Heteroaryl compounds as ligands for IRAK4 degradation

Abstract

The present invention provides compounds and compositions for modulating IRAK4. In some embodiments, the compounds and compositions are provided for the treatment of inflammatory diseases or autoimmune diseases.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 465,603, filed on 11 May 2023, which is incorporated herein by reference in its entirety.

[0002] This disclosure generally relates to compounds and compositions, as well as methods for producing them and the use of said compounds and compositions for treating inflammatory or autoimmune diseases. [Background technology]

[0003] The recruitment of immune cells to the site of injury involves the coordinated interaction of numerous soluble mediators. Several cytokines, including interleukin-1 (IL-1), appear to play a crucial role in these processes. IL-1 triggers pro-inflammatory responses and is involved in tissue degeneration seen in chronic inflammatory states. Therefore, IL-1 is also involved in the process of bone resorption and the regulation of adipose tissue. Thus, IL-1 plays a vital role in many medical conditions, 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, namely IL-1R1 and IL-1RAcP. The resulting heterodimer recruits an adapter molecule called MyD88 and binds to IL-1 receptor-associated kinase (IRAK) (Wesche et al., J. Biol. Chem. 1999, 274, 19403-19410; O'Neill et al., J. Leukoc. Biol. 1998, 63, 650-657; Auron, Cytokine Growth Factor Rev. 1998, 9:221-237; and O'Neill, Biochem. Soc. Trans. 2000, 28, 557-563). Four members of the IRAK family have been identified: IRAK1, IRAK2, IRAK3, and IRAK4. These proteins are characterized by a typical N-terminal death domain and a centrally located kinase domain that mediate interactions with adapter proteins of the MyD88 family. Of the four members of the mammalian IRAK family, IRAK-4 is considered the "master IRAK." IRAK-4 is a serine / threonine kinase that plays a crucial role in Toll / IL-1 receptor (TIR) ​​signaling. Under overexpression conditions, all IRAKs can mediate the activation of nuclear factor κB and the stress-induced mitogen-activated protein kinase (MAPK) signaling cascade. Studies have demonstrated that IRAK4 kinase activity is essential for cytokine production, MAPK activation, and induction of NF-κB regulatory genes in response to TLR ligands (Koziczak-Holbro M. et al., J. Biol. Chem. 2007, 282, 13552-13560).Given the central role of IRAK4 in Toll-like / IL-1R signaling and immunoprotection, compounds that modulate IRAK4 function are likely to be useful in treating inflammation, cell proliferation, and immune-related symptoms and diseases associated with IRAK-mediated signaling (e.g., rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, allergic diseases, psoriasis, asthma, graft rejection, cancer, and sepsis).

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

[0006] The therapeutic use of UPP is attracting considerable interest (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising treatment method involves using proteolytic chimeric molecules (commonly called PROTACs) to remove unwanted proteins through proteolysis (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTACs are ligand-targeted degraders that integrate an E3 ligase with the target protein to be degraded. These divalent molecules typically consist of an E3 ligase ligand and a small linker portion that binds to the target protein. PROTACs can position the E3 ligase at the appropriate distance and orientation relative to the target protein, thereby ubiquitinating the target protein. The ubiquitinated target protein is then recognized and degraded by the proteasome.

[0007] Thus, in one aspect, provided herein is a compound targeted to degrade IRAK4.

[0008] (Summary of the Invention) Described herein are, in certain embodiments, compounds and compositions thereof for degrading IRAK4. In various embodiments, the compounds and compositions thereof can be used for the treatment of inflammatory diseases or autoimmune diseases.

[0009] This embodiment can be more fully understood by reference to the detailed description and examples that illustrate non-limiting embodiments.

[0010] Embodiment 1 is of formula (I): [Chemical formula] [Wherein: R 1 is C1-C6 haloalkyl; R a is H or C1-C6 alkyl; R b is C1-C6 alkyl, 5-6 member heteroaryl, -(C1-C6 alkylene)(5-6 member heteroaryl) or -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and may optionally be substituted by 1-5 R 2 groups; or R a and R b The dotted line between represents a ring structure, where R a and R b together with the nitrogen atom to which they are attached form a 5-10 member monocyclic or bicyclic heterocyclyl, which heterocyclyl may optionally contain 1-2 additional heteroatoms selected from N and O and may optionally be substituted by 1-5 R 2 groups; Each R 2These are independently -NH2, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or a 5-6 membered heteroaryl, wherein the heteroaryl contains 1-2 nitrogen atoms and may optionally be substituted with 1-5 groups selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl; L 1 -C(O)N(H)-, -C(O)-, -(C1-C6 alkylene)N(R 3 )- or C1-C6 alkylene; L 2 The bond is -C(O)-, -N(R 3 )- or O; Each R 3 These are independently H or C1-C6 alkyl; Ring A is a monocyclic 4-6 membered heterocyclylene or a bicyclic 6-9 membered spiroheterocyclylene, the heterocyclylene contains 1-2 nitrogen atoms, and the heterocyclylene contains m R 4 Substituted by the group; Each R 4 These are independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; m is between 0 and 5; R 5 is H or C1-C6 alkyl; Z is CH or N; and * is L 2 [Indicates the binding site to the contained group] It is a compound of or a pharmaceutically acceptable salt thereof.

[0011] Embodiment 2 is R 1 However, the compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof is a C1-C3 haloalkyl compound.

[0012] Embodiment 3 is R 1 However, the compound described in Embodiment 2 or a pharmaceutically acceptable salt thereof is -CHF2.

[0013] Embodiment 4 is, Ra However, it is H or C1-C3 alkyl; R b The heteroaryl is a C1-C3 alkyl, a 6-membered heteroaryl, -(C1-C3 alkylene)(6-membered heteroaryl), or -(C1-C3 alkylene)NH2, wherein the heteroaryl contains 1 to 2 nitrogen atoms and 1 to 2 R 2 It may be substituted as desired by the base; and Each R 2 However, independently, they are -NH2, halo, C1-C3 alkyl, C1-C3 haloalkyl, or -CN. The compound described in any one of Embodiments 1 to 3 or a pharmaceutically acceptable salt thereof.

[0014] Embodiment 5 is, [ka] but, [ka] This is the compound described in Embodiment 4 or a pharmaceutically acceptable salt thereof.

[0015] Embodiment 6 is, R a and R b However, together with the nitrogen atoms bonded to them, they form a 5-8 member monocyclic or bicyclic heterocycline, and the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-3 R 2 It may be substituted as desired by the base; and Each R 2The compound described in any one of Embodiments 1 to 3 or a pharmaceutically acceptable salt thereof is independently -NH2, halo, C1-C3 alkyl, C1-C3 haloalkyl, -CN, or a 5-membered heteroaryl, wherein the heteroaryl contains 1 to 2 nitrogen atoms and may optionally be substituted with 1 to 3 groups selected from C1-C3 alkyl, halo, and C1-C3 haloalkyl.

[0016] Embodiment 7 is, [ka] but, [ka] This is the compound described in Embodiment 6 or a pharmaceutically acceptable salt thereof.

[0017] Embodiment 8 is, L 1 However, -C(O)N(H)-, -C(O)-, -(C1-C3 alkylene)N(R 3 )- or C1-C3 alkylene; L 2 However, the bond is -C(O)-, -N(R 3 )- or O; and Each R 3 However, independently, they are H or C1-C3 alkyl. The compound described in any one of Embodiments 1 to 7 or a pharmaceutically acceptable salt thereof.

[0018] Embodiment 9 is such that ring A is as follows: (i) [ka] (In the formula, Y 1 and Y 2 Independently, CH or N, but Y 1 and Y 2 At least one of them is N); (ii)

Chem.

Chem.

[0019] Embodiment 10 is a compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1 to 9, wherein each R 4 is independently halo, C1-C3 alkyl or C1-C3 haloalkyl.

[0020] Embodiment 11 is a compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1 to 10, wherein m is 0, 1 or 2.

[0021] Embodiment 12 is a compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1 to 11, wherein ring A is

Chem.

[0022] Embodiment 13 is a compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1 to 12, wherein R 5 is H or C1-C3 alkyl.

[0023] Embodiment 14 is a compound or a pharmaceutically acceptable salt thereof as described in Embodiment 13, wherein R 5 is -CH3.

[0024] Embodiment 15 is

Chem.

Chem.

[0025] Embodiment 16 is a compound of formula (IA), (IB), (IIa), (IIb), (IIIa), or (IVa): [ka] (In the formula, R a is H or C1-C6 alkyl; and R b The C1-C6 alkyl, 5-6 membered heteroaryl, -(C1-C6 alkylene)(5-6 membered heteroaryl), or -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and 1-5 R 2 It may be replaced by the base as desired; [ka] (In the formula, [ka] The heterocycline is a 5-10 member monocyclic or bicyclic heterocycline, which may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 It may be replaced by the base as desired; [ka] The compound is one of the compounds described in any one of Embodiments 1 to 15 or a pharmaceutically acceptable salt thereof.

[0026] Embodiment 17 is a compound selected from the compounds in Table 1 and their pharmaceutically acceptable salts.

[0027] Embodiment 18 is a pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0028] Embodiment 19 is a method for modulating interleukin-1 (IL1) receptor-related kinase 4 (IRAK4), characterized by contacting IRAK4 with an effective amount of any one of Embodiments 1 to 17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in Embodiment 18.

[0029] Embodiment 20 is a method for treating an inflammatory disease or autoimmune disease in a subject requiring treatment, characterized by administering an effective amount of any one of Embodiments 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment 18, to the subject, wherein the inflammatory disease or autoimmune disease may optionally be atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryopyrin-associated periodic syndromes, hidradenitis suppurativa, Beckett syndrome, or familial cold autoinflammatory syndrome. Detailed Description of the Invention

[0030] (definition) As used herein, the terms “comprising” and “including” are interchangeable. The terms “comprising” and “including” are construed to identify the presence of any described feature or component mentioned, but do not exclude the presence or addition of one or more features, components, or groups thereof. Furthermore, the terms “comprising” and “including” are also intended to include examples that are encompassed by the term “consisting of.” Consequently, the term “consisting of” may be used instead of the terms “comprising” and “including” to provide more specific embodiments of the present invention.

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

[0032] As used herein, the term "or" is construed as an inclusive "or" meaning any one or any combination. Thus, "A, B or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B and C". An exception to this definition occurs only when the combination of elements, functions, procedures or acts are in some way essential and mutually exclusive.

[0033] In the descriptions herein, any concentration range, % range, ratio range or integer range is understood to include any integer within the described range, and, where appropriate, values of its decimals (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, numerical ranges referred to herein for any physical characteristics such as polymer subunits, size or thickness are understood to include all integers within the range referred to, 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 has 1 to 10 carbon atoms (C1-C 10Alkyl groups are saturated, partially saturated, or unsaturated linear or branched acyclic hydrocarbons having typically 1 to 8 carbon atoms (C1-C8 alkyl), or, in some embodiments, 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 2 to 6 carbon atoms (C2-C6 alkyl). In some embodiments, alkyl groups are saturated alkyl groups. Representative saturated alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl; saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and 2,3-dimethylbutyl. In some embodiments, alkyl groups are unsaturated alkyl groups, also called alkenyl or alkynyl groups. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. The "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3). Alkyl groups can be substituted or unsubstituted.Where an alkyl group described herein is said to be “substituted,” it means any substituent as seen in the exemplary compounds and embodiments disclosed herein, as well as halogens; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo(=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkyl Alkylamino, 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; amide; cyano; isocyanate; isothiocyanato; cyanate; thiocyanato; or may be substituted with -B(OH)2.In certain embodiments, where an alkyl group described herein is said to be “substituted,” it may be substituted with any substituent as found in the exemplary compounds and embodiments disclosed herein, as well as halogens (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] The "cycloalkyl" group is a saturated or partially saturated cyclic alkyl group (C3-C) having 3 to 10 carbon atoms and having a monocyclic or multiple fused or bridging ring, which can be optionally substituted. 10The cycloalkyl group is a cycloalkyl group. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), but in other embodiments, the number of ring carbon atoms is in the range of 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl), or 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. Examples of the saturated cycloalkyl group include monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or multiple ring structures or cross-linked ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, etc. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. Cycloalkyl groups can be substituted or unsubstituted. An example of such a substituted cycloalkyl group is cyclohexanol.

[0036] An "aryl" group is an aromatic carbocyclic group (C6-C) having 6 to 14 carbon atoms and consisting of a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). 14 This refers to an aryl group. In one embodiment, the aryl group has 6 to 14 carbon atoms (C6-C) in the ring portion of the aryl group. 14 It contains aryl atoms, and in other embodiments, 6 to 12 carbon atoms (C6-C6). 12 Aryl) or 6-10 carbon atoms (C6-C 10This includes aryl groups. Certain aryl groups include phenyl, biphenyl, and naphthyl. The aryl group can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl).

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

[0038] "Haloalkyl" refers to an alkyl group substituted with one or more halo groups, as defined above. Examples include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms and is substituted with one or more halo groups (C1-C6 haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halo groups (C1-C3 haloalkyl). The halo groups may all be the same or different. Unless otherwise specified, the haloalkyl group may be substituted as desired.

[0039] A "heteroaryl" group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms in a heteroaromatic ring system, with the remaining atoms being carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms, and in other embodiments, 6 to 9 or even 6 to 10 atoms are contained in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridadinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanil, benzofuranil, indolyl (e.g., indolyl-2-onyl or isoindoline-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., A Examples of heteroaryl groups include, but are not limited to, zabenzimidazolyl (or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]xazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinoline-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups may be substituted or unsubstituted.

[0040] A "heterocyclyl" group is a non-aromatic cycloalkyl group in which the 1 to 4 ring carbon atoms are independently substituted with heteroatoms selected from O, S, and N. In some embodiments, a heterocyclyl group contains 3 to 10 ring members, while other groups contain 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyls can also be bonded to another group at any ring atom (in other words, any carbon or heteroatom of the heterocycle). Heterocycloalkyl groups can be substituted or unsubstituted. Heterocyclyl groups include saturated and partially saturated ring systems. Furthermore, the term "heterocyclyl" is intended to encompass a non-aromatic ring containing at least one heteroatom, which may be fused with an aryl or heteroaryl ring, regardless of its bonding to the rest of the molecule. The term also includes bridging polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl groups include azilidinyl, azetidinyl, azepanil, pyrrolidyl, imidazolidinyl (e.g., imidazolidine-4-onyl or imidazolidine-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, piperidyl, piperazinyl (e.g., piperazine-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranil (e.g., tetrahydro-2H-pyranil), tetrahydrothiopyranil, oxathianil, dithianil, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidine-2(1H)-one. Typical substituted heterocyclyl groups may be monosubstituted or bisubstituted or more. For example, a pyridyl group or morpholinyl group may be 2-, 3-, 4-, 5-, or 6-substituted, or bisubstituted with various substituents as listed below, but is not limited to these.

[0041] Except for alkyl groups, where a group described herein is said to be “substituted,” it may be substituted with any suitable substituent. Exemplary substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogens (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)2, O(alkyl)aminocarbonyl; monocyclic or condensed These are cycloalkyls (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which may be non-condensed polycyclic; or heterocyclyls (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiadinyl), which may be monocyclic or condensed or non-condensed polycyclic; monocyclic or condensed or non-condensed polycyclic aryls or heteroaryls (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridadinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); aryloxys; aralkyloxys; heterocyclyloxys; and heterocyclylalkoxys.

[0042] Alternatively, you can use other commonly used chemical names. For example, divalent groups such as divalent alkyl, divalent phenyl, divalent heteroaryl, and divalent heterocyclyl can also be referred to as alkylene, phenylene, heteroarylene, or heterocyclylene, respectively.

[0043] Embodiments of this disclosure include pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein (e.g., compounds of formula (I)).

[0044] As used herein, the term “pharmaceutically acceptable salt” refers to a salt produced from a pharmaceutically acceptable, non-toxic acid or base, including inorganic acids and bases, as well as organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compound of formula (I) include, but are not limited to, metal salts derived from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts derived from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethensulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloride, isethionic acid, lactate, maleate, malate, mandelate, methanesulfonate, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Specific salts include hydrochloride, formate, and mesylate. Other materials are well known in the relevant technical field; see, for example, 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).

[0045] In this specification, unless otherwise stated, the terms “stereoisomer” or “stereoisomerically pure” mean one stereoisomer of a particular compound that substantially does not contain any other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center substantially does not contain the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers substantially does not contain any other diastereomer of that compound. A typical stereoisomerically pure compound is one in which one stereoisomer of the compound is present in greater proportions than about 80% by weight and the other stereoisomer of the compound in less than about 20% by weight; one stereoisomer of the compound is present in greater proportions than about 90% by weight and the other stereoisomer of the compound in less than about 10% by weight; one stereoisomer of the compound is present in greater proportions than about 95% by weight and the other stereoisomer of the compound is present in less than about 5% by weight; or one stereoisomer of the compound is present in greater proportions than about 97% by weight and the other stereoisomer of the compound is present in less than about 3% by weight. The compounds disclosed herein have a chiral center and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

[0046] The use of stereoisomerically pure forms of the compounds disclosed herein and the use of mixtures of those forms are encompassed in the embodiments disclosed herein. For example, mixtures containing equimolar or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or separated using standard techniques such as chiral columns or chiral resolving agents. For example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers :Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation:Fundamentals and Practical Methods (Springer Science & Business Media, 2007); See Subramanian, G., Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); and Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0047] It should also be noted that the compounds disclosed herein may include E isomers and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the compound is isolated as either an E isomer or a Z isomer. In other embodiments, the compound is a mixture of E and Z isomers.

[0048] A "tautomer" refers to an isomer of a compound that is in equilibrium with it. The concentration of these isomers varies depending on the environment in which the compound exists; for example, it may differ depending on whether the compound is a solid, an organic solution, or an aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomers, which are called tautomers: [ka]

[0049] As will be readily apparent to those skilled in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compound of formula (I) are within the scope of this disclosure.

[0050] Furthermore, it should be noted that the compounds disclosed herein may contain atomic isotopes in proportions not found in nature for one or more atoms. For example, a compound may contain tritium ( 3 H), Iodine-125 ( 125 I), Sulfur 35 ( 35 S) or carbon-14 ( 14 Can it be radiolabeled with radioactive isotopes such as C), or deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen 15 ( 15Isotope enrichment can be achieved by means of N), etc. As used herein, “isotopologue” is an isotope-enriched compound. The term “isotopologue” refers to an atom having an isotope composition other than the natural isotope composition of that atom. The term “isotopologue” may also refer to a compound containing at least one atom having an isotope composition other than the natural isotope composition of that atom. The term “isotopologue” means the amount of each isotope present relative to a given atom. Radiolabeled compounds and isotope-enriched compounds are useful as therapeutic agents, e.g., cancer treatments, research reagents (e.g., binding assay reagents), 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 included within the scope of the embodiments provided herein. In some embodiments, isototopologues of the compounds disclosed herein are provided, for example, isototopologues are compounds rich in deuterium, carbon-13, and / or nitrogen-15. As used herein, “deuterated” means that at least one hydrogen (H) atom is converted into deuterium (D or 2 This refers to compounds substituted with H, i.e., compounds in which deuterium is concentrated at at least one position.

[0051] Regardless of stereoisomer or isotopic composition, it is understood that each compound disclosed herein may be provided in any form of the pharmaceutically acceptable salts discussed herein. Similarly, it is understood that the isotopic composition may vary independently of the stereoisomer composition of each compound referred to herein. Furthermore, the isotopic composition may vary, but is limited to the elements present in each compound or its salts disclosed herein, or independently of the selection of pharmaceutically acceptable salts of each compound.

[0052] Please note that in the event of any discrepancy between the described structure and its name, the described structure will take precedence.

[0053] As used herein, “treatment” means the overall or partial relief of a disorder, disease or condition, or one or more symptoms associated with a disorder, disease or condition, or the reduction or cessation of further progression or worsening of those symptoms, or the relief or eradication of the cause of the disorder, disease or condition itself. In one embodiment, a disorder is a neurodegenerative disease or its symptoms as described herein.

[0054] As used herein, “prevention” means a method of delaying and / or interfering with the onset, recurrence or progression of the whole or partial disability, disease or condition, a method of preventing a subject from acquiring a disability, disease or condition, or a method of reducing the risk of a subject acquiring a disability, disease or condition. In one embodiment, disability is a neurodegenerative disease or its symptoms as described herein.

[0055] In relation to the compounds disclosed herein, the term “effective amount” means an amount that can treat or prevent the disorder, disease or condition, or symptoms thereof, disclosed herein.

[0056] As used herein, the terms “subject” or “patient” include, but are not limited to, animals such as cattle, monkeys, horses, sheep, pigs, birds, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and are mammals in one embodiment and humans in another embodiment. In one embodiment, the subject is a human being who has or is at risk of having a disease or symptoms mediated by S1P5.

[0057] Various features of the present invention may be described in the context of a single embodiment, but these features may also be provided individually or in any suitable combination. Conversely, the present invention may be described herein in the context of a separate embodiment for clarity, but the present invention may also be implemented in a single embodiment.

[0058] compound In one embodiment, the formula provided herein is (I): [ka] [In the formula, R 1 It is a C1-C6 haloalkyl; R a is H or C1-C6 alkyl; R b The heteroaryl is a C1-C6 alkyl, a 5-6 membered heteroaryl, -(C1-C6 alkylene)(5-6 membered heteroaryl), or -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and 1-5 R 2 It may be substituted as desired by the base; or R a and R b The dotted line between them indicates a ring structure, where R a and R b These, together with the nitrogen atoms bonded to them, form a 5-10 member monocyclic or bicyclic heterocycline, the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 It may be substituted by the base as desired; Each R 2 These are independently -NH2, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or a 5-6 membered heteroaryl, wherein the heteroaryl contains 1-2 nitrogen atoms and may optionally be substituted with 1-5 groups selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl; L 1 -C(O)N(H)-, -C(O)-, -(C1-C6 alkylene)N(R 3 )- or C1-C6 alkylene; L 2 The bond is -C(O)-, -N(R 3 )- or O; Each R 3 These are independently H or C1-C6 alkyl; Ring A is a monocyclic 4-6 membered heterocyclylene or a bicyclic 6-9 membered spiroheterocyclylene, the heterocyclylene contains 1-2 nitrogen atoms, and the heterocyclylene contains m R 4 Substituted by the group; Each R 4 These are independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; m is between 0 and 5; R 5 is H or C1-C6 alkyl; Z is CH or N; and * is L 2 [Indicates the binding site to the contained group] It is a compound of or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, R 1 is a C1-C6 haloalkyl. In some embodiments, R 1 R is a C1-C3 haloalkyl. In some embodiments, R 1 is -CHF2 or -CF3. In some embodiments, R 1 It is -CHF2.

[0060] In some embodiments, R 1 is a C1-C6 haloalkyl. In some embodiments, R 1 R is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 1 R is a C1-C3 haloalkyl. In some embodiments, R 1 R is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 1 R is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 1is -CF3. In some embodiments, R 1 is -CHF2.

[0061] In some embodiments, R a is H or C1-C3 alkyl; R b is C1-C3 alkyl, 6-member heteroaryl, -(C1-C3 alkylene)(6-member heteroaryl) or -(C1-C3 alkylene)NH2, wherein said heteroaryl contains 1 to 2 nitrogen atoms and may optionally be substituted by 1 to 2 R 2 groups; and each R 2 is independently -NH2, halo, C1-C3 alkyl, C1-C3 haloalkyl or -CN. In some embodiments, R a is H or -CH3; R b is -CH3, -CH2(pyridyl), -CH2CH2NH2 or pyridyl, wherein said pyridyl may optionally be substituted by 1 R 2 group; and R 2 is -CH3.

[0062] In some embodiments, R a is H or C1-C6 alkyl. In some embodiments, R a is H or C1-C3 alkyl. In some embodiments, R a is H or -CH3.

[0063] In some embodiments, R a is H.

[0064] In some embodiments, R a is C1-C6 alkyl. In some embodiments, R a is C1-C3 alkyl. In some embodiments, R a is methyl, ethyl, n-propyl or isopropyl. In some embodiments, R a is methyl. In some embodiments, Ra R is ethyl. In some embodiments, a is n-propyl. In some embodiments, R a It is isopropyl.

[0065] In some embodiments, R b The is a C1-C6 alkyl, a 5-6 membered heteroaryl, -(C1-C6 alkylene)(5-6 membered heteroaryl), or -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R b The is a C1-C3 alkyl, a 6-membered heteroaryl, -(C1-C3 alkylene)(6-membered heteroaryl), or -(C1-C3 alkylene)NH2, wherein the heteroaryl contains 1 to 2 nitrogen atoms and 1 to 2 R 2 It may be substituted as desired by the base. In some embodiments, R b is -CH3, -CH2(pyridyl), -CH2CH2NH2 or pyridyl, and the pyridyl is one R 2 It may be substituted by the base as desired.

[0066] In some embodiments, R b is a C1-C6 alkyl group. In some embodiments, R b is a C1-C3 alkyl group. In some embodiments, R b is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R b is methyl. In some embodiments, R b R is ethyl. In some embodiments, b is n-propyl. In some embodiments, R b It is isopropyl.

[0067] In some embodiments, R bThis is a 5-6 membered heteroaryl, and the heteroaryl contains 1-2 nitrogen atoms and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R b This is a 5-6 membered heteroaryl, and the heteroaryl contains 1-2 nitrogen atoms and 1-3 R 2 It may be substituted as desired by the base. In some embodiments, R b This is a 5-6 membered heteroaryl, the heteroaryl containing 1-2 nitrogen atoms and 1 or 2 R 2 It may be substituted as desired by the base. In some embodiments, R b This is a 5-6 membered heteroaryl, and the heteroaryl contains 1-2 nitrogen atoms and 1 R 2 It may be substituted as desired by the base. In some embodiments, R b is a 5-6 membered heteroaryl, the heteroaryl containing 1-2 nitrogen atoms and unsubstituted. In some embodiments, R b R is a 5-membered heteroaryl compound containing 1-2 nitrogen atoms. In some embodiments, R b R is a 5-membered heteroaryl compound containing one nitrogen atom. In some embodiments, R b R is a 5-membered heteroaryl compound containing two nitrogen atoms. In some embodiments, R b is pyrrolyl, imidazolyl, or pyrazolyl. In some embodiments, R b R is a 6-membered heteroaryl compound containing 1-2 nitrogen atoms. In some embodiments, R b R is a six-membered heteroaryl compound containing one nitrogen atom. In some embodiments, R b R is a six-membered heteroaryl compound containing two nitrogen atoms. In some embodiments, R b is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, R b It is pyridinyl.

[0068] In some embodiments, R b It is -(C1-C6 alkylene)(5-6 member heteroaryl), and the heteroaryl contains 1-2 nitrogen atoms and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R b It is -(C1-C3 alkylene)(5-6 member heteroaryl), and the heteroaryl contains 1-2 nitrogen atoms and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R b It is -(C1-C3 alkylene)(5-6 member heteroaryl), and the heteroaryl contains 1-2 nitrogen atoms and 1-3 R 2 It may be substituted as desired by the base. In some embodiments, R b is -(C1-C3 alkylene)(5-6 member heteroaryl), and the heteroaryl contains 1-2 nitrogen atoms and 1 or 2 R 2 It may be substituted as desired by the base. In some embodiments, R b It is -(C1-C3 alkylene)(5-6 member heteroaryl), and the heteroaryl contains 1-2 nitrogen atoms and 1 R 2 It may be substituted as desired by the base. In some embodiments, R b The compound is -(C1-C3 alkylene)(5-6 membered heteroaryl), and the heteroaryl contains 1-2 nitrogen atoms and is unsubstituted.

[0069] In some embodiments, R b It is -(C1-C6 alkylene)(5-membered heteroaryl), and the heteroaryl contains 1 to 2 nitrogen atoms and 1 to 5 R 2 It may be substituted as desired by the base. In some embodiments, R bIt is -(C1-C3 alkylene)(5-membered heteroaryl), and the heteroaryl contains 1 to 2 nitrogen atoms and 1 to 5 R 2 It may be substituted as desired by the base. In some embodiments, R b It is -(C1-C3 alkylene)(5-membered heteroaryl), and the heteroaryl contains 1 to 2 nitrogen atoms and 1 to 3 R 2 It may be substituted as desired by the base. In some embodiments, R b is -(C1-C3 alkylene)(5-membered heteroaryl), and the heteroaryl contains 1 to 2 nitrogen atoms and 1 or 2 R 2 It may be substituted as desired by the base. In some embodiments, R b is -(C1-C3 alkylene)(5-membered heteroaryl), and the heteroaryl contains 1 to 2 nitrogen atoms and 1 R 2 It may be substituted as desired by the base. In some embodiments, R b It is -(C1-C3 alkylene)(5-membered heteroaryl), and the heteroaryl contains one nitrogen atom and 1 to 5 R 2 It may be substituted as desired by the base. In some embodiments, R b It is -(C1-C3 alkylene)(5-membered heteroaryl), and the heteroaryl contains 2 nitrogen atoms and 1 to 5 R 2 It may be substituted as desired by the base. In some embodiments, R b is -(C1-C3 alkylene)pyrrolyl, -(C1-C3 alkylene)imidazolyl, or -(C1-C3 alkylene)pyrazolyl. In some embodiments, R b R is -CH2(pyrrolyl), -CH2(imidazolyl), or -CH2(pyrazolyl). In some embodiments, R b These are -CH2CH2 (pyrrolyl), -CH2CH2 (imidazolyl), or -CH2CH2 (pyrazolyl).

[0070] In some embodiments, R b is -(C1-C6 alkylene)NH2. In some embodiments, R b is -(C1-C3 alkylene)NH2. In some embodiments, R b is -CH2NH2, -CH2CH2NH2, or -CH2CH2CH2NH2. In some embodiments, R b It is -CH2CH2NH2.

[0071] In some embodiments, [ka] teeth, [ka] That is the case.

[0072] In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form a 5-10 member monocyclic or bicyclic heterocycline, the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form a 5-8 member monocyclic or bicyclic heterocycline, the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-3 R 2 It may be substituted as desired by the base. In some embodiments, R a and R bThese, together with the nitrogen atoms bonded to them, form a 5-6 member monocyclic heterocycline or an 8 member condensed or bridging bicyclic heterocycline, wherein the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-3 R 2 It may be substituted by the base as desired.

[0073] In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form a 5-10 membered monocyclic heterocycline, and the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form a 5-6 member monocyclic heterocycline, and the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form a 5-6 member monocyclic heterocycline, and the heterocycline may optionally contain one additional heteroatom selected from N and O, and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form a 5-6 member monocyclic heterocycline, the heterocycline containing one additional heteroatom selected from N and O, and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R a and R bThese, together with the nitrogen atoms bonded to them, form a 5-6 member monocyclic heterocycline, the heterocycline containing one oxygen atom and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form a 5-6 member monocyclic heterocycline, containing no additional heteroatoms and 1-5 R 2 The group may be substituted as desired. In some embodiments, a 5-6 member monocyclic heterocycline has 1-3 R 2 The group may be substituted as desired. In some embodiments, a 5-6 member monocyclic heterocycline has 1 or 2 R 2 The group may be substituted as desired. In some embodiments, a 5-6 member monocyclic heterocycline has one R 2 The group may be substituted as desired. In some embodiments, the 5-6 member monocyclic heterocyclil is unsubstituted. In some embodiments, the 5-6 member monocyclic heterocyclil is a 5-member heterocyclil. In some embodiments, the 5-member heterocyclil is pyrrolidinyl or oxazolidinyl. In some embodiments, the 5-6 member monocyclic heterocyclil is a 6-member heterocyclil. In some embodiments, the 6-member heterocyclil is morpholinyl, piperazinyl, or piperidinyl.

[0074] In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form a 5-10 membered bicyclic heterocycline, and the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R a and R bThese, together with the nitrogen atoms bonded to them, form a 5-8 membered bicyclic heterocycline, and the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 It may be substituted as desired by the base. In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form an 8-membered condensed or bridging bicyclic heterocycline, the heterocycline may optionally contain 1 to 2 additional heteroatoms selected from N and O, and 1 to 5 R 2 The group may be substituted as desired. In some embodiments, the bicyclic heterocyclil has 1 to 3 R groups. 2 It is substituted with a group. In some embodiments, the bicyclic heterocycline has one or two R groups. 2 It is substituted with a group. In some embodiments, the bicyclic heterocycline has one R 2 It is substituted by a group. In some embodiments, the bicyclic heterocyclyl is not substituted.

[0075] In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form an 8-membered condensed bicyclic heterocycline, the heterocycline may optionally contain 1 to 2 additional heteroatoms selected from N and O, and 1 to 5 R 2 It may be substituted as desired by the base. In some embodiments, R a and R b These, together with the nitrogen atoms bonded to them, form an 8-membered bridging bicyclic heterocycline, the heterocycline may optionally contain 1 to 2 additional heteroatoms selected from N and O, and 1 to 5 R 2The groups may be substituted as desired. In some embodiments, the bicyclic heterocyclyl contains one oxygen atom. In some embodiments, the bicyclic heterocyclyl contains one additional nitrogen atom. In some embodiments, the bicyclic heterocyclyl contains two additional nitrogen atoms. In some embodiments, the bicyclic heterocyclyl contains one additional nitrogen atom and one oxygen atom. In some embodiments, the bicyclic heterocyclyl is partially unsaturated. In some embodiments, the bicyclic heterocyclyl is fully saturated. In some embodiments, the bicyclic heterocyclyl is a saturated heterocyclic ring fused with a partially unsaturated ring. In some embodiments, the bicyclic heterocyclyl is a saturated heterocyclic ring fused with an aromatic ring. In some embodiments, the bicyclic heterocyclyl is a saturated heterocyclic ring fused with a heteroaryl ring.

[0076] In some embodiments, each R 2 R is independently -NH2, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or a 5-6 membered heteroaryl, wherein the heteroaryl contains 1-2 nitrogen atoms and may optionally be substituted with 1-5 groups selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl. In some embodiments, each R 2 R is independently -NH2, halo, C1-C3 alkyl, C1-C3 haloalkyl, -CN, or a 5-membered heteroaryl, wherein the heteroaryl contains 1-2 nitrogen atoms and may optionally be substituted with 1-3 groups selected from C1-C3 alkyl, halo, and C1-C3 haloalkyl. In some embodiments, each R 2 These are independently -NH2, F, Cl, -CH3 or -CF3, -CN or pyrazolyl, which may be optionally substituted with one or two groups selected from -CH3 and Cl.

[0077] In some embodiments, R 2 It is -NH2.

[0078] In some embodiments, R 2 is a halo. In some embodiments, R 2 is Cl, F, or Br. In some embodiments, R 2 is Cl. In some embodiments, R 2 In some embodiments, R 2 It is Br.

[0079] In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a C1-C3 alkyl group. In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 R is ethyl. In some embodiments, 2 is n-propyl. In some embodiments, R 2 It is isopropyl.

[0080] In some embodiments, R 2 is a C1-C6 haloalkyl. In some embodiments, R 2 R is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 2 R is a C1-C3 haloalkyl. In some embodiments, R 2 R is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 2 R is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 2 is -CF3. In some embodiments, R 2 It is -CHF2.

[0081] In some embodiments, R 2 It is -CN.

[0082] In some embodiments, R 2 R is a 5-6 membered heteroaryl containing 1-2 nitrogen atoms, and the heteroaryl may optionally be substituted with 1-5 groups selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl. In some embodiments, R 2 R is a 5-6 membered heteroaryl containing one nitrogen atom, and the heteroaryl may optionally be substituted with 1-5 l groups selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl. In some embodiments, R 2 This is a 5-6 membered heteroaryl compound containing two nitrogen atoms, and the heteroaryl compound may optionally be substituted with 1-5 groups selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl compounds.

[0083] In some embodiments, R 2 R is a 5-membered heteroaryl, which contains 1 to 2 nitrogen atoms and may optionally be substituted with 1 to 5 groups selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl. In some embodiments, R 2The heteroaryl is a six-membered heteroaryl containing one or two nitrogen atoms and optionally substituted with one to five groups selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl groups. In these variations, the heteroaryl may optionally be substituted with one to five groups selected from C1-C3 alkyl (e.g., methyl, ethyl, or propyl), halo (e.g., F or Cl), and C1-C3 haloalkyl (e.g., -CF3 or -CHF2). In some embodiments, the heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, the heteroaryl is pyrazolyl.

[0084] In some embodiments, [ka] teeth, [ka] That is the case.

[0085] In some embodiments, L 1 -C(O)N(H)-, -C(O)-, -(C1-C6 alkylene)N(R 3 )- or C1-C6 alkylene. In some embodiments, L 1 -C(O)N(H)-, -C(O)-, -(C1-C3 alkylene)N(R 3 )- or C1-C3 alkylene; and R 3 is H or C1-C3 alkyl. In some embodiments, L 1 These are -C(O)N(H)-, -C(O)-, -CH2N(H)-, -CH2N(CH3)-, -CH2CH2N(CH3)-, -CH2-, or -CH2CH2-.

[0086] In some embodiments, L 1 It is -C(O)N(H)-.

[0087] In some embodiments, L 1 It is -C(O)-.

[0088] In some embodiments, L 1 is -(C1-C6 alkylene)N(R 3 )-. In some embodiments, L 1 is -(C1-C3 alkylene)N(R 3 )-. In some embodiments, L 1 is -CH2N(R 3 )-. In some embodiments, L 1 is -CH2CH2N(R 3 )-. In some embodiments, L 1 is -CH2CH2CH2N(R 3 )-. In any of these, R 3 is H or C1-C6 alkyl. In some embodiments, R 3 H is H. In some embodiments, R 3 is a C1-C6 alkyl group. In some embodiments, R 3 is a C1-C3 alkyl group. In some embodiments, R 3 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 R is ethyl. In some embodiments, 3 is n-propyl. In some embodiments, R 3 L is isopropyl. In some embodiments, L 1 is -(C1-C6 alkylene)N(H)-. In some embodiments, L 1 L is -(C1-C6 alkylene)N(C1-C6 alkyl)-. In some embodiments, L 1 L is -CH2N(H)-, -CH2CH2N(H)-, or -CH2CH2CH2N(H)-. In some embodiments, L 1is -CH2N(H)-. In some embodiments, L 1 is -CH2CH2N(H)-. In some embodiments, L 1 L is -CH2N(CH3)-, -CH2CH2N(CH3)-, or -CH2CH2CH2N(CH3)-. In some embodiments, L 1 is -CH2N(CH3)-. In some embodiments, L 1 It is -CH2CH2N(CH3)-.

[0089] In some embodiments, L 1 L is a C1-C6 alkylene. In some embodiments, L 1 L is a C1-C3 alkylene. In some embodiments, L 1 is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, L 1 is -CH2-. In some embodiments, L 1 It is -CH2CH2-.

[0090] In some embodiments, L 2 The bond is -C(O)-, -N(R 3 ) - or O.

[0091] In some embodiments, L 2 L is a bond. In some embodiments, L 2 is -C(O)-. In some embodiments, L 2 It is O.

[0092] In some embodiments, L 2 is -N(R 3 )-. In some transformations, R 3 is H or C1-C6 alkyl. In some embodiments, R 3 H is H. In some embodiments, R 3 is a C1-C6 alkyl group. In some embodiments, R 3is a C1-C3 alkyl group. In some embodiments, R 3 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 R is ethyl. In some embodiments, 3 is n-propyl. In some embodiments, R 3 L is isopropyl. In some embodiments, L 2 is -N(H)-. In some embodiments, L 2 is -N(CH3)-. In some embodiments, L 2 This is -N(CH2CH3)-.

[0093] In some embodiments, ring A is a monocyclic 4-6 membered heterocyclylene or a bicyclic 6-9 membered spiroheterocyclylene, the heterocyclylene contains 1-2 nitrogen atoms, and the heterocyclylene contains m R 4 It is substituted with a group. In some embodiments, ring A is a monocyclic 4-6 membered heterocyclene containing 1-2 nitrogen atoms, and m R 4 It is substituted with a group. In some embodiments, ring A is a bicyclic 6- to 9-membered spiroheterocyclylene, the spiroheterocyclylene contains 1 to 2 nitrogen atoms and m R groups. 4 It is substituted by the base.

[0094] In some embodiments, ring A contains 1 to 2 nitrogen atoms and m R atoms. 4 It is a monocyclic 4-6 membered heterocyclene substituted with a group. In some embodiments, ring A contains 1-2 nitrogen atoms and m R groups. 4 It is a monocyclic four-membered heterocyclene substituted with a group. In some embodiments, ring A contains 1 to 2 nitrogen atoms and m R groups. 4It is a monocyclic five-membered heterocyclene substituted with a group. In some embodiments, ring A contains 1 to 2 nitrogen atoms and m R groups. 4 It is a monocyclic six-membered heterocyclylene substituted with a group. In some embodiments, the monocyclic heterocyclylene contains one nitrogen atom. In some embodiments, the monocyclic heterocyclylene contains two nitrogen atoms. In some embodiments, the monocyclic heterocyclylene is azetidinylene, pyrrolidinylene, piperidinylene, or piperazinerene.

[0095] In some embodiments, ring A is [ka] And here, Y 1 and Y 2 Independently, CH or N, but Y 1 and Y 2 At least one of them is N. In some embodiments, Y 1 CH is Y 2 In some embodiments, Y 2 CH is Y 1 In some embodiments, Y 1 and Y 2 Each of these is N.

[0096] In some embodiments, ring A is [ka] That is the case.

[0097] In some embodiments, ring A contains 1 to 2 nitrogen atoms and m R atoms. 4 It is a bicyclic 6-membered spiroheterocyclylene substituted with a group. In some embodiments, ring A contains 1 to 2 nitrogen atoms and m R groups. 4It is a bicyclic 7-membered spiroheterocyclylene substituted with a group. In some embodiments, ring A contains 1 to 2 nitrogen atoms and m R groups. 4 It is a bicyclic 8-membered spiroheterocyclylene substituted with a group. In some embodiments, ring A contains 1 to 2 nitrogen atoms and m R groups. 4 It is a bicyclic 9-membered spiroheterocyclylene substituted with a group. In some embodiments, the bicyclic spiroheterocyclylene contains one nitrogen atom. In some embodiments, the bicyclic spiroheterocyclylene contains two nitrogen atoms.

[0098] In some embodiments, ring A is [ka] Therefore, one or both of the rings of the spiroheterocyclylene are present in a total of m R 4 It should be understood that substitutions can be made by different elements.

[0099] In some embodiments, each R 4 R is independently a halo, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 4 R is independently a halo, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, each R 4 These are independently F, Cl, -CH3, or -CF3. In some embodiments, each R 4 These are independently F or -CH3.

[0100] In some embodiments, R 4 is a halo. In some embodiments, R 4 is Cl, F, or Br. In some embodiments, R 4 is Cl. In some embodiments, R 4 In some embodiments, R 4 It is Br.

[0101] In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 is a C1-C3 alkyl group. In some embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 R is ethyl. In some embodiments, 4 is n-propyl. In some embodiments, R 4 It is isopropyl.

[0102] In some embodiments, R 4 is a C1-C6 haloalkyl. In some embodiments, R 4 R is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 4 R is a C1-C3 haloalkyl. In some embodiments, R 4 R is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 4 R is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 4 is -CF3. In some embodiments, R 4 It is -CHF2.

[0103] In some embodiments, m is between 0 and 5. In some embodiments, m is 0. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0104] In some embodiments, ring A is [ka] That is the case.

[0105] In some embodiments, R 5 is H or C1-C6 alkyl. In some embodiments, R 5 is H or C1-C3 alkyl. In some embodiments, R 5 is H or -CH3. In some embodiments, R 5 It is -CH3.

[0106] In some embodiments, R 5 H is H.

[0107] In some embodiments, R 5 is a C1-C6 alkyl group. In some embodiments, R 5 is a C1-C3 alkyl group. In some embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 R is ethyl. In some embodiments, 5 is n-propyl. In some embodiments, R 5 It is isopropyl.

[0108] In some embodiments, Z is CH or N. In some embodiments, Z is CH. In some embodiments, Z is N.

[0109] In some embodiments, [ka] teeth, [ka] That is the case.

[0110] In some embodiments, [ka] teeth, [ka] That is the case.

[0111] In some embodiments, [ka] teeth, [ka] That is the case.

[0112] In some embodiments, the compound of formula (I) is of formula (IA): [ka] [In the formula, R a is H or C1-C6 alkyl; R b The is a C1-C6 alkyl, a 5-6 membered heteroaryl, -(C1-C6 alkylene)(5-6 membered heteroaryl), or -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and 1-5 R 2 It may be substituted as desired by the base; and R 1 , R 5 Z, L 1 , L 2 Rings A and * are defined for formula (I). It is a compound of [the compound].

[0113] In some embodiments, the compound of formula (I) is of formula (IB): [ka] [In the formula, [ka] The heterocycline is a 5-10 member monocyclic or bicyclic heterocycline, which may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 It may be substituted as desired by the base; and R 1 , R 5 Z, L 1 , L 2 Rings A and * are defined for formula (I). It is a compound of [the compound].

[0114] In some embodiments, the compound of formula (I) is formula (IIa) or (IIb): [ka] [In the formula, R a , R b , R 1 , R 4 , R 5 m, Z, L 1 , L 2 , Y 1 and Y 2 This is as specified for equation (I). It is a compound of [the compound].

[0115] In some embodiments, the compound of formula (I) is formula (IIIa) or (IVa): [ka] [In the formula, R a , R b , R 1 , R 4 , R 5m, Z, L 1 and L 2 This is as specified for equation (I). It is a compound of [the compound].

[0116] In some embodiments, the compound of formula (I) is (Va), (Vb), (Vc), or (Vd): [ka] [In the formula, rings A, R a , R b , R 1 , R 3 , R 5 Z, L 2 And * are as defined for formula (I); and n is an integer between 1 and 6. It is a compound of [the compound].

[0117] In some embodiments, the compound of formula (I) is (VIa), (VIb), (VIc), or (VId): [ka] [In the formula, rings A, R a , R b , R 1 , R 3 , R 5 Z, L 1 And * are as defined for formula (I). It is a compound of [the compound].

[0118] In some embodiments, the compound of formula (I) is (VIa), (VIb), (VIc), or (VId): [ka] [In the formula, R a , R b , R 1 , R 4 , R 5 Z, L 1 , L 2And * are as defined for formula (I). It is a compound of [the compound].

[0119] In this specification, any description, variation, embodiment, or aspect of any part may be combined with any description, variation, embodiment, or aspect of any other part, and each combination of descriptions is understood to be the same as if they were described specifically and individually. For example, with respect to ring A of formula (I), all descriptions, variations, embodiments, or aspects provided herein are R 1 , R a , R b , R 2 , L 1 , L 2 , R 3 , R 4 , m, R 5 All descriptions, variations, embodiments, or aspects of and Z may be combined, and each combination can be combined in the same way as if it were specifically and individually listed. Furthermore, all descriptions, variations, embodiments, or aspects of formula (I) apply equally to other formulas described in detail herein, where applicable, and for all formulas, each and all descriptions, variations, embodiments, or aspects are understood to be described as if they were described separately and individually. For example, all descriptions, variations, embodiments, or aspects of formula (I) apply equally to any of the formulas detailed herein, where applicable, such as formulas (IA), (IB), (IIa), (IIb), (IIIa), (IVa), (Va), (Vb), (Vc), (Vd), (VIa), (VIb), (VIc), (VId), (VIIa), (VIIb), and (VIIc), and each and all descriptions, variations, embodiments, or aspects are described for all formulas as if they were described separately and individually.

[0120] In some embodiments, compounds selected from the compounds in Table 1 or their pharmaceutically acceptable salts are provided. While certain compounds described in this disclosure, including Table 1, are shown as specific stereoisomers and / or non-stereochemical forms, it will be understood that any or all stereochemical forms, including any enantiomer or diastereomer forms, as well as any tautomers or other forms of the compounds in this disclosure, including Table 1, are also described herein.

[0121] [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]

[0122] In this specification, it is understood that combinations of substituents and / or variables in the depicted formulas are permissible only if such involvement results in a stable compound.

[0123] Furthermore, all compounds of formula (I) existing in the form of free bases or acids can be converted to their pharmaceutically acceptable salts by treatment with a suitable inorganic or organic base or acid using methods known to those skilled in the art. Salts of compounds of formula (I) can be converted to the form of free bases or acids by standard techniques.

[0124] Synthesis method The compounds described herein can be prepared using conventional organic synthesis methods and commercially available starting materials, or by methods provided herein. For illustrative purposes only, the compound of formula (I) may be prepared as outlined in Schemes 1-5, similar to the examples described herein. Those skilled in the art will understand how the methods described in the illustrative schemes and examples may be modified to obtain the desired product.

[0125] The compound of formula A can be prepared as outlined in Scheme 1. Under basic conditions, such as in the presence of DIPEA, intermediate a-1 is coupled with intermediate a-2 to form intermediate a-3, which is then deprotected under basic conditions to form intermediate a-4. Subsequently, intermediate a-4 is coupled with intermediate a-5 using TCFH / NMI to obtain intermediate a-6. This is then deprotected under basic conditions to obtain intermediate a-7. Intermediate a-7 is then coupled with intermediate a-8 (for example, using HATU) to produce intermediate a-9. Under acidic conditions, a-9 is deprotected to obtain the compound of formula A.

[0126] [ka] [wherein X is a halo (e.g., chloro); Pg is a protecting group (e.g., Boc); R is an alkyl group (e.g., methyl or ethyl); R 1 This is as described for equation (I); and [ka] teeth, [ka] This represents the part of equation (I) that corresponds to [the given expression].

[0127] The compound of formula B can be prepared as outlined in Scheme 2. Under basic conditions (e.g., in the presence of DIPEA), intermediate a-1 was coupled with intermediate b-1 to form intermediate b-2, which was then deprotected under basic conditions to obtain intermediate b-3. Subsequently, intermediate b-3 was coupled with intermediate b-5 (e.g., prepared by reducing intermediate b-4 with NaBH4) using TCFH / NMI to obtain intermediate b-6. After oxidation of intermediate b-6, it was reductively aminated together with intermediate a-8 (e.g., using IBX and NaBH(OAc)3) to obtain the compound of formula B.

[0128] [ka] [wherein X is a halo (e.g., chloro); each R is independently an alkyl (e.g., methyl or ethyl); R 1 , R a and R b This is as described for equation (I); and [ka] teeth, [ka] This represents the part of equation (I) that corresponds to [the given expression].

[0129] The compound of formula C can be prepared as outlined in Scheme 3. Intermediate c-2 is obtained by reducing intermediate c-1 (e.g., using NaBH4), and this is converted to intermediate c-3. Next, intermediate c-4 is obtained by cyanidating c-3, and this is reduced (e.g., using DIBAL-H) ​​to obtain intermediate c-5. Next, intermediate c-6 is obtained by reducing c-5 (e.g., using NaBH4), and this is hydrogenated under catalytic conditions to produce intermediate c-7. Intermediate c-7 and intermediate c-8 are coupled using TCFH / NMI to obtain intermediate c-9. After further oxidation of intermediate c-9, it is reductively aminated together with intermediate a-8 (e.g., using IBX and NaBH(OAc)3) to obtain the compound of formula C.

[0130] [ka] [In the formula, Lg is a leaving group (e.g., mesylate); R is an alkyl group (e.g., methyl or ethyl); R 1 , R a and R b This is as described for equation (I); and, [ka] teeth, [ka] This represents the part of equation (I) that corresponds to [the given expression].

[0131] The compound of formula D can be prepared as outlined in Scheme 4. Intermediate b-6 can be prepared in the same manner as described above for the synthesis of the compound of formula B and for Scheme 2. After oxidation of intermediate b-6, it was reductively aminated together with intermediate d-1 (e.g., using IBX and NaBH(OAc)3) to obtain the compound of formula D.

[0132] [ka] [wherein X is a halo (e.g., chloro); R is an alkyl (e.g., methyl or ethyl); and R 1 , R a , R b , R 3 and R 5 This is as described for equation (I).

[0133] The compound of formula E can be prepared as outlined in Scheme 5. In the first reaction system, intermediate e-1 is converted to intermediate e-2, which is then coupled with intermediate e-3 to form intermediate e-4. After reducing e-4 to intermediate e-5 (for example, using Zn under acidic conditions), it is coupled with intermediate a-4 using TCFH / NMI to obtain intermediate e-6, which is then hydrogenated to obtain intermediate e-7. In the second reaction system, intermediate a-8 is coupled with intermediate e-8 under reducing conditions (for example, using NaBH(OAc)3) to obtain intermediate e-9. This is then deprotected under acidic conditions to produce intermediate e-10. Subsequently, under reducing conditions (for example, using NaBH(OAc)3), e-10 is coupled with e-7 to obtain intermediate e-11, which is then deprotected under acidic conditions to obtain the compound of formula E.

[0134] [ka] [In the formula, each Pg is independently a protecting group (e.g., Cbz or Boc); each R is independently an alkyl group (e.g., methyl or ethyl); R 1 This is as stated for equation (I); and, [ka] teeth, [ka] This represents the part of equation (I) that corresponds to [the given expression].

[0135] How to use Embodiments of this disclosure provide a method for modulating IRAK4 in a subject requiring modulation, characterized by administering an effective amount of a compound of formula (I) to the subject. Modulation of IRAK4 (e.g., inhibition or activation) can be evaluated and demonstrated by various methods known in the art. Kits and commercially available assays are available to determine whether and to what extent IRAK4 has been modulated (e.g., inhibited or activated).

[0136] In one embodiment, provided herein is a method for modulating IRAK4, characterized by contacting IRAK4 with an effective amount of the compound of formula (I) or any embodiment or variation thereof. In some embodiments, the compound of formula (I) inhibits IRAK4. In another embodiment, the compound of formula (I) activates IRAK4. In some embodiments, the compound of formula (I) is an agonist of IRAK4. In some embodiments, the compound of formula (I) is an antagonist of IRAK4.

[0137] In some embodiments, provided herein are methods for targeting and degrading IRAK4, characterized by contacting IRAK4 with an effective amount of a compound of formula (I) or any embodiment or modification thereof.

[0138] In some embodiments, the compound of formula (I) adjusts the activity of IRAK4 to approximately 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 IRAK4 by approximately 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, and 80-100%. Adjust to 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0139] Furthermore, provided in certain embodiments of this disclosure is a method for degrading IRAK4 in an object that needs to be degraded, characterized by administering an effective amount of the compound of formula (I) to the object. Degradation of IRAK4 can be evaluated and demonstrated by various methods known in the art. Kits and commercially available assays (e.g., cell line assays) can be used to determine whether and to what extent IRAK4 has been degraded.

[0140] In one embodiment, provided herein is a method for degrading IRAK4, characterized by contacting IRAK4 with an effective amount of the compound of formula (I) or any embodiment or variation thereof. In some embodiments, the compound of formula (I) partially degrades IRAK4. In some embodiments, the compound of formula (I) completely degrades IRAK4.

[0141] In some embodiments, the compound of formula (I) degrades IRAK4 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) contains IRAK4 in amounts of approximately 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, Decompose into 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%.

[0142] In another embodiment, provided herein is a method for treating an inflammatory disease or autoimmune disease in a subject requiring treatment, comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, provided herein is a method for treating an inflammatory disease in a subject requiring treatment, comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, provided herein is a method for treating an autoimmune disease in a subject requiring treatment, comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, provided herein is a method for preventing an inflammatory disease or autoimmune disease in a subject requiring treatment, comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, provided herein is a method for preventing an inflammatory disease in a subject requiring treatment, comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, provided herein is a method for preventing an autoimmune disease in a subject requiring treatment, comprising administering an effective amount of a compound of formula (I) to the subject. Non-exclusive examples of inflammatory or autoimmune diseases include atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryopyrin-associated periodic syndromes, hidradenitis suppurativa, Beckett syndrome, or familial cold autoinflammatory syndrome.

[0143] In some embodiments, administering a compound of formula (I) to a subject predisposed to inflammatory or autoimmune diseases prevents the subject from developing any symptoms of an inflammatory or autoimmune disease (e.g., tumor growth or metastasis). In some embodiments, administering a compound of formula (I) to a subject that has not yet shown any symptoms of an inflammatory or autoimmune disease prevents the subject from developing any symptoms of an inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment reduces the severity of the inflammatory or autoimmune disease in the subject. In some embodiments, administering a compound of formula (I) to a subject in need of treatment stabilizes the inflammatory or autoimmune disease (prevents or delays its worsening). In some embodiments, administering a compound of formula (I) to a subject in need of treatment delays the onset or recurrence of the inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment slows the progression of the inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment provides partial remission of an inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment provides complete remission of an inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment reduces the dose of one or more other drugs required to treat the inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment enhances the effect of other drugs used to treat the inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment slows the progression of the inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment improves the quality of life of a subject with an inflammatory or autoimmune disease.In some embodiments, administering a compound of formula (I) to a subject in need of treatment extends the survival time of subjects with inflammatory or autoimmune diseases.

[0144] In one embodiment, the foregoing provides a method for preventing a subject predisposed to an inflammatory disease or autoimmune disease from developing any symptoms of an inflammatory disease or autoimmune disease, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the foregoing provides a method for preventing a subject that has not yet shown symptoms of an inflammatory disease or autoimmune disease from developing any symptoms of an inflammatory disease or autoimmune disease, the method comprising administering a compound of formula (I) to the subject.

[0145] In some embodiments, the foregoing provides a method for reducing the severity of an inflammatory or autoimmune disease in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the foregoing provides a method for stabilizing an inflammatory or autoimmune disease in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the method prevents the worsening of an inflammatory or autoimmune disease. In some embodiments, the method slows the worsening of an inflammatory or autoimmune disease.

[0146] In another embodiment, provided herein is a method for delaying the onset or recurrence of an inflammatory or autoimmune disease in a subject, the method comprising administering a compound of formula (I) to the subject.

[0147] In some embodiments, the methods provided herein are for slowing the progression of an inflammatory or autoimmune disease in a subject, the methods comprising administering a compound of formula (I) to the subject. In some embodiments, the methods result in partial remission of the inflammatory or autoimmune disease. In some embodiments, the methods result in complete remission of the inflammatory or autoimmune disease.

[0148] In a further embodiment, provided herein is a method for reducing the dose of one or more other agents required to treat an inflammatory or autoimmune disease in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, provided herein is a method for enhancing the effect of another agent used to treat an inflammatory or autoimmune disease in a subject, the method comprising administering a compound of formula (I) to the subject.

[0149] Furthermore, a method is provided for delaying the progression of inflammatory or autoimmune diseases in subjects, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the method improves the quality of life of subjects with inflammatory or autoimmune diseases. In some embodiments, the method extends the survival time of subjects with inflammatory or autoimmune diseases.

[0150] In another embodiment, provided herein are methods for treating symptoms of an inflammatory or autoimmune disease caused by a disease in a subject requiring treatment, comprising administering an effective amount of the compound of formula (I) to the subject. In some embodiments, provided herein are methods for preventing symptoms of an inflammatory or autoimmune disease caused by a disease in a subject requiring treatment, comprising administering an effective amount of the compound of formula (I) to the subject. In some embodiments, administering the compound of formula (I) to a subject predisposed to a disease that causes symptoms of an inflammatory or autoimmune disease prevents the subject from developing symptoms of the inflammatory or autoimmune disease. In some embodiments, administering the compound of formula (I) to a subject that has not yet developed symptoms of an inflammatory or autoimmune disease related to a disease that causes symptoms of an inflammatory or autoimmune disease can prevent the subject from developing symptoms of the inflammatory or autoimmune disease. In some embodiments, administering the compound of formula (I) to a subject requiring treatment reduces the severity of symptoms of an inflammatory or autoimmune disease caused by a disease in the subject. In some embodiments, administering a compound of formula (I) to a subject in need of treatment stabilizes the symptoms of an inflammatory or autoimmune disease (prevents or delays the worsening of symptoms of an inflammatory or autoimmune disease). In some embodiments, administering a compound of formula (I) to a subject in need of treatment delays the onset or recurrence of symptoms of an inflammatory or autoimmune disease caused by the disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment slows the progression of symptoms of an inflammatory or autoimmune disease caused by the disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment results in partial remission of the disease causing symptoms of an inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment results in complete remission of the disease causing symptoms of an inflammatory or autoimmune disease.In some embodiments, administering a compound of formula (I) to a subject in need of treatment reduces the dose of one or more other drugs required to treat a disease causing symptoms of an inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment enhances the effect of other drugs used to treat symptoms of an inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment delays the progression of a disease causing symptoms of an inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment improves the quality of life of a subject with a disease causing symptoms of an inflammatory or autoimmune disease. In some embodiments, administering a compound of formula (I) to a subject in need of treatment extends the survival time of a subject with a disease causing symptoms of an inflammatory or autoimmune disease. In some embodiments, the disease is atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryopyrin-associated periodic syndromes, hidradenitis suppurativa, Beckett syndrome, or familial cold autoinflammatory syndrome.

[0151] In some embodiments, compounds of formula (I) are useful for treating diseases selected from atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryopyrin-associated periodic syndromes, hidradenitis suppurativa, Beckett syndrome, and familial cold autoinflammatory syndrome.

[0152] Pharmaceutical composition and route of administration The compounds provided herein may be administered orally, topically, or parenterally to a subject by conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, lozenges, tablets, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0153] The compounds disclosed herein may be administered orally, topically, or parenterally to a subject in the form of conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations may include excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), and lubricants (e.g., magnesium stearate, light It can be manufactured by conventional methods using conventional organic or inorganic additives such as anhydrous silicic acid, talc, sodium lauryl sulfate, flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfate, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersants (e.g., hydroxypropyl methylcellulose), 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 present at a level that produces the desired effect; for example, in unit doses for both oral and parenteral administration, it ranges from about 0.005 mg per kg of body weight to about 10 mg per kg of body weight of the subject.

[0154] The dose of the compound of formula (I) administered to a subject can vary over a wide range and is subject to the judgment of the healthcare professional. Generally, the compounds disclosed herein can be administered at doses of approximately 0.001 mg to approximately 10 mg per kg of body weight of the subject, 1 to 4 times a day, but the above dose can be appropriately adjusted depending on the subject's age, weight, medical condition, and route of administration. In any case, the amount of compound of formula (I) administered will vary depending on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0155] The compound of formula (I) may be administered orally for convenience. In one embodiment, when administered orally, the compound of formula (I) is administered with food and water. In another embodiment, the compound of formula (I) is administered orally as a solution or suspension, dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid.

[0156] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, percutaneously, rectally, mucous membrane, or by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is at the discretion of the healthcare professional and may be partially modified depending on the site of the condition.

[0157] In one embodiment, what is provided herein is a capsule containing a compound of formula (I) that does not contain additional carriers, excipients, or vehicles.

[0158] In another embodiment, provided herein is a composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may include excipients, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0159] The compositions may take the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, and suspensions. The compositions may be formulated to contain a daily dose, or a suitable portion of a daily dose, in a single tablet or capsule, or in a suitable amount of liquid, as a dosage unit. In one embodiment, the solution is prepared from a water-soluble salt such as hydrochloride. In general, all compositions are manufactured according to known methods in pharmaceutical chemistry. Capsules can be manufactured by mixing the compound of formula (I) with a suitable carrier or diluent and filling a suitable amount of the mixture into a capsule. Common carriers and diluents include, but are not limited to, a wide variety of starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flour and similar edible powders, and other inert powders.

[0160] Tablets can be manufactured by direct compression, wet granulation, or dry granulation. The formulations typically contain not only the compound but also diluents, binders, lubricants, and disintegrants. Typical diluents include, for example, various starches, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugars. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose). Natural and synthetic gums such as acacia, alginates, methylcellulose, and polyvinylpyrrolidine are also convenient. Polyethylene glycol, ethylcellulose, and waxes can also function as binders.

[0161] In tablets, a lubricant may be necessary to prevent dye from adhering to the tablet and the tableting machine. The lubricant can be selected from lubricating solids such as talc, magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell and disintegrate the tablet upon contact with moisture, releasing compounds. These include starch, clay, cellulose, algins, and gums. More specifically, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose, such as sodium lauryl sulfate, can also be used. Tablets may also be coated with sugars as flavoring or odor-modifying agents, or with film-forming protective agents to alter the tablet's solubility. Furthermore, the composition can be formulated as a chewable tablet by using substances such as mannitol in the formulation.

[0162] When administering the compound of formula (I) as a suppository, typical bases can be used. Cocoa butter is a conventional suppository base and can be modified by adding wax to slightly raise its melting point. In particular, water-miscible suppository bases containing polyethylene glycol of various molecular weights are widely used.

[0163] The effects of the compound of formula (I) can be delayed or prolonged by appropriate formulation. For example, pellets of the compound of formula (I) that can dissolve gradually can be prepared and incorporated into tablets or capsules, or as a sustained-release implantable device. This technique also includes preparing pellets with several different dissolution rates and filling a capsule with a mixture of these pellets. The tablets or capsules may be coated with a film that resists dissolution for a predictable period. Even parenteral formulations can be made long-acting by dissolving or suspending the compound of formula (I) in an oily or emulsifying agent that disperses slowly in serum.

[0164] Exemplary Example This disclosure is further illustrated by the following embodiments.

[0165] Embodiment P1. Formula (I): [ka] [In formula: R 1 It is a C1-C6 haloalkyl; R a is H or C1-C6 alkyl; R b The is a C1-C6 alkyl, a 5-6 membered heteroaryl, -(C1-C6 alkylene)(5-6 membered heteroaryl), or -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and 1-5 R 2 It may be substituted as desired by the base; or R a and R b The dotted line between them indicates a ring structure, where R a and R b These, together with the nitrogen atoms bonded to them, form a 5-10 member monocyclic or bicyclic heterocycline, the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 It may be substituted by the base as desired; Each R 2 These are independently -NH2, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or a 5-6 membered heteroaryl, wherein the heteroaryl contains 1-2 nitrogen atoms and may optionally be substituted with 1-5 groups selected from C1-C6 alkyl, halo, and C1-C6 haloalkyl; L 1 -C(O)N(H)-, -C(O)-, -(C1-C6 alkylene)N(R 3 )- or C1-C6 alkylene; L 2 The bond is -C(O)-, -N(R 3 )- or O; Each R3 These are independently H or C1-C6 alkyl; Ring A is a monocyclic 4-6 membered heterocyclylene or a bicyclic 6-9 membered spiroheterocyclylene, the heterocyclylene contains 1-2 nitrogen atoms, and the heterocyclylene contains m R 4 Substituted by the group; Each R 4 These are independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; m is between 0 and 5; R 5 is H or C1-C6 alkyl; Z is CH or N; and * is L 2 [Indicates the binding site to the contained group] Compounds thereof or pharmaceutically acceptable salts thereof.

[0166] Embodiment P2. R 1 The compound described in Embodiment P1 or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C3 haloalkyl group.

[0167] Embodiment P3. R 1 The compound according to Embodiment P2 or a pharmaceutically acceptable salt thereof, wherein the compound is -CHF2 or -CF3.

[0168] Embodiment P4. R 1 However, the compound described in Embodiment P3 or a pharmaceutically acceptable salt thereof is -CHF2.

[0169] Embodiment P5. R a However, it is H or C1-C3 alkyl; R b The heteroaryl is a C1-C3 alkyl, a 6-membered heteroaryl, -(C1-C3 alkylene)(6-membered heteroaryl), or -(C1-C3 alkylene)NH2, wherein the heteroaryl contains 1 to 2 nitrogen atoms and 1 to 2 R 2 It may be substituted as desired by the base; and Each R 2However, independently, they are -NH2, halo, C1-C3 alkyl, C1-C3 haloalkyl, or -CN. A compound described in any one of embodiments P1 to P4 or a pharmaceutically acceptable salt thereof.

[0170] Embodiment P6. R a However, it is either H or -CH3; R b However, it is -CH3, -CH2(pyridyl), -CH2CH2NH2 or pyridyl, and the pyridyl is one R 2 It may be substituted as desired by the base; and R 2 However, the compound described in Embodiment P5 or a pharmaceutically acceptable salt thereof, wherein the compound is -CH3.

[0171] Embodiment P7. [ka] but, [ka] The compound described in Embodiment P6 or a pharmaceutically acceptable salt thereof.

[0172] Embodiment P8. R a and R b However, together with the nitrogen atoms bonded to them, they form a 5-8 member monocyclic or bicyclic heterocycline, and the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-3 R 2 The base may be substituted as desired; and Each R 2The compound according to any one of Embodiments P1 to P4 or a pharmaceutically acceptable salt thereof, wherein is independently -NH2, halo, C1-C3 alkyl, C1-C3 haloalkyl, -CN, or a 5-membered heteroaryl, wherein the heteroaryl contains 1 to 2 nitrogen atoms and may optionally be substituted with 1 to 3 groups selected from C1-C3 alkyl, halo, and C1-C3 haloalkyl.

[0173] Embodiment P9. R a and R b However, together with the nitrogen atoms bonded to them, they form a 5-6 member monocyclic heterocycline or an 8 member condensed or bridging bicyclic heterocycline, and the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-3 R 2 It may be substituted as desired by the base; and Each R 2 The compound described in Embodiment P8 or a pharmaceutically acceptable salt thereof, which is independently -NH2, F, Cl, -CH3, -CF3, -CN, or pyrazolyl, which may optionally be substituted with one or two groups selected from -CH3 and Cl.

[0174] Embodiment P10. [ka] but, [ka] The compound described in Embodiment P9 or a pharmaceutically acceptable salt thereof.

[0175] Embodiment P11. L 1 However, -C(O)N(H)-, -C(O)-, -(C1-C3 alkylene)N(R 3 )- or C1-C3 alkylene; and, R 3The compound described in any one of Embodiments P1 to P10 or a pharmaceutically acceptable salt thereof, wherein the compound is H or a C1-C3 alkyl group.

[0176] Embodiment P12. L 1 The compound according to Embodiment P11 or a pharmaceutically acceptable salt thereof, wherein the compound is -C(O)N(H)-, -C(O)-, -CH2N(H)-, -CH2N(CH3)-, -CH2CH2N(CH3)-, -CH2-, or -CH2CH2-.

[0177] Embodiment P13. L 2 However, the bond is -C(O)-, -N(R 3 )- or O; and R 3 The compound described in any one of Embodiments P1 to P12, wherein the compound is H or a C1-C3 alkyl group, or a pharmaceutically acceptable salt thereof.

[0178] Embodiment P14. L 2 A compound or a pharmaceutically acceptable salt thereof according to Embodiment P13, wherein the bond is -C(O)-, -N(H)-, -N(CH3)-, or O.

[0179] Embodiment P15. Ring A contains 1 to 2 nitrogen atoms and m R 4 A compound according to any one of embodiments P1 to P14, which is a monocyclic 4-6 membered heterocyclene substituted with a group, or a pharmaceutically acceptable salt thereof.

[0180] Embodiment P16. Ring A is [ka] and; Y 1 and Y 2 However, independently, it is CH or N, but Y 1 and Y 2A compound or a pharmaceutically acceptable salt thereof according to Embodiment P15, wherein at least one of the is N.

[0181] Embodiment P17. Y 1 However, CH is; and Y 2 The compound described in Embodiment P16 or a pharmaceutically acceptable salt thereof, wherein N is present.

[0182] Embodiment P18. Y 1 However, N come; and Y 2 However, the compound described in Embodiment P16 or a pharmaceutically acceptable salt thereof is CH.

[0183] Embodiment P19. Y 1 and Y 2 The compound or a pharmaceutically acceptable salt thereof described in Embodiment P16, wherein each of the compounds is N.

[0184] Embodiment P20. Ring A is [ka] The compound described in Embodiment P15 or a pharmaceutically acceptable salt thereof.

[0185] Embodiment P21. Ring A contains 1 to 2 nitrogen atoms and m R 4 A compound according to Embodiment P15 or a pharmaceutically acceptable salt thereof, which is a bicyclic 6- to 9-membered spiroheterocyclylene substituted with a group.

[0186] Embodiment P22. Ring A is [ka] The compound described in Embodiment P21 or a pharmaceutically acceptable salt thereof.

[0187] Embodiment P23. Each R 4 However, the compound according to any one of Embodiments P1 to P22, which is independently a halo, C1-C3 alkyl, or C1-C3 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0188] Embodiment P24. Each R 4 However, the compound according to Embodiment P23 or a pharmaceutically acceptable salt thereof, which is independently F, Cl, -CH3 or -CF3.

[0189] Embodiment P25. Each R 4 However, independently, the compound described in Embodiment P24 or a pharmaceutically acceptable salt thereof, which is F or -CH3.

[0190] Embodiment P26. A compound according to any one of Embodiments P1 to P22 or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0191] Embodiment P27. A compound according to any one of Embodiments P1 to P25 or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

[0192] Embodiment P28. Ring A is [ka] A compound according to any one of embodiments P1 to P27 or a pharmaceutically acceptable salt thereof.

[0193] Embodiment P29. R 5 The compound described in any one of Embodiments P1 to P28 or a pharmaceutically acceptable salt thereof, wherein the compound is H or a C1-C3 alkyl group.

[0194] Embodiment P30. R 5 The compound described in Embodiment P29 or a pharmaceutically acceptable salt thereof, wherein the compound is H or -CH3.

[0195] Embodiment P31. R 5 However, the compound described in Embodiment P30 or a pharmaceutically acceptable salt thereof, wherein the compound is -CH3.

[0196] Embodiment P32. A compound according to any one of Embodiments P1 to P31 or a pharmaceutically acceptable salt thereof, wherein Z is CH.

[0197] Embodiment P33. A compound according to any one of Embodiments P1 to P31 or a pharmaceutically acceptable salt thereof, wherein Z is N.

[0198] Embodiment P34. [ka] but, [ka] A compound according to any one of embodiments P1 to P33 or a pharmaceutically acceptable salt thereof.

[0199] Embodiment P35. [ka] but, [ka] A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments P1 to P34.

[0200] Embodiment P36. [ka] but, [ka] A compound according to any one of embodiments P1 to P35 or a pharmaceutically acceptable salt thereof.

[0201] Embodiment P37. The compound is of formula (IA): [ka] [In the formula, R a but is H or C1-C6 alkyl; and R b The C1-C6 alkyl, 5-6 membered heteroaryl, -(C1-C6 alkylene)(5-6 membered heteroaryl), or -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and 1-5 R 2 [May be substituted as desired by the base] A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments P1 to P7 and P11 to P36.

[0202] Embodiment P38. The compound is of formula (IB): [ka] [In the formula, [ka] The heterocycline is a 5-10 member monocyclic or bicyclic heterocycline, which may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 [May be substituted as desired by the base] A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 4 and 8 to 36.

[0203] Embodiment P39. The compound is of formula (IIa) or (IIb): [ka] A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments P1 to P19 and P23 to P37.

[0204] Embodiment P40. The compound is of formula (IIIa) or (IVa): [ka] A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments P1 to P15, P20, P21 and P23 to P38.

[0205] Embodiment P41. A compound selected from the compounds in Table 1 and their pharmaceutically acceptable salts.

[0206] Embodiment P42. A pharmaceutical composition comprising a compound described in any one of Embodiments P1 to P41 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0207] Embodiment P43. A method for modulating interleukin-1 (IL1) receptor-related kinase 4 (IRAK4), characterized by contacting IRAK4 with an effective amount of a compound described in any one of Embodiments P1 to P41 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment P42.

[0208] Embodiment P44. A method for treating an inflammatory disease or autoimmune disease, characterized by administering an effective amount of a compound described in any one of Embodiments P1 to P41 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment P42, to a subject in need of treatment.

[0209] Embodiment P45. The method of Embodiment P44, wherein the inflammatory or autoimmune disease is atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryopyrin-associated periodic syndromes, hidradenitis suppurativa, Beckett syndrome, or familial cold autoinflammatory syndrome. [Examples]

[0210] The following examples are for illustrative purposes only and are not limiting. The compounds were named using the automated naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures while adhering to the Kahn-Ingold-Prelogue order rule for stereochemistry. Those skilled in the art can modify the procedures described in the illustrated examples to arrive at the target product.

[0211] Salts of the compounds described herein can be prepared by standard methods such as mixing an acid (e.g., TFA, formic acid, or HCl) into the mobile phase during chromatographic purification, or stirring the product after chromatographic purification with an acidic solution (e.g., an aqueous solution of HCl).

[0212] As used in some of the chemical structures provided in the following examples, if a particular atom is designated with "*" or "or1", it indicates that the absolute stereochemistry of that atom could not be determined.

[0213] The following abbreviations may be related to this application. TIFF2026517882000087.tif112156 TIFF2026517882000088.tif149156

[0214] Synthesis Examples LCMS method LCMS method 1 Column: Luna C18 (2) 50 x 3 mm, 3 μm. Temperature: 45°C, Flow rate: 1.5 mL / min, Duration: 2.5 minutes. Mobile phase conditions: Initially 95% H2O + 0.1% FA / 5% MeCN + 0.1% FA, linear gradient to 95% MeCN + 0.1% FA over 1.3 minutes, then held at 95% MeCN + 0.1% FA for 1.2 minutes. MSD: ESI positive.

[0215] LCMS method 2 Column: SunFire C18 75 x 4.6 mm, 3.5 μm. Temperature: 45°C, Flow rate: 1.5 mL / min, Duration: 6 minutes. Mobile phase conditions: Initial 95% H2O + 0.1% FA / 5% MeCN + 0.1% FA, followed by a linear gradient to 95% MeCN + 0.1% FA over 4 minutes, then retention at 95% MeCN + 0.1% FA for 2 minutes. MSD: Positive.

[0216] LCMS method 3 Column: Kinetex Polar C18 2.6 μm, 50 x 3.0 mm. Temperature: 45°C, Flow rate: 1.2 mL / min, Duration: 3 minutes. Mobile phase conditions: Initial 95% H2O + 0.1% FA / 5% CH3CN + 0.1% FA, followed by a linear gradient to 95% MeCN over 1.5 minutes, then retention at 95% MeCN for 1.5 minutes. MSD: Positive.

[0217] LCMS method 4 Column: Kinetex Polar C18 2.6 μm, 50 x 3.0 mm. Temperature: 40 °C, Flow rate: 1.2 mL / min, Duration: 6 minutes. Mobile phase conditions: Initial 95% H2O + 0.1% FA / 5% CH3CN + 0.1% FA, followed by a linear gradient to 95% MeCN over 3.5 minutes, then retention at 95% MeCN for 2.5 minutes. MSD: Positive.

[0218] LCMS method 5 Column: C18 4.6 x 75 mm. Starting gradient: 95% H2O + 0.1% FA / 5% MeCN + 0.1% FA for 10 minutes, followed by 1.5 minutes of equilibration. Gradient from 95% H2O to 0% for 0-8 minutes, then held for 2 minutes.

[0219] LCMS method 6 Column: Kinetex XB-C18, 75 x 3.0 mm, 2.6 μm, Temperature: rt, Flow rate: 1.0 mL / min, Duration: 5 minutes, Mobile phase conditions: Mobile phase A: 5.0 mm ammonium formate (pH 3.3):CH3CN (98:02), Mobile phase B: CH3CN:5.0 mm ammonium formate (pH 3.3) (98:02), Gradient: Linear gradient from 70% mobile phase A and 30% mobile phase B at the start, to 100% mobile phase B over 4.0 minutes. MSD positive.

[0220] LCMS method 7

[0221] Column: XBridge - C8, 50 x 4.6 mm, 3.5 μm; Temperature: Room temperature; Flow rate: 1.5 mL / min; Duration: 6 minutes; Mobile phase conditions: Mobile phase A: 0.1% TFA / H2O, Mobile phase B: 0.1% TFA / acetonitrile; Gradient: 95% mobile phase A and 5% mobile phase B at the start, linear gradient to 5% mobile phase A and 95% mobile phase B over 2.5 minutes. MSD positive.

[0222] Synthesis of intermediates The designation of specific intermediate compounds with numbers such as 1 or 2 is specific to the example in which the number is given. Therefore, although the same intermediate compound number (e.g., 1 or 2) may be used in multiple examples, the chemical structure of the compound differs between different examples.

[0223] Example I-1. Synthesis of a typical intermediate T-1 [ka]

[0224] Step 1. Production of methyl 4-methylsulfonyloxycyclohexanecarboxylate (2) Under nitrogen, a solution of methyl 4-hydroxycyclohexanecarboxylate 1 (5.0 g, 31.61 mmol, 1.0 eq.) in CH2Cl2 (105 mL, 0.3 M) was cooled to 0°C, methanesulfonyl chloride (2.69 mL, 34.77 mmol, 1.1 eq.) was added, and then triethylamine (5.28 mL, 37.93 mmol, 1.2 eq.) was added dropwise. After stirring at 0°C for 2 hours, complete conversion was shown by TLC (CH2Cl2 / MeOH 5.5:0.5, KMnO4 staining). The reaction mixture was quenched by adding water, the phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined organic phases were washed twice with saline, dried on magnesium sulfate, filtered, and concentrated to obtain 2 (7.45 g, 99% yield) as a yellow oil.

[0225] 1 H NMR (400 MHz, CDCl3) δ ppm 1.67 - 1.84 (m, 4 H), 1.87 - 1.99 (m, 2 H), 2.00 - 2.09 (m, 2 H), 2.36 - 2.46 (m, 1 H), 3.02 (s, 3 H), 3.69 (s, 3 H), 4.87 - 4.96 (m, 1 H).

[0226] Step 2. Preparation of methyl 4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexanecarboxylate (4) Under nitrogen, a solution of 2 (1.16 g, 4.91 mmol, 1.0 eq.), 3 (0.80 g, 4.91 mmol, 1.0 eq.), and DMF (12.3 mL, 0.4 M) in a heated and dried round-bottom flask was stirred at room temperature for 5 minutes, after which Cs2CO3 (3.20 g, 9.81 mmol, 2.0 eq.) was added. The resulting mixture was stirred at 90°C for 16 hours. LC-MS confirmed that the conversion of 3 was incomplete (Method 1), and then a second dose of 2 (1.16 g, 4.91 mmol, 1.0 eq.) was added, and the mixture was stirred again at 90°C for 48 hours. LC-MS confirmed that 90% of 3 had been converted. The reaction was quenched by the addition of water. Ethyl acetate was added to separate the phases. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phase was washed once with water and once with saline solution, dried on magnesium sulfate, and concentrated. The residue was incorporated into MTBE and water, and the phases were separated. The organic phase was washed five times with water and once with saline solution, dried on magnesium sulfate, filtered, and concentrated to obtain an orange oily substance. The residue was then purified by normal-phase flash chromatography (80 g silica column, elution: 0-30% MTBE / heptane over 10 CV). The fractions were combined and concentrated to obtain impurity 4 (883 mg). The residue was purified by reverse-phase flash chromatography (100 g C18 RediSep Rf Gold column, holding solution (DMSO), elution: 5% MeOH / 0.1% HCOOH over 4 CV, then 5% to 100% MeOH / 0.1% HCOOH over 15 CV). The fractions were combined and concentrated to obtain 4 (618 mg, 41% yield) as a white solid.

[0227] LC-MS method 1: Retention time: 1.745 min, 99.9% purity (at 215 nm), [M+H] + = 304.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 - 1.60 (m, 2 H), 1.76 - 1.89 (m, 2 H), 2.00 - 2.15 (m, 4 H), 2.36 - 2.47 (m, 1 H), 3.61 (s, 3 H), 4.28 - 4.40 (m, 1 H), 7.14 - 7.47 (m, 1 H), 9.05 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -117.40 (s, 2 F).

[0228] Step 3. Preparation of methyl 4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexanecarboxylate (T-1) Under nitrogen, a solution of 4 (625 mg, 2.06 mmol, 1.0 eq.) and ethyl acetate (20.6 mL, 0.1 M) was degassed by sparging with nitrogen at room temperature for 15 minutes. Pd / C (438 mg, 10% w / w, 0.41 mmol, 0.2 eq.) was added, and sparging was repeated for 15 minutes. The mixture was sparged with H2 for 15 minutes, and then the mixture was stirred at room temperature for 16 hours, with the needle held just above the surface of the solvent. Complete conversion of 4 was confirmed by LC-MS (Method 1). The mixture was filtered through Celite, and the filter cake was thoroughly washed with ethyl acetate. The resulting solution was concentrated to obtain T-1 (563 mg, 99% yield) as a pale orange solid.

[0229] LC-MS method 1: Retention time: 1.297 min, 99.9% purity (at 215 nm), [M+H] + = 274.2. 1 H NMR (400 MHz, CDCl3) δ ppm 1.53 - 1.80 (m, 5 H), 2.12 - 2.42 (m, 9 H), 3.93 - 4.03 (m, 1 H), 6.54 - 6.84 (m, 1 H), 7.07 (s, 1 H). 19 F NMR (377 MHz, CDCl3) δ ppm -112.22 (s, 2 F).

[0230] Synthesis of common intermediates C-1, C-7, and C-8

[0231] Example I-2. Synthesis of a typical intermediate C-1 [ka]

[0232] Step 1. Preparation of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate (3) 3-(6-amino-1-methyl-indazole-3-yl)piperidine-2,6-dione hydrochloride (1) (250 mg, 0.848 mmol, 1.0 equiv) and tert-butyl 4-oxopiperidine-1-carboxylate (2) (304 mg, 1.53 mmol, 1.8 equiv) were suspended in DCE (4.2 mL) under a nitrogen atmosphere, and then acetic acid (146 μL, 2.54 mmol, 3.0 equiv) was added. Sodium triacetoxyborohydride (431 mg, 2.04 mmol, 2.4 equiv) was added all at once, and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. After evaporating the volatile substances under reduced pressure, the crude product was dissolved in a minimum amount of DMSO and purified by reverse-phase flash chromatography (MeOH / 0.1% HCOOH(aq), 5% (3 CV) → 100%, product obtained using 50 g RediSep Rf Gold® C18, 20 CV, λ = 214~254 nm, 75% MeOH). The fraction was evaporated and lyophilized to obtain 3 (313.3 mg, 0.710 mmol, 84% yield) as a brown solid.

[0233] LC-MS method 1: 99.9% purity (at 215 nm), [M+H] += 442.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.19 - 1.32 (m, 2 H), 1.41 (s, 9 H), 1.94 (br d, J = 11.4 Hz, 2 H), 2.10 - 2.19 (m, 1 H), 2.20 - 2.31 (m, 1 H), 2.56 - 2.65 (m, 2 H), 2.87 - 3.05 (m, 2 H), 3.47 - 3.62 (m, 1 H), 3.81 (s, 3 H), 3.89 (br d, J = 13.3 Hz, 2 H), 4.18 (dd, J = 8.7, 5.1 Hz, 1 H), 5.79 (d, J = 8.2 Hz, 1 H), 6.43 (s, 1 H), 6.52 (d, J = 9.3 Hz, 1 H), 7.33 (d, J = 8.7 Hz, 1 H), 10.82 (s, 1 H).

[0234] Step 2. Preparation of 3-[1-methyl-6-(piperidine-1-ium-4-ylamino)indazole-3-yl]piperidine-2,6-dione chloride (C-1) 4.0 M HCl / 1,4-dioxane (2.7 mL, 10.6 mmol, 15.0 equiv) was added to tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate (3) (313.3 mg, 0.710 mmol, 1.0 equiv), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was dried under high vacuum to remove all volatile components. Crude product C-1 (265 mg, 0.702 mmol, 99% yield) was obtained as an off-white solid and used in the next step without purification.

[0235] LC-MS method 1: 99.9% purity (at 215 nm), [M-HCl+H] + = 342.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 - 1.74 (m, 2 H), 2.09 - 2.20 (m, 3 H), 2.22 - 2.36 (m, 1 H), 2.55 - 2.66 (m, 2 H), 2.93 - 3.08 (m, 2 H), 3.32 (br d, J = 12.5 Hz, 2 H), 3.60 - 3.72 (m, 1 H), 3.85 (s, 3 H), 4.21 (dd, J = 9.0, 5.3 Hz, 1 H), 6.63 (br d, J = 8.3 Hz, 2 H), 7.42 (br d, J = 8.7 Hz, 1 H), 8.77 (br d, J = 7.7 Hz, 1 H), 8.88 (br d, J = 9.7 Hz, 1 H), 10.84 (s, 1 H).

[0236] The following compounds were synthesized using the same general route, with a modification to ketone 2 in step 1 (Table 2). [Table 15]

[0237] Example I-3. Synthesis of a typical intermediate C-2 [ka]

[0238] Step 1. Preparation of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]amino]piperidine-1-carboxylate (3) 3-(7-amino-1-methyl-indazole-3-yl)piperidine-2,6-dione hydrochloride (1) (500 mg, 1.70 mmol, 1.0 equiv) and tert-butyl 4-oxopiperidine-1-carboxylate (2) (608 mg, 3.05 mmol, 1.8 equiv) were suspended in DCE (17 mL) under a nitrogen atmosphere, and then acetic acid (291 μL, 5.09 mmol, 3.0 equiv) was added. Sodium triacetoxyborohydride (863 mg, 4.07 mmol, 2.4 equiv) was added all at once, and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. After evaporating the volatile substances under reduced pressure, the crude product was dissolved in a minimum amount of DMSO and purified by reverse-phase flash chromatography (MeCN / 0.1% HCOOH(aq), 5% (3 CV) → 60%, 100 g RediSep Rf Gold® C18, 20 CV, λ = 214~254 nm, 55% MeCN). The fraction was evaporated and freeze-dried to obtain 3 (702 mg, 1.59 mmol, 95% yield) as a brown solid.

[0239] LC-MS method 1: 98.5% purity (at 215 nm), [Mt-Bu+H] + = 386.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9 H), 1.42 - 1.51 (m, 2 H), 1.95 (br d, J = 12.6 Hz, 2 H), 2.10 - 2.20 (m, 1 H), 2.29 (dtd, J = 13.7, 9.0, 4.8 Hz, 1 H), 2.56 - 2.73 (m, 2 H), 2.80 - 3.16 (m, 2 H), 3.42 - 3.58 (m, 1 H), 3.87 (br d, J = 12.6 Hz, 2 H), 4.23 (s, 3 H), 4.25 - 4.32 (m, 1 H), 4.99 (br d, J = 6.6 Hz, 1 H), 6.58 (d, J = 7.3 Hz, 1 H), 6.89 (t, J = 7.7 Hz, 1 H), 6.99 (d, J = 7.9 Hz, 1 H), 10.85 (s, 1 H).

[0240] Step 2. Preparation of 3-[1-methyl-7-(4-piperidylamino)indazole-3-yl]piperidine-2,6-dione hydrochloride (C-2) 4.0 M HCl / 1,4-dioxane (9.7 mL, 38.7 mmol, 15.0 equiv) was added to tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]amino]piperidine-1-carboxylate 3 (1.16 g, 2.58 mmol, 1.0 equiv), and the mixture was stirred for 2 hours. The volatile substances were evaporated under reduced pressure to obtain the crude product as an off-white solid. The crude product was dissolved in a minimum amount of DMSO and purified by reverse-phase flash chromatography (MeCN / 0.02 M HCl(aq), 5% (3 CV) → 30%, 415 g RediSep Rf Gold® C18, 15 CV, λ = 214~254 nm, 5~20% MeCN to obtain the product). The fraction was evaporated and dried, and the residue was co-evaporated with water (3 × 25 mL) to remove all residual HCl. The mixture was then freeze-dried to obtain C-2 (937 mg, 2.48 mmol, 96% yield) as a brown solid.

[0241] LC-MS method 1: 99.9% purity (at 215 nm), [M+H] + = 342.4. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.71 - 1.89 (m, 2 H), 2.03 - 2.21 (m, 3 H), 2.21 - 2.40 (m, 1 H), 2.53 - 2.73 (m, 2 H), 2.92 - 3.10 (m, 2 H), 3.29 (br d, J = 11.9 Hz, 2 H), 3.63 (br t, J = 9.4 Hz, 1 H), 4.27 (s, 3 H), 4.28 - 4.37 (m, 1 H), 6.76 (br d, J = 6.6 Hz, 1 H), 6.95 (t, J = 7.7 Hz, 1 H), 7.15 (br d, J = 8.3 Hz, 1 H), 8.73 - 8.97 (m, 1 H), 9.10 (br d, J = 9.4 Hz, 1 H), 10.87 (s, 1 H).

[0242] Example I-4. Synthesis of a typical intermediate C-3 [ka]

[0243] Step 1. Preparation of tert-butyl N-[3-hydroxy-1-(2-hydroxyethyl)butyl]carbamate (2) Under nitrogen, a solution of 1 (3.0 g, 16.37 mmol, 1.0 eq.), t-BuOH (60.0 mL, 0.18 M), and THF (30.0 mL, 0.18 M) was stirred at room temperature for 5 minutes. Then, OsO4 (1.04 mL, 4.0% w / w / H2O, 0.16 mmol, 0.01 eq.) and NMO (2.30 g, 19.65 mL, 1.2 eq.) were added successively. The resulting mixture was stirred at room temperature for 4 hours. Complete conversion of 1 was confirmed by TLC (heptane / ethyl acetate 4:1, KMnO4 staining). The mixture was concentrated to remove t-BuOH and THF, and the residue was dissolved in ethyl acetate (200 mL) and washed with 10% Na2SO3 aqueous solution (2 x 25 mL), saturated NaHCO3 aqueous solution (25 mL), and saturated NaCl aqueous solution (25 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to obtain a white solid. The residue was then purified by normal-phase flash chromatography (80 g silica column, elution: 0 to 10% methanol / dichloromethane over 10 CV, product eluted with 10% methanol). The fractions were combined and concentrated to obtain 2 (2.83 g, 78% yield) as a white solid.

[0244] 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 9 H), 1.57 (br. s, 1 H), 1.70 - 1.82 (m, 2 H), 2.12 - 2.33 (m, 3 H), 2.79 - 3.05 (m, 1 H), 3.79 - 3.92 (m, 0.5 H), 4.00 (br. s, 1 H), 4.23 (br. s, 1 H), 4.38 - 4.60 (m, 0.5 H), 5.03 - 5.25 (m, 0.5 H).

[0245] Step 2. Preparation of tert-butyl N-[3-oxo-1-(2-oxoethyl)propyl]carbamate (3) Under nitrogen, a solution of 2 (2.83 g, 13.0 mmol, 1.0 eq.), THF (40.0 mL, 0.21 M), and H2O (20.0 mL, 0.21 M) was stirred at room temperature for 5 minutes, after which NaIO4 (3.34 g, 15.6 mmol, 1.2 eq.) was added. The resulting mixture was stirred at room temperature for 2 hours. Complete conversion of 2 was confirmed by TLC (CH2Cl2 / MeOH 95:5, KMnO4 staining). The mixture was concentrated to remove THF. After adding ethyl acetate (200 mL) and saline solution (100 mL), the phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried on magnesium sulfate, filtered, and concentrated to obtain a white semi-solid. The residue was dissolved in dichloromethane (125 mL) and dried at room temperature for 16 hours in the presence of a large and excess amount of magnesium sulfate. After filtering off the solid, the organic phase was concentrated and dried under high vacuum to obtain 3 (2.56 g, 89% yield) as an off-white semi-solid. The product was used directly in the next step without further purification.

[0246] Step 3. Preparation of tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]carbamate (5) To a 16 mL solution of tert-butyl N-[3-oxo-1-(2-oxoethyl)propyl]carbamate 3 (500 mg, 2.32 mmol, 1.2 eq.) and 3-(6-amino-1-methyl-indazole-3-yl)piperidine-2,6-dione 4 (500 mg, 1.94 mmol, 1 eq.) in DCE (16 mL), sodium triacetoxyborohydride (492.4 mg, 2.32 mmol, 1.2 eq.) was added at rt. The reaction mixture was stirred at rt. After 16 hours, LC-MS showed 50% conversion. Sodium triacetoxyborohydride (0.5 eq.) was added, and the mixture was stirred again for more than 4 hours. At this point, LC-MS showed 80% conversion. The reaction mixture was partitioned between DCM and H2O and extracted two more times with DCM. Finally, the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (150 g C18 RediSep Rf Gold column, holding solution (DMSO), elution: 5% MeCN / 0.1% HCOOH over 5 CV, then 100% MeCN / 0.1% HCOOH over 15 CV, then 100% MeCN / 0.1% HCOOH over 3 CV). The pure fraction was evaporated to obtain 5 (330 mg, 38% yield) as a pale orange solid.

[0247] LC-MS method 2: 98.7% purity (at 215 nm), [M+H] + = 442.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H), 1.42 - 1.56 (m, 2 H), 1.76 - 1.88 (m, 2 H), 2.10 - 2.20 (m, 1 H), 2.20 - 2.36 (m, 1 H), 2.58 - 2.65 (m, 2 H), 2.72 - 2.85 (m, 2 H), 3.35 - 3.49 (m, 1 H), 3.73 (d, J = 12.2 Hz, 2 H), 3.88 (s, 3 H), 4.25 (dd, J = 9.0, 5.1 Hz, 1 H), 6.84 (s, 1 H), 6.85 - 6.92 (m, 2 H), 7.47 (d, J = 9.0 Hz, 1 H), 10.84 (s, 1 H).

[0248] Step 4. Preparation of 3-[6-(4-amino-1-piperidyl)-1-methyl-indazole-3-yl]piperidine-2,6-dione hydrochloride (C-3) To a solution of tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]carbamate 5 (330 mg, 0.75 mmol, 1 eq.) in DCM (5 mL), a solution of 4 M HCl / 1,4-dioxane (2.8 mL, 11.21 mmol, 15 eq.) was added at rt. After 16 hours, complete conversion was shown by LC-MS. Volatile substances were removed under reduced pressure, and the excess hydrochloric acid was co-evaporated four times with DCM to obtain C-3 (320 mg, quantitative yield) as an off-white solid. This product was used in the next step without purification.

[0249] LC-MS method 2: 98.9% purity (at 215 nm), [M-HCl+H] + = 342.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 - 2.01 (m, 2 H), 2.06 - 2.21 (m, 3 H), 2.28 - 2.40 (m, 1 H), 2.56 - 2.74 (m, 2 H), 3.07 - 3.28 (m, 2 H), 3.28 - 3.40 (m, 1 H), 3.83 (d, J = 11.5 Hz, 2 H), 3.94 (s, 3 H), 4.32 (dd, J = 9.7, 5.0 Hz, 1 H), 7.21 (br s, 1 H), 7.42 (br s, 1 H), 7.66 (d, J = 8.1 Hz, 1 H), 8.32 (br s, 3 H), 10.88 (s, 1 H).

[0250] Example I-5. Synthesis of a typical intermediate C-4 [ka]

[0251] Step 1. Preparation of tert-butyl N-[3-hydroxy-1-(2-hydroxyethyl)butyl]carbamate (2) Under nitrogen, a solution of 1 (3.0 g, 16.37 mmol, 1.0 eq.), t-BuOH (60.0 mL, 0.18 M), and THF (30.0 mL, 0.18 M) was stirred at room temperature for 5 minutes. Then, OsO4 (1.04 mL, 4.0% w / w / H2O, 0.16 mmol, 0.01 eq.) and NMO (2.30 g, 19.65 mL, 1.2 eq.) were added in sequence. The resulting mixture was stirred at room temperature for 4 hours. Complete conversion of 1 was confirmed by TLC (heptane / ethyl acetate 4:1, KMnO4 staining). The mixture was concentrated to remove t-BuOH and THF. The residue was dissolved in ethyl acetate (200 mL) and washed with 10% Na2SO3 aqueous solution (2 x 25 mL), saturated NaHCO3 aqueous solution (25 mL), and saturated NaCl aqueous solution (25 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to obtain a white solid. The residue was then purified by normal-phase flash chromatography (80 g silica column, elution: 0 to 10% methanol / dichloromethane over 10 CV, product eluted with 10% methanol). The fractions were combined and concentrated to obtain 2 (2.83 g, 78% yield) as a white solid.

[0252] 1 H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 9 H), 1.57 (br. s, 1 H), 1.70 - 1.82 (m, 2 H), 2.12 - 2.33 (m, 3 H), 2.79 - 3.05 (m, 1 H), 3.79 - 3.92 (m, 0.5 H), 4.00 (br. s, 1 H), 4.23 (br. s, 1 H), 4.38 - 4.60 (m, 0.5 H), 5.03 - 5.25 (m, 0.5 H).

[0253] Step 2. Preparation of tert-butyl N-[3-oxo-1-(2-oxoethyl)propyl]carbamate (3) Under nitrogen, a solution of 2 (2.83 g, 13.0 mmol, 1.0 eq.), THF (40.0 mL, 0.21 M), and H2O (20.0 mL, 0.21 M) was stirred at room temperature for 5 minutes, after which NaIO4 (3.34 g, 15.6 mmol, 1.2 eq.) was added. The resulting mixture was stirred at room temperature for 2 hours. Complete conversion of 2 was confirmed by TLC (CH2Cl2 / MeOH 95:5, KMnO4 staining). The mixture was concentrated to remove THF. After adding ethyl acetate (200 mL) and saline solution (100 mL), the phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saline solution, dried on magnesium sulfate, filtered, and concentrated to obtain a white semi-solid. The residue was dissolved in dichloromethane (125 mL) and dried at room temperature for 16 hours in the presence of a large and excess amount of magnesium sulfate. After filtering off the solid, the organic phase was concentrated and dried under high vacuum to obtain 3 (2.56 g, 89% yield) as an off-white semi-solid. The product was used directly in the next step without further purification.

[0254] Step 3. Preparation of tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]-4-piperidyl]carbamate (5) Under nitrogen, solutions of 3 (400 mg, 1.86 mmol, 1.2 eq.), 4 (400 mg, 1.55 mmol, 1.0 eq.), and 1,2-DCE (15.5 mL, 0.1 M) were stirred at room temperature for 5 minutes. Then, NaBH(OAc)3 (788 mg, 3.72 mmol, 2.4 eq.) was added, and the mixture was stirred at room temperature for 16 hours. After confirming that the conversion was incomplete (approximately 70%) by LC-MS (Method 1), a second solution of 3 (100 mg, 0.47 mmol, 0.3 eq.) and NaBH(OAc)3 (788 mg, 3.72 mmol, 2.4 eq.) was added, and the mixture was stirred again for 2.5 hours. Complete conversion of 4 was confirmed by LC-MS (Method 1). The reaction mixture was quenched by adding saturated NH4Cl aqueous solution and then extracted three times with dichloromethane. The combined organic phase was washed once with saline solution, dried on magnesium sulfate, filtered, and concentrated to obtain a pale yellow oily substance. The residue was purified by reverse-phase flash chromatography (50 g C18 RediSep Rf Gold column, holding solution (DMSO), elution: 5% MeCN / 0.1% HCOOH over 4 CV, then 5% to 100% MeCN / 0.1% HCOOH over 15 CV, product eluted with 80% MeCN). The fractions were combined and concentrated to obtain 5 (572 mg, 83% yield) as an off-white solid.

[0255] LC-MS method 1: Retention time: 1.719 min, 99.9% purity (at 215 nm), [M+H] + = 442.2. 1H NMR (400 MHz, CDCl3) δ ppm 1.39 - 1.51 (m, 9 H), 1.53 - 1.71 (m, 3 H), 2.02 (s, 2 H), 2.09 - 2.18 (m, 1 H), 2.31 - 2.43 (m, 1 H), 2.44 - 2.56 (m, 1 H), 2.62 - 2.73 (m, 1 H), 2.79 - 2.88 (m, 1 H), 2.92 - 3.04 (m, 1 H), 3.29 (br. d, J = 10.8 Hz, 1 H), 3.55 - 3.68 (m, 1 H), 4.24 - 4.36 (m, 4H), 6.99 - 7.10 (m, 2 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.95 (s, 1 H), 9.75 (s, 1 H).

[0256] Step 4. Preparation of [1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]-4-piperidyl]ammonium chloride (C-4) Under nitrogen, a solution of 5 (572 mg, 1.30 mmol, 1.0 eq.) and 4.0 M HCl / 1,4-dioxane (6.5 mL, 20 eq.) was stirred at room temperature for 2 hours. Complete conversion of 5 was confirmed by LC-MS (Method 1). The mixture was concentrated under reduced pressure and co-evaporated three times with acetonitrile to obtain C-4 (525 mg, quantitative yield) as an off-white solid.

[0257] LC-MS method 1: Retention time: 1.149 min, 96.0% purity (at 215 nm), [M+H] + = 342.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.74 - 1.90 (m, 2 H), 2.01 - 2.06 (m, 1 H), 2.12 - 2.23 (m, 1 H), 2.25 - 2.41 (m, 2 H), 2.57 - 2.70 (m, 2 H), 2.71 - 2.85 (m, 2 H), 3.11 - 3.33 (m, 3 H), 4.25 (s, 3 H), 4.31 - 4.38 (m, 1 H), 6.98 - 7.06 (m, 2 H), 7.38 - 7.44 (m, 1 H), 7.98 - 8.12 (m, 3 H), 10.88 (s, 1 H).

[0258] Example I-6. Synthesis of a typical intermediate C-5 [ka]

[0259] Step 1. Preparation of tert-butyl (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylate (2) To a solution of tert-butyl 2,5-dihydropyrrole-1-carboxylate 1 (2.5 g, 14.77 mmol, 1 eq.) in tert-butanol (50 mL) and THF (25 mL), osmium tetroxide (0.94 mL, 0.15 mmol, 0.01 eq.) and then NMO (2.08 g, 17.73 mmol, 1.2 eq.) were added at room temperature. The reaction mixture was stirred at rt for 18 hours and then concentrated to dryness. The residue was dissolved in ELISA (200 mL) and washed with 10% Na₂SO₃ (2 x 20 mL), saturated NaHCO₃ (20 mL), and saline (20 mL). The organic phase was dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by normal-phase flash chromatography (0 to 10% MeOH / CH2Cl2, 10 CV, 120 g silica) to obtain 2 (3.04 g, quantitative yield) as a yellow oily substance. 1¹H NMR (400 MHz, chloroform-d) δ ppm 1.46 (s, 9 H), 2.76 - 2.83 (m, 1 H), 2.87 - 2.95 (m, 1 H), 3.28 - 3.40 (m, 2 H), 3.52 - 3.64 (m, 2 H), 4.20 - 4.28 (m, 2 H).

[0260] Step 2. Preparation of tert-butyl N,N-bis(2-oxoethyl)carbamate (3) Sodium periodate (3.84 g, 17.93 mmol, 1.2 eq.) was added to a solution of tert-butyl (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylate 2 (3.04 g, 14.94 mmol, 1 eq.) in THF (50 mL) and water (25 mL). The reaction mixture was stirred at room temperature for 1 hour. Complete conversion was shown by TLC (5% MeOH / CH2Cl2, vanillin staining). The THF was removed by vacuum and saline solution (50 mL) was added. The mixture was extracted with ELISA (3 x 100 mL). The combined organic substances were dissolved on Na2SO4 and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and stirred overnight on MgSO4. Subsequently, MgSO4 was filtered off, and CH2Cl2 was concentrated under vacuum to obtain the target product 3 (2.7 g, 90% yield) as a pale yellow oily substance.

[0261] 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 1.46 (s, 9 H), 3.97 (s, 2 H), 4.18 (s, 2 H), 9.65 (s, 1 H), 9.67 (s, 1 H).

[0262] Step 3. Preparation of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]piperazine-1-carboxylate (5) Sodium triacetoxyborohydride (517.73 mg, 2.44 mmol, 2.4 eq.) was added to a solution of tert-butyl N,N-bis(2-oxoethyl)carbamate 3 (245.77 mg, 1.22 mmol, 1.2 eq.) and 3-(7-amino-1-methyl-indazole-3-yl)piperidine-2,6-dione 4 (262.89 mg, 1.02 mmol, 1 eq.) in DCE (10.2 mL), and the mixture was stirred for 24 hours. LC-MS showed that 3 was present at 40%. Another sodium triacetoxyborohydride (517.73 mg, 2.44 mmol, 2.4 eq.) was added, and stirring was continued for 24 hours. LC-MS showed that 3 was present at 46%. After repeating the addition of sodium triacetoxyborohydride and stirring for 24 hours at least twice, LC-MS showed that compound 3 was 90%. The reaction mixture was quenched with saturated NH4Cl(aq) (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. The crude product was dissolved in the minimum amount of DMSO and purified by reverse-phase flash chromatography (MeCN / 0.1% HCOOH(aq), 5%~100%, 100 g C18 gold column, 20 CV, 65~70% MeCN). The fraction was evaporated to obtain compound 5 (373 mg, 80% yield) as a white solid.

[0263] LC-MS method 1: 89.0% purity (at 215 nm) [M+H] + = 428.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9 H), 2.11 - 2.22 (m, 1 H), 2.26 - 2.40 (m, 1 H), 2.55 - 2.79 (m, 4 H), 3.00 - 3.23 (m, 4 H), 3.88 - 4.07 (m, 2 H), 4.25 (s, 3 H), 4.34 (dd, J = 9.7, 5.0 Hz, 1 H), 7.00 - 7.07 (m, 2 H), 7.41 (d, J = 7.6 Hz, 1 H), 10.88 (s, 1 H).

[0264] Step 4. Preparation of 3-(1-methyl-7-piperazine-1-ylindazole-3-yl)piperidine-2,6-dione (C-5) To tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]piperazine-1-carboxylate 5 (373 mg, 0.87 mmol, 1 eq.), 4 M HCl / 1,4-dioxane (6.54 mL, 26.15 mmol, 30 eq.) was added. The solution was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure, and water was added. The product was purified by reverse-phase flash chromatography (MeCN / 0.1% HCOOH(aq), 5%~40%, 100 g gold column C18, 20 CV) to obtain C-5 (270 mg, 95% yield) as a brown solid.

[0265] LC-MS method 1: 99.9% purity (at 215 nm) [M+H] + = 328.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.12 - 2.23 (m, 1 H), 2.27 - 2.40 (m, 1 H), 2.56 - 2.74 (m, 2 H), 2.77 - 2.96 (m, 2 H), 3.03 - 3.23 (m, 6 H), 4.26 (s, 3 H), 4.35 (dd, J = 9.7, 5.0 Hz, 1 H), 7.05 (d, J = 4.4 Hz, 2 H), 7.40 - 7.45 (m, 1 H), 10.89 (s, 1 H).

[0266] Example I-7. Synthesis of a typical intermediate C-6 [ka]

[0267] Step 1. Preparation of tert-butyl (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylate (2) To a solution of tert-butyl 2,5-dihydropyrrole-1-carboxylate 1 (2.5 g, 14.77 mmol, 1 eq.) in tert-butanol (50 mL) and THF (25 mL), osmium tetroxide (0.94 mL, 0.15 mmol, 0.01 eq.) and then NMO (2.08 g, 17.73 mmol, 1.2 eq.) were added at room temperature. The reaction mixture was stirred at rt for 18 hours and then concentrated to dryness. The residue was dissolved in ELISA (200 mL) and washed with 10% Na₂SO₃ (2 x 20 mL), saturated NaHCO₃ aqueous solution (20 mL), and saline solution (20 mL). The organic phase was dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by normal-phase flash chromatography (0-10% MeOH / CH2Cl2, 10 CV, 120 g silica), and 2 (3.04 g, quantitative) was obtained as a yellow oily substance.

[0268] 1¹H NMR (400 MHz, chloroform-d) δ ppm 1.46 (s, 9 H), 2.76 - 2.83 (m, 1 H), 2.87 - 2.95 (m, 1 H), 3.28 - 3.40 (m, 2 H), 3.52 - 3.64 (m, 2 H), 4.20 - 4.28 (m, 2 H).

[0269] Step 2. Preparation of tert-butyl N,N-bis(2-oxoethyl)carbamate (3) Sodium periodate (3.84 g, 17.93 mmol, 1.2 eq.) was added to a solution of tert-butyl (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylate 2 (3.04 g, 14.94 mmol, 1 eq.) in THF (50 mL) and water (25 mL). The reaction mixture was stirred at room temperature for 1 hour. Complete conversion was shown by TLC (5% MeOH / CH2Cl2, vanillin staining). The THF was removed under vacuum and saline solution (50 mL) was added. The mixture was extracted with ELISA (3 x 100 mL). The combined organic substances were dissolved on Na2SO4 and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and stirred overnight with MgSO4. Subsequently, MgSO4 was filtered off, and CH2Cl2 was concentrated under vacuum to obtain the target product 3 (2.7g, 90% yield) as a pale yellow oily substance.

[0270] 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 1.46 (s, 9 H), 3.97 (s, 2 H), 4.18 (s, 2 H), 9.65 (s, 1 H), 9.67 (s, 1 H).

[0271] Step 3. Preparation of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]piperazine-1-carboxylate (5) Sodium triacetoxyborohydride (646.71 mg, 3.05 mmol, 2.4 eq.) was added to a solution of tert-butyl N,N-bis(2-oxoethyl)carbamate 3 (307.0 mg, 1.53 mmol, 1.2 eq.) and 3-(6-amino-1-methyl-indazole-3-yl)piperidine-2,6-dione 4 (328.38 mg, 1.27 mmol, 1 eq.) in DCE (12.7 mL), and the mixture was stirred at room temperature for 24 hours. LC-MS showed that 5 was present at 26%. Another portion of sodium triacetoxyborohydride (646.71 mg, 3.05 mmol, 2.4 eq.) was added to the mixture, and stirring was continued for 24 hours. LC-MS showed that 5 was present at 60%. Another sodium triacetoxyborohydride (646.71 mg, 3.05 mmol, 2.4 eq.) was added to the mixture and stirred for 24 hours. LC-MS showed no change. The reaction mixture was quenched with saturated NH4Cl(aq) (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was dissolved in a minimum amount of DMSO and purified by reverse-phase flash chromatography (MeCN / 0.1% HCOOH, 5%~100%, 100 g gold column, 20 CV, 65~70% MeCN). By concentration of the fraction, 5 (263 mg, 50% yield) was obtained as an off-white solid.

[0272] LC-MS method 1: 99.9% purity (at 215 nm) [M+H] + = 428.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 - 1.46 (m, 9 H), 2.10 - 2.21 (m, 1 H), 2.24 - 2.37 (m, 1 H), 2.54 - 2.69 (m, 2 H), 3.12 - 3.24 (m, 4 H), 3.43 - 3.56 (m, 4 H), 3.90 (s, 3 H), 4.26 (dd, J = 9.2, 5.0 Hz, 1 H), 6.89 (s, 1 H), 6.92 (br d, J = 9.0 Hz, 1 H), 7.52 (d, J = 9.0 Hz, 1 H), 10.85 (s, 1 H).

[0273] Step 4. Preparation of 3-(1-methyl-6-piperazine-1-ylindazole-3-yl)piperidine-2,6-dione hydrochloride (C-6) 4 M HCl / 1,4-dioxane (22.78 mL, 91.14 mmol, 150 eq.) was added to tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]piperazine-1-carboxylate 5 (260.0 mg, 0.61 mmol, 1 eq.) at room temperature. The mixture was then sonicated for 30 minutes and stirred at room temperature for 1 hour. The solvent was concentrated to dryness, and the residue was purified by reverse-phase flash chromatography (product obtained using MeCN / 0.02 M HCl(aq), 5%~30%, 100 g gold column C18, 15 CV, 0~20% MeCN). The fraction containing the product was evaporated to dryness, and then co-evaporated with water (3 × 10 mL) to completely remove any trace amounts of hydrochloric acid. The residue was freeze-dried to obtain C-6 (221 mg, 98%) as a pale yellow solid.

[0274] LC-MS method 1: 99.9% purity (at 215 nm) [M-HCl+H] + = 328.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 - 2.22 (m, 1 H), 2.24 - 2.37 (m, 1 H), 2.54 - 2.70 (m, 2 H), 3.24 (br s, 4 H), 3.45 - 3.50 (m, 4 H), 3.92 (s, 3 H), 4.28 (dd, J = 9.4, 5.0 Hz, 1 H), 6.93 - 6.99 (m, 2 H), 7.56 (d, J = 8.8 Hz, 1 H), 9.37 (br s, 2 H), 10.85 (s, 1 H).

[0275] Example I-8. Synthesis of a typical intermediate C-9 [ka]

[0276] Step 1. Preparation of tert-butyl 4-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-carbonyl)piperazine-1-carboxylate (3) tert-butylpiperazine-1-carboxylate 2 (67.43 mg, 0.3600 mmol) and 3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-carboxylic acid 1 (80 mg, 0.2800 mmol) were dissolved in DMF (1 mL) under a nitrogen atmosphere. Then, DIPEA (485.09 μL, 2.78 mmol) and HATU (127.07 mg, 0.3300 mmol) were added sequentially, and the reaction mixture was stirred overnight under a nitrogen atmosphere. Complete conversion was confirmed by LC-MS, and the reaction mixture was injected directly into a column and purified by reverse-phase flash chromatography (MeCN / 0.1% HCOOH(aq), 5%~50%) to obtain product 3 (110 mg, 83% yield) as a white solid. LC-MS method 1: 96.3% purity (at 215 nm), RT = 1.55, [M+H] + = 456.2, [Mt-Bu+H] += 400.2.

[0277] Step 2. Preparation of 3-(1-methyl-6-(piperazine-1-carbonyl)-1H-indazole-3-yl)piperidine-2,6-dione (C-9) 4.0 M HCl / dioxane (2.83 mL, 11.31 mmol) was added to tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-carbonyl]piperazine-1-carboxylate 3 (107 mg, 0.2300 mmol). The mixture was sonicated for 30 minutes and then stirred for 1 hour. The volatile substances were evaporated to dryness to obtain product C-9 (90 mg, 99% yield) as a white solid. LC-MS method 1: 99.9% purity (at 215 nm), RT = 0.70, [M+H] + = 356.2.

[0278] Synthesis of common intermediates C-10, C-11, C-12, C-13, C-18, and C-19 Example I-9. Synthesis of a common intermediate C-13 [ka]

[0279] Step 1. Preparation of 6-bromo-3-iodo-1-methyl-indazole (2) In a heated and dried round-bottom flask, 60% sodium hydride w / w / mineral oil (127.45 mg, 3.19 mmol, 1.5 eq.) / DMF (15 mL, 0.14 M) was added. Next, 6-bromo-3-iodo-1H-indazole 1 (700 mg, 2.12 mmol, 1 eq.) was added all at once, and the mixture was stirred at room temperature for 30 minutes. Then, iodomethane (264 μL, 4.25 mmol, 2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere. After 20 hours, complete conversion to compound 2 was shown by LC-MS. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ELISA (3 x 50 mL). The organic layers were combined and washed with water (2 x 50 mL), 1:1 water / saline solution (2 x 50 mL), and saline solution (50 mL), dried on MgSO4, and evaporated to dryness. The residue was then purified by normal-phase FC (80 g gold column, solid retention on silica, 0 to 15% toluene / heptane over 15 CV, product eluted around 7% toluene). The fractions were combined and concentrated to obtain 3 (537 mg, 75% yield) as a white solid. LC-MS method 3: 99.9% purity (at 215 nm), [M+H] + = 336.9; 338.9. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.05 (s, 3 H), 7.31 - 7.40 (m, 2 H), 8.03 - 8.09 (m, 1 H).

[0280] Step 1'. Preparation of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4) In a sealed tube, 2,6-dibenzyloxy-3-bromopyridine 3 (5.5 g, 14.86 mmol, 1 eq.), B2Pin2 (7.5 g, 29.53 mmol, 2 eq.), and KOAc (4.37 g, 44.57 mmol, 3 eq.) were added in a 1,4-dioxane (90 mL, 0.17 M) solution. The solution was bubbling with nitrogen for 15 minutes, after which Pd(dppf)Cl2DCM (1.21 g, 1.49 mmol, 0.1 eq.) was added. Under sonication, the reaction mixture was bubbling with nitrogen for 15 minutes. The tube was sealed, and the reaction mixture was stirred at 90°C. After overnight, LC-MS showed sufficient conversion to compound 4. The reaction mixture was cooled to room temperature, and siRNA and water were added. The aqueous phase was extracted three times with ethyl acetate. The organic phase was combined, washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was then purified by normal-phase flash chromatography (120 g silica column, solid retained on silica, elution: 0 to 30% ethyl acetate / heptane over 18 CV, product eluted at around 15% ethyl acetate). The fractions were combined and concentrated to obtain 4 (452 ​​mg, 7% yield) as a white solid.

[0281] LC-MS method 4: 96.1% purity (at 215 nm), [M+H] + = 418.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (s, 12 H), 5.38 (d, J = 5.9 Hz, 4 H), 6.42 (d, J = 7.8 Hz, 1 H), 7.25 - 7.40 (m, 6 H), 7.42 (d, J = 7.6 Hz, 2 H), 7.53 (d, J = 7.1 Hz, 2 H), 7.85 (d, J = 8.1 Hz, 1 H).

[0282] Step 2. Preparation of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (5) PdCl2(dppf)·CH2Cl2 (106 mg, 0.13 mmol, 0.05 eq.) was added to a sealed tube containing a solution of 6-bromo-3-iodo-1-methyl-indazole 2 (0.88 g, 2.61 mmol, 1 eq.), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 4 (1.09 g, 2.61 mmol, 1 eq.), and Na2CO3 (0.66 g, 6.26 mmol, 2.4 eq.) in 1,4-dioxane (7.8 mL, 0.25 M) and water (2.6 mL, 0.25 M). The solution was degassed using nitrogen for 15 minutes, the tube was sealed, and the reaction mixture was stirred at 90°C. After one night, LC-MS demonstrated complete conversion to compound 5. After cooling to room temperature, water was added to the reaction mixture. The reaction mixture was extracted 3x with ethyl acetate, the organic phases were combined, washed with water, washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was then purified by normal-phase flash chromatography (40 g silica column, solid retained on silica, elution: 0 to 20% ethyl acetate / heptane over 17 CV, product eluted around 17% ethyl acetate). The fractions were combined and concentrated to obtain compound 5 (810 mg, 58% yield) as a white solid.

[0283] LC-MS method 3: 94.1% purity (at 215 nm), [M+H] + = 500.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.05 (s, 3 H), 5.44 (d, J = 8.1 Hz, 4 H), 6.60 (d, J = 8.1 Hz, 1 H), 7.12 (dd, J = 8.7, 1.6 Hz, 1 H), 7.25 - 7.43 (m, 8 H), 7.44 - 7.50 (m, 2 H), 7.63 (d, J = 8.8 Hz, 1 H), 7.91 (d, J = 8.1 Hz, 1 H), 7.95 - 7.98 (m, 1 H).

[0284] Step 3. Preparation of tert-butyl (3S,4S)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3-fluoro-piperidine-1-carboxylateindazole (7) In a sealed tube, 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 5 (300 mg, 0.60 mmol, 1 eq.), tert-butyl (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate 6 (196.29 mg, 0.90 mmol, 1.5 eq.), XPhos Pd G3 (50.74 mg, 0.06 mmol, 0.1 eq.), and Cs2CO3 (390.68 mg, 1.2 mmol, 2 eq.) were added in a 1,4-dioxane (3.0 mL, 0.2 M) solution. The solution was degassed under nitrogen for 15 minutes, the tube was sealed, and the reaction mixture was stirred at 100°C. After overnight, LC-MS showed complete conversion to compound 7. After cooling to room temperature, the reaction mixture was filtered through a Celite pad, rinsed with DCM, and the solution was evaporated and purified by normal-phase flash chromatography (40 g silica column, solid retained on silica, elution: 0-40% siRNA / heptane over 20 CV, product eluted around 20% siRNA). The fractions were combined and concentrated to obtain 7 (294 mg, 77% yield) as a white solid.

[0285] LC-MS method 3: 99.9% purity (at 215 nm), product is non-ionized. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9 H), 1.97 - 2.06 (m, 2 H), 3.19 - 3.28 (m, 1 H), 3.58 - 3.68 (m, 1 H), 3.73 - 3.88 (m, 2 H), 3.90 (s, 3 H), 4.36 - 4.55 (m, 1 H), 5.43 (d, J = 11.7 Hz, 4 H), 5.97 (d, J = 8.3 Hz, 1 H), 6.45 - 6.52 (m, 2 H), 6.55 (d, J = 8.1 Hz, 1 H), 7.26 - 7.43 (m, 10 H), 7.46 (d, J = 7.2 Hz, 2 H), 7.86 (d, J = 8.1 Hz, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -185.84 - 185.48 (m, 1 F).

[0286] Step 4. Preparation of tert-butyl (3S,4S)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3-fluoro-piperidine-1-carboxylateindazole (8) In a reaction vessel connected to a pressure valve, Pd(OH)2 (64.74 mg, 0.09 mmol, 0.2 eq.) was added to a degassed solution of tert-butyl (3S,4S)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3-fluoropiperidine-1-carboxylate 7 (294 mg, 0.46 mmol, 1 eq.) in THF (1.5 mL, 0.15 M) and ethanol (1.5 mL, 0.15 M). A purge cycle using N2 and H2 was performed. The mixture was stirred overnight at 60°C under a pressure of 70 psi. The reaction mixture was filtered on a Celite pad, washed with siRNA and EtOH, and concentrated under reduced pressure. The residue was loaded directly into a reverse-phase FC (50 g RediSep Rf Gold C18 column, holding solution (DMSO), 5% MeCN / 0.1% HCOOH over 4 CV, then 5% to 95% MeCN / 0.1% HCOOH over 20 CV; the product eluted with 65% MeCN). The pure fractions were combined and concentrated to obtain 8 (100 mg, 47% yield) as a blue solid.

[0287] LC-MS method 3: 99.9% purity (at 215 nm), [M+H] + = 460.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9 H), 1.96 - 2.06 (m, 1 H), 2.08 - 2.32 (m, 3 H), 2.58 - 2.63 (m, 2 H), 3.19 - 3.29 (m, 2 H), 3.59 - 3.66 (m, 1 H), 3.74 - 3.81 (m, 1 H), 3.82 (s, 3 H), 3.84 - 3.93 (m, 1 H), 4.19 (dd, J = 8.8, 4.9 Hz, 1 H), 4.37 - 4.55 (m, 1 H), 5.98 (d, J = 8.3 Hz, 1 H), 6.51 (s, 1 H), 6.55 - 6.59 (m, 1 H), 7.35 (d, J = 8.6 Hz, 1 H), 10.82 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -185.89 - -185.48 (m, 1 F).

[0288] Step 5. Preparation of 3-[1-methyl-6-[[(3S,4S)-3-fluoro-4-piperidyl]amino]indazole-3-yl]piperidine-2,6-dione; dihydrochloride (C-13) tert-butyl (3S,4S)-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]amino]-3-fluoropiperidine-1-carboxylate 8 (95 mg, 0.21 mmol, 1 eq.) was mixed with 4 M HCl / dioxane (0.4 mL, 1.65 mmol, 8.0 equiv.). The reaction mixture was stirred at rt for 2 hours. Upon completion, the solvent was removed under reduced pressure, and the residue was co-evaporated with MeCN (2×). The residue was dried under high vacuum, and C-13 (114 mg, 88% yield) was obtained as a white solid dihydrochloride. The product was used in the next step without further purification. LC-MS method 3: 68.8% purity (at 215 nm), [M+H] + = 360.1.

[0289] The following compounds were synthesized using the same general route with a modification to amine 6 in step 3 (Table 3). [Table 16]

[0290] Example I-10. Synthesis of a common intermediate C-14 [ka]

[0291] Step 1. Preparation of 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (2) In a sealed tube, 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 1 (intermediate 5 from the synthesis of C-13) (300 mg, 0.58 mmol, 1 eq.), B2Pin2 (219.92 mg, 0.87 mmol, 1.5 eq.), and KOAc (283.31 mg, 2.89 mmol, 5 eq.) were added in 1,4-dioxane (1.44 mL, 0.4 M). The solution was bubbling with nitrogen for 15 minutes, after which Pd(dppf)Cl2DCM (42.24 g, 0.06 mmol, 0.1 eq.) was added. Under sonication, the reaction mixture was bubbling with nitrogen for 15 minutes. The tube was sealed, and the reaction mixture was stirred at 80°C. After one night, LC-MS demonstrated sufficient conversion to compound 2. The reaction mixture was cooled to room temperature, filtered through a Celite pad, washed with methanol, and evaporated. The crude product was then purified by normal-phase flash chromatography (40 g silica column, solid retention on silica, elution: 0-30% siRNA / heptane over 20 CV, product eluted around 10% siRNA). The fractions were combined and concentrated to obtain compound 2 (297 mg, 90% yield) as a white solid.

[0292] LC-MS method 3: 95.8% purity (at 215 nm), product is non-ionized. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 12 H), 4.11 (s, 3 H), 5.45 (d, J = 10.5 Hz, 4 H), 6.59 (d, J = 8.3 Hz, 1 H), 7.27 - 7.42 (m, 9 H), 7.45 - 7.49 (m, 2 H), 7.67 (dd, J = 8.2, 0.9 Hz, 1 H), 7.89 - 7.92 (m, 2 H).

[0293] Step 2. Preparation of 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-ol (3) In a round-bottom flask, a solution of 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole 2 (297 mg, 0.51 mmol, 1 eq.) in THF (2.6 mL, 0.13 M) and water (1.3 mL, 0.13 M) was added. Sodium perborate tetrahydrate (117.19 mg, 0.76 mmol, 1.5 eq.) was added to this solution, and the reaction mixture was stirred at room temperature. After 1 hour, LC-MS showed complete conversion to compound 3. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with water and saline solution, dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain 3 (270 mg, quantitative yield) as a brown solid.

[0294] LC-MS method 3: 85.6% purity (at 215 nm), [M+H] + = 438.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.91 (s, 3 H), 5.43 (d, J = 9.0 Hz, 4 H), 6.52 - 6.59 (m, 2 H), 7.25 - 7.34 (m, 4 H), 7.34 - 7.43 (m, 5 H), 7.44 - 7.50 (m, 3 H), 7.88 (d, J = 8.1 Hz, 1 H), 9.65 (s, 1 H).

[0295] Step 3. Preparation of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]oxypiperidine-1-carboxylate (5) In a sealed tube, 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-ol 3 (270 mg, 0.62 mmol, 1 eq.) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 4 (206.88 mg, 0.74 mmol, 1.2 eq.) were added to a solution of DMF (4 mL, 0.14 M) and toluene (0.4 mL, 0.14 M). Then, DIPEA (0.21 mL, 1.23 mmol, 2 eq.) and K2CO3 (178.85 mg, 1.3 mmol, 2.1 eq.) were added to the reaction mixture. The tube was sealed, and the reaction mixture was stirred at 95°C. After a further overnight, LC-MS showed a 56% conversion to compound 5. Further, tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 4 (68.96 mg, 0.25 mmol, 0.4 eq.) was added, the tube was sealed, and the reaction mixture was stirred at 95°C. After a further overnight, the major conversion was confirmed by LC-MS. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture, and it was extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was then purified by normal-phase flash chromatography (40 g silica column, solid retention on silica, elution: 0 to 40% ethyl acetate / heptane over 15 CV, product eluted at approximately 30% ethyl acetate). The fractions were combined and concentrated to obtain 5 (100 mg, 26% yield) as a yellow semi-solid.

[0296] LC-MS method 3: 98.3% purity (at 215 nm), product is non-ionized. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9 H), 1.50 - 1.61 (m, 2 H), 1.64 - 1.71 (m, 1 H), 1.91 - 2.00 (m, 2 H), 2.88 - 2.99 (m, 1 H), 3.19 - 3.27 (m, 2 H), 3.99 (s, 3 H), 4.69 (d, J = 4.2 Hz, 1 H), 5.43 (d, J = 9.0 Hz, 4 H), 6.57 (d, J = 8.1 Hz, 1 H), 6.65 (dd, J = 8.9, 2.1 Hz, 1 H), 7.12 (d, J = 2.0 Hz, 1 H), 7.25 - 7.43 (m, 9 H), 7.45 - 7.49 (m, 2 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H).

[0297] Step 4. Preparation of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]oxypiperidine-1-carboxylate (6) In a reactor connected to a pressure valve, Pd(OH)2 (22.62 mg, 0.03 mmol, 0.2 eq.) was added to a degassed solution of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]oxypiperidine-1-carboxylate 5 (100 mg, 0.16 mmol, 1 eq.) in THF (1 mL, 0.08 M) and ethanol (1 mL, 0.08 M). A purge cycle was performed using N2 and H2. The mixture was stirred overnight at 60°C under a pressure of 70 psi. The reaction mixture was filtered on a Celite pad, washed with siRNA and EtOH, and concentrated under reduced pressure. The residue was directly loaded into a reverse-phase FC purifier (50 g C18 RediSep Rf Gold column, holding solution (DMSO), 5% MeCN / 0.1% HCOOH over 4 CV, then 5% to 95% MeCN / 0.1% HCOOH over 20 CV; the product was eluted with 70% MeCN). The pure fractions were combined and concentrated to obtain 6 (30 mg, 38% yield) as a brown solid.

[0298] LC-MS method 3: 98.3% purity (at 215 nm), product is non-ionized. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9 H), 1.51 - 1.61 (m, 2 H), 1.92 - 2.00 (m, 2 H), 2.12 - 2.21 (m, 1 H), 2.27 - 2.37 (m, 1 H), 2.59 - 2.70 (m, 2 H), 3.18 - 3.27 (m, 2 H), 3.64 - 3.71 (m, 2 H), 3.92 (s, 3 H), 4.29 (dd, J = 9.7, 5.0 Hz, 1 H), 4.65 - 4.73 (m, 1 H), 6.76 (dd, J = 9.3, 1.5 Hz, 1 H), 7.13 (s, 1 H), 7.57 (d, J = 8.8 Hz, 1 H), 10.86 (s, 1 H).

[0299] Step 5. Preparation of 3-[1-methyl-6-(4-piperidyloxy)indazole-3-yl]piperidine-2,6-dione; hydrochloride (C-14) tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]oxypiperidine-1-carboxylate 6 (65 mg, 0.15 mmol, 1 eq.) was mixed with 4M hydrochloric acid (0.29 mL, 1.18 mmol, 8.0 eq.) / dioxane. The reaction mixture was stirred at rt for 20 hours. After completion, the solvent was removed under reduced pressure, and the residue was co-evaporated with MeCN (2×). The residue was dried under high vacuum to obtain C-14 (53 mg, 87% yield) as a white solid dihydrochloride. This was used in the next step without further purification.

[0300] LC-MS method 3: 71.0% purity (at 215 nm), [M+H] + = 343.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.82 - 1.90 (m, 2 H), 2.09 - 2.22 (m, 4 H), 2.25 - 2.38 (m, 1 H), 2.59 - 2.65 (m, 1 H), 3.04 - 3.19 (m, 4 H), 3.93 (s, 3 H), 4.30 (dd, J = 9.4, 5.3 Hz, 1 H), 4.73 - 4.80 (m, 1 H), 6.79 (dd, J = 8.7, 1.6 Hz, 1 H), 7.15 - 7.19 (m, 1 H), 7.59 (d, J = 9.0 Hz, 1 H), 8.77 - 8.87 (m, 2 hours), 10.87 (s, 1 hour).

[0301] Example I-11. Synthesis of a common intermediate C-15 [ka]

[0302] Step 1. Preparation of Tert-butyl N-cyclopenta-3-en-1-yl-N-methylcarbamate (2) Iodomethane (764.38 μL, 12.28 mmol, 5.0 eq.) was added at room temperature to a suspension of tert-butyl N-cyclopenta-3-ene-1-ylcarbamate 1 (450.0 mg, 2.46 mmol, 1.0 eq.) and NaH (491.13 mg, 12.28 mmol, 5.0 eq.) in a solution of THF (16.3 mL, 0.15 M). The suspension was stirred at 60°C. After overnight, complete conversion was shown by TLC (Hept. siRNA 9:1). The reaction mixture was cooled and quenched with water. The phases were separated by adding ethyl acetate. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phase was washed once with water and once with saline, dried on magnesium sulfate, and concentrated. The residue was purified by normal-phase flash chromatography (40 g silica column, elution: 0 to 10% ethyl acetate / heptane over 15 CV; the product was eluted with 7% ethyl acetate). The fractions were combined and concentrated to obtain tert-butyl N-cyclopenta-3-en-1-yl-N-methylcarbamate 2 (511 mg, 100% yield) as a colorless oil. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 1.47 (s, 9 H), 2.21 - 2.32 (m, 2 H), 2.57 - 2.62 (m, 2 H), 2.67 (s, 3 H), 4.93 (br s, 1 H), 5.67 - 5.72 (m, 2 H).

[0303] Step 2. Preparation of Tert-butyl N-methyl-N-[rac-(3R,4S)-3,4-dihydroxycyclopentyl]carbamate (3) To a solution of tert-butyl N-cyclopenta-3-en-1-yl-N-methyl-carbamate 2 (535 mg, 2.71 mmol, 1.0 eq.) in tert-butanol (9.0 mL) and THF (4.5 mL, 0.2 M), osmium tetroxide (0.17 mL, 0.03 mmol, 0.01 eq.) was added, followed by NMO (381.26 mg, 3.25 mmol, 1.2 eq.). The reaction mixture was stirred with rt and monitored by TLC. After 16 hours, TLC (10:90 MeOH / DCM, KMnO4) showed complete conversion of 2 in two new spots. The mixture was concentrated to dryness. The residue was dissolved in ELISA and washed with 10% Na2SO3 (2×), saturated NaHCO3, and saline. The organic phase was dried over MgSO4 and concentrated under vacuum. The residue was purified by normal-phase flash chromatography (40 g silica column, DCM injection, elution: 0 to 10% MeOH / DCM over 15 CV; the product was eluted with 9% MeOH). Fractions were selected by TLC (10:90 MeOH / DCM, vanillin staining). The recovered fractions were concentrated to obtain tert-butyl N-methyl-N-[rac-(3R,4S)-3,4-dihydroxycyclopentyl]carbamate 3 (523 mg, 83% yield) as a colorless oil.

[0304] 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 1.47 (s, 9 H), 1.83 - 1.95 (m, 2 H), 1.95 - 2.06 (m, 2 H), 2.21 (br d, J = 2.7 Hz, 2 H), 2.75 (s, 3 H), 4.20 - 4.29 (m, 2 H), 4.76 (dt, J = 16.9, 8.4 Hz, 1 H).

[0305] Step 3. Production of N-methyl-N-[3-oxo-1-(2-oxoethyl)propyl]carbamate (4) To a solution of tert-butyl N-methyl-N-[rac-(3R,4S)-3,4-dihydroxycyclopentyl]carbamate 3 (523 mg, 2.26 mmol, 1.0 eq.) in THF (10 mL) and water (5 mL, 0.15 M), sodium periodate (0.58 g, 2.71 mmol, 1.2 eq.) was added. The reaction mixture was stirred at room temperature and monitored by TLC. After 2 hours, complete conversion was shown by TLC (5% MeOH / DCM, vanillin staining). The THF was removed by distillation under reduced pressure, and NaCl solid / saline solution was added. The mixture was extracted with siRNA (3 x). The combined organic substances were dried on MgSO4 and concentrated under vacuum to obtain tert-butyl N-methyl-N-[3-oxo-1-(2-oxoethyl)propyl]carbamate 4 (478 mg, 92% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 1.47 (s, 9 H), 1.54 - 1.70 (m, 2 H), 2.69 - 2.75 (m, 2 H), 2.78 (s, 3 H), 4.87 - 5.03 (m, 1 H), 9.68 - 9.84 (m, 2 H).

[0306] Step 4. Preparation of Tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-N-methyl-carbamate (6) To a solution of 3-(6-amino-1-methyl-indazole-3-yl)piperidine-2,6-dione 4 (425.0 mg, 1.65 mmol, 1.0 eq.) and tert-butyl N-methyl-N-[3-oxo-1-(2-oxoethyl)propyl]carbamate 5 (452.7 mg, 1.97 mmol, 1.2 eq.) in DCE (8.5 mL, 0.2 M), sodium triacetoxyborohydride (837.0 mg, 3.95 mmol, 2.4 eq.) was added. The reaction mixture was stirred at room temperature under an N2 atmosphere for 48 hours. The reaction was quenched with saturated NH4Cl and extracted with DCM (3 x). The combined organic substances were dried over Na2SO4 and concentrated under vacuum. Subsequently, the residue was purified by normal-phase flash chromatography (40 g silica column, DCM injection, elution: 0 to 10% MeOH / DCM over 15 CV; the product was eluted with 5% MeOH). The recovered fraction was concentrated to obtain tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-N-methyl-carbamate 6 (600 mg, 64.7% yield) as a yellow solid.

[0307] LC-MS method 3: Retention time: 1.860 min, 95% purity (at 254 nm), [M+H] + = 456.3. 1H NMR (400 MHz, chloroform-d) δ ppm 1.49 (s, 9 H), 1.74 - 1.82 (m, 2 H), 1.83 - 1.94 (m, 2 H), 2.31 - 2.41 (m, 1 H), 2.45 - 2.55 (m, 1 H), 2.62 - 2.71 (m, 1 H), 2.72 - 2.75 (m, 1 H), 2.78 (s, 3 H), 2.82 - 2.91 (m, 2 H), 2.94 - 3.04 (m, 1 H), 3.82 (br d, J = 12.7 Hz, 2 H), 3.95 (s, 3 H), 4.25 (dd, J = 7.0, 5.3 Hz, 1 H), 6.64 (br s, 1 H), 6.92 (br d, J = 8.8 Hz, 1 H), 7.51 (d, J = 9.0 Hz, 1 H), 7.97 (s, 1 H).

[0308] Step 5. Preparation of 3-[1-methyl-6-[4-(methylamino)-1-piperidyl]indazole-3-yl]piperidine-2,6-dione hydrochloride (C-15) 4.0 M HCl / dioxane (6.26 mL, 25.02 mmol, 20 eq.) was added to tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-N-methyl-carbamate 6 (600 mg, 1.25 mmol, 1.0 eq.). The mixture was sonicated for 1 minute and then stirred overnight at room temperature. The solvent was evaporated to dryness, and the residue was co-evaporated using MeCN(2x) to obtain 3-[1-methyl-6-[4-(methylamino)-1-piperidyl]indazole-3-yl]piperidine-2,6-dione hydrochloride C-15 (595 mg, 100% yield) as a light brown solid.

[0309] LC-MS method 3: Retention time: 1.339 min, 96% purity (at 215 nm), [M + H] + = 356.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 - 1.95 (m, 2 H), 2.12 - 2.24 (m, 3 H), 2.28 - 2.40 (m, 2 H), 2.56 (br t, J = 5.4 Hz, 3 H), 2.59 - 2.70 (m, 2 H), 2.96 - 3.11 (m, 2 H), 3.18 - 3.26 (m, 1 H), 3.88 (br d, J = 12.7 Hz, 1 H), 3.93 (s, 3 H), 4.30 (dd, J = 9.5, 5.1 Hz, 1 H), 7.04 - 7.31 (m, 2 H), 7.54 - 7.69 (m, 1 H), 9.12 - 9.30 (m, 2 H), 10.87 (s, 1 H).

[0310] Example I-12. Synthesis of a common intermediate C-16 [ka]

[0311] Step 1. Preparation of tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-N-methyl-carbamate (3) Sodium triacetoxyborohydride (318.03 mg, 1.5 mmol, 2.4 eq.) was added to a solution of 3-(6-amino-1-methyl-indazole-3-yl)piperidine-2,6-dione 2 (161.47 mg, 0.63 mmol, 1.0 eq.) and tert-butyl N-methyl-N-[3-oxo-1-(2-oxoethyl)propyl]carbamate 1 (intermediate 4 obtained from the synthesis of C-15) (172 mg, 0.75 mmol, 1.2 eq.) in DCE (3.13 mL, 0.2 M). The reaction mixture was stirred at room temperature under an N2 atmosphere for 4 days. The reaction was quenched with saturated NH4Cl and extracted with DCM(3 x). The combined organic substances were dried over Na2SO4 and concentrated under vacuum. The residue was purified by normal-phase flash chromatography (40 g silica column, DCM injection, elution: 0 to 10% MeOH / DCM over 20 CV, product eluted with 5% MeOH). The recovered fraction was concentrated to obtain 3 (148 mg, 49% yield) as a yellow solid.

[0312] LC-MS method 3: 93.7% purity (at 215 nm), [M+H] + = 456.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (br s, 9 H), 1.62 - 1.75 (m, 2 H), 1.90 - 2.08 (m, 2 H), 2.12 - 2.22 (m, 1 H), 2.23 - 2.38 (m, 2 H), 2.60 - 2.72 (m, 2 H), 2.77 (s, 3 H), 2.78 - 2.83 (m, 1 H), 3.24 - 3.30 (m, 2 H), 3.38 - 3.56 (m, 1 H), 4.26 (s, 3 H), 4.31 - 4.37 (m, 1 H), 6.97 - 7.09 (m, 2H), 7.39 (br d, J = 7.3 Hz, 1 H), 10.88 (s, 1 H).

[0313] Step 2. Preparation of 3-[1-methyl-7-[4-(methylamino)-1-piperidyl]indazole-3-yl]piperidine-2,6-dione hydrochloride (C-16) To a solution of tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]-4-piperidyl]-N-methyl-carbamate 3 (148 mg, 0.32 mmol, 1.0 eq.) in DCM (1.0 mL, 0.32 M), 4.0 M HCl / dioxane (2.44 mL, 9.75 mmol, 20 eq.) was added, and the mixture was stirred overnight at room temperature. After 90 minutes, complete conversion to compound 4 was shown by LC-MS. The solvent was evaporated to dryness, and the residue was co-evaporated using MeCN(2x). The residue was dried under high vacuum to obtain C-16 (142 mg, quantitative yield) as a white solid hydrochloride.

[0314] LC-MS method 3: 95.2% purity (at 215 nm), [M-HCl+H] + = 356.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.76 - 1.89 (m, 2 H), 2.10 - 2.21 (m, 3 H), 2.26 - 2.39 (m, 1 H), 2.60 (br t, J = 5.4 Hz, 3 H), 2.62 - 2.68 (m, 2 H), 2.68 - 2.82 (m, 2 H), 3.08 - 3.22 (m, 1 H), 3.25 - 3.35 (m, 2 H), 4.25 (s, 3 H), 4.34 (dd, J = 9.7, 5.0 Hz, 1 H), 6.99 - 7.07 (m, 2 H), 7.40 (br d, J = 1.7 Hz, 1 H), 8.92 (br s, 2 H), 10.89 (s, 1 H).

[0315] Example I-13. Synthesis of a common intermediate C-17 [ka]

[0316] Step 1. Preparation of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate (3) In a sealed tube, a solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 1 (intermediate 5 obtained from the synthesis of C-13) (759 mg, 1.43 mmol), tert-butyl 4-aminopiperidine-1-carboxylate 2 (430 mg, 2.15 mmol), XPhos Pd G3 (121 mg, 0.14 mmol), and Cs2CO3 (931 mg, 2.87 mmol) in 1,4-dioxane (4.2 mL) was placed. The solution was degassed under nitrogen for 15 minutes, the tube was sealed, and the reaction mixture was stirred at 100°C. After 18 hours, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and the filter cake was washed with DCM. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by normal-phase flash chromatography (siRNA / heptane) to obtain tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate 3 (471 mg, 48% yield) as a white solid.

[0317] LC-MS method 1: 99.9% purity (at 215 nm), product is non-ionized. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 - 1.33 (m, 3 H), 1.41 (s, 9 H), 1.88 - 1.99 (m, 2 H), 2.88 - 3.05 (m, 2 H), 3.45 - 3.58 (m, 1 H), 3.89 (s, 3 H), 3.90 - 3.94 (m, 1 H), 5.41 (s, 2 H), 5.44 (s, 2 H), 5.74 - 5.79 (m, 1 H), 6.39 - 6.44 (m, 2 H), 6.55 (d, J = 8.1 Hz, 1 H), 7.23 - 7.50 (m, 11 H), 7.86 (d, J = 8.1 Hz, 1 H).

[0318] Step 2. Preparation of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylate (4) tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate 3 (903 mg, 1.43 mmol) and 60% NaH (142 mg, 2.14 mmol) were dissolved in THF (5.7 mL) at 0°C. After 1 hour, dimethyl sulfate (0.2 mL, 2.14 mmol) was added dropwise at 0°C. The reaction mixture was then heated at 70°C. After 2.5 hours, volatile components were removed under reduced pressure. The residue was directly purified by reverse-phase C18 column chromatography (MeCN / 0.1% formic acid aqueous solution) to obtain tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylate 4 (345 mg, 38% yield) as a brown solid.

[0319] LC-MS method 1: 99.9% purity (at 215 nm), product is non-ionized. 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9 H), 1.64 - 1.81 (m, 4 H), 2.73 - 2.83 (m, 2 H), 2.85 (s, 3 H), 3.76 - 3.85 (m, 1 H), 4.02 (s, 3 H), 4.19 - 4.34 (m, 2 H), 5.39 (s, 2 H), 5.48 (s, 2 H), 6.48 (d, J = 1.7 Hz, 1 H), 6.51 (d, J = 8.1 Hz, 1 H), 6.73 (dd, J = 9.0, 2.0 Hz, 1 H), 7.23 - 7.47 (m, 10 H), 7.57 (d, J = 9.0 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 1 H).

[0320] Step 3. Preparation of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylate (5) A solution of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylate 4 (507 mg, 0.80 mmol) in THF (2.7 mL) and ethanol (2.7 mL) was degassed for 15 minutes, then Pd(OH)2 (89 mg, 0.13 mmol) was added and the mixture was sparged again for 5 minutes. The reaction mixture was heated overnight at 60°C under positive hydrogen pressure (approximately 60 psi). After 18 hours, the reaction mixture was filtered on a Celite pad. The filter cake was washed with siRNA and EtOH, and the filtrate was concentrated under reduced pressure. The residue was directly purified by reverse-phase C18 column chromatography (MeCN / 0.1% formic acid aqueous solution) to obtain tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylate 5 (289 mg, 79% yield) as a pale pink solid.

[0321] LC-MS method 1: 96.2% purity (at 215 nm), [M+H] + = 456.2. 1 H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9 H), 1.65 - 1.82 (m, 4 H), 2.29 - 2.41 (m, 1 H), 2.50 (dtd, J = 13.9, 7.1, 5.1 Hz, 1 H), 2.61 - 2.72 (m, 1 H), 2.73 - 2.81 (m, 2 H), 2.85 (s, 3 H), 2.99 (ddd, J = 17.7, 8.8, 5.0 Hz, 1 H), 3.74 - 3.87 (m, 1 H), 3.93 (s, 3 H), 4.18 - 4.35 (m, 3 H), 6.45 (d, J = 1.7 Hz, 1 H), 6.85 (dd, J = 9.3, 2.0 Hz, 1 H), 7.50 (d, J = 9.0 Hz, 1 H), 7.89 (s, 1 H).

[0322] Step 4. Preparation of 3-[1-methyl-6-[methyl(4-piperidyl)amino]indazole-3-yl]piperidine-2,6-dione (C-17) tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]methyl-amino]piperidine-1-carboxylate 5 (289.2 mg, 0.6300 mmol) was dissolved in 4M hydrochloric acid / dioxane (3.15 mL, 12.61 mmol). The reaction mixture was stirred at rt for 1 hour. After completion, volatile components were removed under reduced pressure, and the residue was co-evaporated with toluene (2×) and MTBE. The residue was dried under high vacuum to obtain 3-[1-methyl-6-[methyl(4-piperidyl)amino]indazole-3-yl]piperidine-2,6-dione dihydrochloride C-17 (282 mg, quant) as a white solid.

[0323] LC-MS method 1: 98.0% purity (at 215 nm), [M+H] + = 356.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.80 - 1.92 (m, 1 H), 1.93 - 2.06 (m, 2 H), 2.11 - 2.21 (m, 1 H), 2.26 - 2.39 (m, 1 H), 2.55 - 2.71 (m, 2 H), 2.83 - 3.06 (m, 4 H), 3.29 - 3.40 (m, 2 H), 3.44 - 3.52 (m, 1 H), 3.62 - 3.78 (m, 2 H), 3.93 (s, 3 H), 4.00 - 4.15 (m, 1 H), 4.26 - 4.39 (m, 1 H), 6.96 - 7.24 (m, 1 H), 7.49 - 7.76 (m, 1 H), 8.62 - 8.83 (m, 1 H), 8.94 - 9.20 (m, 1 H), 10.87 (s, 1 H).

[0324] Example I-14. Synthesis of a common intermediate C-20 [ka]

[0325] Step 1. Preparation of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidine-1-yl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate (3) Acetic acid (1.1 mL, 19.29 mmol, 20 eq.) was added to a 10 mL ice-cold mixture of 1-(6-amino-1-methyl-indazole-3-yl)hexahydropyrimidine-2,4-dione 1 (250 mg, 0.9600 mmol, 1.0 eq.), tert-butyl 4-oxopiperidine-1-carboxylate 2 (192 mg, 0.9600 mmol, 1.0 eq.), and NaBH(OAc)3 (306 mg, 1.45 mmol, 1.5 eq.) in DCE (10 mL). The mixture was stirred at 0°C for 20 minutes and then at room temperature for 3 days. After separating the phases, the aqueous phase was extracted with DCM (3 × 10 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (MeOH / 0.1% HCOOH(aq), 5%→60% over 20 CV). The fraction was evaporated to obtain 3 (105 mg, 0.225 mmol, quantitative yield) as a pink solid.

[0326] LC-MS method 1: 100% purity (at 215 nm), [M+H]⁺ = 443.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.19 - 1.35 (m, 2 H), 1.42 (s, 9 H), 1.91 - 2.00 (m, 2 H), 2.72 (s, 2 H), 2.86 - 3.07 (m, 2 H), 3.48 - 3.61 (m, 1 H), 3.82 (s, 3 H), 3.84 - 3.93 (m, 4 H), 5.81 - 5.90 (m, 1 H), 6.42 (s, 1 H), 6.47 - 6.57 (m, 1 H), 7.28 (d, J = 9.0 Hz, 1 H), 10.42 - 10.53 (m, 1 H).

[0327] Step 2. Preparation of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidine-1-yl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylate (4) tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidine-1-yl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate 3 (105 mg, 0.24 mmol, 1.0 eq.) was dissolved in DCM (5 mL), and after adding 37% formaldehyde aqueous solution (0.02 mL, 0.28 mmol, 1.2 eq.), NaBH(OAc)3 (75 mg, 0.36 mmol, 1.5 eq.) was added at room temperature. After 2 hours, complete conversion was shown by LC-MS. After removing volatile components, the residue was purified by reverse-phase flash chromatography (MeOH / 1% HCOOH(aq), 5%→60% over 20 CV). The fraction was evaporated to obtain 4 (118 mg, 0.2339 mmol, 90.5% yield) as a pink semi-solid.

[0328] LC-MS method 1: 90.5% purity (at 215 nm), [M+H]⁺ = 457.3. 1 H NMR (400 MHz, CDCl3) δ ppm 1.41 (s, 9 H), 1.55 - 1.72 (m, 4 H), 1.94 (s, 1 H), 2.77 (s, 3 H), 2.87 (t, J = 1.0 Hz, 2 H), 3.69 - 3.81 (m, 1 H), 3.84 (s, 3 H), 3.93 - 4.02 (m, 2 H), 4.11 - 4.26 (m, 2 H), 5.34 (s, 2 H), 6.33 (s, 1 H), 6.76 - 6.82 (m, 1 H), 7.40 - 7.47 (m, 1 H).

[0329] Step 3. Preparation of [3-(2,4-dioxohexahydropyrimidine-1-yl)-1-methyl-1H-indazole-1-ium-6-yl]-methyl-piperidine-1-ium-4-yl-ammonium trichloride (C-20) tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidine-1-yl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylate 4 (118 mg, 0.233 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (2.5 mL), and then 4.0 M HCl / 1,4-dioxane solution (1.16 mL, 4.65 mmol, 20 eq.) was added. The resulting solution was stirred at room temperature. After 4 hours, complete conversion was shown by LC-MS. The solvent was evaporated under vacuum and washed twice with MeCN to obtain C-20 (112 mg, 0.21 mmol, 90% yield) as a pale pink solid.

[0330] LC-MS method 1: 87.1% purity (at 215 nm), [M-3HCl+H] + = 357.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 1 H), 1.74 - 1.92 (m, 2 H), 1.93 - 2.06 (m, 2 H), 2.82 - 2.96 (m, 5 H), 2.96 - 3.12 (m, 2 H), 3.31 - 3.42 (m, 2 H), 3.57 (s, 1 H), 3.81 - 3.99 (m, 4 H), 4.04 - 4.18 (m, 1 H), 5.14 (s, 2 H), 7.04 (br s, 1 H), 7.55 (br s, 1 H), 8.68 - 9.17 (m, 2 H).

[0331] Synthesis of the final compound General method for final product 1 Example S1. Synthesis of P-4 [ka]

[0332] Step 1. Preparation of ethyl 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (3): To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (800 mg, 3.55 mmol, 1.0 eq) / MeCN (17.7 mL), DIPEA (1.54 mL, 8.86 mmol, 2.5 eq.) and tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate 2 (1.01 g, 4.61 mmol, 1.3 eq.) were added. After stirring at 60°C over the weekend, complete conversion to 3 was shown by LC-MS. The solvent was removed under reduced pressure, and the residue was dried under high vacuum to obtain 3 (1.44 g, quantitative yield) as a white solid. The crude product was used in the next step without further purification.

[0333] LC-MS method 1: Retention time: 1.656 min, 99.9% purity (at 215 nm), [M+H] + = 408.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.37 - 1.45 (m, 9 H), 1.56 - 1.92 (m, 1 H), 2.09 - 2.20 (m, 1 H), 2.56 - 2.71 (m, 1 H), 2.76 - 3.03 (m, 1 H), 3.08 - 3.19 (m, 1 H), 3.29 (s, 1 H), 3.37 (br s, 1 H), 3.56 - 3.73 (m, 2 H), 4.11 - 4.25 (m, 2 H), 4.41 - 4.73 (m, 1 H), 4.99 (br s, 1 H), 5.11 (br s, 1 H), 6.85 (br d, J = 8.1 Hz, 1 H), 7.10 (br d, J = 7.8 Hz, 1 H), 8.22 (s, 1 H), 8.73 (d, J = 7.8 Hz, 1 H). 19F NMR (377 MHz, DMSO-d6) δ ppm -184.32 (s, 1 F).

[0334] Step 2. Preparation of 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4) To a solution of ethyl 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate 3 (1.44 mg, 3.53 mmol, 1.0 eq) in THF (5.89 mL) and methanol (5.89 mL), a solution of LiOH·H2O (1.48 g, 35.34 mmol, 10.0 eq.) / water (5.89 mL) was added. After stirring at 60°C for 18 hours, complete conversion to the target product 4 was shown by LC-MS. The reaction mixture was concentrated under vacuum to remove THF / MeOH, and the crude mixture was diluted with water. With vigorous stirring, the mixture was acidified to pH=3 (until a precipitate formed) with 6N hydrochloric acid aqueous solution. The suspension was filtered through a Buchner funnel, and the solid was washed with water. The solid was dried overnight in a stove under vacuum to obtain 4 (1.40 g, quantitative yield) as a white solid. The crude product was used in the next step without further purification.

[0335] LC-MS method 1: Retention time: 1.487 min, 99.9% purity (at 215 nm), [M+H] + = 380.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9 H), 1.66 - 1.95 (m, 1 H), 2.05 - 2.26 (m, 1 H), 2.92 - 3.11 (m, 1 H), 3.28 - 3.30 (m, 1 H), 3.34 - 3.49 (m, 1 H), 3.59 - 3.74 (m, 1 H), 4.52 - 4.75 (m, 1 H), 4.99 (br s, 1 H), 5.11 (br s, 1 H), 6.82 (br d, J = 7.6 Hz, 1 H), 7.12 (br d, J = 7.8 Hz, 1 H), 8.19 (s, 1 H), 8.73 (d, J = 7.8 Hz, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm - 184.32 (s, 1 F).

[0336] Step 3. Preparation of 5-methyl 4-[4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-3-(difluoromethyl)pyrazole-1-yl]cyclohexanecarboxylate (5) To a solution of methyl 4-[4-amino-3-(difluoromethyl)pyrazole-1-hexanecarboxylate T-1 (239 mg, 0.870 mmol, 1.0 equiv.) and 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (332 mg, 0.870 mmol, 1.0 equiv.) in MeCN (4.37 mL, 0.2 M), NMI (208 μL, 2.62 mmol, 3.0 equiv.) was added, followed by TCFH (368 mg, 1.31 mmol, 1.5 equiv.). The resulting mixture was stirred at rt for 1 hour. Nanopure water was added to the reaction mixture. The suspension was sonicated and filtered through a Buchner funnel. The solid was washed with nanopure water and dried under high vacuum to obtain pure 5 (466 mg, 84% yield) without further purification.

[0337] LC-MS method 1: 99.9% purity (at 215 nm), [M+H] + = 635.2 m / z. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 9 H), 1.40 - 1.44 (m, 1 H), 1.48 - 1.59 (m, 2 H), 1.76 - 1.94 (m, 3 H), 1.98 - 2.17 (m, 5 H), 2.36 - 2.45 (m, 1 H), 2.98 - 3.12 (m, 1 H), 3.37 - 3.52 (m, 1 H), 3.62 (s, 3 H), 3.64 - 3.71 (m, 1 H), 4.20 - 4.29 (m, 1 H), 4.58 - 4.80 (m, 1 H), 4.94 - 5.12 (m, 1 H), 6.85 - 6.95 (m, 1 H), 7.02 - 7.23 (m, 2 H), 8.23 ​​- 8.39 (m, 2 H), 8.81 (d, J = 7.8 Hz, 1 H), 9.31 (s, 1 H). 19F NMR (377 MHz, DMSO-d6) δ ppm -184.13 (s, 1 F), -111.44 (s, 2 F).

[0338] Step 4. Preparation of 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]pyrazole-1-yl]cyclohexanecarboxylic acid (6) To a solution of methyl 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]pyrazole-1-yl]cyclohexanecarboxylate 5 (466 mg, 0.730 mmol, 1.0 equiv.) in THF (2.45 mL, 0.15 M), a solution of LiOH·H2O (308 mg, 7.34 mmol, 10 equiv.) / water (2.45 mL, 0.15 M) was added. The resulting mixture was stirred overnight at rt. The solvent was removed under reduced pressure, and the residue was suspended in nanopure water and sonicated. A 6 M aqueous HCl solution was added while vigorously stirring at 0°C until the pH became 3. The solid was filtered through a Buchner funnel and washed with nanopure water to obtain pure 6 (362 mg, 79% yield).

[0339] LC-MS method 1: 99.9% purity (at 215 nm), [M+H] + = 621.3 m / z. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 9 H), 1.39 - 1.43 (m, 1 H), 1.47 - 1.57 (m, 2 H), 1.72 - 1.86 (m, 3 H), 2.00 - 2.15 (m, 5 H), 2.26 - 2.35 (m, 1 H), 2.99 - 3.13 (m, 1 H), 3.42 - 3.52 (m, 2 H), 3.63 - 3.72 (m, 1 H), 4.17 - 4.30 (m, 1 H), 4.95 - 5.12 (m, 1 H), 6.85 - 6.95 (m, 1 H), 7.03 - 7.23 (m, 2 H), 8.28 (s, 1 H), 8.34 (s, 1 H), 8.81 (d, J = 8.1 Hz, 1 H), 9.31 (s, 1 H), 12.09 - 12.23 (m, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.09 (s, 1 F), -111.31 - (s, 2 F).

[0340] Step 5. Preparation of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]carbamoyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (7) 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]pyrazole-1-yl]cyclohexanecarboxylic acid 6 (90 mg, 0.15 mmol) and 3-[6-(4-amino-1-piperidyl)-1-methyl-indazole-3-yl]piperidine-2,6-dione hydrochloride C-3 (60.3 mg, 0.16 mmol) were dissolved in DMF (1.2 mL) and DIPEA (252 μL, 1.45 mmol) was added at 0°C. The mixture was stirred at 0°C for 5 minutes, and then HATU (55.1 mg, 0.15 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes. The mixture was loaded directly onto a 30 g RediSep Rf Gold C18 chromatography column. Elution was performed with MeCN / 0.1% formic acid aqueous solution (5% over 5 CV, then 5 to 35% over 15 CV). The fractions of interest were combined and concentrated to obtain 7 (119 mg, 82% yield) as a white solid.

[0341] LCMS method 1: 94.7% purity (at 254 nm), [M+H] + = 944.4, [M+2H] 2+ = 473.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (br s, 9 H), 1.48 - 1.64 (m, 4 H), 1.66 - 1.94 (m, 8 H), 2.04 - 2.22 (m, 5 H), 2.24 - 2.32 (m, 1 H), 2.57 - 2.65 (m, 2 H), 2.86 (br t, J = 10.4 Hz, 2 H), 2.96 - 3.15 (m, 1 H), 3.37 - 3.53 (m, 2 H), 3.60 - 3.70 (m, 1 H), 3.75 (br d, J = 11.7 Hz, 3 H), 3.89 (s, 3 H), 4.25 (br dd. 8.35 (br s, 1 H), 8.82 (d, J = 8.1 Hz, 1 H), 9.31 (br s, 1 H), 10.84 (s, 1 H).

[0342] Step 6. Preparation of 5-((3R,5R)-3-amino-5-fluoropiperidine-1-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-((1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-yl)piperidine-4-yl)carbamoyl)cyclohexyl)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (P-4) In a round-bottom flask, tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]carbamoyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 7 (100 mg, 0.11 mmol) was dissolved in 4 M HCl solution / dioxane (2 mL, 8.00 mmol). The solution was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in water, and the solution was loaded onto a 30 g RediSep Rf Gold C18 chromatography column. Elution was performed using a MeCN / 0.02 M HCl aqueous solution (5% over 3 CV, then 5-20% over 20 CV, then 20-30% over 15 CV). The required fractions were combined and concentrated. The residue was dissolved in water and freeze-dried to obtain P-4 (63.12 mg, 68% yield) as a pale yellow solid.

[0343] LC-MS method 2: 98.4% purity (at 215 nm), [M-HCl+H] + = 844.5, [M-HCl+2H] 2+ = 422.7. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 - 1.67 (m, 2 H), 1.70 - 1.94 (m, 6 H), 1.94 - 2.04 (m, 3 H), 2.04 - 2.13 (m, 3 H), 2.14 - 2.29 (m, 2 H), 2.33 - 2.45 (m, 2 H), 2.56 - 2.74 (m, 2 H), 3.27 - 3.42 (m, 3 H), 3.45 - 3.52 (m, 1 H), 3.66 - 3.79 (m, 2 H), 3.89 - 4.01 (m, 4 H), 4.22 - 4.31 (m, 1 H), 4.32 - 4.40 (m, 1 H), 4.53 - 4.93 (m, 2 H), 5.10 (d, J = 46.5 Hz, 1 H), 6.90 (d, J = 8.1 Hz, 1 H), 7.08 (t, J = 54.5 Hz, 1 H), 7.30 - 7.47 (m, 1 H), 7.67 - 7.81 (m, 1 H), 7.96 - 8.14 (m, 1 H), 8.23 ​​- 8.48 (m, 6 H), 8.93 (d, J = 7.8 Hz, 1 H), 9.33 (s, 1 H), 10.90 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.59 (s, 1 F), -111.26 (s, 2 F).

[0344] Example S2. Synthesis of P-9

change

[0345] Step 5. Preparation of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]amino]piperidine-1-carbonyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (2) 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]pyrazole-1-yl]cyclohexanecarboxylic acid 1 (70.0 mg, 0.113 mmol, 1.0 equiv) and 3-[1-methyl-7-(4-piperidylamino)indazole-3-yl]piperidine-2,6-dione hydrochloride C-2 (55.4 mg, 0.146 mmol, 1.3 equiv) were dissolved in DMF (0.4 mL), and then DIPEA (196 μL, 1.13 mmol, 10.0 equiv) and HATU (51.4 mg, 0.135 mmol, 1.3 equiv) were added in sequence. The reaction mixture was stirred overnight at room temperature. The reaction mixture was directly injected into a reverse-phase flash chromatography column (MeCN / 0.1% HCOOH(aq), 5% (3 CV) → 70%, 50 g RediSep Rf Gold® C18, 20 CV, λ = 214~254 nm, product obtained with 60 to 65% MeCN). The fraction was evaporated to obtain 2 (82 mg, 0.087 mmol, 77% yield) as a white solid.

[0346] LC-MS method 1: 99.9% purity (at 215 nm), [M+H] + = 945.4, [M+2H] 2+ = 473.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (br s, 9 H), 1.39 - 1.47 (m, 1 H), 1.48 - 1.68 (m, 3 H), 1.82 (br d, J = 15.2 Hz, 3 H), 1.86 - 1.98 (m, 3 H), 1.99 - 2.07 (m, 4 H), 2.14 (br dd, J = 13.3, 5.4 Hz, 2 H), 2.23 - 2.36 (m, 1 H), 2.56 - 2.71 (m, 2 H), 2.78 (br t, J = 11.6 Hz, 1 H), 2.85 - 2.96 (m, 1 H), 2.99 - 3.13 (m, 1 H), 3.41 - 3.54 (m, 2 H), 3.55 - 3.76 (m, 2 H), 3.99 (br d, J = 12.5 Hz, 1 H), 4.24 (s, 4 H), 4.26 - 4.35 (m, 2 H), 4.50 - 4.92 (m, 1 H), 4.94 - 5.17 (m, 2 H), 6.61 (d, J = 7.3 Hz, 1 H), 6.84 - 6.95 (m, 2 H), 6.96 - 7.27 (m, 3 H), 8.29 (s, 1 H), 8.35 (br s, 1 H), 8.81 (br d, J = 7.8 Hz, 1 H), 9.32 (br s, 1 H), 10.85 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -185.51 - -183.43 (m, 1 F), -112.85 - -109.73 (m, 2 F).

[0347] Step 6. Preparation of 5-((3R,5R)-3-amino-5-fluoropiperidine-1-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-((3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-7-yl)amino)piperidine-1-carbonyl)cyclohexyl)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (P-9) 4.0 M HCl / 1,4-dioxane (3.17 mL, 12.7 mmol, 150 equiv) was added to tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]amino]piperidine-1-carbonyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 2 (80.0 mg, 0.085 mmol, 1.0 equiv), and the mixture was sonicated for 30 minutes and then stirred for 1 hour. The solvent was evaporated to dryness, and the residue was purified by reverse-phase flash chromatography (MeCN / 0.02M HCl(aq), 5% (3 CV) → 50%, 50g RediSep Rf Gold® C18, 15 CV, λ= 214~254nm, product obtained from 33 to 39% MeCN) to obtain a non-pure product (50 mg). The pure product was obtained after prepHPLC purification: the fraction containing the product was evaporated to dryness, co-evaporated with water (3 × 10 mL) to completely remove any remaining hydrochloric acid, and the residue was freeze-dried overnight to obtain P-9 (31.48 mg, 0.0371 mmol, 43.842% yield) as a white solid.

[0348] LC-MS method 2: 99.5% purity (at 215 nm), [M+H] + = 844.5, [M+2H] 2+ = 422.7. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 - 1.70 (m, 5 H), 1.72 - 2.10 (m, 10 H), 2.10 - 2.21 (m, 1 H), 2.22 - 2.35 (m, 1 H), 2.35 - 2.45 (m, 1 H), 2.53 - 2.71 (m, 2 H), 2.78 (t, J = 11.4 Hz, 1 H), 2.90 (t, J = 11.3 Hz, 1 H), 3.20 - 3.35 (m, 2 H), 3.35 - 3.55 (m, 2 H), 3.55 - 3.71 (m, 1 H), 3.94 - 4.05 (m, 1 H), 4.25 - 4.34 (m, 5 H), 4.61 (br s, 1 H), 4.83 (br s, 1 H), 5.10 (d, J = 45.0 Hz, 1 H), 6.65 (d, J = 6.7 Hz, 1 H), 6.83 - 6.96 (m, 2 H), 6.97 - 7.32 (m, 2 H), 8.29 (br s, 3 H), 8.33 (s, 1 H), 8.39 (s, 1 H), 8.93 (d, J = 7.8 Hz, 1 H), 9.34 (s, 1 H), 10.86 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.68 (s, 1 F), -111.29 (s, 2 F).

[0349] The following compounds were synthesized using the same general route, with modifications made to CBM(CX) in step 5 (Table 4). [Table 17] [Table 18]

[0350] General method for final product 2 Example S3. Synthesis of P-2 [ka] Step 1. Preparation of ethyl 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (3) To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (800 mg, 3.55 mmol, 1.0 eq.) / MeCN (17.7 mL), DIPEA (1.54 mL, 8.86 mmol, 2.5 eq.) and tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate 2 (1.01 g, 4.61 mmol, 1.3 eq.) were added. After stirring over a weekend at 60°C, complete conversion to 3 was shown by LC-MS. The solvent was removed under reduced pressure, and the residue was dried under high vacuum to obtain 3 (1.44 g, quantitative yield) as a white solid. The crude product was used in the next step without further purification.

[0351] LC-MS method 1: Retention time: 1.656 min, 99.9% purity (at 215 nm), [M+H] + = 408.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 - 1.45 (m, 9 H), 1.56 - 1.92 (m, 1 H), 2.09 - 2.20 (m, 1 H), 2.56 - 2.71 (m, 1 H), 2.76 - 3.03 (m, 1 H), 3.08 - 3.19 (m, 1 H), 3.29 (s, 1 H), 3.37 (br s, 1 H), 3.56 - 3.73 (m, 2 H), 4.11 - 4.25 (m, 2 H), 4.41 - 4.73 (m, 1 H), 4.99 (br s, 1 H), 5.11 (br s, 1 H), 6.85 (br d, J = 8.1 Hz, 1 H), 7.10 (br d, J = 7.8 Hz, 1 H), 8.22 (s, 1 H), 8.73 (d, J = 7.8 Hz, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.32 (s, 1 F).

[0352] Step 2. Preparation of 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4) To a solution of ethyl 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate 3 (1.44 mg, 3.53 mmol, 1.0 eq) in THF (5.89 mL) and methanol (5.89 mL), a solution of LiOH·H2O (1.48 g, 35.34 mmol, 10.0 eq.) / water (5.89 mL) was added. After stirring at 60°C for 18 hours, complete conversion to the target product 4 was shown by LC-MS. The reaction mixture was concentrated under vacuum to remove THF / MeOH, and the crude mixture was diluted with water. With vigorous stirring, the mixture was acidified with 6N hydrochloric acid aqueous solution to pH=3 (precipitate formation). The suspension was filtered through a Buchner funnel, and the solid was washed with water. The solid was dried overnight in a stove under vacuum to obtain 4 (1.40 g, quantitative yield) as a white solid. The crude product was used in the next step without further purification.

[0353] LC-MS method 1: Retention time: 1.487 min, 99.9% purity (at 215 nm), [M+H] + = 380.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9 H), 1.66 - 1.95 (m, 1 H), 2.05 - 2.26 (m, 1 H), 2.92 - 3.11 (m, 1 H), 3.28 - 3.30 (m, 1 H), 3.34 - 3.49 (m, 1 H), 3.59 - 3.74 (m, 1 H), 4.52 - 4.75 (m, 1 H), 4.99 (br s, 1 H), 5.11 (br s, 1 H), 6.82 (br d, J = 7.6 Hz, 1 H), 7.12 (br d, J = 7.8 Hz, 1 H), 8.19 (s, 1 H), 8.73 (d, J = 7.8 Hz, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm - 184.32 (s, 1 F).

[0354] Step 3'. Preparation of [4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexyl]methanol (5) To a solution of methyl 4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexanecarboxylate T-1 (1.23 g, 4.5 mmol, 1.0 eq.) in THF (15.0 mL, 0.1 M) and ethanol (30.0 mL), CaCl2 (1.0 g, 9.0 mmol, 2.0 eq.) was added at 0°C, followed by the addition of NaBH4 (0.68 g, 18.0 mmol, 4.0 eq.). The resulting mixture was stirred overnight and then heated to room temperature. After one night, water was added, and the reaction mixture was stirred at room temperature for 1 hour. The aqueous phase was extracted with SiO(3x). The organic material was washed with saline solution, dried on Na2SO4, and concentrated to dryness to obtain [4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexyl]methanol 5 (1.1 g, 99% yield) as an orange oily substance.

[0355] LC-MS method 1: Retention time: 0.989 min, 99.0% purity (at 215 nm), [M+H] + = 246.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (qd, J = 12.9, 3.2 Hz, 2 H), 1.32 - 1.43 (m, 1 H), 1.62 (qd, J = 12.6, 3.3 Hz, 2 H), 1.82 (br d, J = 11.5 Hz, 2 H), 1.93 - 1.98 (m, 2 H), 3.24 (t, J = 5.7 Hz, 2 H), 3.94 (tt, J = 11.9, 3.8 Hz, 1 H), 4.00 - 4.06 (m, 2 H), 4.44 (t, J = 5.3 Hz, 1 H), 6.72 - 7.02 (m, 1 H), 7.14 (s, 1 H). 19F NMR (377 MHz, DMSO-d6) δ ppm -111.21 (s, 2 F).

[0356] Step 3. Preparation of tert-butyl N-[(3r,5r)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (6) [4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexyl]methanol 5 (511.8 mg, 1.88 mmol, 1.5 eq.), 5-[(3r,5r)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (475.0 mg, 1.25 mmol, 1.0 eq.), and NMI (362.72 μL, 4.58 mmol, 3.6 eq.) were mixed in MeCN (12.5 mL, 0.1 M) with TCFH (440.43 mg, 1.57 mmol, 1.2 eq.). The resulting mixture was stirred overnight at room temperature. Water was added, and the reaction mixture was stirred at room temperature for 1 hour. The solid was filtered through a Buchner funnel and washed with a water / MeCN mixed solvent. Purification by reverse-phase chromatography (50 g C18 RediSep Rf Gold column, retention solution (DMSO), elution: 5% MeOH / 0.1% HCOOH over 4 CV, then 5% to 100% MeOH / 0.1% HCOOH over 15 CV). The pure fractions were combined and concentrated under reduced pressure to obtain tert-butyl N-[(3r,5r)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 6 (421 mg, 55% yield) as a brown solid.

[0357] LC-MS method 1: Retention time: 1.629 min, 99.9% purity (at 215 nm), [M+H] += 607.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.03 - 1.15 (m, 2 H), 1.34 (br s, 9 H), 1.64 - 1.80 (m, 3 H), 1.82 - 1.93 (m, 3 H), 1.99 - 2.07 (m, 2 H), 2.08 - 2.18 (m, 1 H), 2.95 - 3.14 (m, 1 H), 3.26 (t, J = 5.7 Hz, 2 H), 3.37 - 3.52 (m, 1 H), 3.62 - 3.71 (m, 1 H), 4.12 - 4.21 (m, 1 H), 4.47 (t, J = 5.3 Hz, 1 H), 4.69 (br s, 1 H), 4.95 - 5.12 (m, 1 H), 6.86 - 6.94 (m, 1 H), 7.01 - 7.22 (m, 2 H), 8.28 (s, 1 H), 8.34 (br s, 1 H), 8.82 (d, J = 7.8 Hz, 1 H), 9.31 (br s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -186.02 - -179.79 (m, 1F), -113.10 - -108.69 (m, 2F).

[0358] Step 4. tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]amino]-1-piperidyl]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate formate (7) To a solution of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 6 (328.7 mg, 0.54 mmol, 1.0 eq.) in dried DMSO (2.7 mL, 0.1 M), IBX (182.07 mg, 0.65 mmol, 1.2 eq.) was added. The resulting mixture was stirred overnight at room temperature. After overnight stirring, complete conversion to the aldehyde was demonstrated by LC-MS. To the reaction mixture, 3-[1-methyl-6-(4-piperidylamino)indazole-3-yl]piperidine-2,6-dione C-1 (344.51 mg, 1.63 mmol, 1.2 eq.), DCM (2.71 mL, 0.1 M), and DIPEA (0.94 mL, 5.42 mmol, 10.0 eq.) were added. The mixture was stirred at room temperature for 10 minutes, after which sodium triacetoxyborohydride (344.51 mg, 1.63 mmol, 3 eq.) was added. After 1 hour, LC-MS showed complete conversion to compound 3. DCM was evaporated under reduced pressure, and the crude mixture was purified by reverse-phase FC chromatography (50 g C18 RediSep Rf Gold column, holding solution (DMSO), 5% MeCN / 0.1% HCOOH over 4 CV, then 5-70% MeCN / 0.1% HCOOH over 20 CV, the product was eluted with 50% MeCN). The pure fractions were combined and concentrated to obtain 7 (313 mg, 59% yield) as formate as a brown solid.

[0359] LC-MS method 3: 95.5% purity (at 215 nm), [M-HCOOH+H] + = 930.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 - 1.09 (m, 2 H), 1.34 (br s, 9 H), 1.40 - 1.51 (m, 3 H), 1.62 (br d, J = 6.1 Hz, 1 H), 1.70 - 1.83 (m, 3 H), 1.85 - 1.95 (m, 3 H), 1.95 - 2.01 (m, 2 H), 2.01 - 2.07 (m, 2 H), 2.15 (br t, J = 5.1 Hz, 3 H), 2.18 - 2.35 (m, 4 H), 2.60 (br t, J = 6.6 Hz, 2 H), 2.83 - 2.92 (m, 2 H), 3.29 - 3.40 (m, 2 H), 3.61 - 3.73 (m, 1 H), 3.81 (s, 3 H), 4.11 - 4.24 (m, 3 H), 4.95 - 5.13 (m, 1 H), 5.67 - 5.84 (m, 1 H), 6.38 (s, 1 H), 6.52 (br d, J = 8.8 Hz, 1 H), 6.84 - 6.95 (m, 1 H), 6.99 - 7.22 (m, 2 H), 7.32 (d, J = 8.8 Hz, 1 H), 8.16 (s, 1 H), 8.29 (s, 1 H), 8.31 - 8.36 (m, 1 H), 8.82 (br d, J = 8.1 Hz, 1 H), 9.31 (br s, 1 H), 10.82 (s, 1 H).

[0360] Step 5. Preparation of N-[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]amino]-1-piperidyl]methyl]cyclohexyl]pyrazole-4-yl]-5-[(3R,5R)-3-amino-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-2) In a round-bottom flask, tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]amino]-1-piperidyl]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 7 (308.35 mg, 0.33 mmol, 1 eq.) and 4 M HCl / dioxane (10.28 mL, 41.11 mmol, 124 eq.) were added. The reaction mixture was stirred at rt. Complete conversion to P-2 was shown by LC-MS after 18 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by reverse-phase FC (50 g C18 RediSep Rf Gold column, holding solution (H2O), elution: 5% MeCN / 0.02 M HCl over 4 CV, then 5% to 30% MeCN / 0.02 M HCl over 20 CV, the product was eluted with 25% MeCN). The fractions were combined and concentrated to obtain P-2 (149.83 mg, 54% yield) as a brown solid hydrochloride.

[0361] LC-MS method 4: 99.9% purity (at 215 nm), [M-HCl+H] + = 830.3; [M-HCl+2H] 2+ = 415.7. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 - 1.30 (m, 2 H), 1.76 - 2.46 (m, 15 H), 2.58 - 2.65 (m, 2 H), 2.93 - 3.17 (m, 4 H), 3.26 - 3.51 (m, 4 H), 3.54 - 3.65 (m, 2 H), 4.18 - 4.30 (m, 2 H), 4.55 - 4.72 (m, 1 H), 4.75 - 4.96 (m, 1 H), 5.02 - 5.19 (m, 1 H), 6.53 - 6.69 (m, 2 H), 6.91 (br d, J = 8.1 Hz, 1 H), 7.14 (t, J = 54.0 Hz, 1 H), 7.41 (br d, J = 8.8 Hz, 1 H), 8.31 - 8.34 (m, 1 H), 8.40 (s, 4 H), 8.93 (d, J = 7.8 Hz, 1 H), 9.34 (s, 1 H), 9.93 (br s, 1 H), 10.84 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.68 (s, 1 F), -111.54 - -110.76 (m, 2 F).

[0362] Example S4. Synthesis of P-5 [ka] Step 4. Preparation of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]amino]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (2) To a solution of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(2-hydroxyethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 1 (intermediate 6 obtained by synthesis of P-2) (58.6 mg, 0.097 mmol, 1 eq.) in dry DMSO (1.0 mL), IBX (32.6 mg, 0.116 mmol, 1.2 eq.) was added. The resulting mixture was stirred at room temperature. After 16 hours, LC-MS showed that all components had been converted to aldehydes. Aldehyde / DMSO was added to a solution of 3-[6-(4-amino-1-piperidyl)-1-methyl-indazole-3-yl]piperidine-2,6-dione hydrochloride C-3 (44.2 mg, 0.107 mmol, 1.1 eq.) and DIPEA (168 μL, 0.969 mmol, 10 eq.) in DCE (1 mL). The mixture was stirred at room temperature for 10 minutes, and then NaBH(OAc)3 (26.7 mg, 0.126 mmol, 1.3 eq.) was added. The resulting mixture was then stirred at room temperature. After 1 hour, LC-MS indicated that everything was complete. DCE was removed under reduced pressure, and the residue was purified by reverse-phase flash chromatography (50 g C18 RediSep Rf Gold column, holding solution (DMSO), elution: 5% MeCN / 0.1% HCOOH over 3 CV, then 5 to 35% MeCN / 0.1% HCOOH over 15 CV, then 35 to 100% MeCN / 0.1% HCOOH over 1 CV, then 100% MeCN / 0.1% HCOOH over 3 CV (the target product eluted around 30% MeCN)). The fractions were combined and concentrated to obtain 2 (48.4 mg, 54% yield) as a white solid. The product was used in the next step without purification. LC-MS method 1: 99.9% purity (at 215 nm), [M+2H] 2+ = 466.

[0363] Step 5. Manufacturing of 5-((3R,5R)-3-amino-5-fluoropiperidine-1-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(((1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-yl)piperidine-4-yl)amino)methyl)cyclohexyl)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide dihydrochloride (P-5) tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]amino]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 2 (48.4 mg, 0.052 mmol, 1 eq.) was dissolved in 4 M HCl / 1,4-dioxane (1.95 mL, 7.80 mmol, 150 eq.) solution. The mixture was stirred at room temperature. After 2 hours, completeness was indicated by LC-MS. Volatile substances were evaporated under vacuum. The residue was purified by reverse-phase flash chromatography (30 g C18 RediSep Rf Gold column, holding solution (water), elution: 5% MeCN / 0.02 M HCl over 5 CV, then 5 to 20% MeCN / 0.02 M HCl over 15 CV, then 20% MeCN / 0.02 M HCl over 5 CV, then 20 to 100% MeCN / 0.02 M HCl over 2 CV, then 100% MeCN / 0.02 M HCl over 3 CV). The fractions were combined and concentrated to obtain P-5 (16.61 mg, 38% yield) as a white solid.

[0364] LC-MS method 2: 99.6% purity (at 215 nm), [M-2HCl+2H] 2+ = 415.7, [M-2HCl+H] + = 830.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 - 1.32 (m, 2 H), 1.58 - 1.86 (m, 5 H), 1.88 - 2.02 (m, 2 H), 2.04 - 2.23 (m, 5 H), 2.26 - 2.36 (m, 2 H), 2.58 - 2.68 (m, 3 H), 2.77 - 2.97 (m, 3 H), 3.22 - 3.53 (m, 5 H), 3.86 - 3.92 (m, 3 H), 3.92 - 4.03 (m, 2 H), 4.16 - 4.36 (m, 2 H), 4.47 - 4.93 (m, 2 H), 5.10 (d, J = 46.2 Hz, 1 H), 6.78 - 6.99 (m, 3 H), 6.99 - 7.31 (m, 1 H), 7.48 - 7.57 (m, 1 H), 8.06 - 8.29 (m, 3 H), 8.33 (s, 1 H), 8.42 (s, 1 H), 8.47 - 8.69 (m, 2 H), 8.91 - 9.00 (m, 1 H), 9.33 (s, 1 H), 10.85 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.50 (s, 1 F), -111.28 (s, 2 F).

[0365] Example S5. Synthesis of P-18 [ka]

[0366] Step 1. Preparation of ethyl 5-[(3S,4S)-3-(tert-butoxycarbonylamino)-4-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (3) To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (94 mg, 0.42 mmol, 1 eq.) in MeCN (2.0 mL), DIPEA (181.36 μL, 1.04 mmol, 3 eq.) was added, followed by tert-butyl N-[(3S,4S)-4-fluoro-3-piperidyl]carbamate 2 (100 mg, 0.46 mmol, 1.1 eq.). The resulting mixture was then stirred at 90°C. After 16 hours, LC-MS indicated completion of the reaction. MeCN was evaporated under vacuum to obtain 3 (169.7 mg, quantitative yield) as a brown semi-solid, which was used directly in the next step. LC-MS method 1: 99.9% purity (at 215 nm), [M+H] + = 408.2.

[0367] Step 2. Preparation of 5-[(3S,4S)-3-(tert-butoxycarbonylamino)-4-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4) A solution of ethyl 5-[(3S,4S)-3-(tert-butoxycarbonylamino)-4-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate 3 (169.7 mg, 0.42 mmol, 1 eq.) in THF (694.2 μL) and methanol (694.2 μL) was added to a solution of LiOH·H2O (174.93 mg, 4.17 mmol, 10 eq.) / water (694.2 mL). The resulting mixture was stirred at 60°C. After 2 hours, LC-MS indicated that the process was complete. The volatile components were evaporated under vacuum, and the mixture was diluted with water. The solution was then acidified to pH 3 with 6N hydrochloric acid aqueous solution while vigorously stirring. The white precipitate was filtered off, and the solid was washed three times with cold water. The solid was then dissolved in THF and evaporated three times with the THF to obtain 4 (16.61 mg, 38% yield) as an off-white solid. LC-MS method 1: 99.9% purity (at 215 nm), [M-tBu+H] + = 324.2. 1 H NMR (400 MHz, DMSO-d6 ) δ ppm 1.40 (s, 9 H), 1.59 - 1.77 (m, 2 H), 3.12 - 3.21 (m, 1 H), 3.51 - 3.64 (m, 2 H), 4.17 - 4.39 (m, 2 H), 4.55 - 4.74 (m, 2 H), 6.80 - 6.92 (m, 1 H), 7.19 - 7.33 (m, 1 H), 8.73 (d, J = 7.8 Hz, 1 H), 11.44 - 11.96 (m, 1 H).

[0368] Step 3. Preparation of tert-butyl ((3S,4S)-1-(3-((3-(difluoromethyl)-1-((1r,4S)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazole-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidine-5-yl)-4-fluoropiperidine-3-yl)carbamate (6) [4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexyl]methanol 5 (intermediate 6 obtained from the synthesis of P-2) (110 mg, 0.40 mmol, 1.5 eq.), 5-[(3S,4S)-3-(tert-butoxycarbonylamino)-4-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (102.09 mg, 0.27 mmol, 1 eq.), and NMI (78 μL, 0.98 mmol, 3.65 eq.) were dissolved in MeCN (4.03 mL) and TCFH (94.66 mg, 0.34 mmol, 1.25 eq.) was added. The resulting mixture was stirred at room temperature. After 16 hours, completion was indicated by LC-MS. Volatile substances were evaporated under vacuum. The resulting residue was purified by reverse-phase flash chromatography (50 g C18 RediSep Rf Gold column, holding solution (DMSO), elution: 5% MeCN / 0.1% HCOOH over 3 CV, then 5-100% MeCN / 0.1% HCOOH over 15 CV, then 100% MeCN / 0.1% HCOOH over 3 CV, the target product was eluted at approximately 75% MeCN). The fractions were combined and concentrated to obtain 6 (116.2 mg, 71% yield) as an orange solid.

[0369] LC-MS method 1: 99.9% purity (at 215 nm), [M+H] + = 607.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 - 1.09 (m, 2 H), 1.21 - 1.28 (m, 2 H), 1.35 (s, 9 H), 1.66 - 1.78 (m, 3 H), 1.81 - 1.92 (m, 2 H), 2.00 - 2.10 (m, 2 H), 2.13 - 2.25 (m, 1 H), 3.07 (s, 1 H), 3.24 -3.28 (m, 2 H), 3.42 - 3.52 (m, 1 H), 3.53 - 3.68 (m, 1 H), 4.11 - 4.22 (m, 2 H), 4.42 - 4.51 (m, 1 H), 4.58 - 4.78 (m, 1 H), 6.85 - 6.92 (m, 1 H), 6.93 - 7.21 (m, 1 H), 7.22 - 7.30 (m, 1 H), 8.28 (s, 1 H), 8.35 (s, 1 H), 8.81 (d, J = 7.8 Hz, 1 H), 9.33 (br s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -183.02 - -179.35 (m, 1 F), -112.72 - -109.70 (m, 2 F).

[0370] Step 4. Preparation of tert-butyl N-[(3S,4S)-1-[3-[[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]amino]-1-piperidyl]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-4-fluoro-3-piperidyl]carbamate (7) To a solution of tert-butyl ((3S,4S)-1-(3-((3-(difluoromethyl)-1-((1r,4S)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazole-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidine-5-yl)-4-fluoropiperidine-3-yl)carbamate 6 (75 mg, 0.12 mmol, 1 eq.) in dry DMSO (1.0 mL), IBX (41.5 mg, 0.15 mmol, 1.2 eq.) was added. The resulting mixture was stirred at room temperature. After 16 hours, complete conversion to the aldehyde was demonstrated by LC-MS. The aldehyde solution was added to a solution of 3-[1-methyl-6-(4-piperidylamino)indazole-3-yl]piperidine-2,6-dione hydrochloride C-1 (64.97 mg, 0.14 mmol, 1.1 eq.) and DIPEA (215 μL, 1.24 mmol, 10 eq.) in DCE (1.0 mL). The mixture was stirred at rt for 10 minutes, and NaBH(OAc)3 (34.05 mg, 0.16 mmol, 1.3 eq.) was added. The resulting mixture was stirred at room temperature. After 1 hour, LC-MS indicated completeness. DCE was removed under reduced pressure, and the residue was purified by reverse-phase flash chromatography (50 g C18 RediSep Rf Gold column, holding solution (DMSO), elution: 5% MeCN / 0.1% HCOOH over 3 CV, then 5 to 35% MeCN / 0.1% HCOOH over 15 CV, then 35 to 100% MeCN / 0.1% HCOOH over 1 CV, then 100% MeCN / 0.1% HCOOH over 3 CV (the target product eluted around 30% MeCN)). The fractions were combined and concentrated to obtain 7 (37 mg, 32% yield) as a pale yellow solid. The product was used in the next step without purification. LCMS method 1: [M+2H] 2+ = 465.8.

[0371] Step 5. N-[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]amino]-1-piperidyl]methyl]cyclohexyl]pyrazole-4-yl]-5-[(3S,4S)-3-amino-4-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-18) tert-butyl N-[(3S,4S)-1-[3-[[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]amino]-1-piperidyl]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-4-fluoro-3-piperidyl]carbamate 7 (35 mg, 0.038 mmol, 1 eq.) was dissolved in 4 M HCl / 1,4-dioxane (1.41 mL, 5.64 mmol, 150 eq.) solution. The mixture was stirred at rt. After 2 hours, LC-MS indicated that the process was complete. Volatile components were evaporated under vacuum. The residue was purified by reverse-phase flash chromatography (30 g C18 RediSep Rf Gold column, holding solution (water), elution: 5% MeCN / 0.02 M HCl over 5 CV, then 5 to 20% MeCN / 0.02 M HCl over 15 CV, then 20% MeCN / 0.02 M HCl over 5 CV, then 20 to 100% MeCN / 0.02 M HCl over 2 CV, then 100% MeCN / 0.02 M HCl over 3 CV). The fractions were combined and concentrated to obtain P-18 (18.22 mg, 57% yield) as a 2HCl salt, as a brown solid. LC-MS method 2: 97.7% purity (at 215 nm), [M-2HCl+2H] 2+ = 415.8; [M-2HCl+H] + = 830.5. 1H NMR (400 MHz, DMSO-d6 ) δ ppm 1.16 - 1.32 (m, 2 H), 1.57 - 2.04 (m, 8 H), 2.04 - 2.12 (m, 2 H), 2.13 - 2.30 (m, 4 H), 2.59 - 2.65 (m, 2 H), 2.96 - 3.16 (m, 3 H), 3.19 - 3.30 (m, 1 H), 3.31 - 3.52 (m, 4 H), 3.53 - 3.67 (m, 3 H), 3.84 (s, 3 H), 4.17 - 4.31 (m, 3 H), 4.41 - 4.65 (m, 2H), 4.84 - 5.09 (m, 1 H), 6.33 - 6.73 (m, 2 H), 6.87 (d, J = 7.8 Hz, 1 H), 6.98 - 7.30 (m, 1 H), 7.32 - 7.42 (m, 1 H), 8.33 (s, 1 H), 8.40 (s, 1 H), 8.44 - 8.67 (m, 3 H), 8.94 (d, J = 8.1 Hz, 1 H), 9.35 (s, 1 H), 9.41 - 9.59 (m, 1 H), 10.83 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -181.60 (s, 1 F), -111.38 (s, 2 F).

[0372] Example S6. Synthesis of P-27 [ka]

[0373] Step 1. Preparation of ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate (3) Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (1.5 g, 6.65 mmol, 1 eq.), MeCN (33.24 mL, 0.2 M), and DIPEA (2.89 mL, 16.62 mmol, 2.5 eq.) were placed in a sealed tube, and then morpholine 2 (639.65 μL, 7.31 mmol, 1.1 eq.) was added. The tube was sealed, and the mixture was stirred at 90°C for 16 hours. The solvent was evaporated under reduced pressure, and the mixture was dried under high vacuum to obtain ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate 3 (2.96 g, 99% yield) as an orange solid. LC-MS method 1: Retention time: 1.432 min, 99% purity (at 215 nm), [M + H] + = 277.2. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 1.39 (t, J = 7.1 Hz, 3 H), 3.76 - 3.86 (m, 8 H), 4.35 (q, J = 7.1 Hz, 2 H), 6.41 (d, J = 8.1 Hz, 1 H), 8.29 - 8.34 (m, 2 H).

[0374] Step 2. Preparation of 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4) After stirring for 5 minutes, a solution of ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate 3 (1.84 g, 6.66 mmol, 1.0 eq.) in THF (17.8 mL, 0.1 M) and methanol (17.8 mL) was added to a solution of LiOH·H2O (2.8 g, 66.6 mmol, 10 eq.) / water (17.8 mL). The mixture was stirred at 60°C for 3 hours, then the water bath was removed and the mixture was stirred over the weekend (72 hours). The reaction mixture was concentrated under reduced pressure, and the crude mixture was diluted with a small amount of water and acidified to pH 3 with 6N hydrochloric acid. The resulting precipitate was filtered off and rinsed with water. The solid was dried under high vacuum to obtain 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (1.65 g, 99% yield) as a brown solid. LC-MS method 1: Retention time: 1.192 min, 99% purity (at 215 nm), [M + H] + = 249.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (br d, J = 5.9 Hz, 8 H), 6.84 (d, J = 8.1 Hz, 1 H), 8.19 (s, 1 H), 8.74 (d, J = 7.8 Hz, 1 H), 11.73 (s, 1 H).

[0375] Step 3. Preparation of N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide (6) [4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexyl]methanol 5 (intermediate 6 obtained from the synthesis of P-2) (403.12 mg, 1.64 mmol, 1.2 eq.), 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (340.0 mg, 1.37 mmol, 1.0 eq.), and NMI (0.43 mL, 5.48 mmol, 4.0 eq.) were dissolved in MeCN (9 mL, 0.15 M) and TCFH (480.37 mg, 1.71 mmol, 1.25 eq.). The resulting mixture was stirred at room temperature for 1 hour. After 1 hour, the volatile components were evaporated, and the resulting mixture was purified by reverse-phase chromatography (50 g C18 RediSep Rf Gold column, holding solution (DMSO), elution: 5% MeOH / 0.1% HCOOH over 4 CV, then 5% to 50% MeOH / 0.1% HCOOH over 15 CV, the product was eluted with 50% MeOH). The pure fractions were combined and concentrated under reduced pressure to obtain N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide 6 (338 mg, 52% yield) as a brown solid.

[0376] LC-MS method 3: Retention time: 1.707 min, 99.9% purity (at 215 nm), [M+H] + = 476.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 - 1.15 (m, 2 H), 1.38 - 1.48 (m, 1 H), 1.66 - 1.79 (m, 2 H), 1.80 - 1.90 (m, 2 H), 1.99 - 2.08 (m, 2 H), 3.26 (t, J = 5.7 Hz, 2 H), 3.68 - 3.74 (m, 4 H), 3.76 - 3.83 (m, 4 H), 4.12 - 4.23 (m, 1 H), 4.47 (t, J = 5.4 Hz, 1 H), 6.90 (d, J = 7.8 Hz, 1 H), 6.95 - 7.25 (m, 1 H), 8.28 (s, 1 H), 8.38 (s, 1 H), 8.82 (d, J = 8.1 Hz, 1 H), 9.39 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.19 (s, 2 F).

[0377] Step 4. Preparation of N-[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]amino]-1-piperidyl]methyl]cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide formate (P-27) N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide 6 (120.0 mg, 0.25 mmol, 1 eq.) was dissolved in DMSO (1.5 mL), to which IBX (84.0 mg, 0.3 mmol, 1.2 eq.) was added at room temperature. The mixture was then stirred at room temperature. After 18 hours, complete conversion to the aldehyde was demonstrated by LC-MS. Next, a DMSO solution of the aldehyde was slowly added to a 1.5 mL solution of 3-[1-methyl-6-(4-piperidylamino)indazole-3-yl]piperidine-2,6-dione dihydrochloride C-1 (115.1 mg, 0.28 mmol, 1.1 eq.), DIPEA (0.44 mL, 2.5 mmol, 10 eq.), and NaBH(OAc)3 (158.95 mg, 0.75 mmol, 3 eq.) in CH2Cl2 (1.5 mL). The resulting mixture was stirred at room temperature. After 2 hours, LC-MS demonstrated the complete conversion of the aldehyde. After removing the solvent under reduced pressure, the solution was purified by reverse-phase FC (50 g C18 RediSep Rf Gold column, holding solution (DMSO), elution: 5% MeCN / 0.1% HCOOH over 5 CV, then 5 to 100% MeCN / 0.1% HCOOH over 20 CV, then 100% MeCN / 0.1% HCOOH over 5 CV, the product eluted at approximately 35% MeCN). The fractions were combined, concentrated, and lyophilized to obtain crude P-27 (67 mg, 82% purity (at 215 nm)). This was purified by preparative LC-MS (acidic conditions using formic acid as a modifier) ​​to obtain P-27 (50 mg, 24% yield) as a formate salt, which was a pink solid.

[0378] LC-MS method 2: 97.4% purity (at 215 nm), [M-HCOOH+H] + = 799.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 - 1.12 (m, 2 H), 1.34 - 1.48 (m, 2 H), 1.53 - 1.67 (m, 1 H), 1.68 - 1.82 (m, 2 H), 1.87 - 2.00 (m, 4 H), 2.01 - 2.31 (m, 9 H), 2.56 - 2.63 (m, 2 H), 2.79 - 2.87 (m, 2 H), 3.69 - 3.75 (m, 4 H), 3.75 - 3.83 (m, 7 H), 4.14 - 4.24 (m, 2 H), 5.74 (br d, J = 7.8 Hz, 1 H), 6.38 (s, 1 H), 6.52 (dd, J = 8.8, 1.7 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1 H), 7.09 (t, J = 54.0 Hz, 1 H), 7.32 (d, J = 8.8 Hz, 1 H), 8.16 (s, 1 H), 8.29 (s, 1 H), 8.38 (s, 1 H), 8.83 (d, J = 8.1 Hz, 1 H), 9.40 (s, 1 H), 10.81 (s, 1 H).

[0379] Example S7. Synthesis of P-30 [ka]

[0380] Step 4. Preparation of formate (2) of tert-butyl N-[rac-(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate To a solution of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 1 (intermediate 6 obtained from the synthesis of P-2) (125 mg, 0.21 mmol, 1.0 eq.) in dried DMSO (1 mL, 0.10 M), IBX (69.24 mg, 0.25 mmol, 1.2 eq.) was added. The resulting mixture was stirred overnight at room temperature. After overnight stirring, complete conversion to the aldehyde was demonstrated by LC-MS. To the reaction mixture, 3-[1-methyl-7-[4-(methylamino)-1-piperidyl]indazole-3-yl]piperidine-2,6-dione hydrochloride C-16 (97.09 mg, 0.23 mmol, 1.2 eq.), DCM (1 mL, 0.1 M), and DIPEA (0.36 mL, 2.06 mmol, 10.0 eq.) were added. After stirring the mixture at room temperature for 10 minutes, sodium triacetoxyborohydride (131.01 mg, 0.62 mmol, 3 eq.) was added. After 1 hour, LC-MS showed complete conversion to compound 6. DCM was evaporated under reduced pressure, and the crude mixture was purified by reverse-phase FC purification (50 g C18 RediSep Rf Gold column, holding solution (DMSO), 5% MeCN / 0.1% HCOOH over 4 CV, then 5-60% MeCN / 0.1% HCOOH over 20 CV; the product was eluted with 50% MeCN). The pure fractions were combined and concentrated, and 2 (152 mg, 70% yield) was obtained as formate as a brown solid. The target product contained IBX residue.

[0381] LCMS method 3: 90.2% purity (at 254 nm), [M-HCOOH+H] + = 944.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 - 1.12 (m, 2 H), 1.34 (s, 9 H), 1.48 - 1.59 (m, 1 H), 1.64 - 1.98 (m, 10 H), 2.00 - 2.07 (m, 2 H), 2.11 - 2.21 (m, 2 H), 2.28 (s, 3 H), 2.30 - 2.35 (m, 3 H), 2.57 - 2.66 (m, 2 H), 2.68 - 2.77 (m, 2 H), 3.18 - 3.25 (m, 3 H), 3.39 - 3.52 (m, 5 H), 3.63 - 3.72 (m, 1 H), 4.14 - 4.23 (m, 1 H), 4.26 (s, 3 H), 4.33 (dd, J = 9.7, 5.0 Hz, 1 H), 4.94 - 5.12 (m, 1 H), 6.85 - 6.94 (m, 1 H), 6.95 - 7.19 (m, 4 H), 7.32 - 7.41 (m, 1 H), 8.15 (s, 1 H), 8.29 (s, 1 H), 8.34 (br s, 1 H), 8.82 (br d, J = 8.1 Hz, 1 H), 9.31 (br s, 1 H), 10.88 (s, 1 H).

[0382] Step 5. Preparation of N-[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-yl]-5-[(3R,5R)-3-amino-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-30) In a round-bottom flask, tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 2 (152 mg, 0.16 mmol, 1 eq.) and 4 M HCl / dioxane (4.99 mL, 19.97 mmol, 124 eq.) were added. The reaction mixture was stirred at room temperature. After 1 hour, LC-MS showed complete conversion to compound P-30. The reaction mixture was concentrated under vacuum, and the residue was purified by reverse-phase FC (50 g C18 RediSep Rf Gold column, holding solution (H2O), elution: 5% MeCN / 0.02 M HCl over 4 CV, then 5% to 30% MeCN / 0.02 M HCl over 20 CV, the product was eluted with 25% MeCN). The fractions were combined and concentrated to obtain P-30 (42.38 mg, 31% yield) as a white solid dihydrochloride.

[0383] LC-MS method 2: 99.9% purity (at 215 nm), [M-2HCl+H] + = 844.4;[M-2HCl+2H] 2+ = 422.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 - 1.35 (m, 2 H), 1.77 - 2.03 (m, 7 H), 2.03 - 2.25 (m, 7 H), 2.34 - 2.44 (m, 1 H), 2.57 - 2.66 (m, 2 H), 2.79 - 2.88 (m, 5 H), 2.92 - 3.01 (m, 1 H), 3.16 - 3.25 (m, 1 H), 3.51 (br s, 6 H), 4.22 - 4.29 (m, 4 H), 4.35 (dd, J = 9.5, 5.1 Hz, 1 H), 4.51 - 4.67 (m, 1 H), 4.76 - 4.95 (m, 1 H), 5.10 (br d, J = 48.0 Hz, 1 H), 6.89 (br d, J = 7.6 Hz, 1 H), 6.99 - 7.28 (m, 3 H), 7.43 (dd, J = 6.6, 2.4 Hz, 1 H), 8.26 (br s, 3 H), 8.33 (s, 1 H), 8.41 (s, 1 H), 8.94 (d, J = 8.1 Hz, 1 H), 9.34 (s, 1 H), 9.56 (br s, 1 H), 10.89 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.64 (br s, 1 F), -111.82 - -110.85 (m, 2 F).

[0384] The following compounds were synthesized using the same general route, with modifications to amine 2 in step 1 and CBM(CX) in step 4 (Table 5). [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30]

[0385] General method for final product 3 Example S8. Synthesis of P-7 [ka]

[0386] Step 1. Preparation of [4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexyl]methanol (2) To a solution of methyl 4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexanecarboxylate 1 (intermediate 4 obtained from the synthesis of T-1) (730.0 mg, 2.26 mmol, 1 eq.) in 1:2 THF (3.8 mL) / ethanol (7.5 mL), CaCl2 (501.2 mg, 4.52 mmol, 2 eq.) was added at 0°C, followed by NaBH4 (341.6 mg, 9.03 mmol, 4 eq.). The resulting mixture was stirred at room temperature. After 16 hours at the same temperature, complete conversion was shown by LC-MS. The product was then extracted three times with siRNA, washed once with water and once with saline to remove organic matter, and finally dried over MgSO4. Depositphotos was removed under reduced pressure, and the residue was purified by normal-phase flash chromatography (80 g silica column, holding solution (DCM), elution: 0% Depositphotos over 3 CV, then 0 to 100% Depositphotos over 10 CV, then 100% Depositphotos over 3 CV (the target product eluted at around 50% Depositphotos)). The fractions were combined and concentrated to obtain 2 (371.9 mg, 58% yield) as a colorless oil.

[0387] LC-MS method 1: 97.5% purity (at 215 nm), [M+H] + = 276.2. 1 H NMR (400 MHz, CDCl3-d) δ ppm 1.14 - 1.30 (m, 3 H), 1.70 - 1.87 (m, 2 H), 1.97 - 2.09 (m, 2 H), 2.25 - 2.34 (m, 2 H), 3.54 (d, J = 6.1 Hz, 2 H), 4.18 (tt, J = 12.1, 3.9 Hz, 1 H), 7.10 (t, J = 53.3 Hz, 1 H), 8.22 (s, 1 H). 19 F NMR (377 MHz, CDCl3-d) δ ppm -117.64 (d, J = 53.13, 2 F).

[0388] Step 2. Preparation of [4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexyl]methylmethanesulfonate (3) [4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexyl]methanol 2 (428.5 mg, 1.52 mmol) and Et3N (0.28 mL, 1.98 mmol) in DCM (7.62 mL) were mixed dropwise with MsCl (0.13 mL, 1.68 mmol) at 0°C. The reaction mixture was then slowly heated to room temperature and stirred at that temperature. After 3 hours, TLC (3:7 heptane / RINKAN) indicated completion of the reaction. The reaction mixture was then partitioned with water and RINKAN. The phases were separated, and the organic phase was washed three times with water, once with 1N hydrochloric acid, and once with saline solution, and then dried over MgSO4. RINKAN was removed under reduced pressure to obtain 3 (529 mg, 93% yield) as a pale yellow oil. The product was used without further purification in the next step.

[0389] LC-MS method 1: 94.8% purity (at 215 nm), [M+H] + = 354.0. 1 H NMR (400 MHz, CDCl3-d) δ ppm 1.22 - 1.37 (m, 3 H), 1.80 - 1.90 (m, 2 H), 2.05 - 2.13 (m, 2 H), 2.27 - 2.36 (m, 2 H), 3.04 (s, 3 H), 4.08 - 4.14 (m, 2 H), 4.15 - 4.24 (m, 1 H), 7.11 (t, J = 53.4 Hz, 1 H), 8.22 (s, 1 H). 19 F NMR (377 MHz, CDCl3-d) δ ppm -117.64 (d, J = 53.13, 2 F).

[0390] Step 3. Preparation of 2-[4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexyl]acetaldehyde (4) A solution of [4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexyl]methylmethanesulfonate 3 (529.0 mg, 1.5 mmol, 1 eq.) and NaCN (183.4 mg, 3.74 mmol, 2.5 eq.) in DMSO (7.49 mL) was heated to 50°C and stirred at the same temperature. After 16 hours at 50°C, LC-MS indicated that the reaction was complete. The reaction mixture was cooled to rt and quenched with water with vigorous stirring. Then, siRNA was added and the product was extracted twice more with siRNA. The combined organic layers were washed once with concentrated NaHCO3 aqueous solution and once with saline. Finally, the latter was dried over MgSO4 and siRNA was removed under reduced pressure to obtain 4 (342 mg, 79% yield) as a yellow oily substance.

[0391] LC-MS method 1: 98.8% purity (at 215 nm), [M+H] + = 285.2. 1 H NMR (400 MHz, CDCl3-d) δ ppm 1.30 - 1.46 (m, 2 H), 1.76 - 1.96 (m, 3 H), 2.06 - 2.16 (m, 2 H), 2.29 - 2.37 (m, 2 H), 2.37 - 2.40 (m, 2 H), 4.20 (tt, J = 12.0, 3.9 Hz, 1 H), 7.12 (t, J = 54.2 Hz, 1 H), 8.22 (s, 1 H). 19 F NMR (377 MHz, CDCl3-d) δ ppm -117.68 (s, 2 F).

[0392] Step 4. Preparation of 2-[4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexyl]acetaldehyde (5) To a solution of 2-[4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexyl]acetonitrile 4 (342 mg, 1.18 mmol, 1 eq.) in DCM (5.88 mL), a solution of 1 M DIBAL-H / DCM (3.53 mL, 3.53 mmol, 3 eq.) was added at -78°C. The reaction mixture was then stirred at the same temperature. After 2 hours, LC-MS indicated that the reaction was complete. The reaction was slowly quenched with Rochelle salt solution at -78°C, and the solution was stirred at rt for 1 hour. The product was then extracted three times with siRNA, and the combined organic layers were washed twice with 1 M hydrochloric acid and once with brine. The organic layers were then dried over MgSO4, and siRNA was removed under reduced pressure to obtain 5 (264 mg, 78% yield) as a yellow oil.

[0393] LC-MS method 1: 99.9% purity (at 215 nm), [M+H] + = 288.2. 1 H NMR (400 MHz, DMSO-d6 ) δ ppm 1.36 (q, J = 6.5 Hz, 2 H), 1.75 (qd, J = 12.5, 3.2 Hz, 2 H), 1.85 (d, J = 12.5 Hz, 2 H), 2.02 - 2.15 (m, 2 H), 3.40 - 3.50 (m, 2 H), 4.19 - 4.32 (m, 1 H), 4.32 - 4.40 (m, 1 H), 7.30 (t, J = 52.3 Hz, 1 H), 9.06 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -117.36 (s, 2 F).

[0394] Step 5. Production of 2-[4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexyl]ethanol (6) To a solution of 2-[4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexyl]acetaldehyde 5 (264 mg, 0.92 mmol, 1 eq.) in methanol (4.59 mL), NaBH4 (69.52 mg, 1.84 mmol) was added at 0°C. The resulting mixture was stirred under rt. After 16 hours, complete conversion was shown by LC-MS. The product was extracted three times with siRNA, and the combined organic matter was washed twice with brine. Finally, the organic matter was dried over MgSO4, and siRNA was removed under reduced pressure to obtain 6 (216 mg, 68% yield) as a yellow oil.

[0395] LC-MS method 1: 83.3% purity (at 215 nm), [M+H] + = 290.2 1 H NMR (400 MHz, DMSO-d6 ) δ ppm 1.03 - 1.15 (m, 2 H), 1.36 (q, J = 6.5 Hz, 2 H), 1.41 - 1.52 (m, 1 H), 1.69 - 1.81 (m, 2 H), 1.85 (br d, J = 12.5 Hz, 2 H), 2.02 - 2.12 (m, 2 H), 3.37 - 3.52 (m, 2 H), 4.22 - 4.32 (m, 1 H), 4.33 - 4.39 (m, 1 H), 7.30 (t, J = 53.2 Hz, 1 H), 9.06 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -117.36 (s, 2 F).

[0396] Step 6. Production of 2-[4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexyl]ethanol (7) 2-[4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]cyclohexyl]ethanol 6 (216.1 mg, 0.75 mmol, 1 eq.) was dissolved in siRNA (3.74 mL) and bubbled with N2 for 5 minutes. Next, 10% Pd / C (238.5 mg, 0.22 mmol, 0.3 eq.) was added, and the solution was bubbled with N2 for another 5 minutes. Next, the solution was bubbled with H2 for 5 minutes, and the resulting mixture was stirred under H2 at rt. After 3 hours, complete conversion was shown by LC-MS. The solution was filtered through a Celite pad and washed thoroughly with siRNA. Finally, the filtrate was concentrated under reduced pressure to obtain 7 (169 mg, 81% yield) as a yellow oil. The product was used in the next step without purification. LC-MS method 1: 92.9% purity (at 215 nm), [M+H] + = 260.2

[0397] Step 7. Preparation of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(2-hydroxyethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (9) TCFH (168.6 mg, 0.60 mmol, 1.2 eq.) was added at 0°C to a solution of 2-[4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexyl]ethanol 7 (168.8 mg, 0.65 mmol, 1.3 eq.), 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 8 (intermediate 4 obtained from the synthesis of P-4) (190 mg, 0.50 mmol, 1 eq.), and NMI (0.14 mL, 1.75 mmol, 3.5 eq.) in MeCN (2.50 mL). The reaction mixture was then stirred at room temperature. After 16 hours, LC-MS indicated that the reaction was complete. MeCN was removed under reduced pressure, and the residue was purified by reverse-phase flash chromatography (30 g C18 column, holding solution (DMSO), elution: 5% MeOH / 0.1% HCOOH over 3 CV, then 5 to 100% MeOH / 0.1% HCOOH over 15 CV, then 100% MeOH / 0.1% HCOOH over 3 CV (the target product eluted around 80% MeCN)). The fractions were combined and concentrated to obtain 9 (155.6 mg, 50% yield) as an off-white solid. LC-MS method 1: 99.9% purity (at 215 nm), [M+H] + = 621.2 1H NMR (400 MHz, DMSO-d6 ) δ ppm 1.04 - 1.17 (m, 3 H), 1.29 - 1.44 (m, 12 H), 1.65 - 1.77 (m, 3 H), 1.80 - 1.93 (m, 3 H), 1.97 - 2.07 (m, 2 H), 2.10 - 2.18 (m, 1 H), 2.94 - 3.14 (m, 1 H), 3.36 - 3.53 (m, 3 H), 3.61 - 3.72 (m, 1 H), 4.11 - 4.23 (m, 1 H), 4.31 - 4.40 (m, 1 H), 4.94 - 5.13 (m, 1 H), 6.83 - 6.90 (m, 1 H), 6.91 - 7.23 (m, 2 H), 8.28 (s, 1 H), 8.33 (br s, 1 H), 8.82 (d, J = 8.1 Hz, 1 H), 9.31 (br s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.27 - -183.87 (m, 1 F), -112.01 - -110.10 (m, 2 F).

[0398] Step 8'. Preparation of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(2-oxoethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (10) To a solution of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(2-hydroxyethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 9 (140 mg, 0.23 mmol, 1.0 eq.) in dried DMSO (2.2 mL), IBX (76 mg, 0.27 mmol, 1.2 eq.) was added. The resulting mixture was stirred overnight at room temperature. LC-MS analysis indicated that the reaction was complete. The reaction mixture was used in the next step without purification. Since product 10 could not be isolated, the reaction yield was estimated to be 95%. LCMS method 1: 99.9% purity (at 254 nm), [M+H] + = 619.2; IBX residue can be visualized at 215 nm.

[0399] Step 8. Preparation of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]amino]-1-piperidyl]ethyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (11) To a suspension of 3-[1-methyl-7-(4-piperidylamino)indazole-3-yl]piperidine-2,6-dione hydrochloride C-2 (50 mg, 0.13 mmol, 1.1 eq.) in DCE (1.1 mL), DIPEA (210 μL, 1.21 mmol, 10.0 eq.) was added, and the mixture was stirred at room temperature for 10 minutes. Then, a solution of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(2-oxoethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 10 (75 mg, 0.12 mmol, 1.0 eq.) in DMSO (1.1 mL) was added. The mixture was stirred again for 10 minutes, then NaBH(OAc)3 (33 mg, 0.16 mmol, 1.3 eq.) was added, and the reaction mixture was stirred at room temperature for 1 hour. Complete conversion was shown by LC-MS analysis. DCE was evaporated under reduced pressure, and the resulting solution was loaded directly onto a C18 RediSep Rf Gold column and purified by reverse-phase flash chromatography (5% MeCN / 0.1% formic acid FA over 5 CV, then 5% to 45% MeCN / 0.1% formic acid over 20 CV). The fraction containing the product was evaporated to obtain tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]amino]-1-piperidyl]ethyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 11 [71.1 mg (52% yield)] as a brown solid.

[0400] LC-MS method 1: Purity 84.3% (at 215 nm), 97.4% (at 254 nm); [M+H] + = 947.3;[M+2H] 2+ = 472.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83 - 0.92 (m, 4 H), 1.11 (s, 9 H), 1.19 (s, 2 H), 1.22 - 1.45 (m, 12 H), 1.62 (br s, 2 H), 1.73 (br d, J = 13.2 Hz, 2 H), 1.82 - 1.93 (m, 2 H), 1.96 - 2.08 (m, 2 H), 2.09 - 2.31 (m, 3 H), 2.40 - 2.46 (m, 1 H), 2.56 - 2.69 (m, 2 H), 2.85 - 2.96 (m, 1H), 3.08 (s, 3H), 4.14 (dd, J = 5.7, 3.3 Hz, 1 H), 4.24 (s, 3 H), 4.96 - 5.01 (m, 1 H), 6.54 (d, J = 7.3 Hz, 1 H), 6.89 (t, J = 7.7 Hz, 1 H), 6.99 (d, J = 8.1 Hz, 1 H), 7.65 - 7.74 (m, 2 H), 8.28 (s, 1 H), 8.33 (s, 1 H), 8.82 (d, J = 7.8 Hz, 1 H), 9.31 (s, 1 H), 10.85 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6): The spectrum did not show sufficient signal for clear identification.

[0401] Step 9. N-[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]amino]-1-piperidyl]ethyl]cyclohexyl]pyrazole-4-yl]-5-[(3R,5R)-3-amino-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide bis-HCl salt (P-7) To tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]amino]-1-piperidyl]ethyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 11 (65 mg, 0.07 mmol, 1.0 eq.), a solution of 4.0 M HCl (2.6 mL, 10.3 mmol, 150 eq.) / 1,4-dioxane was added. The mixture was stirred at room temperature for 1 hour. Complete conversion was shown by HPLC. The solvent was removed under reduced pressure, and approximately 10 drops of DMSO were added with water. This solution was loaded onto a C18 RediSep Rf Gold column and purified by reverse-phase flash chromatography (5% MeCN / 0.02M HCl over 5 CV, then 5 to 20% MeCN / 0.02M HCl over 20 CV). The product was eluted with 22% MeCN. The pure fractions were combined, evaporated under reduced pressure, and freeze-dried to obtain N-[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]amino]-1-piperidyl]ethyl]cyclohexyl]pyrazole-4-yl]-5-[(3R,5R)-3-amino-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-7) as the bis-HCl salt [31.77 mg (54% yield)].

[0402] LC-MS method 2: 99.5% purity (at 215 nm); [M+H] + = 844.5;[M+2H] 2+ = 422.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 - 1.25 (m, 2 H), 1.35 - 1.48 (m, 1 H), 1.62 - 1.92 (m, 7 H), 1.93- 2.25 (m, 7 H), 2.25 - 2.35 (m, 1 H), 2.36 - 2.46 (m, 1 H), 2.53 - 2.72 (m, 3 H), 2.99 - 3.23 (m, 4 H), 3.28 -3.59 (m, 6 H), 4.18 - 4.35 (m, 5 H), 4.54 - 4.70 (m, 1 H), 4.80 - 4.95 (m, 1 H), 5.10 (d, J = 46.0 Hz, 1 H),6.61 - 6.70 (m, 1 H), 6.87 - 6.96 (m, 2 H), 6.99 - 7.29 (m, 2 H), 8.28 - 8.45 (m, 5 H), 8.93 (d, J = 8.1 Hz, 1H), 9.33 (s, 1 H), 10.18 - 10.35 (m, 1 H), 10.86 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.63 (s, 1 F), -111.26 (s, 2 F).

[0403] Example S9. Synthesis of P-34 [ka]

[0404] Step 7. Preparation of N-[3-(difluoromethyl)-1-[4-(2-hydroxyethyl)cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide (3) In a round-bottom flask, 2-[4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexyl]ethanol 2 (intermediate 7 obtained from the synthesis of P-7) (60 mg, 0.17 mmol, 1.1 eq.), 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid 1 (intermediate 4 obtained from the synthesis of P-27) (37.7 mg, 0.15 mmol, 1 eq.), MeCN (1.2 mL), and NMI (50 μL, 0.63 mmol, 3.7 eq.) were added, and the mixture was stirred at 0°C. After 5 minutes, TCFH (57 mg, 0.20 mmol, 1.2 eq.) was added, and the mixture was stirred at 0°C. After 5 minutes, the reaction mixture was stirred at room temperature. After 3 hours, complete conversion was shown by LC-MS. Water was added to the mixture, and MeCN was removed under reduced pressure until a persistent precipitate formed. The suspension was extracted with ethyl acetate (2x). The combined organic layers were washed with brine (2x), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography (24 g silica column, pre-adsorbed, elution: 0 to 5% DCM / MeOH over 15 CV). The fractions were combined and concentrated to obtain 3 (60 mg, 58% yield) as a white solid. LC-MS method 3: 80.5% purity (at 215 nm), [M+H] + = 490.2.

[0405] Step 8. Preparation of N-[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-7-yl]-methyl-amino]-1-piperidyl]ethyl]cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-34) N-[3-(difluoromethyl)-1-[4-(2-hydroxyethyl)cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide 3 (28 mg, 0.05 mmol, 1 eq.) was dissolved in anhydrous DMSO (1 mL), to which IBX (15 mg, 0.06 mmol, 1.2 eq.) was added. The resulting mixture was stirred at room temperature. After 3 hours, complete conversion to the corresponding aldehyde was demonstrated by LC-MS. To the reaction mixture, 3-[1-methyl-7-[methyl(4-piperidyl)amino]indazole-3-yl]piperidine-2,6-dione hydrochloride C-17 (39 mg, 0.09 mmol, 2 eq.), DCE (1 mL), and DIPEA (50 μL, 0.29 mmol, 6.2 eq.) were added. The mixture was stirred at room temperature, and after 10 minutes, NaBH(OAc)3 (15 mg, 0.07 mmol, 1.5 eq.) was added. After 2 hours, complete conversion was shown by LC-MS. The DCM was evaporated under reduced pressure, and the crude mixture was purified by reverse-phase FC (30 g C18 RediSep Rf Gold column, holding solution (DMSO), 5% MeOH / 0.1% HCOOH over 4 CV, then 5-80% MeOH / 0.1% HCOOH over 15 CV). The fractions were combined and concentrated to obtain impurities. These were co-evaporated with MeOH and water (1x) and DCM containing a small amount of triethylamine to obtain the corresponding free base. The obtained substance was dissolved in a minimum amount of DCM and injected for purification by normal-phase flash chromatography (24 g silica column, elution: 0 to 10% DCM / MeOH over 20 CV). The pure fractions were combined and concentrated to obtain P-34 (23 mg, 61% yield) as a white solid.

[0406] LC-MS method 2: Retention time: 2.391 min, 99% purity (at 215 nm), [M+2H] 2+ = 414.2;[M+H] + = 827.5. 1H NMR(400 MHz, DMSO-d6) δ ppm 1.03 - 1.17 (m, 2 H), 1.28 - 1.40 (m, 3 H), 1.51 - 1.64 (m, 2 H), 1.65 - 1.78 (m, 4 H), 1.79 - 1.94 (m, 4 H), 1.98 - 2.06 (m, 2 H), 2.14 - 2.22 (m, 1 H), 2.24 - 2.32 (m, 2 H), 2.35 - 2.41 (m, 1 H), 2.52 - 2.53 (m, 1 H), 2.58 - 2.66 (m, 1 H), 2.70 (s, 3 H), 2.80 - 2.89 (m, 2 H), 2.93 - 3.02 (m, 1 H), 3.70 - 3.76 (m, 4 H), 3.76 - 3.84 (m, 4 H), 4.11 - 4.22 (m, 1 H), 4.24 (s, 3 H), 4.35 (dd, J = 9.5, 5.1 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1 H), 6.95 - 7.24 (m, 3 H), 7.43 (dd, J = 8.1, 0.5 Hz, 1 H), 8.29 (s, 1 H), 8.37 (s, 1 H), 8.83 (d, J = 8.1 Hz, 1 H), 9.40 (s, 1 H), 10.89 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.20 (s, 2 F).

[0407] The following compounds were synthesized using the same general route, with modifications to the acid (8) in step 7 and the CBM (CX) in step 8 (Table 6). [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36] [Table 37]

[0408] General method for final product 4 Example S10. Synthesis of P-28 [ka]

[0409] Step 1. Preparation of ethyl 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (3) To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (800 mg, 3.55 mmol, 1.0 eq.) in MeCN (17.7 mL), DIPEA (1.54 mL, 8.86 mmol, 2.5 eq.) and tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate 2 (1.01 g, 4.61 mmol, 1.3 eq.) were added. After stirring over the weekend at 60°C, complete conversion to 3 was shown by LC-MS. The solvent was removed under reduced pressure, and the residue was dried under high vacuum to obtain 3 (1.44 g, quantitative yield) as a white solid. The crude product was used in the next step without further purification.

[0410] LC-MS method 1: Retention time: 1.656 min, 99.9% purity (at 215 nm), [M+H] + = 408.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.37 - 1.45 (m, 9 H), 1.56 - 1.92 (m, 1 H), 2.09 - 2.20 (m, 1 H), 2.56 - 2.71 (m, 1 H), 2.76 - 3.03 (m, 1 H), 3.08 - 3.19 (m, 1 H), 3.29 (s, 1 H), 3.37 (br s, 1 H), 3.56 - 3.73 (m, 2 H), 4.11 - 4.25 (m, 2 H), 4.41 - 4.73 (m, 1 H), 4.99 (br s, 1 H), 5.11 (br s, 1 H), 6.85 (br d, J = 8.1 Hz, 1 H), 7.10 (br d, J = 7.8 Hz, 1 H), 8.22 (s, 1 H), 8.73 (d, J = 7.8 Hz, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.32 (s, 1 F).

[0411] Step 2. Preparation of 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4) To a solution of ethyl 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate 3 (1.44 mg, 3.53 mmol, 1.0 eq) in THF (5.89 mL) and methanol (5.89 mL), a solution of LiOH·H2O (1.48 g, 35.34 mmol, 10.0 eq.) / water (5.89 mL) was added. After stirring at 60°C for 18 hours, complete conversion to the target product 4 was shown by LC-MS. The reaction mixture was concentrated under vacuum to remove THF / MeOH, and the crude mixture was diluted with water. The mixture was acidified to pH=3 (until a precipitate formed) with 6N hydrochloric acid aqueous solution while vigorously stirring. The suspension was filtered through a Buchner funnel, and the solid was washed with water. The solid was dried overnight in a stove under vacuum to obtain 4 (1.40 g, quantitative yield) as a white solid. The crude product was used in the next step without further purification.

[0412] LC-MS method 1: Retention time: 1.487 min, 99.9% purity (at 215 nm), [M+H] + = 380.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9 H), 1.66 - 1.95 (m, 1 H), 2.05 - 2.26 (m, 1 H), 2.92 - 3.11 (m, 1 H), 3.28 - 3.30 (m, 1 H), 3.34 - 3.49 (m, 1 H), 3.59 - 3.74 (m, 1 H), 4.52 - 4.75 (m, 1 H), 4.99 (br s, 1 H), 5.11 (br s, 1 H), 6.82 (br d, J = 7.6 Hz, 1 H), 7.12 (br d, J = 7.8 Hz, 1 H), 8.19 (s, 1 H), 8.73 (d, J = 7.8 Hz, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm - 184.32 (s, 1 F).

[0413] Step 3. Preparation of tert-butyl N-[(3r,5r)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (6) [4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexyl]methanol 5 (intermediate 6 obtained from the synthesis of P-2) (511.8 mg, 1.88 mmol, 1.5 eq.), 5-[(3r,5r)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (475.0 mg, 1.25 mmol, 1.0 eq.), and NMI (362.72 μL, 4.58 mmol, 3.6 eq.) were mixed in MeCN (12.5 mL, 0.1 M) with TCFH (440.43 mg, 1.57 mmol, 1.2 eq.). The resulting mixture was stirred overnight at room temperature. Water was added, and the reaction mixture was stirred at room temperature for 1 hour. The solid was filtered through a Buchner funnel and washed with a water / MeCN mixture. Purification by reverse-phase chromatography (50 g C18 RediSep Rf Gold column, holding solution (DMSO), elution: 5% MeOH / 0.1% HCOOH over 4 CV, then 5% to 100% MeOH / 0.1% HCOOH over 15 CV). The pure fractions were combined and concentrated under reduced pressure to obtain tert-butyl N-[(3r,5r)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 6 (421 mg, 55% yield) as a brown solid.

[0414] LC-MS method 1: Retention time: 1.629 min, 99.9% purity (at 215 nm), [M+H] + = 607.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 - 1.15 (m, 2 H), 1.34 (br s, 9 H), 1.64 - 1.80 (m, 3 H), 1.82 - 1.93 (m, 3 H), 1.99 - 2.07 (m, 2 H), 2.08 - 2.18 (m, 1 H), 2.95 - 3.14 (m, 1 H), 3.26 (t, J = 5.7 Hz, 2 H), 3.37 - 3.52 (m, 1 H), 3.62 - 3.71 (m, 1 H), 4.12 - 4.21 (m, 1 H), 4.47 (t, J = 5.3 Hz, 1 H), 4.69 (br s, 1 H), 4.95 - 5.12 (m, 1 H), 6.86 - 6.94 (m, 1 H), 7.01 - 7.22 (m, 2 H), 8.28 (s, 1 H), 8.34 (br s, 1 H), 8.82 (d, J = 7.8 Hz, 1 H), 9.31 (br s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -186.02 - -179.79 (m, 1F), -113.10 - -108.69 (m, 2F).

[0415] Step 4. Preparation of Tert-butyl N-[(3r,5r)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (7) To a solution of tert-butyl N-[rac-(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 6 (86.0 mg, 0.14 mmol, 1.0 eq.) in dried DMSO (1 mL, 0.14 M), IBX (47.6 mg, 0.17 mmol, 1.2 eq.) was added. The resulting mixture was stirred overnight at room temperature. After overnight stirring, LC-MS (Method 3) demonstrated the complete conversion to the target product, tert-butyl N-[rac-(3R,5R)-1-[3-[[3-(difluoromethyl)-1-(4-formylcyclohexyl)pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate. To the reaction mixture, 3-[1-methyl-6-[4-(methylamino)-1-piperidyl]indazole-3-yl]piperidine-2,6-dione hydrochloride C-15 (66.11 mg, 0.17 mmol, 1.2 eq.), DCE (1 mL), and DIPEA (0.24 mL, 1.41 mmol, 10.0 eq.) were added. The mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (38.74 mg, 0.18 mmol, 1.3 eq.) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. Purification was performed by reverse-phase chromatography (C18 RediSep Rf Gold 50 g, 5-40% MeCN / 0.1% formic acid / water, 20 CV). The pure fractions were combined and concentrated to obtain tert-butyl N-[rac-(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 7 (66 mg, 44% yield) as a brown solid.The target product contained IBX residue.

[0416] LC-MS method 3: Retention time: 1.736 min, 89.3% purity (at 215 nm), [M + 2H] 2+ = 472.8 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.00 - 1.17 (m, 3 H), 1.27 - 1.41 (m, 8 H), 1.48 - 1.64 (m, 3 H), 1.67 - 1.83 (m, 4 H), 1.86 - 1.97 (m, 2 H), 1.99 - 2.07 (m, 2 H), 2.12 - 2.18 (m, 1 H), 2.23 - 2.34 (m, 5 H), 2.59 - 2.67 (m, 2 H), 2.70 - 2.78 (m, 4 H), 2.89 (s, 3 H), 3.63 - 3.72 (m, 1 H), 3.82 - 3.91 (m, 5 H), 4.15 - 4.28 (m, 2 H), 4.94 - 5.01 (m, 1 H), 5.09 (br s, 1 H), 6.78 - 6.96 (m, 3 H), 7.03 - 7.20 (m, 2 H), 7.48 (d, J = 9.0 Hz, 1 H), 7.96 (s, 1 H), 8.29 (s, 1 H), 8.34 (br s, 1 H), 8.82 (d, J = 7.8 Hz, 1 H), 9.31 (br s, 1 H), 10.85 (s, 1 H).

[0417] Step 7. Preparation of N-[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-yl]-5-[(3r,5r)-3-amino-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-28) 4.0 M HCl / dioxane (2.62 mL, 10.49 mmol, 150.0 eq.) was added to tert-butyl N-[rac-(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 7 (66 mg, 0.07 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. Purification was performed by reverse-phase chromatography (50 g C18 RediSep Rf Gold column, holding solution (H2O), elution: 5% MeOH / 0.02 M HCl over 4 CV, followed by 5%~50% MeCN / 0.02 M HCl over 15 CV). The pure fractions were combined, concentrated under reduced pressure, and freeze-dried overnight to obtain N-[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-yl]-5-[rac-(3R,5R)-3-amino-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide P-28 (28 mg, 47% yield).

[0418] LC-MS method 2: Retention time: 1.911 min, 99.6% purity (at 215 nm), [M - HCl + H] + = 844; [M - 2HCl + 2H] 2+ = 422.6. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 - 1.31 (m, 2 H), 1.75 - 1.96 (m, 6 H), 2.03 - 2.20 (m, 6 H), 2.26 - 2.34 (m, 1 H), 2.37 - 2.44 (m, 1 H), 2.56 - 2.69 (m, 2 H), 2.75 - 2.96 (m, 6 H), 3.10 - 3.18 (m, 1 H), 3.28 - 3.51 (m, 5 H), 3.88 - 3.93 (m, 3 H), 3.98 (br d, J = 12.2 Hz, 2 H), 4.19 - 4.30 (m, 2 H), 4.59 (br s, 1 H), 4.78 - 4.95 (m, 1 H), 5.01 - 5.18 (m, 1 H), 6.87 - 6.98 (m, 3 H), 7.00 - 7.28 (m, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 8.27 (br d, J = 4.2 Hz, 2 H), 8.33 (s, 1 H), 8.41 (s, 1 H), 8.94 (d, J = 7.8 Hz, 1 H), 9.34 (s, 1 H), 9.52 (br s, 1 H), 10.86 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -183.67 (s, 2 F), -111.29 (br s, 1 F).

[0419] Example S11. Synthesis of P-29 [ka]

[0420] Step 1. Preparation of ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate (3) In a sealed tube, ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (1.5 g, 6.65 mmol, 1 eq.), MeCN (33.24 mL, 0.2 M), and DIPEA (2.89 mL, 16.62 mmol, 2.5 eq.) were added, followed by morpholine 2 (639.65 μL, 7.31 mmol, 1.1 eq.). The tube was sealed, and the mixture was stirred at 90°C for 16 hours. The solvent was evaporated under reduced pressure, and the mixture was dried under high vacuum to obtain ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate 3 (2.96 g, 99% yield) as an orange solid. LC-MS method 1: Retention time: 1.432 min, 99% purity (at 215 nm), [M + H] + = 277.2. 1 H NMR (400 MHz, chloroform-d) δ ppm 1.39 (t, J = 7.1 Hz, 3 H), 3.76 - 3.86 (m, 8 H), 4.35 (q, J = 7.1 Hz, 2 H), 6.41 (d, J = 8.1 Hz, 1 H), 8.29 - 8.34 (m, 2 H).

[0421] Step 2. Preparation of 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4) Ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate 3 (1.84 g, 6.66 mmol, 1.0 eq.) was mixed with THF (17.8 mL, 0.1 M) and methanol (17.8 mL) for 5 minutes, then a solution of LiOH·H2O (2.8 g, 66.6 mmol, 10 eq.) / water (17.8 mL) was added. The mixture was stirred at 60°C for 3 hours, then the oil bath was removed and the mixture was stirred over the weekend (72 hours). The reaction mixture was concentrated under reduced pressure, the crude mixture was diluted with a small amount of water, and acidified to pH 3 with 6 N HCl. The resulting precipitate was filtered and washed with water. The solid was dried under high vacuum to obtain 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (1.65 g, 99% yield) as a brown solid. LC-MS method 1: Retention time: 1.192 min, 99% purity (at 215 nm), [M + H] + = 249.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (br d, J = 5.9 Hz, 8 H), 6.84 (d, J = 8.1 Hz, 1 H), 8.19 (s, 1 H), 8.74 (d, J = 7.8 Hz, 1 H), 11.73 (s, 1 H).

[0422] Step 3. Preparation of N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide (6) [4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]cyclohexyl]methanol 5 (intermediate 6 obtained from the synthesis of P-2) (403.12 mg, 1.64 mmol, 1.2 eq.), 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (340.0 mg, 1.37 mmol, 1.0 eq.), and NMI (0.43 mL, 5.48 mmol, 4.0 eq.) were dissolved in MeCN (9 mL, 0.15 M) and TCFH (480.37 mg, 1.71 mmol, 1.25 eq.). The resulting mixture was stirred at room temperature for 1 hour. After 1 hour, the volatile substances were evaporated, and the resulting mixture was purified by reverse-phase chromatography (50 g C18 RediSep Rf Gold column, retention solution (DMSO), elution: 5% MeOH / 0.1% HCOOH over 4 CV, then 5% to 50% MeOH / 0.1% HCOOH over 15 CV, the product was eluted with 50% MeOH). The pure fractions were combined and concentrated under reduced pressure to obtain N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide 6 (338 mg, 52% yield) as a brown solid. LC-MS Method 3: Retention time: 1.707 min, 99.9% purity (at 215 nm), [M+H] + = 476.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 - 1.15 (m, 2 H), 1.38 - 1.48 (m, 1 H), 1.66 - 1.79 (m, 2 H), 1.80 - 1.90 (m, 2 H), 1.99 - 2.08 (m, 2 H), 3.26 (t, J = 5.7 Hz, 2 H), 3.68 - 3.74 (m, 4 H), 3.76 - 3.83 (m, 4 H), 4.12 - 4.23 (m, 1 H), 4.47 (t, J = 5.4 Hz, 1 H), 6.90 (d, J = 7.8 Hz, 1 H), 6.95 - 7.25 (m, 1 H), 8.28 (s, 1 H), 8.38 (s, 1 H), 8.82 (d, J = 8.1 Hz, 1 H), 9.39 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.19 (s, 2 F).

[0423] Step 4. Preparation of N-[3-(difluoromethyl)-1-[4-[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-29) N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide 6 (100.0 mg, 0.21 mmol, 1.0 eq.) was dissolved in dried DMSO (2 mL, 0.1 M) and IBX (70.0 mg, 0.25 mmol, 1.2 eq.) was added. The resulting mixture was stirred overnight at room temperature. After overnight stirring, LC-MS (Method 3) demonstrated the complete conversion to the target product, N-[3-(difluoromethyl)-1-(4-formylcyclohexyl)pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide. To the reaction mixture, [1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]methyl-ammonium chloride C-15 (98.91 mg, 0.25 mmol, 1.2 eq.), DCE (2.1 mL, 0.05 M), and DIPEA (0.37 mL, 2.10 mmol, 10 eq.) were added. The mixture was stirred at rt for 10 minutes. Sodium triacetoxyborohydride (133.72 mg, 0.63 mmol, 3.0 eq.) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum. Purification was performed by reverse-phase chromatography (50 g C18 RediSep Rf Gold column, holding solution (DMSO), elution: 5% MeCN / 0.1% HCOOH over 4 CV, followed by 5%~50% MeCN / 0.1% HCOOH over 15 CV). The pure fractions were combined, concentrated under reduced pressure, and freeze-dried overnight to obtain N-[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-yl]-5-morpholino-pyrazolo[1,5-a]pyrimidine-3-carboxamide P-29 (25.4 mg, 14% yield) as a yellow solid. LC-MS method 4: Retention time: 2.399 min, 96.0% purity (at 215 nm), [M + H]+ = 813.4;[M + 2H] 2+ = 407.3. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.94 - 1.16 (m, 3 H), 1.49 - 1.64 (m, 3 H), 1.69 - 1.81 (m, 4 H), 1.86 - 1.96 (m, 2 H), 2.01 - 2.09 (m, 2 H), 2.12 - 2.20 (m, 1 H), 2.22 (s, 3 H), 2.25 (br d, J = 6.8 Hz, 2 H), 2.55 - 2.65 (m, 3 H), 2.70 - 2.78 (m, 2 H), 3.70 - 3.75 (m, 4 H), 3.78 - 3.86 (m, 6 H), 3.89 (s, 3 H), 4.13 - 4.21 (m, 1 H), 4.25 (dd, J = 8.9, 5.0 Hz, 1 H), 6.84 (d, J = 1.5 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 2 H), 7.10 (s, 1 H), 7.48 (d, J = 9.0 Hz, 1 H), 8.29 (s, 1 H), 8.38 (s, 1 H), 8.83 (d, J = 7.8 Hz, 1 H), 9.40 (s, 1 H), 10.85 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.19 (s, 2 F).

[0424] The following compounds were synthesized using the same general route, with a modification to amine 2 in step 1 (Table 7). [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44]

[0425] 5 General Methods for Final Products Example S12. Synthesis of P-37 [ka]

[0426] Step 1. Preparation of benzyl 4-methylsulfonyloxypiperidine-1-carboxylate (2) Methanesulfonyl chloride (0.821 mL, 10.6 mmol, 1.25 eq.) was added dropwise to a 100 mL ice-cold DCM (Digital Cement Liquid) solution of 4-hydroxypiperidine-1-carboxylate 1 (2.00 g, 8.50 mmol, 1.0 eq.) and triethylamine (1.78 mL, 12.8 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature. After 1 hour, complete conversion was shown by LC-MS. Water (50 mL) and saturated NaHCO3 (aq) (50 mL) were added to the reaction mixture to separate the phases, and the aqueous layer was extracted with DCM (3 × 50 mL). The combined organic substances were washed with saline solution (50 mL), dried over MgSO4, filtered, and evaporated under reduced pressure to obtain 2 (2.80 g, 8.50 mmol, quantitative yield) as a pale orange oil.

[0427] LC-MS method 1: 95.8% purity (at 215 nm), [M+H] + = 314.1. 1 H NMR (400 MHz, CDCl3) δ ppm 1.77 - 1.92 (m, 2 H), 1.93 - 2.08 (m, 2 H), 3.05 (s, 3 H), 3.43 (ddd, J = 13.7, 7.9, 3.9 Hz, 2 H), 3.70 - 3.85 (m, 2 H), 4.91 (tt, J = 7.5, 3.8 Hz, 1 H), 5.14 (s, 2 H), 7.27 - 7.43 (m, 5 H).

[0428] Step 2. Preparation of benzyl 4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]piperidine-1-carboxylate (4) A mixed solution of benzyl 4-methylsulfonyloxypiperidine-1-carboxylate 2 (1.00 g, 3.19 mmol, 1.2 eq.), 3-(difluoromethyl)-4-nitro-1H-pyrazole 3 (450 mg, 2.76 mmol, 1.0 eq.), and potassium carbonate (800 mg, 5.80 mmol, 2.1 eq.) in DMF (22 mL) was stirred at 100°C under a nitrogen atmosphere. After 24 hours, complete conversion was shown by LC-MS. Water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with siRNA (3 × 50 mL). The combined organic substances were washed with 1:1 water / saline solution (3 × 50 mL) and saline solution (50 mL), dried on MgSO4, and evaporated to dryness. The crude product was purified by normal-phase flash chromatography (80 g silica column, preabsorbed, elution: heptane / toluene, 95:5~70:30, 12 CV) to obtain 4 (644 mg, 1.46 mmol, 53% yield) as a pale yellow oily substance.

[0429] LC-MS method 1: 86.0% purity (at 215 nm), [M+H] + = 381.1. 1H NMR (400 MHz, CDCl3) δ ppm 1.90 - 2.01 (m, 2 H), 2.22 (br d, J = 12.1 Hz, 2 H), 2.88 - 3.04 (m, 2 H), 4.37 (tt, J = 11.7, 4.0 Hz, 3 H), 5.16 (s, 2 H), 7.12 (t, J = 53.3 Hz, 1 H), 7.32 - 7.43 (m, 5 H), 8.21 (s, 1 H). 19 F NMR (377 MHz, CDCl3) δ ppm -117.79 (s, 2 F).

[0430] Step 3. Preparation of benzyl 4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]piperidine-1-carboxylate (5) Zinc (2.21 g, 33.9 mmol, 20.0 eq.; activated with 1.0 M HCl(aq)) was added to a solution of benzyl 4-[3-(difluoromethyl)-4-nitropyrazole-1-yl]piperidine-1-carboxylate 4 (644 mg, 1.46 mmol, 1.0 eq.) in i-PrOH (17 mL). Acetic acid (0.970 mL, 16.9 mmol, 10.0 eq.) was then added to the solution, and the reaction mixture was stirred at room temperature. After 1 hour, complete conversion was demonstrated by LC-MS. The reaction mixture was filtered through a Celite pad and evaporated to dryness. The residue was taken up with ethyl acetate (50 mL), washed with saturated NaHCO3 (aq) (10 mL) and saline solution (10 mL), dried on MgSO4, and evaporated to dryness to obtain 5 (500 mg, 1.24 mmol, 73% yield) as a brown oily substance.

[0431] LC-MS method 1: 86.9% purity (at 215 nm), [M+H] + = 351.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73 (qd, J = 12.2, 4.5 Hz, 2 H), 1.91 - 2.01 (m, 2 H), 2.86 - 3.10 (m, 2 H), 4.08 (br d, J = 12.8 Hz, 4 H), 4.17 - 4.30 (m, 1 H), 5.09 (s, 2 H), 6.88 (t, J = 54.2 Hz, 1 H), 7.18 (s, 1 H), 7.31 - 7.39 (m, 5 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.51 (s, 2 F).

[0432] Step 4. Preparation of benzyl 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]pyrazole-1-yl]piperidine-1-carboxylate (7) TCFH (614 mg, 2.19 mmol, 1.2 eq.) was added in one go to a solution of 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 6 (intermediate 4 obtained from the synthesis of P-2) (692 mg, 1.82 mmol, 1.0 eq.), benzyl 4-[4-amino-3-(difluoromethyl)pyrazole-1-yl]piperidine-1-carboxylate 5 (708 mg, 1.92 mmol, 1.05 eq.), and NMI (506 μL, 6.38 mmol, 3.5 eq.) in MeCN (12.1 mL). The reaction mixture was then stirred at room temperature. After 24 hours, complete conversion was shown by LC-MS. Volatile substances were evaporated under reduced pressure. The residue was purified by reverse-phase flash chromatography (150 g C18 RediSep Rf Gold column, holding solution (DMSO), MeOH / 0.1% HCOOH(aq), 40%→90%, 15 CV). The fractions were combined and concentrated to obtain 7 (823 mg, 1.10 mmol, 60% yield) as an off-white solid.

[0433] LC-MS method 1: 95.0% purity (at 215 nm), [M+H] + = 712.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (br s, 9 H), 1.68 - 1.97 (m, 4 H), 2.03 (br d, J = 10.6 Hz, 2 H), 2.09 - 2.22 (m, 1 H), 2.88 - 3.18 (m, 3 H), 3.36 - 3.56 (m, 1 H), 3.67 (br d, J = 7.0 Hz, 1 H), 4.12 (br d, J = 13.2 Hz, 2 H), 4.42 - 4.56 (m, 1 H), 4.57 - 4.92 (m, 1 H), 4.97 (d, J = 45.4 Hz, 1 H), 5.10 (s, 2 H), 6.89 (br d, J = 8.1 Hz, 1 H), 6.92 - 7.26 (m, 2 H), 7.29 - 7.36 (m, 1 H), 7.38 (s, 2 H), 7.39 (s, 2 H), 8.29 (s, 1 H), 8.38 (br s, 1 H), 8.82 (d, J = 7.8 Hz, 1 H), 9.31 (br s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -186.27 - -182.64 (m, 1 F), -114.40 - -109.21 (m, 2 F).

[0434] Step 5. Preparation of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-(4-piperidyl)pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (8) Benzyl 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]pyrazole-1-yl]piperidine-1-carboxylate 7 (739 mg, 1.04 mmol, 1.0 eq.) was dissolved in methanol (4.0 mL), and the solution was sparged with nitrogen under sonication. After 20 minutes, Pd / C 10% w / w (200 mg, 0.181 mmol, 0.18 eq.) was added, and the mixture was further sparged with nitrogen under sonication. After 20 minutes, the nitrogen balloon was replaced with one filled with hydrogen, and the reaction mixture was sparged. After 10 minutes, the reaction mixture was stirred under a hydrogen atmosphere. After 18 hours, complete conversion was shown by LC-MS. The reaction mixture was filtered through Celite, and the Celite was thoroughly washed with MeOH. The filtrate was evaporated under reduced pressure, and the residue was incorporated into siRNA. Heptane was added until a precipitate formed. The suspension was evaporated to dryness to obtain 8 (620 mg, 0.987 mmol, 95% yield) as a pink solid.

[0435] LC-MS method 1: 92.0% purity (at 215 nm), [M+H] + = 578.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 - 0.87 (m, 1 H), 1.20 - 1.27 (m, 1 H), 1.34 (br s, 9 H), 1.69 - 1.82 (m, 3 H), 1.88 - 1.95 (m, 2 H), 2.07 - 2.23 (m, 1 H), 2.53 - 2.61 (m, 2 H), 3.03 (br d, J = 12.8 Hz, 3 H), 3.37 - 3.51 (m, 1 H), 3.67 (br d, J = 2.1 Hz, 1 H), 4.19 - 4.33 (m, 1 H), 4.45 - 4.87 (m, 1 H), 5.04 (d, J = 46.3 Hz, 1 H), 6.89 (br d, J = 8.1 Hz, 1 H), 6.92 - 7.33 (m, 2 H), 8.29 (s, 1 H), 8.33 (br s, 1 H), 8.82 (d, J = 7.8 Hz, 1 H), 9.32 (br s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -187.05 - -180.57 (m, 1 F), -113.62 - -108.43 (m, 2 F).

[0436] Step 6. Preparation of 3-[1-methyl-6-[(2R)-4-(2,2-dimethoxyethyl)-2-methyl-piperazin-1-yl]indazole-3-yl]piperidine-2,6-dione (10) DIPEA (397 μL, 2.28 mmol, 10.0 eq.) was added to a suspension of 3-[1-methyl-6-[(2R)-2-methylpiperazine-4-ium-1-yl]indazole-3-yl]piperidine-2,6-dione chloride C-19 (99 mg, 0.228 mmol, 1.0 eq.) in DCE (4.5 mL), followed by the addition of 2,2-dimethoxyacetaldehyde 9 (60 w / w% aqueous solution in H2O, 52 μL, 0.342 mmol, 1.5 eq.). The mixture was stirred at room temperature. After 10 minutes, sodium triacetoxyborohydride (96.6 mg, 0.456 mmol, 2.0 eq.) was added all at once, and the reaction mixture was stirred at room temperature. After 18 hours, complete conversion was shown by LC-MS. Water (10 mL) was added to the reaction mixture to separate the phases, and the aqueous phase was extracted with DCM (3 × 15 mL). The combined organic substances were washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under reduced pressure to obtain 10 (98 mg, 0.228 mmol, quantitative yield) as a brown oily substance. This was used in the next step without further purification.

[0437] LC-MS method 2: 99.9% purity (at 215 nm), [M+H] + = 430.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (d, J = 6.5 Hz, 3 H), 2.09 - 2.21 (m, 1 H), 2.24 - 2.36 (m, 2 H), 2.45 - 2.48 (m, 2 H), 2.56 - 2.66 (m, 2 H), 2.76 (br d, J = 11.1 Hz, 1 H), 2.93 (br d, J = 10.0 Hz, 1 H), 2.98 - 3.08 (m, 1 H), 3.09 - 3.17 (m, 2 H), 3.29 (d, J = 3.9 Hz, 6 H), 3.43 - 3.53 (m, 1 H), 3.64 - 3.74 (m, 1 H), 3.88 (s, 3 H), 4.03 - 4.15 (m, 1 H), 4.25 (dd, J = 8.9, 5.0 Hz, 1 H), 4.53 (t, J = 5.2 Hz, 1 H), 6.78 (s, 1 H), 6.89 (dd, J = 9.1, 1.4 Hz, 1 H), 7.49 (d, J = 9.0 Hz, 1 H), 8.65 (br s, 1 H), 10.84 (s, 1 H).

[0438] Step 7. Preparation of 3-[1-methyl-6-[(2R)-4-(2,2-dihydroxyethyl)-2-methyl-piperazine-4-ium-1-yl]indazole-3-yl]piperidine-2,6-dione chloride (11) 4.0 M HCl / 1,4-dioxane (2.84 mL, 11.4 mmol, 50.0 eq.) and water (82 μL, 4.56 mmol, 20.0 eq.) were added to a solution of 3-[1-methyl-6-[(2R)-4-(2,2-dimethoxyethyl)-2-methyl-piperazin-1-yl]indazole-3-yl]piperidine-2,6-dione 10 (98 mg, 0.228 mmol, 1.0 eq) in 1,4-dioxane (2.2 mL), and the reaction mixture was stirred at room temperature. After 18 hours, complete conversion was shown by LC-MS. The volatile components were evaporated under reduced pressure to obtain 11 (99 mg, 0.228 mmol, quantitative yield) as a yellow solid. This was used in the next step without further purification. LC-MS method 2: 99.9% purity (at 215 nm), [M-HCl+H] + = 402.2.

[0439] Step 8. Preparation of tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[1-[2-[(3R)-4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-3-methyl-piperazine-1-yl]ethyl]-4-piperidyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate (12) DIPEA (556 μL, 3.19 mmol, 20.0 eq.) was used to extract DCE (3.2) from tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-(4-piperidyl)pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 8 (92.2 mg, 0.160 mmol, 1.0 eq.) and 3-[1-methyl-6-[(2R)-4-(2,2-dihydroxyethyl)-2-methyl-piperazine-4-ium-1-yl]indazole-3-yl]piperidine-2,6-dione chloride 11 (83.9 mg, 0.191 mmol, 1.2 eq.). The solution was added (mL), and the mixture was then stirred at room temperature. After 10 minutes, sodium triacetoxyborohydride (101.4 mg, 0.479 mmol, 3.0 eq.) was added all at once, and the reaction mixture was then stirred at room temperature. After 18 hours, complete conversion was shown by LC-MS. The volatile substances were evaporated under reduced pressure, and the residue was purified by reverse-phase flash chromatography (100 g C18 RediSep Rf Gold column, holding solution (DMSO), MeCN / 0.1% HCOOH (aq), 5% (3 CV) → 50%, 20 CV). The fractions were combined and concentrated to obtain 12 (102 mg, 0.0994 mmol, 62% yield) as a pink solid.

[0440] LC-MS method 2: 92.1% purity (at 215 nm), [M+2H] 2+ = 473.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (br d, J = 6.4 Hz, 3 H), 1.34 (br s, 9 H), 1.86 - 2.03 (m, 4 H), 2.11 - 2.23 (m, 4 H), 2.26 - 2.34 (m, 1 H), 2.35 - 2.43 (m, 1 H), 2.61 - 2.65 (m, 1 H), 2.78 (br d, J = 10.4 Hz, 1 H), 2.96 (br d, J = 10.4 Hz, 2 H), 3.06 (br d, J = 10.3 Hz, 3 H), 3.32 (br d, J = 12.0 Hz, 3 H), 3.37 - 3.52 (m, 4 H), 3.63 - 3.75 (m, 4 H), 3.88 (s, 3 H), 4.06 - 4.16 (m, 1 H), 4.25 (br dd, J = 9.3, 5.1 Hz, 2 H), 4.47 - 4.92 (m, 2 H), 4.95 - 5.16 (m, 1 H), 6.78 (s, 1 H), 6.90 (br d, J = 7.6 Hz, 2 H), 6.93 - 7.29 (m, 2 H), 7.49 (d, J = 8.9 Hz, 1 H), 8.29 (s, 1 H), 8.36 (br s, 1 H), 8.82 (br d, J = 7.9 Hz, 1 H), 9.32 (br s, 1 H), 10.84 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -186.79 - -182.12 (m, 1 F), -113.88 - -107.91 (m, 2 F).

[0441] Step 9. Preparation of 5-((3R,5R)-3-amino-5-fluoropiperidine-1-yl)-N-(3-(difluoromethyl)-1-(1-(2-((3R)-4-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-yl)-3-methylpiperazine-1-yl)ethyl)piperidine-4-yl)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-37) 4.0 M HCl / 1,4-dioxane (3.65 mL, 14.6 mmol, 150 eq.) was added to tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[1-[2-[(3R)-4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]-3-methyl-piperazine-1-yl]ethyl]-4-piperidyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 12 (92.2 mg, 0.0976 mmol, 1.0 eq.). The mixture was sonicated for 30 minutes and then stirred at room temperature. After 1 hour, complete conversion was shown by LC-MS. The solvent was evaporated to dryness, and the residue was purified by reverse-phase flash chromatography (100 g C18 RediSep Rf Gold column, holding solution (DMSO), MeCN / 0.02 M HCl(aq), 5% (3 CV) → 40%, 20 CV). The fractions were combined, concentrated, and lyophilized to obtain P-37 (33.27 mg, 0.0387 mmol, 40% yield) as a white solid.

[0442] LC-MS method 3: 98.3% purity (at 215 nm), [M+H] + = 845.5, [M+2H] 2+ = 423.2, [M+3H] 3+ = 282.6. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 - 1.30 (m, 4 H), 1.98 (t, J = 12.8 Hz, 1 H), 2.08 (t, J = 11.9 Hz, 1 H), 2.12 - 2.23 (m, 1 H), 2.31 - 2.43 (m, 5 H), 2.57 - 2.72 (m, 2 H), 3.12 - 3.28 (m, 3 H), 3.32 - 3.45 (m, 5 H), 3.65 - 3.77 (m, 4 H), 3.78 - 3.88 (m, 3 H), 3.89 - 4.04 (m, 4 H), 4.23 - 4.42 (m, 1 H), 4.42 - 4.57 (m, 1 H), 4.58 - 4.74 (m, 2 H), 4.75 - 5.01 (m, 1 H), 5.10 (d, J = 46.6 Hz, 1 H), 6.85 - 7.06 (m, 3 H), 7.21 (t, J = 53.7 Hz, 1 H), 7.51 - 7.77 (m, 1 H), 8.33 (s, 1 H), 8.42 (br s, 3 H), 8.47 (br s, 1 H), 8.94 (d, J = 7.8 Hz, 1 H), 9.37 (s, 1 H), 10.55 - 10.80 (m, 1 H), 10.87 (br s, 1 H), 10.97 - 11.36 (m, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.63 (s, 1 F), -111.63 (s, 2 F).

[0443] Example S13. Synthesis of P-40 [ka]

[0444] Step 1. Preparation of 3-[6-[4-(2,2-dimethoxyethyl)piperazin-1-yl]-1-methyl-indazole-3-yl]piperidine-2,6-dione (3) To a solution of 3-(1-methyl-6-piperazine-1-ylindazole-3-yl)piperidine-2,6-dione dihydrochloride C-6 (180 mg, 0.45 mmol, 1 eq.) and DIPEA (0.31 mL, 1.8 mmol, 4 eq.) in CH2Cl2 (4.5 mL), 2,2-dimethoxyacetaldehyde 2 (0.14 mL, 0.90 mmol, 2 eq.) and NaBH(OAc)3 (285.9 mg, 1.35 mmol, 3 eq.) were added. The mixture was then stirred at room temperature. After 2 hours, complete conversion was shown by LC-MS. The mixture was then concentrated to remove CH2Cl2, and the residue was purified by reverse-phase flash chromatography (30 g C18 RediSep Rf Gold column, holding solution (DMSO + formic acid), elution: 5% MeCN / 0.1% HCOOH over 5 CV, then 5-100% MeCN / 0.1% HCOOH over 30 CV, then 100% MeCN / 0.1% HCOOH over 5 CV). The fractions were combined and concentrated to obtain 3 (121 mg, 60% yield) as a brown solid.

[0445] LC-MS method 1: 92.3% purity (at 215 nm), [M+H] + = 416.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.10 - 2.21 (m, 1 H), 2.23 - 2.36 (m, 2 H), 2.52 - 2.74 (m, 6 H), 3.26 (br s, 6 H), 3.28 - 3.30 (m, 6 H), 4.26 (dd, J = 9.3, 5.1 Hz, 1 H), 4.51 - 4.60 (m, 1 H), 6.83 - 6.88 (m, 1 H), 6.91 (br d, J = 8.8 Hz, 1 H), 7.50 (d, J = 9.0 Hz, 1 H), 10.84 (s, 1 H).

[0446] Step 2. Preparation of 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]piperazine-1-yl]acetaldehyde (4) 3-[6-[4-(2,2-dimethoxyethyl)piperazin-1-yl]-1-methyl-indazole-3-yl]piperidine-2,6-dione 3 (121 mg, 0.27 mmol, 1 eq.) was placed in a round-bottom flask, and at room temperature, water (0.10 mL) and 4 M HCl / 1,4-dioxane (1.01 mL, 4.03 mmol, 15 eq.) were added and the mixture was stirred at 50°C. After 3 hours, complete conversion was shown by LC-MS. The solvent was removed under reduced pressure, and excess hydrochloric acid was removed with MeCN(3x) to obtain 4 (143 mg, quantitative yield) as a yellow solid, which was used in the next step without purification. LC-MS method 1: 81.4% purity (at 215 nm), [M+H2O+H] + = 388.2.

[0447] Step 3. tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[1-[2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]piperazine-1-yl]ethyl]-4-piperidyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate(6) 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]piperazine-1-yl]acetaldehyde 4 (140 mg, 0.27 mmol, 1.4 eq.), tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-(4-piperidyl)pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 5 (intermediate 8 obtained from the synthesis of P-37) (140 mg, 0.22 mmol, 1 eq.), and DIPEA (0.17 mL, 1.11 mmol, 5 eq.) in DMSO (0.5 mL) and CH2Cl2 (2 NaBH(OAc)3 (142 mg, 0.67 mmol, 3 eq.) was added to a mL solution at room temperature. The mixture was then stirred at room temperature. After 18 hours, complete conversion with impurities was shown by LC-MS. CH2Cl2 was removed under reduced pressure, and the residue in DMSO was purified by reverse-phase flash chromatography (50 g C18 RediSep Rf Gold column, holding solution (DMSO + formic acid), elution: 5% MeCN / 0.1% HCOOH over 5 CV, then 5-100% MeCN / 0.1% HCOOH over 20 CV, then 100% MeCN / 0.1% HCOOH over 5 CV). The fractions were combined, concentrated, and lyophilized to obtain 6 (78 mg, 38% yield) as a pale yellow solid. LCMS method 1: 88.0% purity (at 254 nm), [M+H] + = 931.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 - 1.45 (m, 11 H), 1.76 - 2.03 (m, 6 H), 2.06 - 2.22 (m, 4 H), 2.57 - 2.64 (m, 5 H), 2.97 - 3.06 (m, 2 H), 3.18 - 3.24 (m, 4 H), 3.44 - 3.72 (m, 4 H), 3.89 (s, 3 H), 4.15 (s, 2 H), 4.94 - 5.13 (m, 1 H), 6.83 - 6.95 (m, 3 H), 7.06 - 7.16 (m, 1 H), 7.49 (d, J = 8.8 Hz, 1 H), 8.17 (s, 1 H), 8.29 (s, 1 H), 8.33 - 8.38 (m, 1 H), 8.82 (d, J = 7.6 Hz, 1 H), 9.29 - 9.39 (m, 1 H), 10.79 - 10.92 (m, 1 H).

[0448] Step 4. N-[3-(difluoromethyl)-1-[1-[2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]piperazine-1-yl]ethyl]-4-piperidyl]pyrazole-4-yl]-5-[(3R,5R)-3-amino-5-fluoro-1-piperidyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-40) tert-butyl N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[1-[2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazole-6-yl]piperazine-1-yl]ethyl]-4-piperidyl]pyrazole-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidine-5-yl]-5-fluoro-3-piperidyl]carbamate 6 (46 mg, 0.05 mmol, 1 eq.) was mixed with 4 M HCl / 1,4-dioxane (0.62 mL, 2.47 mmol, 50 eq.). The reaction mixture was stirred at room temperature. After 16 hours, complete conversion was shown by LC-MS. Volatile components were removed under reduced pressure, and excess HCl was removed by co-evaporation (3x) with MeCN. Next, the residue was purified by reverse-phase flash chromatography (30 g C18 RediSep Rf Gold column, holding solution (water), elution: 5% MeCN / 0.1% HCOOH over 5 CV, then 5-100% MeCN / 0.1% HCOOH over 20 CV, then 100% MeCN / 0.1% HCOOH over 5 CV). The fractions were combined, concentrated, and lyophilized to obtain P-40 (21.4 mg, 51% yield) as a pale pink solid.

[0449] LC-MS method 2: 96.1% purity (at 215 nm), [M+H] + = 831.4, [M+2H] 2+ = 416.2, [M+3H]3+ = 277.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 - 1.11 (m, 1 H), 1.58 - 1.78 (m, 1 H), 1.90 - 2.04 (m, 4 H), 2.11 - 2.21 (m, 4 H), 2.26 - 2.34 (m, 1 H), 2.52 - 2.54 (m, 3 H), 2.59 - 2.66 (m, 6 H), 2.92 - 3.12 (m, 4 H), 3.17 - 3.26 (m, 4 H), 3.29 - 3.43 (m, 2 H), 3.55 - 3.61 (m, 1 H), 3.67 - 3.74 (m, 1 H), 3.89 (s, 3 H), 4.17 - 4.29 (m, 3 H), 4.95 - 5.09 (m, 1 H), 6.84 (s, 1 H), 6.92 (d, J = 8.1 Hz, 2 H), 7.02 - 7.30 (m, 1 H), 7.49 (d, J = 9.0 Hz, 1 H), 8.29 (s, 1 H), 8.40 (s, 1 H), 8.82 (d, J = 7.8 Hz, 1 H), 9.34 (s, 1 H), 10.85 (s, 1 H). 19 F NMR (377 MHz, DMSO-d6) δ -183.57 (s, 1 F), -111.18 (d, J = 49.0 Hz, 2 F).

[0450] The following compounds were synthesized using the same general route with modifications to CBM(CX) in step 6 (Table 8). [Table 45] [Table 46]

[0451] Biological examples Example B1. IRAK4 PhosphoSens Biochemical Assay (BIOCHEM) Method The PhosphoSens® biochemical assay was performed according to the distributor's instructions (AssayQuant Technologies Inc., Marlborough, MA). A 1.25 X stock solution of IRAK4 (PV4002, ThermoFisher Scientific, Waltham, MA), a 5 X stock solution of ATP, and the Sox-conjugated peptide substrate AQT0326 (CSKS-AQT0326B, AssayQuant Technologies) were prepared in 1X kinase reaction buffer [containing 50 mM HEPES (pH 7.5), 0.01% Brij-35, 0.5 mM EGTA, 20 mM MgCl2, and 1 mM DTT]. To obtain final concentrations of 200 μM ATP and 10 μM peptide substrate, a mixture of ATP (10 μL) and substrate solution was added to a Corning 3574 384-well white unbound surface microtiter plate (containing 0.5 μL of serially diluted test compounds prepared in DMSO). The enzyme solution (40 μL) with a final IRAK4 concentration of 1 nM was added to initiate the reaction, and the λ was measured every 71 seconds for 240 minutes at room temperature using a BioTek Synergy H4 plate reader. EX 360 / λ EM Monitoring was performed using 485 (Agilent Technologies, Santa Clara, CA). The initial linear portion of the progression curve was fitted according to a linear equation to determine the slope, and converted to % inhibition relative to the 100% activity value of the control that was not treated with the inhibitor. IC of each compound 50 The values ​​were obtained by fitting a % inhibitor-compound concentration curve using Dotmatics software (Dotmatics, Bishops Stortford, Hertfordshire, England).

[0452] Example B2. Reagent preparation Cell culture media were prepared in a sterile tissue culture hood by adding 10% FBS and 1% penicillin-streptomycin to 500 mL of RPMI1640 medium (without phenol red). The medium was filtered through a Nalgene Bottle Top Filter and stored at 4°C.

[0453] Cell titer Glo (CTG) buffer and substrate (CellTiter-Glo Luminescent Cell Viability Assay, Promega Ref. # G7573) were stored at -20°C. 100 mL of CTG buffer was warmed in a bead bath and added to a bottle containing the CTG substrate in a tissue culture hood. The solution was mixed homogenously using a pipette. The CTG reagent was dispensed into 15 mL Falcon tubes and stored at -20°C.

[0454] For a homogeneous time-resolved fluorescence (HTRF) assay, the Cisbio HTRF kit was used, containing the following: Resolved buffer #1 4X, Blocking reagent #3 100X, 20X antibody 1 (anti-IRAK4 d2), 20X antibody 2 (Anti-IRAK4 k), and detection buffer.

[0455] The 4X decomposition buffer was stored at 4°C. To use as a 1X decomposition buffer, the 4X solution was diluted with deionized water (distilled water, Gibco Cat. # 15230279) and 100X blocking reagent in a volume ratio of 1:3:0.04.

[0456] Aliquots of 20X antibody solution were stored at -80°C, and the detection buffer was stored at 4°C. To use as a 1X antibody solution, aliquots of 20X antibody solution were diluted with detection buffer at a volume ratio of 1:19.

[0457] Example B3. Procedure for homogeneous time-resolved fluorescence (ALE THP1 HTRF) of advanced fatty acid oxidation end product THP1. Cells were lysed with shaking at room temperature for 45 minutes. A BCA protein assay was performed and normalized to the target total protein concentration using 1X lysis buffer. Next, a 1X antibody solution was prepared by adding 380 μL of detection buffer to an aliquot of 20 μL of 20X antibody solution and mixing thoroughly. The 1X antibody solutions were combined in a 1:1 ratio and vortexed briefly. 20 μL of 1X anti-IRAK4-k antibody solution was maintained as the control well. 384-well plates (ProxiPlate-384 Plus, Perkin Elmer Cat.# 6008289) were loaded by adding 4 μL of the mixed antibody solution to empty wells using a single-channel repeater. Using a multi-channel repeater, 16 μL of decomposition solution was added per well, and all formed foam was defoamed using a 20 μL pipette tip and the end of a Kimwipe. Each control was prepared in 3-row configuration in 10 columns. Buffer controls were prepared in wells A10, B10, and C10 by adding 16 μL of degradation buffer and 4 μL of detection buffer. Cryptate controls were prepared in wells D10, E10, and F10 by adding 16 μL of degradation buffer, 2 μL of detection buffer, and 2 μL of 1 X anti-IRAK4-k antibody solution. Negative controls were prepared in wells G10, H10, and I10 by adding 16 μL of degradation buffer and 4 μL of mixed antibody solution. The plate was sealed with a clear seal and covered with an aluminum lid. The plate was centrifuged at 800 g for 5 minutes and incubated overnight in the dark at room temperature. The next day, the plate was centrifuged at 800 g for 5 minutes. Samples were analyzed using a plate reader (Envision, PerkinElmer) with the Desnor 384 HTRF program.

[0458] A summary of the ALE THP1 HTRF data for the tested compounds is shown in Table 9 below. [Table 47] [Table 48]

[0459] Although the present invention is described in some detail by examples and embodiments for the purpose of clarity of understanding, these descriptions and embodiments should not be construed as limiting the scope of the invention. All disclosures of patent and scientific documents cited herein are expressly incorporated herein in their entirety by reference.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula: R 1 C 1 -C 6 It is a haloalkyl; R a is H or C 1 -C 6 It is alkyl; R b is C 1 -C 6 alkyl, 5- or 6-membered heteroaryl, -(C 1 -C 6 alkylene)(5- or 6-membered heteroaryl) or -(C 1 -C 6 alkylene)NH 2 wherein the heteroaryl contains 1 to 2 nitrogen atoms and may optionally be substituted by 1 to 5 R 2 groups; or R a and R b The dotted line between them indicates a ring structure, where R a and R b These, together with the nitrogen atoms bonded to them, form a 5-10 membered monocyclic or bicyclic heterocycline, the heterocycline may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 It may be replaced by the base as desired; Each R 2 -NH is independent of 2 Hello, C 1 -C 6 Alkyl, C 1 -C 6 A haloalkyl, -CN, or 5-6 membered heteroaryl, wherein the heteroaryl contains 1-2 nitrogen atoms and C 1 -C 6 alkyl, halo, and C 1 -C 6 They may optionally be substituted with 1 to 5 groups selected from haloalkyl groups; L 1 -C(O)N(H)-, -C(O)-, -(C 1 -C 6 Alkilen)N(R 3 )-or C 1 -C 6 It is alkylene; L 2 The bond is -C(O)-, -N(R 3 )- or O; Each R 3 H or C 1 -C 6 It is alkyl; Ring A is a monocyclic 4-6 membered heterocyclylene or a bicyclic 6-9 membered spiroheterocyclylene, the heterocyclylene contains 1-2 nitrogen atoms, and the heterocyclylene contains m R 4 It is substituted by the group; Each R 4 It is independently, Halo, C 1 -C 6 Alkyl or C 1 -C 6 It is a haloalkyl; m is between 0 and 5; R 5 is H or C 1 -C 6 It is alkyl; Z is CH or N; and * is L 2 [Indicates the bonding point to the contained group] Compounds thereof or pharmaceutically acceptable salts thereof.

2. R 1 However, C 1 -C 3 A compound according to claim 1, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

3. R 1 However, -CHF 2 The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

4. R a However, H or C 1 -C 3 It is alkyl; R b However, C 1 -C 3 Alkyl, 6-membered heteroaryl, -(C 1 -C 3 Alkilen) (6-membered heteroaryl) or -(C) 1 -C 3 Alkilen) NH 2 The heteroaryl contains 1 to 2 nitrogen atoms and 1 to 2 R 2 It may be substituted as desired by the base; and Each R 2 However, independently, -NH 2 Hello, C 1 -C 3 Alkyl, C 1 -C 3 It is a haloalkyl or -CN. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 【Request Item 5】 【Chemistry 2】 but, 【Transformation 3】 The compound according to claim 4 or a pharmaceutically acceptable salt thereof.

6. R a and R b However, they may form a 5-8 member monocyclic or bicyclic heterocycline together with the nitrogen atoms bonded to them, and may optionally contain 1-2 additional heteroatoms selected from N and O, and optionally 1-3 R 2 It may be substituted by the base; and Each R 2 -NH is independent of 2 Hello, C 1 -C 3 Alkyl, C 1 -C 3 The heteroaryl is a haloalkyl, -CN, or 5-membered heteroaryl, wherein the heteroaryl contains 1 to 2 nitrogen atoms and optionally C 1 -C 3 alkyl, halo, and C 1 -C 3 It may be substituted with 1 to 3 groups selected from haloalkyl groups. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 【Request Item 7】 【Chemistry 4】 but, 【Transformation 5】 The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

8. L 1 is -C(O)N(H)-, -C(O)-, -(C 1 -C 3 -alkylene)N(R 3 )- or C 1 -C 3 -alkylene; L 2 However, the bond is -C(O)-, -N(R 3 )- or O; and Each R 3 is independently H or C 1 -C 3 alkyl A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. Ring A is the following: (i) 【Transformation 6】 (Here, Y 1 and Y 2 Independently, CH or N, but Y 1 and Y 2 At least one of them is N); (ii) 【Transformation 7】 ； or (iii) 【Transformation 8】 A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. Each R 4 However, they became independent, Hello, C 1 -C 3 Alkyl or C 1 -C 3 A compound according to any one of claims 1 to 9, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

11. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

12. Ring A is 【Chemistry 9】 A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. R 5 However, H or C 1 -C 3 A compound according to any one of claims 1 to 12, which is alkyl, or a pharmaceutically acceptable salt thereof.

14. R 5 However, -CH 3 The compound according to claim 13 or a pharmaceutically acceptable salt thereof. 【Request Item 15】 【Chemistry 10】 but, 【Chemistry 11】 A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

16. Formulas (IA), (IB), (IIa), (IIb), (IIIa), or (IVa): 【Chemistry 12】 [In the formula, R a is H or C 1 -C 6 It is alkyl; and R b C 1 -C 6 Alkyl, 5-6 member heteroaryl, -(C 1 -C 6 Alkylene) (5-6 member heteroaryl) or -(C 1 -C 6 Alkilen) NH 2 The heteroaryl contains 1 to 2 nitrogen atoms and 1 to 5 R 2 [May be substituted as desired by the base]; 【Chemistry 13】 [In the formula, 【Chemistry 14】 The heterocycline is a 5-10 member monocyclic or bicyclic heterocycline, which may optionally contain 1-2 additional heteroatoms selected from N and O, and 1-5 R 2 [May be substituted as desired by the base]; 【Chemistry 15】 A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

17. A compound selected from the compounds in Table 1 and their pharmaceutically acceptable salts.

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 (IL1) receptor-related kinase 4 (IRAK4), characterized by contacting IRAK4 with an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 18.

20. A method for treating an inflammatory disease or autoimmune disease in a subject requiring treatment, characterized by administering 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, to the subject, wherein the inflammatory disease or autoimmune disease may optionally be atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryopyrin-associated periodic syndromes, hidradenitis suppurativa, Beckett syndrome, or familial cold autoinflammatory syndrome.

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