Heteroaryl compounds as ligand directed degradation agents for IRAK4

Abstract

Provided herein are compounds and compositions thereof for modulating IRAK4. In some embodiments, compounds and compositions for the treatment of inflammatory or autoimmune diseases are provided.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 465,603, filed May 11, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure generally relates to compounds, compositions, methods of their preparation, and the use of said compounds and compositions in the treatment of inflammatory or autoimmune diseases. Background Technology

[0004] The recruitment of immune cells to the site of injury involves the synergistic interactions of numerous soluble mediators. Several cytokines, including interleukin-1 (IL-1), appear to play a crucial role in these processes. IL-1 generates pro-inflammatory responses and contributes to the tissue degeneration processes observed in chronic inflammatory states. IL-1 is also involved in bone resorption and adipose tissue regulation. Therefore, IL-1 plays a critical role in a variety of pathological conditions, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, cancer, and sepsis.

[0005] IL-1 treatment of cells induces the formation of a complex consisting of two IL-1 receptor chains (IL-1R1 and IL-1RAcP), and the resulting dimer recruits an adaptor molecule named MyD88, which binds to IL-1 receptor-associated kinase (IRAK) (Wesche et al., J. Biol. Chem. 1999, 274, 19403-19410; O'Neill et al., J. Leukoc. Biol. 1998, 63, 650-657; Auron, Cytokine Growth Factor Rev. 1998, 9:221-237; and O'Neill, Biochem. Soc. Trans. 2000, 28, 557-563). Four members of the IRAK family have been identified: IRAK1, IRAK2, IRAK4, and IRAK5. These proteins are characterized by a typical N-terminal death domain and a centrally located kinase domain that mediates interactions with MyD88 family adaptor proteins. Of the four members of the mammalian IRAK family, IRAK-4 is considered the “major IRAK.” IRAK-4 is a serine / threonine kinase that plays a crucial role in signal transduction mediated by the Toll / IL-1 receptor (TIR). Under overexpression conditions, all IRAK family members mediate activation of nuclear factor-κB and stress-induced activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Studies have demonstrated that RAK4 kinase activity in response to TLR ligands is essential for cytokine production, MAPK activation, and the induction of NF-κB-regulated genes (Koziczak-Holbro M. et al., J. Biol. Chem. 2007, 282, 13552-13560). Given the crucial role of IRAK4 in the Toll-like receptor / IL-1R signaling pathway and immune protection, compounds that modulate IRAK4 function may be useful in treating inflammation, cell proliferation and immune-related conditions, and diseases associated with IRAK-mediated signal transduction, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, allergic diseases, psoriasis, asthma, graft rejection, cancer, and sepsis.

[0006] Protein degradation is a highly regulated and crucial process for maintaining cellular homeostasis. The selective recognition and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). UPP is key to the regulation of almost all cellular processes. Protein ubiquitination is accomplished by E3 ubiquitin ligases, which bind to the protein and add ubiquitin molecules, thus labeling the protein for proteasome degradation.

[0007] The use of UPPs for therapeutic applications has garnered significant attention (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising therapeutic approach utilizes the proteolytic action of targeted chimeras (commonly known as PROTACs) to effectively remove unwanted proteins through protein degradation (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTACs are ligand-directed degraders that aggregate E3 ligases with target proteins to be degraded. These bivalent molecules typically consist of E3 ligase ligands linked to small molecules that bind to the target protein via a linker. PROTACs position the E3 ligase at the appropriate distance and orientation to the target protein, thereby ubiquitinizing the target protein. The ubiquitinated target protein is then degraded via proteasome recognition.

[0008] Therefore, in one respect, this article provides compounds that target IRAK4 for degradation. Summary of the Invention

[0009] In some embodiments, compounds and compositions thereof for degrading IRAK4 are described herein. In various embodiments, the compounds and compositions thereof can be used to treat inflammatory diseases or autoimmune diseases.

[0010] The embodiments of the present invention can be fully understood by referring to the specific implementation methods and examples intended to illustrate non-limiting embodiments.

[0011] Scheme 1 is a compound of formula (I):

[0012]

[0013] (I)

[0014] Or its pharmaceutically acceptable salt, wherein:

[0015] R 1 It is a C1-C6 haloalkyl group;

[0016] R a It is H or C1-C6 alkyl;

[0017] R b It is a C1-C6 alkyl, a 5- to 6-membered heteroaryl, a -(C1-C6 alkylene)(5- to 6-membered heteroaryl), or a -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is determined by 1-5 R... 2 Group substitution;

[0018] or R a and R b The dashed lines between them represent a ring structure, where Ra and R b Together with the nitrogen atoms to which they are attached, they form 5- to 10-membered monocyclic or bicyclic heterocyclic groups, optionally containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-5 R... 2 Group substitution;

[0019] Each R 2 Independently, it is -NH2, halogroup, C1-C6 alkyl, C1-C6 haloalkyl, -CN or 5 to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 2 nitrogen atoms and is optionally substituted by 1 to 5 groups selected from C1-C6 alkyl, halogroup and C1-C6 haloalkyl;

[0020] L 1 -C(O)N(H)-, -C(O)-, -(C1-C6 alkylene)N(R) 3 )- or C1-C6 alkylene;

[0021] L 2 For bond, -C(O)-, -N(R) 3 - or O;

[0022] Each R 3 Independently H or C1-C6 alkyl;

[0023] Ring A is a monocyclic 4- to 6-membered subheterocyclic group or a bicyclic 6- to 9-membered spirosubheterocyclic group, wherein the heterocyclic group contains 1-2 nitrogen atoms, and wherein the subheterocyclic group is subjected to m R... 4 Group substitution;

[0024] Each R 4 It is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl;

[0025] m is 0-5;

[0026] R 5 It is H or C1-C6 alkyl;

[0027] Z is CH or N; and

[0028] * indicates that it contains L 2 The connection points of the parts.

[0029] Implementation scheme 2 is the compound or a pharmaceutically acceptable salt thereof as described in implementation scheme 1, wherein:

[0030] R 1 It is a C1-C3 haloalkyl group.

[0031] Implementation scheme 3 is the compound or a pharmaceutically acceptable salt thereof as described in implementation scheme 2, wherein:

[0032] R1 It is -CHF2.

[0033] Implementation scheme 4 is a compound or a pharmaceutically acceptable salt thereof according to any one of implementation schemes 1-3, wherein:

[0034] R a It is H or C1-C3 alkyl;

[0035] R b It is a C1-C3 alkyl, a 6-membered heteroaryl, a -(C1-C3 alkylene)(6-membered heteroaryl), or a -(C1-C3 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is denoted by 1-2 R... 2 Group substitution; and

[0036] Each R 2 It can be -NH2, halogen, C1-C3 alkyl, C1-C3 haloalkyl or -CN independently.

[0037] Implementation scheme 5 is the compound or a pharmaceutically acceptable salt thereof as described in implementation scheme 4, wherein:

[0038] for or .

[0039] Implementation scheme 6 is a compound or a pharmaceutically acceptable salt thereof according to any one of implementation schemes 1-3, wherein:

[0040] R a and R b Together with the nitrogen atoms to which they are attached, they form 5- to 8-membered monocyclic or bicyclic heterocyclic groups, optionally containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-3 R... 2 Group substitution, and

[0041] Each R 2 Independently, it is -NH2, halogroup, C1-C3 alkyl, C1-C3 haloalkyl, -CN, or 5-membered heteroaryl.

[0042] The heteroaryl group contains 1-2 nitrogen atoms and is optionally substituted by 1-3 groups selected from C1-C3 alkyl, halogen, and C1-C3 haloalkyl groups.

[0043] Implementation scheme 7 is the compound or a pharmaceutically acceptable salt thereof as described in implementation scheme 6, wherein:

[0044] for

[0045] or .

[0046] Implementation scheme 8 is a compound or a pharmaceutically acceptable salt thereof according to any one of implementation schemes 1-7, wherein:

[0047] L 1 -C(O)N(H)-, -C(O)-, -(C1-C3 alkylene)N(R) 3 )- or C1-C3 alkylene;

[0048] L 2 For bond, -C(O)-, -N(R) 3 )- or O; and

[0049] Each R 3 It is independently H or C1-C3 alkyl.

[0050] Implementation scheme 9 is a compound or a pharmaceutically acceptable salt thereof according to any one of implementation schemes 1-8, wherein:

[0051] Ring A is: (i) ; and Y 1 and Y 2 Independently CH or N, provided that Y 1 and Y 2 At least one of them is N;

[0052] (ii) ;or

[0053] (iii) .

[0054] Implementation scheme 10 is a compound or a pharmaceutically acceptable salt thereof according to any one of implementation schemes 1-9, wherein:

[0055] Each R 4 It is independently a halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0056] Implementation scheme 11 is a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-10, wherein:

[0057] m can be 0, 1, or 2.

[0058] Implementation scheme 12 is a compound or a pharmaceutically acceptable salt thereof according to any one of implementation schemes 1-11, wherein:

[0059] Ring A is

[0060] or .

[0061] Scheme 13 is a compound according to any one of Schemes 1-12 or a pharmaceutically acceptable salt thereof, wherein

[0062] R 5 It is H or C1-C3 alkyl.

[0063] Implementation scheme 14 is the compound or a pharmaceutically acceptable salt thereof as described in implementation scheme 13, wherein:

[0064] R 5 It is -CH3.

[0065] Implementation scheme 15 is a compound or a pharmaceutically acceptable salt thereof according to any one of implementation schemes 1-14, wherein:

[0066] for

[0067] or .

[0068] Embodiment 16 is a compound according to any one of embodiments 1-15 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IA), (IB), (IIa), (IIb), (IIIa), or (IVa):

[0069]

[0070] (IA)

[0071] in:

[0072] R a It is H or C1-C6 alkyl; and

[0073] R b It is a C1-C6 alkyl, a 5- to 6-membered heteroaryl, a -(C1-C6 alkylene)(5- to 6-membered heteroaryl), or a -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is determined by 1-5 R... 2 Group substitution;

[0074]

[0075] (IB)

[0076] in:

[0077] A 5- to 10-membered monocyclic or bicyclic heterocyclic group optionally containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-5 R... 2 Group substitution;

[0078]

[0079] (IIa)

[0080]

[0081] (IIb)

[0082]

[0083] (IIIa)

[0084]

[0085] (IVa).

[0086] Implementation scheme 17 is a compound selected from the compounds in Table 1 and their pharmaceutically acceptable salts.

[0087] Embodiment 18 is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-17, and a pharmaceutically acceptable excipient.

[0088] Embodiment 19 is a method for modulating interleukin-1 (IL1) receptor-associated kinase 4 (IRAK4), the method comprising contacting IRAK4 with an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-17, or a pharmaceutical composition according to Embodiment 18.

[0089] Implementation Scheme 20 is a method for treating an inflammatory or autoimmune disease in a subject in need, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1-17, or contact with a pharmaceutical composition according to Implementation Scheme 18, wherein optionally the inflammatory or autoimmune disease is atopic dermatitis, asthma, lupus erythematosus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin-associated periodic syndrome, hidradenitis suppurativa, Bechet's syndrome, or familial cold autoinflammatory syndrome. Detailed Implementation

[0090] definition

[0091] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be interpreted as specifically describing the presence of the stated feature or component, but do not exclude the presence or addition of one or more features, components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to encompass examples covered by the term “consisting of…”. Therefore, the term “consisting of…” can be used in place of the terms “comprising” and “including” to provide more specific embodiments of the invention.

[0092] The term "composed of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the features or components it comprises. In another embodiment, the term "composed of" excludes any other features or components from the scope of any subsequent expression, except those features or components that are not essential to the desired technical effect.

[0093] As used herein, the term "or" should be interpreted as inclusive "or," meaning any one or any combination. Therefore, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition will only occur when the combination of elements, functions, steps, or actions is inherently mutually exclusive to some extent.

[0094] In this specification, unless otherwise stated, any concentration range, percentage range, ratio range, or integer range shall be understood to include any integer within the range, and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer). Furthermore, unless otherwise stated, any numerical range relating to any physical characteristic, such as polymer subunits, size, or thickness, as described herein shall be understood to include any integer within the range. As used herein, unless otherwise stated, “about” and “approximately” mean ±20%, ±10%, ±5%, or ±1% of the range, value, or structure referred to.

[0095] The "alkyl" group has 1 to 10 carbon atoms (C1-C1). 10An alkyl group is a saturated, partially saturated, or unsaturated straight-chain or branched acyclic hydrocarbon, typically with 1 to 8 carbon atoms (C1-C8 alkyl) or, in some embodiments, 1 to 6 (C1-C6 alkyl), 1 to 3 (C1-C3 alkyl), or 2 to 6 (C2-C6 alkyl) carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, etc. In some embodiments, the alkyl group is an unsaturated alkyl group, also defined as an alkenyl or ynyl group. 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). The alkyl group may be substituted or unsubstituted. When an alkyl group as described herein is referred to as “substituted,” it may be substituted by: any one or more substituents present in the exemplary compounds and embodiments disclosed herein, and halogens; hydroxyl groups; alkoxy groups; cycloalkyloxy groups, aryloxy groups, heterocyclic alkyloxy groups, heterocyclic alkyloxy groups, cycloalkylalkyloxy groups, arylalkyloxy groups, heterocyclic alkyloxy groups, heterocyclic alkyloxy groups, heterocyclic alkyloxy groups; oxo (=O); amino groups, alkylamino groups, cycloalkylamino groups, arylamino groups, heterocyclic amino groups, heterocyclic alkylamino groups, heterocyclic alkylamino groups, cycloalkylalkylamino groups. Arylalkylamino, heterocyclic alkylamino, heteroarylalkylamino, heterocyclic alkylalkylamino; imino; imide; amido; guanidin; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; arylalkoxyamino; hydrazine; acylhydrazine; hydrazine; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphonooxy; acyl; formyl; carboxyl; ester; carbamate; acylamino; cyano; isocyano; isothiocyano; cyano; thiocyano; or -B(OH)2.In some embodiments, when the alkyl group described herein is referred to as “substituted,” it may be substituted by any one or more substituents present in the exemplary compounds and embodiments disclosed herein, and halogens (chlorine, iodine, bromine, or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; mercapto; thioether; imino; imide; amidine; guanidinyl; enamino; aminocarbonyl; acylamino; phosphonate; phosphono; thiocarbonyl; sulfinyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; urea; ethyl carbamate; oxime; hydroxylamine; alkoxyamine; arylalkoxyamine; N-oxide; hydrazine; acylhydrazine; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0096] "Cycloalkyl" groups are derived from 3 to 10 carbon atoms (C3-C4) of a single ring or multiple fused or bridged rings that may be optionally substituted. 10 The cycloalkyl group is a saturated or partially saturated cycloalkyl group. In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (C3-C8 cycloalkyl), while in other embodiments, the number of cyclic carbon atoms ranges from 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl), or 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. These saturated cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or polycyclic or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, etc. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. Cycloalkyl groups can be substituted or unsubstituted. These substituted cycloalkyl groups include, for example, cyclohexanol.

[0097] An "aryl" group is a group consisting of 6 to 14 carbon atoms (C6-C5) having a monocyclic (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracene). 14 The aryl group is an aromatic carbocyclic group. In some embodiments, the aryl group contains 6-14 carbons (C6-C5). 14 Aryl), and in other embodiments contains 6 to 12 (C6-C) groups. 12 Aryl groups or even 6 to 10 carbon atoms (C6-C) 10Aryl groups. Specific aryl groups include phenyl, biphenyl, naphthyl, etc. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0098] "Halogen" or "halogen group" refers to fluorine, chlorine, bromine, or iodine.

[0099] "Haloalkyl" refers to an alkyl group as defined above, which is substituted with one or more halogen substituents as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms and is substituted with one or more halogen groups (C1-C6 haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halogen groups (C1-C3 haloalkyl). The halogen groups may be all the same or may be different. Unless otherwise specified, the haloalkyl group may be optionally substituted.

[0100] A "heteroaryl" group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms in the heteroaryl ring system, wherein the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms, and in other embodiments, it contains 6 to 9 or even 6 to 10 heteroatoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as: pyrrolo, pyrazol, imidazo, triazol, tetrazol, oxazol, isoxazol, benzo[d]isooxazol (e.g., benzo[d]isooxazol), thiazolyl, pyrrolo, pyridazinyl, pyrazinyl, thiophene, benzo[thiophene], furanyl, benzo[thiophene], indole (e.g., indole-2-one or isoindoline-1-one), azaindole (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), inzol, benzo[imidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridinyl (e.g., ... The aryl groups can be substituted or unsubstituted. These groups include benzo[i]imidazolyl or 1H-imidazo[4,5-b]pyridyl, pyrazolopyridyl, triazol[i]pyridyl, benzo[i]triazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzo[i]oxazolyl (e.g., benzo[d]oxazolyl), benzo[i]thiazolyl, benzo[i]thiadiazolyl, isoxazol[i]pyridyl, thianaphthalenyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-keto), tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0101] "Heterocyclic group" is a non-aromatic cycloalkyl group in which 1 to 4 ring carbon atoms are independently replaced by heteroatoms selected from O, S, and N. In some embodiments, the heterocyclic group comprises 3 to 10 ring members, while other such rings have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclic group may also be bonded to other groups on any ring atom (i.e., any carbon atom or heteroatom of the heterocycle). The heterocyclic alkyl group may be substituted or unsubstituted. The heterocyclic group encompasses saturated and partially saturated ring systems. Furthermore, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom that may be fused to an aryl or heteroaryl ring, whether or not it is attached to the remainder of the molecule. The phrase also includes bridging polycyclic systems containing heteroatoms. Representative examples of heterocyclic groups include, but are not limited to, aziridine, aziridine, aziridine, pyrrolidinyl, imidazolyl (e.g., imidazoline-4-one or imidazoline-2,4-diketone), pyrazolyl, thiazolyl, tetrahydrothiophene, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropiperanyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiaranyl, oxathiadinyl, dithiadinyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quininecycloyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclic groups may be monosubstituted or more than once substituted, such as, but not limited to, pyridinyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted by the various substituents listed below.

[0102] When groups (other than alkyl groups) are referred to herein as “substituted,” they may be substituted by any suitable one or more substituents. Illustrative examples of substituents are those present in the exemplary compounds and embodiments disclosed herein, as well as halogens (chlorine, iodine, bromine, or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; mercapto; thioether; imino; imide; amidine; guanidinyl; enamino; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; urea; ethyl carbamate; oxime; hydroxylamine; alkoxyamine; arylalkoxyamine; N-oxide; hydrazine; acylhydrazine; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, It can be a monocyclic, fused, or non-fused polycyclic compound (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclic compound, which can be a monocyclic, fused, or non-fused polycyclic compound (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); a monocyclic, fused, or non-fused polycyclic or heteroaryl compound (e.g., phenyl, naphthyl, pyrrolidinyl, indolyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridineyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiopheneyl, or benzofuranyl); aryloxy; aralkyloxy; heterocyclicoxy; and heterocyclic alkoxy.

[0103] Certain commonly used alternative chemical names can be used. For example, divalent groups such as divalent "alkyl" groups, divalent "phenyl" groups, divalent "heteroaryl" groups, and divalent "heterocyclic" groups can also be called "alkylene" groups, "phenylene" groups, "heteroaryl" groups, or "heterocyclic" groups, respectively.

[0104] Embodiments of this disclosure are intended to cover pharmaceutically acceptable salts, tautomers, isotopes, and stereoisomers of compounds provided herein, such as compounds of formula (I).

[0105] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable nontoxic acid or base, including inorganic acids and inorganic bases as well as organic acids and organic bases. Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts prepared from lysine, N,N'-diphenylmethylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, aminobenzoic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous 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, and methanesulfonic acid. Therefore, specific examples of salts include hydrochloride salts, formate salts, and methanesulfonate salts. Others known in the art can be found, for example, in Remington's Pharmaceutical Sciences, 18. th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0106] As used herein and unless otherwise stated, the terms "stereoisomer" or "stereoisomerically pure" mean a stereoisomer of a compound that is substantially free of other stereoisomers of a particular compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of its opposite enantiomers. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds include, by weight, more than about 80% of one stereoisomer of the compound and less than about 20% of other stereoisomers of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of other stereoisomers of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of other stereoisomers of the compound; and more than about 97% of one stereoisomer of the compound and less than 3% of other stereoisomers of the compound. The compounds disclosed herein may have a chiral center and may occur as racemates, enantiomers alone, diastereomers, or mixtures thereof. All such isomeric forms are included in the embodiments disclosed herein, including mixtures thereof.

[0107] The use of the stereoisomers of the compounds disclosed herein, as well as mixtures of those forms, is covered in the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be used for asymmetric synthesis or resolution using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates andResolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and OpticalResolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCHVerlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., EnantiomerSeparation: Fundamentals and Practical Methods (Springer Science & BusinessMedia, 2007); Subramanian, G. Chiral Separation Techniques: A PracticalApproach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0108] It should also be noted that the compounds disclosed herein may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In some embodiments, the compound may be isolated as an E or Z isomer. In other embodiments, the compound is a mixture of E and Z isomers.

[0109] "Tautomers" refer to the isomers of a compound that are in equilibrium with each other. The concentration of the isomers will depend on the environment in which the compound exists and may vary, for example, depending on whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomers, which are called tautomers of each other:

[0110] .

[0111] As will be readily understood by those skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compound of formula (I) are within the scope of this disclosure.

[0112] It should also be noted that the compounds disclosed herein may contain atomic isotopes in non-natural proportions on one or more atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as, for example, tritium ( 3 H), Iodine-125 ( 125 I), sulfur-35 ( 35 S) or carbon-14 ( 14 C) or it may be enriched by isotopes, such as using deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15 ( 15 N) enrichment. As used herein, an "isotope" is an isotopically enriched compound. The term "isotopically enriched" means having atoms with an isotopic composition other than that of a naturally occurring atom. "Isotopically enriched" can also mean a compound containing at least one atom with an isotopic composition different from that of a naturally occurring atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled and isotopically enriched compounds can be used as therapeutic agents, such as cancer therapeutic agents, research reagents, such as binding assays, and diagnostic reagents, such as in vivo imaging agents. All isotopic variants of the compounds described herein, whether or not radioactive, are intended to be covered within the scope of the embodiments provided herein. In some embodiments, isotopes of the compounds disclosed herein are provided, for example, compounds enriched with deuterium, carbon-13, and / or nitrogen-15. As used herein, "deuteration" means that at least one hydrogen (H) has been deuterated (using D or D) 2 H represents a substituted compound, that is, the compound is enriched in deuterium at at least one position.

[0113] It should be understood that, independent of stereoisomer or isotopic composition, each compound disclosed herein may be provided in the form of any pharmaceutically acceptable salt discussed herein. Similarly, it should be understood that the isotopic composition may vary independently of the stereoisomer composition of each compound described herein. Furthermore, while the isotopic composition is limited to those elements present in the respective compounds or their salts disclosed herein, it may also vary independently of the choice of pharmaceutically acceptable salts for the respective compounds.

[0114] It should be noted that if there is a difference between the name of the described structure and the name of the structure, the described structure shall prevail.

[0115] As used herein, “treatment” means the complete or partial relief of a symptom, disease, or condition, or one or more symptoms associated with a symptom, disease, or condition, or the slowing or cessation of further progression or worsening of these symptoms, or the relief or elimination of one or more causes of the symptom, disease, or condition itself. In one embodiment, the symptom is a neurodegenerative disease or its symptoms as described herein.

[0116] As used herein, “prevention” means wholly or partially delaying and / or preventing the onset, recurrence, or spread of a symptom, disease, or illness; preventing a subject from developing a symptom, disease, or illness; or a method for reducing the risk of a subject developing a symptom, disease, or illness. In one embodiment, the symptom is a neurodegenerative disease or a symptom thereof as described herein.

[0117] The term “effective amount” in relation to the compounds disclosed herein means an amount that is sufficient to treat or prevent the conditions, diseases, or symptoms disclosed herein.

[0118] As used herein, the terms “subject” or “patient” include animals, including but not limited to animals such as: cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, which in one embodiment are mammals and in another embodiment are humans. In one embodiment, a subject is a person who has or is at risk of having an S1P5-mediated disease or its symptoms.

[0119] While various features of the invention may be described in the context of a single embodiment, these features may also be provided individually or in any suitable combination. Conversely, although the invention may be described in the context of a single embodiment for clarity, the invention may also be implemented in a single embodiment.

[0120] compound

[0121] In one respect, this article provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0122]

[0123] (I)

[0124] in:

[0125] R 1 It is a C1-C6 haloalkyl group;

[0126] R a It is H or C1-C6 alkyl;

[0127] R b It is a C1-C6 alkyl, a 5- to 6-membered heteroaryl, a -(C1-C6 alkylene)(5- to 6-membered heteroaryl), or a -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is determined by 1-5 R... 2 Group substitution;

[0128] or R a and R b The dashed lines between them represent a ring structure, where R a and R b Together with the nitrogen atoms to which they are attached, they form 5- to 10-membered monocyclic or bicyclic heterocyclic groups, optionally containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-5 R... 2 Group substitution;

[0129] Each R 2 Independently, it is -NH2, halogroup, C1-C6 alkyl, C1-C6 haloalkyl, -CN or 5 to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 2 nitrogen atoms and is optionally substituted by 1 to 5 groups selected from C1-C6 alkyl, halogroup and C1-C6 haloalkyl;

[0130] L 1 -C(O)N(H)-, -C(O)-, -(C1-C6 alkylene)N(R) 3 )- or C1-C6 alkylene;

[0131] L 2 For bond, -C(O)-, -N(R) 3 - or O;

[0132] Each R 3 Independently H or C1-C6 alkyl;

[0133] Ring A is a monocyclic 4- to 6-membered subheterocyclic group or a bicyclic 6- to 9-membered spirosubheterocyclic group, wherein the heterocyclic group contains 1-2 nitrogen atoms, and wherein the subheterocyclic group is subjected to m R... 4 Group substitution;

[0134] Each R 4It is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl;

[0135] m is 0-5;

[0136] R 5 It is H or C1-C6 alkyl;

[0137] Z is CH or N; and

[0138] * indicates that it contains L 2 The connection points of the parts.

[0139] In some implementation schemes, R 1 It is a C1-C6 haloalkyl group. In some embodiments, R 1 It is a C1-C3 haloalkyl group. In some embodiments, R 1 For -CHF2 or -CF3. In some implementations, R 1 It is -CHF2.

[0140] In some implementation schemes, R 1 It is a C1-C6 haloalkyl group. In some embodiments, R 1 It is a C1-C6 haloalkyl group containing 1-13 halogen atoms. In some embodiments, R 1 It is a C1-C3 haloalkyl group. In some embodiments, R 1 It is a C1-C3 haloalkyl group containing 1-7 halogen atoms. In some embodiments, R 1 It can be -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 1 For -CF3. In some implementations, R 1 It is -CHF2.

[0141] In some implementation schemes, R a H or C1-C3 alkyl; R b It is a C1-C3 alkyl, a 6-membered heteroaryl, a -(C1-C3 alkylene)(6-membered heteroaryl), or a -(C1-C3 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is denoted by 1-2 R... 2 Group substitution; and

[0142] Each R 2 Independently, it is -NH2, a halogroup, a C1-C3 alkyl group, a C1-C3 haloalkyl group, or -CN. In some embodiments, R a For H or -CH3; R bIt is -CH3, -CH2 (pyridyl), -CH2CH2NH2 or pyridyl, wherein the pyridyl group is optionally fused with one R 2 Group substitution, and R 2 It is -CH3.

[0143] In some implementation schemes, R a It is H or C1-C6 alkyl. In some embodiments, R a It is an H or C1-C3 alkyl group. In some embodiments, R a It can be H or -CH3.

[0144] In some implementation schemes, R a For H.

[0145] In some implementation schemes, R a It is a C1-C6 alkyl group. In some embodiments, R a It is a C1-C3 alkyl group. In some embodiments, R a It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R a It is methyl. In some embodiments, R a It is ethyl. In some embodiments, R a It is n-propyl. In some embodiments, R a It is isopropyl.

[0146] In some implementation schemes, R b It is a C1-C6 alkyl, a 5- to 6-membered heteroaryl, a -(C1-C6 alkylene)(5- to 6-membered heteroaryl), or a -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is determined by 1-5 R... 2 Group substitution. In some embodiments, R b It is a C1-C3 alkyl, a 6-membered heteroaryl, a -(C1-C3 alkylene)(6-membered heteroaryl), or a -(C1-C3 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is denoted by 1-2 R... 2 Group substitution. In some embodiments, R b It is -CH3, -CH2 (pyridyl), -CH2CH2NH2 or pyridyl, wherein the pyridyl group is optionally fused with one R 2 Group substitution.

[0147] In some implementation schemes, R b It is a C1-C6 alkyl group. In some embodiments, R b It is a C1-C3 alkyl group. In some embodiments, R b It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R bIt is methyl. In some embodiments, R b It is ethyl. In some embodiments, R b It is n-propyl. In some embodiments, R b It is isopropyl.

[0148] In some implementation schemes, R b It is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group contains 1-2 nitrogen atoms and optionally is denoted by 1-5 R groups. 2 Group substitution. In some embodiments, R b It is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group contains 1-2 nitrogen atoms and optionally is denoted by 1-3 R groups. 2 Group substitution. In some embodiments, R b It is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group contains 1-2 nitrogen atoms and optionally is denoted by 1 or 2 R atoms. 2 Group substitution. In some embodiments, R b It is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group contains 1-2 nitrogen atoms and optionally is denoted by 1 R 2 Group substitution. In some embodiments, R b It is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group contains 1-2 nitrogen atoms and is unsubstituted. In some embodiments, R b It is a 5-membered heteroaryl group containing 1-2 single atoms. In some embodiments, R b It is a 5-membered heteroaryl group containing one nitrogen atom. In some embodiments, R b It is a 5-membered heteroaryl group containing two nitrogen atoms. In some embodiments, R b It is pyrrole, imidazole, or pyrazolyl. In some embodiments, R b It is a 6-membered heteroaryl group containing 1-2 nitrogen atoms. In some embodiments, R b It is a 6-membered heteroaryl group containing one nitrogen atom. In some embodiments, R b It is a 6-membered heteroaryl group containing 2 nitrogen atoms. In some embodiments, R b It is pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, R b It is pyridyl.

[0149] In some implementation schemes, R b It is -(C1-C6 alkylene)(5 to 6-membered heteroaryl), wherein the heteroaryl group contains 1 to 2 nitrogen atoms and optionally is denoted by 1 to 5 R... 2 Group substitution. In some embodiments, R bIt is -(C1-C3 alkylene)(5 to 6-membered heteroaryl), wherein the heteroaryl group contains 1 to 2 nitrogen atoms and optionally is denoted by 1 to 5 R... 2 Group substitution. In some embodiments, R b It is -(C1-C3 alkylene)(5 to 6-membered heteroaryl), wherein the heteroaryl group contains 1 to 2 nitrogen atoms and optionally is denoted by 1 to 3 R... 2 Group substitution. In some embodiments, R b It is -(C1-C3 alkylene)(5 to 6-membered heteroaryl), wherein the heteroaryl group contains 1 to 2 nitrogen atoms and optionally is denoted by 1 or 2 R atoms. 2 Group substitution. In some embodiments, R b It is -(C1-C3 alkylene)(5 to 6-membered heteroaryl), wherein the heteroaryl group contains 1 to 2 nitrogen atoms and optionally is via 1 R 2 Group substitution. In some embodiments, R b It is -(C1-C3 alkylene)(5 to 6-membered heteroaryl), wherein the heteroaryl contains 1 to 2 nitrogen atoms and is unsubstituted.

[0150] In some implementation schemes, R b It is -(C1-C6 alkylene)(5-heteroaryl), wherein the heteroaryl group contains 1-2 nitrogen atoms and optionally is denoted by 1-5 R... 2 Group substitution. In some embodiments, R b It is -(C1-C3 alkylene)(5-heteroaryl), wherein the heteroaryl group contains 1-2 nitrogen atoms and optionally is denoted by 1-5 R... 2 Group substitution. In some embodiments, R b It is -(C1-C3 alkylene)(5-heteroaryl), wherein the heteroaryl group contains 1-2 nitrogen atoms and optionally is denoted by 1-3 R... 2 Group substitution. In some embodiments, R b It is -(C1-C3 alkylene)(5-heteroaryl), wherein the heteroaryl group contains 1-2 nitrogen atoms and optionally is derived from 1 or 2 R atoms. 2 Group substitution. In some embodiments, R b It is -(C1-C3 alkylene)(5-heteroaryl), wherein the heteroaryl group contains 1-2 nitrogen atoms and optionally is via 1 R 2 Group substitution. In some embodiments, R b It is -(C1-C3 alkylene)(5-heteroaryl), wherein the heteroaryl group contains one nitrogen atom and optionally is denoted by 1-5 R... 2 Group substitution. In some embodiments, R bIt is -(C1-C3 alkylene)(5-heteroaryl), wherein the heteroaryl group contains 2 nitrogen atoms and optionally is denoted by 1-5 R... 2 Group substitution. In some embodiments, R b It is -(C1-C3 alkylene)pyrrole, -(C1-C3 alkylene)imidazolyl, or -(C1-C3 alkylene)pyrazole. In some embodiments, R b It is -CH2 (pyrrole), -CH2 (imidazolyl), or -CH2 (pyrazolyl). In some embodiments, R b It can be -CH2CH2 (pyrrole), -CH2CH2 (imidazolyl), or -CH2CH2 (pyrazolyl).

[0151] In some implementation schemes, R b It is -(C1-C6 alkylene)NH2. In some embodiments, R b It is -(C1-C3 alkylene)NH2. In some embodiments, R b It is -CH2NH2, -CH2CH2NH2, or -CH2CH2CH2NH2. In some embodiments, R b It is -CH2CH2NH2.

[0152] In some implementation schemes, for or .

[0153] In some implementation schemes, R a and R b Together with the nitrogen atoms to which they are attached, they form additional heteroatoms optionally containing 1-2 selected from N and O and optionally via 1-5 R... 2 A 5- to 10-membered monocyclic or bicyclic heterocyclic group with substituted radicals. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form additional heteroatoms optionally containing 1-2 selected from N and O and optionally via 1-3 R... 2 A 5- to 8-membered monocyclic or bicyclic heterocyclic group with substituted groups. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form 5- to 6-membered monocyclic heterocyclic groups or 8-membered fused or bridged bicyclic heterocyclic groups, wherein the heterocyclic group optionally contains 1-2 additional heteroatoms selected from N and O and optionally is via 1-3 R... 2 Group substitution.

[0154] In some implementation schemes, R a and R bTogether with the nitrogen atoms to which they are attached, they form additional heteroatoms optionally containing 1-2 selected from N and O and optionally via 1-5 R... 2 A 5- to 10-membered monocyclic heterocyclic group substituted with a functional group. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form additional heteroatoms optionally containing 1-2 selected from N and O and optionally via 1-5 R... 2 A 5- to 6-membered monocyclic heterocyclic group substituted with a functional group. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form an additional heteroatom optionally selected from N and O and optionally via 1-5 R atoms. 2 A 5- to 6-membered monocyclic heterocyclic group substituted with a functional group. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form a structure that optionally contains one nitrogen atom and optionally is fused with 1-5 R atoms. 2 A 5- to 6-membered monocyclic heterocyclic group substituted with a functional group. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form a group that optionally contains one oxygen atom and optionally passes through 1-5 R atoms. 2 A 5- to 6-membered monocyclic heterocyclic group substituted with a functional group. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form a structure that does not contain any other heteroatoms and is optionally subjected to 1-5 R... 2 A 5- to 6-membered monocyclic heterocyclic group substituted with a radical. In some embodiments, the 5- to 6-membered monocyclic heterocyclic group is optionally substituted with 1-3 R radicals. 2 Group substitution. In some embodiments, the 5- to 6-membered monocyclic heterocyclic group is optionally substituted with one or two R groups. 2 Group substitution. In some embodiments, the 5- to 6-membered monocyclic heterocyclic group is optionally substituted with one R group. 2 Group substitution. In some embodiments, the 5- to 6-membered monocyclic heterocyclic group is unsubstituted. In some embodiments, the 5- to 6-membered monocyclic heterocyclic group is a 5-membered heterocyclic group. In some embodiments, the 5-membered heterocyclic group is pyrrolidinyl or oxazolyl. In some embodiments, the 5- to 6-membered monocyclic heterocyclic group is a 6-membered heterocyclic group. In some embodiments, the 6-membered heterocyclic group is morpholinyl, piperazineyl, or piperidinyl.

[0155] In some implementation schemes, R a and R b Together with the nitrogen atoms to which they are attached, they form additional heteroatoms optionally containing 1-2 selected from N and O and optionally via 1-5 R... 2A 5- to 10-membered bicyclic heterocyclic group substituted with a functional group. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form additional heteroatoms optionally containing 1-2 selected from N and O and optionally via 1-5 R... 2 A 5- to 8-membered bicyclic heterocyclic group substituted with a functional group. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form additional heteroatoms optionally containing 1-2 selected from N and O and optionally via 1-5 R... 2 An 8-membered fused or bridged bicyclic heterocyclic group with substituent groups. In some embodiments, the bicyclic heterocyclic group is substituted with 1-3 R groups. 2 Group substitution. In some embodiments, the bicyclic heterocyclic group is substituted with one or two R groups. 2 Group substitution. In some embodiments, the bicyclic heterocyclic group is subjected to one R... 2 Group substitution. In some embodiments, the bicyclic heterocyclic group is unsubstituted.

[0156] In some implementation schemes, R a and R b Together with the nitrogen atoms to which they are attached, they form additional heteroatoms optionally containing 1-2 selected from N and O and optionally via 1-5 R... 2 An 8-membered fused bicyclic heterocyclic group substituted with a functional group. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form additional heteroatoms optionally containing 1-2 selected from N and O and optionally via 1-5 R... 2 An 8-membered bridging bicyclic heterocyclic group with substituent groups. In some embodiments, the bicyclic heterocyclic group contains one oxygen atom. In some embodiments, the bicyclic heterocyclic group contains one additional nitrogen atom. In some embodiments, the bicyclic heterocyclic group contains two additional nitrogen atoms. In some embodiments, the bicyclic heterocyclic group contains one additional nitrogen atom and one oxygen atom. In some embodiments, the bicyclic heterocyclic group is partially unsaturated. In some embodiments, the bicyclic heterocyclic group is fully saturated. In some embodiments, the bicyclic heterocyclic group is a saturated heterocycle fused to a partially unsaturated ring. In some embodiments, the bicyclic heterocyclic group is a saturated heterocycle fused to an aromatic ring. In some embodiments, the bicyclic heterocyclic group is a saturated heterocycle fused to a heteroaryl ring.

[0157] In some implementations, each R 2Independently, it is -NH2, a halogroup, a C1-C6 alkyl group, a C1-C6 haloalkyl group, -CN, or a 5- to 6-membered heteroaryl group, wherein the heteroaryl group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 groups selected from C1-C6 alkyl, halogroup, and C1-C6 haloalkyl groups. In some embodiments, each R 2 Independently, it is -NH2, halogroup, C1-C3 alkyl, C1-C3 haloalkyl, -CN, or 5-membered heteroaryl, wherein the heteroaryl contains 1-2 nitrogen atoms and is optionally substituted by 1-3 groups selected from C1-C3 alkyl, halogroup, and C1-C3 haloalkyl. In some embodiments, each R 2 The pyrazolyl group is independently -NH2, F, Cl, -CH3 or -CF3, -CN, or optionally substituted with 1-2 groups selected from -CH3 and Cl.

[0158] In some implementation schemes, R 2 It is -NH2.

[0159] In some implementation schemes, R 2 It is a halogenated group. In some implementations, R 2 It is Cl, F, or Br. In some implementations, R 2 For Cl. In some implementations, R 2 For F. In some implementations, R 2 It is Br.

[0160] In some implementation schemes, R 2 It is a C1-C6 alkyl group. In some embodiments, R 2 It is a C1-C3 alkyl group. In some embodiments, R 2 It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 It is methyl. In some embodiments, R 2 It is ethyl. In some embodiments, R 2 It is n-propyl. In some embodiments, R 2 It is isopropyl.

[0161] In some implementation schemes, R 2 It is a C1-C6 haloalkyl group. In some embodiments, R 2 It is a C1-C6 haloalkyl group containing 1-13 halogen atoms. In some embodiments, R 2 It is a C1-C3 haloalkyl group. In some embodiments, R 2 It is a C1-C3 haloalkyl group containing 1-7 halogen atoms. In some embodiments, R 2It can be -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 2 For -CF3. In some implementations, R 2 It is -CHF2.

[0162] In some implementation schemes, R 2 For -CN.

[0163] In some implementation schemes, R 2 It is a 5- to 6-membered heteroaryl group containing 1-2 nitrogen atoms and optionally substituted with 1-5 groups selected from C1-C6 alkyl, haloyl, and C1-C6 haloalkyl groups. In some embodiments, R 2 It is a 5- to 6-membered heteroaryl group containing one nitrogen atom and optionally substituted with 1 to 5 groups selected from C1-C6 alkyl, haloyl, and C1-C6 haloalkyl groups. In some embodiments, R 2 It is a 5- to 6-membered heteroaryl group containing 2 nitrogen atoms and optionally substituted with 1 to 5 groups selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl groups.

[0164] In some implementation schemes, R 2 It is a 5-membered heteroaryl group containing 1-2 nitrogen atoms and optionally substituted with 1-5 groups selected from C1-C6 alkyl, haloyl, and C1-C6 haloalkyl groups. In some embodiments, R 2 It is a 6-membered heteroaryl group containing 1-2 nitrogen atoms and optionally substituted with 1-5 groups selected from C1-C6 alkyl, halogen, and C1-C6 haloalkyl groups. In any of these variations, the heteroaryl group is optionally substituted with 1-5 groups selected from C1-C3 alkyl (such as methyl, ethyl, or propyl), halogen (such as F or Cl), and C1-C3 haloalkyl (such as -CF3 or -CHF2). In some embodiments, the heteroaryl group is pyrroleyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, the heteroaryl group is pyrazolyl.

[0165] In some implementation schemes, for:

[0166] or .

[0167] In some implementations, 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 It is an H or C1-C3 alkyl group. In some embodiments, L 1 It can be -C(O)N(H)-, -C(O)-, -CH2N(H)-, -CH2N(CH3)-, -CH2CH2N(CH3)-, -CH2- or -CH2CH2-.

[0168] In some implementations, L 1 It is -C(O)N(H)-.

[0169] In some implementations, L 1 It is -C(O)-.

[0170] In some implementations, L 1 -(C1-C6 alkylene)N(R) 3 In some implementations, L 1 -(C1-C3 alkylene)N(R) 3 In some implementations, L 1 -CH2N(R) 3 In some implementations, L 1 -CH2CH2N(R) 3 In some implementations, L 1 -CH2CH2CH2N(R) 3 In any of these variants, R 3 It is H or C1-C6 alkyl. In some embodiments, R 3 For H. In some implementations, R 3 It is a C1-C6 alkyl group. In some embodiments, R 3 It is a C1-C3 alkyl group. In some embodiments, R 3 It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is n-propyl. In some embodiments, R 3 It is isopropyl. In some embodiments, L 1 It is -(C1-C6 alkylene)N(H)-. In some embodiments, L 1 It is -(C1-C6 alkylene)N(1-C6 alkyl)-. In some embodiments, L 1It can be -CH2N(H)-, -CH2CH2N(H)-, or -CH2CH2CH2N(H)-. In some embodiments, L 1 It is -CH2N(H)-. In some implementations, L 1 It is -CH2CH2N(H)-. In some implementations, L 1 It can be -CH2N(CH3)-, -CH2CH2N(CH3)-, or -CH2CH2CH2N(CH3)-. In some embodiments, L 1 It is -CH2N(CH3)-. In some implementations, L 1 It is -CH2CH2N(CH3)-.

[0171] In some implementations, L 1 It is a C1-C6 alkylene group. In some embodiments, L 1 It is a C1-C3 alkylene group. In some embodiments, L 1 It is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some implementations, L 1 For -CH2-. In some implementations, L 1 It is -CH2CH2-.

[0172] In some implementations, L 2 For bond, -C(O)-, -N(R) 3 )- or O.

[0173] In some implementations, L 2 As a key. In some implementations, L 2 For -C(O)-. In some implementations, L 2 It is O.

[0174] In some implementations, L 2 -N(R) 3 In some variants, R 3 It is H or C1-C6 alkyl. In some embodiments, R 3 For H. In some implementations, R 3 It is a C1-C6 alkyl group. In some embodiments, R 3 It is a C1-C3 alkyl group. In some embodiments, R 3 It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is n-propyl. In some embodiments, R 3 It is isopropyl. In some embodiments, L2 For -N(H)-. In some implementations, L 2 It is -N(CH3)-. In some implementations, L 2 It is -N(CH2CH3)-.

[0175] In some embodiments, ring A is a monocyclic 4- to 6-membered heterocyclic sub-heterocyclic group or a bicyclic 6- to 9-membered spirocyclic sub-heterocyclic group, wherein the heterocyclic sub-heterocyclic group contains 1-2 nitrogen atoms, and wherein the heterocyclic sub-heterocyclic group is subjected to an R... 4 Group substitution. In some embodiments, ring A contains 1-2 nitrogen atoms and is modified by m R groups. 4 A monocyclic 4- to 6-membered heterocyclic group with substituent groups. In some embodiments, ring A is a ring containing 1-2 nitrogen atoms and substituted with m R groups. 4 6- to 9-membered spiroheterocyclic groups substituted with functional groups.

[0176] In some embodiments, ring A contains 1-2 nitrogen atoms and is connected by m R atoms. 4 A 4- to 6-membered heterocyclic subcyclic group with substituent groups. In some embodiments, ring A is a ring containing 1-2 nitrogen atoms and substituted with m R groups. 4 A monocyclic 4-membered heterocyclic group with substituent groups. In some embodiments, ring A is a group containing 1-2 nitrogen atoms and undergoing m R... 4 A monocyclic 5-membered heterocyclic group with substituent groups. In some embodiments, ring A is a group containing 1-2 nitrogen atoms and substituted with m R groups. 4 A monocyclic 6-membered heterocyclic group with substituted radicals. In some embodiments, the monocyclic heterocyclic group contains one nitrogen atom. In some embodiments, the monocyclic heterocyclic group contains two nitrogen atoms. In some embodiments, the monocyclic heterocyclic group is a zazonium butyl, pyrrolidine, or piperazine group.

[0177] In some implementations, ring A is , where Y 1 and Y 2 Independently CH or N, provided that Y 1 and Y 2 At least one of them is N. In some implementations, Y 1 For CH and Y 2 For N. In some implementations, Y 2 For CH and Y 1 For N. In some implementations, Y 1 and Y 2 Each is N.

[0178] In some implementations, ring A is .

[0179] In some embodiments, ring A contains 1-2 nitrogen atoms and optionally is circulated through m R atoms. 4 A bicyclic 6-membered spiroheterocyclic group with substituent radicals. In some embodiments, ring A is a group containing 1-2 nitrogen atoms and optionally substituted with m R groups. 4 A bicyclic 7-membered spiroheterocyclic group with substituent groups. In some embodiments, ring A is a group containing 1-2 nitrogen atoms and optionally substituted with m R groups. 4 A bicyclic 8-membered spiroheterocyclic group with substituent groups. In some embodiments, ring A is a group containing 1-2 nitrogen atoms and optionally substituted with m R groups. 4 A group-substituted bicyclic 9-membered spiroheterocyclic group. In some embodiments, the bicyclic spiroheterocyclic group contains one nitrogen atom. In some embodiments, the bicyclic spiroheterocyclic group contains two nitrogen atoms.

[0180] In some implementations, ring A is It should be understood that any one or two ring systems of a spiro-heterocyclic group can be subjected to a total of m R... 4 Group substitution.

[0181] In some implementations, each R 4 Independently, it is a halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R... 4 Independently, it is a halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, each R... 4 Independently, it can be F, Cl, -CH3, or -CF3. In some implementations, each R... 4 It can be either F or -CH3.

[0182] In some implementation schemes, R 4 It is a halogenated group. In some implementations, R 4 It is Cl, F, or Br. In some implementations, R 4 For Cl. In some implementations, R 4 For F. In some implementations, R 4 It is Br.

[0183] In some implementation schemes, R 4 It is a C1-C6 alkyl group. In some embodiments, R 4 It is a C1-C3 alkyl group. In some embodiments, R 4 It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 4 It is methyl. In some embodiments, R 4 It is ethyl. In some embodiments, R 4 It is n-propyl. In some embodiments, R 4 It is isopropyl.

[0184] In some implementation schemes, R 4 It is a C1-C6 haloalkyl group. In some embodiments, R 4 It is a C1-C6 haloalkyl group containing 1-13 halogen atoms. In some embodiments, R 4 It is a C1-C3 haloalkyl group. In some embodiments, R 4 It is a C1-C3 haloalkyl group containing 1-7 halogen atoms. In some embodiments, R 4 It can be -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 4 For -CF3. In some implementations, R 4 It is -CHF2.

[0185] In some implementations, m is 0-5. In some implementations, m is 0. In some implementations, m is 1 or 2. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is 5.

[0186] In some implementations, ring A is:

[0187] or .

[0188] In some implementation schemes, R 5 It is H or C1-C6 alkyl. In some embodiments, R 5 It is an H or C1-C3 alkyl group. In some embodiments, R 5 It is H or -CH3. In some implementations, R 5 It is -CH3.

[0189] In some implementation schemes, R 5 For H.

[0190] In some implementation schemes, R 5 It is a C1-C6 alkyl group. In some embodiments, R 5 It is a C1-C3 alkyl group. In some embodiments, R 5 It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5 It is methyl. In some embodiments, R 5 It is ethyl. In some embodiments, R 5 It is n-propyl. In some embodiments, R5 It is isopropyl.

[0191] In some implementations, Z is CH or N. In some implementations, Z is CH. In some implementations, Z is N.

[0192] In some implementation schemes, for:

[0193] or .

[0194] In some implementation schemes, for:

[0195]

[0196] or .

[0197] In some implementation schemes, for:

[0198] or .

[0199] In some embodiments, the compound of formula (I) is a compound of formula (IA):

[0200]

[0201] (IA)

[0202] in:

[0203] R a H or C1-C6 alkyl; R b It is a C1-C6 alkyl, a 5- to 6-membered heteroaryl, a -(C1-C6 alkylene)(5- to 6-membered heteroaryl), or a -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is determined by 1-5 R... 2 Group substitution; and R 1 R 5 Z, L 1 L 2 Ring A and * are as described in equation (I).

[0204] In some embodiments, the compound of formula (I) is a compound of formula (IB):

[0205]

[0206] (IB)

[0207] in It is a 5- to 10-membered monocyclic or bicyclic heterocyclic group containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-5 R... 2 Group substitution; and R 1 R 5 Z, L 1 L 2 Ring A and * are as described in equation (I).

[0208] In some embodiments, the compound of formula (I) is a compound of formula (IIa) or (IIb):

[0209]

[0210] (IIa)

[0211]

[0212] (IIb)

[0213] Where R a R b R 1 R 4 R 5 m, Z, L 1 L 2 Y 1 and Y 2 As described in equation (I).

[0214] In some embodiments, the compound of formula (I) is a compound of formula (IIIa) or (IVa):

[0215]

[0216] (IIIa)

[0217]

[0218] (IVa)

[0219] Where R a R b R 1 R 4 R 5 m, Z, L 1 and L 2 As described in equation (I).

[0220] In some embodiments, the compound of formula (I) is of formula (Va), (Vb), (Vc), or (Vd): Compound:

[0221]

[0222] (Va)

[0223]

[0224] (Vb)

[0225]

[0226] (Vc)

[0227]

[0228] (Vd)

[0229] Among them, rings A and R a R b R 1 R 3 R 5 Z, L 2 And * as described in equation (I); where n is an integer from 1 to 6.

[0230] In some embodiments, the compound of formula (I) is a compound of formula (VIa), (VIb), (VIc), or (VId):

[0231]

[0232] (VIa)

[0233]

[0234] (VIb)

[0235]

[0236] (VIc)

[0237]

[0238] (VId)

[0239] Among them, rings A and R a R b R 1 R 3 R 5 Z, L 1 And as described in equation (I).

[0240] In some embodiments, the compound of formula (I) is of formula (VIa), (VIb), (VIc), or (VId):

[0241]

[0242] (VIIa)

[0243]

[0244] (VIIb)

[0245]

[0246] (VIIc)

[0247] Where R a R b R 1 R 4 R 5 Z, L 1 L 2 And as described in equation (I).

[0248] In the description herein, it should be understood that each description, variation, implementation, or aspect of a part may be combined with each description, variation, implementation, or aspect of other parts, as if each combination of each and every description were specifically and separately listed. For example, each description, variation, implementation, or aspect of ring A of formula (I) provided herein may be combined with R 1 R a R b R 2 L 1 L 2 R 3 R 4 m, R 5 Each description, variation, implementation, or aspect of Z is described as if each and each combination were specifically and separately listed. It should also be understood that, where applicable, all descriptions, variations, implementations, or aspects of equation (I) are equally applicable to the other equations detailed herein, and are similarly described as if each and each description, variation, implementation, or aspect of all equations were separate and separately listed. For example, where applicable, all descriptions, variations, implementations, or aspects of equation (I) are equally applicable to the other equations detailed herein, such as equations (IA), (IB), (IIa), (IIb), (IIIa), (IVa), (Va), (Vb), (Vc), (Vd), (VIa), (VIb), (VIc), (VId), (VIIa), (VIIb), and (VIIc) are similarly described as if each and each description, variation, implementation, or aspect of all equations were separate and separately listed.

[0249] In some embodiments, compounds selected from Table 1 or their pharmaceutically acceptable salts are provided. Although some compounds described in this disclosure and included in Table 1 are presented as specific stereoisomers and / or in non-stereochemical forms, it should be understood that any or all stereochemical forms of any compound of this disclosure and included in Table 1 are described herein, including any enantiomeric or diastereomeric forms, as well as any tautomers or other forms.

[0250] Table 1.

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266] Or its pharmaceutically acceptable salt.

[0267] It should be understood that the combination of substituents and / or variables in the formulas described in this specification is only permitted if such combination produces a stable compound.

[0268] Furthermore, all compounds of formula (I) existing in the form of free bases or acids can be converted into their pharmaceutically acceptable salts by treatment with suitable inorganic or organic bases or inorganic or organic acids using methods known to those skilled in the art. Salts of compounds of formula (I) can be converted into their free base or free acid forms using standard techniques.

[0269] Synthesis method

[0270] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or the methods provided herein. By way of example, and not limitation, compounds of formula (I) can be prepared as outlined in Schemes 1-5 and as described in the examples listed herein. It should be noted that those skilled in the art will know how to modify the illustrative schemes and methods listed in the examples to obtain the desired product.

[0271] Compound A can be prepared as outlined in Scheme 1. Under basic conditions (such as in the presence of DIPEA), the coupling of intermediate a-1 with intermediate a-2 forms 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, which is then deprotected under basic conditions to produce intermediate a-7, which is then coupled with intermediate a-8 (e.g., using HATU) to produce intermediate a-9. Deprotection of a-9 under acidic conditions yields compound A.

[0272] Option 1.

[0273]

[0274] Where X is a halogen group such as chlorine; Pg is a protecting group such as Boc; R is an alkyl group such as methyl or ethyl; R 1 As described in equation (I); and Expression (I) corresponds to The part.

[0275] Compound B can be prepared as outlined in Scheme 2. Under basic conditions (such as in the presence of DIPEA), the coupling of intermediate a-1 with intermediate b-1 forms intermediate b-2, which is then deprotected under basic conditions to form intermediate b-3. Subsequently, intermediate b-3 is coupled with intermediate b-5 (which can be prepared by reducing intermediate b-4, for example, using NaBH4) using TCFH / NMI to obtain intermediate b-6. The subsequent oxidation of intermediate b-6, followed by reductive amination with a-8 (e.g., using IBX and NaBH(OAc)3), yields compound B.

[0276] Option 2.

[0277]

[0278] Where X is a halogen group such as chlorine; each R is independently an alkyl group such as methyl or ethyl; R 1 R a and R b As described in equation (I); and Expression (I) corresponds to The part.

[0279] Compound C can be prepared as outlined in Scheme 3. Reduction of intermediate c-1 (e.g., using NaBH4) yields intermediate c-2, which is then converted to intermediate c-3. Cyanidation of c-3 yields intermediate c-4, which is then reduced (e.g., using DIBAL-H) ​​to produce intermediate c-5. C-5 is then reduced (e.g., using NaBH4) to yield intermediate c-6, which is then hydrogenated under catalytic conditions to produce intermediate c-7. Intermediate c-7 is subsequently coupled with intermediate c-8 using TCFH / NMI to yield intermediate c-9. Further oxidation of intermediate c-9, followed by reductive amination with intermediate a-8 (e.g., using IBX and NaBH(OAc)3), yields compound C.

[0280] Option 3.

[0281]

[0282] Where Lg is a leaving group such as methanesulfonate; R is an alkyl group such as methyl or ethyl; R 1 R a and R b As described in equation (I); and Expression (I) corresponds to The part.

[0283] Compound D can be prepared as outlined in Scheme 4. Intermediate b-6 can be prepared as described above with respect to the synthesis of compounds of formula B and Scheme 2. Subsequently, intermediate b-6 is oxidized, followed by reductive amination with intermediate d-1 using, for example, IBX and NaBH(OAc)3 to obtain compound D.

[0284] Option 4.

[0285]

[0286] Where X is a halogen group such as chlorine; R is an alkyl group such as methyl or ethyl; and R 1 R a R b R 3 and R 5 As described in equation (I).

[0287] Compound E can be prepared as outlined in Scheme 5. In the first series of reactions, intermediate e-1 is converted to intermediate e-2, which is then coupled with intermediate e-3 to form intermediate e-4. e-4 is reduced to intermediate e-5 (e.g., using Zn under acidic conditions), and then coupled with intermediate a-4 using TCFH / NMI to obtain intermediate e-6, which is then hydrogenated to produce intermediate e-7. In the second series of reactions, intermediate a-8 is coupled with intermediate e-8 under reducing conditions (e.g., using NaBH(OAc)3) to produce intermediate e-9, which is then deprotected under acidic conditions to produce intermediate e-10. Subsequently, e-10 is coupled with e-7 under reducing conditions (e.g., using NaBH(OAc)3) to obtain intermediate e-11, which is then deprotected under acidic conditions to obtain compound E.

[0288] Option 5.

[0289]

[0290] Each Pg is independently a protecting group such as Cbz or Boc; each R is independently an alkyl group such as methyl or ethyl; R 1 As described in equation (I); and Expression (I) corresponds to The part.

[0291] How to use

[0292] Embodiments of this disclosure provide a method for modulating IRAK4 in a subject in need, the method comprising 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 a wide variety of methods known in the art. Kits and commercially available assays can be used to determine whether IRAK4 is modulated and to what extent (e.g., inhibition or activation).

[0293] In one aspect, this document provides a method for modulating IRAK4, the method comprising contacting IRAK4 with an effective amount of a compound of formula (I) or any embodiment thereof or a variant thereof. In some embodiments, the compound of formula (I) inhibits IRAK4. In other embodiments, 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.

[0294] In some embodiments, this document provides a method for targeting IRAK4 for degradation, the method comprising contacting IRAK4 with an effective amount of a compound of formula (I) or any embodiment thereof or a variant thereof.

[0295] In some embodiments, the compound of formula (I) adjusts the activity of IRAK4 to 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) adjusts the activity of IRAK4 to about 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%, or 80-100%. 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%.

[0296] In some embodiments of this disclosure, a method for degrading IRAK4 in a subject of need is also provided, the method comprising administering an effective amount of the compound of formula (I) to the subject. The degradation of IRAK4 can be evaluated and demonstrated by a wide variety of methods known in the art. Kits and commercially available assays (including cell-based assays) can be used to determine whether IRAK4 has been degraded and to what extent.

[0297] In one aspect, this document provides a method for degrading IRAK4, the method comprising contacting IRAK4 with an effective amount of a compound of formula (I) or any embodiment thereof. In some embodiments, the compound of formula (I) partially degrades IRAK4. In some embodiments, the compound of formula (I) completely degrades IRAK4.

[0298] 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) degrades IRAK4 by about 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%, or 80-100%. 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%.

[0299] In another aspect, this document provides a method for treating an inflammatory disease or autoimmune disease in a subject of need, the method comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, this document provides a method for treating an inflammatory disease in a subject of need, the method comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, this document provides a method for treating an autoimmune disease in a subject of need, the method comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, this document provides a method for preventing an inflammatory disease or autoimmune disease in a subject of need, the method comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, this document provides a method for preventing an inflammatory disease in a subject of need, the method comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, this document provides a method for preventing an autoimmune disease in a subject of need, the method comprising administering an effective amount of a compound of formula (I) to the subject. Non-limiting examples of inflammatory or autoimmune diseases include atopic dermatitis, asthma, lupus erythematosus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cold inflammatory cyclic syndrome, hidradenitis suppurativa, Bechet's syndrome, or familial cold autoinflammatory syndrome.

[0300] In some embodiments, compound (I) is administered to a subject susceptible to an inflammatory disease or autoimmune disease to prevent the subject from developing any symptoms of the inflammatory disease or autoimmune disease. In some embodiments, compound (I) is administered to a subject who has not yet exhibited symptoms of an inflammatory disease or autoimmune disease to prevent the subject from developing any symptoms of the inflammatory disease or autoimmune disease. In some embodiments, compound (I) is administered to a subject in need to reduce the severity of the inflammatory disease or autoimmune disease. In some embodiments, compound (I) is administered to a subject in need to stabilize the inflammatory disease or autoimmune disease (preventing or delaying the worsening of the inflammatory disease or autoimmune disease). In some embodiments, compound (I) is administered to a subject in need to delay the onset or recurrence of the inflammatory disease or autoimmune disease. In some embodiments, compound (I) is administered to a subject in need to slow the progression of the inflammatory disease or autoimmune disease. In some embodiments, compound (I) is administered to a subject in need to provide partial relief of the inflammatory disease or autoimmune disease. In some embodiments, compound (I) is administered to a subject in need to provide complete relief of the inflammatory disease or autoimmune disease. In some embodiments, administering compound (I) to a subject in need reduces the dose of one or more other drugs required for treating the inflammatory disease or autoimmune disease. In some embodiments, administering compound (I) to a subject in need enhances the effect of another drug used to treat the inflammatory disease or autoimmune disease. In some embodiments, administering compound (I) to a subject in need delays the progression of the inflammatory disease or autoimmune disease. In some embodiments, administering compound (I) to a subject in need improves the quality of life of the subject suffering from the inflammatory disease or autoimmune disease. In some embodiments, administering compound (I) to a subject in need prolongs the survival of the subject suffering from the inflammatory disease or autoimmune disease.

[0301] In one aspect, this document provides a method for preventing a subject susceptible to an inflammatory disease or autoimmune disease from developing any symptoms of said inflammatory disease or autoimmune disease, the method comprising administering a compound of formula (I) to the subject. In some embodiments, this document provides a method for preventing a subject who has not yet exhibited symptoms of an inflammatory disease or autoimmune disease from developing any symptoms of said inflammatory disease or autoimmune disease, the method comprising administering a compound of formula (I) to the subject.

[0302] In some aspects, this document provides methods for reducing the severity of an inflammatory disease or autoimmune disease in a subject, the methods comprising administering a compound of formula (I) to the subject. In some embodiments, this document provides methods for stabilizing an inflammatory disease or autoimmune disease in a subject, the methods comprising administering a compound of formula (I) to the subject. In some embodiments, the methods prevent the inflammatory disease or autoimmune disease from worsening. In some embodiments, the methods delay the worsening of the inflammatory disease or autoimmune disease.

[0303] In another aspect, this article provides a method for delaying the onset or recurrence of an inflammatory disease or autoimmune disease in a subject, the method comprising administering a compound of formula (I) to the subject.

[0304] In some embodiments, this document provides a method for slowing the progression of an inflammatory disease or autoimmune disease in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the method provides partial remission of the inflammatory disease or autoimmune disease. In some embodiments, the method provides complete remission of the inflammatory disease or autoimmune disease.

[0305] In other aspects, this document provides a method for reducing the dosage of one or more other drugs needed 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, this document provides a method for enhancing the effect of another drug used to treat an inflammatory or autoimmune disease in a subject, the method comprising administering a compound of formula (I) to the subject.

[0306] This article also provides methods for delaying the progression of an inflammatory disease or autoimmune disease in a subject, the methods comprising administering a compound of formula (I) to the subject. In some embodiments, the methods improve the quality of life of subjects suffering from inflammatory diseases or autoimmune diseases. In some embodiments, the methods prolong survival of subjects suffering from inflammatory diseases or autoimmune diseases.

[0307] In another aspect, this document provides a method for treating inflammatory or autoimmune symptoms caused by a disease in a subject in need, the method comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, this document provides a method for preventing inflammatory or autoimmune symptoms caused by a disease in a subject in need, the method comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, administering a compound of formula (I) to a subject susceptible to a disease causing inflammatory or autoimmune symptoms prevents the subject from developing any inflammatory or autoimmune symptoms. In some embodiments, administering a compound of formula (I) to a subject who has not yet exhibited inflammatory or autoimmune symptoms caused by a disease prevents the subject from developing any inflammatory or autoimmune symptoms. In some embodiments, administering a compound of formula (I) to a subject in need reduces the severity of inflammatory or autoimmune symptoms caused by the subject's disease. In some embodiments, administering compound (I) to a subject in need reduces inflammatory or autoimmune symptoms of the disease caused by the subject's stable condition (prevents or delays the worsening of said inflammatory or autoimmune symptoms). In some embodiments, administering compound (I) to a subject in need delays the onset or recurrence of inflammatory or autoimmune symptoms caused by the disease. In some embodiments, administering compound (I) to a subject in need slows the progression of inflammatory or autoimmune symptoms caused by the disease. In some embodiments, administering compound (I) to a subject in need provides partial relief of the disease causing inflammatory or autoimmune symptoms. In some embodiments, administering compound (I) to a subject in need provides complete relief of the disease causing inflammatory or autoimmune symptoms. In some embodiments, administering compound (I) to a subject in need reduces the dosage of one or more other drugs required to achieve complete relief of the disease causing inflammatory or autoimmune symptoms. In some embodiments, administering compound (I) to a subject in need enhances the effect of another drug used to treat the inflammatory or autoimmune symptoms of the disease. In some embodiments, administering compound (I) to a subject in need delays the progression of a disease causing inflammatory or autoimmune symptoms. In some embodiments, administering compound (I) to a subject in need improves the quality of life of the subject suffering from a disease causing inflammatory or autoimmune symptoms. In some embodiments, administering compound (I) to a subject in need prolongs the survival of the subject suffering from a disease causing inflammatory or autoimmune symptoms.In some implementations, the disease is atopic dermatitis, asthma, lupus erythematosus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoinflammatory syndrome, hidradenitis suppurativa, Behçet's syndrome, or familial cold autoinflammatory syndrome.

[0308] In some implementations, the compound of formula (I) is used to treat conditions selected from atopic dermatitis, asthma, lupus erythematosus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoinflammatory syndrome, hidradenitis suppurativa, Behçet's syndrome, or familial cold autoinflammatory syndrome.

[0309] Pharmaceutical Compositions and Routes of Administration

[0310] The compounds described herein can be administered to subjects orally, topically, or parenterally in conventional forms such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0311] The compounds disclosed herein can be formulated in conventional forms, such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions, for oral, topical, or parenteral administration to a subject. Suitable formulations can be prepared using conventional methods, employing conventional organic or inorganic additives, such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylene pyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), and disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or calcium citrate). Lubricants (e.g., magnesium stearate, light anhydrous silicate, talc, or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspensions (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 at a level that will exert the desired effect; for example, a unit dose of about 0.005 mg / kg of subject body weight to about 10 mg / kg of subject body weight for both oral and parenteral administration.

[0312] The dosage of compound (I) administered to subjects varies considerably and can be determined by a healthcare professional. Generally, the compounds disclosed herein can be administered 1 to 4 times daily at doses of approximately 0.001 mg / kg of subject body weight to approximately 10 mg / kg of subject body weight, but these doses may be appropriately varied based on the subject's age, weight, medical condition, and type of administration. In any given case, the amount of compound (I) administered will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0313] For convenience, the compound of formula (I) can be administered orally. In one embodiment, when administered orally, the compound of formula (I) is taken with food and water. In another embodiment, the compound of formula (I) is dispersed in water or fruit juice (e.g., apple juice or orange juice) or any other liquid and is administered orally as a solution or suspension.

[0314] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, via mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is determined by the healthcare practitioner and may depend in part on the location of the medical condition.

[0315] In one embodiment, this document provides a capsule containing a compound of formula (I) without any additional carrier, excipient or mediator.

[0316] In another embodiment, the composition provided herein comprises an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or mediator, wherein the pharmaceutically acceptable carrier or mediator may include excipients, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0317] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, and suspensions. The composition may be formulated to contain a daily dose or a convenient portion of a daily dose in a dosage unit, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt such as hydrochloride. Typically, all compositions are prepared according to methods known in medicinal chemistry. Capsules may be prepared by mixing a compound of formula (I) with a suitable carrier or diluent and filling an appropriate amount of the mixture into a capsule. Common carriers and diluents include, but are not limited to, inert powdered substances such as many different kinds of starch, powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol, and sucrose), cereal powders, and similar edible powders.

[0318] Tablets can be prepared by direct compression, wet granulation, or dry granulation. Their formulation typically incorporates diluents, binders, lubricants, disintegrants, and compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives may also be used. Typical tablet binders are substances such as starch, gelatin, and sugars (such as lactose, fructose, glucose, etc.). Natural and synthetic gums are also suitable, including gum arabic, alginate, methylcellulose, polyvinylpyrrolidone, etc. Polyethylene glycol, ethylcellulose, and waxes can also be used as binders.

[0319] Lubricants may be necessary in tablet formulations to prevent tablets and punches from sticking to the die. Lubricants can be selected from smooth solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell upon contact with moisture, causing the tablet to break and release a compound. These include starch, clay, cellulose, alginate, and gums. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, lignocellulose, powdered natural sponges, cation exchange resins, alginate, guar gum, citrus pomace, and carboxymethyl cellulose, as well as sodium lauryl sulfate, can be used. Tablets can be sugar-coated as a flavoring and sealing agent, or coated with film-forming protectants to modify the tablet's dissolution characteristics. Compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0320] When compounds of formula (I) need to be administered as suppositories, typical bases can be used. Cocoa butter is a traditional suppository base, which can be modified by adding wax to slightly increase its melting point. Water-miscible suppository bases (specifically including polyethylene glycol of various molecular weights) are widely used.

[0321] The effects of compounds of formula (I) can be delayed or prolonged through appropriate formulation. For example, slow-dissolving microspheres of compounds of formula (I) can be prepared and incorporated into tablets or capsules, or used as sustained-release implantable devices. The technique also includes preparing several pellets with different dissolution rates and filling capsules with a mixture of these pellets. Tablets or capsules can be film-coated to resist dissolution over a predictable period. Parenteral formulations can even be made long-acting by dissolving or suspending compounds of formula (I) in an oily or emulsified medium that allows for slow dispersion in serum.

[0322] Exemplary implementation plan

[0323] This disclosure is further described through the following implementation scheme.

[0324] Implementation scheme P1. Compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0325]

[0326] (I)

[0327] in:

[0328] R 1 It is a C1-C6 haloalkyl group;

[0329] R a It is H or C1-C6 alkyl;

[0330] R b It is a C1-C6 alkyl, a 5- to 6-membered heteroaryl, a -(C1-C6 alkylene)(5- to 6-membered heteroaryl), or a -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is determined by 1-5 R... 2 Group substitution;

[0331] or R a and R b The dashed lines between them represent a ring structure, where R a and R b Together with the nitrogen atoms to which they are attached, they form 5- to 10-membered monocyclic or bicyclic heterocyclic groups, optionally containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-5 R... 2 Group substitution;

[0332] Each R 2 Independently, it is -NH2, halogroup, C1-C6 alkyl, C1-C6 haloalkyl, -CN or 5 to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 2 nitrogen atoms and is optionally substituted by 1 to 5 groups selected from C1-C6 alkyl, halogroup and C1-C6 haloalkyl;

[0333] L 1 -C(O)N(H)-, -C(O)-, -(C1-C6 alkylene)N(R) 3 )- or C1-C6 alkylene;

[0334] L 2 For bond, -C(O)-, -N(R) 3 - or O;

[0335] Each R 3 Independently H or C1-C6 alkyl;

[0336] Ring A is a monocyclic 4- to 6-membered subheterocyclic group or a bicyclic 6- to 9-membered spirosubheterocyclic group, wherein the heterocyclic group contains 1-2 nitrogen atoms, and wherein the subheterocyclic group is subjected to m R... 4 Group substitution;

[0337] Each R 4It is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl;

[0338] m is 0-5;

[0339] R 5 It is H or C1-C6 alkyl;

[0340] Z is CH or N; and

[0341] * indicates that it contains L 2 The connection points of the parts.

[0342] Implementation Scheme P2. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P1, wherein:

[0343] R 1 It is a C1-C3 haloalkyl group.

[0344] Implementation Scheme P3. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P2, wherein:

[0345] R 1 It can be either -CHF2 or -CF3.

[0346] Implementation Scheme P4. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P3, wherein:

[0347] R 1 It is -CHF2.

[0348] Implementation Scheme P5. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P4, wherein:

[0349] R a It is H or C1-C3 alkyl;

[0350] R b It is a C1-C3 alkyl, a 6-membered heteroaryl, a -(C1-C3 alkylene)(6-membered heteroaryl), or a -(C1-C3 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is denoted by 1-2 R... 2 Group substitution; and

[0351] Each R 2 It can be -NH2, halogen, C1-C3 alkyl, C1-C3 haloalkyl or -CN independently.

[0352] Implementation Scheme P6. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P5, wherein: R a It is H or -CH3;

[0353] R bIt is -CH3, -CH2 (pyridyl), -CH2CH2NH2 or pyridyl, wherein the pyridyl group is optionally fused with one R 2 Group substitution; and

[0354] R 2 It is -CH3.

[0355] Implementation Scheme P7. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P6, wherein:

[0356] for or .

[0357] Implementation Scheme P8. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P4, wherein:

[0358] R a and R b Together with the nitrogen atoms to which they are attached, they form 5- to 8-membered monocyclic or bicyclic heterocyclic groups, optionally containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-3 R... 2 Group substitution; and

[0359] Each R 2 Independently, it is -NH2, halogen, C1-C3 alkyl, C1-C3 haloalkyl, -CN, or 5-membered heteroaryl, wherein the heteroaryl contains 1-2 nitrogen atoms and is optionally substituted by 1-3 groups selected from C1-C3 alkyl, halogen, and C1-C3 haloalkyl.

[0360] Implementation Scheme P9. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P8, wherein:

[0361] R a and R b Together with the nitrogen atoms to which they are attached, they form 5- to 6-membered monocyclic heterocyclic groups or 8-membered fused or bridged bicyclic heterocyclic groups, wherein the heterocyclic group optionally contains 1-2 additional heteroatoms selected from N and O, and optionally via 1-3 R... 2 Group substitution; and

[0362] Each R 2 Independently, it is a -NH2, F, Cl, -CH3 or -CF3, -CN or pyrazolyl group optionally substituted with 1-2 groups selected from -CH3 and Cl.

[0363] Implementation Scheme P10. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P9, wherein:

[0364] for

[0365] or .

[0366] Implementation Scheme P11. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P10, wherein:

[0367] L 1 -C(O)N(H)-, -C(O)-, -(C1-C3 alkylene)N(R) 3 )- or C1-C3 alkylene; and

[0368] R 3 It is H or C1-C3 alkyl.

[0369] Implementation Scheme P12. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P11, wherein:

[0370] L 1 It can be -C(O)N(H)-, -C(O)-, -CH2N(H)-, -CH2N(CH3)-, -CH2CH2N(CH3)-, -CH2- or -CH2CH2-.

[0371] Implementation Scheme P13. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P12, wherein:

[0372] L 2 For bond, -C(O)-, -N(R) 3 )- or O; and

[0373] R 3 It is H or C1-C3 alkyl.

[0374] Implementation Scheme P14. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P13, wherein:

[0375] L 2 It is a bond, -C(O)-, -N(H)-, -N(CH3)- or O.

[0376] Implementation Scheme P15. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P14, wherein: ring A is a ring containing 1-2 nitrogen atoms and having m R atoms 4 Four- to six-membered heterocyclic groups substituted with functional groups.

[0377] Implementation Scheme P16. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P15, wherein:

[0378] Ring A is ; and Y 1 and Y 2 Independently CH or N, provided that Y 1 and Y 2 At least one of them is N.

[0379] Implementation Scheme P17. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P16, wherein:

[0380] Y 1 For CH; and

[0381] Y 2 Let N be the number of elements in the array.

[0382] Implementation Scheme P18. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P16, wherein:

[0383] Y 1 For N; and

[0384] Y 2 For CH.

[0385] Implementation Scheme P19. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P16, wherein:

[0386] Y 1 and Y 2 Each is N.

[0387] Implementation Scheme P20. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P15, wherein:

[0388] Ring A is .

[0389] Implementation Scheme P21. The compound or its pharmaceutically acceptable salt according to Implementation Scheme P15, wherein: ring A is containing 1-2 nitrogen atoms and is subjected to m R... 4 Substituent bicyclic 6- to 9-membered spiroheterocyclic groups.

[0390] Implementation Scheme P22. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P21, wherein: ring A is .

[0391] Implementation Scheme P23. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P22, wherein:

[0392] Each R 4 It is independently a halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0393] Implementation Scheme P24. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P23, wherein:

[0394] Each R 4 It can be F, Cl, -CH3 or -CF3 independently.

[0395] Implementation Scheme P25. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P24, wherein:

[0396] Each R 4 It can be either F or -CH3.

[0397] Implementation Scheme P26. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P22, wherein:

[0398] m is 0.

[0399] Implementation Scheme P27. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P25, wherein:

[0400] m is 1 or 2.

[0401] Implementation Scheme P28. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P27, wherein:

[0402] Ring A is

[0403] or .

[0404] Implementation Scheme P29. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P28, wherein:

[0405] R 5 It is H or C1-C3 alkyl.

[0406] Implementation Scheme P30. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P29, wherein:

[0407] R 5 It can be H or -CH3.

[0408] Implementation Scheme P31. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P30, wherein:

[0409] R 5 It is -CH3.

[0410] Implementation Scheme P32. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P31, wherein:

[0411] Z stands for CH.

[0412] Implementation Scheme P33. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P31, wherein:

[0413] Z is N.

[0414] Implementation Scheme P34. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P33, wherein:

[0415] for

[0416] or .

[0417] Implementation Scheme P35. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P34, wherein:

[0418] for

[0419]

[0420] or .

[0421] Implementation Scheme P36. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P35, wherein:

[0422] for

[0423] or .

[0424] Implementation Scheme P37. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P7 and P11-P36, wherein the compound is a compound of formula (IA):

[0425]

[0426] (IA)

[0427] in:

[0428] R a It is H or C1-C6 alkyl; and

[0429] R b It is a C1-C6 alkyl, a 5- to 6-membered heteroaryl, a -(C1-C6 alkylene)(5- to 6-membered heteroaryl), or a -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is determined by 1-5 R... 2 Group substitution.

[0430] Implementation Scheme P38. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1-4 and 8-36, wherein the compound is a compound of formula (IB):

[0431]

[0432] (IB)

[0433] in:

[0434] A 5- to 10-membered monocyclic or bicyclic heterocyclic group optionally containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-5 R... 2 Group substitution.

[0435] Implementation Scheme P39. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P19 and P23-P37, wherein the compound is a compound of formula (IIa) or (IIb):

[0436]

[0437] (IIa)

[0438]

[0439] (IIb).

[0440] Implementation Scheme P40. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P15, P20, P21 and P23-P38, wherein the compound is a compound of formula (IIIa) or (IVa):

[0441]

[0442] (IIIa)

[0443]

[0444] (IVa).

[0445] Implementation Scheme P41. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from the compounds in Table 1.

[0446] Implementation Scheme P42. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P41, and a pharmaceutically acceptable excipient.

[0447] Implementation Scheme P43. A method for modulating interleukin-1 (IL1) receptor-associated kinase 4 (IRAK4), the method comprising contacting IRAK4 with an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P41, or a pharmaceutical composition according to Implementation Scheme P42.

[0448] Implementation Scheme P44. A method for treating an inflammatory or autoimmune disease in a subject of need, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P41 or a pharmaceutical composition according to Implementation Scheme P42.

[0449] Implementation Plan P45. The method described in Implementation Plan P44, wherein the inflammatory disease or autoimmune disease is atopic dermatitis, asthma, lupus erythematosus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoinflammatory syndrome, hidradenitis suppurativa, Behçet's syndrome, or familial cold autoinflammatory syndrome.

[0450] Example

[0451] The following examples are intended to illustrate and not limit. Compounds were named using the automatic name generation tool provided by ChemBiodraw Ultra (Cambridgesoft), which generates systematic names of chemical structures, supporting the Cahn-Ingold-Prelog rule for stereochemistry. Those skilled in the art can modify the operations shown in the illustrative examples to obtain the desired products.

[0452] Salts of the compounds described herein can be prepared by standard methods, such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or by stirring the product with an acid solution (e.g., an aqueous HCl solution) after chromatographic purification.

[0453] As used in some of the chemical structures provided in the following examples, the absolute stereochemistry of the indicated atom is not yet determined, as indicated by "*" or "or1".

[0454] The following abbreviations may be relevant to this application.

[0455] abbreviation

[0456] AcOH: Acetic acid

[0457] Aq or aq.: Contains water

[0458] BCA determination: Dipyridinecarboxylic acid determination

[0459] BuOH: Butanol

[0460] CBM: Cereblon combination part

[0461] CV: Column volume

[0462] DCE: 1,2-Dichloroethane

[0463] DCM: Dichloromethane

[0464] DIPEA: N,N-Diisopropylethylamine

[0465] DMF: Dimethylformamide

[0466] DMSO: Dimethyl sulfoxide

[0467] eq: equivalent

[0468] ESI: Electrospray Ionization

[0469] Et3N: Triethylamine

[0470] EtOAc: Ethyl acetate

[0471] EtOH: Ethanol

[0472] FA: Formic acid

[0473] FBS: Fetal bovine serum

[0474] FC: Rapid Chromatography

[0475] h: hours

[0476] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0477] HPLC: High Performance Liquid Chromatography

[0478] IBX: 2-Iodobenzoic acid

[0479] LCMS: Liquid Chromatography-Mass Spectrometry

[0480] MeCN: Acetonitrile

[0481] MeOH: Methanol

[0482] min: minutes

[0483] MsCl: Methanesulfonyl chloride

[0484] MSD: Mass Spectrometry Selective Detector

[0485] MTBE: Methyl tert-butyl ether

[0486] NMI: 1-Methylimidazole

[0487] NMO: N-methylmorpholine N-oxide

[0488] Pd(dppf)Cl2: bis(diphenylphosphino)ferrocene)palladium(II) dichloride

[0489] prep: preparative

[0490] quant.: quantitative

[0491] RP: Inverse

[0492] rt or rt: room temperature

[0493] RT: Retention Time

[0494] tBuOH: tert-butanol

[0495] TCFH: Chloro-N,N,N',N'-Tetramethylformamidin hexafluorophosphate

[0496] TFA: Trifluoroacetic acid

[0497] THF: Tetrahydrofuran

[0498] TLC: Thin-layer chromatography

[0499] Synthesis Examples

[0500] LCMS method

[0501] LCMS Method 1

[0502] Column: Luna C18 (2) 50 X 3 mm, 3 μm. Temperature: 45 °C, Flow rate: 1.5 mL / min, Run time: 2.5 min. Mobile phase conditions: Initial 95% H2O 0.1% FA / 5% MeCN 0.1% FA, followed by a linear gradient to 95% MeCN 0.1% FA over 1.3 min, then held at 95% MeCN 0.1% FA for 1.2 min. MSD: ESI positive.

[0503] LCMS Method 2

[0504] Column: SunFire C18 75 x 4.6 mm, 3.5 μm. Temperature: 45 °C, Flow rate: 1.5 mL / min, Run time: 6 min. Mobile phase conditions: Initial 95% H₂O + 0.1% FA / 5% MeCN + 0.1% FA, followed by a 4-min linear gradient to 95% MeCN + 0.1% FA, then held at 95% MeCN + 0.1% FA for 2 min. MSD: Positive

[0505] LCMS Method 3

[0506] Column: Kinetex Polar C18 2.6 μm, 50 x 3.0 mm. Temperature: 45 °C, Flow rate: 1.2 mL / min, Run time: 3 min. Mobile phase conditions: Initial 95% H₂O + 0.1% FA / 5% CH₃CN + 0.1% FA, followed by a linear gradient to 95% MeCN for 1.5 min, then held at 95% MeCN for 1.5 min. MSD: positive.

[0507] LCMS Method 4

[0508] Column: Kinetex Polar C18 2.6 μm, 50 x 3.0 mm. Temperature: 40 °C, Flow rate: 1.2 mL / min, Run time: 6 min. Mobile phase conditions: Initial 95% H₂O + 0.1% FA / 5% CH₃CN + 0.1% FA, followed by a linear gradient to 95% MeCN for 3.5 min, then held at 95% MeCN for 2.5 min. MSD: positive.

[0509] LCMS Method 5

[0510] Column: C18 4.6 x 75mm, initial gradient at 95% H2O + 0.1% FA / 5% MeCN + 0.1% FA for 10 min, run for 1.5 min, equilibrium gradient from 0 to 8 min at 95% H2O to 0% and hold for 2 min.

[0511] LCMS Method 6

[0512] Column: Kinetex XB - C18, 75 x 3.0 mm, 2.6 μm; Temperature: rt; Flow rate: 1.0 mL / min; Run time: 5 min; 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: Initially 70% mobile phase A and 30% mobile phase B linear gradient to 100% mobile phase B, held for 4.0 min. MSD positive.

[0513] LCMS Method 7

[0514] Column: XBridge - C8, 50 x 4.6 mm, 3.5 μm; Temperature: rt; Flow rate: 1.5 mL / min; Run time: 6 min; Mobile phase conditions: Mobile phase A: 0.1% TFA / H2O, Mobile phase B: 0.1% TFA / acetonitrile; Gradient: Initially 95% mobile phase A and 5% mobile phase B linear gradient to 5% mobile phase A and 95% mobile phase B, held for 2.5 min. MSD positive.

[0515] Synthesis Examples

[0516] Referring to a specific intermediate compound by a number (such as 1 or 2) is specific to the embodiment describing that compound. Therefore, multiple embodiments may refer to the same intermediate compound number, such as 1 or 2, but the chemical structure of the compound will differ between the different embodiments.

[0517] Example I-1. Synthesis of general intermediate T-1

[0518]

[0519] Step 1. Preparation of methyl 4-methylsulfonylcyclohexanecarboxylate (2). A solution of methyl 4-hydroxycyclohexanecarboxylate 1 (5.0 g, 31.61 mmol, 1.0 equivalent) in CH2Cl2 (105 mL, 0.3 M) was cooled to 0 °C under nitrogen atmosphere. Methanesulfonyl chloride (2.69 mL, 34.77 mmol, 1.1 equivalent) was then added, followed by dropwise addition of triethylamine (5.28 mL, 37.93 mmol, 1.2 equivalent). After stirring at 0 °C for 2 h, TLC (CH2Cl2 / MeOH 5.5:0.5, KMnO4 staining) showed complete transformation. The reaction was quenched by adding water, and the phases were separated and the aqueous phase was extracted three times with CH2Cl2. The combined organic phases were washed twice with brine, dried over magnesium sulfate, filtered, and concentrated to give 2 (7.45 g, 99% yield) as a yellow oil.

[0520] 1 H NMR (400 MHz, CDCl3) δ ppm 1.67 - 1.84 (m, 4 H), 1.87 - 1.99 (m, 2H), 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).

[0521] Step 2. Preparation of methyl 4-[3-(difluoromethyl)-4-nitro-pyrazole-1-yl]cyclohexanecarboxylate (4). Under nitrogen atmosphere, in a flame-dried round-bottom flask, a solution of 2 (1.16 g, 4.91 mmol, 1.0 equivalent), 3 (0.80 g, 4.91 mmol, 1.0 equivalent), and DMF (12.3 mL, 0.4 M) was stirred at room temperature for 5 min, followed by the addition of Cs₂CO₃ (3.20 g, 9.81 mmol, 2.0 equivalent). The resulting mixture was stirred at 90 °C for 16 h. Incomplete conversion of 3 was observed by LCMS (Method 1), followed by the addition of a second batch of 2 (1.16 g, 4.91 mmol, 1.0 equivalent) and stirring resumed at 90 °C for 48 h. 90% conversion of 3 was observed by LCMS. The reaction was quenched by the addition of water. Ethyl acetate was added, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, followed by washing the combined organic phase once with water and once with brine, drying over magnesium sulfate, and concentrating. The residue was placed in MTBE and water, and the phases were separated. The organic phase was washed five times with water and once with brine, dried over magnesium sulfate, filtered, and concentrated to obtain orange oil. The residue was then purified by normal-phase rapid chromatography (80 g silica column, gradient: 10 CV 0 to 30 % MTBE / heptane). The fractions were combined and concentrated to obtain impurity 4 (883 mg). The residue was then purified by reversed-phase rapid chromatography (100 g C18 RediSep Rf Gold column, DMSO loading, gradient: 4 CV 5 % MeOH / 0.1 % HCOOH, followed by 15 CV 5% to 100 % MeOH / 0.1 % HCOOH). The fractions were combined and concentrated to give 4 (618 mg, 41% yield) as a white solid.

[0522] LCMS Method 1: Retention time: 1.745 min at 215 nm, 99.9% purity, [M+H] + = 304.2.

[0523] 1 H 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).

[0524] 19 F NMR (377 MHz, DMSO-d6) δ ppm -117.40 (s, 2 F).

[0525] Step 3. Preparation of methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexanecarboxylate (T-1). 4 (625 mg, 2.06 mmol, 1.0 equivalent) and ethyl acetate (20.6 mL, 0.1 M) were degassed at room temperature by bubbling with nitrogen for 15 min under nitrogen atmosphere. Pd / C (438 mg, 10% w / w, 0.41 mmol, 0.2 equivalent) was added and bubbling resumed for 15 min. The mixture was then bubbled with H2 for 15 min, followed by stirring with a needle just above the solvent surface at room temperature for 16 h. Complete conversion of 4 was observed by LCMS (Method 1). The mixture was filtered through diatomaceous earth, the filter cake was thoroughly washed with ethyl acetate, and the resulting solution was concentrated to give T-1 (563 mg, 99% yield) as a light orange solid.

[0526] LCMS Method 1: Retention time: 1.297 min at 215 nm, 99.9% purity, [M+H] + = 274.2.

[0527] 1 H NMR (400 MHz, CDCl3) δ ppm 1.53 - 1.80 (m, 5 H), 2.12 - 2.42 (m, 9H), 3.93 - 4.03 (m, 1 H), 6.54 - 6.84 (m, 1 H), 7.07 (s, 1 H).

[0528] 19 F NMR (377 MHz, CDCl3) δ ppm -112.22 (s, 2 F).

[0529] Synthetic general intermediates C-1, C-7 and C-8

[0530] Example I-2. Synthesis of universal intermediate C-1

[0531]

[0532] Step 1. Preparation of tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidin-1-carboxylate (3). 3-(6-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione hydrochloride (1) (250 mg, 0.848 mmol, 1.0 equivalence) and tert-butyl 4-oxopiperidin-1-carboxylate (2) (304 mg, 1.53 mmol, 1.8 equivalence) were suspended in a DCE (4.2 mL) under a nitrogen atmosphere, followed by the addition of acetic acid (146 µL, 2.54 mmol, 3.0 equivalence). Sodium triacetoxyborohydride (431 mg, 2.04 mmol, 2.4 equivalence) was added in a single addition, and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The volatiles were evaporated under reduced pressure, and the residue was dissolved in a minimal amount of DMSO and purified by reversed-phase rapid chromatography (MeOH / 0.1% HCOOH(aq), 5% (3 CV) → 100%, 50 g RediSep RfGold® C18, 20 CV, λ = 214-254 nm, product containing 75% MeOH) to obtain fractions that, after evaporation and lyophilization, were a brownish-brown solid, yielding 3 (313.3 mg, 0.710 mmol, 84% yield).

[0533] LCMS Method 1: At 215 nm, 99.9% purity, [M+H] + = 442.2.

[0534] 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, 3H), 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 = 8.7Hz, 1 H), 10.82 (s, 1 H).

[0535] Step 2. Preparation of 3-[1-methyl-6-(piperidin-1-onthiol-4-ylamino)indazole-3-yl]piperidin-2,6-dione chloride (C-1). 4.0 M HCl was added to 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (3) (313.3 mg, 0.710 mmol, 1.0 equivalent) in 1,4-dioxane (2.7 mL, 10.6 mmol, 15.0 equivalent) and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was then dried under high vacuum to remove all volatiles. Crude product C-1 (265 mg, 0.702 mmol, 99% yield) as a grayish-white solid was obtained and used for the next step without purification.

[0536] LCMS Method 1: At 215 nm, 99.9% purity, [M-HCl+H] + = 342.2.

[0537] 1 H 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, 1H), 8.77 (br d, J = 7.7 Hz, 1 H), 8.88 (br d, J = 9.7 Hz, 1 H), 10.84 (s, 1H).

[0538] The following compounds were synthesized via the same general route, with ketone 2 modified in step 1 (Table 2).

[0539] Table 2.

[0540]

[0541] Example I-3. Synthesis of universal intermediate C-2

[0542]

[0543] Step 1. Preparation of tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]amino]piperidin-1-carboxylate (3). 3-(7-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione hydrochloride (1) (500 mg, 1.70 mmol, 1.0 equivalent) and tert-butyl 4-oxopiperidin-1-carboxylate (2) (608 mg, 3.05 mmol, 1.8 equivalent) were suspended in a DCE (17 mL) under a nitrogen atmosphere, followed by the addition of acetic acid (291 µL, 5.09 mmol, 3.0 equivalent). Sodium triacetoxyborohydride (863 mg, 4.07 mmol, 2.4 equivalent) was added in a single addition, and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The volatiles were evaporated under reduced pressure, and the crude material was then dissolved in a minimal amount of DMSO and purified by reversed-phase rapid chromatography (MeCN / 0.1% HCOOH(aq), 5% (3 CV) → 60%, 100 g RediSep Rf Gold® C18, 20 CV, λ = 214-254 nm, product containing 55% MeCN) to obtain fractions that, after evaporation and lyophilization, were a brownish-brown solid, 3 (702 mg, 1.59 mmol, 95% yield).

[0544] LCMS Method 1: At 215 nm, 98.5% purity, [Mt-Bu+H] + = 386.4.

[0545] 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).

[0546] Step 2. Preparation of 3-[1-methyl-7-(4-piperidinylamino)indazole-3-yl]piperidine-2,6-dione hydrochloride (C-2). 4.0 M HCl was added to 1,4-dioxane (9.7 mL, 38.7 mmol, 15.0 equivalents) with tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]amino]piperidine-1-carboxylate 3 (1.16 g, 2.58 mmol, 1.0 equivalents) and the mixture was stirred for 2 hours. The volatiles were evaporated under reduced pressure to produce a crude product as a grayish-white solid. The crude material was dissolved in a minimal amount of DMSO and purified by reversed-phase rapid chromatography (MeCN / 0.02 M HCl(aq), 5% (3 CV) → 30%, 415 g RediSep Rf Gold® C18, 15 CV, λ = 214-254 nm, product containing 5-20% MeCN) to obtain fractions. After evaporation to dryness, the residue was co-evaporated with water (3 × 25 mL) to remove all residual HCl, and lyophilized as a brown solid, C-2 (937 mg, 2.48 mmol, 96% yield).

[0547] LCMS Method 1: At 215 nm, 99.9% purity, [M+H] + = 342.4.

[0548] 1H 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).

[0549] Example I-4. Synthesis of universal intermediate C-3

[0550]

[0551] Step 1. Preparation of N-[3-hydroxy-1-(2-hydroxyethyl)butyl]carbamate tert-butyl ester (2). Under nitrogen atmosphere, a solution of 1 (3.0 g, 16.37 mmol, 1.0 equivalent), t-BuOH (60.0 mL, 0.18 M), and THF (30.0 mL, 0.18 M) was stirred at room temperature for 5 min, followed by the addition of excess OsO4 (1.04 mL, 4.0 % w / w in H2O, 0.16 mmol, 0.01 equivalent) and NMO (2.30 g, 19.65 mmol, 1.2 equivalent). The resulting mixture was stirred at room temperature for 4 h. Complete conversion of 1 was observed by TLC (heptane / ethyl acetate 4:1, KMnO4 staining). The mixture was concentrated to remove t-BuOH and THF. The residue was then dissolved in ethyl acetate (200 mL) and washed with 10% aq. Na₂SO₃ solution (2 x 25 mL), saturated NaHCO₃ solution (25 mL), and saturated NaCl solution (25 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to give a white solid. The residue was then purified by normal-phase rapid chromatography (80 g silica gel column, gradient: 10 CV₀ to 10% methanol / dichloromethane, product eluted in 10% methanol). The fractions were combined and concentrated to give 2 (2.83 g, 78% yield) as a white solid.

[0552] 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).

[0553] Step 2. Preparation of N-[3-oxo-1-(2-oxoethyl)propyl] tert-butyl carbamate (3). A solution of 2 (2.83 g, 13.0 mmol, 1.0 equivalent), THF (40.0 mL, 0.21 M), and H2O (20.0 mL, 0.21 M) was stirred at room temperature for 5 min under nitrogen atmosphere, followed by the addition of NaIO4 (3.34 g, 15.6 mmol, 1.2 equivalent). The resulting mixture was stirred at room temperature for 2 h. Complete transformation of 2 was observed by TLC (CH2Cl2 / MeOH 95:5, KMnO4 staining). The mixture was concentrated to remove THF. Ethyl acetate (200 mL) and brine (100 mL) were added, followed by phase separation and extraction of the liquid phase three times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a white semi-solid. The residue was dissolved in dichloromethane (125 mL) and dried at room temperature in the presence of a large excess of magnesium sulfate. The solid was filtered, and the organic phase was then concentrated and dried under high vacuum to give 3 (2.56 g, 89% yield) as a grayish-white semi-solid. The product was used directly in the next step without further characterization.

[0554] Step 3. Preparation of N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]tert-butyl carbamate (5). Sodium triacetoxyborohydride (492.4 mg, 2.32 mmol, 1.2 equivalents) was added to a solution of N-[3-oxo-1-(2-oxoethyl)propyl]tert-butyl carbamate 3 (500 mg, 2.32 mmol, 1.2 equivalents) and 3-(6-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione 4 (500 mg, 1.94 mmol, 1 equivalent) in a DCE (16 mL). The reaction mixture was stirred in rt. After 16 h, LCMS showed 50% conversion. An additional 0.5 equivalent of sodium triacetoxyborohydride was added, and stirring was resumed for over 4 h. At this time point, LCMS showed 80% conversion. The reaction mixture was partitioned between DCM and H2O, followed by two more extractions with DCM. Finally, the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (150 g C18 RediSep Rf Gold column, DMSO loading, gradient: 5 CV 5% MeCN / 0.1% HCOOH, followed by 15 CV 5 to 100% MeCN / 0.1% HCOOH, followed by 3 CV 100% MeCN / 0.1% HCOOH). The pure fraction was evaporated to give 5 (330 mg, 38% yield) as a light orange solid.

[0555] LCMS Method 2: 98.7% purity at 215 nm, [M+H] + = 442.2.

[0556] 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, 2H), 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).

[0557] Step 4. Preparation of 3-[6-(4-amino-1-piperidinyl)-1-methyl-indazole-3-yl]piperidine-2,6-dione hydrochloride (C-3). A solution of tert-butyl N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]carbamate 5 (330 mg, 0.75 mmol, 1 equivalent) in DCM (5 mL) was added to a solution of 1,4-dioxane (2.8 mL, 11.21 mmol, 15 equivalents). After 16 h, LCMS showed complete conversion. The volatiles were evaporated under reduced pressure, and excess HCl was co-evaporated four times with DCM to give C-3 (320 mg, quantitative yield) as a grayish-white solid. The product was used for the next step without purification.

[0558] LCMS Method 2: At 215 nm, 98.9% purity, [M-HCl+H] + = 342.2.

[0559] 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, 1H), 8.32 (br s, 3 H), 10.88 (s, 1 H).

[0560] Example I-5. Synthesis of universal intermediate C-4

[0561]

[0562] Step 1. Preparation of N-[3-hydroxy-1-(2-hydroxyethyl)butyl]carbamate tert-butyl ester (2). Under nitrogen atmosphere, a solution of 1 (3.0 g, 16.37 mmol, 1.0 equivalent), t-BuOH (60.0 mL, 0.18 M), and THF (30.0 mL, 0.18 M) was stirred at room temperature for 5 min, followed by the excessive addition of OsO4 (1.04 mL, 4.0 % w / w in H2O, 0.16 mmol, 0.01 equivalent) and NMO (2.30 g, 19.65 mmol, 1.2 equivalent). The resulting mixture was stirred at room temperature for 4 h. Complete conversion of 1 was observed by TLC (heptane / ethyl acetate 4:1, KMnO4 staining). The mixture was concentrated to remove t-BuOH and THF. The residue was then 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 give a white solid. The residue was then purified by normal-phase rapid chromatography (80 g silica gel, gradient: 10 CV 0 to 10% methanol / dichloromethane, product eluted in 10% methanol). The fractions were combined and concentrated to give fraction 2 (2.83 g, 78% yield) as a white solid.

[0563] 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).

[0564] Step 2. Preparation of N-[3-oxo-1-(2-oxoethyl)propyl] tert-butyl carbamate (3). Under nitrogen atmosphere, a solution of 2 (2.83 g, 13.0 mmol, 1.0 equivalent), THF (40.0 mL, 0.21 M), and H2O (20.0 mL, 0.21 M) was stirred at room temperature for 5 min, followed by the addition of NaIO4 (3.34 g, 15.6 mmol, 1.2 equivalent). The resulting mixture was stirred at room temperature for 2 h. Complete conversion of 2 was observed by TLC (CH2Cl2 / MeOH 95:5, KMnO4 staining). The mixture was concentrated to remove THF. Ethyl acetate (200 mL) and brine (100 mL) were added, followed by phase separation and extraction of the aqueous phase three times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a white semi-solid. The residue was dissolved in dichloromethane (125 mL) and dried at room temperature for 16 h in the presence of a large excess of magnesium sulfate. The solid was filtered, and the organic phase was then concentrated and dried under high vacuum to give 3 (2.56 g, 89% yield) as a grayish-white semi-solid. The product was used directly in the next step without further purification.

[0565] Step 3. Preparation of N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]-4-piperidinyl]tert-butyl carbamate (5). Under nitrogen atmosphere, solutions of 3 (400 mg, 1.86 mmol, 1.2 equivalents), 4 (400 mg, 1.55 mmol, 1.0 equivalents), and 1,2-DCE (15.5 mL, 0.1 M) were stirred at room temperature for 5 minutes, followed by the addition of NaBH(OAc)3 (788 mg, 3.72 mmol, 2.4 equivalents), and the mixture was stirred at room temperature for 16 h. Incomplete conversion (approximately 70%) was observed by LCMS (Method 1). Then, the second phase 3 (100 mg, 0.47 mmol, 0.3 equivalents) and NaBH(OAc)3 (788 mg, 3.72 mmol, 2.4 equivalents) were added, and stirring was resumed for 2.5 h. Complete conversion of 4 was observed by LCMS (Method 1). The reaction was quenched by adding saturated NH4Cl aqueous solution, followed by extraction three times with dichloromethane. The combined organic phases were washed once with brine, dried over magnesium sulfate, filtered, and concentrated to give a pale yellow oil. The residue was purified by reversed-phase rapid chromatography (50 g C18 RediSep Rf Gold column, DMSO loading, gradient: 4 CV 5% MeCN / 0.1% HCOOH, followed by 15 CV 5% to 100% MeCN / 0.1% HCOOH, with the product eluting in 80% MeCN). The fractions were combined and concentrated to give 5 (572 mg, 83% yield) as a grayish-white solid.

[0566] LCMS Method 1: Retention time: 1.719 min at 215 nm, 99.9% purity, [M+H] + = 442.2.

[0567] 1H NMR (400 MHz, CDCl3) δ ppm 1.39 - 1.51 (m, 9 H), 1.53 - 1.71 (m, 3H), 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, 4 H),6.99 - 7.10 (m, 2 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.95 (s, 1 H), 9.75 (s, 1H).

[0568] Step 4. Preparation of [1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-7-yl]-4-piperidinyl]ammonium chloride (C-4). A solution of 5 (572 mg, 1.30 mmol, 1.0 equivalent) and 4.0 M HCl in 1,4-dioxane (6.5 mL, 20 equivalent) was stirred at room temperature for 2 h under nitrogen. Complete conversion of 5 was observed by LCMS (Method 1). The mixture was concentrated under reduced pressure and co-evaporated three times to give C-4 (525 mg, quantitative yield) as a grayish-white solid.

[0569] LCMS Method 1: Retention time: 1.149 min at 215 nm, 96.0% purity, [M+H] + = 342.4.

[0570] 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, 3H), 10.88 (s, 1H).

[0571] Example I-6. Synthesis of universal intermediate C-5

[0572]

[0573] Step 1. Preparation of (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2). Osmium tetroxide (0.94 mL, 0.15 mmol, 0.01 equivalent) was added to a solution of 2,5-dihydropyrrolidine-1-carboxylic acid tert-butyl ester 1 (2.5 g, 14.77 mmol, 1 equivalent) in tert-butanol (50 mL) and THF (25 mL) at room temperature, followed by the addition of NMO (2.08 g, 17.73 mmol, 1.2 equivalent). The reaction was stirred at rt for 18 h, and then concentrated to dryness. The residue was dissolved in EtOAc (200 mL) and washed with 10% Na2SO3 (2 x 20 mL), saturated NaHCO3 (20 mL), and brine (20 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The residue was then purified by normal-phase rapid chromatography (0 to 10% MeOH / CH2Cl2, 10CV, 120 g silica gel) to give 2 (3.04 g, quantified) as a yellow oil.

[0574] 1 H 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,2H).

[0575] Step 2. Preparation of N,N-bis(2-oxoethyl)carbamate tert-butyl ester (3). Sodium periodate (3.84 g, 17.93 mmol, 1.2 equivalent) was added to a solution of (3R,4S)-3,4-dihydroxypyrrolidine-1-carbamate tert-butyl ester 2 (3.04 g, 14.94 mmol, 1 equivalent) in THF (50 mL) and water (25 mL). The reaction was stirred at room temperature for 1 h. TLC (5% MeOH / CH2Cl2, vanillin staining) showed complete conversion. THF was removed under vacuum and brine (50 mL) was added. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic matter was dissolved in Na2SO4 and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and stirred overnight with MgSO4. The MgSO4 was then filtered off and the CH2Cl2 was concentrated in a vacuum to give the desired product 3 (2.7 g, 90% yield) as a pale yellow oil.

[0576] 1 H 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, 1H), 9.67 (s, 1H).

[0577] Step 3. Preparation of tert-butyl 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]piperazine-1-carboxylate (5). Sodium triacetoxyborohydride (517.73 mg, 2.44 mmol, 2.4 equivalents) was added to a solution of N,N-bis(2-oxoethyl)carboxylate 3 (245.77 mg, 1.22 mmol, 1.2 equivalents) and 3-(7-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione 4 (262.89 mg, 1.02 mmol, 1 equivalent) in a DCE (10.2 mL), and the mixture was stirred for 24 h. LCMS showed 40% 3-... Another portion of sodium triacetoxyborohydride (517.73 mg, 2.44 mmol, 2.4 equivalences) was added and stirring continued for 24 h; LCMS showed 46% β-carboxylic acid (β-carboxylic acid). After repeating the addition of sodium triacetoxyborohydride and stirring for 24 h twice more, LCMS showed 90% β-carboxylic acid (β-carboxylic acid). 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 material was dissolved in a minimal amount of DMSO and purified by reversed-phase rapid chromatography (MeCN / 0.1% HCOOH (aq), 5% to 100%, 100 g C18 gold column, 20 CV, product containing 65–70% MeCN). The evaporation fraction gave β-carboxylic acid (373 mg, 80% yield) as a white solid.

[0578] LCMS Method 1: At 215 nm, 89.0% purity, [M+H] + = 428.2

[0579] 1 H 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, 2H), 7.41 (d, J = 7.6 Hz, 1 H), 10.88 (s, 1 H).

[0580] Step 4. Preparation of 3-(1-methyl-7-piperazin-1-yl-indazole-3-yl)piperidine-2,6-dione (C-5). 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]piperazin-1-carboxylic acid tert-butyl ester 5 (373 mg, 0.87 mmol, 1 equivalent) was added to 1,4-dioxane (6.54 mL, 26.15 mmol, 30 equivalents) in 4 M HCl. The solution was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and water was added. The product was purified by reversed-phase rapid chromatography (MeCN / 0.1% HCOOH(aq), 5% to 40%, 100 g gold column C18, 20 CV) to give C-5 (270 mg, 95% yield) as a brown solid.

[0581] LCMS Method 1: At 215 nm, 99.9% purity, [M+H] + = 328.4.

[0582] 1 H 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).

[0583] Example I-7. Synthesis of universal intermediate C-6

[0584]

[0585] Step 1. Preparation of (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2). Osmium tetroxide (0.94 mL, 0.15 mmol, 0.01 equivalent) was added to a solution of 2,5-dihydropyrrolidine-1-carboxylic acid tert-butyl ester 1 (2.5 g, 14.77 mmol, 1 equivalent) in tert-butanol (50 mL) and THF (25 mL) at room temperature, followed by the addition of NMO (2.08 g, 17.73 mmol, 1.2 equivalent). The reaction was stirred at rt for 18 h, and then concentrated to dryness. The residue was dissolved in EtOAc (200 mL) and washed with 10% Na2SO3 (2 x 20 mL), saturated NaHCO3 (20 mL), and brine (20 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The residue was then purified by normal-phase rapid chromatography (0 to 10% MeOH / CH2Cl2, 10CV, 120 g silica gel) to give 2 (3.04 g, quantified) as a yellow oil.

[0586] 1 H 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,2H).

[0587] Step 2. Preparation of N,N-bis(2-oxoethyl)carbamate tert-butyl ester (3). Sodium periodate (3.84 g, 17.93 mmol, 1.2 equivalent) was added to a solution of (3R,4S)-3,4-dihydroxypyrrolidine-1-carbamate tert-butyl ester 2 (3.04 g, 14.94 mmol, 1 equivalent) in THF (50 mL) and water (25 mL). The reaction was stirred at room temperature for 1 h. TLC (5% MeOH / CH2Cl2, vanillin staining) showed complete conversion. THF was removed under vacuum and brine (50 mL) was added. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic matter was dried over Na2SO4 and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and stirred overnight with MgSO4. The MgSO4 was then filtered off and the CH2Cl2 was concentrated in a vacuum to give the desired product 3 (2.7 g, 90% yield) as a pale yellow oil.

[0588] 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, 1H), 9.67 (s, 1H).

[0589] Step 3. Preparation of tert-butyl 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]piperazine-1-carboxylate (5). Sodium triacetoxyborohydride (646.71 mg, 3.05 mmol, 2.4 equivalents) was added to a solution of N,N-bis(2-oxoethyl)carboxylate 3 (307.0 mg, 1.53 mmol, 1.2 equivalents) and 3-(6-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione 4 (328.38 mg, 1.27 mmol, 1 equivalent) in a DCE (12.7 mL), and the mixture was then stirred at room temperature for 24 h. LCMS showed 26% 5. Another batch of sodium triacetoxyborohydride (646.71 mg, 3.05 mmol, 2.4 equivalences) was added to the mixture and stirring was continued for 24 h. LCMS showed 60% 5. Another batch of sodium triacetoxyborohydride (646.71 mg, 3.05 mmol, 2.4 equivalences) was added to the mixture and stirring was continued for 24 h. LCMS 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 material was dissolved in a minimal amount of DMSO and purified by reversed-phase rapid chromatography (MeCN / 0.1% HCOOH, 5% to 100%, 100 g gold column, 20 CV, product containing 65-70% MeCN). The concentrated fraction gave 5 as a grayish-white solid (263 mg, 50% yield).

[0590] LCMS Method 1: At 215 nm, 99.9% purity, [M+H] + = 428.4.

[0591] 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, 1H), 6.92 (br d, J = 9.0 Hz, 1 H), 7.52 (d, J = 9.0 Hz, 1 H), 10.85 (s, 1 H).

[0592] Step 4. Preparation of 3-(1-methyl-6-piperazin-1-yl-indazole-3-yl)piperidine-2,6-dione hydrochloride (C-6). 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]piperazin-1-carboxylic acid tert-butyl ester 5 (260.0 mg, 0.61 mmol, 1 equivalent) was added to 1,4-dioxane (22.78 mL, 91.14 mmol, 150 equivalent) in 4 M HCl. The mixture was then sonicated for 30 min and subsequently stirred at room temperature for one hour. The solvent was concentrated to dryness, and the residue was purified by reversed-phase rapid chromatography (MeCN / 0.02 M HCl(aq), 5% to 30%, 100 g gold column C18, 15 CV, product containing 0–20% MeCN). The product-containing integral was evaporated to dryness, then co-evaporated with water (3 × 10 mL) to completely remove any trace HCl, and the residue was lyophilized to give C-6 (221 mg, 98%) as a pale yellow oil.

[0593] LCMS Method 1: At 215 nm, 99.9% purity, [M-HCl+H] + = 328.4.

[0594] 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 = 8.8Hz, 1 H), 9.37 (br s, 2 H), 10.85 (s, 1 H).

[0595] Example I-8. Synthesis of universal intermediate C-9

[0596]

[0597] Step 1. Preparation of tert-butyl piperazine-1-carboxylate (3). 2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-6-carbonyl)piperazine-1-carboxylate 2 (67.43 mg, 0.3600 mmol) and 1-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-carboxylic acid 1 (80 mg, 0.2800 mmol) were dissolved in DMF (1 mL) under a nitrogen atmosphere, followed by the sequential addition of DIPEA (485.09 µL, 2.78 mmol) and HATU (127.07 mg, 0.3300 mmol), and the reaction mixture was stirred overnight under a nitrogen atmosphere. After complete conversion was observed by LCMS, the reaction mixture was injected directly onto a column for purification by reversed-phase rapid chromatography (MeCN / 0.1% HCOOH(aq), 5% to 50%) to give product 3 (110 mg, 83% yield) as a white solid.

[0598] LCMS Method 1: At 215 nm, 96.3% purity, RT = 1.55, [M+H] + = 456.2, [Mt-Bu+H] + =400.2.

[0599] Step 2. Preparation of 3-(1-methyl-6-(piperazin-1-carbonyl)-1H-indazole-3-yl)piperidine-2,6-dione (C-9). 4.0 M HCl was added to 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-carbonyl]piperazin-1-carboxylic acid tert-butyl ester 3 (107 mg, 0.2300 mmol) in dioxane (2.83 mL, 11.31 mmol), and the mixture was sonicated for 30 min, followed by stirring for 1 h. The volatiles were evaporated to dryness to give product C-9 (90 mg, 99% yield) as a white solid.

[0600] LCMS Method 1: At 215 nm, 99.9% purity, RT = 0.70, [M+H] + = 356.2.

[0601] Synthetic general intermediates C-10, C-11, C-12, C-13, C-18, and C-19

[0602] Example I-9. Synthesis of universal intermediate C-13

[0603]

[0604] Step 1. Preparation of 6-bromo-3-iodo-1-methyl-indazole (2). 60% w / w sodium hydride in mineral oil (127.45 mg, 3.19 mmol, 1.5 equivalents) in DMF (15 mL, 0.14 M) was added to a flame-dried round-bottom flask. Then, 6-bromo-3-iodo-1H-indazole 1 (700 mg, 2.12 mmol, 1 equivalent) was added in a single addition, and the mixture was stirred at room temperature for 30 min. Iodomethane (264 µL, 4.25 mmol, 2 equivalents) was then added to the reaction mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere. LCMS showed complete conversion to compound 2 after 20 h. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The organic layers were combined and washed with water (2 x 50 mL), 1:1 water / saline (2 x 50 mL), and saline (50 mL), dried over MgSO4, and evaporated to dryness. The residue was then purified by normal-phase FC (80 g gold column, HPLC loading on silica gel, 15 CV 0 to 15% EtOAc / heptane, product eluted in approximately 7% EtOAc). The fractions were combined and concentrated to give 3 (537 mg, 75% yield) as a white solid.

[0605] LCMS Method 3: At 215 nm, 99.9% purity, [M+H] + = 336.9; 338.9.

[0606] 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).

[0607] Step 1'. Preparation of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (4). 2,6-dibenzyloxy-3-bromopyridine 3 (5.5 g, 14.86 mmol, 1 equivalent), B2Pin 2 (7.5 g, 29.53 mmol, 2 equivalents), and KOAc (4.37 g, 44.57 mmol, 3 equivalents) in 1,4-dioxane (90 mL, 0.17 M) were added to a sealed tube. The solution was bubbled with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl2 DCM (1.21 g, 1.49 mmol, 0.1 equivalents). Nitrogen was bubbled through the reaction mixture under sonication for 15 minutes. The tube was sealed and the reaction mixture was stirred. After an overnight period, LCMS showed excellent conversion to compound 4. The reaction mixture was cooled to room temperature, and EtOAc and water were added. The aqueous phase was extracted three times with EtOAc. The organic phases were combined, washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was then purified by normal-phase rapid chromatography (120 g silica column, LC loading on silica, gradient: 18 CV 0 to 30% EtOAc / heptane, product containing about 15% EtOAc). The fractions were combined and concentrated to give 4 as a white solid (452 ​​mg, 7% yield).

[0608] LCMS Method 4: At 215 nm, 96.1% purity, [M+H] + = 418.2.

[0609] 1H 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, 2H), 7.53 (d, J = 7.1 Hz, 2 H), 7.85 (d, J = 8.1 Hz, 1 H).

[0610] Step 2. Preparation of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (5). 6-bromo-3-iodo-1-methyl-indazole 2 (0.88 g, 2.61 mmol, 1 equivalent), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine 4 (1.09 g, 2.61 mmol, 1 equivalent) were added to a sealed tube in 1,4-dioxane (7.8 mL, 0.25 M) with Na2CO3 (0.66 g, 6.26 mmol, 2.4 equivalent) and water (2.6 mL, 0.25 M), followed by the addition of PdCl2(dppf)·CH2Cl2 (106 mg, 0.13 mmol, 0.05 equivalent). The solution was degassed with nitrogen for 15 min, the tube was sealed, and the reaction mixture was stirred at 90 °C. After an overnight period, LC-MS showed complete conversion to compound 5. After cooling to room temperature, water was added to the reaction mixture. The reaction mixture was extracted three times with EtOAc, the organic phases were combined, washed with water, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was then purified by normal-phase rapid chromatography (40 g silica column, HPLC loading on silica, gradient: 17 CV 0 to 20% EtOAc / heptane, the compound eluted in about 17% EtOAc). The fractions were combined and concentrated to give 5 as a white solid (810 mg, 58% yield).

[0611] LCMS Method 3: At 215 nm, 94.1% purity, [M+H] + = 500.1.

[0612] 1H NMR (400 MHz, DMSO-d6) δ ppm 4.05 (s, 3 H), 5.44 (d, J = 8.1 Hz, 4H), 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 = 8.1Hz, 1 H), 7.95 - 7.98 (m, 1 H).

[0613] Step 3. Preparation of (3S,4S)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]amino]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester indazole (7). In a sealed tube, 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 5 (300 mg, 0.60 mmol, 1 equivalent), (3S,4S)-4-amino-3-fluoro-piperidin-1-carboxylic acid tert-butyl ester 6 (196.29 mg, 0.90 mmol, 1.5 equivalent), XPhosPd G3 (50.74 mg, 0.06 mmol, 0.1 equivalent), and Cs2CO3 (390.68 mg, 1.2 mmol, 2 equivalent) were added to 1,4-dioxane (3.0 mL, 0.2 M). The solution was degassed with nitrogen for 15 min, the tube was sealed, and the reaction mixture was stirred at 100 °C. After an overnight period, LC-MS showed complete conversion to compound 7. After cooling to room temperature, the reaction mixture was filtered through a diatomaceous earth pad, washed with DCM, and the solution was evaporated and purified by normal-phase rapid chromatography (40 g silica gel, HPLC loading on silica gel, gradient: 20 CV 0 to 40% EtOAc / heptane, product eluted in about 20% EtOAc). The fractions were combined and concentrated to give 7 (294 mg, 77% yield) as a white solid.

[0614] LCMS Method 3: At 215 nm, the product is 99.9% pure and does not ionize.

[0615] 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, 3H), 4.36 - 4.55 (m, 1 H), 5.43 (d, J = 11.7 Hz, 4 H), 5.97 (d, J = 8.3 Hz, 1H), 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).

[0616] 19 F NMR (377 MHz, DMSO-d6) δ ppm -185.84 - -185.48 (m, 1 F).

[0617] Step 4. Preparation of (3S,4S)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester indazole (8). In a reactor connected to a pressure valve, Pd(OH)2 (64.74 mg, 0.09 mmol, 0.2 equivalents) was added to a degassed solution of (3S,4S)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester 7 (294 mg, 0.46 mmol, 1 equivalent) in THF (1.5 mL, 0.15 M) and ethanol (1.5 mL, 0.15 M). A purging cycle with N2 and H2 was performed. The mixture was stirred overnight at 60 °C and 70 psi. The reaction mixture was filtered through a diatomaceous earth filter, washed with EtOAc and EtOH, and concentrated under reduced pressure. The residue was directly loaded onto a reversed-phase FC column for purification (50 g RediSep Rf Gold C18 column, DMSO loading, 4 CV 5% MeCN / 0.1% HCOOH followed by 20 CV 5 to 95% MeCN / 0.1% HCOOH, with the product eluting in 65% MeCN). The purified fractions were combined and concentrated to give 8 (100 mg, 47% yield) as a blue solid.

[0618] LCMS Method 3: At 215 nm, 99.9% purity, [M+H] + = 460.2.

[0619] 1 H 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, 1H).

[0620] 19 F NMR (377 MHz, DMSO-d6) δ ppm -185.89 - -185.48 (m, 1 F).

[0621] Step 5. Preparation of 3-[1-methyl-6-[[(3S,4S)-3-fluoro-4-piperidinyl]amino]indazole-3-yl]piperidin-2,6-dione; dihydrochloride (C-13). 4 M HCl was added to (3S,4S)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-3-fluoro-piperidin-1-carboxylic acid tert-butyl ester 8 (95 mg, 0.21 mmol, 1 equivalent) in dioxane (0.4 mL, 1.65 mmol, 8.0 equivalent). The reaction mixture was stirred at rt for 2 h. 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 give C-13 (114 mg, 88% yield) as a white solid as the dihydrochloride. The product is used in the next step without further purification.

[0622] LCMS Method 3: At 215 nm, 68.8% purity, [M+H] + = 360.1.

[0623] The following compounds were synthesized via the same general route, with amine 6 modified in step 3 (Table 3).

[0624] Table 3.

[0625]

[0626]

[0627] Example I-10. Synthesis of universal intermediate C-14

[0628]

[0629] Step 1. 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)inazole (2). 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 1 – a synthetic intermediate from C-13 – was added to a sealed tube in 1,4-dioxane (1.44 mL, 0.4 M) in the form of B2Pin2 (219.92 mg, 0.87 mmol, 1.5 equivalent) and KOAc (283.31 mg, 2.89 mmol, 5 equivalent). The solution was bubbled with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl2 DCM (42.24 g, 0.06 mmol, 0.1 equivalence). Nitrogen was bubbled through the reaction mixture under sonication for 15 minutes. The tube was sealed and the reaction mixture was stirred at 80 °C. After an overnight period, LC-MS showed complete conversion to compound 2. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, washed with methanol, and evaporated. The crude material was then purified by normal-phase rapid chromatography (40 g silica column, solid-phase loading on silica, gradient: 20 CV 0 to 30% EtOAc / heptane, product eluted in approximately 10% EtOAc). The fractions were combined and concentrated to give compound 2 as a white solid (297 mg, 90% yield).

[0630] LCMS Method 3: At 215 nm, the product is 95.8% pure and does not ionize.

[0631] 1H 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).

[0632] Step 2. Preparation of 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-ol (3). 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indazole 2 (297 mg, 0.51 mmol, 1 equivalent) was added to a round-bottom flask in THF (2.6 mL, 0.13 M) and water (1.3 mL, 0.13 M). Sodium perborate tetrahydrate (117.19 mg, 0.76 mmol, 1.5 equivalent) was added to the solution, and the reaction mixture was stirred at rt. After 1 h, LCMS showed complete conversion to compound 3. The reaction mixture was cooled to room temperature, and EtOAc and water were added. The aqueous phase was extracted three times with EtOAc. The organic phases were combined, washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to give 3 (270 mg, quantitative yield) as a brown solid.

[0633] LCMS Method 3: At 215 nm, 85.6% purity, [M+H] + = 438.1.

[0634] 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.91 (s, 3 H), 5.43 (d, J = 9.0 Hz, 4H), 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).

[0635] Step 3. Preparation of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]oxypiperidine-1-carboxylate (5). 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-ol 3 (270 mg, 0.62 mmol, 1 equivalent) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 4 (206.88 mg, 0.74 mmol, 1.2 equivalent) in DMF (4 mL, 0.14 M) and toluene (0.4 mL, 0.14 M) were added to a sealed tube. DIPEA (0.21 mL, 1.23 mmol, 2 equivalents) and K₂CO₃ (178.85 mg, 1.3 mmol, 2.1 equivalents) were then added to the reaction mixture. The tube was sealed and the reaction mixture was stirred at 95 °C. After an overnight period, LCMS showed 56% conversion to compound 5. More tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 4 (68.96 mg, 0.25 mmol, 0.4 equivalents) was added, the tube was sealed, and the reaction mixture was stirred at 95 °C. After another overnight period, LCMS showed major conversion. After cooling to room temperature, EtOAc and water were added to the reaction mixture, which was then extracted three times with EtOAc. The organic phases were combined, washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was then purified by normal-phase rapid chromatography (40 g silica column, solid-phase loading on silica, gradient: 15 CV 0 to 40% EtOAc / heptane, product eluted in approximately 30% EtOAc). The fractions were combined and concentrated to give 5 (100 mg, 26% yield) as a yellow semi-solid.

[0636] LCMS Method 3: At 215 nm, the product is 98.3% pure and does not ionize.

[0637] 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, 4H), 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 = 8.8Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H).

[0638] Step 4. Preparation of tert-butyl 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]oxypiperidin-1-carboxylate (6). Pd(OH)₂ (22.62 mg, 0.03 mmol, 0.2 equivalents) was added to a degassed solution of 5-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]oxypiperidin-1-carboxylate (100 mg, 0.16 mmol, 1 equivalent) in THF (1 mL, 0.08 M) and ethanol (1 mL, 0.08 M) in a reactor connected to a pressure valve. A purging cycle with N₂ and H₂ was performed. The mixture was stirred overnight at 60 °C and 70 psi. The reaction mixture was filtered through a diatomaceous earth pad, washed with EtOAc and EtOH, and concentrated under reduced pressure. The residue was directly loaded onto a reversed-phase FC column for purification (50 g C18 RediSep Rf Gold column, DMSO loading, followed by 4 CV 5% MeCN / 0.1% HCOOH, then 20 CV 5% to 95% MeCN / 0.1% HCOOH, with the product eluting in 70% MeCN). The purified fractions were combined and concentrated to give 6 (30 mg, 38% yield) as a brown solid.

[0639] LCMS Method 3: At 215 nm, the product is 98.3% pure and does not ionize.

[0640] 1H 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).

[0641] Step 5. Synthesis of 3-[1-methyl-6-(4-piperidinyloxy)indazole-3-yl]piperidine-2,6-dione; hydrochloride (C-14). 4 MHCl was added to 6-(65 mg, 0.15 mmol, 1 equivalent) of 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]oxypiperidine-1-carboxylic acid tert-butyl ester (0.29 mL, 1.18 mmol, 8.0 equivalent) in dioxane. The reaction mixture was stirred at rt for 20 h. 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 give C-14 (53 mg, 87% yield) as a white solid as the dihydrochloride, which was used for the next step without further purification.

[0642] LCMS Method 3: At 215 nm, 71.0% purity, [M+H] + = 343.1.

[0643] 1H 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 H), 10.87 (s, 1 H).

[0644] Example I-11. Synthesis of universal intermediate C-15

[0645]

[0646] Step 1. Preparation of N-cyclopent-3-en-1-yl-N-methyl-carbamate tert-butyl ester (2). Iodimethane (764.38 µL, 12.28 mmol, 5.0 equivalent) was added to a suspension of N-cyclopent-3-en-1-ylcarbamate tert-butyl ester 1 (450 mg, 2.46 mmol, 1.0 equivalent) and NaH (491.13 mg, 12.28 mmol, 5.0 equivalent) in THF (16.3 mL, 0.15 M) at room temperature. The suspension was stirred at 60 °C. TLC (Hept. EtOAc 9:1) showed complete conversion after overnight incubation. The reaction was cooled and quenched by adding water. Ethyl acetate was added and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, followed by washing the combined organic phases once with water and once with brine, drying over magnesium sulfate, and concentrating. The residue was then purified by normal-phase rapid chromatography (40 g silica gel, gradient: 15 CV 0 to 10% EtOAc / heptane, product eluted in 7% EtOAc). The fractions were combined and concentrated to give N-cyclopent-3-en-1-yl-N-methyl-carbamate tert-butyl ester 2 (511 mg, 100% yield) as a colorless oil.

[0647] 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).

[0648] Step 2. Preparation of N-methyl-N-[racemic-(3R,4S)-3,4-dihydroxycyclopentane]tert-butyl carbamate (3). Osmium tetroxide (0.17 mL, 0.03 mmol, 0.01 equivalent) was added to a solution of N-cyclopent-3-en-1-yl-N-methyl-tert-butyl carbamate 2 (535 mg, 2.71 mmol, 1.0 equivalent) in tert-butanol (9.0 mL) and THF (4.5 mL, 0.2 M), followed by the addition of NMO (381.26 mg, 3.25 mmol, 1.2 equivalent). The reaction was stirred at rt and monitored by TLC. After 16 hours, TLC (10:90 MeOH / DCM, KMnO4) showed complete conversion to two new spots. The mixture was concentrated to dryness. The residue was dissolved in EtOAc and washed with 10% Na2SO3 (2x), saturated NaHCO3, and brine. The organic phase was dried over MgSO4 and concentrated under vacuum. The residue was then purified by normal-phase rapid chromatography (40 g silica column, DCM injection, elution: 15 CV 0 to 10% MeOH / DCM, product eluted in 9% MeOH). The fractions were selected by TLC (10:90 MeOH / DCM, vanillin staining). The collected fractions were concentrated to give N-methyl-N-[racemic-(3R,4S)-3,4-dihydroxycyclopentyl]carbamate tert-butyl 3 (523 mg, 83% yield) as a colorless oil.

[0649] 1 H 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).

[0650] Step 3. Preparation of N-methyl-N-[3-oxo-1-(2-oxoethyl)propyl] tert-butyl carbamate (4). Sodium periodate (0.58 g, 2.71 mmol, 1.2 equivalent) was added to a solution of N-methyl-N-[racemic-(3R,4S)-3,4-dihydroxycyclopentyl] tert-butyl carbamate 3 (523 mg, 2.26 mmol, 1.0 equivalent) in THF (10 mL) and water (5 mL, 0.15 M). The reaction was stirred at room temperature and monitored by TLC. After 2 hours, TLC (5% MeOH / DCM, vanillin staining) showed complete conversion. THF was removed under vacuum and NaCl solid / salt solution was added. The mixture was extracted with EtOAc (3x). The combined organic compounds were dried over MgSO4 and concentrated under vacuum to give N-methyl-N-[3-oxo-1-(2-oxoethyl)propyl]carbamate tert-butyl 4 (478 mg, 92% yield) as a white solid.

[0651] 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).

[0652] Step 4. Preparation of N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester (6). Sodium triacetoxyborohydride (837.0 mg, 3.95 mmol, 2.4 equivalents) was added to a solution of 3-(6-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione 4 (425.0 mg, 1.65 mmol, 1.0 equivalent) and N-methyl-N-[3-oxo-1-(2-oxoethyl)propyl]carbamate tert-butyl ester 5 (452.7 mg, 1.97 mmol, 1.2 equivalent) in DCE (8.5 mL, 0.2 M). The reaction was stirred at room temperature for 48 hours under a N2 atmosphere. The reaction was then quenched with saturated NH4Cl and extracted with DCM (3x). The combined organic compounds were dried over Na2SO4 and concentrated under vacuum. The residue was then purified by normal-phase rapid chromatography (40 g silica column, DCM loading, gradient: 15 CV 0 to 10% MeOH / DCM, product eluted in 5% MeOH). The collected fractions were concentrated to give N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl 6 (600 mg, 64.7% yield) as a yellow solid.

[0653] LCMS Method 3: Retention time: 1.860 min at 254 nm, 95% purity, [M+H] + = 456.3.

[0654] 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).

[0655] Step 5. Preparation of 3-[1-methyl-6-[4-(methylamino)-1-piperidinyl]indazole-3-yl]piperidin-2,6-dione hydrochloride (C-15). N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl 6 (600 mg, 1.25 mmol, 1.0 equivalent) was added to 4.0 M HCl in dioxane (6.26 mL, 25.02 mmol, 20 equivalent) and the mixture was sonicated for 1 minute, followed by stirring overnight at room temperature. The solvent was evaporated to dryness and the residue was co-evaporated using MeCN (2x) to give 3-[1-methyl-6-[4-(methylamino)-1-piperidinyl]indazol-3-yl]piperidin-2,6-dione as a light brown solid; hydrochloride C-15 (595 mg, 100% yield).

[0656] LCMS Method 3: Retention time: 1.339 min at 215 nm, 96% purity, [M+H] + = 356.3.

[0657] 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, 2H), 2.96 - 3.11 (m, 2 H), 3.18 - 3.26 (m, 1 H), 3.88 (br d, J = 12.7 Hz, 1H), 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).

[0658] Example I-12. Synthesis of universal intermediate C-16

[0659]

[0660] Step 1. Preparation of N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester (3). Sodium triacetoxyborohydride (318.03 mg, 1.5 mmol, 2.4 equivalences) was added to a solution of 3-(6-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione 2 (161.47 mg, 0.63 mmol, 1.0 equivalences) and N-methyl-N-[3-oxo-1-(2-oxoethyl)propyl]carbamate tert-butyl ester 1 – the synthetic intermediate 4- from C-15 (172 mg, 0.75 mmol, 1.2 equivalences) in DCE (3.13 mL, 0.2 M). The reaction was stirred at room temperature for 4 days under a N2 atmosphere. The reaction was then quenched with saturated NH4Cl and extracted with DCM (3x). The combined organic compounds were dried over Na2SO4 and concentrated under vacuum. The residue was then purified by normal-phase rapid chromatography (40 g silica column, DCM injection, gradient: 20 CV 0 to 10% MeOH / DCM, product eluted in 5% MeOH). The collected fractions were concentrated to give 3 (148 mg, 49% yield) as a yellow solid.

[0661] LCMS Method 3: At 215 nm, 93.7% purity, [M+H] + = 456.2.

[0662] 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (br s, 9 H), 1.62 - 1.75 (m, 2H), 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).

[0663] Step 2. Preparation of 3-[1-methyl-7-[4-(methylamino)-1-piperidinyl]indazole-3-yl]piperidin-2,6-dione hydrochloride (C-16). A solution of N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester 3 (148 mg, 0.32 mmol, 1.0 equivalent) in DCM (1.0 mL, 0.32 M) was added to 4.0 M HCl in dioxane (2.44 mL, 9.75 mmol, 20 equivalent) and the mixture was stirred overnight at room temperature. After 90 minutes, LCMS showed complete conversion to compound 4. The solvent was evaporated to dryness and the residue was co-evaporated using MeCN (2 x). The residue was dried under high vacuum to give C-16 as a white solid as hydrochloride (142 mg, quantitative yield).

[0664] LCMS Method 3: At 215 nm, 95.2% purity, [M-HCl+H] + = 356.2.

[0665] 1H 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, 2H), 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).

[0666] Example I-13. Synthesis of universal intermediate C-17

[0667]

[0668] Step 1. Preparation of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate (3). A solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 1 – the synthetic intermediate 5- from 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 added to a sealed tube. The solution was degassed with nitrogen for 15 min, the tube was sealed, and the reaction mixture was stirred at 100 °C. After 18 h, the reaction mixture was cooled to room temperature, filtered through a diatomaceous earth 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 rapid chromatography (EtOAc / heptane) to give tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid 3 (471 mg, 48% yield) as a white solid.

[0669] LCMS Method 1: At 215 nm, the product is 99.9% pure and does not ionize.

[0670] 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, 3H), 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).

[0671] Step 2. Preparation of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylate (4). 3-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate tert-butyl 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 h at 0 °C, 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 h, the volatiles were removed under reduced pressure. The residue was purified directly by reversed-phase C18 column chromatography (MeCN / 0.1% formic acid aqueous solution) to give 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylic acid tert-butyl 4 (345 mg, 38% yield) as a brown solid.

[0672] LCMS Method 1: At 215 nm, the product is 99.9% pure and does not ionize.

[0673] 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, 1H), 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).

[0674] Step 3. Preparation of tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidin-1-carboxylate (5). A solution of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidin-1-carboxylate 4 (507 mg, 0.80 mmol) in THF (2.7 mL) and ethanol (2.7 mL) was degassed for 15 min, followed by the addition of Pd(OH)2 (89 mg, 0.13 mmol) and bubbling resumed for 5 min. The reaction mixture was heated overnight at 60 °C under positive hydrogen pressure (approximately 60 psi). After 18 h, the reaction mixture was filtered through a diatomaceous earth pad. The filter cake was washed with EtOAc and EtOH, and the filtrate was concentrated under reduced pressure. The residue was purified directly by reversed-phase C18 column chromatography (MeCN / 0.1% formic acid aqueous solution) to give 5 tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidin-1-carboxylate (289 mg, 79% yield) as a light pink solid.

[0675] LCMS Method 1: At 215 nm, 96.2% purity, [M+H] + = 456.2.

[0676] 1H 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).

[0677] Step 4. Preparation of 3-[1-methyl-6-[methyl(4-piperidinyl)amino]indazole-3-yl]piperidine-2,6-dione (C-17). 5 tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylic acid (289.2 mg, 0.6300 mmol) was dissolved in 4 M HCl in dioxane (3.15 mL, 12.61 mmol). The reaction mixture was stirred at rt for 1 h. After completion, the volatiles were removed under reduced pressure, and the residue was co-evaporated with toluene (2×) and MTBE. The residue was dried under high vacuum to give 3-[1-methyl-6-[methyl(4-piperidinyl)amino]indazole-3-yl]piperidine-2,6-dione dihydrochloride C-17 (282 mg, quantified) as a white solid.

[0678] LCMS Method 1: At 215 nm, 98.0% purity, [M+H] + = 356.2.

[0679] 1H 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).

[0680] Example I-14. Synthesis of universal intermediate C-20

[0681]

[0682] Step 1. Preparation of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate (3). Acetic acid (1.1 mL, 19.29 mmol, 20 equivalents) was added to a mixture of 1-(6-amino-1-methyl-indazole-3-yl)hexahydropyrimidin-2,4-dione 1 (250 mg, 0.9600 mmol, 1.0 equivalent), 4-oxopiperidin-1-carboxylate 2 (192 mg, 0.9600 mmol, 1.0 equivalent) and NaBH(OAc)3 (306 mg, 1.45 mmol, 1.5 equivalent) in a DCE (10 mL). The mixture was stirred at 0 °C for 20 min and then stirred at room temperature for 3 days. The phases were separated, and the aqueous phase was then extracted with DCM (3 × 10 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude material was purified by reversed-phase rapid chromatography (MeOH / 0.1% HCOOH(aq), 20 CV 5%→60%). The evaporation fraction was given as a pink solid, 3 (105 mg, 0.225 mmol, quantitative yield).

[0683] LCMS Method 1: At 215 nm, 100% purity, [M+H]+ = 443.2.

[0684] 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, 1H), 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).

[0685] Step 2. Preparation of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylate (4). 3-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate tert-butyl 3 (105 mg, 0.24 mmol, 1.0 equivalent) was dissolved in DCM (5 mL), followed by the addition of 37% formaldehyde aqueous solution (0.02 mL, 0.28 mmol, 1.2 equivalent) at room temperature, followed by the addition of NaBH(OAc)3 (75 mg, 0.36 mmol, 1.5 equivalent). After 2 h, LCMS showed complete conversion. The volatiles were removed and the residue was purified by reversed-phase rapid chromatography (MeOH / 0.1% HCOOH(aq), 20 CV 5%→60%). The evaporation fraction was given as a pink semi-solid, 4 (118 mg, 0.2339 mmol, 90.5% yield).

[0686] LCMS Method 1: At 215 nm, 90.5% purity, [M+H]+ = 457.3.

[0687] 1H 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, 1H), 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).

[0688] Step 3. Preparation of [3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-1H-indazol-1-onthiol-6-yl]-methyl-piperidin-1-onthiol-4-yl-ammonium chloride (C-20). 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-methyl-amino]piperidin-1-carboxylic acid tert-butyl ester 4 (118 mg, 0.233 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (2.5 mL), followed by the addition of a 4.0 M HCl solution (1.16 mL, 4.65 mmol, 20 equivalent) in 1,4-dioxane, and the resulting solution was stirred at room temperature. After 4 h, LCMS showed complete conversion. The solvent was evaporated in a vacuum and then azeotropically distilled with MeCN to give C-20 as a light pink solid (112 mg, 0.21 mmol, 90% yield).

[0689] LCMS Method 1: At 215 nm, 87.1% purity, [M-3HCl+H] + = 357.2.

[0690] 1H 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).

[0691] Synthetic final product

[0692] Final Product General Method 1

[0693] Example S1. Synthesis of P-4

[0694]

[0695] Step 1. Preparation of ethyl 5-[(3R,5R)-3-(tert-Butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (3): DIPEA (1.54 mL, 8.86 mmol, 2.5 equivalents) and N-[(3R,5R)-5-fluoro-3-piperidinyl]carbamate tert-butyl ester (1.01 g, 4.61 mmol, 1.3 equivalents) were added to a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (800 mg, 3.55 mmol, 1.0 equivalent) in MeCN (17.7 mL). After stirring over the weekend at 60 °C, LCMS showed complete conversion to 3. The solvent was removed under reduced pressure and the residue was dried under high vacuum to give 3 (1.44 g, quantitative yield) as a white solid. The crude product is used in the next step without further purification.

[0696] LCMS Method 1: Retention time: 1.656 min at 215 nm, 99.9% purity, [M+H] + = 408.2.

[0697] 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).

[0698] 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.32 (s, 1 F).

[0699] Step 2. Preparation of 5-[(3R,5R)-3-(tert-Butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4). A solution of LiOH·H₂O (1.48 g, 35.34 mmol, 10.0 equivalent) in water (5.89 mL) was added to a solution of ethyl 5-[(3R,5R)-3-(tert-Butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 3 (1.44 mg, 3.53 mmol, 1.0 equivalent) in THF (5.89 mL) and methanol (5.89 mL). After stirring at 60 °C for 18 h, LCMS showed complete conversion to the desired product 4. The reaction mixture was concentrated under vacuum to remove THF / MeOH and the crude mixture was diluted with water. The mixture was acidified with a 6N HCl aqueous solution under vigorous stirring until pH = 3 (precipitation). The suspension was filtered through a Buchner funnel and the solid was washed with water. The solid was dried overnight in an oven under vacuum to give 4 (1.40 g, quantitative yield) as a white solid. The crude product was used for the next step without further purification.

[0700] LCMS Method 1: Retention time: 1.487 min at 215 nm, 99.9% purity, [M+H] += 380.1.

[0701] 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).

[0702] 19 F NMR (377 MHz, DMSO-d6) δ ppm – 184.32 (s, 1 F).

[0703] Step 3. Preparation of 5-methyl 4-[4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidin-3-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]cyclohexanecarboxylic acid (5). NMI (208 µL, 2.62 mmol, 1.0 equivalent) was added to a solution of methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexanecarboxylate T-1 (239 mg, 0.870 mmol, 1.0 equivalent) and 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (332 mg, 0.870 mmol, 1.0 equivalent) in MeCN (4.37 mL, 0.2 M), followed by the addition of TCFH (368 mg, 1.31 mmol, 1.5 equivalent). The resulting mixture was stirred at rt for 1 h. Nano-pure water was added to the reaction mixture. The suspension was sonicated and then 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.

[0704] LCMS Method 1: Purified at 215 nm with 99.9% purity, [M+H] += 635.2 m / z。

[0705] 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, 1H), 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)。

[0706] 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.13 (s, 1 F), -111.44 (s, 2 F)。

[0707] Step 4. Preparation of 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidin-3-carbonyl]amino]pyrazol-1-yl]cyclohexanecarboxylic acid (6). A solution of methyl cyclohexanecarboxylate 5 (466 mg, 0.730 mmol, 1.0 equivalent) in THF (2.45 mL, 0.15 M) in water (2.45 mL, 0.15 M) was added to a solution of methyl cyclohexanecarboxylate 5 (466 mg, 0.730 mmol, 1.0 equivalent) in THF (2.45 mL, 0.15 M). 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. At 0 °C, 6 M HCl aqueous solution was added with vigorous stirring until pH = 3. The solid was filtered through a Buchner funnel and washed with nanopure water to obtain pure 6 (362 mg, 79% yield).

[0708] LCMS Method 1: At 215 nm, 99.9% purity, [M+H] + = 621.3 m / z.

[0709] 1 H 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, 1H), 12.09 - 12.23 (m, 1 H).

[0710] 19F NMR (377 MHz, DMSO-d6) δ ppm -184.09 (s, 1 F), -111.31 - (s, 2 F).

[0711] Step 5. Preparation of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]carbamoyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (7). DIPEA (252 μL, 1.45 mmol) was added to a solution of 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidin-3-carbonyl]amino]pyrazol-1-yl]cyclohexanecarboxylic acid 6 (90 mg, 0.15 mmol) and 3-[6-(4-amino-1-piperidinyl)-1-methyl-indazole-3-yl]piperidin-2,6-dione hydrochloride C-3 (60.3 mg, 0.16 mmol) in DMF (1.2 mL). The mixture was stirred at 0 °C for 5 min, followed by the addition of HATU (55.1 mg, 0.15 mmol). The resulting mixture was stirred at room temperature for 30 min. The mixture was then directly loaded onto a 30 g RediSep RfGold C18 column. The fraction was eluted with MeCN / 0.1% formic acid aqueous solution (5% 5 CV, followed by elution with 15 CV from 5% to 35%). The desired fractions were combined and concentrated to give 7 (119 mg, 82% yield) as a white solid.

[0712] LCMS Method 1: At 254 nm, 7% purity, [M+H] + = 944.4, [M+2H] 2+ = 473.0.

[0713] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (br s, 9 H), 1.48 - 1.64 (m, 4H), 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, J = 9.2, 5.0 Hz, 2 H), 4.93 - 5.14 (m, 1 H), 6.81 - 7.24(m, 5 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 8.28 (s, 1H), 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)。

[0714] Step 6. Preparation of 5-((3R,5R)-3-amino-5-fluoropiperidin-1-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-4-yl)carbamoyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (P-4). In a round-bottom flask, N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]carbamoyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 7 (100 mg, 0.11 mmol) was dissolved in 4 M HCl solution in 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 column. Elution was performed using a MeCN / 0.02 M HCl aqueous solution (5% 3 CV, followed by 20 CV 5 to 20%, then 15 CV 20 to 30%). The desired fractions were combined and concentrated. The residue was dissolved in water, frozen, and lyophilized to give P-4 as a pale yellow solid (63.12 mg, 68% yield).

[0715] LCMS Method 2: At 215 nm, 98.4% purity, [M-HCl+H] + = 844.5, [M-HCl+2H] 2+ =422.7.

[0716] 11H 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).

[0717] 19 19F NMR (377 MHz, DMSO-d6) δ ppm -184.59 (s, 1 F), -111.26 (s, 2 F).

[0718] Example S2. Synthesis of P-9

[0719]

[0720] Step 5. Preparation of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]amino]piperidin-1-carbonyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (2). 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidin-3-carbonyl]amino]pyrazol-1-yl]cyclohexanecarboxylic acid 1 (70.0 mg, 0.113 mmol, 1.0 equivalent) and 3-[1-methyl-7-(4-piperidinylamino)indazole-3-yl]piperidin-2,6-dione hydrochloride C-2 (55.4 mg, 0.146 mmol, 1.3 equivalent) were dissolved in DMF (0.4 mL), followed by the sequential addition of DIPEA (196 µL, 1.13 mmol, 10.0 equivalent) and HATU (51.4 mg, 0.135 mmol, 1.3 equivalent). The reaction mixture was stirred overnight at room temperature. The reaction mixture was directly injected onto a column for reversed-phase rapid chromatography purification (MeCN / 0.1% HCOOH(aq), 5% (3 CV) → 70%, 50 g RediSep Rf Gold® C18, 20 CV, λ = 214-254 nm, product containing 60-65% MeCN). The evaporation fraction yielded 2 (82 mg, 0.087 mmol, 77% yield) as a white solid.

[0721] LCMS Method 1: At 215 nm, 99.9% purity, [M+H] + = 945.4, [M+2H] 2+ = 473.0.

[0722] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (br s, 9 H), 1.39 - 1.47 (m, 1H), 1.48 - 1.68 (m, 3 H), 1.82 (br d, J = 15.2 Hz, 3 H), 1.86 - 1.98 (m, 3H), 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)。

[0723] 19 F NMR (377 MHz, DMSO-d6) δ ppm -185.51 - -183.43 (m, 1 F), -112.85 --109.73 (m, 2 F)。

[0724] Step 6. Preparation of 5-((3R,5R)-3-amino-5-fluoropiperidin-1-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)amino)piperidin-1-carbonyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (P-9). Add 4.0 M HCl to N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]amino]piperidin-1-carbonyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 2 (80.0 mg, 0.085 mmol, 1.0 equivalent) in 1,4-dioxane (3.17 mL, 12.7 mmol, 150 equivalent) and sonicate the mixture for 30 minutes, followed by stirring for 1 hour. The solvent was evaporated to dryness and the residue was purified by reversed-phase rapid chromatography (MeCN / 0.02 M HCl(aq), 5% (3 CV) → 50%, 50 g RediSepRf Gold® C18, 15 CV, λ = 214-254 nm, product containing 33-39% MeCN) to produce an impure product (50 mg). The pure product was obtained by preparative HPLC purification (MeCN / HCl(aq)): the fraction containing the product was evaporated to dryness, then co-evaporated with water (3 × 10 mL) to completely remove any trace amounts of residual HCl, and the residue was lyophilized overnight to give P-9 as a white solid (31.48 mg, 0.0371 mmol, 43.842% yield).

[0725] LCMS Method 2: At 215 nm, 99.5% purity, [M+H] + = 844.5, [M+2H] 2+ = 422.7.

[0726] 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 = 7.8Hz, 1 H), 9.34 (s, 1 H), 10.86 (s, 1 H).

[0727] 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.68 (s, 1 F), -111.29 (s, 2 F).

[0728] The following compounds were synthesized via the same general route, with CBM (CX) modified in step 5 (Table 4).

[0729] Table 4.

[0730]

[0731] General Method 2 for Final Product

[0732] Example S3. Synthesis of P-2

[0733]

[0734] Step 1. Preparation of tert-butyl 5-[(3R,5R)-3-(tert-butyloxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (3). DIPEA (1.54 mL, 8.86 mmol, 2.5 equivalents) and N-[(3R,5R)-5-fluoro-3-piperidinyl]carboxylate tert-butyl 2 (1.01 g, 4.61 mmol, 1.3 equivalents) were added to a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (800 mg, 3.55 mmol, 1.0 equivalent) in MeCN (17.7 mL). After stirring over a weekend at 60 °C, LCMS showed complete conversion to 3. The solvent was removed under reduced pressure and the residue was dried under high vacuum to give 3 (1.44 g, quantitative yield) as a white solid. The crude product is used in the next step without further purification.

[0735] LCMS Method 1: Retention time: 1.656 min at 215 nm, 99.9% purity, [M+H] + = 408.2.

[0736] 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).

[0737] 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.32 (s, 1 F).

[0738] Step 2. Preparation of 5-[(3R,5R)-3-(tert-Butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4). A solution of LiOH·H₂O (1.48 g, 35.34 mmol, 10.0 equivalent) in water (5.89 mL) was added to a solution of ethyl 5-[(3R,5R)-3-(tert-Butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 3 (1.44 mg, 3.53 mmol, 1.0 equivalent) in THF (5.89 mL) and methanol (5.89 mL). After stirring at 60 °C for 18 h, LCMS showed complete conversion to the desired product 4. The reaction mixture was concentrated under vacuum to remove THF / MeOH and the crude mixture was diluted with water. The mixture was acidified with a 6N HCl aqueous solution under vigorous stirring until pH = 3 (precipitation). The suspension was filtered through a Buchner funnel and the solid was washed with water. The solid was dried overnight in an oven under vacuum to give 4 (1.40 g, quantitative yield) as a white solid. The crude product was used for the next step without further purification.

[0739] LCMS Method 1: Retention time: 1.487 min at 215 nm, 99.9% purity, [M+H] + = 380.1.

[0740] 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).

[0741] 19 F NMR (377 MHz, DMSO-d6) δ ppm – 184.32 (s, 1 F).

[0742] Step 3'. Preparation of [4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methanol (5). CaCl2 (1.0 g, 9.0 mmol, 2.0 eq) was added to a solution of methyl 4-[4-amino-3-(difluoromethyl)pyrazol-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) 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 overnight incubation, water was added and the reaction mixture was stirred at room temperature for 1 hour. The aqueous phase was extracted with EtOAc (3 x). The organic matter was washed with brine, dried over Na2SO4 and concentrated to dryness to give [4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methanol 5 (1.1 g, 99% yield) as orange oil.

[0743] LCMS Method 1: Retention time: 0.989 min at 215 nm, 99.0% purity, [M+H] + = 246.2.

[0744] 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 = 11.5Hz, 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).

[0745] 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.21 (s, 2 F).

[0746] Step 3. Preparation of N-[(3r,5r)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (6). TCFH (440.43 mg, 1.5 mmol, 1.2 equivalence) was added to a solution of [4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methanol 5 (511.8 mg, 1.88 mmol, 1.5 equivalence), 5-[(3r,5r)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (475.0 mg, 1.25 mmol, 1.0 equivalence), and NMI (362.72 µL, 4.58 mmol, 3.6 equivalence) in MeCN (12.5 mL, 0.1 M). 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 solids were filtered through a Buchner funnel and washed with a water / MeCN mixture. Purification was performed by reversed-phase chromatography (50 g C18 RediSep Rf Gold column, DMSO loading, gradient: 4 CV 5% MeOH / 0.1% HCOOH, followed by 15 CV 5% to 100% MeOH / 0.1% HCOOH). The purified fractions were combined and concentrated under reduced pressure to give N-[(3r,5r)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 6 (421 mg, 55% yield) as a brown solid.

[0747] LCMS Method 1: Retention time: 1.629 min at 215 nm, 99.9% purity, [M+H] + = 607.2.

[0748] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 - 1.15 (m, 2 H), 1.34 (br s, 9H), 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, 1H), 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)。

[0749] 19 F NMR (377 MHz, DMSO-d6) δ ppm -186.02 - -179.79 (m, 1 F), -113.10 --108.69 (m, 2F)。

[0750] Step 4. Preparation of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-1-piperidinyl]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]carbamate tert-butyl carbamate (7). Add IBX (182.07 mg, 0.65 mmol, 1.2 equivalents) to a solution of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]carbamate tert-butyl ester 6 (328.7 mg, 0.54 mmol, 1.0 equivalent) in dry DMSO (2.7 mL, 0.1 M). Stir the resulting mixture overnight at room temperature. After overnight stirring, LCMS showed complete conversion to an aldehyde. 3-[1-methyl-6-(4-piperidinylamino)inzol-3-yl]piperidin-2,6-dione C-1 (344.51 mg, 1.63 mmol, 1.2 equivalents), DCM (2.71 mL, 0.1 M), and DIPEA (0.94 mL, 5.42 mmol, 10.0 equivalents) were added to the reaction mixture. The mixture was stirred at room temperature for 10 min, followed by the addition of sodium triacetoxyborohydride (344.51 mg, 1.63 mmol, 3 equivalents). After 1 h, LCMS showed complete conversion to compound 3. DCM was evaporated under reduced pressure, and the crude mixture was purified by reverse-phase FC (50 g C18 RediSepRf Gold column, DMSO loading, 4 CV 5% MeCN / 0.1% HCOOH followed by 20 CV 5% to 70% MeCN / 0.1% HCOOH, with the product eluted in 50% MeCN). The purified fractions were combined and concentrated to give 7 (313 mg, 59% yield) as a brown solid as a formate. The product was expected to contain IBX residue.

[0751] LCMS Method 3: At 215 nm, 95.5% purity, [M-HCOOH+H] + = 930.4.

[0752] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 - 1.09 (m, 2 H), 1.34 (br s, 9H), 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, 1H), 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, 1H), 8.82 (br d, J = 8.1 Hz, 1 H), 9.31 (br s, 1 H), 10.82 (s, 1 H)。

[0753] Step 5. Preparation of N-[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-1-piperidinyl]methyl]cyclohexyl]pyrazol-4-yl]-5-[(3R,5R)-3-amino-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-2). 4 M HCl in N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-1-piperidinyl]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 7 (308.35 mg, 0.33 mmol, 1 equivalent) and dioxane (10.28 mL, 41.11 mmol, 124 equivalent) was added to a round-bottom flask. The reaction was stirred at rt. LCMS showed complete conversion to P-2 after 18 h. The reaction mixture was concentrated under vacuum, and the residue was purified by reversed-phase FC (50 g C18 RediSep Rf Gold column, HPLC loading (H2O), gradient: 4 CV 5% MeCN / 0.02 M HCl, followed by 20 CV 5% to 30% MeCN / 0.02 M HCl, with the product eluting in 25% MeCN). The fractions were combined and concentrated to give P-2 as a brown solid as hydrochloride (149.83 mg, 54% yield).

[0754] LCMS Method 4: At 215 nm, 99.9% purity, [M-HCl+H] + = 830.3; [M-HCl+2H] 2+ =415.7.

[0755] 11H 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).

[0756] 19 19F NMR (377 MHz, DMSO-d6) δ ppm -184.68 (s, 1 F), -111.54 - -110.76 (m, 2 F).

[0757] Example S4. Synthesis of P-5

[0758]

[0759] Step 4. Preparation of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]amino]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (2). IBX (32.6 mg, 0.116 mmol, 1.2 equivalents) was added to a solution of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(2-hydroxyethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 1-from the synthetic intermediate 6- (58.6 mg, 0.097 mmol, 1 equivalent) in dry DMSO (1.0 mL). The resulting mixture was stirred at rt. After 16 h, LCMS showed complete conversion to an aldehyde. The aldehyde in DMSO was then added to a solution of 3-[6-(4-amino-1-piperidinyl)-1-methyl-indazole-3-yl]piperidine-2,6-dione hydrochloride C-3 (44.2 mg, 0.107 mmol, 1.1 equivalents) and DIPEA (168 µL, 0.969 mmol, 10 equivalents) in DCE (1 mL). The mixture was stirred at rt for 10 min and NaBH(OAc)3 (26.7 mg, 0.126 mmol, 1.3 equivalents) was added. The resulting mixture was then stirred at room temperature. After 1 h, LCMS showed complete conversion. The DCE was removed under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (50 g C18 RediSep Rf Gold column, DMSO loading, gradient: 3 CV 5% MeCN / 0.1% HCOOH, followed by 15 CV 5 to 35% MeCN / 0.1% HCOOH, then 1 CV 35 to 100% MeCN / 0.1% HCOOH, followed by 3 CV 100% MeCN / 0.1% HCOOH (expected product elution in approximately 30% MeCN)). The fractions were combined and concentrated to give 2 (48.4 mg, 54% yield) as a white solid. The product was used unpurified for the next step.

[0760] LCMS Method 1: At 215 nm, 99.9% purity, [M+2H] 2+ = 466.

[0761] Step 5. Preparation of 5-((3R,5R)-3-amino-5-fluoropiperidin-1-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)amino)methyl)cyclohexyl)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide dihydrochloride (P-5). N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]amino]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 2 (48.4 mg, 0.052 mmol, 1 equivalent) was dissolved in 4 M HCl solution in 1,4-dioxane (1.95 mL, 7.80 mmol, 150 equivalent). The mixture was stirred at rt. After 2 h, LCMS showed complete conversion. The volatiles were removed under vacuum. The residue was purified by reversed-phase rapid chromatography (30 g C18 RediSep Rf Gold column, HPLC loading (water), gradient: 5 CV 5% MeCN / 0.02 M HCl, followed by 15 CV 5 to 20% MeCN / 0.02 M HCl, followed by 5 CV 20% MeCN / 0.02 M HCl, followed by 2 CV 20 to 100% MeCN / 0.02 M HCl, followed by 3 CV 100% MeCN / 0.02 M HCl). The fractions were combined and concentrated to give P-5 as a white solid (16.61 mg, 38% yield).

[0762] LCMS Method 2: At 215 nm, 99.6% purity, [M-2HCl+2H] 2+ = 415.7, [M-2HCl+H] + =830.4.

[0763] 11H 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).

[0764] 19 19F NMR (377 MHz, DMSO-d6) δ ppm -184.50 (s, 1 F), -111.28 (s, 2 F).

[0765] Example S5. Synthesis of P-18

[0766]

[0767] Step 1. Preparation of ethyl 5-[(3S,4S)-3-(tert-butoxycarbonylamino)-4-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (3). DIPEA (181.36 µL, 1.04 mmol, 3 equivalents) was added to a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (94 mg, 0.42 mmol, 1 equivalent) in MeCN (2.0 mL), followed by the addition of N-[(3S,4S)-4-fluoro-3-piperidinyl]tert-butyl carbamate 2 (100 mg, 0.46 mmol, 1.1 equivalents). The resulting mixture was stirred at 90 °C. After 16 h, LCMS indicated complete 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.

[0768] LCMS Method 1: At 215 nm, 99.9% purity, [M+H] + = 408.2.

[0769] Step 2. Preparation of 5-[(3S,4S)-3-(tert-Butoxycarbonylamino)-4-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4). A solution of ethyl 5-[(3S,4S)-3-(tert-Butoxycarbonylamino)-4-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 3 (169.7 mg, 0.42 mmol, 1 equivalent) 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 equivalents) in water (694.2 mL). The resulting mixture was stirred at 60 °C. After 2 h, LCMS showed complete reaction. The volatiles were evaporated under vacuum, and the mixture was diluted in water. The solution was then acidified to pH 3 with 6 N HCl aqueous solution under vigorous stirring. The white precipitate was separated by filtration, and the solid was washed three times with cold water. The solid was then dissolved in THF and co-evaporated three times with THF to give 4 (16.61 mg, 38% yield) as a grayish-white solid.

[0770] LCMS Method 1: At 215 nm, 99.9% purity, [M-tBu+H] + = 324.2.

[0771] 1H 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, 1H), 11.44 - 11.96 (m, 1 H).

[0772] Step 3. Preparation of ((3S,4S)-1-(3-((3-(difluoromethyl)-1-((1r,4S)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-fluoropiperidine-3-yl)carbamate tert-butyl (6). TCFH (94.66 mg, 0.34 mmol, 1.25 equivalents) was added to a solution of [4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methanol, a synthetic intermediate from P-2 (110 mg, 0.40 mmol, 1.5 equivalence), 5-[(3S,4S)-3-(tert-butoxycarbonylamino)-4-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (102.09 mg, 0.27 mmol, 1 equivalence), and NMI (78 µL, 0.98 mmol, 3.65 equivalences) in MeCN (4.03 mL). The resulting mixture was stirred at room temperature. After 16 h, LCMS showed completion. The volatiles were evaporated under vacuum. The resulting residue was purified by reversed-phase rapid chromatography (50 g C18 RediSep Rf Gold column, DMSO loading, gradient: 3 CV 5% MeCN / 0.1% HCOOH, followed by 15 CV 5 to 100% MeCN / 0.1% HCOOH, then 3 CV 100% MeCN / 0.1% HCOOH, with the desired product eluting at approximately 75% MeCN). The fractions were combined and concentrated to give 6 (116.2 mg, 71% yield) as an orange solid.

[0773] LCMS Method 1: At 215 nm, 99.9% purity, [M+H] + = 607.3.

[0774] 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, 1H), 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)。

[0775] 19 F NMR (377 MHz, DMSO-d6) δ ppm -183.02 - -179.35 (m, 1 F), -112.72 --109.70 (m, 2 F)。

[0776] Step 4. Preparation of N-[(3S,4S)-1-[3-[[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-1-piperidinyl]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-4-fluoro-3-piperidinyl]tert-butyl carbamate (7). IBX (41.5 mg, 0.15 mmol, 1.2 equivalents) was added to a solution of ((3S,4S)-1-(3-((3-(difluoromethyl)-1-((1r,4S)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-fluoropiperidin-3-yl)carbamate tert-butyl ester 6 (75 mg, 0.12 mmol, 1 equivalent) in dry DMSO (1.0 mL). The resulting mixture was stirred at rt. After 16 h, LCMS showed complete conversion to aldehyde. Next, the aldehyde solution was added to a solution of 3-[1-methyl-6-(4-piperidinylamino)inzol-3-yl]piperidine-2,6-dione hydrochloride C-1 (64.97 mg, 0.14 mmol, 1.1 equivalents) and DIPEA (215 µL, 1.24 mmol, 10 equivalents) in DCE (1.0 mL). The mixture was stirred at rt for 10 min and NaBH(OAc)3 (34.05 mg, 0.16 mmol, 1.3 equivalents) was added. The resulting mixture was then stirred at room temperature. After 1 h, LCMS showed complete reaction. The DCE was removed under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (50 g C18 RediSep RfGold column, DMSO loading, gradient: 3 CV 5% MeCN / 0.1% HCOOH, followed by 15 CV 5 to 35% MeCN / 0.1% HCOOH, then 1 CV 35 to 100% MeCN / 0.1% HCOOH, followed by 3 CV 100% MeCN / 0.1% HCOOH (expected product elution at approximately 30% MeCN)). The fractions were combined and concentrated to give 7 (37 mg, 32% yield) as a pale yellow solid. The product was used unpurified for the next step.

[0777] LCMS Method 1: [M+2H] 2+ = 465.8.

[0778] Step 5. N-[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-1-piperidinyl]methyl]cyclohexyl]pyrazol-4-yl]-5-[(3S,4S)-3-amino-4-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-18). N-[(3S,4S)-1-[3-[[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-1-piperidinyl]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-4-fluoro-3-piperidinyl]tert-butyl carbamate 7 (35 mg, 0.038 mmol, 1 equivalent) was dissolved in 4 M HCl solution in 1,4-dioxane (1.41 mL, 5.64 mmol, 150 equivalent). The mixture was stirred at rt. After 2 h, LCMS showed complete conversion. The volatiles were evaporated under vacuum. The residue was purified by reversed-phase rapid chromatography (30 g C18 RediSep Rf Gold column, HPLC loading (water), gradient: 5 CV 5% MeCN / 0.02 M HCl, followed by 15 CV 5 to 20% MeCN / 0.02 M HCl, followed by 5 CV 20% MeCN / 0.02 M HCl, followed by 2 CV 20 to 100% MeCN / 0.02 M HCl, followed by 3 CV 100% MeCN / 0.02 M HCl). The fractions were combined and concentrated to give P-18 (18.22 mg, 57% yield) as a brown solid as a diHCl salt.

[0779] LCMS Method 2: At 215 nm, 97.7% purity, [M-2HCl+2H] 2+ = 415.8; [M-2HCl+H] + =830.5.

[0780] 11H 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, 2 H), 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).

[0781] 19 19F NMR (377 MHz, DMSO-d6) δ ppm -181.60 (s, 1 F), -111.38 (s, 2 F).

[0782] Example S6. Synthesis of P-27

[0783]

[0784] Step 1. Preparation of ethyl 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylate (3). ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (1.5 g, 6.65 mmol, 1 equivalent), MeCN (33.24 mL, 0.2 M), and DIPEA (2.89 mL, 16.62 mmol, 2.5 equivalent) were added to a sealed tube, followed by the addition of morpholine 2 (639.65 µL, 7.31 mmol, 1.1 equivalent). The tube was sealed, and the mixture was stirred at 90 °C for 16 h. The solvent was evaporated under reduced pressure and dried under vacuum to give ethyl 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylate 3 (2.96 g, 99% yield) as an orange solid.

[0785] LCMS Method 1: Retention time: 1.432 min at 215 nm, 99% purity, [M+H] + = 277.2.

[0786] 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,2H).

[0787] Step 2. Preparation of 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4). After stirring for 5 minutes, a solution of LiOH·H2O (2.8 g, 66.6 mmol, 1.0 equivalent) in water (17.8 mL) was added to a solution of ethyl 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 3 (1.84 g, 6.66 mmol, 1.0 equivalent) in THF (17.8 mL, 0.1 M) and methanol (17.8 mL). The mixture was stirred at 60 °C for 3 h, then the oil bath was removed and the mixture was stirred over the weekend (72 h). The reaction mixture was concentrated under reduced pressure, then 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 give 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 as a brown solid (1.65 g, 99% yield).

[0788] LCMS Method 1: Retention time: 1.192 min at 215 nm, 99% purity, [M+H]+ = 249.2.

[0789] 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, 1H).

[0790] Step 3. Preparation of N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide (6). TCFH (480.37 mg, 1.71 mmol, 1.2 equivalence) was added to a solution of [4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methanol 5-, the synthetic intermediate from P-2, 6- (403.12 mg, 1.64 mmol, 1.2 equivalence), 5-morpholinylpyrazololo[1,5-a]pyrimidine-3-carboxylic acid 4 (340.0 mg, 1.37 mmol, 1.0 equivalence), and NMI (0.43 mL, 5.48 mmol, 4.0 equivalence) in MeCN (9 mL, 0.15 M). The resulting mixture was stirred at room temperature for 1 h. After 1 h, the volatiles were evaporated and the resulting mixture was purified by reversed-phase chromatography (50 g C18 RediSep Rf Gold column, DMSO loading, gradient: 4 CV 5% MeOH / 0.1% HCOOH, followed by 15 CV 5% to 50% MeOH / 0.1% HCOOH, with the product eluted in 50% MeOH). The purified fractions were combined and concentrated under reduced pressure to give N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide 6 (338 mg, 52% yield) as a brown solid.

[0791] LCMS Method 3: Retention time: 1.707 min at 215 nm, 99.9% purity, [M+H] + = 476.2.

[0792] 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, 1H)。

[0793] 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.19 (s, 2 F)。

[0794] Step 4. Preparation of N-[3-(difluoromethyl)-1-[4-[[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-1-piperidinyl]methyl]cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (P-27). IBX (84.0 mg, 0.3 mmol, 1.2 equivalents) was added to a solution of N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazololo[1,5-a]pyrimidine-3-carboxamide 6 (120.0 mg, 0.25 mmol, 1 equivalent) in DMSO (1.5 mL) at room temperature. The mixture was then stirred at room temperature. After 18 h, LCMS showed complete conversion to the aldehyde. Then, a solution of the aldehyde in DMSO was slowly added to a solution of 3-[1-methyl-6-(4-piperidinylamino)inzol-3-yl]piperidine-2,6-dione dihydrochloride C-1 (115.1 mg, 0.28 mmol, 1.1 equivalence), DIPEA (0.44 mL, 2.5 mmol, 10 equivalence), and NaBH(OAc)3 (158.95 mg, 0.75 mmol, 3 equivalence) in CH2Cl2 (1.5 mL). The resulting mixture was stirred at room temperature. After 2 h, LCMS showed complete conversion to the aldehyde. The solvent was removed under reduced pressure, and the product was then purified by reversed-phase FC (50 g C18 RediSep Rf Gold column, DMSO loading, gradient: 5 CV 5% MeCN / 0.1% HCOOH, followed by 20 CV 5 to 100% MeCN / 0.1% HCOOH, followed by 5 CV 100% MeCN / 0.1% HCOOH, with the product eluting at approximately 35% MeCN). The fractions were combined, concentrated, and lyophilized to obtain crude P-27 (67 mg, 82% purity at 215 nm), which was then purified by preparative LCMS (using formic acid as a modifier under acidic conditions) to obtain P-27 as a pink solid as a formate (50 mg, 24% yield).

[0795] LCMS Method 2: At 215 nm, 97.4% purity, [M-HCOOH+H] + = 799.4.

[0796] 11H 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).

[0797] Example S7. Synthesis of P-30

[0798]

[0799] Step 4. Preparation of N-[racemic-(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]carbamate tert-butyl carbamate (2). IBX (69.24 mg, 0.25 mmol, 1.2 equivalents) was added to a solution of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]carbamate tert-butyl ester 1-from the synthetic intermediate 6- (125 mg, 0.21 mmol, 1.0 equivalent) in dry DMSO (1 mL, 0.10 M). The resulting mixture was stirred overnight at room temperature. After overnight stirring, LCMS showed complete conversion to an aldehyde. 3-[1-methyl-7-[4-(methylamino)-1-piperidinyl]indazol-3-yl]piperidin-2,6-dione hydrochloride C-16 (97.09 mg, 0.23 mmol, 1.2 equivalents), DCM (1 mL, 0.1 M), and DIPEA (0.36 mL, 2.06 mmol, 10.0 equivalents) were added to the reaction mixture. The mixture was stirred at room temperature for 10 min, followed by the addition of sodium triacetoxyborohydride (131.01 mg, 0.62 mmol, 3 equivalents). After 1 h, LCMS showed complete conversion to compound 6. DCM was evaporated under reduced pressure, and the crude mixture was purified by reverse-phase FC (50 g C18 RediSep Rf Gold column, DMSO loading, 4 CV 5% MeCN / 0.1% HCOOH followed by 20 CV 5% to 60% MeCN / 0.1% HCOOH, with the product eluted in 50% MeCN). The purified fractions were combined and concentrated to give 2 (152 mg, 70% yield) as a brown solid as formate. The product was expected to contain IBX residue.

[0800] LCMS Method 3: At 254 nm, 90.2% purity, [M-HCOOH+H] + = 944.4.

[0801] 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, 1H), 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)。

[0802] Step 5. Preparation of N-[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-7-yl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazol-4-yl]-5-[(3R,5R)-3-amino-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-30). 4 M HCl in N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 2 (152 mg, 0.16 mmol, 1 equivalent) and dioxane (4.99 mL, 19.97 mmol, 124 equivalent) was added to a round-bottom flask. The reaction was stirred at rt. LCMS showed complete conversion to compound P-30 after 1 h. The reaction mixture was concentrated under vacuum, and the residue was purified by reverse-phase FC (50 g C18 RediSep Rf Gold column, HPLC loading (H2O), gradient: 4 CV 5% MeCN / 0.02 M HCl, followed by 20 CV 5% to 30% MeCN / 0.02 M HCl, with the product eluting in 25% MeCN). The fractions were combined and concentrated to give P-30 as a white solid as dihydrochloride (42.38 mg, 31% yield).

[0803] LCMS Method 2: At 215 nm, 99.9% purity, [M-2HCl+H] + = 844.4; [M-2HCl+2H] 2+ =422.8.

[0804] 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, 6H), 4.22 - 4.29 (m, 4 H), 4.35 (dd, J = 9.5, 5.1 Hz, 1 H), 4.51 - 4.67 (m, 1H), 4.76 - 4.95 (m, 1 H), 5.10 (br d, J = 48.0 Hz, 1 H), 6.89 (br d, J = 7.6Hz, 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).

[0805] 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.64 (br s, 1 F), -111.82 - -110.85 (m, 2 F).

[0806] The following compounds were synthesized via the same general route, with amine 2 modified in step 1 and CBM (CX) modified in step 4 (Table 5).

[0807] Table 5.

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814] Final product general method 3

[0815] Example S8. Synthesis of P-7

[0816]

[0817] Step 1. Preparation of [4-[3-(difluoromethyl)-4-nitro-pyrazole-1-yl]cyclohexyl]methanol (2). At 0 °C, CaCl2 (501.2 mg, 4.52 mmol, 2 equivalents) was added to a solution of methyl 4-[3-(difluoromethyl)-4-nitro-pyrazole-1-yl]cyclohexanecarboxylate 1-, an intermediate from the synthesis of T-1, in a 1:2 THF (3.8 mL) / ethanol (7.5 mL) solution, followed by NaBH4 (341.6 mg, 9.03 mmol, 4 equivalents). The resulting mixture was stirred at rt. After 16 h, LCMS showed complete conversion at this temperature. The reaction was quenched dropwise with water and stirred at rt for 1 h. Next, the product was extracted three times with EtOAc, and the organic matter was combined and washed once with water, once with brine, and finally dried over MgSO4. EtOAc was removed under reduced pressure, and the residue was purified by normal-phase rapid chromatography (80 g silica column, DCM loading, gradient: 3 CV 0% EtOAc / heptane, followed by 10 CV 0 to 100% EtOAc / heptane, then 3 CV 100% EtOAc / heptane (expected product elution at approximately 50% EtOAc)). The fractions were combined and concentrated to give fraction 2 (371.9 mg, 58% yield) as a colorless oil.

[0818] LCMS Method 1: At 215 nm, 97.5% purity, [M+H] + = 276.2.

[0819] 1H 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).

[0820] 19 F NMR (377 MHz, CDCl3-d) δ ppm -117.64 (d, J = 53.13, 2 F).

[0821] Step 2. Preparation of [4-[3-(difluoromethyl)-4-nitro-pyrazole-1-yl]cyclohexyl]methyl methanesulfonic acid (3). MsCl (0.13 mL, 1.68 mmol) was added dropwise to a solution of [4-[3-(difluoromethyl)-4-nitro-pyrazole-1-yl]cyclohexyl]methanol 2 (428.5 mg, 1.52 mmol) and Et3N (0.28 mL, 1.98 mmol) in DCM (7.62 mL) at 0 °C. The reaction was then slowly heated to rt and stirred at that temperature. After 3 h, TLC (3:7 heptane / EtOAc) showed the reaction was complete. The reaction was then partitioned between water and EtOAc. The phases were separated, and the organic phase was washed three times with water, once with 1 NHCl, and once with brine, followed by drying with MgSO4. EtOAc was removed under reduced pressure to give 3 (529 mg, 93% yield) as a pale yellow oil. The product was used for the next step without further purification.

[0822] LCMS Method 1: At 215 nm, 94.8% purity, [M+H] + = 354.0.

[0823] 1H 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).

[0824] 19 F NMR (377 MHz, CDCl3-d) δ ppm -117.64 (d, J = 53.13, 2 F).

[0825] Step 3. Preparation of 2-[4-[3-(difluoromethyl)-4-nitro-pyrazole-1-yl]cyclohexyl]acetaldehyde (4). A solution of methyl 4-[3-(difluoromethyl)-4-nitro-pyrazole-1-yl]cyclohexyl]methanesulfonate 3 (529.0 mg, 1.5 mmol, 1 equivalent) and NaCN (183.4 mg, 3.74 mmol, 2.5 equivalent) in DMSO (7.49 mL) was heated to 50 °C and stirred at that temperature. After 16 h at 50 °C, LCMS showed complete conversion. The reaction was cooled to rt and quenched with water under vigorous agitation. EtOAc was then added, and the product was extracted twice more with EtOAc. The combined organic layers were then washed once with concentrated NaHCO3 aqueous solution and once with brine. Finally, the resulting product was dried with MgSO4 and EtOAc was removed under reduced pressure to give 4 (342 mg, 79% yield) as a yellow oil.

[0826] LCMS Method 1: At 215 nm, 98.8% purity, [M+H] + = 285.2.

[0827] 1H 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).

[0828] 19 F NMR (377 MHz, CDCl3-d) δ ppm -117.68 (s, 2 F).

[0829] Step 4. Preparation of 2-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]cyclohexyl]acetaldehyde (5). A 1M solution of DIBAL-H in DCM (3.53 mL, 3.53 mmol, 3 equivalents) was added to a solution of 2-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]cyclohexyl]acetonitrile 4 (342 mg, 1.18 mmol, 1 equivalent) in DCM (5.88 mL) at -78 °C. The reaction was then stirred at this temperature. After 2 h, LCMS showed complete conversion. The reaction was slowly quenched with a solution of Rochelle salt at -78 °C, and the solution was stirred at rt for 1 h. The product was then extracted three times with EtOAc, and the combined organic layers were washed twice with 1 M HCl and once with brine. The organic layer was then dried with MgSO4 and EtOAc was removed under reduced pressure to obtain 5 (264 mg, 78% yield) as a yellow oil.

[0830] LCMS Method 1: At 215 nm, 99.9% purity, [M+H] + = 288.2.

[0831] 1H 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).

[0832] 19 F NMR (377 MHz, DMSO-d6) δ ppm -117.36 (s, 2 F).

[0833] Step 5. Preparation of 2-[4-[3-(difluoromethyl)-4-nitro-pyrazole-1-yl]cyclohexyl]ethanol (6). NaBH4 (69.52 mg, 1.84 mmol) was added to a solution of 2-[4-[3-(difluoromethyl)-4-nitro-pyrazole-1-yl]cyclohexyl]acetaldehyde 5 (264 mg, 0.92 mmol, 1 equivalent) in methanol (4.59 mL) at 0 °C. The resulting mixture was stirred at rt. After 16 h, LCMS showed complete conversion. Water was added and the reaction was stirred at rt for 1 h. The product was extracted three times with EtOAc and the combined organic matter was washed twice with brine. Finally, the organic matter was dried over MgSO4 and EtOAc was removed under reduced pressure to give 6 (216 mg, 68% yield) as a yellow oil.

[0834] LCMS Method 1: At 215 nm, 83.3% purity, [M+H] + = 290.2

[0835] 1H 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, 1H), 4.33 - 4.39 (m, 1 H), 7.30 (t, J = 53.2 Hz, 1 H), 9.06 (s, 1 H).

[0836] 19 F NMR (377 MHz, DMSO-d6) δ ppm -117.36 (s, 2 F).

[0837] Step 6. Preparation of 2-[4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]ethanol (7). N2 was bubbled through a solution of 2-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]cyclohexyl]ethanol 6 (216.1 mg, 0.75 mmol, 1 equivalent) in EtOAc (3.74 mL) for 5 min. Then 10% Pd / C (238.5 mg, 0.22 mmol, 0.3 equivalent) was added and N2 was bubbled through the solution for another 5 min. Then H2 was bubbled through the solution for 5 min and the resulting mixture was stirred at 1 atm H2. After 3 h, LCMS showed complete conversion. The solution was filtered through a diatomaceous earth pad and thoroughly washed with EtOAc. Finally, the filtrate was concentrated under reduced pressure to give 7 (169 mg, 81% yield) as a yellow oil. The product is used in the next step without purification.

[0838] LCMS Method 1: At 215 nm, 92.9% purity, [M+H] + = 260.2

[0839] Step 7. Preparation of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(2-hydroxyethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (9). TCFH (168.6 mg, 0.65 mmol, 1.3 equivalents) was added to a solution of 2-[4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]ethanol 7 (168.8 mg, 0.65 mmol, 1.3 equivalents), 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 8-, a synthetic intermediate from P-4, 4- (190 mg, 0.50 mmol, 1 equivalent), and NMI (0.14 mL, 1.75 mmol, 3.5 equivalents) in MeCN (2.50 mL). The reaction was then stirred at rt. After 16 h, LCMS showed complete conversion. MeCN was removed under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (30 g C18 column, DMSO loading, gradient: 3 CV 5% MeOH / 0.1% HCOOH, followed by 15 CV 5 to 100% MeOH / 0.1% HCOOH, then 3 CV 100% MeOH / 0.1% HCOOH (expected product elution at approximately 80% MeCN)). The fractions were combined and concentrated to give 9 (155.6 mg, 50% yield) as a grayish-white solid.

[0840] LCMS Method 1: At 215 nm, 99.9% purity, [M+H] + = 621.2

[0841] 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).

[0842] 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.27 - -183.87 (m, 1 F), -112.01 --110.10 (m, 2 F).

[0843] Step 8'. Preparation of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(2-oxoethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (10). Add IBX (76 mg, 0.27 mmol, 1.2 equivalents) to a solution of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(2-hydroxyethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazololo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 9 (140 mg, 0.23 mmol, 1.0 equivalent) in dry DMSO (2.2 mL). The resulting mixture was stirred overnight at room temperature. LCMS analysis showed complete conversion. The reaction mixture was used for the next step without purification. Since product 10 was not separated, the reaction yield was estimated to be 95%.

[0844] LCMS Method 1: At 254 nm, 99.9% purity, [M+H] + = 619.2; IBX residues are visible at 215 nm.

[0845] Step 8. Preparation of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]amino]-1-piperidinyl]ethyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (11). DIPEA (210 µL, 1.21 mmol, 10.0 equivalent) was added to a suspension of 3-[1-methyl-7-(4-piperidinylamino)inzol-3-yl]piperidin-2,6-dione hydrochloride C-2 (50 mg, 0.13 mmol, 1.1 equivalent) in DCE (1.1 mL), and the mixture was stirred at room temperature for 10 min. Then, N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(2-oxoethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 10 (75 mg, 0.12 mmol, 1.0 equivalent) was added to 1.1 mL DMSO. The mixture was stirred again for 10 min, and then NaBH(OAc)3 (33 mg, 0.16 mmol, 1.3 equivalence) was added. The reaction was stirred at room temperature for 1 h. LCMS showed complete conversion. The DCE was evaporated under reduced pressure, and the resulting solution was directly loaded onto a C18 RediSep Rf Gold column and purified by reversed-phase rapid chromatography (5% MeCN / 0.1% formic acid FA, held for 5 CV, followed by 5 to 45% MeCN / 0.1% formic acid, held for 20 CV). The fraction containing the product was evaporated to give 71.1 mg (52% yield) of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]amino]-1-piperidinyl]ethyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 11 as a brown solid.

[0846] LCMS Method 1: 84.3% purity at 215 nm and 97.4% purity at 254 nm; [M+H] + = 947.3; [M+2H] 2+ = 472.8.

[0847] 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 = 13.2Hz, 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, 1 H), 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, 1H), 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).

[0848] 19 F NMR (377 MHz, DMSO-d6): The spectrum did not show any signal strong enough to be clearly assigned.

[0849] Step 9. Preparation of N-[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-7-yl]amino]-1-piperidinyl]ethyl]cyclohexyl]pyrazol-4-yl]-5-[(3R,5R)-3-amino-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide bis-HCl salt (P-7). Add 4.0 M solution of HCl (2.6 mL, 10.3 mmol, 150 equivalents) in 1,4-dioxane to N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]amino]-1-piperidinyl]ethyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 11 (65 mg, 0.07 mmol, 1.0 equivalents). Stir the mixture at room temperature for 1 h. HPLC indicated complete conversion. Remove the solvent under reduced pressure and water and add approximately 10 drops of DMSO. The solution was then loaded onto a C18 RediSep Rf Gold column and purified by reversed-phase rapid chromatography (5% MeCN / HCl 0.02 M, 5 CV, followed by 5 to 20% MeCN / 0.02 M HCl, 20 CV). The product was eluted with 22% MeCN. The purified fractions were combined, evaporated under reduced pressure, and lyophilized to give 31.77 mg (54% yield) of N-[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-7-yl]amino]-1-piperidinyl]ethyl]cyclohexyl]pyrazol-4-yl]-5-[(3R,5R)-3-amino-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-7) as a bis-HCl salt.

[0850] LCMS Method 2: 99.5% purity at 215 nm; [M+H] + = 844.5; [M+2H] 2+ = 422.8.

[0851] 11H 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, 6H), 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).

[0852] 19 19F NMR (377 MHz, DMSO-d6) δ ppm -184.63 (s, 1 F), -111.26 (s, 2 F).

[0853] Example S9. Synthesis of P-34

[0854]

[0855] Step 7. Preparation of N-[3-(difluoromethyl)-1-[4-(2-hydroxyethyl)cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide (3). 2-[4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]ethanol, 2-intermediate 7- from the synthesis of P-7 (60 mg, 0.17 mmol, 1.1 equivalent), 5-morpholinylpyrazololo[1,5-a]pyrimidine-3-carboxylic acid, 1-intermediate 4- from the synthesis of P-27 (37.7 mg, 0.15 mmol, 1 equivalent), MeCN (1.2 mL), and NMI (50 µL, 0.63 mmol, 3.7 equivalent) were added to a round-bottom flask and the mixture was stirred at 0 °C. After 5 min, TCFH (57 mg, 0.20 mmol, 1.2 equivalence) was added and the reaction was stirred at 0 °C. After 5 min, the reaction was stirred at room temperature. After 3 h, LCMS showed complete conversion. Water was added to the mixture and MeCN was removed under reduced pressure until a persistent precipitate appeared. The suspension was then extracted with EtOAc (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 rapid chromatography (24 g silica column, pre-absorption, gradient: 15 CV 0 to 5% DCM / MeOH). The fractions were combined and concentrated to give 3 (60 mg, 58% yield) as a white solid.

[0856] LCMS Method 3: At 215 nm, 80.5% purity, [M+H] + = 490.2.

[0857] Step 8. Preparation of N-[3-(difluoromethyl)-1-[4-[2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]-methyl-amino]-1-piperidinyl]ethyl]cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-34). IBX (15 mg, 0.06 mmol, 1.2 equivalents) was added to a solution of N-[3-(difluoromethyl)-1-[4-(2-hydroxyethyl)cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazololo[1,5-a]pyrimidine-3-carboxamide 3 (28 mg, 0.05 mmol, 1 equivalent) in anhydrous DMSO (1 mL). The resulting mixture was stirred at room temperature. After 3 h, LCMS showed complete conversion to the corresponding aldehyde. 3-[1-methyl-7-[methyl(4-piperidinyl)amino]indazol-3-yl]piperidin-2,6-dione hydrochloride C-17 (39 mg, 0.09 mmol, 2 equivalents), DCE (1 mL), and DIPEA (50 µL, 0.29 mmol, 6.2 equivalents) were added to the reaction mixture. The mixture was stirred at room temperature, and after 10 min, NaBH(OAc)3 (15 mg, 0.07 mmol, 1.5 equivalents) was added. After 2 h, LCMS showed complete conversion. DCM was evaporated under reduced pressure, and the crude mixture was purified by reverse-phase FC (30 g C18 RediSep Rf Gold column, DMSO loading, 4 CV 5% MeOH / 0.1% HCOOH, followed by 15 CV 5 to 80% MeOH / 0.1% HCOOH). The fractions were combined and concentrated to obtain an impure material, which was then co-evaporated with MeOH and water (1x), followed by co-evaporation with DCM containing a small amount of triethylamine to obtain the corresponding free base. The resulting material was then dissolved in a minimal amount of DCM and purified by normal-phase rapid chromatography (24 g silica gel, gradient: 20 CV 0 to 10% DCM / MeOH). The pure fractions were combined and concentrated to give P-34 as a white solid (23 mg, 61% yield).

[0858] LCMS Method 2: Retention time: 2.391 min at 215 nm, 99% purity, [M+2H] 2+ = 414.2; [M+H] + = 827.5.

[0859] 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), 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).

[0860] 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.20 (s, 2 F).

[0861] The following compounds were synthesized via the same general route, with the acid (8) modified in step 7 and the CBM (CX) modified in step 8 (Table 6).

[0862] Table 6.

[0863]

[0864]

[0865] General Method 4 for Final Product

[0866] Example S10. Synthesis of P-28

[0867]

[0868] Step 1. Preparation of ethyl 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (3). DIPEA (1.54 mL, 8.86 mmol, 2.5 equivalents) and N-[(3R,5R)-5-fluoro-3-piperidinyl]carbamate tert-butyl ester (1.01 g, 4.61 mmol, 1.3 equivalents) were added to a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (800 mg, 3.55 mmol, 1.0 equivalent) in MeCN (17.7 mL). After stirring over a weekend at 60 °C, LCMS showed complete conversion to 3. The solvent was removed under reduced pressure and the residue was dried under high vacuum to give 3 (1.44 g, quantitative yield) as a white solid. The crude product is used in the next step without further purification.

[0869] LCMS Method 1: Retention time: 1.656 min at 215 nm, 99.9% purity, [M+H] + = 408.2.

[0870] 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).

[0871] 19 F NMR (377 MHz, DMSO-d6) δ ppm -184.32 (s, 1 F).

[0872] Step 2. Preparation of 5-[(3R,5R)-3-(tert-Butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4). A solution of LiOH·H₂O (1.48 g, 35.34 mmol, 10.0 equivalent) in water (5.89 mL) was added to a solution of ethyl 5-[(3R,5R)-3-(tert-Butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 3 (1.44 mg, 3.53 mmol, 1.0 equivalent) in THF (5.89 mL) and methanol (5.89 mL). After stirring at 60 °C for 18 h, LCMS showed complete conversion to the desired product 4. 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 with 6N HCl aqueous solution under vigorous stirring (to form a precipitate). The suspension was filtered through a Buchner funnel, and the solid was washed with water. The solid was dried overnight in a furnace under vacuum to give 4 (1.40 g, quantitative yield) as a white solid. The crude product was used for the next step without further purification.

[0873] LCMS Method 1: Retention time: 1.487 min at 215 nm, 99.9% purity, [M+H] + = 380.1.

[0874] 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).

[0875] 19 F NMR (377 MHz, DMSO-d6) δ ppm – 184.32 (s, 1 F).

[0876] Step 3. Preparation of N-[(3r,5r)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (6). TCFH (440.43 mg, 1.57 mmol, 1.2 equivalents) was added to a solution of [4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methanol, a synthetic intermediate from P-2, 6-(511.8 mg, 1.88 mmol, 1.5 equivalents), 5-[(3r,5r)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 (475.0 mg, 1.25 mmol, 1.0 equivalents), and NMI (362.72 µL, 4.58 mmol, 3.6 equivalents) in MeCN (12.5 mL, 0.1 M). 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. It was purified by reversed-phase chromatography (50 g C18 RediSep Rf Gold column, DMSO loading, gradient: 4 CV 5% MeOH / 0.1% HCOOH, followed by 15 CV 5% to 100% MeOH / 0.1% HCOOH). The purified fractions were combined and concentrated under reduced pressure to give N-[(3r,5r)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 6 (421 mg, 55% yield) as a brown solid.

[0877] LCMS Method 1: Retention time: 1.629 min at 215 nm, 99.9% purity, [M+H] + = 607.2.

[0878] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 - 1.15 (m, 2 H), 1.34 (br s, 9H), 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, 1H), 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)。

[0879] 19 F NMR (377 MHz, DMSO-d6) δ ppm -186.02 - -179.79 (m, 1 F), -113.10 --108.69 (m, 2F)。

[0880] Step 4. Preparation of N-[(3r,5r)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (7). Add IBX (47.6 mg, 0.17 mmol, 1.2 equivalents) to a solution of N-[racemic-(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]carbamate tert-butyl ester 6 (86.0 mg, 0.14 mmol, 1.0 equivalent) in dry DMSO (1 mL, 0.14 M). Stir the resulting mixture overnight at room temperature. LCMS (Method 3) showed complete conversion to the desired product N-[racemic-(3R,5R)-1-[3-[[3-(difluoromethyl)-1-(4-formylcyclohexyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate after overnight stirring. 3-[1-methyl-6-[4-(methylamino)-1-piperidinyl]indazol-3-yl]piperidin-2,6-dione hydrochloride C-15 (66.11 mg, 0.17 mmol, 1.2 equivalents), DCE (1 mL), and DIPEA (0.24 mL, 1.41 mmol, 10.0 equivalents) were added to the reaction mixture. The mixture was stirred at room temperature for 10 minutes, sodium triacetoxyborohydride (38.74 mg, 0.18 mmol, 1.3 equivalences) was added, and the mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum. Purification was performed by reversed-phase chromatography (C18 RediSep Rf Gold 50 g, 5 to 40% MeCN / 0.1% formic acid / water, 20 CV). The pure fractions were combined and concentrated to give N-[racemic-(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 7 (66 mg, 44% yield) as a brown solid. The product was expected to contain IBX residues.

[0881] LCMS Method 3: Retention time: 1.736 min at 215 nm, 89.3% purity, [M + 2H] 2+ = 472.8

[0882] 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, 1H), 8.29 (s, 1 H), 8.34 (br s, 1 H), 8.82 (d, J = 7.8 Hz, 1 H), 9.31 (br s, 1H), 10.85 (s, 1 H).

[0883] Step 7. Preparation of N-[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazol-4-yl]-5-[(3r,5r)-3-amino-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-28). 4.0 M HCl was added to N-[racemic-(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 7 (66. mg, 0.07 mmol, 1.0 equivalent) in dioxane (2.62 mL, 10.49 mmol, 150.0 equivalent). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under vacuum. Purification was performed by reversed-phase chromatography (50 g C18 RediSep Rf Gold column, HPLC loading (H2O), gradient: 4 CV 5% MeOH / 0.02 M HCl followed by 15 CV 5% to 50% MeCN / 0.02 M HCl). The purified fractions were combined, concentrated under reduced pressure, and lyophilized overnight to give N-[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazol-4-yl]-5-[racemic-(3R,5R)-3-amino-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide P-28 (28 mg, 47% yield).

[0884] LCMS Method 2: Retention time: 1.911 min at 215 nm, 99.6% purity, [M-HCl + H] + =844; [M - 2HCl + 2H] 2+ = 422.6.

[0885] 11H 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).

[0886] 19 19F NMR (377 MHz, DMSO-d6) δ ppm -183.67 (s, 2 F), -111.29 (br s, 1 F).

[0887] Example S11. Synthesis of P-29

[0888]

[0889] Step 1. Preparation of ethyl 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylate (3). ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (1.5 g, 6.65 mmol, 1 equivalent), MeCN (33.24 mL, 0.2 M), and DIPEA (2.89 mL, 16.62 mmol, 2.5 equivalent) were added to a sealed tube, followed by the addition of morpholine 2 (639.65 µL, 7.31 mmol, 1.1 equivalent). The tube was sealed, and the mixture was stirred at 90 °C for 16 h. The solvent was evaporated under reduced pressure and dried under high vacuum to give ethyl 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylate 3 (2.96 g, 99% yield) as an orange solid.

[0890] LCMS Method 1: Retention time: 1.432 min at 215 nm, 99% purity, [M+H] + = 277.2.

[0891] 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,2H).

[0892] Step 2. Preparation of 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4). After stirring for 5 minutes, a solution of LiOH·H2O (2.8 g, 66.6 mmol, 1.0 equivalent) in water (17.8 mL) was added to a solution of ethyl 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 3 (1.84 g, 6.66 mmol, 1.0 equivalent) in THF (17.8 mL, 0.1 M) and methanol (17.8 mL). The mixture was stirred at 60 °C for 3 h, then the oil bath was removed and the mixture was stirred over the weekend (72 h). The reaction mixture was concentrated under reduced pressure, then 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 give 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4 as a brown solid (1.65 g, 99% yield).

[0893] LCMS Method 1: Retention time: 1.192 min at 215 nm, 99% purity, [M+H]+ = 249.2.

[0894] 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, 1H).

[0895] Step 3. Preparation of N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide (6). TCFH (480.37 mg, 1.71 mmol, 1.2 equivalence) was added to a solution of [4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methanol 5-, the synthetic intermediate from P-2, 6- (403.12 mg, 1.64 mmol, 1.2 equivalence), 5-morpholinylpyrazololo[1,5-a]pyrimidine-3-carboxylic acid 4 (340.0 mg, 1.37 mmol, 1.0 equivalence), and NMI (0.43 mL, 5.48 mmol, 4.0 equivalence) in MeCN (9 mL, 0.15 M). The resulting mixture was stirred at room temperature for 1 h. After 1 h, the volatiles were evaporated and the resulting product was purified by reversed-phase chromatography (50 g C18 RediSep Rf Gold column, DMSO loading, gradient: 4 CV 5% MeOH / 0.1% HCOOH, followed by 15 CV 5% to 50% MeOH / 0.1% HCOOH, with the product eluting in 50% MeOH). The pure fractions were combined and concentrated under reduced pressure to give N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide 6 (338 mg, 52% yield) as a brown solid.

[0896] LCMS Method 3: Retention time: 1.707 min at 215 nm, 99.9% purity, [M+H] + = 476.2.

[0897] 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, 1H)。

[0898] 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.19 (s, 2 F)。

[0899] Step 4. Preparation of N-[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-29). Add IBX (70.0 mg, 0.25 mmol, 1.2 equivalents) to a solution of N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazololo[1,5-a]pyrimidine-3-carboxamide 6 (100.0 mg, 0.21 mmol, 1.0 equivalent) in dry DMSO (2 mL, 0.1 M). Stir the shortened mixture overnight at room temperature. After overnight stirring, LCMS (Method 3) showed complete conversion to the desired product N-[3-(difluoromethyl)-1-(4-formylcyclohexyl)pyrazol-4-yl]-5-morpholinyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide. [1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-methyl-ammonium chloride C-15 (98.91 mg, 0.25 mmol, 1.2 equivalents), DCE (2.1 mL, 0.05 M), and DIPEA (0.37 mL, 2.10 mmol, 10 equivalents) were added to the reaction mixture. The mixture was stirred at rt for 10 min. Sodium triacetoxyborohydride (133.72 mg, 0.63 mmol, 3.0 equivalents) was added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum. Purification was performed by reversed-phase chromatography (50 g C18 RediSep Rf Gold column, DMSO loading, gradient: 4 CV 5% MeCN / 0.1% HCOOH followed by 15 CV 5% to 50% MeCN / 0.1% HCOOH). The purified fractions were combined, concentrated under reduced pressure, and lyophilized overnight to give N-[3-(difluoromethyl)-1-[4-[[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazol-4-yl]-5-morpholinyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide P-29 (25.4 mg, 14% yield) as a yellow solid.

[0900] LCMS Method 4: Retention time: 2.399 min at 215 nm, 96.0% purity, [M+H] + = 813.4;[M + 2H] 2+ = 407.3.

[0901] 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).

[0902] 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.19 (s, 2 F).

[0903] The following compounds were synthesized via the same general route, with amine 2 modified in step 1 (Table 7).

[0904] Table 7.

[0905]

[0906]

[0907]

[0908] Final product general method 5

[0909] Example S12. Synthesis of P-37

[0910]

[0911]

[0912] Step 1. Preparation of 4-methylsulfonylpiperidine-1-carboxylate (2). Methanesulfonyl chloride (0.821 mL, 10.6 mmol, 1.25 equivalence) was added dropwise to a chilled solution of 4-hydroxypiperidine-1-carboxylate 1 (2.00 g, 8.50 mmol, 1.0 equivalence) and triethylamine (1.78 mL, 12.8 mmol, 1.5 equivalence) in DCM (100 mL). The reaction mixture was stirred at room temperature. After 1 h, LCMS showed complete conversion. Water (50 mL) and saturated NaHCO3(aq) (50 mL) were added to the reaction mixture, and the phases were separated. The aqueous layer was then extracted with DCM (3 × 50 mL). The combined organic matter was washed with brine (50 mL), dried over MgSO4, filtered, and evaporated under reduced pressure to give 2 (2.80 g, 8.50 mmol, quantitative yield) as a light orange oil.

[0913] LCMS Method 1: At 215 nm, 95.8% purity, [M+H] + = 314.1.

[0914] 1 H NMR (400 MHz, CDCl3) δ ppm 1.77 - 1.92 (m, 2 H), 1.93 - 2.08 (m, 2H), 3.05 (s, 3 H), 3.43 (ddd, J = 13.7, 7.9, 3.9 Hz, 2 H), 3.70 - 3.85 (m, 2H), 4.91 (tt, J = 7.5, 3.8 Hz, 1 H), 5.14 (s, 2 H), 7.27 - 7.43 (m, 5 H).

[0915] Step 2. Preparation of benzyl 4-[3-(difluoromethyl)-4-nitro-pyrazole-1-yl]piperidine-1-carboxylate (4). A mixture of 4-methylsulfonyloxypiperidine-1-carboxylate 2 (1.00 g, 3.19 mmol, 1.2 equivalents), 3-(difluoromethyl)-4-nitro-1H-pyrazole 3 (450 mg, 2.76 mmol, 1.0 equivalents), and potassium carbonate (800 mg, 5.80 mmol, 2.1 equivalents) in DMF (22 mL) was stirred at 100 °C under a nitrogen atmosphere. After 24 h, LCMS showed complete conversion. Water (100 mL) was added to the mixture, and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic matter was washed with 1:1 water / saline solution (3 × 50 mL) and saline solution (50 mL), dried over MgSO4 and evaporated to dryness. The crude material was purified by normal-phase rapid chromatography (80 g silica column, pre-absorption, gradient: heptane / EtOAc, 95:5 to 70:30, 12 CV) to give 4 (644 mg, 1.46 mmol, 53% yield) as a pale yellow oil.

[0916] LCMS Method 1: At 215 nm, 86.0% purity, [M+H] + = 381.1.

[0917] 1 H 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).

[0918] 19 F NMR (377 MHz, CDCl3) δ ppm -117.79 (s, 2 F).

[0919] Step 3. Preparation of 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]piperidine-1-carboxylate (5). Zinc (2.21 g, 33.9 mmol, 20.0 equivalent; activated with 1.0 M HCl(aq)) was added to a solution of 4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine-1-carboxylate 4 (644 mg, 1.46 mmol, 1.0 equivalent) in i-PrOH (17 mL). Acetic acid (0.970 mL, 16.9 mmol, 10.0 equivalent) was then added to the solution and the reaction mixture was stirred at room temperature. After 1 h, LCMS showed complete conversion. The reaction mixture was filtered through a diatomaceous earth mat and evaporated to dryness. The residue was placed in EtOAc (50 mL), washed with saturated NaHCO3 (aq) (10 mL) and brine (10 mL), dried over MgSO4 and evaporated to dryness to give 5 (500 mg, 1.24 mmol, 73% yield) as brown oil.

[0920] LCMS Method 1: At 215 nm, 86.9% purity, [M+H] + = 351.1.

[0921] 1 H 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, 1H), 7.31 - 7.39 (m, 5 H).

[0922] 19 F NMR (377 MHz, DMSO-d6) δ ppm -111.51 (s, 2 F).

[0923] Step 4. Preparation of 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidin-3-carbonyl]amino]pyrazol-1-yl]piperidin-1-carboxylic acid benzyl ester (7). TCFH (614 mg, 2.19 mmol, 1.2 equivalents) was added in a single step to a solution of 5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidin-3-carboxylic acid 6-derived from the P-2 synthesis intermediate 4- (692 mg, 1.82 mmol, 1.0 equivalent), 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]piperidin-1-carboxylic acid benzyl ester 5 (708 mg, 1.92 mmol, 1.05 equivalent), and NMI (506 µL, 6.38 mmol, 3.5 equivalent) in MeCN (12.1 mL), followed by stirring of the reaction mixture at room temperature. After 24 h, LCMS showed complete conversion. The volatiles were evaporated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (150 g C18 RediSep Rf Gold column, DMSO loading, MeOH / 0.1% HCOOH (aq), 40%→90%, 15 CV). The fractions were combined and concentrated to give 7 (823 mg, 1.10 mmol, 60% yield) as a grayish-white solid.

[0924] LCMS Method 1: At 215 nm, 95.0% purity, [M+H] + = 712.3.

[0925] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (br s, 9 H), 1.68 - 1.97 (m, 4H), 2.03 (br d, J = 10.6 Hz, 2 H), 2.09 - 2.22 (m, 1 H), 2.88 - 3.18 (m, 3H), 3.36 - 3.56 (m, 1 H), 3.67 (br d, J = 7.0 Hz, 1 H), 4.12 (br d, J = 13.2Hz, 2 H), 4.42 - 4.56 (m, 1 H), 4.57 - 4.92 (m, 1 H), 4.97 (d, J = 45.4 Hz, 1H), 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)。

[0926] 19 F NMR (377 MHz, DMSO-d6) δ ppm -186.27 - -182.64 (m, 1 F), -114.40 --109.21 (m, 2 F)。

[0927] Step 5. Preparation of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-(4-piperidinyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (8). 4-[3-(difluoromethyl)-4-[[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidin-3-carbonyl]amino]pyrazol-1-yl]piperidin-1-carboxylic acid benzyl ester 7 (739 mg, 1.04 mmol, 1.0 equivalent) was dissolved in methanol (4.0 mL), and the solution was then bubbled with nitrogen under sonication. After 20 min, 10% w / w Pd / C (200 mg, 0.181 mmol, 0.18 equivalent) was added, followed by further bubbling of the mixture under sonication with nitrogen. After 20 min, the nitrogen balloon was switched to a hydrogen-filled balloon, and the reaction was bubbled. After 10 min, the reaction mixture was stirred under a hydrogen atmosphere. After 18 h, LCMS showed complete conversion. The reaction mixture was filtered through diatomaceous earth, which was then thoroughly washed with MeOH. The filtrate was evaporated under reduced pressure, and the residue was placed in EtOAc. Heptane was added until a precipitate formed. The suspension was evaporated to dryness to give 8 (620 mg, 0.987 mmol, 95% yield) as a pink solid.

[0928] LCMS Method 1: 92.0% purity at 215 nm, [M+H] + = 578.3.

[0929] 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)。

[0930] 19 F NMR (377 MHz, DMSO-d6) δ ppm -187.05 - -180.57 (m, 1 F), -113.62 --108.43 (m, 2 F)。

[0931] 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 equivalent) was added to a suspension of 3-[1-methyl-6-[(2R)-2-methylpiperazin-4-onthiol-1-yl]indazole-3-yl]piperidine-2,6-dione chloride C-19 (99 mg, 0.228 mmol, 1.0 equivalent) in DCE (4.5 mL), followed by the addition of 2,2-dimethoxyacetaldehyde 9 (60% w / w solution in H2O, 52 µL, 0.342 mmol, 1.5 equivalent), and the mixture was stirred at room temperature. After 10 min, sodium triacetoxyborohydride (96.6 mg, 0.456 mmol, 2.0 equivalent) was added in a single batch, and the reaction mixture was stirred at room temperature. After 18 h, LCMS showed complete conversion. Water (10 mL) was added to the reaction mixture to separate the phases, and the aqueous phase was then extracted with DCM (3 × 15 mL). The combined organic matter was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give 10 (98 mg, 0.228 mmol, quantitative yield) as a brown oil, which was used for the next step without purification.

[0932] LCMS Method 2: At 215 nm, 99.9% purity, [M+H] + = 430.4.

[0933] 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, 2H), 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, 1H), 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, 1H).

[0934] Step 7. Preparation of 3-[1-methyl-6-[(2R)-4-(2,2-dihydroxyethyl)-2-methyl-piperazin-4-onthiol-1-yl]indazole-3-yl]piperidine-2,6-dione chloride (11). 4.0 M HCl in 1,4-dioxane (2.84 mL, 11.4 mmol, 50.0 equivalent) and water (82 µL, 4.56 mmol, 20.0 equivalent) was added to a solution of 10 (98 mg, 0.228 mmol, 1.0 equivalent) in 1,4-dioxane (2.2 mL), followed by stirring of the reaction mixture at room temperature. After 18 h, LCMS showed complete conversion. The volatiles were evaporated under reduced pressure to produce 11 (99 mg, 0.228 mmol, quantitative yield) as a yellow solid, which was used for the next step without purification.

[0935] LCMS Method 2: At 215 nm, 99.9% purity, [M-HCl+H] + = 402.2.

[0936] Step 8. Preparation of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[1-[2-[(3R)-4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-3-methyl-piperazin-1-yl]ethyl]-4-piperidinyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (12). DIPEA (556 µL, 3.19 mmol, 20.0 equivalents) was added to a suspension of N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-(4-piperidinyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 8 (92.2 mg, 0.160 mmol, 1.0 equivalent) and 3-[1-methyl-6-[(2R)-4-(2,2-dihydroxyethyl)-2-methyl-piperazin-4-onthiol-1-yl]indazol-3-yl]piperidin-2,6-dione chloride 11 (83.9 mg, 0.191 mmol, 1.2 equivalent) in DCE (3.2 mL), and the mixture was then stirred at room temperature. Ten min later, sodium triacetoxyborohydride (101.4 mg, 0.479 mmol, 3.0 equivalence) was added in a single addition, followed by stirring of the reaction mixture at room temperature. After 18 h, LC-MS showed complete conversion. The volatiles were evaporated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (100 g C18 RediSep Rf Gold column, DMSO loading, MeCN / 0.1% HCOOH (aq), 5% (3 CV) → 50%, 20 CV). The fractions were combined and concentrated to give 12 (102 mg, 0.0994 mmol, 62% yield) as a pink solid.

[0937] LCMS Method 2: At 215 nm, 92.1% purity, [M+2H] 2+ = 473.4.

[0938] 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, 1H), 2.35 - 2.43 (m, 1 H), 2.61 - 2.65 (m, 1 H), 2.78 (br d, J = 10.4 Hz, 1H), 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, 2H), 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)。

[0939] 19 F NMR (377 MHz, DMSO-d6) δ ppm -186.79 - -182.12 (m, 1 F), -113.88 --107.91 (m, 2 F)。

[0940] Step 9. Preparation of 5-((3R,5R)-3-amino-5-fluoropiperidin-1-yl)-N-(3-(difluoromethyl)-1-(1-(2-((3R)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3-methylpiperazin-1-yl)ethyl)piperidin-4-yl)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-37). 4.0 M HCl was added to N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[1-[2-[(3R)-4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-3-methyl-piperazin-1-yl]ethyl]-4-piperidinyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 12 (92.2 mg, 0.0976 mmol, 1.0 equivalents) in 1,4-dioxane (3.65 mL, 14.6 mmol, 150 equivalents). The mixture was sonicated for 30 min and then stirred at room temperature. After 1 h, LCMS showed complete conversion. The solvent was evaporated to dryness and the residue was purified by reversed-phase rapid chromatography (100 g C18 RediSep Rf Gold column, DMSO loading, MeCN / 0.02 M HCl (aq), 5% (3 CV) → 40%, 20 CV). The fractions were combined, concentrated, and lyophilized to give P-37 as a white solid (33.27 mg, 0.0387 mmol, 40% yield).

[0941] LCMS Method 3: At 215 nm, 98.3% purity, [M+H] + = 845.5, [M+2H] 2+ = 423.2, [M+3H] 3+ = 282.6.

[0942] 11H 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, 1H), 10.97 - 11.36 (m, 1 H).

[0943] 19 19F NMR (377 MHz, DMSO-d6) δ ppm -184.63 (s, 1 F), -111.63 (s, 2 F).

[0944] Example S13. Synthesis of P-40

[0945]

[0946] Step 1. Preparation of 3-[6-[4-(2,2-dimethoxyethyl)piperazin-1-yl]-1-methyl-indazole-3-yl]piperidine-2,6-dione (3). 2,2-Dimethoxyacetaldehyde 2 (0.14 mL, 0.90 mmol, 2 equivalents) and NaBH(OAc)3 (285.9 mg, 1.35 mmol, 3 equivalents) were added to a solution of 3-(1-methyl-6-piperazin-1-yl-indazole-3-yl)piperidine-2,6-dione dihydrochloride C-6 (180 mg, 0.45 mmol, 1 equivalent) and DIPEA (0.31 mL, 1.8 mmol, 4 equivalents) in CH2Cl2 (4.5 mL). The mixture was then stirred at room temperature. After 2 h, LCMS showed complete conversion. The mixture was then concentrated to remove CH2Cl2, and the residue was purified by reverse-phase FC (30 g C18 RediSep Rf Gold column, HPLC loading (DMSO + formic acid), gradient: 5 CV 5% MeCN / 0.1% HCOOH, followed by 30 CV 5 to 100% MeCN / 0.1% HCOOH, followed by 5 CV 100% MeCN / 0.1% HCOOH). The fractions were combined and concentrated to give 3 (121 mg, 60% yield) as a brown solid.

[0947] LCMS Method 1: At 215 nm, 92.3% purity, [M+H] + = 416.2.

[0948] 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 (brd, J = 8.8 Hz, 1 H), 7.50 (d, J = 9.0 Hz, 1 H), 10.84 (s, 1 H).

[0949] Step 2. Preparation of 2-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]piperazin-1-yl]acetaldehyde (4). Water (0.10 mL) and 4 M HCl in 1,4-dioxane (1.01 mL, 4.03 mmol, 1 equivalent) were added to a round-bottom flask containing 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 equivalent) at room temperature, followed by stirring at 50 °C. After 3 h, LCMS showed complete conversion. The solvent was removed under reduced pressure, and excess HCl was azeotropically distilled with MeCN (3 x) to give 4 (143 mg, quantitative yield) as a yellow solid, which was used unpurified for the next step.

[0950] LCMS Method 1: At 215 nm, 81.4% purity, [M+H2O+H] + = 388.2.

[0951] Step 3. N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[1-[2-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]piperazin-1-yl]ethyl]-4-piperidinyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate (6). At room temperature, acetaldehyde 4-(140 mg, 0.27 mmol, 1.4 equivalent), N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-(4-piperidinyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 5-(140 mg, 0.22 mmol, 1 equivalent), a synthetic intermediate from P-37, was added to a solution of 2-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]piperazin-1-yl]acetaldehyde 4-(140 mg, 0.27 mmol, 1.4 equivalent), N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-(4-piperidinyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]carbamate tert-butyl ester 8-(140 mg, 0.22 mmol, 1 equivalent), and DIPEA (0.17 mL, 1.11 mmol, 5 equivalent) in DMSO (0.5 mL) and CH2Cl2 (2 mL) with NaBH(OAc)3 (142 mg, 0.22 mmol, 1 equivalent). 0.67 mmol (3 equivalents). The mixture was then stirred at room temperature. After 18 h, LCMS showed complete conversion with impurities. CH2Cl2 was removed under reduced pressure and the residue in DMSO was purified by reverse-phase FC (50 g C18 RediSep Rf Gold column, LC loading (DMSO + formic acid), gradient: 5 CV 5% MeCN / 0.1% HCOOH, followed by 20 CV 5 to 100% MeCN / 0.1% HCOOH, followed by 5 CV 100% MeCN / 0.1% HCOOH). The fractions were combined, concentrated, and lyophilized to give 6 (78 mg, 38% yield) as a pale yellow solid.

[0952] LCMS Method 1: At 254 nm, 88.0% purity, [M+H] + = 931.2.

[0953] 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)。

[0954] Step 4. N-[3-(difluoromethyl)-1-[1-[2-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]piperazin-1-yl]ethyl]-4-piperidinyl]pyrazol-4-yl]-5-[(3R,5R)-3-amino-5-fluoro-1-piperidinyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (P-40). 4 M HCl was added to N-[(3R,5R)-1-[3-[[3-(difluoromethyl)-1-[1-[2-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]piperazin-1-yl]ethyl]-4-piperidinyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-piperidinyl]tert-butyl carbamate 6 (46 mg, 0.05 mmol, 1 equivalent) in 1,4-dioxane (0.62 mL, 2.47 mmol, 50 equivalent). The reaction mixture was stirred at room temperature. After 16 h, LCMS showed complete conversion. The volatiles were removed under reduced pressure and excess HCl was distilled off by azeotropic distillation with MeCN (3x). The residue was then purified by reversed-phase rapid chromatography (30 g C18 RediSep RfGold column, HPLC loading (water), gradient: 5 CV 5% MeCN / 0.1% HCOOH, followed by 20 CV 5 to 100% MeCN / 0.1% HCOOH, followed by 5 CV 100% MeCN / 0.1% HCOOH). The fractions were combined, concentrated, and lyophilized to give P-40 (21.4 mg, 51% yield) as a light pink solid.

[0955] LCMS Method 2: At 215 nm, 96.1% purity, [M+H] + = 831.4, [M+2H] 2+ = 416.2, [M+3H]3+ = 277.9.

[0956] 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, 1H), 8.40 (s, 1H), 8.82 (d, J = 7.8 Hz, 1H), 9.34 (s, 1H), 10.85 (s, 1H).

[0957] 19 F NMR (377 MHz, DMSO-d6) δ -183.57 (s, 1 F), -111.18 (d, J = 49.0Hz, 2 F).

[0958] The following compounds were synthesized via the same general route, with CBM (CX) modified in step 6 (Table 8).

[0959] Table 8.

[0960]

[0961]

[0962] Biological Examples

[0963] Example B1. IRAK4 PhosphoSens Biochemical Assay (BIOCHEM) Procedure

[0964] PhosphoSens® biochemical assays were performed as described by the marketer (AssayQuant Technologies Inc., Marlborough, MA). 1.25X IRAK4 stock solution (PV4002, ThermoFisherScientific, Waltham, MA) and 5X ATP stock solution, along with the Sox conjugated peptide substrate and AQT0326 (CSKS-AQT0326B, AssayQuant Technologies), were prepared in 1X enzyme reaction buffer, which consisted of: 0 mM HEPES, pH 7.5, 0.01% Brij-35, 0.5 mM EGTA, 20 mM MgCl2, and 1 mM DTT. 10 mL of ATP and substrate solution were mixed to achieve a final concentration of 200 mM ATP and 10 mM peptide substrate. The resulting solution was added to a Corning 3574 384-well, white, non-bound surface microtiter plate containing 0.5 mL of sequentially diluted test compound prepared in DMSO. 40 mL of enzyme solution was added to initiate the reaction at a final IRAK4 concentration of 1 nM, and λ was monitored every 71 seconds at room temperature using a BioTek Synergy H4 plate reader (Agilent Technologies, Santa Clara, CA). EX 360 / λ EM 485, monitored for 240 minutes. The initial linear portion of the process curve was fitted according to the linear equation to generate the slope, and converted to inhibition rate % based on the 100% activity value of the untreated inhibitor control. IC50 for each compound. 50 The values ​​were obtained by fitting the % inhibition-compound concentration curve using Dotmatics software (Dotmatics, Bishops Stortford, Hertfordshire, England).

[0965] Example B2. Reagent Preparation

[0966] Cell culture medium was prepared under sterile conditions by adding 10% FBS and 1% penicillin-streptomycin to 500 mL of phenol red-free RPMI 1640 medium. The medium was filtered through a Nalgene Bottle Top Filter and stored at 4°C.

[0967] Cell titer Glo (CTG) buffer and substrate (CellTiter-Glo luminescent cell viability assay, Promega Ref. # G7573) should be stored at -20°C. Warm 100 mL of CTG buffer in a bead bath and add it to the CTG substrate vial in a tissue culture hood. Mix the solutions by pipette until homogeneous. Aliquot the CTG reagent into 15 mL centrifuge tubes and store at -20°C.

[0968] For uniform time-resolved fluorescence (HTRF) assays, the Cisbio HTRF kit was used, which contains: lysis buffer #1 4X, blocking reagent #3 100X, 20X antibody 1 (anti-IRAK4 d2), 20X antibody 2 (anti-IRAK4 k), and detection buffer.

[0969] Store the 4X lysis buffer at 4°C. For use as a 1X lysis buffer, dilute the 4X solution with deionized water (distilled water, Gibco Cat.# 15230279) and 100X blocking agent at a volume ratio of 1:3:0.04.

[0970] Store aliquots of the 20X antibody solution at -80°C and the detection buffer at 4°C. For use as a 1X antibody solution, dilute aliquots of the 20X antibody solution with the detection buffer at a volume ratio of 1:19.

[0971] Example B3. Uniform time-resolved fluorescence (ALE THP1 HTRF) procedure for the final product of advanced lipid oxidation, THP1.

[0972] Cells were lysed by shaking at room temperature for 45 min. BCA protein was measured and normalized to the desired total protein concentration using 1X lysis buffer. Next, a 1X antibody solution was prepared by adding 380 µL of detection buffer to 20 µL of 20X antibody solution and mixing thoroughly. The 1X antibody solutions were mixed 1:1 and briefly centrifuged. For control wells, 20 µL of 1X anti-IRAK4-k antibody solution was reserved. In 384-well plates (ProxiPlate-384 Plus, Perkin Elmer Cat.# 6008289), 4 µL of the mixed antibody solution was added to empty wells using a single-channel pipette. Using a multi-channel pipette, 16 µL of lysate was added to each well, and any air bubbles formed were extinguished using a 20 µL pipette tip and Kimwipe edge. Three copies of each control were prepared in column 10. Buffer controls were prepared in wells A10, B10, and C10 by adding 16 µL of lysis buffer and 4 µL of detection buffer. In wells D10, E10, and F10, cryptate controls were prepared by adding 16 µL of lysis buffer, 2 µL of detection buffer, and 2 µL of 1X anti-IRAK4-k antibody solution. Negative controls were prepared in wells G10, H10, and I10 by adding 16 µL of lysis buffer and 4 µL of mixed antibody buffer. The plates were sealed with a clear seal and covered with an aluminum cap. The plates were shaken at 800 g for 5 min and incubated overnight in the dark at room temperature. The next day, the plates were shaken at 800 g for 5 min. Samples were analyzed using a Desnor 384 HTRF program via a plate reader (Envision, PerkinElmer).

[0973] Table 9 below provides a summary of the ALE THP1 HTRF data for the tested compounds.

[0974] Table 9. BIOCHEM and ALE THP1 HTRF results for the compounds.

[0975]

[0976]

[0977]

[0978] Although the invention has been described in detail through illustration and examples for purposes of clarity, these descriptions and examples should not be construed as limiting the scope of the invention. All disclosures of patents and scientific literature cited herein are expressly and completely incorporated herein by reference in their entirety.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in: R 1 It is a C1-C6 haloalkyl group; R a It is H or C1-C6 alkyl; R b It is a C1-C6 alkyl, a 5- to 6-membered heteroaryl, a -(C1-C6 alkylene)(5- to 6-membered heteroaryl), or a -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is determined by 1-5 R... 2 Group substitution; or R a and R b The dashed lines between them represent a ring structure, where R a and R b Together with the nitrogen atoms to which they are attached, they form 5- to 10-membered monocyclic or bicyclic heterocyclic groups, optionally containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-5 R... 2 Group substitution; Each R 2 Independently, it is -NH2, halogroup, C1-C6 alkyl, C1-C6 haloalkyl, -CN or 5 to 6-membered heteroaryl, wherein the heteroaryl contains 1 to 2 nitrogen atoms and is optionally substituted by 1 to 5 groups selected from C1-C6 alkyl, halogroup and C1-C6 haloalkyl; L 1 -C(O)N(H)-, -C(O)-, -(C1-C6 alkylene)N(R) 3 )- or C1-C6 alkylene; L 2 For bond, -C(O)-, -N(R) 3 - or O; Each R 3 Independently H or C1-C6 alkyl; Ring A is a monocyclic 4- to 6-membered subheterocyclic group or a bicyclic 6- to 9-membered spirosubheterocyclic group, wherein the heterocyclic group contains 1-2 nitrogen atoms, and wherein the subheterocyclic group is subjected to m R... 4 Group substitution; Each R 4 It is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl; m is 0-5; R 5 It is H or C1-C6 alkyl; Z is CH or N; and * indicates that it contains L 2 The connection points of the parts.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 It is a C1-C3 haloalkyl group.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein: R 1 It is -CHF2.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein: R a It is H or C1-C3 alkyl; R b It is a C1-C3 alkyl, a 6-membered heteroaryl, a -(C1-C3 alkylene)(6-membered heteroaryl), or a -(C1-C3 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is denoted by 1-2 R... 2 Group substitution; and Each R 2 It can be -NH2, halogen, C1-C3 alkyl, C1-C3 haloalkyl or -CN independently.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein: for or .

6. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein: R a and R b Together with the nitrogen atoms to which they are attached, they form 5- to 8-membered monocyclic or bicyclic heterocyclic groups, optionally containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-3 R... 2 Group substitution, and Each R 2 Independently, it is -NH2, halogen, C1-C3 alkyl, C1-C3 haloalkyl, -CN, or 5-membered heteroaryl, wherein the heteroaryl contains 1-2 nitrogen atoms and is optionally substituted by 1-3 groups selected from C1-C3 alkyl, halogen, and C1-C3 haloalkyl.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein: for or .

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein: L 1 -C(O)N(H)-, -C(O)-, -(C1-C3 alkylene)N(R) 3 )- or C1-C3 alkylene; L 2 For bond, -C(O)-, -N(R) 3 )- or O; and Each R 3 It is independently H or C1-C3 alkyl.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein: Ring A is (i) ; and Y 1 and Y 2 Independently CH or N, provided that Y 1 and Y 2 At least one of them is N; (ii) ; or (iii) .

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein: Each R 4 It is independently a halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein: m can be 0, 1, or 2.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein: Ring A is or .

13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein: R 5 It is H or C1-C3 alkyl.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein: R 5 It is -CH3.

15. The compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein: for or .

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, wherein the compound is a compound of formula (IA), (IB), (IIa), (IIb), (IIIa) or (IVa): (IA) in: R a It is H or C1-C6 alkyl; and R b It is a C1-C6 alkyl, a 5- to 6-membered heteroaryl, a -(C1-C6 alkylene)(5- to 6-membered heteroaryl), or a -(C1-C6 alkylene)NH2, wherein the heteroaryl contains 1-2 nitrogen atoms and optionally is determined by 1-5 R... 2 Group substitution; (ONE) in: A 5- to 10-membered monocyclic or bicyclic heterocyclic group optionally containing 1-2 additional heteroatoms selected from N and O, and optionally via 1-5 R... 2 Group substitution; (IIa) (IIb) (IIIa) (IVa)。 17. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from the compounds in Table 1.

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

19. A method for modulating interleukin-1 (IL1) receptor-associated kinase 4 (IRAK4), the method comprising contacting IRAK4 with an effective amount of a compound according to any one of claims 1-17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18.

20. A method of treating an inflammatory disease or autoimmune disease in a subject in need, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-17, or contact with a pharmaceutical composition according to claim 18, optionally wherein the inflammatory disease or autoimmune disease is atopic dermatitis, asthma, lupus erythematosus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoinflammatory syndrome, hidradenitis suppurativa, Behçet's syndrome, or familial cold autoinflammatory syndrome.

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