TBM-D" which can then be further coupled with CBM-A' (a derivative of intermediate CBM-A in Scheme 1) under basic conditions to give compound LDD-a, a compound represented by formula (I).

[0156] Scheme 10 [ka] wherein A and ring D are as described in formula (I). Scheme 10 illustrates a synthetic method for compound LDD-b. TBM-D' (a derivative of intermediate TBM-D in Scheme 4) and 2,2-dimethoxyacetaldehyde can be coupled under basic conditions using a reducing agent to obtain TBM-D1. TBM-D1 is treated with a strong acid to obtain TBM-D2, which can then be coupled with CBM-A' (a derivative of intermediate CBM-A in Scheme 1) under basic conditions using a reducing agent to obtain compound LDD-b, a compound represented by formula (I).

[0157] Scheme 11 [ka] wherein A and ring D are as described in formula (I). Scheme 11 illustrates an alternative synthesis of compound LDD-b. TBM-D1 can be reacted with a strong acid, followed by coupling with CBM-A′ under basic conditions using a reducing agent to give compound LDD-b, a compound of formula (I).

[0158] Scheme 12 [ka] wherein A, ring B, and ring D are as described in formula (I). Scheme 12 illustrates a synthetic method for compound LDD-c. The alcohol group of TBM-F (see Scheme 6) is converted to a leaving group, followed by coupling with CBM-A' (a derivative of intermediate CBM-A in Scheme 1) using a reducing agent under basic conditions to obtain compound LDD-c, which is a compound represented by formula (I).

[0159] Scheme 13 [ka] wherein A and ring D are as described in formula (I). Scheme 13 illustrates a synthetic approach to compound LDD-d. CBM-A' (a derivative of intermediate CBM-A in Scheme 1) and 2-bromoacetic acid can be coupled under basic conditions to give CBM-A''. CBM-A'' can then be coupled with TBM-D' (a derivative of intermediate TBM-D in Scheme 4) under basic conditions to give compound LDD-d, a compound represented by formula (I).

[0160] Scheme 14 [ka] In the formula, A, R 3 and ring D is as described in formula (I). Scheme 14 illustrates a synthetic approach to compound LDD-e. CBM-A' (a derivative of intermediate CBM-A in Scheme 1) and 2,2-dimethoxyacetaldehyde are coupled in the presence of a reducing agent, followed by reaction with a strong acid to give CBM-A1. CBM-A1 is then coupled with TBM-D3 (a derivative of intermediate TBM-D in Scheme 4) in the presence of a reducing agent to give compound LDD-e, a compound represented by formula (I).

[0161] How to use An embodiment of the present disclosure provides a method for modulating IRAK3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by Formula (I). Modulation (e.g., inhibition and activation) of IRAK3 can be assessed and demonstrated by various methods known in the art. Kits and commercially available assays can be used to determine the presence or absence and degree of modulation (e.g., inhibition or activation) of IRAK3.

[0162] In some embodiments, methods for modulating IRAK3 are provided, comprising contacting IRAK3 with an effective amount of a compound of Formula (I), or any embodiment, or variant thereof. In some embodiments, a compound of Formula (I) inhibits IRAK3. In other embodiments, a compound of Formula (I) activates IRAK3. In some embodiments, a compound of Formula (I) causes degradation of IRAK3.

[0163] In some embodiments, provided herein are methods of targeting IRAK3 for degradation, comprising contacting IRAK3 with an effective amount of a compound of Formula (I), or any embodiment, or variant thereof.

[0164] In some embodiments, a 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%, 90 to 100%, 100 to 100%, 110 to 100%, 120 to 100%, 130 to 100%, 140 to 100%, 150 to 100%, 160 to 100%, 170 to 100%, 180 to 100%, 190 to 100%, 210 to 210%, 220 to 220%, 230 to 230%, 240 to 240%, 250 to 250%, 260 to 260%, 270 to 270%, 280 to 280%, 290 to 290%, 300 to 300%, 310 to 310%, 320 to 320%, 330 to 330%, 340 to 340%, 350 to 350%, 360 to 360%, 370 to 370%, 380 to 380%, 390 to 390%, 400 to 400%, 410 to 410%, 420 to 420%, 430 to 430%, Adjust 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%.

[0165] In addition, in certain embodiments of the present disclosure, there is provided a method for degrading IRAK3 in a subject in need thereof, comprising administering an effective amount of a compound represented by formula (I) to the subject.Degradation of IRAK3 can be assessed and verified by various methods known in the art.Kits and commercially available assays (including cell-based assays) can be used to determine the presence and extent of degradation of IRAK3.

[0166] In certain embodiments, provided herein are methods for degrading IRAK3, comprising contacting IRAK3 with an effective amount of a compound of Formula (I), or any embodiment, or variant thereof. In some embodiments, a compound of Formula (I) partially degrades IRAK3. In some embodiments, a compound of Formula (I) completely degrades IRAK3.

[0167] 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 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%.

[0168] 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 represented by 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 represented by Formula (I). Examples of cancer include, but are not limited to, bladder cancer, breast cancer, esophageal cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma, and gastric cancer.

[0169] In some embodiments, administering a compound of Formula (I) to a subject prone to 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 has not yet developed symptoms of cancer prevents the subject from developing any 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 cancer (prevents or slows the progression of cancer). In some embodiments, administering a compound of Formula (I) to a subject in need thereof delays 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 a partial remission of cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof provides a complete remission of cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof reduces the dosage of one or more other medications required for the treatment of cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof improves the effectiveness of another medication 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 of a subject with cancer.

[0170] In certain embodiments, provided herein are methods for preventing a subject predisposed to developing cancer from developing cancer, the methods comprising administering to the subject a compound represented by Formula (I).

[0171] In some embodiments, provided herein are methods for reducing the severity of cancer in a subject, comprising administering to the subject a compound represented by Formula (I). In some embodiments, provided herein are methods for stabilizing cancer in a subject, comprising administering to the subject a compound represented by Formula (I). In some embodiments, the method prevents the cancer from worsening.

[0172] In another aspect, provided herein is a method of delaying the onset or recurrence of cancer in a subject, comprising administering to the subject a compound of Formula (I).

[0173] In some embodiments, provided herein are methods for slowing the progression of cancer in a subject, comprising administering a compound of Formula (I) to the subject. In some embodiments, the methods provide partial remission of the cancer. In some embodiments, the methods provide complete remission of the cancer.

[0174] In a further aspect, provided herein is a method for reducing the dosage of one or more other pharmaceutical agents 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 improving the efficacy of another pharmaceutical agent used to treat cancer in a subject, the method comprising administering to the subject a compound of Formula (I).

[0175] Also provided herein is a method for slowing the progression of cancer in a subject, comprising administering a compound of Formula (I) to the subject. In some embodiments, the method improves the quality of life of a subject with cancer. In some embodiments, the method extends the survival time of a subject with cancer.

[0176] 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.

[0177] In some embodiments, provided herein are methods for improving immunity in a subject receiving a vaccine, comprising administering to the subject an effective amount of a compound represented by Formula (I). In some embodiments, the compound represented by Formula (I) is administered to the subject before administration of the vaccine. In some embodiments, the compound represented by Formula (I) is administered to the subject simultaneously with administration of the vaccine. In some embodiments, the compound represented by Formula (I) is administered to the subject after administration of the vaccine. In some embodiments, the compound represented by Formula (I) is formulated as a component of a vaccine. In some embodiments, the compound represented by Formula (I) is formulated separately from the vaccine.

[0178] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered orally, topically, or parenterally to a subject in conventional preparations (e.g., capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions).

[0179] The compounds disclosed herein can be administered orally, topically, or parenterally to a subject in conventional preparations (e.g., 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 hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, light anhydrous silica, or the like), and / or soluble or soluble ... The pharmaceutical composition may be prepared by a conventional method using conventional organic or inorganic additives such as citric acid, talc, or sodium lauryl sulfate, flavorings (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound of formula (I) in the pharmaceutical composition may be a concentration that produces the desired effect: for example, for both oral and parenteral administration, the unit dose may be about 0.005 mg / kg to about 10 mg / kg of subject body weight.

[0180] The dosage of a compound of Formula (I) administered to a subject varies widely and is subject to the judgment of a medical professional. Generally, the compounds disclosed herein may be administered at a dose of about 0.005 mg / kg to about 10 mg / kg of subject body weight, one to four times daily, although this dosage may vary appropriately depending on the subject's age, body weight, and condition, as well as the type of administration. In certain embodiments, the dosage 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 / kg of subject body weight, or about 0.25 mg / kg to about 0.5 mg / kg of subject body weight. In certain embodiments, the dosage is administered once daily. In any case, the amount of a compound of Formula (I) administered will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0181] 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.

[0182] In another embodiment, provided herein is a unit dose formulation 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).

[0183] In certain embodiments, provided herein are unit dose formulations comprising about 0.1 mg or about 100 mg of a compound of Formula (I).

[0184] In another embodiment, provided herein is a unit dose formulation comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg of a compound of Formula (I).

[0185] The compound of Formula (I) may be administered once, twice, three times, four times, or more times daily. In certain embodiments, doses of 100 mg or less are administered as a single daily dose, and doses of more than 100 mg are administered twice daily in an amount equivalent to one-half of the total daily dose.

[0186] The compound of formula (I) can be administered orally for convenience.In some embodiments, when administered orally, the compound of formula (I) is administered with food or water.In other embodiments, the compound of formula (I) is dispersed in water, juice (for example, apple juice or orange juice), or any other liquid, and is orally administered as a solution or suspension.

[0187] Compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The method of administration is left to the discretion of the health care practitioner, and may depend in part on the site of the medical condition.

[0188] In certain embodiments, provided herein are capsules comprising a compound of Formula (I) without added carriers, excipients, or vehicles.

[0189] In another embodiment, provided herein is a composition comprising an effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may comprise an excipient, a diluent, or a mixture thereof. In certain embodiments, the composition is a pharmaceutical composition.

[0190] The compositions may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories, suspensions, and the like. The compositions may be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule, or a convenient amount of liquid. In some embodiments, solutions are prepared from water-soluble salts (e.g., hydrochlorides). Generally, all compositions are prepared according to known methods of pharmaceutical chemistry. Capsules may be prepared by mixing a compound of Formula (I) with a suitable carrier or diluent and filling a capsule with the appropriate amount of the mixture. Typical carriers and diluents include, but are not limited to, inert powdered substances, such as many types of starch, powdered cellulose (e.g., crystalline cellulose and microcrystalline cellulose, in particular), sugars (e.g., fructose, mannitol, and sucrose), whole grain flour, and similar edible powders.

[0191] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations usually incorporate diluents, binders, lubricants, and disintegrants, as well as compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (e.g., sodium chloride), and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, etc.). Natural and synthetic gums are also convenient, including acacia, alginate, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also function as binders.

[0192] In tablet formulations, lubricants may be required to prevent the tablet and punch from sticking to the dye. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wetted with water, breaking down the tablet and releasing the compound. These include starch, clay, cellulose, algin, and gum. More specifically, for example, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose can be used, as well as sodium lauryl sulfate. To alter the tablet's dissolution, the tablet can be coated with sugar as a flavoring and sealant, or a film-forming protective agent. The composition can also be formulated as a chewable tablet, for example, by using a substance such as mannitol in the formulation.

[0193] When it is desired to administer the compound of formula (I) as a suppository, typical bases can be used. Cocoa butter is a traditional 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.

[0194] The effect of the compound of formula (I) can be delayed or prolonged by appropriate formulation. For example, slowly soluble pellets of the compound of formula (I) can be prepared and incorporated into tablets or capsules, or as a sustained-release implantable device. This technique also includes creating pellets with several different dissolution rates and filling a capsule with a mixture of the pellets. The tablet or capsule can be coated with a film that is difficult to dissolve for a predictable period of time. Even parenteral preparations can be made long-acting by dissolving or suspending the compound of formula (I) in an oily or emulsified vehicle and allowing it to slowly dissolve in serum.

[0195] Example of implementation The present disclosure is further illustrated by the following embodiments.

[0196] Embodiment 1 Formula (I): [ka] [In the formula, A is C1-C6 alkyl, phenyl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl, or 6- to 10-membered heterocyclyl, and the phenyl, cycloalkyl, heteroaryl, and heterocyclyl are each independently selected from the group consisting of x R 1 substituted with a group, wherein the heteroaryl and heterocyclyl contain 1 to 3 heteroatoms selected from N and O; Each R 1 is independently halo, C-C alkyl, C-C cycloalkyl, C-C alkoxy, C-C haloalkyl, or —SO(C-C alkyl); or two R on adjacent carbon atoms 1 The groups taken together form a fused C3-C6 cycloalkyl or fused [ka] Forming a base; R a and R b are each H or together form an oxo group; R c is H or C1-C6 alkyl; x is 0 to 5; R 2 is H or C1-C6 alkyl; R 3 is H or C1-C6 alkyl; R 4 is H or C1-C6 alkyl; X 1 is CH or N; X 2 is N or CH2; Ring B is a C3-C6 cycloalkylene or a 5- to 7-membered heterocyclylene ring containing 1 or 2 nitrogen atoms; Each R 5 is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; w is 0 to 5; L 1 is -C(O)(CH2) n -, -(CH2) n - or -(CH2) n C(O)-; n is 1 to 6; Ring C is a 5- to 10-membered heterocyclylene ring containing 1 or 2 nitrogen atoms; Each R 6 is independently halo, C1-C6 haloalkyl, or C1-C6 alkyl; y is 0 to 5, Ring D is [ka] and; R 7a and R 7b are each H or together form an oxo group; Each R 8 is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; z is 0 to 4; X 3 is N or CR 9 and; R 9 is H or C1-C6 alkyl; R 10 is H or C1-C6 alkyl; Each R 11 is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; v is 0 to 4; and each [ka] are independently a single bond or a double bond. or a pharmaceutically acceptable salt thereof.

[0197] Embodiment 2 A is C1-C3 alkyl, phenyl, C3-C5 cycloalkyl, 5- to 6-membered heteroaryl, or 8- to 10-membered heterocyclyl, and the phenyl, cycloalkyl, heteroaryl, and heterocyclyl are each independently selected from x R 1 substituted with a group, 2. A compound according to embodiment 1 or a pharmaceutically acceptable salt thereof.

[0198] Embodiment 3 x is 0 to 3; 3. A compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof.

[0199] Embodiment 4 Each R 1 is independently halo, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or -SO2(C1-C3 alkyl); Or, two R on adjacent carbon atoms 1 The groups taken together form a fused C3-C5 cycloalkyl or fused [ka] Forming a base; R a and R b are each H or taken together to form an oxo group; and R c is H or C1-C3 alkyl; A compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof.

[0200] Embodiment 5 Each R 1 is independently F, -CH3, cyclopropyl, -OCH3, or -SO2(CH3); Or, two R on adjacent carbon atoms 1 The groups taken together form a fused cyclopropyl, cyclobutyl, [ka] Forming 5. A compound according to embodiment 4, or a pharmaceutically acceptable salt thereof.

[0201] EMBODIMENT 6 A, [ka] That is, 6. A compound according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof.

[0202] EMBODIMENT 7 R 2 is H or C1-C3 alkyl. 7. A compound according to any one of embodiments 1 to 6, or a pharmaceutically acceptable salt thereof.

[0203] EMBODIMENT 8 R 2 is H or -CH3. 8. The compound of embodiment 7, or a pharmaceutically acceptable salt thereof.

[0204] EMBODIMENT 9 R 3 is H or C1-C3 alkyl. A compound according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof.

[0205] EMBODIMENT 10 R 3 is H or -CH3. 10. The compound of embodiment 9, or a pharmaceutically acceptable salt thereof.

[0206] EMBODIMENT 11 R 4 is H or C1-C3 alkyl. 11. A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof.

[0207] EMBODIMENT 12 R 4 is H or -CH3. 12. A compound according to embodiment 11, or a pharmaceutically acceptable salt thereof.

[0208] EMBODIMENT 13 X 1 is CH, 13. A compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof.

[0209] EMBODIMENT 14 X 1 is N, 13. A compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof.

[0210] EMBODIMENT 15 X 2 is N, 15. A compound according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof.

[0211] EMBODIMENT 16 X 2 is CH2, 15. A compound according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof.

[0212] EMBODIMENT 17 formula: [ka] but, [ka] That is, 17. A compound according to any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof.

[0213] EMBODIMENT 18 Ring B is a C4-C6 cycloalkylene or a 6- to 7-membered heterocyclylene containing one nitrogen atom; 18. A compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof.

[0214] EMBODIMENT 19 Ring B is [ka] That is, 19. A compound according to embodiment 18, or a pharmaceutically acceptable salt thereof.

[0215] EMBODIMENT 20 w is 0 to 2; 20. A compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof.

[0216] EMBODIMENT 21 Each R 5 is independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; 21. A compound according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof.

[0217] EMBODIMENT 22 Each R 5 are independently F, -CF3, or -CH3; 22. A compound according to embodiment 21, or a pharmaceutically acceptable salt thereof.

[0218] EMBODIMENT 23 formula: [ka] but, [ka] That is, 23. A compound according to any one of embodiments 1 to 22, or a pharmaceutically acceptable salt thereof.

[0219] EMBODIMENT 24 L 1 -C(O)CH2-, -(CH2) n - or -CH2C(O)-; and n is 1 to 5; 24. A compound according to any one of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof.

[0220] EMBODIMENT 25 L 1 is -C(O)CH2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, or -CH2C(O)-; 25. A compound according to embodiment 24, or a pharmaceutically acceptable salt thereof.

[0221] EMBODIMENT 26 Ring C is a 6- to 8-membered heterocyclylene ring containing 1 or 2 nitrogen atoms; 26. A compound according to any one of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof.

[0222] EMBODIMENT 27 Ring C is [ka] That is, 27. A compound according to embodiment 26, or a pharmaceutically acceptable salt thereof.

[0223] EMBODIMENT 28 y is 0 to 3; 28. A compound according to any one of embodiments 1 to 27, or a pharmaceutically acceptable salt thereof.

[0224] EMBODIMENT 29 Each R 6 is independently halo, C1-C3 haloalkyl, or C1-C3 alkyl; 29. A compound according to any one of embodiments 1 to 28, or a pharmaceutically acceptable salt thereof.

[0225] EMBODIMENT 30 Each R 6 is independently Cl, —CF3, or —CH3; 30. A compound according to embodiment 29, or a pharmaceutically acceptable salt thereof.

[0226] EMBODIMENT 31 formula: [ka] but, [ka] That is, 31. A compound according to any one of embodiments 1 to 30, or a pharmaceutically acceptable salt thereof.

[0227] EMBODIMENT 32 Ring D is [ka] That is, 32. A compound according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof.

[0228] EMBODIMENT 33 Ring D is [ka] That is, 32. A compound according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof.

[0229] EMBODIMENT 34 Ring D is [ka] That is, 32. A compound according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof.

[0230] EMBODIMENT 35 z is 0 to 2; 35. A compound according to embodiment 34, or a pharmaceutically acceptable salt thereof.

[0231] EMBODIMENT 36 Each R 8 is independently halo, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; 36. A compound according to embodiment 34 or 35, or a pharmaceutically acceptable salt thereof.

[0232] EMBODIMENT 37 Each R 8 is independently F, Cl, -CH3, -OCH3, or -CF3; 37. A compound according to embodiment 36, or a pharmaceutically acceptable salt thereof.

[0233] EMBODIMENT 38 Ring D is [ka] That is, 38. A compound according to any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof.

[0234] EMBODIMENT 39 X 3 is N, 39. A compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof.

[0235] EMBODIMENT 40 X 3 is CR 9 and R 9 is H or C1-C3 alkyl; 39. A compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof.

[0236] EMBODIMENT 41 X 3 is CR 9 and R 9 is H or -CH3, 41. A compound according to embodiment 40, or a pharmaceutically acceptable salt thereof.

[0237] EMBODIMENT 42 R 10 is H or C1-C3 alkyl; 42. A compound according to any one of embodiments 1 to 41, or a pharmaceutically acceptable salt thereof.

[0238] EMBODIMENT 43 R 10 is H or -CH3, 43. A compound according to embodiment 42, or a pharmaceutically acceptable salt thereof.

[0239] EMBODIMENT 44 v is 0 to 2; 44. A compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof.

[0240] EMBODIMENT 45 Each R 11 is independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; 45. A compound according to any one of embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0241] EMBODIMENT 46 Each R 11 is independently F, -CH3, or -CF3; 46. ​​A compound according to embodiment 45, or a pharmaceutically acceptable salt thereof.

[0242] EMBODIMENT 47 formula: [ka] but, [ka] That is, 47. A compound according to any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof.

[0243] EMBODIMENT 48 The compound has the formula (II): [ka] Denoted by A compound according to any one of embodiments 1 to 12, 14, 15, 17 to 38, and 40 to 47, or a pharmaceutically acceptable salt thereof.

[0244] EMBODIMENT 49 The compound has formula (IIIa), (IIIb), or (IIIc): [ka] Denoted by 47. A compound according to any one of embodiments 1 to 12, 14, 15, 17 to 32, 34 to 38, and 40 to 47, or a pharmaceutically acceptable salt thereof.

[0245] EMBODIMENT 50 The compound has formula (IVa) or (IVb): [ka] Denoted by 48. A compound according to any one of embodiments 1 to 12, 14, 15, 17 to 31, 34 to 38, and 40 to 47, or a pharmaceutically acceptable salt thereof.

[0246] EMBODIMENT 51 A compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0247] EMBODIMENT 52 52. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0248] EMBODIMENT 53 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 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 52.

[0249] EMBODIMENT 54 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 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 52.

[0250] EMBODIMENT 55 55. The method of embodiment 54, 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.

[0251] EMBODIMENT 56 A method for enhancing the immunity of a vaccinated subject, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 52.

[0252] EMBODIMENT 57 The method of embodiment 56, wherein the subject is administered a vaccine before, simultaneously with, or after administration of an effective amount of a compound of any one of embodiments 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 52. [Example]

[0253] The following examples are offered for illustrative purposes, not limitation. Compounds were named using an automated name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names from compound structures based on the Cahn-Ingold-Prelog rules for stereochemistry. Those skilled in the art can modify the procedures described in the illustrative examples to obtain desired products.

[0254] Salts of the compounds described herein can be prepared by standard methods, such as by chromatographic purification using an acid (e.g., TFA, formic acid, or HCl) in the mobile phase, or by stirring the product after chromatographic purification with an acidic solution (e.g., aqueous HCl).

[0255] The following abbreviations may be relevant to this application: Abbreviation [Table 31] [Table 32]

[0256] Synthesis Examples Overview of the procedure The synthetic compounds were prepared from two main components: a target-binding moiety (TBM) and a cereblon-binding moiety (CBM). The synthesis procedures for these components can be found in their respective sections below. The TBM and CBM were then coupled via a two- or three-step procedure to form heterobifunctional molecules (i.e., ligand-targeted degraders, LDDs). Table 2 lists the components used to synthesize each example and the sections in which the procedures are described. [Table 33] [Table 34] [Table 35]

[0257] Cereblon-binding site (CBM) procedure Table 3 shows the general procedure used to synthesize each CBM molecule. [Table 36] [Table 37] [Table 38]

[0258] Example S1: General procedure for CBM-A [ka] Synthesis of CBM-A: Step 1 [ka] To a sealed tube was added tert-butyl 4-(4-bromo-2-methoxyphenyl)piperazine-1-carboxylate (250 mg, 0.67 mmol, 1 eq.), KPO (324.85 mg, 1.53 mmol, 2.3 eq.), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (337.2 mg, 0.81 mmol, 1.2 eq.), and Pd(PPh) (77.81 mg, 0.07 mmol, 0.1 eq.), which is intermediate A-1b. The tube was then flushed with nitrogen for 5 min. A mixture of 1,4-dioxane (2.5857 mL, 0.2 M) and water (0.6464 mL, 0.2 M) (degassed by sparging with nitrogen for 10 minutes) was added, and the resulting mixture was sparged with nitrogen for an additional 5 minutes. The vial was sealed and heated at 90 °C overnight for 16 hours. LCMS showed complete conversion to intermediate A-3b. The crude mixture was filtered through Celite, washed with DCM, and concentrated. The crude residue was purified by silica gel chromatography (0% to 25% EtOAc / heptane). The combined fractions were concentrated to give intermediate A-3b, tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-methoxyphenyl)piperazine-1-carboxylate (252 mg, 64% yield), as a yellow solid.

[0259] LCMS: [M+H] +=582.3.

[0260] 1 HNMR (400MHz, chloroform-d) δ ppm 1.50(s,9H),3.03(t,J=4.8Hz,4H),3.62(t,J=4.8Hz,4H),3.73(s,3H),5.41(d,J=7.1Hz,4H),6.48(d,J=8.1Hz,1H), 6.92(d,J=8.3Hz,1H),7.08(dd,J=8.1,1.7Hz,1H),7.18(d,J=1.7Hz,1H),7.29-7.48(m,10H),7.64(d,J=8.1Hz,1H). [Table 39] [Table 40]

[0261] Synthesis of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Intermediate A-2) [ka] In a sealed tube, 2,6-dibenzyloxy-3-bromo-pyridine (1.0 g, 2.701 mmol, 1.0 eq.), bis(pinacolato)diboron (1.0 g, 4.051 mmol, 1.5 eq.), KOAc (795.2 mg, 8.103 mmol, 3.0 eq.), and Pd(dppf)Cl₂·DCM (220.57 mg, 0.270 mmol, 0.1 eq.) were dissolved in 1,4-dioxane (4.0 mL, 0.6 M) and sparged with nitrogen for 10 min. The tube was sealed and heated at 90 °C overnight. The reaction mixture was cooled to room temperature. The reaction was filtered through Celite, washed with 2-MeTHF, and the filtrate was evaporated. The residue was purified by silica gel chromatography (0% to 10% EtOAc / heptane) to give 900 mg of Intermediate A-2 contaminated with bis(pinacolato)diboron. A second purification by silica gel chromatography (0% to 4.5% EtOAc) gave Intermediate A-2, 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (210 mg, 19% yield) as a white solid.

[0262] LCMS: [M-pin+H] + =336.2, [M+H] + =418.2.

[0263] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.28(s,12H),5.38(d,J=5.9Hz,4H),6.42(d,J=7.8Hz,1H),7.24-7.40(m,6H),7.40-7.44(m,2H),7.53(d,J=7.1Hz,2H),7.84(d,J=7.8Hz,1H).

[0264] Synthesis of CBM-A: Step 2 [ka] A solution of intermediate A-3b, tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)-2-methoxyphenyl]piperazine-1-carboxylate (155 mg, 0.27 mmol, 1 eq.) in THF (1.5 mL, 0.09 M) and ethanol (1.5 mL, 0.09 M), was degassed for 15 min, then Pd(OH) (37.42 mg, 0.05 mmol, 0.2 eq.) was added and sparged again for 5 min. Hydrogen was then bubbled through the reaction mixture for 5 min, and the mixture was stirred under a hydrogen atmosphere in a 50 °C water bath. After 2 h, LCMS showed complete conversion to compound intermediate A-4b. The crude mixture was filtered through Celite, washed with DCM, and concentrated. The crude product was purified by reverse-phase column chromatography (5% to 50% MeCN / water (containing 0.1% formic acid)). The fractions were combined and concentrated to give intermediate A-4b, tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-2-methoxyphenyl)piperazine-1-carboxylate (84 mg, 78% yield) as a yellow solid.

[0265] LCMS: [M+H] + =404.4.

[0266] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.50(s,9H),3.03(t,J=4.8Hz,4H),3.62(t,J=4.8Hz,4H),3.73(s,3H),5.41(d,J=7.1Hz,4H),6.48(d,J=8.1Hz,1H), 6.92(d,J=8.3Hz,1H),7.08(dd,J=8.1,1.7Hz,1H),7.18(d,J=1.7Hz,1H),7.29-7.48(m,10H),7.64(d,J=8.1Hz,1H). [Table 41]

[0267] General procedure for the synthesis of CBM-A: Step 3 [ka] To a solution of intermediate A-4b, tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)-2-methoxy-phenyl]piperazine-1-carboxylate (130 mg, 0.32 mmol, 1 eq.) in DCM (1.4 mL, 0.23 M), was added 4 M HCl in 1,4-dioxane (1.2 mL, 4.82 mmol, 15 eq.). The reaction mixture was stirred at room temperature overnight. LCMS showed complete conversion to compound CBM-12. The reaction mixture was concentrated under reduced pressure, and the residue was co-evaporated with MeOH (2x) and MTBE (2x) to afford CBM-12, 3-(3-methoxy-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (103 mg, 85% yield) as a tan solid as the bis-HCl salt.

[0268] LCMS: [M+H] + =304.2.

[0269] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.94-2.06(m,1H),2.14-2.29(m,1H),2.43-2.49(m,1H),2.58-2.71(m,1H),3.17(br s,4H),3.18-3.25(m,4H),3.75-3.82(m,4H),6.71-6.77(m,1H),6.84-6.91(m,2H),9.08(br s,2H),10.80(s,1H). [Table 42]

[0270] Example S2: General Procedure for CBM-B [ka] Synthesis of CBM-B: Step 1 [ka] To a solution of 2-(4-bromophenyl)acetonitrile (25.0 g, 127.5 mmol, 1.0 eq.) (Intermediate B-1a) in toluene (255 mL) was added tert-butyl prop-2-enoate (18.7 mL, 127.5 mmol, 1.0 eq.) (Intermediate B-2), N-benzyl-N,N-diethylethaneammonium chloride (BTEAC) (2.9 g, 12.7 mmol, 0.1 eq.), and potassium carbonate (17.6 g, 127.5 mmol, 1.0 eq.). The mixture was stirred at 65° C. under nitrogen for 3 hours, then cooled to room temperature and filtered through a glass-fritted filter. The mixture was concentrated to give a crude mixture that was purified by reverse-phase flash chromatography (5% to 100% MeCN / water (containing 0.1% formic acid)) to give 12.8 g (27% yield) of intermediate B-3a, tert-butyl 4-(4-bromophenyl)-4-cyanobutanoate, as a pale yellow oil.

[0271] LCMS: [M+H] + =324.2.

[0272] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.37(s,3H),1.97-2.15(m,2H),2.28(t,J=7.5Hz,2H),4.25(t,J=7.4Hz,1H),7.35(d,J=8.3Hz,2H),7.62(d,J=8.3Hz,2H). [Table 43] [Table 44] [Table 45]

[0273] Synthesis of CBM-B: Step 2 [ka] To a solution of tert-butyl (2S)-2-methylpiperazine-1-carboxylate (340 mg, 1.7 mmol, 1.1 equiv.), intermediate B-4a, in 1,4-dioxane (3.00 mL, 0.5 M) was added CsCO (1.01 g, 3.08 mmol, 2.0 equiv.), tert-butyl 4-(4-bromophenyl)-4-cyanobutanoate (500 mg, 1.54 mmol, 1 equiv.), intermediate B-3a, Xphos (147 mg, 0.31 mmol, 0.2 equiv.), and Pd(dba) (141 mg, 0.15 mmol, 0.1 equiv.). The reaction mixture was degassed with N for 15 minutes and stirred at 90 °C. After 18 h, LCMS indicated complete conversion to intermediate B-5a. The reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (0% to 80% EtOAc / heptane). The combined fractions were concentrated to give Intermediate B-5a, tert-butyl (2S)-4-(4-(4-(tert-butoxy)-1-cyano-4-oxobutyl)phenyl)-2-methylpiperazine-1-carboxylate (452 ​​mg, 61% yield), as a brown oil.

[0274] LCMS: 93.4% purity at 215 nm, [M+H] + =444.4.

[0275] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.18(d,J=6.6Hz,3H),1.38(s,9H),1.42(s,9H),1.92-2.11(m,2H),2.26(t,J=8.0H z,2H),2.58-2.68(m,1H),2.83(dd,J=12.2,3.7Hz,1H),3.09-3.20(m,1H),3.50(br d,J=12.0Hz,1H),3.59(br d,J=11.7Hz,1H),3.79(br d,J=13.0Hz,1H),4.08(t,J=7.3Hz,1H),4.15-4.25(m,1H),6.94(d,J=8.6Hz,2H),7.20(d,J=8.8Hz,2H). [Table 46] [Table 47] [Table 48] [Table 49] [Table 50] [Table 51]

[0276] Synthesis of CBM-B: Step 3 [ka] To a solution of intermediate B-5a, tert-butyl (2S)-4-[4-(4-tert-butoxy-1-cyano-4-oxo-butyl)phenyl]-2-methyl-piperazine-1-carboxylate (400 mg, 0.90 mmol, 1.0 equiv.) in acetic acid (4.50 mL, 0.2 M), concentrated sulfuric acid (0.14 mL, 2.71 mmol, 3.0 equiv.) was added. The reaction mixture was stirred at 110 °C. After 45 min, LCMS showed complete conversion to CBM-3. The solvent was evaporated, and the residue was purified by reverse-phase flash chromatography (5% to 65% MeCN / water). The fractions were combined and concentrated to give CBM-3, 3-(4-((S)-3-methylpiperazin-1-yl)phenyl)piperidine-2,6-dione (207 mg, 76% yield) as a brown solid as the bis-sulfate salt.

[0277] LCMS: [M+H] + =288.2.

[0278] 1HNMR(400MHz,DMSO-d6)δ ppm 1.23(br d,J=6.1Hz,3H),1.81(s,1H),1.94-2.05(m,1H),2.06-2.21(m,1H),2.57-2.71(m,2H),2.79 -2.91(m,1H),3.03-3.13(m,1H),3.15(s,1H),3.26-3.35(m,3H),3.63-3.79(m,3H),4.75(br d,J=15.2Hz,1H),6.95(br d,J=8.3Hz,2H),7.09(br d,J=8.3Hz,2H),10.78(s,1H). Table 52 Table 53 Table 54 Table 55

[0279] Example S3 General Procedure for CBM-C

change

change

[0280] LCMS: [M+H] + =388.2.

[0281] 1 HNMR (400MHz, DMSO-d6) δ ppm 1.41(s,9H), 2.00-2.10(m, 2H), 2.27-2.33(m, 1H), 2.39-2.45(m, 1H), 3.05-3.12(m, 3H), 3 .32(s, 4H), 3.41-3.49(m, 4H), 6.94(d, J=8.8Hz, 2H), 7.12(d, J=8.8Hz, 2H), 10.85(s,1H). [Table 56] [Table 57]

[0282] Synthesis of (S)-3-(4-aminophenyl)-3-methylpiperidine-2,6-dione (C-1a) and (R)-3-(4-aminophenyl)-3-methylpiperidine-2,6-dione (C-1b) [ka]

[0283] Step 1: Under a nitrogen atmosphere, LiHMDS (666 mL, 666 mmol, 1 M in THF) was added to a solution of 2-(4-nitrophenyl)propanenitrile:2-(4-nitrophenyl)acetonitrile (90 g, 555 mmol) in anhydrous THF (2500 mL) at −78° C. The mixture was stirred at −78° C. for 1 hour, and then iodomethane (86.7 g, 611 mmol) was added. After stirring at −78° C. for 1 hour, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0° C. and quenched by the dropwise addition of citric acid (1000 mL, 10%) at 0° C., followed by extraction with ethyl acetate (1000 mL×2). The combined organic layers were washed with brine (1500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 1:1 to 10:1) to obtain 2-(4-nitrophenyl)propanenitrile (36.8 g, 37.6% yield) as a yellow solid.

[0284] 1 HNMR(400MHz,CDCl3)δ:8.25(d,J=8.4Hz,2H),7.55(d,J=8.4Hz,2H),4.05-3.99(m,2H),1.68(d,J=4.8Hz,3H).

[0285] Step 2: Methyl 4-cyano-4-(4-nitrophenyl)pentanoate: To a solution of 2-(4-nitrophenyl)propanenitrile (65 g, 369 mmol) in toluene (650 mL) was added methyl prop-2-enoate (63.5 g, 738 mmol), KCO (102 g, 738 mmol), and BTEAC (16.8 g, 73.8 mmol). The reaction was stirred at 65 °C for 4 h. The reaction was filtered, and the filtrate was concentrated to give methyl 4-cyano-4-(4-nitrophenyl)pentanoate (75 g, crude) as a yellow solid, which was used directly without further purification.

[0286] Step 3: 3-Methyl-3-(4-nitrophenyl)piperidine-2,6-dione: To a solution of methyl 4-cyano-4-(4-nitrophenyl)pentanoate (75 g, 286 mmol) in acetic acid (700 mL) was added H2SO4 (2.8 g, 28.6 mmol), and the reaction was then stirred for 12 h at 120° C. The reaction mixture was cooled to room temperature, concentrated, and the residue was washed with MTBE (100 mL) and dried to give crude 3-methyl-3-(4-nitrophenyl)piperidine-2,6-dione (72 g, crude) as a gray solid, which was used directly without further purification.

[0287] Step 4: rac-3-(4-aminophenyl)-3-methylpiperidine-2,6-dione: To a solution of 3-methyl-3-(4-nitrophenyl)piperidine-2,6-dione (72 g, 290 mmol) in ethanol (720 mL) was added Fe (81 g, 1450 mmol), NHCl (155 g, 2900 mmol), and water (360 mL), and the reaction was then stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was extracted with ethyl acetate (400 mL × 3), and the combined organic layers were washed with brine (600 mL), dried over anhydrous NaSO, filtered, and concentrated to give 3-(4-aminophenyl)-3-methyl-piperidine-2,6-dione (50.2 g, 79.3% yield) as a gray solid.

[0288] 1HNMR(400MHz,CDCl3)δ:8.0(br s,1H),7.04-7.01(m,1H),6.66(t,J=2.0Hz,1H),3.73(br s,2H),2.56-2.41(m,1H),2.38-2.33(m,2H),2.32-2.08(m,1H),1.53(s,3H).

[0289] SFC: (S)-3-(4-aminophenyl)-3-methylpiperidine-2,6-dione (Intermediate C-1a) and (R)-3-(4-aminophenyl)-3-methylpiperidine-2,6-dione (Intermediate C-1b): Separation conditions: Apparatus: Thar SFC350 preparative SFC; Column: Daicel Chiralcel OJ, 250 x 50 mm, internal diameter: 10 μm; Mobile phase: A: CO2, B: IPA (containing 0.1% ammonium hydroxide); Gradient: B%=60%; Flow rate: 200 g / min; Wavelength: 220 nM; Column temperature: 40 °C; System back pressure: 100 bar. 55 g of rac-3-(4-aminophenyl)-3-methylpiperidine-2,6-dione was separated into 25.9 g of (S)-3-(4-aminophenyl)-3-methylpiperidine-2,6-dione (intermediate C-1a) [peak 1] and 26.5 g of (R)-3-(4-aminophenyl)-3-methylpiperidine-2,6-dione (intermediate C-1b) [peak 2].

[0290] Synthesis of 1-(6-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (C-1c) [ka]

[0291] Step 1: 1-Methyl-6-nitro-1H-indazol-3-amine: To a solution of 2-fluoro-4-nitro-benzonitrile (5.0 g, 30.1 mmol, 1.0 eq) in dimethylacetamide (25.0 mL) was added methylhydrazine (10.4 g, 90.3 mmol, 11.9 mL, 3.0 eq), N-ethyl-N-isopropylpropan-2-amine (4.28 g, 33.1 mmol, 5.8 mL, 1.1 eq), and dimethylacetamide (25.0 mL). The mixture was stirred at 150 °C for 0.5 h. The mixture was diluted with petroleum ether (300 mL) and ethyl acetate (30 mL). The mixture was stirred for 1 h and filtered to give a residue. 1-Methyl-6-nitro-indazol-3-amine (7.0 g, crude) was obtained as a brown solid and used directly without further purification.

[0292] LCMS: [M+H] + :193.1.

[0293] 1 HNMR (400MHz, DMSO-d6): δ 8.35(s,1H),7.90(d,J=8.8Hz,1H),7.69(d,J=8.4Hz,1H),5.78(s,2H),3.86(s,3H).

[0294] Step 2: 3-((1-Methyl-6-nitro-1H-indazol-3-yl)amino)propanoic acid: To 1-methyl-6-nitro-indazol-3-amine (1.2 g, 6.24 mmol, 1.0 eq) was added aluminum oxide (1.91 g, 18.73 mmol, 3.0 eq), dioxane (5.0 mL), and acrylic acid (0.9 g, 12.49 mmol, 0.9 mL, 2.0 eq). The mixture was stirred at 110 °C for 12 h. The mixture was diluted with dichloromethane (100 mL), filtered, and concentrated to give 3-((1-methyl-6-nitro-1H-indazol-3-yl)amino)propanoic acid (15 g, crude) as a brown oil, which was used directly without further purification.

[0295] LCMS: [M+H] + :265.0.

[0296] Step 3: Methyl 3-((1-methyl-6-nitro-1H-indazol-3-yl)amino)propanoate: To a solution of 3-((1-methyl-6-nitro-1H-indazol-3-yl)amino)propanoic acid (15.0 g, 56.77 mmol, 1.0 eq) in methanol (70 mL) and toluene (70 mL) was added trimethylsilicone diazomethane (2 M, 85.2 mL, 3.0 eq) at 0 °C. The mixture was stirred at 15 °C for 12 h. The reaction mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (1% to 20% EtOAc / petroleum ether) to give methyl 3-((1-methyl-6-nitro-1H-indazol-3-yl)amino)propanoate (4.5 g, crude) as a brown solid.

[0297] Step 4: Methyl 3-(1-(1-methyl-6-nitro-1H-indazol-3-yl)ureido)propanoate: To a solution of methyl 3-((1-methyl-6-nitro-1H-indazol-3-yl)amino)propanoate (4.5 g, 16.17 mmol, 1.00 eq) in acetic acid (50 mL) was added potassium cyanate (6.89 g, 80.86 mmol, 5.0 eq). The mixture was stirred at 15 °C for 12 h. The mixture was concentrated, diluted with water (150 mL), and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 3-(1-(1-methyl-6-nitro-1H-indazol-3-yl)ureido)propanoate (6.100 g, crude) as a brown oil, which was used directly without further purification.

[0298] LCMS: [M+H] + :322.6.

[0299] Step 5: 1-(1-Methyl-6-nitro-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione: To methyl 3-(1-(1-methyl-6-nitro-1H-indazol-3-yl)ureido)propanoate (6.0 g, 18.67 mmol, 1.0 eq) was added HCl (12 M, 50.0 mL, 32.13 eq) at 0° C. The mixture was stirred at 15° C. for 12 hours. Water (100 mL) was added to the reaction mixture. The mixture was concentrated and lyophilized to give a residue. The residue was purified by semi-preparative reverse-phase HPLC (23%-48% MeCN / water (containing 0.05% ammonium hydroxide)) to give 1-(1-methyl-6-nitro-indazol-3-yl)hexahydropyrimidine-2,4-dione (1.0 g, 3.46 mmol, 18.5% yield) as a yellow solid.

[0300] LCMS: [M+H] + :290.0.

[0301] 1 HNMR(400MHz,DMSO-d6):δ 10.66(s,1H),8.70(d,J=1.2Hz,1H),8.05-7.88(m,2H),4.14(s,3H),3.98(t,J=6.8Hz,2H),2.78(t,J=6.8Hz,2H).

[0302] Step 6: 1-(6-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate C-1c): To a solution of 1-(1-methyl-6-nitro-indazol-3-yl)hexahydropyrimidine-2,4-dione (1.0 g, 3.46 mmol, 1.0 eq) in ethanol (40 mL) and water (20 mL) was added iron (0.965 g, 17.29 mmol, 5.0 eq) and ammonium chloride (1.85 g, 34.57 mmol, 10.0 eq). The mixture was stirred at 85 °C for 1 h. The mixture was filtered and concentrated to give a residue that was purified by silica gel column chromatography (1% to 5% MeOH / DCM) to give 1-(6-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (0.599 g, 2.31 mmol, 67% yield, 100% purity) as a white solid.

[0303] LCMS: [M+H] + :260.0.

[0304] 1 HNMR(400MHz,DMSO-d6):δ 10.48(s,1H),7.27(d,J=8.8Hz,1H),6.47(dd,J=1.6,8.8Hz,1H),6.39(d,J=1.2Hz ,1H),5.41(s,2H),3.85(t,J=6.8Hz,2H),3.80-3.72(m,3H),2.71(t,J=6.8Hz,2H).

[0305] Synthesis of CBM-C: Step 2 [ka] To a solution of tert-butyl 4-[4-(3S)-3-methyl-2,6-dioxo-3-piperidyl]phenyl]piperazine-1-carboxylate (300 mg, 0.7700 mmol), intermediate C-3a, in 1,4-dioxane (5 mL) was added 4 M HCl in dioxane (3.88 mL, 15.52 mmol) at room temperature. The reaction was stirred at room temperature for 5 hours. HPLC and LCMS indicated complete conversion of the starting material to the desired product. The reaction mixture was chased with acetonitrile and concentrated to dryness to afford CBM-22, the desired (S)-3-methyl-3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione bishydrochloride salt (280 mg, quant.) as a white solid.

[0306] LCMS: [M+H] + =288.2

[0307] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.39(s,3H),2.02-2.12(m,2H),2.29-2.37(m,1H),2.40-2.45(m,1H),3.19(br s,4H),3.32-3.40(m,4H),6.98(d,J=8.8Hz,2H),7.16(d,J=8.8Hz,2H),9.20(br s,3H),10.86(s,1H). [Table 58]

[0308] Example S4 CBM-5 Procedure Synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (CBM-5) [ka]

[0309] Step 1: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate: In a round-bottom flask, add 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5.0 g, 15.47 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (3.17 g, 17.02 mmol), and 1 eq. of tert-butyl piperazine-1-carboxylate (3.17 g, 17.02 mmol). A mixture of 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.647 g, 0.77 mmol, 0.05 eq), methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.647 g, 0.77 mmol, 0.05 eq), and cesium carbonate (7.56 g, 23.21 mmol, 1.5 eq), and dioxane (100.00 mL) was added. The reaction vessel was purged with nitrogen and heated at 110 °C for 40 h. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (50 mL). The combined organic layers were concentrated in vacuo to give a residue that was purified by silica gel column chromatography (0% to 100% EtOAc / petroleum ether). The resulting material was triturated in EtOAc / petroleum ether (2 mL / 2 mL) and filtered. The filter cake was dried under vacuum to give the product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (0.300 g, yield: 4.52%) as a white solid.

[0310] LCMS: [M+H] + =429.1.

[0311] 1 HNMR(400MHz,CDCl3):δ 8.04(br s,1H),7.76(d,J=11.6Hz,1H),7.00(dd,J=11.6,2.4Hz,1H),6.89(s,1H),5.21(dd,J=17.6,6.8Hz,1H),4. 48-4.21(m,2H),3.67-3.53(m,4H),3.35-3.20(m,4H),2.98-2.76(m,2H),2.42-2.15(m,2H),1.50(s,9H).

[0312] Step 2: 3-(1-Oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (CBM-5): To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (0.150 g, 0.35 mmol, 1 eq) in dichloromethane (2.00 mL) was added trifluoroacetic acid (0.798 g, 7.00 mmol, 0.52 mL, 20 eq) in one portion. The mixture was then stirred at 25 °C for approximately 1 hour. The solvent was removed in vacuo to give a residue that was partitioned between water (5.00 mL) and dichloromethane (3.00 mL). The aqueous layer was washed with dichloromethane (3.00 mL × 2), and the aqueous layer was concentrated under high pressure using a water bath at 45 °C to give the product 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (CBM-5) (64.43 mg, 42% yield, 98.9% purity, TFA salt) as a pale red viscous material.

[0313] LCMS: [M+H] + =329.1.

[0314] 1 HNMR(400MHz,DMSO-d6)10.97(s,1H),8.89(br s,2H),7.58(d,J=8.4Hz,1H),7.21-7.06(m,2H),5.06(dd,J=13.6,5.2Hz,1H),4.43-4.17(m,2H),3.59-3. 44(m,4H),3.31-3.20(m,4H),2.98-2.84(m,1H),2.61-2.56(m,1H),2.43-2.32(m,1H),2.02-1.91(m,1H).

[0315] Example S5 CBM-7 Procedure Synthesis of 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (CBM-7) [ka]

[0316] Step 1: tert-Butyl 4-(3-bromo-4-formylphenyl)piperazine-1-carboxylate: To a solution of 2-bromo-4-fluorobenzaldehyde (8 g, 39.4 mmol) and tert-butyl piperazine-1-carboxylate (8.81 g, 47.3 mmol) in DMF (80 mL) was added K2CO3 (10.9 g, 78.8 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (200 mL) and water (200 mL). The aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (10% to 50% EtOAc / petroleum ether) to give the product tert-butyl 4-(3-bromo-4-formyl-phenyl)piperazine-1-carboxylate (11.8 g, 81.1% yield) as an off-white solid.

[0317] 1 HNMR:(400MHz,DMSO-d6)δ:9.96(s,1H),7.68(d,J=8.8Hz,1H),7.16(s,1H),7.04-7.01(m,1H),3.45(s,8H),1.43(s,9H).

[0318] Step 2: tert-Butyl 4-(3-bromo-4-(((2,6-dioxopiperidin-3-yl)amino)methyl)phenyl)piperazine-1-carboxylate: To a stirred solution of 3-aminopiperidine-2,6-dione (3.92 g, 23.8 mmol, HCl salt) in MeOH (250 mL) was added a solution of NH3 / MeOH until pH=7. The reaction was stirred at 20 °C. AcOH was then added dropwise until pH=6. At this point, tert-butyl 4-(3-bromo-4-formyl-phenyl)piperazine-1-carboxylate (8.8 g, 23.8 mmol) was added and stirred at 20 °C for 10 minutes. NaBH3CN (4.49 g, 71.5 mmol) was then added at 0 °C. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated, the residue was filtered, and the cake was washed with petroleum ether / EtOAc (5:1, 50 mL) to give tert-butyl 4-[3-bromo-4-[[(2,6-dioxo-3-piperidyl)amino]methyl]phenyl]piperazine-1-carboxylate (7.5 g, 65.4% yield) as a white solid.

[0319] 1 HNMR:(400MHz,DMSO-d6)δ:10.74(s,1H),7.34(d,J=8.8Hz,1H),7.12(d,J=2.0Hz,1H),6.97-6.95(m,1H),3.78(d,J=6.0H) z,1H),3.42(t,J=4.8Hz,4H),3.11(t,J=5.2Hz,4H),2.73-2.68(m,1H),2.56-2.54(m,1H),2.13-2.10(m,1H),1.42(s,9H).

[0320] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate: To a solution of tert-butyl 4-[3-bromo-4-[[(2,6-dioxo-3-piperidyl)amino]methyl]phenyl]piperazine-1-carboxylate (5 g, 10.4 mmol) and dicyclohexyl(3-dicyclohexylphosphoniumylpropyl)phosphonium ditetrafluoroborate (636 mg, 1.04 mmol) in DMF (50 mL) was added diacetoxypalladium (233 mg, 1.04 mmol) and KCO (2.15 g, 15.6 mmol) under nitrogen. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80 °C for 48 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by preparative separation (20% to 50% MeCN / water (containing 0.1% TFA)) to give tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazine-1-carboxylate (3 g, 67.4% yield) as a gray solid.

[0321] LCMS: [M+H] + =429.1.

[0322] Step 4: 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (CBM-7): tert-Butyl 4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazine-1-carboxylate (5 g, 11.7 mmol) was added to HCl (12 N, 15 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with MeCN at 0-10 °C. The resulting precipitate was filtered, and the cake was dried to give 3-(1-oxo-6-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (4.3 g, HCl salt, 100% yield) as a gray solid.

[0323] 1HNMR:(400MHz,DMSO-d6)δ:10.98(s,1H),9.34(s,2H),7.49(d,J=5.2Hz,1H),7.33-7.27(m,2H),5.13-5.09(m,1H),4.30(dd,J=17.2Hz, J=58.2Hz,2H),3.46(d,J=4.8Hz,4H),3.23(d,J=4.8Hz,1H),2.93-2.78(m,1H),2.62-2.51(m,1H),2.48-2.37(m,1H),2.01-1.98(m,1H).

[0324] Example S6 CBM-10 Procedure Synthesis of 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (CBM-10) [ka]

[0325] Step 1: tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate: A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (30.0 g, 60.0 mmol), tert-butyl piperazine-1-carboxylate (16.8 g, 89.9 mmol), RuPhos-Pd-G (10 g, 12.0 mmol), and CsCO (23.4 g, 71.9 mmol) in degassed 1,4-dioxane (150 mL) was heated at 75 °C for 18 h and then cooled to room temperature. The mixture was filtered through Celite, and the filter cake was washed with EtOAc (3 x 150 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (gradient: 0 to 40% EtOAc / hexane) to give the title compound tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (35.6 g, 98% yield) as a solid.

[0326] MS(ESI)[M+H]+ 607.5.

[0327] Step 2: tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate: A mixture of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]piperazine-1-carboxylate (35.6 g, 58.8 mmol) and Pearlman's catalyst (8.90 g, 25 wt% loading) in EtOH (300 mL) and THF (300 mL) was hydrogenated (1 atm) at 50° C. for 10 h. The mixture was filtered through Celite, and the filter cake was washed with a 1:1 mixture of MeCN and MeOH (4×250 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (gradient: 0 to 100% EtOAc / hexane) to give the title compound tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (21.0 g, 84% yield) as a solid.

[0328] MS(ESI)[M+H] + 428.3.

[0329] Step 3: 3-(1-Methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (CBM-10): To a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]piperazine-1-carboxylate (21.0 g, 49.1 mmol) in 1,4-dioxane (150 mL) was added 4 N HCl in 1,4-dioxane (98.2 mL, 393 mmol) and the reaction mixture was stirred at room temperature for 20 h. Et2O (250 mL) was added and the precipitate was collected by filtration, washed with Et2O (3 x 30 mL), then dried in vacuo and lyophilized to give the title compound 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (17.6 g, 98% yield) as a solid.

[0330] MS(ESI)[M+H] + 328.2.

[0331] 1 HNMR(500MHz,DMSO-d6)δ 10.85(s,1H),9.46(s,2H),7.56(d,J=8.9Hz,1H),7.04-6.90(m,2H),4.28(dd,J=9.4,5.0Hz,1H),3. 92(s,3H),3.53-3.41(m,4H),3.23(s,4H),2.73-2.55(m,2H),2.39-2.26(m,1H),2.23-2.08(m,1H).

[0332] Example S7 CBM-11 Procedure Synthesis of 3-(1-methyl-7-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (CBM-11) [ka]

[0333] Step 1: 7-Bromo-3-iodo-1-methyl-1H-indazole: Three batches were performed. To a solution of 7-bromo-3-iodo-1H-indazole (480 g, 1.49 mol, 1 equiv) in THF (2.4 L) at 0 °C, t-BuOK (334 g, 2.97 mol, 2 equiv) was added in one portion. After the addition, the suspension was stirred at 0 °C for 1 h. Then, a solution of CHI (422 g, 2.97 mol, 185 mL, 2 equiv) in THF (400 mL) was added dropwise to the cooled (0 °C) reaction mixture. The suspension was then stirred at 25 °C for 3 h. TLC (PE / EtOAc = 5 / 1, Rf = 0.5) indicated the reaction was complete. The three reaction mixtures were combined, and the resulting suspension was poured into water (10 L) and stirred for 10 min. The aqueous layer was extracted with EtOAc (5.0 L, then 3.0 L). The combined organic layers were washed with brine (3.0 L), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc = 25 / 1, 5 / 1) to give 7-bromo-3-iodo-1-methyl-1H-indazole (900 g, 2.67 mol, 60% yield) as a yellow solid.

[0334] 1 HNMR(400MHz,DMSO-d6)δ ppm 7.72(d,J=8.4Hz,1H),7.49(d,J=7.2Hz,1H),7.11(t,J=7.6Hz,1H),4.34(s,3H).

[0335] Step 2: 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole: Three batches were performed. To a solution of 7-bromo-3-iodo-1-methyl-1H-indazole (313 g, 929 mmol, 1 equiv.) in 1,4-dioxane (2.0 L) and HO (1.0 L) was added (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (389 g, 929 mmol, 80% purity, 1 equiv.), KPO (493 g, 2.32 mol, 2.5 equiv.), and Pd(PPh) (21.5 g, 18.6 mmol, 0.02 equiv.). The suspension was then purged with N three times and stirred at 90 °C for 12 h. The three batches were combined for workup, and then the reaction mixture was poured into water (10 L) and stirred for 10 minutes. The aqueous layer was extracted with EtOAc (5 L, then 3 L). The combined organic layers were washed with brine (3 L), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc = 25 / 1, 5 / 1). The residue was triturated with PE / EtOAc (2 / 1) at 25 °C for 3 hours, and then the solid was collected by vacuum filtration to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (920 g, 63% yield) as an off-white solid.

[0336] 1 HNMR(400MHz,DMSO-d6)δ ppm 7.86(d,J=8.4Hz,1H),7.54(dd,J=8.0,0.8Hz,1H),7.37(dd,J=7.2,0.8Hz,1H),7.33(m, 2H),7.28(m,8H),6.94(t,J=7.6Hz,1H),6.60(d,J=7.6Hz,1H),5.43(s,4H),4.36(s,3H).

[0337] Step 3: tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-yl)piperazine-1-carboxylate: To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (100 g, 200 mmol) and tert-butyl piperazine-1-carboxylate (55.8 g, 300 mmol) in 1,4-dioxane (700 mL) was added CsCO (130 g, 400 mmol), RuPhos (18.6 g, 40 mmol), and Pd(dba) (18.3 g, 20 mmol). The suspension was then purged with N three times and stirred at 110 °C for 12 h. TLC (PE / EtOAc = 3 / 1, Rf = 0.6) indicated the reaction was complete. The reaction was cooled to 20 °C and filtered through Celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (100-200 mesh silica gel, PE / EtOAc = 20 / 1, 3 / 1) to give the product. The product was further triturated in PE / EtOAc = 2 / 1, 200 mL for 1 hour. The solid was collected by filtration and dried in vacuo to give tert-butyl tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-yl)piperazine-1-carboxylate (84 g, 133 mmol, 67% yield, 96% purity) as a yellow solid.

[0338] 1 HNMR(400MHz DMSO-d6)δ ppm 7.85(d,J=8.4Hz,1H),7.27-7.45(m,12H),6.96-6.99(m,2H),6.53(d,J=8.0Hz,1H),5.47(s,2H) ,5.40(s,2H),4.41(s,3H),4.10-4.16(m,2H),3.20-3.23(m,4H),2.84-2.89(m,2H),1.51(s,9H).

[0339] Step 4: tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazine-1-carboxylate: To a suspension of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-yl)piperazine-1-carboxylate (42 g, 69.3 mmol) and AcOH (4.16 g, 69.3 mmol, 3.97 mL) in THF (210 mL) and EtOH (210 mL) was added 10% Pd / C (8.0 g) and 20% Pd(OH) (8.0 g, 57 mmol), and the black suspension was then purged three times with H and stirred at 50 °C under 50 psi for 12 h. The suspension was filtered through Celite, and the filter cake was washed with hot THF (2 L). The filtrate was concentrated in vacuo at 45 °C to give the crude product. The crude material was purified by silica gel chromatography (100-200 mesh silica gel, DCM / MeOH = 0 / 1, 10 / 1) to give a solid. The solid was further triturated in MTBE (50 mL) for 1 hour. The solid was collected by filtration and dried in vacuo. tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazine-1-carboxylate (18.6 g, 41.7 mmol, 30% yield, 96% purity) was obtained as a blue solid.

[0340] MS(ESI)[M+H] + 428.4.

[0341] Step 5: 3-(1-Methyl-7-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (CBM-11): To a solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazine-1-carboxylate (18.6 g, 43.5 mmol, 1 eq) in DCM (420 mL) was added HCl / EtOAc (4 M, 93.0 mL), and the suspension was stirred at 20° C. for 2 h. The solid was collected by filtration and stirred under vacuum at 45° C. for 2 h. The solid was collected by filtration and stirred under vacuum at 45° C. for 2 h. The solid was suspended in MeCN (100 mL) and stirred under vacuum at 45° C. for 2 h. This procedure was repeated two more times. Obtained 3-(1-methyl-7-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (16.5 g, 41.2 mmol, 95% yield, 2HCl) as a pale blue solid.

[0342] 1 HNMR(400MHz,DMSO-d6)δ ppm 10.87(s,1H),9.49-9.58(m,2H),7.45(d,J=6.8Hz,1H),7.03-7.06(m,2H),4.33-4.37(m,1H) ),4.24(s,3H),3.15-3.44(m,8H),2.60-2.67(m,2H),2.31-2.50(m,1H),2.14-2.18(m,1H).

[0343] Example S8 CBM-19 Procedure Synthesis of 1-methyl-3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (CBM-19) [ka]

[0344] Step 1: tert-Butyl 4-(4-(1-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate: To a solution of MeOH (0.02 mL, 0.57 mmol, 1.0 equiv.) in THF (6.0 mL) was added DIAD (0.11 mL, 0.57 mmol, 1.0 equiv.), followed by tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazine-1-carboxylate (300 mg, 0.57 mmol, 1.0 equiv.), intermediate A-4a, at 0 °C. A solution of PPh (224.4 mg, 0.86 mmol, 1.5 equiv.) in THF (3.62 mL; total concentration 0.06 M) was then added dropwise, and the mixture was allowed to warm to room temperature and stirred for 18 h. The solvent was concentrated under reduced pressure, and the crude residue was purified by reverse-phase column chromatography (5% to 70% MeCN / water (containing 0.1% formic acid)). Fractions were concentrated to a minimum amount of water, neutralized with NaHCO3, and extracted with DCM (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated to give tert-butyl 4-(4-(1-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (156 mg, 84%) as an off-white solid.

[0345] LCMS: [M+H] + =388.2.

[0346] 1 HNMR(400MHz,DMSO-d6):δ ppm 1.42(s,9H),1.95-2.05(m,1H),2.07-2.19(m,1H),2.56-2.66(m,1H),2.69-2.81(m,1H),3.02(s,3H),3.04 -3.09(m,4H),3.41-3.48(m,4H),3.84(dd,J=11.0,4.9Hz,1H),6.91(d,J=8.6Hz,2H),7.06(d,J=8.6Hz,2H).

[0347] Step 2: 1-methyl-3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (CBM-19): To a solution of tert-butyl 4-[4-(1-methyl-2,6-dioxo-3-piperidyl)phenyl]piperazine-1-carboxylate (184 mg, 0.47 mmol) in DCM (4.74 mL, 0.10 M) was added 4 M HCl in dioxane (1.78 mL, 7.12 mmol, 15.0 equiv.). The reaction was stirred at room temperature for 18 h. The solvent was concentrated under reduced pressure to afford the HCl salt of 1-methyl-3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (CBM-19) (153 mg, 99.9% yield) as a white solid.

[0348] LCMS: [M+H] + =288.2.

[0349] 1 HNMR(400MHz,DMSO-d6):δ ppm 1.95-2.04(m,1H),2.09-2.20(m,1H),2.64(s,1H),2.70-2.82(m,1H),3.02(s,3H),3.18-3.26(m ,4H),3.30-3.37(m,4H),3.82-3.91(m,1H),6.95(d,J=8.6Hz,2H),7.10(d,J=8.6Hz,2H),8.89(br s,1H).

[0350] Example S9 CBM-25 Procedure Synthesis of 3-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione (CBM-25) [ka]

[0351] Step 1: tert-Butyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: To a 250 mL screw-cap flask was added DMSO (34.7 mL) and molecular sieves (approximately 10 beads, 3A). The solvent was stirred at room temperature with nitrogen bubbling for 10 minutes. Then, 3-(4-bromophenyl)piperidine-2,6-dione (1.86 g, 6.94 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (2.03 g, 4.16 mmol), DMPAO (1.34 g, 6.94 mmol), CuI (660.62 mg, 3.47 mmol), and tetrabutylammonium acetate (6.28 g, 20.81 mmol) were added, and nitrogen was bubbled through the solution for 10 minutes. The reaction mixture was stirred at 110 °C until the reaction was complete (approximately 16 hours). Water was added, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was first purified by reverse-phase column chromatography (5-100% MeCN / water (containing 0.1% formic acid)) and then by silica gel column chromatography (0-100% EtOAc / heptane) to afford tert-butyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (136 mg, 0.35 mmol, 5% yield) as an off-white solid.

[0352] LCMS: [M+H] + =386.2.

[0353] 1 HNMR(400MHz,DMSO-d6):δ ppm 1.38(s,9H),1.93-2.02(m,1H),2.07(s,2H),2.56-2.65(m,1H),3.69(dd,J=10.8,4.9 Hz,1H),3.98-4.04(m,5H),6.38(d,J=8.6Hz,2H),7.00(d,J=8.3Hz,2H),10.75(s,1H).

[0354] Step 2: 3-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione (CBM-25): In a round-bottom flask, tert-butyl 6-[4-(2,6-dioxo-3-piperidyl)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate 3 (152.8 mg, 0.40 mmol) was dissolved in DCM (2 mL). Trifluoroacetic acid (0.61 mL, 7.93 mmol) was then added and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and co-evaporated three times with acetonitrile to give 3-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione (CBM-25) (204.1 mg, yield: quant., TFA salt) as a grey oil, which was used directly without further purification.

[0355] 1 HNMR(400MHz,DMSO-d6):δ ppm 1.93-2.01(m,1H),2.08-2.14(m,1H),2.57-2.65(m,1H),3.70(dd,J=11.0,4.9H z,1H),4.13-4.17(m,4H),6.42(d,J=8.6Hz,2H),7.02(d,J=8.6Hz,2H),8.43(br s,2H),10.76(s,1H).

[0356] Example S10 CBM-26 Procedure Synthesis of 1-(4-(piperazin-1-yl)phenyl)pyrimidine-2,4(1H,3H)-dione (CBM-26) [ka]

[0357] Step 1: tert-Butyl 3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-carboxylate: To a solution of tert-butyl 2,4-dioxo-1H-pyrimidine-3-carboxylate (300 mg, 1.41 mmol, 1.0 equiv.) in EtOAc (10 mL) was added [4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]boronic acid (562 mg, 1.84 mmol, 1.3 equiv.), EtN (0.49 mL, 3.53 mmol, 2.5 equiv.), followed by Cu(OAc) (385 mg, 2.12 mmol, 1.5 equiv.). The reaction was stirred under air at room temperature overnight. The reaction was diluted with EtOAc and water. The layers were separated, and the organic layer was washed with NH4Cl (2x), water, brine, dried over sodium sulfate, filtered, and concentrated. The mixture was purified by reverse-phase column chromatography (5% to 100% MeCN / water (with 0.1% formic acid)) to afford tert-butyl 3-[4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]-2,6-dioxo-pyrimidine-1-carboxylate (260 mg, 39% yield) as an off-white solid.

[0358] LCMS: [M+H] + =473.2.

[0359] 1 HNMR(400MHz,DMSO-d6):δ ppm 1.42(s,9H),1.51(s,9H),3.11-3.20(m,4H),3.41-3.51(m,4H),5.81(d ,J=7.8Hz,1H),6.99-7.07(m,2H),7.26-7.34(m,2H),7.74-7.80(m,1H).

[0360] Step 2: 1-(4-(piperazin-1-yl)phenyl)pyrimidine-2,4(1H,3H)-dione (CBM-26): To a solution of tert-butyl 3-[4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]-2,6-dioxo-pyrimidine-1-carboxylate (260 mg, 0.550 mmol, 1.0 equiv.) in CHCl (2 mL) was added HCl (1 mL, 5.5 mmol, 10 equiv.) at room temperature for 4 h. The solvent was evaporated and co-evaporated with MeCN (3x) and MTBE (2x) to afford 1-(4-piperazin-1-ylphenyl)pyrimidine-2,4-dione (CBM-26) (240 mg, quant., bis-HCl salt) as an off-white solid.

[0361] LCMS: [M+H] + =473.2.

[0362] 1 HNMR(400MHz,DMSO-d6):δ 3.22(br s,4H),3.38-3.47(m,4H),5.63(dd,J=7.8,2.2Hz,1H),7.06(d,J=9.0Hz,2H),7.28(d,J=9.0Hz,2H),7.63(d,J=7.8Hz,1H),9.17(br s,2H),11.38(s,1H).

[0363] Example S11 CBM-30 Procedure Synthesis of 5-fluoro-1-(4-(piperazin-1-yl)phenyl)pyrimidine-2,4(1H,3H)-dione (CBM-30) [ka]

[0364] Step 1: 5-Fluoro-1-(4-nitrophenyl)pyrimidine-2,4(1H,3H)-dione: To a solution of 5-fluoro-1H-pyrimidine-2,4-dione (500 mg, 3.84 mmol, 1.0 equiv.) in DMSO (10 mL) was added 1-fluoro-4-nitro-benzene (542 mg, 3.84 mmol, 1.0 equiv.) and K2CO3 (1.33 g, 9.61 mmol, 2.5 equiv.) at room temperature. The reaction mixture was then heated to 80 °C for 1.5 h. LCMS indicated 55-60% conversion. The reaction mixture was cooled to room temperature, and water (5 mL) was added. The mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was concentrated and purified by reverse-phase column chromatography (5% to 50% MeCN / water (containing 0.1% formic acid)) to give 5-fluoro-1-(4-nitrophenyl)pyrimidine-2,4(1H,3H)-dione (291 mg, 30%) as a white solid.

[0365] LCMS: [M+H] + =252.2.

[0366] 1 HNMR (400MHz, DMSO-d6): δ ppm 7.72-7.82 (m, 2H), 8.29-8.41 (m, 3H), 12.04-12.15 (m, 1H).

[0367] Step 2: 1-(4-aminophenyl)-5-fluoropyrimidine-2,4(1H,3H)-dione: To a solution of 5-fluoro-1-(4-nitrophenyl)pyrimidine-2,4(1H,3H)-dione (360 mg, 1.43 mmol, 1.0 equiv.) in 1,4-dioxane (3 mL) and water (3 mL) was added Fe (640 mg, 11.47 mmol, 8.0 equiv.) and NH4Cl (613 mg, 11.47 mmol, 8.0 equiv.) at room temperature. The reaction mixture was heated at 75 °C overnight. LCMS showed complete conversion. The mixture was filtered through Celite and washed with MeCN to give 1-(4-aminophenyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (260 mg, 82%) as an off-white solid.

[0368] LCMS:[M+H] + =222.2.

[0369] 1 HNMR(400MHz,DMSO-d6):δ ppm 5.35(s,2H),6.52-6.64(m,2H),6.98-7.06(m,2H),7.16-7.27(m,1H),8.05(d,J=6.6Hz,1H).

[0370] 19 FNMR(377MHz,DMSO-d6):δ ppm -170.47(d,J=6.8Hz,1F).

[0371] Step 3: tert-Butyl 4-(4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate: To a solution of 1-(4-aminophenyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (150 mg, 0.68 mmol, 1.0 equiv.) and tert-butyl N,N-bis(2-oxoethyl)carbamate (205 mg, 1.02 mmol, 1.5 equiv.) in DCE (5 mL) was added NaBH(OAc) (287 mg, 1.36 mmol, 2.0 equiv.) at room temperature. The reaction mixture was stirred at room temperature overnight. LCMS showed the enamine intermediate along with traces of the desired product. NaBH(OAc)3 (287 mg, 1.36 mmol, 2.0 equiv.) was added and the mixture was stirred at room temperature overnight. LCMS showed approximately 50% conversion. NaBH(OAc)3 (287 mg, 1.36 mmol, 2.0 equiv.) was added and stirred at room temperature for 72 h. LCMS showed almost complete conversion. Water and CHCl2 were added and the layers were separated. The aqueous layer was extracted with CHCl2 (2x), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reverse-phase column chromatography (5-100% MeCN / water with 0.1% FA) to afford tert-butyl 4-(4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate (60 mg, 23% yield) as an off-white solid.

[0372] LCMS: [M+H] + =391.2.

[0373] 1 HNMR(400MHz,DMSO-d6):δ ppm 1.42(s,9H),3.11-3.21(m,4H),3.42-3.50(m,4H),6.98-7.04(m,2H),7.23-7.31(m,2H),8.12(d,J=6.6Hz,1H),11.85(br s,1H).

[0374] 19FNMR(377MHz,DMSO-d6):δ ppm -170.13(br d,J=5.4Hz,1F).

[0375] Step 4: 5-Fluoro-1-(4-(piperazin-1-yl)phenyl)pyrimidine-2,4(1H,3H)-dione (CBM-30): To a solution of tert-butyl 4-(4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate (60 mg, 0.15 mmol, 1.0 equiv.) in CHCl (2 mL) was added HCl (1 mL, 3.75 mmol, 25 equiv.) at room temperature, and the reaction mixture was stirred at room temperature for 5 hours. LCMS showed complete conversion. The solvent was evaporated and co-evaporated with MeCN (3x) and CH2Cl2 (2x) to give 5-fluoro-1-(4-(piperazin-1-yl)phenyl)pyrimidine-2,4(1H,3H)-dione (CBM-30) (60 mg, yield: quant., bis-HCl salt) as an off-white solid.

[0376] LCMS: [M+H] + =291.2.

[0377] 1 HNMR(400MHz,DMSO-d6):δ ppm 3.19-3.27(m,4H),3.38-3.45(m,4H),7.02-7.10(m,2H),7.26-7.35(m,2H),8.12(d,J=6.6Hz,1H),8.93(br dd,J=2.2,1.5Hz,2H),11.88(d,J=5.1Hz,1H).

[0378] 19 FNMR(377MHz,DMSO-d6):δ ppm -170.14- -169.97(m,1F).

[0379] Example S12 CBM-31 Procedure Synthesis of 1-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (CBM-31) [ka]

[0380] Step 1: tert-Butyl 4-(4-((2-cyanoethyl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate: A solution of tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (1.37 g, 5.14 mmol), saturated aqueous Na2CO3 (57 mL, 5.71 mmol), and prop-2-enenitrile (6.85 mL, 104.57 mmol) in THF (10 mL) was stirred at room temperature for 48 hours. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with NaCl and dried over MgSO4. The mixture was concentrated to dryness and purified by silica gel column chromatography (0% to 100% EtOAc / heptane) to afford tert-butyl 4-(4-((2-cyanoethyl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.6 g, 97% yield) as a brown solid.

[0381] LCMS: [M+H] + =320.2.

[0382] 1 HNMR(400MHz,CDCl3):δ ppm 1.41(s,9H),1.71(ddd,J=24.0,12.0,4.2Hz,2H),1.88-1.95(m,2H),2.65(t,J=6.6Hz,2H),2.87(br s,2H),3.10(q,J=6.6Hz,2H),4.00(br s,2H),4.09-4.22(m,1H),4.66(t,J=6.4Hz,1H),7.00(br s,1H),7.25(br s,1H).

[0383] Step 2: tert-Butyl 4-(4-(N-(2-cyanoethyl)cyanamido)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a solution of tert-butyl 4-(4-((2-cyanoethyl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.6 g, 5.01 mmol) in EtOH (20 mL) was added slowly a solution of cyanogen bromide (6.68 mL, 20.04 mmol) and NaOAc (1.42 mL, 12.52 mmol) in EtOH (5 mL) at 0° C. The reaction was stirred until complete by LCMS (approximately 18 hours). The mixture was concentrated to dryness, and the residue was washed with 5% aqueous citric acid and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and the residue was purified by silica gel column chromatography (0% to 100% EtOAc / heptane) to give tert-butyl 4-(4-(N-(2-cyanoethyl)cyanamido)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.5 g, 81% yield) as an orange oil.

[0384] LCMS: [M+Na] + =367.0.

[0385] 1 HNMR(400MHz,CDCl3):δ ppm 1.41(s,9H),1.74(ddd,J=24.9,12.2,4.4Hz,2H),1.91-1.98(m,2H),2.79-2.99(m,J=6.4,6.4Hz,4H),3 .77(t,J=6.5Hz,2H),3.96-4.02(m,2H),4.25-4.36(m,1H),7.49(d,J=0.7Hz,1H),7.97(d,J=0.7Hz,1H).

[0386] Step 3: 1-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (CBM-31): A solution of tert-butyl 4-(4-(N-(2-cyanoethyl)cyanamido)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.5 g, 4.36 mmol) in 6 N aqueous HCl (4.5 mL, 27 mmol) was heated to 100 °C until the reaction was complete by LCMS (approximately 3 h). The reaction mixture was concentrated to dryness, and the crude material was suspended in a mixture of 30% MeOH / DCM and neutralized with saturated NaHCO solution (pH approx. 7). The aqueous layer was concentrated to dryness, and the residue was purified by reverse-phase column chromatography (0% to 100% MeCN / water (containing 0.1% formic acid)). After lyophilization, 1-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (CBM-31) (764.7 mg, 67% yield) was obtained as a tan solid.

[0387] LCMS: [M+H] + =264.2.

[0388] 1 HNMR(400MHz,DMSO-d6):δ ppm 1.74(ddd,J=24.0,11.7,4.2Hz,2H),1.85-1.94(m,2H),2.53-2.61(m,2H),2.68(t,J=6.8Hz,2H),2.97 -3.06(m,J=12.5Hz,2H),3.75(t,J=6.8Hz,2H),4.04-4.20(m,1H),7.59(s,1H),7.92(s,1H),10.36(br s,1H).

[0389] Target Binding Site (TBM) Procedure Example S13 General procedure for TBM-D [ka] Synthesis of TBM-D: Step 1 [ka] A round-bottom flask was charged with intermediate D-1a, 5,8-dibromoimidazo[1,2-a]pyrazine (5.0 g, 18 mmol, 1 equiv.), intermediate D-2a, tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (5.29 g, 19.8 mmol, 1.1 equiv.), and pivalic acid (27.66 g, 271 mmol, 15 equiv.). The flask was then placed in a preheated oil bath at 100 °C. After 2 h, LCMS indicated complete conversion with traces of the deprotected product. The brown residue was quenched with saturated NaHCO3 solution (to pH 7–9) and extracted with MeTHF (3x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a dark red residue. The residue was then purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The combined fractions were concentrated to give intermediate D-3a, tert-butyl 4-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (5.99 g, 70% yield), as a brown solid.

[0390] LCMS: [M+H] + =462.2, 464.2.

[0391] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.42(s,9H),1.76(qd,J=12.1,4.2Hz,2H),1.99(br dd,J=12.3,2.3Hz,2H),2.78-2.99(m,2H),3.97-4.12(m,2H),4.30-4.39(m,1H),7.59(s, 1H),7.70(d,J=1.2Hz,1H),7.76(s,1H),7.98(d,J=1.0Hz,1H),8.18(s,1H),10.00(s,1H). [Table 59] [Table 60]

[0392] Synthesis of 5,8-dibromo-3-methylimidazo[1,2-a]pyrazine (intermediate D-1c) [ka] To a round-bottom flask was added 2-bromo-1,1-diethoxy-propane 1 (1.59 mL, 9.9 mmol, 5 equiv.) / IPA (9.9 mL, 0.2 M). To the reaction mixture was added HBr (1.18 mL, 21.7 mmol, 11 equiv.), and the reaction mixture was heated to 95° C. and stirred overnight. The resulting yellow solution was cooled to room temperature, neutralized with solid NaHCO3, filtered, and rinsed with isopropanol. The resulting solution was placed in a flask, and 3,6-dibromopyrazin-2-amine (500 mg, 2.0 mmol) was added. The mixture was heated to reflux at 95° C. and reacted overnight. The solution was cooled to room temperature and concentrated. The residue was dissolved in EtOAc, washed with NaHCO3 (2x) and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reverse-phase column chromatography (5% to 100% in water (containing 0.1% formic acid)). The combined fractions were concentrated to give intermediate D-1c, 5,8-dibromo-3-methylimidazo[1,2-a]pyrazine (212 mg, 36% yield), as a yellow solid.

[0393] LCMS: [M+H] + =292.0.

[0394] 1 HNMR(400MHz,DMSO-d6)δ ppm 2.82(s,3H),7.72(s,1H),7.84(s,1H).

[0395] Synthesis of 8-chloro-5,6-dimethylimidazo[1,2-a]pyrazine (Intermediate D-1d) [ka] A pressure tube was charged with 3-bromo-5,6-dimethyl-pyrazin-2-amine (200 mg, 0.99 mmol), aqueous 2-chloroacetaldehyde (50% w / w, 1.34 mL, 9.9 mmol), and 1,4-dioxane (0.825 mL), purged with N, sealed, and heated to 90 °C until the reaction was complete by LCMS analysis (approximately 2 h). The reaction mixture was concentrated to dryness, and the crude material was taken up in DMSO / 1 M aqueous NaOH and purified by reverse-phase column chromatography (5% MeCN / water with pH 10 buffer, followed by 5–100% MeCN / water with formic acid) to afford intermediate D-1d, 8-chloro-5,6-dimethylimidazo[1,2-a]pyrazine (128 mg, 71% yield), as an off-white solid.

[0396] LCMS: [M+H] + =182.2.

[0397] 1 HNMR(400MHz,DMSO-d6)δ ppm 2.45(s,3H),2.58(s,3H),7.86(d,J=1.0Hz,1H),8.18(d,J=1.0Hz,1H).

[0398] Synthesis of (2S,4S)-tert-butyl 4-(4-amino-1H-pyrazol-1-yl)-2-methylpiperidine-1-carboxylate (Intermediate D-2b) [ka]

[0399] Step 1: To a solution of tert-butyl (2S,4R)-4-hydroxy-2-methyl-piperidine-1-carboxylate 1 (500.0 mg, 2.32 mmol, 1 eq.) in CHCl (15 mL) at room temperature, EtN (0.97 mL, 6.97 mmol, 3 equiv.) and MsCl (0.27 mL, 3.48 mmol, 1.5 equiv.) were added. After 90 min, LCMS showed the expected mass. The reaction was quenched with saturated NHCl solution and diluted with CHCl. ​​The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated to give tert-butyl (2S,4R)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (701 mg, 95% yield) as a pale yellow solid.

[0400] LCMS: [M+H] + =194.2.

[0401] 1 HNMR(400MHz,chloroform-d)δ ppm 1.19(d,J=7.1Hz,3H),1.44-1.49(m,9H),1.66(br dd,J=12.1,5.0Hz,1H),1.83(dt,J=12.1,6.2Hz,1H),1.99(dt,J=12.6,2.3H z,1H),2.07-2.21(m,1H),2.93(td,J=13.7,2.7Hz,1H),3.03(s,3H),4.10(br d,J=12.7Hz,1H),4.48-4.63(m,1H),4.89-5.02(m,1H).

[0402] Step 2: To a solution of tert-butyl (2S,4R)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (778 mg, 2.65 mmol, 1.2 eq.) and 4-nitro-1H-pyrazole 3 (250 mg, 2.21 mmol, 1 eq.) in DMF (10.2 mL) at room temperature was added CsCO (1.1 g, 3.1 mmol, 1.4 eq.). The reaction flask was placed in an oil bath pre-equilibrated to 90 °C. After 18 h, LCMS showed complete conversion. The reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine (3x), dried over sodium sulfate, filtered, concentrated, and purified by reverse-phase column chromatography (5% to 100% MeOH / water with 0.1% formic acid). The fractions were combined and concentrated to give tert-butyl (2S,4S)-2-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (529 mg, 75% yield) as an orange oil.

[0403] LCMS: [M-tBu+H] + =255.2.

[0404] Step 3: To a solution of tert-butyl (2S,4S)-2-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (529 mg, 1.68 mmol, 1 eq.) in ethanol (8.5 mL) under nitrogen, Pd / C (267.47 mg, 0.25 mmol, 0.15 eq.) was added. The atmosphere in the flask was replaced with hydrogen by bubbling hydrogen into the mixture. The reaction mixture was then stirred at room temperature under 1 atm of hydrogen. After 1.5 h, LCMS indicated complete conversion. The mixture was filtered through Celite, washed with EtOAc, and concentrated under reduced pressure to afford intermediate D-2b, tert-butyl (2S,4S)-4-(4-amino-1H-pyrazol-1-yl)-2-methylpiperidine-1-carboxylate (486 mg, 98% yield), as a purple oil.

[0405] LCMS: [M+H] +=281.4.

[0406] 1 HNMR(400MHz,DMSO-d6)δ ppm 0.93(d,J=6.6Hz,3H),1.39-1.42(m,9H),1.89-1.97(m,2H),2.00-2.11(m,2H),3.23-3.30(m,1H),3 .60-3.69(m,1H),3.69-3.87(m,2H),3.87-3.98(m,1H),4.14-4.23(m,1H),6.92(s,1H),7.10(s,1H).

[0407] Synthesis of (2R,4R)-tert-butyl 4-(4-amino-1H-pyrazol-1-yl)-2-methylpiperidine-1-carboxylate (Intermediate D-2c) [ka]

[0408] Step 1: To a solution of triphenylphosphine (1.50 g, 5.71 mmol, 1.50 equiv.), tert-butyl (2R,4S)-4-hydroxy-2-methyl-piperidine-1-carboxylate (0.82 g, 3.8 mmol, 1.00 equiv.), and 4-nitro-1H-pyrazole (0.65 g, 5.71 mmol, 1.50 equiv.) in anhydrous THF (19.00 mL) was slowly added diisopropyl azodicarboxylate (1.12 mL, 5.71 mmol) in THF (19.00 mL, total concentration 0.10 M) under argon at 0 °C. The reaction was allowed to warm to room temperature over 18 h. The reaction was concentrated under reduced pressure and purified by reverse-phase column chromatography (5% to 90% MeOH / water (containing 0.1% formic acid)). The fractions were combined and concentrated to give tert-butyl (2R,4R)-2-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.14 g, 91% yield) as a colorless semi-solid.

[0409] LCMS: [M+H] + =211.2.

[0410] 1 HNMR(400MHz,DMSO-d6)δ ppm 0.98(d,J=6.6Hz,3H),1.41(s,9H),2.03-2.18(m,4H),3.31(ddd,J=14.2,9.4,5.5Hz,1 H),3.60-3.74(m,1H),3.90-4.03(m,1H),4.47-4.57(m,1H),8.30(s,1H),8.99(s,1H).

[0411] Step 2: To a solution of tert-butyl (2R,4R)-2-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.14 g, 3.49 mmol, 1.00 equiv.) in ethanol (34.89 mL, 0.10 M) was added 10% w / w Pd / C (371 mg, 0.35 mmol, 0.10 equiv.). H2 gas was sparged into the mixture using a rubber balloon and stainless steel needle. After 10 minutes of sparging, the exhaust needle was removed, and the reaction was stirred at room temperature for 18 hours under an H2 atmosphere. LCMS showed complete conversion to the desired product. The crude mixture was filtered through 2 inches of Celite and washed with additional MeOH. Concentration of the mixture afforded intermediate D-2c, tert-butyl (2R,4R)-4-(4-amino-1H-pyrazol-1-yl)-2-methylpiperidine-1-carboxylate (1.05 g, yield: quant.) as a purple solid, which was used without further purification.

[0412] LCMS: [M+H] + =281.4.

[0413] 1 HNMR(400MHz,DMSO-d6)δ ppm 0.93(d,J=6.8Hz,3H),1.40(s,9H),1.87-2.10(m,4H),3.22-3.31(m,1H),3.60-3.69(m,1H ),3.75-3.86(m,2H),3.93(sxt,J=6.6Hz,1H),4.13-4.25(m,1H),6.92(s,1H),7.10(s,1H).

[0414] Synthesis of (3R,4R)-tert-butyl 4-(4-amino-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (Intermediate D-2e) [ka]

[0415] Step 1: At 0 °C under nitrogen, a solution of 4-nitro-1H-pyrazole (618.9 mg, 5.47 mmol, 2 eq.), diisopropyl azodicarboxylate (1.1 mL, 5.47 mmol, 2 eq.), and polymer-bound triphenylphosphine (1.82 g, 5.47 mmol, 2 eq.) in anhydrous THF (7 mL, 0.2 M) was slowly added with a solution of tert-butyl (3R,4S)-3-fluoro-4-hydroxy-piperidine-1-carboxylate (600 mg, 2.74 mmol, 1 eq.) in anhydrous THF (7 mL, 0.2 M). After 19 h at room temperature, the reaction mixture was filtered and concentrated in vacuo, and the crude residue was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The fractions were combined and concentrated to give tert-butyl (3R,4R)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (404 mg, 47% yield) as a yellow oil.

[0416] LCMS: [M-tBu+H] + =259.2.

[0417] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.37(d,J=6.4Hz,2H),1.43(s,9H),1.95(qd,J=12.4,4.4Hz,1H),2.04-2.14(m,1H),3.98(br d,J=13.2Hz,1H),4.22-4.39(m,1H),4.68(qd,J=10.7,4.6Hz,1H),4.74-4.95(m,1H),8.35(s,1H),9.09(s,1H).

[0418] 19FNMR(377MHz,DMSO-d6)δ ppm -188.01(br dd,J=50.4,5.4Hz,1F).

[0419] Step 2: A solution of tert-butyl (3R,4R)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (404 mg, 1.29 mmol, 1 eq.) in ethanol (23 mL, 0.06 M) was purged with nitrogen three times, and Pd / C (137 mg, 0.13 mmol, 0.1 eq.) was added. The mixture was then purged with hydrogen gas (balloon) three times and then stirred at room temperature under a hydrogen atmosphere for 19 hours. The mixture was filtered through Celite and rinsed with EtOAc and EtOH. The filtrate was concentrated in vacuo to afford intermediate D-2e, tert-butyl (3R,4R)-4-(4-amino-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (370 mg, 65% yield), as a purple oil, which was used without further purification.

[0420] LCMS: [Mt-Bu+H] + =229.2.

[0421] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.18(d,J=6.1Hz,2H),1.42(s,9H),1.80-1.97(m,2H),3.77-3.97(m,2H),4 .22-4.37(m,2H),4.57-4.83(m,2H),6.95-7.02(m,1H),7.11-7.20(m,1H).

[0422] 19 FNMR(377MHz,DMSO-d6)δ ppm -186.81- -186.56(m,1F).

[0423] Synthesis of (3R,4S)-tert-butyl 4-(4-amino-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (Intermediate D-2f) [ka]

[0424] Step 1: At 0 °C under nitrogen, a solution of 4-nitro-1H-pyrazole (645 mg, 5.71 mmol), diisopropyl azodicarboxylate (1.1 mL, 5.49 mmol), and polymer-bound triphenylphosphine (1.98 g, 5.94 mmol) in anhydrous THF (18 mL) was slowly added with a solution of tert-butyl (3R,4R)-3-fluoro-4-hydroxy-piperidine-1-carboxylate (607 mg, 2.77 mmol) in anhydrous THF (18 mL). After 18 h at room temperature, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). Collected fractions gave tert-butyl (3R,4S)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (511 mg, 1.63 mmol, 59% yield) as a white solid.

[0425] LCMS: [M-tBu+H] + =259.2.

[0426] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.19(br d,J=6.1Hz,1H),1.42(s,9H),1.99-2.08(m,1H),2.24-2.36(m,1H),2.84-3.10(m,1H),4.09-4 .22(m,1H),4.24-4.43(m,1H),4.68-4.83(m,1H),4.99-5.19(m,1H),8.35(s,1H),8.95(s,1H).

[0427] 19 FNMR(377MHz,DMSO-d6)δ ppm -203.26- -202.52(m,1F).

[0428] The mixture was then purged with hydrogen gas (balloon) three times and then stirred at room temperature under hydrogen (balloon) for 19 hours. The mixture was flushed with nitrogen, filtered through Celite, and rinsed with MeOH (50 mL). The filtrate was dried under vacuum to afford intermediate D-2f, tert-butyl (3R,4S)-4-(4-amino-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (453 mg, 1.05 mmol, 66% yield), as a purple oil, which was used directly without further purification.

[0429] LCMS: [M+H] + =285.2.

[0430] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.14-1.27(m,1H),1.41(s,9H),1.81-1.93(m,1H),1.99-2.18(m,1H),2.79-3.01(m,1H),4.12(br d,J=2.9Hz,1H),4.18-4.31(m,1H),4.36-4.48(m,1H),4.67-4.82(m,2H),4.84-5.07(m,1H),7.02(s,1H),7.12-7.17(m,1H).

[0431] 19 FNMR(377MHz,DMSO-d6)δ ppm -202.38- -201.24(m,1F).

[0432] Synthesis of (3S,4R)-tert-butyl 4-(4-amino-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (Intermediate D-2h) [ka]

[0433] Step 1: A solution of 4-nitro-1H-pyrazole (643 mg, 5.69 mmol), tert-butyl (3S,4S)-3-fluoro-4-hydroxy-piperidine-1-carboxylate (604 mg, 2.76 mmol), and polymer-bound triphenylphosphine (1.91 g, 5.74 mmol) in anhydrous THF (18 mL) was prepared and cooled to 0 °C under nitrogen. A solution of diisopropyl azodicarboxylate (1.1 mL, 5.59 mmol) in anhydrous THF (18 mL) was then slowly added. After 17 h at room temperature, the reaction mixture was filtered, concentrated, and purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). Collected fractions gave tert-butyl (3S,4R)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (511 mg, 1.62 mmol, 59% yield) as a white solid.

[0434] LCMS: [M-tBu+H] + =259.2.

[0435] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.19-1.24(m,1H),1.41(s,9H),2.01(br dd,J=12.7,3.2Hz,1H),2.22-2.37(m,1H),3.15-3.36(m,1H),4.15(br s,1H),4.22-4.38(m,1H),4.68-4.81(m,1H),5.00-5.18(m,1H),8.34(s,1H),8.94(s,1H).

[0436] 19 FNMR(377MHz,DMSO-d6)δ ppm -205.91- -197.72(m,1F).

[0437] Step 2: A solution of tert-butyl (3S,4R)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (511 mg, 1.62 mmol) in ethanol (16 mL) was purged with nitrogen three times, and Pd / C (187.0 mg, 0.18 mmol) was added. The mixture was then purged with hydrogen gas (balloon) three times and then stirred at room temperature under hydrogen (balloon) for 22 hours. The mixture was flushed with nitrogen, filtered through Celite, and rinsed with MeOH (50 mL). The filtrate was concentrated in vacuo to afford tert-butyl (3S,4R)-4-(4-amino-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (427 mg, 1.05 mmol, 64% yield) as a red oil, which was used directly without further purification.

[0438] LCMS: [M+H] + =285.2.

[0439] 1 H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.28 (m, 1H), 1.41 (s, 9H), 1.85 (br dd, J = 12.8, 3.1 Hz, 1H), 2.07 (qd, J = 12.7, 4.7 Hz, 1H), 3.05-3.25 (m, 1H), 4.05-4.13 (m, 1H), 4.20-4.28 (m, 1H), 4.30-4.48 (m, 1H), 4.81-5.02 (m, 1H), 6.95 (s, 1H), 7.04 (s, 1H). Two protons were not observed.

[0440] 19 FNMR(377MHz,DMSO-d6)δ ppm -202.48- -200.97(m,1F).

[0441] Synthesis of (3S,4S)-tert-butyl 4-(4-amino-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (Intermediate D-2i) [ka]

[0442] Step 1: A solution of 4-nitro-1H-pyrazole (414 mg, 3.66 mmol), tert-butyl (3S,4R)-3-fluoro-4-hydroxy-piperidine-1-carboxylate (375 mg, 1.71 mmol), and polymer-bound triphenylphosphine (1.31 g, 3.93 mmol) in anhydrous THF (18 mL) was prepared and cooled to 0 °C under nitrogen. A solution of diisopropyl azodicarboxylate (0.66 mL, 3.34 mmol) in anhydrous THF (18 mL) was slowly added. After 18 h at room temperature, the reaction mixture was filtered, concentrated, and purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)) to afford tert-butyl (3S,4S)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (452 ​​mg, 1.42 mmol, 83% yield) as a yellow solid.

[0443] LCMS: [M-tBu+H] + =259.2.

[0444] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.21-1.25(m,1H),1.43(s,9H),1.88-2.04(m,1H),2.08-2.13(m,1H),3.98(br d,J=12.6Hz,1H),4.22-4.39(m,1H),4.62-4.74(m,1H),4.75-4.83(m,1H),4.84-4.96(m,1H),8.35(s,1H),9.09(s,1H).

[0445] 19 FNMR(377MHz,DMSO-d6)δ ppm -188.02(br dd,J=49.0,5.5Hz,1F).

[0446] Step 2: A solution of tert-butyl (3S,4S)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (441 mg, 1.40 mmol) in ethanol (12 mL) was purged with nitrogen three times, and Pd / C (20.2 mg, 0.20 mmol) was added. The mixture was then purged with hydrogen gas (balloon) three times and then stirred at room temperature under hydrogen (balloon) for 18 hours. Since no conversion was observed, the reaction mixture was purged with nitrogen three times, and additional Pd / C (54.6 mg, 0.5100 mmol) was added. The mixture was then purged with hydrogen gas (balloon) three times and then stirred at room temperature under hydrogen (balloon) for 17 hours. The mixture was flushed with nitrogen, filtered through Celite, and rinsed with MeOH (100 mL). The filtrate was concentrated to give tert-butyl (3S,4S)-4-(4-amino-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (425 mg, 1.50 mmol, yield: quant.) as a red oil, which was used directly without further purification.

[0447] LCMS: [M-tBu+H] + =229.2.

[0448] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.14-1.17(m,1H),1.41(s,9H),1.82-1.92(m,2H),3.81(br s,2H),3.91(br d,J=13.0Hz,2H),4.29-4.38(m,1H),4.54-4.66(m,1H),4.68-4.78(m,1H),6.96(s,1H),7.12(s,1H).

[0449] 19 FNMR(377MHz,DMSO-d6)δ ppm -186.83- -186.56(m,1F).

[0450] Synthesis of (S)-tert-butyl 4-(4-amino-1H-pyrazol-1-yl)azepane-1-carboxylate (Intermediate D-2j) and (R)-tert-butyl 4-(4-amino-1H-pyrazol-1-yl)azepane-1-carboxylate (Intermediate D-2k) [ka]

[0451] Step 1: Triethylamine (2.59 mL, 18.58 mmol, 4 eq.) was added to a solution of tert-butyl 4-hydroxyazepane-1-carboxylate 1 (1.0 g, 4.64 mmol, 1 eq.) in DCM (15.48 mL). The flask was cooled to 0 °C, and methanesulfonyl chloride (1.08 mL, 13.93 mmol, 3 eq.) was added dropwise. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 h. After stirring for 18 h, the reaction was quenched with water (50 mL), and the organic layer was extracted three times with DCM, washed with brine, dried over Na2SO4, and evaporated in vacuo to give tert-butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate (1.35 g, 99% yield) as an orange oil, which was used directly without further purification.

[0452] 1 HNMR(400MHz,CDCl3)δ ppm 1.46(s,9H),1.60-1.75(m,2H),1.94-2.10(m,4H),3.02(s,3H),3.32-3.56(m,4H),4.84-4.97(m,1H).

[0453] Step 2: To a round-bottom flask containing 4-nitro-1H-pyrazole (0.51 g, 4.51 mmol, 1 eq.) was added a solution of tert-butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate (1.32 g, 4.51 mmol, 1 eq.) in DMF (10.25 mL). CS2CO3 (2.94 g, 9.02 mmol, 2 eq.) was then added, and the reaction mixture was stirred at 90 °C for 18 h under a nitrogen atmosphere. After heating for 18 h, LCMS indicated complete conversion. The reaction was cooled to room temperature, and water was added. The aqueous layer was extracted with EtOAc (3x), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness to give an orange oil, which was purified by silica gel column chromatography (0% to 100% EtOAc / heptane). The fractions were combined and concentrated to give tert-butyl (rac)-4-(4-nitro-1H-pyrazol-1-yl)azepane-1-carboxylate (0.873 g) as a yellow oil. The material was then separated by chiral SFC to give two enantiomers: Enantiomer 1 (assigned as the (S) configuration, 0.381 g, 27% yield) as a pale yellow oil, and Enantiomer 2 (assigned as the (R) configuration, 0.393 g, 28% yield) as a pale yellow oil. Note: The absolute stereochemistry was arbitrarily assigned from the first and second eluting enantiomers of the chiral separation.

[0454] Enantiomer 1: LCMS: [M-Boc+H] + =211.2. 1 HNMR(400MHz,DMSO-d6)δ ppm 1.42(s,9H),1.58-1.73(m,1H),1.79-1.90(m,1H),1.90-2.03(m,2H),2.07(s,2H),3.20-3.2 9(m,1H),3.34-3.42(m,2H),3.50-3.66(m,1H),4.35-4.48(m,1H),8.26(s,1H),8.92(s,1H).

[0455] Enantiomer 2: LCMS: [M-Boc+H] + =211.2. 1HNMR(400MHz,DMSO-d6)δ ppm 1.42(s,9H),1.58-1.73(m,1H),1.79-1.90(m,1H),1.90-2.03(m,2H),2.07(s,2H),3.20-3.2 9(m,1H),3.34-3.42(m,2H),3.50-3.66(m,1H),4.35-4.48(m,1H),8.26(s,1H),8.92(s,1H).

[0456] Step 3: To a solution of enantiomer 1, tert-butyl (S)-4-(4-nitro-1H-pyrazol-1-yl)azepane-1-carboxylate (0.33 g, 1.05 mmol, 1.0 eq.) in ethanol (10.47 mL, 0.1 M) under nitrogen, Pd / C (167 mg, 0.16 mmol, 0.2 eq.) was added. The atmosphere in the flask was replaced with hydrogen by bubbling through the mixture for 10 minutes. The reaction mixture was stirred under 1 atm of hydrogen at room temperature for 48 hours. The mixture was filtered through Celite and washed with EtOAc. The filtrate was then evaporated to dryness and purified by silica gel column chromatography (0% to 100% EtOAc / heptane). The fractions were combined and concentrated to give intermediate D-2j, tert-butyl (S)-4-(4-amino-1H-pyrazol-1-yl)azepane-1-carboxylate (185 mg, 57% yield) as a red solid.

[0457] LCMS: [M+H] + =281.2.

[0458] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.41(s,9H),1.53-1.70(m,1H),1.72-1.86(m,3H),1.91-2.04(m,3H),3.14-3.26(m,2H),3 .46-3.58(m,1H),3.72-3.82(m,1H),4.02-4.11(m,1H),6.88(s,1H),7.00(d,J=0.7Hz,1H). 1 One proton was missing in the HNMR spectrum.

[0459] Step 3': To a solution of enantiomer 2, tert-butyl (R)-4-(4-nitro-1H-pyrazol-1-yl)azepane-1-carboxylate (0.38 g, 1.23 mmol) in ethanol (12.3 mL) under nitrogen, Pd / C (394 mg, 0.37 mmol) was added. The atmosphere in the flask was replaced with hydrogen by bubbling hydrogen through the mixture. The mixture was stirred overnight at room temperature under 1 atm of hydrogen. The mixture was filtered through Celite, and the pad was rinsed with EtOAc. The filtrate was then passed through a silica pad. The filtrate was then concentrated to give intermediate D-2k, tert-butyl (R)-4-(4-amino-1H-pyrazol-1-yl)azepane-1-carboxylate (285 mg, 67% yield), as a red solid, which was used directly without further purification.

[0460] LCMS: [M+H] + =281.2.

[0461] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.42(s,9H),1.58-1.68(m,2H),1.72-1.89(m,4H),3.17-3.26(m,2H), 3.47-3.59(m,2H),4.04-4.13(m,1H),6.88(s,1H),7.01-7.02(m,1H). [Table 61] [Table 62] [Table 63] [Table 64] [Table 65]

[0462] Synthesis of TBM-D: Step 2 [ka] To a solution of intermediate D-4b, 2-(2,4-difluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.37 g, 8.76 mmol, 1.5 equiv.) and intermediate D-3a, tert-butyl 4-[4-[(5-bromoimidazo[1,2-a]pyrazin-8-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (2.7 g, 5.84 mmol, 1 equiv.) in 1,4-dioxane (21.2 mL, 0.2 M) in a sealed tube was added NaHCO (1.47 g, 17.52 mmol, 3 equiv.) and water (9.7 mL, 0.2 M), followed by bubbling with N for 5 min. Pd(PPh3)4 (675 mg, 0.58 mmol, 0.1 equiv.) was then added and N2 was bubbled through for 10 minutes. The resulting solution was stirred at 90 °C in a sealed tube under a N2 atmosphere for 16 hours. The resulting mixture was cooled to room temperature, water and EtOAc were added to the solution, and the layers were separated. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give a yellow oil. The yellow oil was then purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The fractions were combined and concentrated to give intermediate D-5b tert-butyl 4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.65 g, 88% yield) as a pale orange solid.

[0463] LCMS: [M+H] + =510.2.

[0464] 1HNMR(400MHz,DMSO-d6)δ ppm 1.42(s,9H),1.71-1.84(m,2H),1.97-2.04(m,2H),2.29(s,3H),3.15-3.19(m,1H),3.98-4.14(m,3H),4 .31-4.41(m,1H),7.41-7.48(m,2H),7.58-7.63(m,J=5.6Hz,3H),7.81(s,1H),8.25(s,1H),9.99(s,1H). [Table 66] [Table 67]

[0465] Synthesis of 7-fluoro-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Intermediate D-4l) [ka]

[0466] Step 1: To a solution of 6-bromo-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine (600 mg, 2.59 mmol, 1.0 equiv.) in DMF (6 mL) was added NaH (155 mg, 3.88 mmol, 1.5 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 20 minutes, and then MeI (0.32 mL, 5.17 mmol, 2.0 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water (3×), brine (2×), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-40% EtOAc / heptane) to give the product 6-bromo-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine (420 mg, 66% yield) as a pale yellow solid.

[0467] Step 2: In a sealed tube, 6-bromo-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine (200 mg, 0.81 mmol), B2pin2 (310 mg, 1.22 mmol), and KOAc (239 mg, 2.44 mmol) were mixed under N2. 1,4-Dioxane (4 mL) was added, and N2 was bubbled through the solution for 10 min. Pd(dppf)Cl2·CHCl2 (66 mg, 0.08 mmol) was then added, and N2 was bubbled through for 5 min. The tube was sealed and heated at 90 °C overnight. The reaction mixture was cooled to room temperature. The reaction mixture was filtered through Celite, washed with EtOAc, and the filtrate was evaporated. The crude product was purified by normal phase chromatography (0% to 30% EtOAc / heptane) to afford intermediate D-4l, 7-fluoro-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (120 mg, 40% corrected yield) as a pale yellow semisolid.

[0468] LCMS: [M+H] + =294.2. [Table 68] [Table 69] [Table 70] [Table 71] [Table 72] [Table 73] [Table 74] [Table 75] [Table 76] [Table 77] [Table 78] [Table 79] [Table 80] [Table 81] [Table 82] [Table 83]

[0469] Synthesis of (R)-tert-butyl 4-(3-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)pyridin-1-yl)piperidine-1-carboxylate (Intermediate D-5l) from Intermediate D-5l' [ka]

[0470] Step 1: To a solution of tert-butyl (3R)-3-[[5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]pyrrolidine-1-carboxylate (290 mg, 0.68 mmol, 1 eq.) in MeOH (5 mL, 0.14 M) was added 4 M HCl in 1,4-dioxane (2.53 mL, 10.1 mmol, 15 eq.), and the reaction was stirred at room temperature for 2 h. The solvent was evaporated and co-evaporated with MeOH and MTBE to give (R)-5-(2,4-difluoro-5-methylphenyl)-N-(1,2-pyrazin-3-yl)imidazo[1,2-a]pyrazin-8-amine (283 mg, 80% yield) as a brown solid as the bis-HCl salt.

[0471] LCMS: [M+H] + =330.2.

[0472] 1 HNMR(400MHz,DMSO-d6)δ ppm 2.16-2.21(m,1H),2.23-2.35(m,4H),3.22-3.39(m,2H),3.39-3.48(m,1H),3.48-3.56(m,1H),4.79-4.8 4(m,1H),7.43-7.51(m,2H),7.54-7.61(m,1H),7.71-7.79(m,2H),8.97-9.10(m,1H),9.20-9.33(m,1H).

[0473] Step 2: To (R)-5-(2,4-difluoro-5-methylphenyl)-N-(154-pyrrolidin-3-yl)imidazo[1,2-a]pyrazin-8-amine (280 mg, 0.77 mmol, 1 eq.) in DMSO (2.56 mL, 0.3 M) at room temperature, DIPEA (0.67 mL, 3.8 mmol, 5 eq.) was added, followed by tert-butyl 4-oxopiperidine-1-carboxylate (152.51 mg, 0.77 mmol, 1 eq.) and AcOH (0.03 mL, 0.54 mmol, 0.7 eq.) under N2. The solution was stirred for 10–15 min. NaBH(OAc)3 (324 mg, 1.53 mmol, 2 eq.) was then added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the reaction mixture was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The combined fractions were concentrated to afford intermediate D-5l, (R)-tert-butyl 4-(3-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)pyrrolidin-1-yl)piperidine-1-carboxylate (320 mg, 82% yield), as the formate salt as an orange semi-solid.

[0474] LCMS: [M+H] + =513.2.

[0475] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.20-1.33(m,2H),1.39(s,9H),1.74-1.86(m,2H),1.86-1.99(m,1H), 2.15-2.26(m,1H),2.28(s,3H),2.29-2.37(m,1H),2.59-2.70(m,2H), 2.75-2.91(m,3H),2.96-3.03(m,1H),3.75-3.90(m,2H),4.55-4.69(m ,1H),7.31(s,1H),7.38-7.50(m,2H),7.51-7.60(m,3H),8.16(s,1H).

[0476] 19FNMR(377MHz,DMSO-d6)δ ppm -112.17(q,J=9.1Hz,1F),-111.44(q,J=8.2Hz,1F).

[0477] Synthesis of (S)-tert-butyl 4-(3-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)pyrrolidin-1-yl)piperidine-1-carboxylate (intermediate D-5p) from intermediate D-5p' [ka]

[0478] Step 1: To a solution of (S)-tert-butyl 3-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)pyrrolidine-1-carboxylate (273 mg, 0.64 mmol, 1 equiv.) in MeOH (5 mL, 0.13 M) was added 4 M HCl in 1,4-dioxane (2.38 mL, 9.54 mmol, 15 equiv.) and the reaction was stirred at room temperature for 48 h. The solvent was evaporated and co-evaporated with MeOH and MTBE to give (S)-5-(2,4-difluoro-5-methylphenyl)-N-(pyrrolidin-3-yl)imidazo[1,2-a]pyrazin-8-amine (310 mg, quantitative yield) as a brown solid as the bis-HCl salt.

[0479] LCMS: [M+H] + =330.2.

[0480] 1 HNMR(400MHz,DMSO-d6)δ ppm 2.13-2.23(m,1H),2.24-2.37(m,4H),3.24-3.48(m,3H),3.51-3.61(m ,1H),4.76-4.89(m,1H),7.43-7.54(m,2H),7.55-7.62(m,1H),7.82(br s,1H),7.88(br s,1H),8.95-9.34(m,2H),9.49(br s,1H).

[0481] Step 2: To (S)-5-(2,4-difluoro-5-methylphenyl)-N-(pyrrolidin-3-yl)imidazo[1,2-a]pyrazin-8-amine (308 mg, 0.74 mmol, 1 equiv.) in CHCl (3 mL, 0.2 M) and DMSO (0.50 mL, 0.2 M) at room temperature, DIPEA (0.65 mL, 3.7 mmol, 5 equiv.) was added, followed by tert-butyl 4-oxopiperidine-1-carboxylate (148 mg, 0.74 mmol, 1 equiv.) and AcOH (0.04 mL, 0.74 mmol, 1 equiv.) under N under N. The solution was stirred for 10–15 min. NaBH(OAc) (316 mg, 1.49 mmol, 2 equiv.) was then added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the reaction mixture was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The combined fractions were concentrated to afford intermediate D-5p, tert-butyl (S)-4-(3-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)pyrrolidin-1-yl)piperidine-1-carboxylate (344 mg, 79% yield), as the formate salt as an orange semi-solid.

[0482] LCMS: [M+H] + =513.2.

[0483] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.21-1.34(m,2H),1.39(s,9H),1.75-1.85(m,2H),1.88-1.98(m,1H),2.15-2 .37(m,5H),2.59-2.71(m,2H),2.74-2.89(m,3H),2.97-3.04(m,1H),3.83(br d,J=12.0Hz,2H),4.57-4.67(m,1H),7.31(s,1H),7.43(t,J=9.9Hz,1H),7.49(d,J=7.1Hz,1H),7.52-7.59(m,3H),8.16(s,1H).

[0484] Synthesis of TBM-D: Step 3 [ka] To a solution of intermediate D-5b, tert-butyl 4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.65 g, 5.2 mmol, 1 equiv.) in MeOH (14 mL, 0.37 M) was added 4 M HCl in 1,4-dioxane (19.5 mL, 78 mmol, 15 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was co-evaporated with MeOH (2x) and MTBE (2x) to give TBM-2, 5-(2,4-difluoro-5-methylphenyl)-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (2.62 g, quantitative yield) as a tan solid as the bis-HCl salt.

[0485] LCMS: [M+H] + =410.2.

[0486] 1 HNMR(400MHz,DMSO-d6)δ ppm 2.16-2.24(m,4H),2.27-2.31(m,3H),2.99-3.12(m,2H),3.34-3.43(m,2H),4.49-4.59(m,1H),7.49(br t,J=9.9Hz,1H),7.57-7.63(m,2H),7.81(s,1H),7.86(br s,1H),7.96(s,1H),8.23(s,1H),8.95-9.09(m,1H),9.19-9.32(m,1H),10.77-10.90(m,1H).

[0487] 19 FNMR(377MHz,DMSO-d6)δ ppm -111.93(s,1F),-110.28(s,1F). [Table 84] [Table 85] [Table 86] [Table 87] [Table 88] [Table 89] [Table 90] [Table 91]

[0488] Example S14 General procedure for TBM-E [ka] Synthesis of TBM-E: Step 1 [ka] A solution of intermediate E-2, 5-bromo-N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (150 mg, 0.33 mmol), intermediate E-3d, p-tolylboronic acid (75 mg, 0.55 mmol), Xphos (61 mg, 0.05 mmol), and NaHCO (85 mg, 1.01 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was degassed by bubbling nitrogen through for 10 minutes. Xphos-Pd-G (44 mg, 0.05 mmol) was added, and nitrogen was bubbled through the mixture for an additional 10 minutes. The reaction mixture was then heated to 90 °C for 18 hours. The reaction mixture was then cooled to room temperature, filtered through Celite, rinsed with EtOAc, and concentrated. The residue was purified by reverse-phase column chromatography (5% to 100% MeCN / water (containing 0.1% formic acid)) and collected fractions to afford TBM-31, N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(p-tolyl)imidazo[1,2-a]pyrazin-8-amine (126 mg, 0.27 mmol, 82% yield), as a white semisolid.

[0489] LCMS: [M+H] + =462.3.

[0490] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.88-2.01(m,4H),2.16-2.25(m,2H),2.40(s,3H),2.47(br d,J=5.3Hz,2H),2.99(br d,J=11.6Hz,2H),3.27(s,6H),4.11(tat,J=10.5,5.2Hz,1H),4.49(t,J=5.1Hz,1H),7.38(d,J=7.8Hz,2H),7.41( s,1H),7.57(d,J=7.9Hz,2H),7.63(d,J=1.0Hz,1H),7.79(s,1H),7.86(d,J=1.0Hz,1H),8.24(s,1H),9.86(s,1H). [Table 92] [Table 93]

[0491] Synthesis of 5-bromo-N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (Intermediate E-2) [ka]

[0492] Step 1: To a solution of intermediate D-3a, tert-butyl 4-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (7.15 g, 15.45 mmol) in DCM (150 mL), was added 4 M HCl in 1,4-dioxane (38.0 mL, 152 mmol). After 17 h at room temperature, the reaction mixture was concentrated in vacuo to afford intermediate E-1, 5-bromo-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (7.26 g, 19.86 mmol, quant.), as a brown solid. The product was used directly in the next step without further purification.

[0493] LCMS: [M+H] + =362.0.

[0494] 1 HNMR (400 MHz, DMSO-d₆) δ ppm 2.11-2.22 (m, 4H), 2.97-3.10 (m, 2H), 3.37 (br d, J = 12.6 Hz, 2H), 4.51 (br t, J = 7.3 Hz, 1H), 7.68 (s, 1H), 7.79 (s, 1H), 7.87 (d, J = 0.9 Hz, 1H), 8.09 (d, J = 1.2 Hz, 1H), 8.17 (s, 1H), 10.38 (s, 1H). One proton was not observed.

[0495] Step 2: To a solution of 5-bromo-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (5.6 g, 15.45 mmol), DIPEA (10.0 mL, 57.41 mmol), and 2,2-dimethoxyacetaldehyde (60 wt % aqueous solution, 0.77 mL, 53 mmol) in DCM (150 mL) was added NaBH(OAc) (6.64 g, 31.3 mmol). After 19 h at room temperature, the reaction mixture was concentrated and purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). Collected fractions gave intermediate E-2, 5-bromo-N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (6.60 g, 14.40 mmol, 93% yield) as a brown oil.

[0496] LCMS: [M+H] + =516.2.

[0497] 1 H NMR (400 MHz, DMSO-d₆) δ ppm 1.81-1.99 (m, 4H), 2.18-2.31 (m, 2H), 2.50-2.53 (m, 1H), 3.01 (br d, J = 11.6 Hz, 2H), 3.27 (s, 6H), 4.11 (tt, J = 10.4, 5.1 Hz, 1H), 4.50 (t, J = 5.1 Hz, 1H), 7.59 (s, 1H), 7.70 (d, J = 1.0 Hz, 1H), 7.75 (s, 1H), 7.98 (d, J = 1.0 Hz, 1H), 8.13-8.17 (m, 1H), 9.96-10.06 (m, 1H). One proton was not observed. [Table 94] [Table 95] [Table 96] [Table 97] [Table 98] [Table 99] [Table 100] [Table 101] [Table 102]

[0498] Synthesis of N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-ethylimidazo[1,2-a]pyrazin-8-amine (TBM-28) from TBM-28' [ka] To a solution of TBM-28', N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-vinylimidazo[1,2-a]pyrazin-8-amine (115 mg, 0.17 mmol, 1 eq.) in methanol (2.9 mL) under N2, Pd / C (17 mg, 0.02 mmol, 0.1 eq.) was added at room temperature. H2 was then bubbled through the mixture, which was then stirred under an H2 atmosphere. The mixture was filtered through Celite, rinsed with MeOH, and concentrated. The residue was then purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The fractions were combined and concentrated to give TBM-28, N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-ethylimidazo[1,2-a]pyrazin-8-amine (30 mg, 40% yield) as a pale yellow oil.

[0499] 1HNMR(400MHz,DMSO-d6)δ ppm 1.29(t,J=7.5Hz,3H),1.79-2.09(m,6H),2.13-2.25(m,2H),2.83(q,J=7.3Hz,2H),2.98(br d,J=11.2Hz,2H),3.27-3.27(m,6H),4.03-4.16(m,1H),4.49(t,J=5.1Hz,1H),7.24(s, 1H),7.63-7.66(m,1H),7.74(s,1H),7.95-7.98(m,1H),8.17-8.19(m,1H),9.59(s,1H).

[0500] Example S15 General procedure for TBM-F [ka] Synthesis of TBM-F: Step 1 [ka] A round-bottom flask was charged with intermediate F-1a, 1-((trans)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-1H-pyrazol-4-amine (1.64 g, 3.36 mmol, 1 eq.), 5,8-dibromoimidazo[1,2-a]pyrazine 6 (0.93 g, 3.36 mmol, 1 eq.), and pivalic acid (4.68 g, 45.8 mmol, 13.6 eq.). The reaction was placed in a preheated oil bath at 100 °C. After 2 h, the reaction was quenched with saturated NaHCO solution (to pH 7–9) and extracted with MeTHF (3x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a dark red residue, which was then purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The combined fractions were concentrated to give Intermediate F-2a, 5-bromo-N-(1-((trans)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (1.56 g, 67% yield), as a pale orange solid.

[0501] LCMS: [M+H] + =643.2, 645.2.

[0502] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.01(s,9H),1.03-1.13(m,2H),1.42-1.53(m,3H),1.60-1.72(m,2H),1.72-1.80(m,2H),1.94-2.02(m,2H),3.71(br t,J=5.9Hz,2H),4.00-4.08(m,1H),7.42-7.50(m,6H),7.59(s,1H),7.60-7.65(m,4H) ,7.70(d,J=1.0Hz,1H),7.73(s,1H),7.98(d,J=1.0Hz,1H),8.13(s,1H),9.97(s,1H). [Table 103]

[0503] Synthesis of 1-((trans)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-1H-pyrazol-4-amine (Intermediate F-1a) and 1-((cis)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-1H-pyrazol-4-amine (Intermediate F-1b) [ka]

[0504] Step 1: To a solution of 4-(2-hydroxyethyl)cyclohexanol (5 g, 34.7 mmol, 1 eq.) in DCM (63 mL) was added N-methylimidazole (8.29 mL, 104 mmol, 3 eq.), iodine (17.6 g, 69 mmol, 2 eq.), and tert-butylchlorodiphenylsilane (11.72 mL, 45 mmol, 1.3 eq.). After stirring at room temperature under a nitrogen atmosphere for 18 h, the reaction was washed with 10% sodium thiosulfate solution (2 x 80 mL) and brine (1 x 80 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated to give a dark orange oil. The residue was then purified by silica gel column chromatography (0% to 30% EtOAc / heptane). After two purifications by silica gel column chromatography, the fractions were combined and concentrated to give cis (cis)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexan-1-ol (4.62 g, 35% yield) as a colorless oil and trans (trans)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexan-1-ol (2.6 g, 19% yield) as a colorless oil; 54% combined yield.

[0505] cis:LCMS:[M+Na+H] + =405.4. 1 HNMR(400MHz,DMSO-d6)δ ppm 0.99(s,9H),1.25-1.40(m,6H),1.42-1.54(m,5H),3.64-3.71(m,3H),4.20(d,J=3.4Hz,1H),7.40-7.48(m,6H),7.58-7.63(m,4H).

[0506] trans:LCMS:[M+Na+H] + =405.4. 1HNMR(400MHz,DMSO-d6)δ ppm 0.78-0.91(m,2H),0.99(s,9H),1.01-1.11(m,2H),1.24-1.36(m,1H),1.40(q,J=6.4Hz,2H),1.53-1.62(m,2H),1.72 -1.79(m,2H),3.22-3.31(m,1H),3.66(t,J=6.5Hz,2H),4.41(d,J=4.6Hz,1H),7.40-7.48(m,6H),7.57-7.63(m,4H).

[0507] Step 2: To a solution of cis (cis)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexan-1-ol (2.2 g, 5.23 mmol, 1 eq.), triphenylphosphine (2058 mg, 7.85 mmol, 1.5 eq.), and 4-nitro-1H-pyrazole (887 mg, 7.9 mmol, 1.5 eq.) in anhydrous THF (10 mL) at 0 °C, diisopropyl azodicarboxylate (1.54 mL, 7.6 mmol, 1.5 eq.) was slowly added as a solution in anhydrous THF (15 mL). The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was concentrated and purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The fractions were combined and concentrated to give 1-((trans)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-4-nitro-1H-pyrazole (960 mg, 38% yield) as a colorless oil.

[0508] LCMS: [M+H] + =478.4.

[0509] 1HNMR(400MHz,DMSO-d6)δ ppm 1.00(s,9H),1.02-1.12(m,2H),1.43-1.54(m,3H),1.67-1.81(m,4H),2.01(br d,J=11.0Hz,2H),3.70(t,J=5.7Hz,2H),4.15-4.24(m,1H),7.42-7.49(m,6H),7.59-7.65(m,4H),8.24(s,1H),8.91(s,1H).

[0510] Step 3: To a solution of 1-((trans)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-4-nitro-1H-pyrazole (329 mg, 0.69 mmol, 1 eq.) in ethanol (8 mL, 0.08 M) under nitrogen, Pd / C (110 mg, 0.1 mmol, 0.15 eq.) was added. The atmosphere of the flask was replaced with hydrogen (purged five times). The reaction mixture was stirred under 1 atm of hydrogen at room temperature for 3 h. The reaction mixture was filtered through Celite and rinsed with EtOAc (3 x 20 mL). The solution was concentrated to give intermediate F-1a, 1-((trans)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-1H-pyrazol-4-amine (339 mg, quantitative yield) as a purple oil, which was used without further purification.

[0511] LCMS: [M+H] + =448.2.

[0512] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.00(s,9H),1.01-1.05(m,1H),1.38-1.50(m,3H),1.50-1.63(m,2H),1.71(br d,J=12.0Hz,2H),1.84-1.94(m,2H),3.69(t,J=6.2Hz,2H),3.73-3.89(m,2H),6. 87(d,J=0.7Hz,1H),7.01(d,J=0.7Hz,1H),7.41-7.49(m,6H),7.57-7.66(m,4H).

[0513] Step 2': Diisopropyl azodicarboxylate (0.46 mL, 2.35 mmol) was slowly added to a solution of triphenylphosphine (617 mg, 2.35 mmol), trans-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexan-1-ol (600 mg, 1.57 mmol, 1.0 eq.), and 4-nitro-1H-pyrazole (266 mg, 2.35 mmol, 1.5 eq.) in anhydrous THF (6 mL, 0.2 M) at 0 °C. The reaction was warmed to room temperature and stirred for 18 h. The solvent was evaporated, and the residue was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The fractions were combined and concentrated to give 1-((cis)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-4-nitro-1H-pyrazole (520 mg, 1.087 mmol, 69% yield) as a yellow solid.

[0514] LCMS: [M+H] + =478.2.

[0515] 1 HNMR(400MHz,DMSO-d6)δ ppm 0.99(s,9H),1.36-1.48(m,2H),1.50-1.56(m,2H),1.59(q,J=6.8Hz,2H),1.72-1.86(m,3H),1.96-2.06(m,2H),3 .68(t,J=6.4Hz,2H),4.21-4.35(m,1H),7.39-7.50(m,6H),7.57-7.66(m,4H),8.26(d,J=0.5Hz,1H),8.93(s,1H).

[0516] Step 3': Nitrogen was bubbled through a solution of 1-((cis)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-4-nitro-1H-pyrazole (520 mg, 1.09 mmol, 1.0 eq.) in methanol (2.18 mL, 0.5 M) for 5 min. Pd / C 10% (232 mg, 0.22 mmol, 0.2 eq.) was then added, and nitrogen was bubbled through for another 5 min. H2 (1 atm) was then bubbled through the solution for 5 min, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 18 h. The reaction mixture was filtered through Celite and washed with EtOAc. The residue was concentrated in vacuo to give intermediate F-1b, 1-((cis)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-1H-pyrazol-4-amine (465 mg, 1.039 mmol, 95% yield) as a purple oil, which was used in the next step without further purification.

[0517] LCMS: [M+H] + =448.4.

[0518] 1 HNMR(400MHz,DMSO-d6)δ ppm 0.99(s,9H),1.32-1.44(m,2H),1.44-1.51(m,2H),1.55(q,J=6.8Hz,2H),1.60-1.70(m,2H),1.70-1.79(m,1H),1.83-1.96(m,2) H),3.68(t,J=6.5Hz,2H),3.72-3.80(m,1H),3.90-4.00(m,1H),6.88(s,1H),7.04(s,1H),7.39-7.50(m,6H),7.57-7.66(m,4H). 1 One proton was missing in the HNMR spectrum. [Table 104] [Table 105]

[0519] Synthesis of TBM-F: Step 2 [ka]

[0520] To a solution of intermediate D-4b, 2-(2,4-difluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.69 g, 2.54 mmol, 1.5 eq.) and intermediate F-2a, 5-bromo-N-(1-((trans)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (1.09 g, 1.69 mmol) in 1,4-dioxane (15 mL) was added NaHCO (0.43 g, 5.1 mmol, 3 eq.) and water (5 mL). Nitrogen was bubbled through the reaction mixture for 10 min. Pd(PPh3)4 (0.2 g, 0.17 mmol, 0.1 eq.) was then added and nitrogen was bubbled through for an additional 10 minutes. The resulting solution was stirred at 90 °C under a nitrogen atmosphere in a sealed tube for 18 hours. The reaction mixture was filtered through Celite, rinsed with EtOAc, and concentrated. The resulting residue was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The combined fractions were concentrated to give intermediate F-4a, N-(1-((trans)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-amine (1.07 g, 89% yield), as a pale orange oil.

[0521] LCMS: [M-TBDPS+H] + =453.2.

[0522] 1HNMR(400MHz,DMSO-d6)δ ppm 1.00-1.03(m,9H),1.04-1.18(m,2H),1.45-1.53(m,3H),1.61-1.80(m,4H),1.95-2.04(m,2H),2.29(s,3H),3.72(br t,J=6.0Hz,2H),4.02-4.13(m,1H),7.41-7.49(m,8H),7.58-7.65(m,7H),7.78(s,1H),8.19(s,1H),9.96(s,1H).

[0523] 19 FNMR(377MHz,DMSO-d6)δ ppm -112.22- -112.10(m,1F),-111.33- -111.21(m,1F). [Table 106]

[0524] Synthesis of tert-butyl 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate F-3) [ka]

[0525] Step 1: To a solution of 6-bromo-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine (200 mg, 0.86 mmol, 1.0 eq.) in CHCl (2 mL, 0.4 M) was added tert-butoxycarbonyl tert-butyl carbonate (207 mg, 0.95 mmol, 1.1 eq.) and EtN (0.26 mL, 1.9 mmol, 2.2 eq.). The resulting solution was stirred at room temperature for 2 h. LCMS showed traces of the desired product. DMAP (105 mg, 0.86 mmol, 1.0 eq.) was added, and the reaction mixture was stirred overnight. The reaction mixture was diluted with CHCl and saturated NaHCO and extracted with CHCl. ​​The organic layer was then washed with saturated NaHCO, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The combined fractions were concentrated to give tert-butyl 6-bromo-7-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (180 mg, 63% yield) as a white solid.

[0526] LCMS: [M-Boc+H] + =232.0.

[0527] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.49(s,9H),3.78(t,J=4.5Hz,2H),4.24(t,J=4.5Hz,2H),6.99(d,J=9.8Hz,1H),8.08(br s,1H).

[0528] 19 FNMR(377MHz,DMSO-d6)δ ppm -113.57(s,1F).

[0529] Step 2: A mixture of tert-butyl 6-bromo-7-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (190 mg, 0.57 mmol, 1.0 eq.), B2pin2 (218 mg, 0.86 mmol, 1.5 eq.), and KOAc (168 mg, 1.72 mmol, 3.0 eq.) in 1,4-dioxane (2.3 mL, 0.25 M) was sparged with nitrogen for 10 min. Pd(dppf)Cl2·CHCl2 (47 mg, 0.06 mmol, 0.1 eq.) was then added, and nitrogen was bubbled through for an additional 5 min. The resulting solution was stirred at 90 °C in a sealed tube overnight. The reaction mixture was filtered through Celite, rinsed with EtOAc, and concentrated. The resulting residue was purified by silica gel column chromatography (0–30% EtOAc / heptane). The fractions were combined and concentrated to give intermediate F-3, tert-butyl 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (170 mg, 65% yield) as a pale yellow solid.

[0530] LCMS: [M+H] + =380.2.

[0531] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.27(s,12H),1.49(s,9H),3.78(t,J=4.3Hz,2H),4.25(t,J=4.4Hz,2H),6.67(d,J=9.8Hz,1H),8.04(br d,J=5.1Hz,1H).

[0532] 19 FNMR(377MHz,DMSO-d6)δ ppm -107.09(s,1F). [Table 107] [Table 108] [Table 109] [Table 110] [Table 111]

[0533] Synthesis of TBM-F: Step 3 [ka] To a stirred solution of intermediate F-4a, N-(1-((trans)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-amine (1.07 g, 1.55 mmol, 1 eq.) in THF (16 mL), a solution of 1 M TBAF in THF (3.5 mL, 3.5 mmol, 2.2 eq.) was added at room temperature for 3 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (0% to 30% MeOH in DCM). The combined fractions were concentrated, and the residue was purified by reverse-phase column chromatography (5% MeOH to 100% MeOH in water (containing 0.1% formic acid)). The fractions were combined and concentrated to give TBM-43, 2-((trans)-4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (425 mg, 59% yield) as a pale yellow solid.

[0534] LCMS: [M+H] + =453.2.

[0535] 1HNMR(400MHz,DMSO-d6)δ ppm 1.04-1.17(m,2H),1.37(q,J=6.5Hz,2H),1.41-1.50(m,1H),1.71(qd, J=12.5,2.9Hz,2H),1.80-1.88(m,2H),1.99-2.07(m,2H),2.27-2.30( m,3H),3.43-3.49(m,2H),4.04-4.14(m,1H),4.31-4.38(m,1H),7.40- 7.48(m,2H),7.58-7.64(m,3H),7.78(s,1H),8.20(s,1H),9.96(s,1H). [Table 112] [Table 113] [Table 114]

[0536] Example S16 General procedure for TBM-G [ka] Synthesis of TBM-G: Step 1 [ka] To a solution of ethyl 2-((trans)-3-(4-nitro-1H-pyrazol-1-yl)cyclobutyl)acetate (414 mg, 1.6 mmol, 1 eq.), intermediate G-1a, in ethanol (8 mL, 0.2 M) under nitrogen was added Pd / C (261 mg, 0.25 mmol, 0.15 eq.). The atmosphere in the flask was replaced with hydrogen (purged five times). The mixture was stirred under 1 atm of hydrogen at room temperature for 20 h. The reaction mixture was filtered through Celite and rinsed with EtOAc (3 x 50 mL). The resulting filtrate was concentrated to give ethyl 2-((trans)-3-(4-amino-1H-pyrazol-1-yl)cyclobutyl)acetate, intermediate G-2a (391 mg, 94% yield), as a purple oil, which was used without further purification.

[0537] LCMS: [M+H] + =224.2.

[0538] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.15-1.23(m,4H),2.05-2.16(m,2H),2.52-2.59(m,4H),3.79(br s,2H),4.05(q,J=7.1Hz,2H),4.76(quint,J=7.6Hz,1H),6.93(s,1H),7.07(s,1H). [Table 115]

[0539] Synthesis of ethyl 2-((trans)-3-(4-nitro-1H-pyrazol-1-yl)cyclobutyl)acetate (intermediate G-1a) and ethyl 2-((cis)-3-(4-nitro-1H-pyrazol-1-yl)cyclobutyl)acetate (intermediate G-1d) [ka] To a solution of ethyl 2-(3-hydroxycyclobutyl)acetate (850 mg, 5.37 mmol, 1 eq.), polymer-bound triphenylphosphine (3.58 g, 10.75 mmol, 2 eq.), and 4-nitro-1H-pyrazole 2 (1.22 g, 10.75 mmol, 2 eq.) in anhydrous THF (13 mL, 0.2 M) at 0 °C, diisopropyl azodicarboxylate (2.11 mL, 10.75 mmol, 2 eq.) was slowly added as a solution in anhydrous THF (13 mL, 0.2 M), and the reaction was allowed to warm to room temperature. After stirring under a nitrogen atmosphere for 20 h, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (0–10% EtOAc / DCM). The combined fractions were concentrated to give 747 mg of a mixture of cis and trans isomers. The isomers were separated by chiral SFC to give intermediate G-1a, ethyl 2-((trans)-3-(4-nitro-1H-pyrazol-1-yl)cyclobutyl)acetate (414 mg, 30% yield) as a white solid, and intermediate G-1d, ethyl 2-((cis)-3-(4-nitro-1H-pyrazol-1-yl)cyclobutyl)acetate (239 mg, 18% yield) as a colorless oil. Intermediate G-1a:

[0540] LCMS: [M+H] + =254.2.

[0541] 1 HNMR(400MHz,chloroform-d)δ ppm 1.28(t,J=7.1Hz,3H),2.36-2.45(m,2H),2.59(d,J=7.6Hz,2H),2.73-2.83(m,2H),2.85 -2.97(m,1H),4.16(q,J=7.1Hz,2H),4.89(quin,J=7.5Hz,1H),8.12(s,1H),8.18(s,1H).

[0542] Synthesis of (trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexane-1-carboxylate methyl ester (intermediate G-1b) [ka]

[0543] Step 1: To a solution of methyl cis-4-hydroxycyclohexanecarboxylate (3 g, 19 mmol) in CHCl (65 mL) was added EtN (7.66 mL, 56.9 mmol) and MsCl (1.91 mL, 24.7 mmol). After 3 h at room temperature, the reaction mixture was quenched with saturated aqueous NHCl and diluted with CHCl. ​​The organic layer was separated, dried over NaSO, filtered, and concentrated in vacuo to give methyl cis-4-methylsulfonyloxycyclohexanecarboxylate (4.5 g, 19 mmol, quant.) as a pale yellow solid, which was used in the next step without further purification.

[0544] 1 HNMR(400MHz,CDCl3)δ ppm 1.67-1.83(m,4H),1.87-1.98(m,2H),1.99-2.09(m,2H),2.35-2.45(m,1H),3.01(s,3H),3.68(s,3H),4.87-4.96(m,1H).

[0545] Step 2: To a solution of cis-methylsulfonyloxycyclohexanecarboxylate (4.26 g, 18 mmol) and 4-nitro-1H-pyrazole (1.7 g, 15.03 mmol) in DMF (20 mL) was added CsCO (6.86 g, 21.05 mmol). After 4 h at 90 °C, the reaction mixture was cooled to room temperature and partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was separated and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (3 ×) and brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by reverse-phase column chromatography (5% to 100% MeCN / water (containing 0.1% formic acid)) to obtain methyl (trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate G-1b) (1.24 g, 4.90 mmol, 33%) as a yellow solid.

[0546] 1HNMR(400MHz,CDCl3)δ ppm 1.60-1.72(m,2H),1.81(qd,J=12.6,2.7Hz,2H),2.19-2.33(m,4H),2.37-2.4 6(m,1H),3.71(s,3H),4.15(tt,J=11.7,3.8Hz,1H),8.08(s,1H),8.16(s,1H).

[0547] Synthesis of (cis)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexane-1-carboxylate methyl ester (intermediate G-1c) [ka]

[0548] Step 1: Under nitrogen, a solution of methyl trans-4-hydroxycyclohexanecarboxylate (100 mg, 0.63 mmol, 1 eq.) in CHCl (2 mL, 0.32 M) was cooled to 0 °C, followed by the addition of methanesulfonyl chloride (64 μL, 0.82 mmol, 1.3 eq.) and triethylamine (0.13 mL, 0.95 mmol, 1.5 eq.). After stirring at 0 °C for 2 h, the reaction was quenched by the addition of water. The layers were then separated, and the aqueous layer was extracted three times with CHCl. ​​The combined organic layers were washed twice with brine, dried over magnesium sulfate, filtered, and concentrated to give methyl trans-4-methylsulfonyloxycyclohexanecarboxylate (150 g, quantitative yield) as a pale yellow solid.

[0549] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.43-1.58(m,4H),1.88-2.08(m,4H),2.30-2.41(m,1H),3.17(s,3H),3.59(s,3H),4.53-4.62(m,1H).

[0550] Step 2: In a flame-dried round-bottom flask under nitrogen, a solution of methyl trans-4-methylsulfonyloxycyclohexanecarboxylate (150 mg, 0.64 mmol, 1 eq.), 4-nitro-1H-pyrazole (72 mg, 0.64 mmol, 1 eq.), and DMF (3 mL, 0.21 M) was stirred at room temperature for 5 minutes, after which Cs2CO3 (415 mg, 1.27 mmol, 2.0 eq.) was added. The resulting mixture was stirred at 90 °C for 16 hours. The reaction was quenched by the addition of water. Ethyl acetate was added, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were then washed once with water and once with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by reverse-phase column chromatography (5% to 100% MeOH / water with 0.1% formic acid). The fractions were combined and concentrated to give intermediate G-1c, methyl (cis)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (68.1 mg, 42% yield) as a tan solid.

[0551] LCMS: [M+H] + =254.4.

[0552] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.61-1.73(m,2H),1.89-1.96(m,4H),2.00-2.07(m,2H),2.70(quin,J=4.5Hz,1H),3.64(s,3H),4.25-4.38(m,1H),8.26(s,1H),8.91(s,1H).

[0553] Synthesis of (trans)-3-(4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carboxylate methyl ester (intermediate G-1e) [ka]

[0554] To a solution of 4-nitro-1H-pyrazole (1.04 g, 9.22 mmol), methyl cis-3-hydroxycyclobutanecarboxylate (800 mg, 6.15 mmol), and triphenylphosphine (8.22 g, 12.29 mmol) in anhydrous THF (15 mL) at 0 °C under nitrogen, a solution of diisopropyl azodicarboxylate (1.82 mL, 9.22 mmol) in THF (5 mL) was slowly added. The next morning, the reaction mixture was filtered, concentrated in vacuo, and purified by reverse-phase column chromatography (5% to 100% MeCN / water (containing 0.1% formic acid)). The collected fractions were concentrated to give methyl (trans)-3-(4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (Intermediate G-1e) (963 mg with 30% triphenylphosphine oxide, corresponding to 675 mg of the desired compound, 49% yield).

[0555] LCMS: [M+H] + =226.2.

[0556] 1 HNMR(400MHz,DMSO-d6)δ ppm 2.63-2.71(m,2H),2.76-2.85(m,2H),3.19-3.29(m,1H),3.66-3.70(m,3H),5.06-5.16(m,1H),8.34(s,1H),9.01(s,1H). [Table 116]

[0557] Synthesis of TBM-G: Step 2 [ka] A round-bottom flask was charged with ethyl 2-((trans)-3-(4-amino-1H-pyrazol-1-yl)cyclobutyl)acetate (391 mg, 1.75 mmol, 1 eq.), intermediate G-2a, 5,8-dibromoimidazo[1,2-a]pyrazine 5 (485 mg, 1.75 mmol, 1 eq.), and pivalic acid (2.68 g, 26.3 mmol, 15 eq.). The reaction was placed in a preheated oil bath at 100 °C for 45 min. The brown residue was quenched with saturated NaHCO solution (to pH 7–9) and extracted with MeTHF (3x). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give a dark red residue, which was then purified by reverse-phase column chromatography (5%–100% MeOH / water with 0.1% formic acid). The fractions were combined and concentrated to give intermediate G-3a, 2-((trans)-3-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclobutyl)ethyl acetate (533 mg, 70% yield) as a brown solid.

[0558] LCMS: [M+H] + =419.0, 421.0.

[0559] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.19(t,J=7.1Hz,3H),2.19(br t,J=8.7Hz,2H),2.56-2.66(m,5H),4.07(q,J=7.3Hz,2H),4.94-5.03(m,1H),7.59(s,1H) ),7.70(d,J=1.0Hz,1H),7.79(s,1H),7.99(d,J=1.2Hz,1H),8.17(s,1H),10.00(s,1H). [Table 117] [Table 118]

[0560] Synthesis of TBM-G: Step 3 [ka] In a sealed tube, intermediate D-4b, 2-(2,4-difluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (485 mg, 1.9 mmol, 1.5 eq.), intermediate G-3a, ethyl 2-((trans)-3-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclobutyl)acetate (533 mg, 1.3 mmol, 1 eq.), and NaHCO (320 mg, 3.8 mmol, 3 eq.) were added in 1,4-dioxane (3 mL, 0.32 M) and water (1 mL, 0.32 M). Nitrogen was bubbled through the reaction for 10 min. Next, Pd(PPh3)4 (220 mg, 0.19 mmol, 0.15 eq.) was added, and nitrogen was bubbled through for an additional 10 minutes. The resulting solution was stirred at 90 °C in a sealed tube under a nitrogen atmosphere for 18 hours. The reaction mixture was filtered through Celite, rinsed with EtOAc, and concentrated. The resulting residue was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The combined fractions were concentrated to give intermediate G-4a, ethyl 2-((trans)-3-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclobutyl)acetate (562 mg, 91% yield), as a yellow semisolid.

[0561] LCMS: [M+H] + =467.2.

[0562] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.19(t,J=7.1Hz,3H),2.20(br t,J=8.7Hz,2H),2.29(s,3H),2.55-2.69(m,5H),4.07(q,J=7.1Hz,2H),4.95-5.05(m ,1H),7.42-7.50(m,2H),7.58-7.64(m,3H),7.84(s,1H),8.23(s,1H),10.00(s,1H). [Table 119] [Table 120] [Table 121]

[0563] Synthesis of TBM-G: Step 4 [ka] To a stirred solution of intermediate G-4a, ethyl 2-((trans)-3-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclobutyl)acetate (562 mg, 1.2 mmol, 1 eq.) in THF (8 mL) was added LiAlH (137 mg, 3.61 mmol, 3 eq.) at 0 °C and allowed to stand overnight. The reaction was quenched at 0 °C with water (0.5 mL) and 1 N NaOH (0.5 mL) and stirred at room temperature for 20 min. The precipitate was filtered, and the filtrate was concentrated to give TBM-51, 2-((trans)-3-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclobutyl)ethan-1-ol (451 mg, 65% yield) as a pale yellow oil, which was used without further purification.

[0564] LCMS: [M+H] + =425.2. [Table 122] [Table 123]

[0565] Example S17 General procedure for TBM-H [ka] Synthesis of TBM-H: Step 1 [ka] In a sealed tube, intermediate D-4m, benzyl A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (146.93 mg, 0.59 mmol), intermediate H-2 (2-((trans)-4-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (200 mg, 0.49 mmol), and KPO (313 mg, 1.48 mmol) in THF (3.7 mL) and water (1.3 mL) was purged with nitrogen for 10 minutes; then Pd(dtbpf)Cl (32 mg, 0.05 mmol) was added, and the mixture was again purged with nitrogen for 10 minutes. The mixture was then stirred at 90 °C for 16 hours. The mixture was cooled to room temperature, and water was added. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by reverse-phase column chromatography (5 to 100% ACN / water (containing 0.1% formic acid)) to afford TBM-57, 2-((trans)-4-(4-((5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (137.3 mg, 63% yield), as an orange oil.

[0566] LCMS: [M+H] + =447.2.

[0567] 1HNMR (400MHz, DMSO-d6) δ ppm 1.38(q, J=6.4Hz, 2H), 1.64-1.76(m, 2H), 1.79-1.88(m, 4H), 1.99-2.06(m, 4H), 2.75(t, J=6.2Hz, 2H), 3.17(d, J=3.7Hz, 2H), 3.43-3.48(m, 2H), 4.04-4.13(m, 2H) ), 4.16(t, J=6.0Hz, 2H), 4.33-4.38(m, 1H), 7.30(s,1H), 7.61(d, J=1.2Hz, 1H), 7.74(s,1H), 7.78(d, J=1.2Hz, 1H), 7.80(s,1H), 8.19-8.20(m, 1H), 9.76(s,1H). [Table 124]

[0568] Synthesis of 2-((trans)-4-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (Intermediate H-2) [ka]

[0569] Step 1: A solution of intermediate G-1b, (trans)-methyl 4-(4-nitro-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (7.38 g, 29.1 mmol, 1.0 equiv) was dissolved in 2:1 MeOH / THF (150 mL) and cooled to 0 °C. Calcium chloride (6.47 g, 58.3 mmol, 2.0 equiv) and sodium borohydride (4.41 g, 117 mmol, 4.0 equiv) were then added sequentially. The reaction mixture was stirred overnight at room temperature. Water (50 mL) and brine (50 mL) were added to the mixture while stirring vigorously. The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by normal-phase column chromatography (0% to 100% EtOAc / heptane). The fractions were collected and concentrated to give ((trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)methanol (3.3 g, 14.6 mmol, 50% yield) as a yellow solid.

[0570] LCMS: [M+H] + =276.2.

[0571] 1 HNMR (400MHz, DMSO-d6) δ ppm 1.08 (qd, J=12.8, 3.2Hz, 2H), 1.34-1.50 (m, 1H), 1.75 (qd, J=12.5, 3.5Hz, 2H), 1.86 (br d.

[0572] Step 2: Methanesulfonyl chloride (1.25 mL, 16.1 mmol, 1.1 equiv) was added dropwise to a cooled (0 °C) solution of ((trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)methanol (3.3 g, 14.6 mmol, 1.0 equiv) and triethylamine (2.66 mL, 19.0 mmol, 1.3 equiv) in DCM (73 mL). The reaction mixture was stirred at room temperature for 2 h. Water (100 mL) was added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with DCM (3 x 50 mL). The organic layers were combined and diluted with 1.0 M HCl. (aq) and brine (50 mL), then dried over MgSO, filtered, and evaporated under reduced pressure to give ((trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)methyl methanesulfonate (4.25 g, 14.0 mmol, 96% yield) as a yellow solid, which was used without further purification.

[0573] LCMS: [M+H] + =304.2.

[0574] 1 HNMR (400MHz, DMSO-d6) δ ppm 1.16-1.29(m, 2H), 1.66-1.83(m, 3H), 1.88(br d, J=12.0Hz, 2H), 2.09(br dd, J=12.8, 3.5Hz, 2H), 3.18(s,3H), 4.08(d, J=6.2Hz, 2H), 4.24(tt, J=11.8, 3.9Hz, 1H), 8.26(s,1H), 8.92(s,1H).

[0575] Step 3: A solution of ((trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)methyl methanesulfonate (4.25 g, 14.0 mmol, 1.0 equiv) and sodium cyanide (1.58 g, 32.2 mmol, 2.3 equiv) in DMSO (45 mL) was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature, and then water (100 mL) and EtOAc (50 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were diluted with saturated NaHCO3(aq) (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-((trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)acetonitrile (3.1 g, 13.2 mmol, 94% yield) as an orange oil, which was used without further purification.

[0576] LCMS: [M+H] + =285.2.

[0577] 1 HNMR (400MHz, DMSO-d6) δ ppm 1.26 (qd, J=12.7, 3.3Hz, 2H), 1.63-1.75 (m, 1H), 1.75-1.86 (m, 2H), 1.89 (br d, J=12.0Hz, 2H), 2.03-2.13(m, 2H), 2.51-2.55(m, 2H), 4.24(tt, J=11.8, 3.9Hz, 1H), 8.26(s,1H), 8.90(s,1H).

[0578] Step 4: DIBAL-H 1.0M / DCM (39.7 mL, 39.7 mmol, 3.0 equiv) was added dropwise to a solution of 2-((trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)acetonitrile (3.1 g, 13.2 mmol, 1.0 equiv) / DCM (66 mL) cooled to -78 °C (dry ice / acetone bath) under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 2.5 h. Aqueous Rochelle salt solution (50 mL) was carefully added to the reaction mixture and stirred overnight at room temperature. EtOAc (150 mL) was added, and the organic layer was then extracted with 1.0 M HCl. (aq) (3x20 mL), dried over MgSO4, filtered and evaporated under reduced pressure to give 2-((trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)acetaldehyde (3.42 g, 12.6 mmol, 95% yield) as an orange oil which was used without further purification.

[0579] LCMS: [M+H] + =238.2.

[0580] 1 HNMR (400MHz, DMSO-d6) δ ppm 1.12-1.20(m, 2H), 1.74-1.84(m, 5H), 2.02-2.06(m, 2H), 2.37(dd, J=6.6, 1. 8Hz, 2H), 4.19-4.26(m, 1H), 8.25(s, 1H), 8.91(s, 1H), 9.68(t, J=1.9Hz, 1H).

[0581] Step 5: Sodium borohydride (998 mg, 26.4 mmol, 2.0 equiv) was added in one portion to a cooled suspension (0 °C) of 2-((trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)acetaldehyde (3.13 g, 13.2 mmol, 1.0 equiv) in methanol (66 mL). The reaction mixture was stirred at room temperature overnight. Water (80 mL) was added to the reaction mixture, and then the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography (0% to 100% EtOAc / heptane) to give 2-((trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (1.81 g, 7.56 mmol, 57% yield) as a pale yellow solid.

[0582] LCMS: [M+H] + =240.2.

[0583] 1 HNMR (400MHz, DMSO-d6) δ ppm 1.02-1.14(m, 2H), 1.36(q, J=6.6Hz, 2H), 1.39-1.53(m, 1H), 1.67-1.80(m, 2H), 1.84(br d.

[0584] Step 6: 2-((trans)-4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (1.81 g, 7.56 mmol, 1.0 equiv) was dissolved in ethyl acetate (38 mL), and the solution was degassed by bubbling nitrogen through it for 20 minutes under sonication. Pd / C 10% w / w (1.61 g, 1.51 mmol, 0.2 equiv) was added, and the mixture was degassed by bubbling nitrogen through it for an additional 20 minutes under sonication. The nitrogen balloon was replaced with one filled with hydrogen, and hydrogen was bubbled through the reaction mixture for 10 minutes. The reaction mixture was then stirred overnight under a static hydrogen atmosphere. The reaction mixture was filtered through Celite, and the Celite was washed thoroughly with EtOAc and MeOH. The solvent was evaporated under reduced pressure to give intermediate H-1, 2-((trans)-4-(4-amino-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (1.45 g, 6.92 mmol, 91% yield) as a purple solid, which was used without further purification.

[0585] LCMS: [M+H] + =210.2.

[0586] 1 HNMR (400MHz, DMSO-d6) δ ppm 0.98-1.12(m, 2H), 1.31-1.37(m, 2H), 1.38-1.47(m, 1H), 1.60(br dd, J=12.3, 3.3Hz, 2H), 1.79(br d, J=12.7Hz, 2H), 1.88-1.98(m, 2H), 3.38-3.52(m, 2H), 3.58-4.19(br s, 2H), 3.87(tt, J=11.9, 3.8Hz, 1H), 4.33(t, J=5.1Hz, 1H), 6.87(s,1H), 7.02(s,1H).

[0587] Step 7: Intermediate D-1a, 5,8-dibromoimidazo[1,2-a]pyrazine (2.41 g, 8.69 mmol) and pivalic acid (2.13 g, 20.85 mmol) were added sequentially to a solution of intermediate H-1, 2-((trans)-4-(4-amino-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (2.0 g, 9.56 mmol) in 1,4-dioxane (43.44 mL). The mixture was heated to 95 °C in an oil bath overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and HO, and the aqueous layer was adjusted to pH 9 with 2 M NaOH. The aqueous layer was extracted with EtOAc (3x), and the combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated. The crude residue was purified by reverse-phase column chromatography (5% to 100% MeCN / water (containing 0.1% formic acid)). The collected fractions were concentrated to give intermediate H-2, 2-((trans)-4-(4-((5-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (1.28 g, 51% yield), as a brown solid.

[0588] LCMS: [M+H] + =405.0.

[0589] 1 HNMR (400MHz, DMSO-d6) δ ppm 1.11(br dd, J=14.3, 11.4Hz, 2H), 1.37(q, J=6.8Hz, 2H), 1.41-1.51(m, 1H), 1.70(qd, J=12.5, 3.3Hz, 2H), 1.83(br d, J=13.7Hz, 2H), 2.02(br d, J=12.2Hz, 2H), 3.39-3.52(m, 2H), 4.08(tt, J=11.9, 3.9Hz, 1H), 4.34(t, J=5.1Hz, 1H), 7.5 9(s,1H), 7.70(d, J=1.0Hz, 1H), 7.73(s,1H), 7.98(d, J=1.0Hz, 1H), 8.14(s,1H), 9.97(s,1H). [Table 125] [Table 126]

[0590] Example S18 Procedure for TBM-59 Synthesis of 2-((trans)-4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (TBM-59) [ka]

[0591] Step 1: In a sealed tube, intermediate H-1 (2-((trans)-4-(4-amino-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol) (250 mg, 1.19 mmol, 1.0 equiv.), intermediate D-1b (5-chloro-8-iodoimidazo[1,2-a]pyridine) (332.6 mg, 1.19 mmol, 1.0 equiv.), rac-BINAP (74.6 mg, 0.120 mmol, 0.1 equiv.), and cesium carbonate (1.95 g, 5.97 mmol, 5.0 equiv.) were combined with toluene (9.5 mL). Nitrogen was then bubbled through the mixture under sonication for 30 min. Pd(OAc)2 (26.9 mg, 0.120 mmol, 0.1 equiv.) was then quickly added, and nitrogen was continued to be bubbled through for an additional 10 min. The tube was sealed, and the reaction mixture was stirred at 120 °C for 4 h. The reaction mixture was cooled to room temperature, and the volatiles were evaporated. The crude material was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). Fractions were collected and concentrated to give 2-((trans)-4-(4-((5-chloroimidazo[1,2-a]pyridin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (275 mg, 0.739 mmol, 62% yield) as a yellow semi-solid.

[0592] LCMS: [M+H] + =360.2.

[0593] 1 HNMR(400MHz、CDCl3)δ ppm 1.10-1.24(m、2H)、1.56(br t、J=4.6Hz、3H)、1.78(qd、J=12.6、3.1Hz、2H)、1.97(br d、J=12.5Hz、2H)、2.01(s,1H)、2.24(br d、J=11.6Hz、2H)、3.74(br t、J=6.3Hz、1H)、3.77-3.98(m、2H)、4.10(tt、J=12.0、3.7Hz、1H)、6.53(d、J=8.2Hz、1H)、6.79(d、J=8.1Hz、1H)、7.49(s,1H)、7.52-7.67(m、3H)、7.75(d、J=1.1Hz、1H)、8.19(br s,1H).

[0594] Step 2: In a sealed tube, 2-((trans)-4-(4-((5-chloroimidazo[1,2-a]pyridin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (275 mg, 0.764 mmol, 1.0 equiv), 2-(2,4-difluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate D-4b) (233 mg, 0.917 mmol, 1.2 equiv), and sodium bicarbonate (232 mg, 2.29 mmol, 3.0 equiv) were combined with 1,4-dioxane (0.6 mL) and water (0.2 mL), and then nitrogen was bubbled through the mixture under sonication for 30 minutes. Pd(PPh3)4 (177 mg, 0.153 mmol, 0.2 equiv) was then added quickly, and nitrogen was continuously bubbled through for an additional 10 minutes. The tube was sealed, and the reaction mixture was stirred at 110 °C for 18 hours. The reaction mixture was cooled to room temperature, and then the volatiles were evaporated. The crude residue was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). Fractions were collected and concentrated to give TBM-59, 2-((trans)-4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)ethan-1-ol (135 mg, 0.282 mmol, 37% yield), as a brown semisolid.

[0595] LCMS: [M+H] + =452.2.

[0596] 1HNMR (400MHz, DMSO-d6) δ ppm 1.03-1.17(m, 2H), 1.38(q, J=6.6Hz, 2H), 1.41-1.55(m, 1H), 1.75(qd, J=12.5, 3.2Hz, 2H), 1.85(br d, J=11.9Hz, 2H), 2.05(br d, J=10.6Hz, 2H), 2.28(s,3H), 3.40-3.54(m, 2H), 4.08(tt, J=11.9, 3.9Hz, 1H), 4.35(t, J=5.0Hz, 1H), 6.51(d, J=7.8Hz) , 1H), 6.74(d, J=7.7Hz, 1H), 7.41(t, J=10.0Hz, 1H), 7.45(d, J=1.8Hz, 1H), 7.49-7.58(m, 3H), 7.87(s,1H), 8.10(s,1H).

[0597] 19 FNMR (377MHz, DMSO-d6) δ ppm -112.35(q, J=9.1Hz, 1F), -111.89(q, J=8.2Hz, 1F).

[0598] Example S19 TBM-60 Procedure Synthesis of 5-(2,4-difluoro-5-methylphenyl)-N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-N-methylimidazo[1,2-a]pyrazin-8-amine (TBM-60) [ka]

[0599] Step 1: To a solution of TBM-2, 5-(2,4-difluoro-5-methylphenyl)-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (bis-HCl salt, 1.0 g, 2.07 mmol, 1 equiv.) in DCM (4.5 mL, 0.42 M) and DMSO (0.40 mL, 0.42 M) was added 2,2-dimethoxyacetaldehyde (60% w / w in water, 0.63 mL, 4.14 mmol, 2 equiv.) and NaBH(OAc)3 (878.76 mg, 4.15 mmol, 2 equiv.). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated, and the residue was purified by reverse-phase column chromatography (5%-40% MeOH / water (containing 0.1% formic acid)). The fractions were collected and concentrated to give 5-(2,4-difluoro-5-methylphenyl)-N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (936 mg, 91% yield) as a tan solid.

[0600] LCMS: [M+H] + =498.2.

[0601] 1 HNMR (400MHz, DMSO-d6) δ ppm 1.87-2.02(m, 4H), 2.18-2.27(m, 2H), 2.29(s,3H), 3.00(br d, J=11.7Hz, 2H), 3.27(s, 6H), 4.08-4.17(m, 1H), 4.50(t, J=5.0Hz, 1H), 7.42-7. 48(m, 2H), 7.58-7.65(m, 3H), 7.80(s,1H), 8.14(s,1H), 8.23(s,1H), 9.98(s,1H).

[0602] 19 FNMR (377MHz, DMSO-d6) δ ppm -112.17(q, J=9.5Hz, 1F), -111.25(q, J=8.2Hz, 1F).

[0603] Step 2: To a solution of 5-(2,4-difluoro-5-methylphenyl)-N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (250 mg, 0.5000 mmol, 1.0 equiv.) in THF (5 mL) was added NaH (24.12 mg, 0.6000 mmol, 1.2 equiv.) at 0 °C. The reaction was stirred at room temperature for 15-20 minutes. Then, MeI (0.03 mL, 0.5300 mmol, 1.05 equiv.) was added. The reaction mixture was stirred at room temperature overnight. LCMS showed a mixture of starting material and three products, two of which had the expected mass. Mel (0.03 mL, 0.5300 mmol, 1.05 equiv.) was added, and after 2 h, the reaction was quenched with water and extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reverse-phase column chromatography (5-100% MeCN / water with 0.1% formic acid) to give the product (LCMS high pH purity: 80%). The mixture was further purified by reverse-phase column chromatography (0-100% MeCN / water with pH 10 buffer) to give TBM-60, 5-(2,4-difluoro-5-methylphenyl)-N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-N-methylimidazo[1,2-a]pyrazin-8-amine (40 mg, 16%) as a white solid.

[0604] LCMS: [M+H] + =512.3.

[0605] 1 HNMR (400MHz, DMSO-d6) δ ppm 1.97(br s, 4H), 2.16-2.24(m, 2H), 2.28(br s,3H), 2.43-2.47(m, 2H), 2.94-3.04(m, 2H), 3.27(br s, 6H), 3.97(br s,3H), 4.03-4.15(m, 1H), 4.44-4.54(m, 1H), 7.38-7.50(m, 2H), 7.55-7.68(m, 4H), 8.04-8.12(m, 1H).

[0606] 19 FNMR (377MHz, DMSO-d6) δ ppm -112.15- -111.82(m, 1F), -111.14- -110.99(m, 1F).

[0607] Procedure for compounds 1 to 120 Example S20 Representative Procedure for LDD-I [ka] Step 1: TBM-1 (68.0 mg, 0.16 mmol) was dissolved in a mixture of DMF (0.80 mL) and DIPEA (113 μL, 0.65 mmol). 2-Bromoacetic acid (14.0 μL, 0.19 mmol) was then added, and the solution was stirred at room temperature. HPLC showed complete conversion to the product and slight impurities. The mixture was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The combined fractions were evaporated to give 2-(4-(4-((5-(m-tolyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)acetic acid (54 mg, 77% yield) as a white solid.

[0608] LCMS: [M+H] + =433.2.

[0609] 1 HNMR (400MHz, DMSO-d6) δ ppm 1.99-2.08(m, 4H), 2.41(s,3H), 2.53-2.59(m, 2H), 3.10(br d, J=11.5Hz, 3H), 4.16-4.24(m, 1H), 7.31-7.34(m, 1H), 7.43(s, 1H), 7.45-7.52(m, 3H) ), 7.64(d, J=1.0Hz, 1H), 7.81(s,1H), 7.89(d, J=1.0Hz, 1H), 8.25(s,1H), 9.90(s,1H).

[0610] Step 2: To a solution of CBM-1 (53.4 mg, 0.12 mmol), DIPEA (102 μL, 0.59 mmol), and 2-(4-(4-((5-(m-tolyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)acetic acid (53 mg, 0.12 mmol) in DMF (1 mL) was added PyAOP (61 mg, 0.12 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was purified by reverse-phase column chromatography (5% to 100% MeCN / water (containing 0.1% formic acid)). The fractions were collected and evaporated to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(4-((5-(m-tolyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)acetyl)piperazin-1-yl)isoindoline-1,3-dione (22.4 mg, 25% yield, formate salt) as a pale yellow solid.

[0611] LCMS: [M+H] + =756.2.

[0612] 1 HNMR(400MHz, DMSO-d6)δ ppm 1.90-2.06(m, 5H), 2.23(br. t, J=10.4Hz, 2H), 2.40(s,3H), 2.53-2.62(m, 2H), 2.83-2.90(m, 1H), 2.92-2.99(m, 2H), 3.25(s,2H), 3.46-3.51(m, 2H), 3.53-3 .59(m, 2H), 3.59-3.65(m, 2H), 3.74-3.80(m, 2H), 4.09-4.19(m, 1H), 5.07(dd, J=12.8, 5.5Hz, 1H), 7.25-7.34(m, 2H), 7.38(br. d, J=1.0Hz, 1H), 7.42(s,1H), 7.44-7.47(m, 2H), 7.50(br. s, 1H), 7.64 (s, 1H), 7.70 (d, J=8.3Hz, 1H), 7.80 (s, 1H), 7.89 (s, 1H), 8.23 ​​(s, 1H), 9.88 (s, 1H), 11.08 (s, 1H). [Table 127] [Table 128] [Table 129] [Table 130] [Table 131] [Table 132]

[0613] Example S21 General Procedure for LDD-J [ka] Step 1: To a solution of TBM-2, 5-(2,4-difluoro-5-methylphenyl)-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine bishydrochloride (1.0 g, 2.07 mmol, 1 equiv.) in DCM (4.5 mL, 0.42 M) and DMSO (0.40 mL, 0.42 M) was added 2,2-dimethoxyacetaldehyde (60% w / w) in water (0.63 mL, 4.14 mmol, 2 equiv.) and NaBH(OAc)3 (879 mg, 4.15 mmol, 2 equiv.). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated, and the residue was purified by reverse-phase column chromatography (5% to 100% MeOH / water (containing 0.1% formic acid)). The fractions were combined and concentrated to give 5-(2,4-difluoro-5-methylphenyl)-N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (936 mg, 91% yield) as a tan solid.

[0614] LCMS: [M+H] + =498.2.

[0615] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.87-2.02(m,4H),2.18-2.27(m,2H),2.29(s,3H),3.00(br d,J=11.7Hz,2H),3.27(s,6H),4.08-4.17(m,1H),4.50(t,J=5.0Hz,1H),7.42-7. 48(m,2H),7.58-7.65(m,3H),7.80(s,1H),8.14(s,1H),8.23(s,1H),9.98(s,1H).

[0616] 19 FNMR(377MHz,DMSO-d6)δ ppm -112.17(q,J=9.5Hz,1F),-111.25(q,J=8.2Hz,1F).

[0617] Step 2: To a round-bottom flask was added 5-(2,4-difluoro-5-methylphenyl)-N-(1-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (871 mg, 1.75 mmol, 1 equiv.), 4 M HCl / dioxane (13.14 mL, 52.57 mmol, 30 equiv.), and water (0.48 mL, 4.1 M). The reaction was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was co-evaporated with MeCN (3x) to give 2-(4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)acetaldehyde (880 mg) as the HCl salt as a yellow solid.

[0618] LCMS: [M+H2O+H] + =470.2.

[0619] 1HNMR(400MHz,DMSO-d6)δ ppm 2.20-2.41(m,7H),3.29-3.42(m,4H),3.60-3.76(m,2H),4.35-4.62(m,1H),4.87-5.03(m,1H),7.45-7.54 (m,2H),7.61(t,J=8.2Hz,1H),7.74-7.80(m,1H),7.82(d,J=4.6Hz,2H),8.24(s,1H),9.92-10.11(m,1H).

[0620] 19 FNMR (377MHz, DMSO-d6) δ ppm -112.07(s, 1F), -110.60(s, 1F).

[0621] Step 3: To a solution of 2-(4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)acetaldehyde hydrochloride (100 mg, 0.20 mmol, 1 equiv.), CBM-2 (3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione) (56 mg, 0.20 mmol, 1 equiv.), and DIPEA (0.25 mL, 1.43 mmol, 7 equiv.) in DCM (0.73 mL, 0.14 M) and DMSO (0.73 mL, 0.14 M) under N atmosphere, NaBH(OAc) (87 mg, 0.4100 mmol, 2 equiv.) was added. The reaction mixture was stirred at room temperature for 40 h. The solvent was evaporated, and the residue was purified by reverse-phase column chromatography (5% to 95% MeCN / water (containing 0.1% formic acid)). The combined fractions were concentrated to give Example 8, 3-(4-(4-(2-(4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (37 mg, 25% yield) as a white solid.

[0622] LCMS: [M+H] + =709.3.

[0623] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.86-2.05(m,5H),2.09-2.18(m,3H),2.29(s,3H),2.42-2.48(m,1H),2.54-2.69(m,6H),3.01(br d,J=11.2Hz,2H),3.11(br s,4H),3.72(dd,J=11.2,5.1Hz,1H),4.08-4.18(m,1H),6.89(d,J=8.6Hz,2H),7.04(d,J=8.6Hz, 2H),7.41-7.48(m,2H),7.58-7.65(m,3H),7.80(s,1H),8.23(s,1H),9.98(s,1H),10.77(s,1H).

[0624] 19 FNMR(377MHz,DMSO-d6)δ ppm -112.16(q,J=8.6Hz,1F),-111.26(q,J=10.0Hz,1F). Table 133 Table 134 Table 135 Table 136 Table 137 Table 138 Table 139 Table 140 Table 141 Table 142 Table 143 Table 144 Table 145 Table 146 Table 147 Table 148 Table 149 Table 150 Table 151 Table 152 Table 153 Table 154 Table 155 Table 156 Table 157 Table 158 Table 159 Table 160 Table 161 Table 162 Table 163 Table 164 Table 165 Table 166 Table 167 Table 168 Table 169 Table 170 Table 171 Table 172 Table 173 Table 174

[0625] Example S22 Representative Procedure for LDD-K

change

[0626] Step 2: To a solution of 2-(4-(4-((5-ethylimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)acetaldehyde (27 mg, 0.07 mmol, 1 eq.) and DIPEA (0.06 mL, 0.35 mmol, 5 eq.) in CHCl (0.69 mL) was added 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione dihydrochloride (29 mg, 0.08 mmol, 1.2 eq.) and NaBH(OAc) (29 mg, 0.14 mmol, 2 eq.). The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated, and the residue was purified by reverse-phase column chromatography (5% to 100% MeCN / water (containing 0.1% formic acid)). The combined fractions were concentrated and purified again by reverse-phase column chromatography (5% to 100% MeCN / water). The combined fractions were concentrated and lyophilized to give Example 70, 3-(4-(4-(2-(4-(4-((5-ethylimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (5 mg, 11% yield) as an off-white solid.

[0627] LCMS: [M+H]+ =611.4.

[0628] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.29(t,J=7.3Hz,3H),1.84-2.05(m,6H),2.07-2.19(m,3H),2.41-2.47(m,3H),2.52-2.65(m,6H),2.84(q,J=7.6Hz,2H),3.00(br d,J=11.7Hz,2H),3.09-3.13(m,4H),3.72(dd,J=10.8,4.6Hz,1H),4.04-4.16(m,1H),6.89(d,J=8.8Hz,2H),7.05(d,J=8.8Hz,2H), 7.24(s,1H),7.64(d,J=1.2Hz,1H),7.74-7.75(m,1H),7.96(d,J=1.0Hz,1H),8.18(s,1H),8.19(s,1H),9.58(s,1H),10.77(s,1H). Table 175 Table 176 Table 177 Table 178 Table 179 Table 180 Table 181 Table 182

[0629] Example S23 Representative Procedure for LDD-L

change

[0630] LCMS: [M+H] + =451.2.

[0631] Step 2: To a solution of 2-((trans)-4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)acetaldehyde (330 mg, 0.73 mmol, 1 eq.) in DCM (7.5 mL) was added CBM-2 (3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione (380 mg, 1.1 mmol, 1.5 equiv., bisHCl salt) and DIPEA (0.38 mL, 2.2 mmol, 3 eq.) at room temperature. NaBH(OAc) (310 mg, 1.47 mmol, 3 eq.) was then added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 20 h. The DCM was removed under reduced pressure, and the residue was purified by reverse-phase column chromatography (5% to 100% MeCN / water (containing 0.1% formic acid)). The combined fractions were concentrated and lyophilized to afford 3-(4-(4-(2-((trans)-4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (Compound 11) (427 mg, 80% yield) as a white solid, as the intact formate salt.

[0632] LCMS: [M+H] + =708.3.

[0633] 1HNMR(400MHz,DMSO-d6)δ ppm 1.07-1.21(m,2H),1.32-1.46(m,3H),1.73(qd,J=12.3,3.1Hz,2H),1.84-1.92(m,2H),1.95-2.19(m,4H),2.29(s,3H),2.39(br t,J=7.2Hz,2H),2.41-2.49(m,2H),2.52-2.54(m,3H),2.58-2.67(m,1H),3 .08-3.15(m,4H),3.72(dd,J=10.9,5.0Hz,1H),4.10(tt,J=11.9,3.8Hz,1H) ,6.89(d,J=8.8Hz,2H),7.05(d,J=8.8Hz,2H),7.42-7.48(m,2H),7.58-7.6 3(m,3H),7.78(s,1H),8.14(s,1H),8.21(s,1H),9.96(s,1H),10.77(s,1H).

[0634] 19 FNMR(377MHz,DMSO-d6)δ ppm -112.17(q,J=8.2Hz,1F),-111.27(q,J=9.1Hz,1F). Table 183 Table 184 Table 185 Table 186 Table 187 Table 188 Table 189 Table 190 Table 191 Table 192 Table 193 Table 194 Table 195 Table 196 Table 197 Table 198 Table 199 Table 200 Table 201 Table 202 Table 203 Table 204 Table 205

[0635] Example S24 Representative Procedure for LDD-M

change

[0636] LCMS: [M+H] + =332.2.

[0637] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.95-2.05(m,1H),2.06-2.20(m,1H),2.41-2.47(m,1H),2.58-2.67(m,1H),2.68-2.75(m,4H),3.12-3.17(m ,4H),3.21(s,2H),3.73(dd,J=11.0,4.9Hz,1H),6.89(d,J=8.6Hz,2H),7.05(d,J=8.6Hz,2H),10.77(s,1H).

[0638] Step 2: To a solution of 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)acetic acid (45 mg, 0.14 mmol, 1 eq.) in DMF (0.68 mL) at room temperature, DIPEA (0.24 mL, 1.36 mmol, 10 eq.) and TBM-2, 5-(2,4-difluoro-5-methylphenyl)-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine dihydrochloride (92 mg, 0.19 mmol, 1.4 eq.) were added. The resulting solution was stirred at room temperature for 10 minutes. PyAOP (92 mg, 0.18 mmol, 1.3 eq.) was then added in one portion. The reaction mixture was stirred at room temperature for 2.5 hours. The crude mixture was purified by reverse-phase column chromatography (5% to 100% MeCN / water (containing 0.1% formic acid)). The combined fractions were concentrated and purified again by preparative LCMS to give 3-(4-(4-(2-(4-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (Compound 23) (25 mg, 24% yield) as a white solid.

[0639] LCMS: [M+H] + =723.4.

[0640] 1HNMR(400MHz, DMSO-d6) δ ppm 1.64 - 1.78 (m, 1H), 1.89 - 2.17 (m, 5H), 2.29 (s, 3H), 2.40 - 2.48 (m, 1H), 2.54 - 2.66 (m, 5H), 2.70 - 2.81 (m, 1H), 3.11 - 3.22 (m, 6H), 3.34 - 3.41 (m, 1H), 3.70 (dd, J = 11.0, 4.9 Hz, 1H), 4.20 (br d, J = 12.7 Hz, 1H), 4.41 - 4.51 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 7.42 - 7.48 (m, 2H), 7.58 - 7.63 (m, 3H), 7.80 (s, 1H), 8.24 (s, 1H), 10.00 (s, 1H), 10.76 (s, 1H).

[0641] 19 FNMR(377MHz, DMSO-d6) δ ppm -112.23 - -112.05 (m, 1F), -111.29 - -111.14 (m, 1F).

Table 206

Table 207

[0642] Example S25 Representative Procedure for LDD-N

Chem.

[0643] LCMS: [M+H] + =503.2.

[0644] 1 HNMR(400MHz,DMSO-d6)δ ppm 1.85-1.93(m,2H),2.12-2.22(m,3H),2.30(s,3H),2.54-2.61(m,2H),3.19(s,3H),4.20(t,J=6.4Hz,2H),4.66 -4.79(m,1H),7.42-7.50(m,2H),7.59-7.66(m,3H),7.80-7.86(m,1H),8.22-8.26(m,1H),9.96-10.03(m,1H).

[0645] Step 2: In a flask under N2 atmosphere, 2-((cis)-3-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclobutyl)ethyl methanesulfonate (42 mg, 0.08 mmol), CBM-2 (3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione) (39 mg, 0.13 mmol), 18-crown-6 (11 mg, 0.04 mmol), and K2CO3 (24 mg, 0.17 mmol) were dissolved in DMF (2 mL). The reaction was then stirred at 70 °C for 3 h, and LCMS showed 15% conversion. The reaction was stopped, concentrated, and purified by reverse-phase column chromatography (5%-50% MeCN / 0.02 M HCl aqueous solution). The fractions were collected and further purified by preparative HPLC (C18, MeCN / HCl 0.02M as eluent) to give 3-(4-(4-(2-((cis)-3-(4-((5-(2,4-difluoro-5-methylphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)cyclobutyl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (compound 96) (8.6 mg, 15% yield) as a pale yellow semi-solid.

[0646] LCMS: [M+H] + =680.4, [M+2H] 2+ =340.7.

[0647] 1HNMR(400MHz,DMSO-d6)δ ppm 1.91-2.12(m,5H),2.12-2.23(m,3H),2.26-2.36(m,4H),2.55-2.70(m,4H),3.04-3.19(m,6H),3.54-3.61(m,3H), 4.70-4.80(m,1H),6.97(d,J=8.8Hz,2H),7.11(d,J=8.6Hz,2H),7.45-7.50(m,2H),7.60(t,J=8.3Hz,1H),7.72(br s,1H),7.76(s,1H),7.82(s,1H),8.23(s,1H),10.33-10.47(m,2H),10.80(s,1H). [Table 208] [Table 209]

[0648] Example S26 Representative Procedure for LDD-O [ka] Step 1: To a solution of CBM-2, 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione dihydrochloride (500 mg, 1.44 mmol) in DCM (14.4 mL), 2,2-dimethoxyacetaldehyde (60% w / w in water, 0.33 mL, 2.17 mmol) and NaBH(OAc)3 (0.61 g, 2.89 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. The suspension was then concentrated to dryness and purified by reverse-phase column chromatography (5% to 100% MeCN / water (containing 0.1% formic acid)). Collected fractions were concentrated to afford 3-(4-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (408 mg, 73% yield) as a tan solid.

[0649] LCMS: [M+H] + =362.2.

[0650] 1HNMR(400MHz,DMSO-d6)δ ppm 1.92-2.06(m,1H),2.06-2.21(m,1H),2.42-2.49(m,3H),2.55-2.60(m,4H),2.60-2.70(m,1H),3.04-3.14(m,4H),3.27 (s,6H),3.72(dd,J=11.0,4.9Hz,1H),4.52(t,J=5.1Hz,1H),6.88(d,J=8.8Hz,2H),7.05(d,J=8.8Hz,2H),10.77(s,1H).

[0651] Step 2: To a flask containing 3-(4-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (147 mg, 0.410 mmol) was added 4.0 M HCl / 1,4-dioxane (3.05 mL, 12.2 mmol), followed by water (0.050 mL). The reaction was stirred at room temperature for 5 h. The mixture was then concentrated to dryness, chased with MeCN (3x), and dried under vacuum to give 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)acetaldehyde dihydrochloride (189 mg, 99% yield) as a tan solid.

[0652] LCMS: [M+H] + =316.2

[0653] Step 3: To a suspension of TBM-21, 5,6-dimethyl-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (95 mg, 0.31 mmol) and 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)acetaldehyde dihydrochloride (181 mg, 0.40 mmol) in DCM (4.07 mL) was added DIPEA (0.21 mL, 1.22 mmol). The mixture was stirred for 10 min, then NaBH(OAc) (84 mg, 0.40 mmol) was added. Stirring was continued for 18 h, after which additional aldehyde (95 mg, 0.310 mmol) and NaBH(OAc) (84 mg, 0.40 mmol) were added. After an additional 18 h, the reaction mixture was concentrated and purified by reverse-phase column chromatography (5% to 100% MeCN / water (with 0.1% formic acid)), followed by preparative HPLC to afford 3-(4-(4-(2-(4-(4-((5,6-dimethylimidazo[1,2-a]pyrazin-8-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (Compound 84) (6.9 mg, 3% yield) as an off-white solid.

[0654] LCMS: [M+H] + =611.4.

[0655] 1HNMR(400MHz,DMSO-d6)δ ppm 1.86-2.04(m,5H),2.07-2.18(m,3H),2.37(s,3H),2.44(s,3H),2.53-2.58(m,4H),2.58-2.65(m,1H),3.00(br d,J=12.2Hz,2H), 3.09-3.13(m,4H), 3.72(dd,J=11.0,4.9Hz,1H), 4.04-4.17(m,1H), 6.89(d,J=8.8Hz,2H), 7.05(d,J=8.6Hz,2H), 7.58(d,J=1.0Hz,1H), 7.78(s,1H), 7.84(d,J=1.0Hz,1H), 8.22(s,1H), 8.43(s,2H), 9.52(s,1H), 10.77(s,1H), and seven Hs were not observed. [Table 210] [Table 211] [Table 212] [Table 213] [Table 214]

[0656] Biological Examples Example B1 IRAK3-ePL overexpression degradation assay Stable cell lines were generated using the following protocol: 3x10 5Lenti-X 293T cells (Clonetech) were seeded in 12-well plates in 0.8 mL of medium and incubated overnight at 37°C / 5% CO2. The packaging plasmid (0.4 μg, pMD), envelope plasmid (0.4 μg, pSP), and lentiviral transfection 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. At the same time, 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 previously seeded cells, and the cells were incubated for approximately 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 approximately 30 hours. 0.5x10 6 293T CRBN OE / GSPT1 G575N KI Cells were seeded into 12-well plates with 0.5 mL medium / well and incubated at 37°C / 5% CO2 for approximately 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 to transduce cells, and the remaining portion was stored at -80°C. The virus was then transduced into the 293T CRBN OE / GSPT1 G575N KICells were added individually to each well (0.5 mL virus), 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 approximately 24 hours at 37°C / 5% CO2. After aspirating the medium from the plates, the cells were washed with DPBS, trypsinized, and seeded into 10 cm dishes in 15 mL of medium and 1 μg / mL puromycin. After incubating the cells for approximately 72 hours at 37°C / 5% CO2, the medium was aspirated from the plates, the cells were washed with DPBS, and trypsinized. Cells were seeded into 15 cm dishes in 40 mL of medium containing 1.0 μg / mL puromycin (Gibco) and incubated for approximately 72 hours at 37°C / 5% CO2. After incubation, the medium was removed, the cells were washed with DPBS, and trypsinized. The majority of cells were resuspended in Invitrogen freezing medium and stored (approximately 6–8 x 10 6 cells / vial).

[0657] A dose-response curve resolution assay for IRAK3-ePL cells was performed using the following protocol. Test compounds were dispensed into white 284-well tissue culture-treated plates using an acoustic liquid handler. Ten-point serial 3-fold dilutions were prepared in duplicate, starting from a 10 μM dose, based on a 25 μL assay volume. Negative control wells containing 0.2% DMSO alone were incubated to calculate 100% signal. Positive control wells containing 30 μM ataluren (a luciferase inhibitor) were incubated to calculate background signal levels. To ensure uniformity of DMSO across wells, all wells were backfilled to a final concentration of 0.2% DMSO. IRAK3-ePL expressing cells (IRAK3-ePL Lenti-X 293TC) were cultured in 10 wells. RBN / 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 wells of a 384-well plate that had been previously spotted with compounds and incubated overnight at 37°C / 5% CO2. After incubation, the 384-well plate was removed from the incubator and left at room temperature for 30 minutes. InCELL Hunter reagent was prepared according to the manufacturer's instructions (EA reagent, cell lysis buffer, and substrate reagent in a 1:1:4 ratio, catalog no. 96-0002, DiscoverX) and added to the 384-well plate at 25 μL per well. After incubating the plate at room temperature for 1 hour, the luminescence signal was read using a ViewLux plate reader. Data were processed and analyzed using ActivityBase software. Briefly, the mean luminescence values ​​of the positive control wells were subtracted from the remaining wells for background correction, and all luminescence values ​​were normalized to the DMSO control wells. The mean value of the DMSO control wells was equal to 100% of the relative IRAK3-ePL protein level. 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 IRAK3-ePL protein concentration was plotted on the y-axis. The EC of compounds on the degradation of IRAK3-ePL was 50 The values ​​(50% effective concentration) were fitted to a four-parameter logistic model (sigmoidal dose-response model) (FIT = (A + {(B A) / 1 + {(C / x)}} D ]}) where C is the inflection point (EC 50 ), where D is the correlation coefficient, and A and B are the minimum and maximum values ​​of fit, respectively.

[0658] Determining the maximum percentage loss of target protein after compound treatment max The Y was calculated by determining the minimum remaining percentage of the target protein after compound treatment. min was calculated (%D max =100-Y min ).

[0659] Example B2 IRAK endogenous HTRF degradation assay Cells (approximately 50k) were seeded into Cisbio 96-well low-volume white plates (Cisbio: Catalog No. 66PL96005). Compounds were dissolved in DMSO and serially diluted 3-fold using a TECAN D300E. Cells were incubated with compounds overnight. Cisbio's Total-IRAK3 HTRF kit was used for degradation analysis (Cisbio: 63ADK101PEH). Cryptate and D2 antibodies were diluted in detection buffer as recommended by the manufacturer. 2µL of each solution was then added to 16µL of lysate. Buffer controls (cell lysis buffer + detection buffer), cryptate controls (cell lysis buffer + cryptate antibody + detection buffer), and negative controls (cell lysis buffer + cryptate antibody + D2 antibody) were prepared as recommended by the manufacturer. After incubation with the antibody, the HTRF signal was measured using a Perkin Elmer Envision reader, and the HTRF signal was calculated using the following formula: (fluorescence wavelength 665 nm / fluorescence wavelength 615 nm). * 10,000. All HTRF values ​​were normalized to the mean value of DMSO. The mean value of the DMSO control wells was equal to 100% of the relative IRAK3 protein concentration. Normalized luminescence values ​​were plotted as a function of compound concentration. Compound concentration was plotted on the x-axis and the corresponding relative IRAK3 protein concentration was plotted on the y-axis. EC of compounds on IRAK3 degradation 50 The values ​​(50% effective concentration) were fitted to a four-parameter logistic model (sigmoidal dose-response model) (FIT = (A + {(B A) / 1 + {(C / x)}} D ]}) where C is the inflection point (EC 50 ), where D is the correlation coefficient, and A and B are the minimum and maximum values ​​of fit, respectively. Y was calculated by determining the minimum remaining percentage of the target protein after compound treatment. min was calculated. D max is Y min (%D max =100-Y min ).

[0660] Example B3 IRAK3 Biochemical Binding Assay The LanthaScreen® Europium Kinase Binding Assay was performed as described by the supplier (ThermoFisher Scientific, Waltham, MA). Briefly, 100X solutions of compounds were prepared in DMSO to achieve final concentrations by serially diluting 10 mM stock solutions at 3-fold intervals in a 384-well reagent plate. 1 μL of serially diluted compound was added to the corresponding well of a 384-well reagent plate containing 32.3 μL of 1X buffer (50 mM HEPES pH 7.4, 10 nM MgCl2, 1 mM EGTA, 0.01% Brij-35). 5 μL of buffer-diluted compound was transferred to the corresponding well of a 384-well assay plate. 5 μL of 3X tracer was transferred to each well of the assay plate to achieve a final tracer concentration of 10 nM. Finally, 5 μL of a mixture of 3X Eu-Anti-GST and IRAK3 was transferred to each well to achieve final concentrations of 2 nM and 10 nM, respectively. The reaction was incubated for 1 hour at room temperature. The TR-FRET signal of the interaction was measured 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 fluorescence signal percentage at each compound concentration was used to calculate the percentage of inhibition (% inhibition). Plots of % inhibition versus inhibitor concentration were fitted according to the dose-response equation (Equation 1), and IC values ​​were calculated using Dotmatics software (Dotmatics, Bishops Stortford, Hertfordshire, England). 50 and Hill slope values ​​were calculated.

number

[0661] The present invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, but the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein by reference in their entireties.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, A is C １ -C ６ Alkyl, phenyl, C ３ -C ６ cycloalkyl, 5- to 6-membered heteroaryl, or 6- to 10-membered heterocyclyl, and the phenyl, cycloalkyl, heteroaryl, and heterocyclyl are each independently selected from the group consisting of x R １ substituted with a group, wherein the heteroaryl and heterocyclyl contain 1 to 3 heteroatoms selected from N and O; Each R １ are independently halo, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, or —SO ２ (C １ -C ６ alkyl); or two R on adjacent carbon atoms １ The groups are joined together to form a fused C ３ -C ６ cycloalkyl or fused 【Chemistry 2】 forming a group; R ａ and R ｂ are each H or together form an oxo group; R ｃ is H or C １ -C ６ is alkyl; x is 0 to 5; R ２ is H or C １ -C ６ is alkyl; R ３ is H or C １ -C ６ is alkyl; R ４ is H or C １ -C ６ is alkyl; X １ is CH or N; X ２ is N or CH ２ and Ring B is C ３ -C ６ cycloalkylene or a 5- to 7-membered heterocyclylene containing 1 or 2 nitrogen atoms; Each R ５ are independently halo, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; w is 0 to 5; L １ is -C(O)(CH ２ ) ｎ -, -(CH ２ ) ｎ - or -(CH ２ ) ｎ C(O)—; n is 1 to 6; Ring C is a 5- to 10-membered heterocyclylene ring containing 1 or 2 nitrogen atoms; Each R ６ are independently halo, C １ -C ６ haloalkyl, or C １ -C ６ is alkyl; y is 0 to 5; Ring D is 【Transformation 3】 and R ７ａ and R ７ｂ are each H or together form an oxo group; Each R ８ are independently halo, C １ -C ６ Alkyl, C １ -C ６ haloalkyl, or C １ -C ６ is alkoxy; z is 0 to 4; X ３ is N or CR ９ and R ９ is H or C １ -C ６ is alkyl; R １０ is H or C １ -C ６ is alkyl; Each R １１ are independently halo, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; v is 0 to 4; and each 【Chemistry 4】 are independently a single bond or a double bond. or a pharmaceutically acceptable salt thereof.

2. A is C １ -C ３ Alkyl, phenyl, C ３ -C ５ cycloalkyl, 5- to 6-membered heteroaryl, or 8- to 10-membered heterocyclyl, and the phenyl, cycloalkyl, heteroaryl, and heterocyclyl are each independently selected from the group consisting of x R １ substituted with a group; x is 0 to 3; and Each R １ But independently, Halo, C １ -C ３ Alkyl, C ３ -C ５ Cycloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, or —SO ２ (C １ -C ３ alkyl); or two R on adjacent carbon atoms １ The groups are joined together to form a fused C ３ -C ５ cycloalkyl or fused 【Transformation 5】 forming a group; R ａ and R ｂ are each H or taken together to form an oxo group; and R ｃ is H or C １ -C ３ is alkyl, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. A is, 【Transformation 6】 That is, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R ２ is H or C １ -C ３ is alkyl; R ３ is H or C １ -C ３ is alkyl; and R ４ is H or C １ -C ３ is alkyl, The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. X １ is N, The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. formula: 【Transformation 7】 but, 【Transformation 8】 That is, 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. Ring B is C ４ -C ６ cycloalkylene or a 6- to 7-membered heterocyclylene containing one nitrogen atom; w is 0 to 2; and Each R ５ But independently, Halo, C １ -C ３ Alkyl, or C １ -C ３ haloalkyl, The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. formula: 【Chemistry 9】 but, 【Chemistry 10】 That is, The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. L １ is -C(O)CH ２ -, -(CH ２ ) ｎ - or -CH ２ C(O)—; and n is 1 to 5; The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. Ring C is a 6- to 8-membered heterocyclylene ring containing 1 or 2 nitrogen atoms; y is 0 to 3; and Each R ６ But independently, Halo, C １ -C ３ haloalkyl, or C １ -C ３ is alkyl, 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. formula: 【Chemistry 11】 but, 【Chemistry 12】 That is, 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. Ring D is 【Chemistry 13】 That is, 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. X ３ But, CR ９ and R ９ is H or C １ -C ３ is alkyl; R １０ is H or C １ -C ３ is alkyl; v is 0 to 2; and Each R １１ But independently, Halo, C １ -C ３ Alkyl, or C １ -C ３ haloalkyl, 13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. formula: 【Chemistry 14】 but, 【Chemistry 15】 That is, 14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. The compound has the formula (IIIa), (IIIb), or (IIIc): 【Chemistry 16】 15. The compound according to any one of claims 1 to 14, wherein:

16. The compound has the formula (IVa) or (IVb): 【Chemistry 17】 16. The compound according to any one of claims 1 to 15, wherein:

17. A compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

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

19. 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 claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18.

20. (i) 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 claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, wherein the cancer may be 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; or (ii) a method for enhancing the immunity of a vaccinated subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18.

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