CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Serial No. 63/369,115, filed July 22, 2022, which is incorporated herein by reference in its entirety.

BACKGROUND

E3 ubiquitin ligases like Cereblon confer substrate specificity for ubiquitination, and therefore are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. Bifunctional compounds, such as those described in U.S. Patent Application Publication Nos. 2015/0291562 and 2014/0356322 (both incorporated herein by reference), function to recruit endogenous proteins to an E3 ubiquitin ligase for ubiquitination and degradation. In particular, the publications describe bifunctional or proteolysis targeting chimeric compounds (PROTAC® protein degraders), which find utility as modulators of targeted ubiquitination of a variety of polypeptides and proteins, which are then degraded via the proteasome system.

Interleukin-1 (IL-1) Receptor-Associated Kinase-4 (IRAK-4) is a serine/threonine kinase enzyme that plays an essential role in signal transduction by Toll/IL-1 receptors (TIRs). Diverse IRAK enzymes are key components in the signal transduction pathways mediated by interleukin-1 receptor (IL-1R) and Toll-like receptors (TLRs) (Janssens, S, et al. Mol. Cell. 11(2), 2003, 293-302). There are four members in the mammalian IRAK family: IRAK-1 , IRAK-2, IRAK-3, and IRAK-4. These proteins are characterized by a typical N- terminal death domain that mediates interaction with MyD88-family adaptor proteins and a centrally located kinase domain. Upon recruitment of MyD88 and IRAK-4 to the Tollinterleukin domain, activation leads to phosphorylation of IRAK-1 and/or IRAK-2 leading to engagement of TRAF6. Subsequent signaling results in activation of NF-KB and the release of various cytokines and chemokines. The MYD88 L265P mutation occurring in 91% Waldenstrom’s macroglobulinemia, 29% ABC DLBCL, 9% MALT lymphomas, and 3% CLL coordinates a constitutively active signalosome in which IRAK-4-mediated phosphorylation of IRAK-1 promotes the assembly of additional signaling proteins driving survival in these cancers.

Since IRAK-4 possesses kinase-dependent signaling activity (Lee KL, Ambler CM, Anderson DR, et al. J Med Chem. 2017;60(13):5521-42), degradation of IRAK-4 is a valuable inhibition and degradation target by small molecules. SUMMARY

Provided herein are compounds that degrade the IRAK-4 protein kinase. As such, these compounds are useful in the treatment of a variety of indications, including cancer and inflammation. Provided herein are compounds of Formula I: or a pharmaceutically acceptable salt thereof.

In embodiments, the compound of Formula I is a compound of Formulae Ih, li, or Ij:

or a pharmaceutically acceptable salt thereof. In embodiments, the compound of Formula I is a compound of Formulae Ik, Im, Io, or Ip: or a pharmaceutically acceptable salt thereof. In embodiments, the compound of Formula I is a compound of Formulae Iq or Ir:

or a pharmaceutically acceptable salt thereof. Also provided herein are pharmaceutical compositions comprising any one of the compounds described herein and a pharmaceutically acceptable excipient. Also provided herein are methods of treating a disease or disorder comprising administering to a subject an effective amount of any one of the compounds described herein. DETAILED DESCRIPTION Provided herein are compounds that degrade the IRAK-4 protein kinase. As such, these compounds, as well as pharmaceutical compositions that comprise these compounds, are useful in the treatment of a variety of indications, including cancer and inflammation diseases and disorders such as rheumatoid arthritis. Definitions In the specification, the singular forms (e.g., “a,” “an,” “the,” etc.) also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification controls. All percentages and ratios used herein, unless otherwise indicated, are by weight. Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. The terms “hal,” “halo,” or “halogen,” as used herein, refer to an atom selected from the group consisting of fluorine, chlorine, bromine, and iodine. The term “alkyl,” as used herein, refers to saturated, straight-chain or branched hydrocarbon radicals containing, in certain embodiments, from one to twenty, including from one to ten, or from one to six, carbon atoms. Branched means that one or more lower C _1-6 alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. Examples of C _1-6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, n-hexyl radicals; and examples of C _1-20 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals. Examples of C _1-20 alkyl radicals include but are not limited to hexadecamethyl, hexadecaethyl, hexadecopropyl, octadecamethyl, octadecaethyl, octadecapropyl and the like. The terms “haloalkyl”, “haloalkenyl”, or “haloalkynyl”, as used herein refer to an alkyl, alkenyl or alkynyl, including straight-chain and branched, that is substituted with one or more halogens or halo groups. Examples of haloalkyl include but are not limited to CF ₃ , CH ₂ CF ₃ , and CCl ₃ . The term “cycloalkyl,” as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound. Included within the term “cycloalkyl” are C _3-10 ring members C _3-8 ring members, and C _3-6 ring members. Also included within the term “cycloalkyl” are monocyclic C ₄ , C ₅ , C ₆ , and C ₇ cycloalkyl groups. Cycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged rings) or spirocyclic ring systems. Examples of C _3-8 cycloalkyl (3- to 8-membered cycloalkyl) include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C _3-12 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl and the like. “Heterocyclyl” or “heterocycloalkyl,” as used herein, are cyclic systems containing carbon and at least one heteroatom selected from N, O, S, and P, wherein there is not delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms, i.e., the cyclic ring system in non-aromatic. Included within the term “heterocycloalkyl” are 3–10 ring members, 4–7 ring members, 3–6 ring members, or 4–6 ring members. Also included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged rings) or spirocyclic ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl. As used herein, the term “aryl” means an aromatic carbocyclic system containing 1, 2 or 3 rings, wherein such rings may be fused, wherein fused is defined above. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated. The term “aryl” includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. In embodiments, aryl groups have 6 carbon atoms. In embodiments, aryl groups have from six to ten carbon atoms. In embodiments, aryl groups have from six to sixteen carbon atoms. In embodiments, the aryl group has six to ten carbon atoms. As used herein, the term “heteroaryl” means an aromatic carbocyclic system containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, and S and having 1, 2, or 3 rings wherein such rings may be fused, wherein fused is defined above. The term “heteroaryl” includes, but is not limited to, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8- tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta-[c]pyridinyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6- tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7- tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7-tetrahydro- 2H-indazolyl. In embodiment, heteroaryl is 5-10 membered heteroaryl. In another embodiment, heteroaryl is 5-6 membered heteroaryl. It is to be understood that if an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be bonded or otherwise attached to a designated moiety through differing ring atoms (i.e., shown or described without denotation of a specific point of attachment), then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term “pyridinyl” means 2-, 3- or 4-pyridinyl, the term “thienyl” means 2- or 3-thienyl, and so forth. The term “independently selected” is used herein to indicate that, for a variable which occurs in more than one location in a genus, the identity of the variable is determined separately in each instance. For example, if R ^x appears as a substituent on two different atoms, the two instances of R ^x may be the same moiety, or different moieties. The same is true if a single atom is substituted with more than one instance of R ^x . The identity of R ^x in each instance is determined independently of the identity of the other(s). It will be appreciated that the compounds, as described herein, may be substituted with one, two, three, four, five or more (up to the total possible number of substituents for the particular compound) independently selected substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas disclosed herein, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. The permissible substituents may include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Examples of substituents on the moieties disclosed herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, cycloalkenyl, non-aromatic heterocycle groups) include, but are not limited to, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroaryl, aryl, cycloalkyl, cycloalkenyl, non-aromatic heterocycle, hydroxyl, carbamoyl, oxo, amino, nitro, azido, -SH, and -CN. As described herein, compounds of the disclosure may optionally be substituted with one or more substituents, such as those described generally above, or as exemplified by particular classes, subclasses, and species of the disclosure. Unless otherwise indicated, an optionally substituted group may have a substituent at any or each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent independently selected from a specified group, the substituent may be either the same or different at each substituted every position. It is also to be understood that floating substituents on ring-containing scaffolds (e.g., cycloalkyl, heterocycloalkyl, aryl, and heteroaryl) are groups that can be designated to any substitutable position defined by the ring. In a non-limiting example, the substituent: covers, for example, both A “pharmaceutical composition” is a formulation containing one or more therapeutic agents (e.g., one or more compounds of the present disclosure) in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk form, e.g., for storage. Alternatively, the pharmaceutical composition is in unit dosage form. It can be advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active reagent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active agents and the particular therapeutic effect to be achieved, and the limitations in the art of compounding such an active agent for the treatment of individuals. A compound of the present disclosure may be administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable excipient. The formulation may be adapted for administration by any of a variety of routes including oral, buccal, rectal, vaginal, intranasal, intraocular, transdermal, subcutaneous, intravenous, or intramuscular. The term “pharmaceutical” or “pharmaceutically acceptable” when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the recipient. As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17 ^th Ed., (Mack Publishing Company, Easton, 1985), p.1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt. Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. Some of the compounds of the present disclosure may exist in unsolvated as well as solvated forms such as, for example, hydrates. “Pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes any excipient that is acceptable for veterinary use and/or human pharmaceutical use. A “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient. The terms “treat,” “treating,” and “treatment,” etc., as used herein, refer to any action providing a benefit to a patient for which the present compounds may be administered, including the treatment of any disease state or condition which is modulated through the target protein to which the present compounds bind. Disease states or conditions, including cancer, inflammatory diseases/disorders, autoimmune diseases/disorders, neurodegenerative diseases, and/or cardiovascular diseases/disorders, which may be treated using compounds according to the present disclosure are set forth hereinabove. The term “disease state or condition” is used to describe any disease state or condition wherein protein dysregulation (i.e., the amount of protein expressed in a patient is elevated) occurs and where degradation of the protein in a subject or patient may provide beneficial therapy or relief of symptoms to a subject or patient in need thereof. In certain instances, the disease state or condition may be cured. The term “neoplasia” or “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors. Exemplary cancers which may be treated by the present compounds either alone or in combination with at least one additional anti-cancer agent include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt’s lymphoma and Non-Hodgkin’s lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing’s sarcoma, hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin’s disease, Wilms’ tumor and teratocarcinomas. Additional cancers which may be treated using compounds according to the present disclosure include, for example, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T- cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitt’s Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML. Compounds Provided herein are compounds that are degraders of the protein kinase IRAK-4 and are thus useful in the treatment of cancer and inflammation, including rheumatoid arthritis. Provided herein are compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein ITM is:

wherein A is C(O)N(R ^a ) or N(R ^a )C(O); W* is N, C, or CH; W ¹ and W ⁶ are each independently C(O), O, N, CR ² , C(R ² ) ₂ , or NR ² ; W ² , W ³ , W ⁴ , W ⁵ , W ⁷ , W ⁸ , W ⁹ , W ¹⁰ , W ¹¹ , W ¹² , W ¹³ , W ¹⁴ , and W ¹⁵ are each independently selected from C, N, CR ² , C(R ² ) ₂ , and NR ² , wherein at least three of W ² , W ³ , W ⁴ , and W ⁵ are C, C(R ² ) ₂ , or CR ² , and wherein at least four of W ⁷ , W ⁸ , W ⁹ , W ¹⁰ , W ¹¹ , W ¹² , W ¹³ , W ¹⁴ , and W ¹⁵ are C, CR ² , or C(R ² ) ₂ ; R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, OC _1-6 alkyl, C _3-10 cycloalkyl, C _6-10 aryl, and 3-10 membered heterocycloalkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, OC _1-6 alkyl, C _3-10 cycloalkyl, C _6-10 aryl, and 3-10 membered heterocycloalkyl are optionally substituted with one, two, three, four, or five R ³ ; each R ² is independently selected from H, halo, C _1-6 alkyl, C _1-6 haloalkyl; each R ³ is independently selected from H, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _6-10 aryl, and 3–10 membered heterocycloalkyl; is a single bond or a double bond; and is the point of attachment to LNK; LNK is: wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each L is independently selected from C(R ^L ) ₂ , C(O), O, S, S(O) ₂ , N(R ^L ), C _3-10 cycloalkyl, 3–10 membered heterocycloalkyl, and C _6-10 aryl, wherein C _3-10 cycloalkyl, 3–10 membered heterocycloalkyl, and C _6-10 aryl are optionally substituted with one, two, three, four, or five R ^La ; each R ^L is independently selected from H, halo, C _1-6 alkyl, C _1-6 haloalkyl, OC _1-6 alkyl, N(C _1-6 alkyl) ₂ , NH ₂ , OH, SH, CN, and C _3-10 cycloalkyl; each R ^La is independently selected from H, halo, and C _1-6 alkyl; and CLM is: wherein Q ¹ and Q ⁴ are each independently selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), N, and NH; Q ² and Q ³ are each independently CR ¹³ or N; R ⁴ , R ⁶ , R ⁷ , R ⁹ , and R ¹¹ are each independently selected from H, C _1-6 alkyl, OC _1-6 alkyl, and C _1-6 haloalkyl; R ⁵ , R ⁸ , R ¹⁰ , and R ¹² are selected from H, halo, =O, C _1-6 alkyl, OC _1-6 alkyl, and C _1-6 haloalkyl; each R ¹³ is individually selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and OC _1-6 alkyl; ring B is selected from C ₆ aryl, 6-membered heteroaryl, and 6-membered heterocycloalkyl; and is the point of attachment to LNK. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, A is C(O)N(R ^a ) or N(R ^a )C(O); W* is N or C; W ¹ and W ⁶ are each independently C(O), N, CR ² , or C(R ² ) ₂ ; W ² , W ³ , W ⁴ , W ⁵ , W ⁷ , W ⁸ , W ⁹ , W ¹⁰ , W ¹¹ , W ¹² , W ¹³ , W ¹⁴ , and W ¹⁵ are each independently selected from C, N, CR ² , C(R ² ) ₂ , and NR ² , wherein at least three of W ² , W ³ , W ⁴ , and W ⁵ are C, C(R ² ) ₂ , or CR ² and wherein at least five of W ⁷ , W ⁸ , W ⁹ , W ¹⁰ , W ¹¹ , W ¹² , W ¹³ , W ¹⁴ , and W ¹⁵ are C, CR ² , or C(R ² ) ₂ ; R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3-10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ² is independently H or C _1-6 alkyl; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3-10 membered heterocycloalkyl; n is 1, 2, 3, 4, 5, 6, 7, or 8; each L is independently selected from C(R ^L ) ₂ , N(R ^L ), C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl, wherein C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl, are optionally substituted with one, two, or three R ^La ; each R ^L is independently selected from H, halo, and C _1-6 alkyl; each R ^La is independently selected from H, halo, and C _1-6 alkyl; Q ¹ and Q ⁴ are each independently selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; Q ² and Q ³ are each independently selected from CR ¹³ and N; R ⁴ , R ⁶ , R ⁷ , R ⁹ , and R ¹¹ are each independently selected from H and C _1-6 alkyl; R ⁵ , R ⁸ , R ¹⁰ , and R ¹² are selected from H, halo, =O, and C _1-6 alkyl; each R ¹³ is individually selected from H and C _1-6 alkyl; and ring B is selected from C ₆ aryl, 6-membered heteroaryl, and 6-membered heterocycloalkyl. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, A is C(O)N(R ^a ) or N(R ^a )C(O); W* is N or C; W ¹ and W ⁶ are each independently C(O), N, CR ² , or C(R ² ) ₂ ; W ² , W ³ , W ⁴ , W ⁵ , W ⁷ , W ⁸ , W ⁹ , W ¹⁰ , W ¹¹ , W ¹² , W ¹³ , W ¹⁴ , and W ¹⁵ are each independently selected from C, N, CR ² , C(R ² ) ₂ , and NR ² , wherein at least three of W ² , W ³ , W ⁴ , and W ⁵ are C, CR ² , or C(R ² ) ₂ and wherein at least six of W ⁷ , W ⁸ , W ⁹ , W ¹⁰ , W ¹¹ , W ¹² , W ¹³ , W ¹⁴ , and W ¹⁵ are C, CR ² , or C(R ² ) ₂ ; R ^a is H or C _1-6 alkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 4–7 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 4–7 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ² is independently H or C _1-6 alkyl; and each R ³ is independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, and 3–6 membered heterocycloalkyl; n is 1, 2, 3, 4, 5, or 6; each L is independently selected from C(R ^L ) ₂ , N(R ^L ), C _3-6 cycloalkyl, and 4–7 membered heterocycloalkyl, wherein C _3-6 cycloalkyl, and 4–7 membered heterocycloalkyl, are optionally substituted with one, two, or three R ^La ; each R ^L is independently selected from H, halo, and C _1-6 alkyl; each R ^La is independently H or halo; Q ¹ and Q ⁴ are each independently selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; Q ² and Q ³ are each independently CR ¹³ or N; R ⁴ , R ⁶ , R ⁷ , R ⁹ , and R ¹¹ are each independently H or C _1-6 alkyl; R ⁵ , R ⁸ , R ¹⁰ , and R ¹² are selected from H, halo, =O, and C _1-6 alkyl; each R ¹³ is individually H or C _1-6 alkyl; and ring B is selected from C ₆ aryl, 6-membered heteroaryl, and 6-membered heterocycloalkyl. In embodiments of Formula I, the ITM of Formula ITM-I is:

or a pharmaceutically acceptable salt thereof, wherein at least two of W ¹ , W ² , W ⁵ , and W ⁶ are C, CR ² , or C(R ² ) ₂ . In still another embodiment of Formula I, the ITM of Formula ITM-I is: or a pharmaceutically acceptable salt thereof. In embodiments of Formula I, the compound is Formulae Ia or Ib:

or a pharmaceutically acceptable salt thereof. In embodiments of Formula I, the compound is selected from Formulae Ic, Id, and Ie:

or a pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl, pyridinyl, pyrimidinyl, triazinyl, piperazinyl, and piperidinyl.

In embodiments of Formula I, the compound is Formulae If or Ig: or a pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl, pyridinyl, pyrimidinyl, triazinyl, piperazinyl, and piperidinyl. In embodiments of Formula Ia: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3-10 membered heterocycloalkyl; Q ¹ is selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; R ⁴ is H and C _1-6 alkyl; R ⁵ is selected from H, halo, =O, and C _1-6 alkyl; and each R ¹³ is individually H or C _1-6 alkyl. In embodiments of Formula Ib: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; R ⁶ and R ⁷ are each independently H or C _1-6 alkyl; and R ⁸ is selected from H, halo, =O, and C _1-6 alkyl. In embodiments of Formula Ic: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ¹ is selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; R ⁴ is selected from H and C _1-6 alkyl; R ⁵ is selected from H, halo, =O, and C _1-6 alkyl; and each R ¹³ is individually H or C _1-6 alkyl. In embodiments of Formula Id: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ² is CR ¹³ or N; R ⁹ is selected from H and C _1-6 alkyl; R ¹⁰ is selected from H, halo, =O, and C _1-6 alkyl; each R ¹³ is individually H or C _1-6 alkyl; and ring B is selected from C ₆ aryl, 6-membered heteroaryl, and 6-membered heterocycloalkyl. In an embodiment of Formula Ie: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3-10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ³ is CR ¹³ or N; Q ⁴ is selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; R ¹¹ is H or C _1-6 alkyl; R ¹² is selected from H, halo, =O, and C _1-6 alkyl; and each R ¹³ is individually H or C _1-6 alkyl. In embodiments of Formula If: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ² is CR ¹³ or N; R ⁹ is H or C _1-6 alkyl; R ¹⁰ is selected from H, halo, =O, and C _1-6 alkyl; each R ¹³ is individually H or C _1-6 alkyl; and ring B is selected from phenyl, pyridinyl, pyrimidinyl, triazinyl, piperazinyl, and piperidinyl. In embodiments of Formula Ig: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ³ is CR ¹³ or N; Q ⁴ is selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; R ¹¹ is H or C _1-6 alkyl; R ¹² is selected from H, halo, =O, and C _1-6 alkyl; and each R ¹³ is individually H or C _1-6 alkyl. In embodiments of Formula I, the LNK of Formula LNK is selected from Formulae LNK-I, LNK-II, and LNK-III: or a pharmaceutically acceptable salt thereof, wherein Q ⁵ , Q ⁶ , Q ⁷ , Q ⁸ , Q ⁹ , and Q ¹⁰ are each individually CH or N; W ¹⁶ and W ¹⁷ are selected from a bond, C(R ¹⁴ ) ₂ , C(O), and N(R ¹⁵ ); each R ¹⁴ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; each R ¹⁵ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; R ¹⁶ is selected from H, halo, CN, C _1-6 alkyl, and OC _1-6 alkyl; p1, p2, p5, and p6 are 1, 2, or 3; p3, p4, and p7 are 0, 1, 2, or 3; and is the point of attachment to ILM or CLM. In embodiments of Formula I, the compound is selected from Formulae Ih, Ii, or Ij:

or a pharmaceutically acceptable salt thereof. In embodiments of Formula I, the compound is selected from Formulae Ik, Im, Io, and Ip: or a pharmaceutically acceptable salt thereof. In embodiments of Formula I, the compound is Formulae Iq or Ir:

or a pharmaceutically acceptable salt thereof. In embodiments of Formula Ih: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ¹ is selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; Q ⁵ , Q ⁶ , and Q ⁷ are each individually CH or N; W ¹⁶ is selected from a bond, C(R ¹⁴ ) ₂ , C(O), and N(R ¹⁵ ); R ⁴ is H or C _1-6 alkyl; R ⁵ is selected from H, halo, =O, and C _1-6 alkyl; each R ¹³ is individually H or C _1-6 alkyl; each R ¹⁴ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; each R ¹⁵ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; R ¹⁶ is selected from H, halo, CN, C _1-6 alkyl, and OC _1-6 alkyl; p1 and p2 are 1, 2, or 3; and p3 is 0, 1, 2, or 3. In embodiments of Formula Ii: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3-10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ⁵ , Q ⁶ , and Q ⁷ are each individually CH or N; W ¹⁶ is selected from a bond, C(R ¹⁴ ) ₂ , C(O), and N(R ¹⁵ ); R ⁶ and R ⁷ are each independently H or C _1-6 alkyl; and R ⁸ is selected from H, halo, =O, and C _1-6 alkyl; each R ¹⁴ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; each R ¹⁵ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; R ¹⁶ is selected from H, halo, CN, C _1-6 alkyl, and OC _1-6 alkyl; p1 and p2 are 1, 2, or 3; and p3 is 0, 1, 2, or 3. In embodiments of Ij: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3-10 membered heterocycloalkyl; Q ¹ is selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; Q ⁸ and Q ⁹ are each individually selected from CH and N; R ⁴ is H or C _1-6 alkyl; R ⁵ is selected from H, halo, =O, and C _1-6 alkyl; each R ¹³ is individually H or C _1-6 alkyl; p4 is 0, 1, 2, or 3; and p5 and p6 are 1, 2, and 3. In embodiments of Formula Ik: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3-10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3-10 membered heterocycloalkyl; Q ¹ is selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; Q ⁵ , Q ⁶ , and Q ⁷ are each individually selected from CH and N; W ¹⁶ is selected from a bond, C(R ¹⁴ ) ₂ , C(O), and N(R ¹⁵ ); R ⁴ is H or C _1-6 alkyl; R ⁵ is selected from H, halo, =O, and C _1-6 alkyl; each R ¹³ is individually H or C _1-6 alkyl; each R ¹⁴ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; each R ¹⁵ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; R ¹⁶ is selected from H, halo, CN, C _1-6 alkyl, and OC _1-6 alkyl; p1 and p2 are 1, 2, or 3; and p3 is 0, 1, 2, or 3. In embodiments of Formula Im: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ² is CR ¹³ or N; Q ⁵ , Q ⁶ , and Q ⁷ are each individually selected from CH and N; W ¹⁶ is selected from a bond, C(R ¹⁴ ) ₂ , C(O), and N(R ¹⁵ ); R ⁹ is H or C _1-6 alkyl; R ¹⁰ is selected from H, halo, =O, and C _1-6 alkyl; and each R ¹³ is individually H or C _1-6 alkyl; each R ¹⁴ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; each R ¹⁵ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; R ¹⁶ is selected from H, halo, CN, C _1-6 alkyl, and OC _1-6 alkyl; p1 and p2 are 1, 2, or 3; p3 is 0, 1, 2, or 3; and ring B is selected from phenyl, pyridinyl, pyrimidinyl, triazinyl, piperazinyl, and piperidinyl. In embodiments of Formula Io: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3-10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ³ is CR ¹³ or N; Q ⁴ is selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; Q ¹⁰ is CH or N; W ¹⁷ is selected from a bond, C(R ¹⁴ ) ₂ , C(O), and N(R ¹⁵ ); R ¹¹ is H or C _1-6 alkyl; R ¹² is selected from H, halo, =O, and C _1-6 alkyl; each R ¹³ is individually selected from H and C _1-6 alkyl; each R ¹⁴ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; each R ¹⁵ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; and p7 is 0, 1, 2, or 3. In embodiments of Formula Ip: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3-10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ² is CR ¹³ or N; Q ⁸ and Q ⁹ are each individually CH or N; R ⁹ is H or C _1-6 alkyl; R ¹⁰ is selected from H, halo, =O, and C _1-6 alkyl; and each R ¹³ is individually H or C _1-6 alkyl; p4 is 0, 1, 2, or 3; p5 and p6 are 1, 2, or 3; and ring B is selected from phenyl, pyridinyl, pyrimidinyl, triazinyl, piperazinyl, and piperidinyl. In embodiments of Formula Iq: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ² is CR ¹³ or N; Q ⁵ , Q ⁶ , and Q ⁷ are each individually selected from CH and N; W ¹⁶ is selected from a bond, C(R ¹⁴ ) ₂ , C(O), and N(R ¹⁵ ); R ⁹ is H or C _1-6 alkyl; R ¹⁰ is selected from H, halo, =O, and C _1-6 alkyl; and each R ¹³ is individually H or C _1-6 alkyl; each R ¹⁴ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; each R ¹⁵ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; R ¹⁶ is selected from H, halo, CN, C _1-6 alkyl, and OC _1-6 alkyl; p1 and p2 are 1, 2, or 3; p3 is 0, 1, 2, or 3; and ring B is selected from phenyl, pyridinyl, pyrimidinyl, triazinyl, piperazinyl, and piperidinyl. In embodiments of Formula Ir: A is C(O)N(R ^a ) or N(R ^a )C(O); R ^a is selected from H, C _1-6 alkyl, and C _1-6 haloalkyl; R ¹ is selected from H, C _1-6 alkyl, OC _1-6 alkyl, and 3–10 membered heterocycloalkyl, wherein C _1-6 alkyl, OC _1-6 alkyl, and 3-10 membered heterocycloalkyl are optionally substituted with one, two, or three R ³ ; each R ³ is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, and 3–10 membered heterocycloalkyl; Q ³ is selected from CR ¹³ and N; Q ⁴ is selected from CR ¹³ , C(R ¹³ ) ₂ , C(O), and N; Q ¹⁰ is selected from CH and N; W ¹⁷ is selected from a bond, C(R ¹⁴ ) ₂ , C(O), and N(R ¹⁵ ); R ¹¹ is selected from H and C _1-6 alkyl; R ¹² is selected from H, halo, =O, and C _1-6 alkyl; each R ¹³ is individually selected from H and C _1-6 alkyl; each R ¹⁴ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; each R ¹⁵ is individually selected from H, C _1-6 alkyl, and OC _1-6 alkyl; and p7 is 0, 1, 2, or 3. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, W* is C. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, W* is N. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, W ¹ and W ⁶ are each independently selected from CH, CH ₂ , C(O), and N. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, W ¹ is C(O). In embodiments of Formula I or a pharmaceutically acceptable salt thereof, W ¹ is N. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, W ⁶ is CH. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, W ⁶ is CH ₂ . In embodiments of Formula I or a pharmaceutically acceptable salt thereof, A is C(O)N(R ^a ). In embodiments of Formula I or a pharmaceutically acceptable salt thereof, A is N(R ^a )C(O). In embodiments of Formula I or a pharmaceutically acceptable salt thereof, ring B is selected from phenyl, pyridinyl, and piperazinyl. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, ring B is phenyl. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, ring B is pyridinyl. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, ring B is piperazinyl. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ¹ is OC _1-6 alkyl or 4–7 heterocycloalkyl and R ³ is C _1-6 alkyl or 3–6 membered heterocycloalkyl. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ⁴ is H. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ⁵ is H. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ⁵ is halo. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ⁵ is OC _1-6 alkyl. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ⁶ is H. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ⁷ is H. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ⁸ is H or halo. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ⁸ is halo. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ⁹ is H. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ¹⁰ is H. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ¹⁰ is halo. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ¹⁰ is =O. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ¹⁰ is OC _1-6 alkyl. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ¹¹ is H. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ¹² is H. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, Q ¹ is C(O) or CH ₂ . In embodiments of Formula I or a pharmaceutically acceptable salt thereof, Q ² is N or CH. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, Q ³ is N or CH. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, Q ⁴ is N or CH. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, Q ⁵ is N or CH. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, Q ⁶ is N or CH. In embodiments off Formula I or a pharmaceutically acceptable salt thereof, Q ⁷ is N or CH. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, Q ⁸ is N or CH. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, Q ⁹ is N or CH. In another embodiment of Formula I or a pharmaceutically acceptable salt thereof, Q ¹⁰ is N or CH. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, wherein W ¹⁶ is CH ₂ , NH, or N(CH ₃ ). In embodiments of Formula I or a pharmaceutically acceptable salt thereof, W ¹⁷ is a bond. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, W ¹⁷ is C(O). In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ¹⁶ is H. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ¹⁶ is halo. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p1 is 1. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p1 is 2. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p2 is 1. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p2 is 2. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p3 is 0. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p3 is 1. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p3 is 2. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p4 is 1. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p5 is 1. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p5 is 2. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p6 is 1. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p6 is 2. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, p7 is 1. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ^a is H. In embodiments of Formula I or a pharmaceutically acceptable salt thereof, R ^a is C _1-6 alkyl. In embodiments of Formula I, LNK is selected from: or a pharmaceutically acceptable salt thereof. In embodiments of Formula I, the compound is selected from

or a pharmaceutically acceptable salt thereof. Also provided herein are pharmaceutical compositions comprising any one of the compounds described herein, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients. In embodiments, the pharmaceutical composition further comprises an additional bioactive agent, wherein the bioactive agent is an anti-cancer agent, an anti-inflammatory agent, an anti-neurodegenerative agent, or an anti-immunological agent. The compounds disclosed herein may exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, and the like). The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. Chiral centers, of which the absolute configurations are known, are labelled by prefixes R and S, assigned by the standard sequence-rule procedure, and preceded when necessary by the appropriate locants (Pure & Appl. Chem.45, 1976, 11–30). Certain examples contain chemical structures that are depicted or labelled as an (R*) or (S*). When (R*) or (S*) is used in the name of a compound or in the chemical representation of the compound, it is intended to convey that the compound is a pure single isomer at that stereocenter; however, absolute configuration of that stereocenter has not been established. Thus, a compound designated as (R*) refers to a compound that is a pure single isomer at that stereocenter with an absolute configuration of either (R) or (S), and a compound designated as (S*) refers to a compound that is a pure single isomer at that stereocenter with an absolute configuration of either (R) or (S). It is generally well known in the art that any compound that will be converted in vivo to provide a compound disclosed herein is a prodrug within the scope of the present disclosure. Compounds provided herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can used in various studies such as NMR spectroscopy, metabolism experiments, and/or assays. In the compounds provided herein, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise stated, when a position is designated specifically as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% incorporation of deuterium). In embodiments, the compounds provided herein have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Methods of Treatment This application pertains to methods of treating or ameliorating a disease state or condition that is modulated through or causally related to the target protein, i.e., IRAK-4. Provided herein are methods of treating a disease or disorder comprising administering to a subject an effective amount of a compound disclosed herein, or a therapeutically effective amount of a pharmaceutical composition disclosed herein. In embodiments, the disease or disorder is a neurodegenerative disease or disorder, an inflammatory disease or disorder, an immunological disease or disorder, and/or a cancer associated with signaling through signaling pathways regulated by IRAK-4, and/or the myddosome complex. In embodiments, the neurodegenerative and/or neuroinflammatory disease or disorder is stroke, traumatic brain injury, optic neuritis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, or graft versus host disease. In embodiments, the inflammatory disease or disorder is ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn’s disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, inflammation associated with or caused by multiple sclerosis, endocrine opthalmopathy, Grave’s disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren’s syndrome, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (e.g., including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal disease, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, fibrositis, gastritis, gastroenteritis, nasal sinusitis, ocular allergy, silica induced diseases, chronic obstructive pulmonary disease (COPD), cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, juvenile rheumatoid arthritis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Cryopyrin Associated Periodic Syndrome (CAPS), or osteoarthritis. In embodiments, the immunological disease or disorder is multiple sclerosis, rheumatoid arthritis, spondyloarthropathy, systemic lupus erythematosus, antibody-mediated inflammatory or autoimmune disease, graft-versus-host disease, sepsis, diabetes, psoriasis, atheroma, atherosclerosis, Sjogren’s syndrome, progressive systemic sclerosis, scleroderma, acute coronary syndrome, ischemia reperfusion, Crohn’s disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis. In embodiments, the cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt’s lymphoma and Non-Hodgkin’s lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing’s sarcoma, hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin’s disease, Wilms' tumor and teratocarcinomas, T-lineage Acute lymphoblastic Leukemia (T-ALL), T- lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitt’s Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, or Philadelphia chromosome positive CML. Administration / Dosages / Formulations Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable preparations (for example, sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

To prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this disclosure.

The ointments, pastes, creams, and gels may contain, in addition to an active compound of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Compounds of the present disclosure can be administered intratympanically, wherein a long, narrow, bore needle is passed through the ear canal and through the eardrum to administer medications into the middle ear space where they are absorbed by the inner ear. According to the methods of treatment of the present disclosure, disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the disclosure, in such amounts and for such time as is necessary to achieve the desired result. The term “effective amount” of a compound of the disclosure, as used herein, means a sufficient amount of the compound so as to decrease the symptoms of a disorder in a subject. As is well understood in the medical arts an effective amount of a compound of this disclosure will be at a reasonable benefit/risk ratio applicable to any medical treatment. In general, compounds of the disclosure will be administered in effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. An effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g., humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, e.g., in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca.1 to 50 mg active ingredient. In embodiments, an effectiveamount or dose of the compounds of the present disclosure may range from about 0.1 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. In general, treatment regimens according to the present disclosure comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this disclosure per day in single or multiple doses. Therapeutic amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. Upon improvement of a subject’s condition, a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained; when the symptoms have been alleviated to the desired level, treatment should cease. The subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

The disclosure also provides for a pharmaceutical combination, e.g., a kit, comprising a) a first agent which is a compound of the disclosure as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.

Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylenepolyoxypropylene-block polymers; wool fat; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such a propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions. Further, non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition and a pharmaceutically acceptable carrier, are other embodiments of the present disclosure.

Kits

Also provided herein are kits comprising a compound capable of degrading IRAK-4 protein kinase selected from one or more compounds of disclosed herein, or pharmaceutically acceptable salts thereof, and instructions for use in treating a disorder associated with IRAK-4 protein kinases.

The disclosure provides a kit comprising a compound capable of degrading IRAK-4 protein kinase selected from a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

Also provided herein are kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof for the treatment of any of the indications disclosed herein.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings of the present disclosure as set forth. EXAMPLES The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art. The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings of the present disclosure as set forth. Abbreviations AcOH or HOAc Acetic acid Ac ₂ O Acetic anhydride AIBN Azobisisobutyronitrile BrettPhos Pd G4 Dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2- yl)phenyl]phenyl]phosphane;methanesulfonic acid;N-methyl-2- phenylaniline;palladium CCl ₄ Carbon tetrachloride CDCl ₃ Chloroform-d CDI Carbonyldiimidazole Cs ₂ CO ₃ Cesium carbonate DAST Diethylaminosulfur trifluoride DCE Dichloroethane DCM Dichloromethane DIEA or DIPEA Diisopropylethylamine DMAP Dimethylaminopyridine DMF N,N-Dimethylformamide DMP Dess-Martin periodinane DMSO Dimethyl sulfoxide DMSO-d ₆ Deuterated dimethyl sulfoxide (C ₂ D ₆ SO) EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI Electrospray ionization EtOH Ethanol eq Equivalent(s) g Gram(s) h or hr. Hour(s) HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate Hz Hertz HCl Hydrochloric acid HNO ₃ Nitric acid HPLC High performance liquid chromatography H ₂ SO ₄ Sulfuric acid i-PrOH Iso-propanol K ₂ CO ₃ Potassium carbonate K ₃ PO ₄ Potassium phosphate LCMS Liquid chromatography-mass spectrometry m-CPBA Meta-Chloroperbenzoic acid MeCN Acetonitrile m/z Mass/charge MS Mass spectrometry MHz Megahertz MeOH Methanol μL Microliter(s) μm Micrometer(s) μmol Micromole(s) mg Milligram(s) mm Millimeter(s) mL Milliliter(s) mM Millimolar mmol Millimole(s) NaBH(OAc) ₃ Sodium triacetoxyborohydride NaN ₃ Sodium azide NH4Cl Ammonium chloride NMR Nuclear magnetic resonance NBS N-bromosuccinimide OMs Methanesulfonate OTf Trifluoromethanesulfonate Pd/C Palladium on carbon Pd2(dba) ₃ Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane Pd(OAc) ₂ Palladium (II) acetate PMB para-Methoxybenzyl PPh ₃ Triphenylphosphine psi Pound(s) per square inch Py Pyridine SFC Supercritical fluid chromatography SPhos Pd G3 (2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) [2-(2′- amino-1,1′-biphenyl)]palladium(II) methanesulfonate TBAF tetra-n-Butylammonium fluoride t-BuOK Potassium tert-butoxide tBuXPhos Pd G1 Chloro[2-(di-tert-butylphosphino)-2’,4’,6’-triisopropy l-1,1’- biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) TEA Triethylamine TFA Trifluoroacetic acid TF ₂ O Trifluoromethanesulfonic anhydride THF Tetrahydrofuran TLC Thin-layer chromatography TMSOTf Trimethylsilyl trifluoromethanesulfonate Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Xphos Pd G3 (2-Dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’- biphenyl)[2- (2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate Scheme 1.

A compound of formula INT-I, wherein R is an ether, may be reacted with a reagent INT-II (commercially available or readily prepared using standard reaction techniques known to one skilled in the art) under reductive amination or alkylation conditions to produce a compound of formula INT-III, wherein L is as defined herein. Compounds of formula INT-III can be furnished from N-alkylation where Y is an appropriate leaving group (e.g. OMs, OTs, Cl, etc.) or through reductive amination where Y is an aldehyde or ketone. When Y is a leaving group, suitable reaction conditions are those for an alkylation reaction, e.g. diisopropylethylamine, potassium iodide, DMSO or acetonitrile, 80 °C. When Y is a carbonyl, suitable reaction conditions are those for a reductive amination reaction, e.g. sodium cyanoborohydride, methanol, dichloromethane, acetic acid, room temperature. Compounds of formula INT-III can then be reacted with compounds of formula INT-IV wherein Z is CH ₂ or C=O, R ₂ is either H or OMe, and X is an alcohol, triflate, or a halide to produce compounds of formula CMPD-V. Scheme A. Synthetic sequence for the preparation of N-[7-isopropoxy-2-(4- piperidyl)imidazo[1,2-a]pyridin-6-yl]pyrazolo[1,5-a]pyrimidi ne-3-carboxamide (INT-1), an example of generic intermediate INT-I in Scheme 1.

Synthesis of example INT-1. Step 1: tert-butyl 5-bromo-4-isopropoxy-pyridin-2-amine To a solution of sodium (12.93 g, 562.4 mmol, 13.33 mL, 4.49 eq) in isopropanol (260 mL) was added 5-bromo-4-chloro-pyridin-2-amine (26.0 g, 125.3 mmol, 1 eq). The reaction mixture was stirred at 82 °C for 12 h. The reaction mixture was cooled to room temperature and poured into ice, then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with a gradient from 0 to 80% ethyl acetate in petroleum ether gradient.5-bromo-4-isopropoxy-pyridin-2-amine (10 g, 43.3 mmol, 34% yield) was obtained as light yellow solid. MS (ESI) m/z: 231.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.02 (s, 1H), 5.98 (s, 1H), 4.64 - 4.49 (m, 1H), 1.40 (d, J = 6.0 Hz, 6H). Step 2: tert-butyl 4-(6-bromo-7-isopropoxy-imidazo[1,2-a]pyridin-2-yl)piperidin e-1- carboxylate To a solution of 5-bromo-4-isopropoxy-pyridin-2-amine (950 mg, 4.11 mmol, 1 eq) and tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (1.51 g, 4.93 mmol, 1.2 eq) in ethyl alcohol (20 mL) was added sodium bicarbonate (691 mg, 8.22 mmol, 2 eq). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Waters Xbridge C18150 x 50mm x 10mm; mobile phase: [water(10mM ammonium bicarbonate)-acetonitrile]; B%: 50-80%). The desired compound tert-butyl 4-(6-bromo-7- isopropoxy-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxyla te (1.1 g, 2.51 mmol, 61% yield) was obtained as white solid. MS (ESI) m/z: 438.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.17 (s, 1H), 7.12 (s, 1H), 6.85 (s, 1H), 4.69 - 4.49 (m, 1H), 4.31 - 4.09 (m, 2H), 3.00 - 2.79 (m, 3H), 2.12 - 1.97 (m, 2H), 1.74 - 1.57 (m, 2H), 1.47 (s, 9H), 1.43 (d, J = 6.0 Hz, 6H). Step 3: tert-butyl 4-[7-isopropoxy-6-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino )imidazo[1,2- a]pyridin-2-yl]piperidine-1-carboxylate To a solution of tert-butyl 4-(6-bromo-7-isopropoxy-imidazo[1,2-a]pyridin-2- yl)piperidine-1-carboxylate (1 g, 2.28 mmol, 1 eq) and pyrazolo[1,5-a]pyrimidine-3- carboxamide (370 mg, 2.28 mmol, 1 eq) in dioxane (10 mL) was added BrettPhos Pd G4 (210 mg, 0.23 mmol, 0.1 eq) and cesium carbonate (1.49 g, 4.56 mmol, 2 eq). The reaction mixture was stirred at 90 °C for 12 h under an atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% methanol in dichloromethane. The desired compound tert-butyl 4-[7-isopropoxy-6-(pyrazolo[1,5-a]pyrimidine-3- carbonylamino)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carbox ylate (1.11 g, 2.14 mmol, 93% yield) was obtained as yellow solid. MS (ESI) m/z: 520.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.43 (s, 1H), 9.50 (s, 1H), 8.85 (dd, J = 1.6, 7.2 Hz, 1H), 8.76 (s, 1H), 8.70 (dd, J = 1.6, 4.0 Hz, 1H), 7.20 (s, 1H), 7.08 (dd, J = 4.0, 7.2 Hz, 1H), 6.93 (s, 1H), 4.81 - 4.69 (m, 1H), 4.29 - 4.13 (m, 2H), 2.97 - 2.81 (m, 3H), 2.14 - 2.05 (m, 2H), 1.79 - 1.62 (m, 2H), 1.55 (d, J = 6.0 Hz, 6H), 1.48 (s, 9H). Step 4: N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]py razolo[1,5-a]pyrimidine-3- carboxamide To a solution of tert-butyl 4-[7-isopropoxy-6-(pyrazolo[1,5-a]pyrimidine-3- carbonylamino)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carbox ylate (1.2 g, 2.31 mmol, 1 eq) in dichloromethane (10 mL) was added a solution of hydrogen chloride in methanol (4 M, 120 mL). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted in a 10:1 mixture of dichloromethane: methanol (20 mL). Ammonium hydroxide was added to adjust the pH of the solution between 8-9, then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1 to dichloromethane: methanol = 10: 1) to afford N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2- a]pyridin-6-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (950 mg, 2.26 mmol, 98% yield) as a yellow solid. MS (ESI) m/z: 420.1 [M+H] ⁺ . Example 1: N-[2-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin- 5-yl]-3-fluoro-azetidin- 3-yl]methyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin -6-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide Step 1: tert-butyl 3-fluoro-3-[[4-[7-isopropoxy-6-(pyrazolo[1,5-a]pyrimidine-3- carbonylamino)imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]methyl ]azetidine-1-carboxylate To a solution of N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (800 mg, 1.91 mmol, 1 eq) and tert-butyl 3- fluoro-3-(p-tolylsulfonyloxymethyl)azetidine-1-carboxylate (1.37 g, 3.81 mmol, 2 eq) in DMSO (3 mL) was added N,N-diisopropylethylamine (1.23 g, 9.54 mmol, 5 eq). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by the addition of water (10 mL), and then diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with a gradient from 0 to 10% methanol in dichloromethane to afford tert-butyl 3-fluoro-3-[[4-[7-isopropoxy-6-(pyrazolo[1,5- a]pyrimidine-3-carbonylamino)imidazo[1,2-a]pyridin-2-yl]-1-p iperidyl]methyl]azetidine-1- carboxylate (700 mg, 1.15 mmol, 60% yield) as a yellow solid. MS (ESI) m/z: 607.4 [M+H] ⁺ . Step 2: N-[2-[1-[(3-fluoroazetidin-3-yl)methyl]-4-piperidyl]-7-isopr opoxy-imidazo[1,2- a]pyridin-6-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide To a solution of tert-butyl 3-fluoro-3-[[4-[7-isopropoxy-6-(pyrazolo[1,5-a]pyrimidine-3- carbonylamino)imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]methyl ]azetidine-1-carboxylate (500 mg, 0.82 mmol, 1 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (3.08 g, 27.01 mmol, 2.00 mL). The reaction mixture was stirred at 25 °C for 0.5 h and then concentrated under reduced pressure to give a residue which was diluted with a 10:1 solution of dichloromethane:methanol (20 mL). Ammonium hydroxide was added to adjust the pH of the solution between 8 and 9 before concentrating under reduced pressure. The residue was purified by prep-HPLC (Waters Xbridge 150*25mm*5μm; mobile phase: [water(10mM ammonium bicarbonate)-acetonitrile]; B%: 21-51%) to afford N-[2-[1-[(3- fluoroazetidin-3-yl)methyl]-4-piperidyl]-7-isopropoxy-imidaz o[1,2-a]pyridin-6-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (280 mg, 0.55 mmol, 67% yield) as an off-white solid. MS (ESI) m/z: 507.2 [M+H] ⁺ . Step 3: N-[2-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin- 5-yl]-3-fluoro-azetidin-3- yl]methyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6 -yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide To a solution of N-[2-[1-[(3-fluoroazetidin-3-yl)methyl]-4-piperidyl]-7-isopr opoxy- imidazo[1,2-a]pyridin-6-yl]pyrazolo[1,5-a]pyrimidine-3-carbo xamide (90 mg, 0.18 mmol, 1 eq) in DMSO (3 mL) was added N,N-diisopropylethylamine (115 mg, 0.89 mmol, 5 eq) and 2- (2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (98 mg, 0.36 mmol, 2 eq). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched by addition of water (10 mL), and then diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative thin layer chromatography (eluted with dichloromethane: methanol = 10:1). The residue was then further purified by preparative HPLC (Phenomenex Synergi C18150*25mm*10μm; mobile phase: [water(0.225%formic acid)-acetonitrile]; B%: 3-33%) to afford N-[2-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-5-yl]-3-fluoro-azetidin-3-yl]methyl]-4-piperidyl] -7-isopropoxy-imidazo[1,2-a]pyridin- 6-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (56.6 mg, 0.074 mmol, 41% yield, 99% purity) as a yellow solid. MS (ESI) m/z: 763.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.08 (s, 1H), 10.47 (s, 1H), 9.46 (s, 1H), 9.40 (dd, J = 1.2, 6.8 Hz, 1H), 8.88 (dd, J = 1.2, 4.0 Hz, 1H), 8.72 (s, 1H), 8.17 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.36 (dd, J = 4.4, 7.2 Hz, 1H), 7.06 (s, 1H), 6.91 (d, J = 1.6 Hz, 1H), 6.77 (dd, J = 1.6, 8.0 Hz, 1H), 5.07 (dd, J = 5.2, 12.8 Hz, 1H), 4.95 - 4.81 (m, 1H), 4.28 - 4.10 (m, 4H), 3.03 - 2.80 (m, 6H), 2.63 - 2.55 (m, 2H), 2.35 - 2.24 (m, 2H), 2.07 - 1.98 (m, 1H), 1.96 - 1.89 (m, 2H), 1.76 - 1.59 (m, 2H), 1.47 (d, J = 6.0 Hz, 6H). Table 1. The following compounds were prepared in an analogous fashion as described for the synthesis of Example 1 according to the general synthetic sequence in Scheme 1. Example 9: N-[2-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin- 5-yl]-3-fluoro-azetidin- 3-yl]methyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin -6-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide Step 1: tert-butyl 4-(2-(5-bromo-2-imino-4-isopropoxypyridin-1(2H)-yl)acetyl)pi perazine-1- carboxylate A solution of 5-bromo-4-isopropoxypyridin-2-amine (2.6 g, 11.25 mmol, 1 eq), tert- butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (7.02 g, 22.85 mmol, 2.03 eq) in ethanol (15 mL) was stirred at 25 °C for 12 h. The reaction mixture was filtered and the cake was washed with petroleum ether (20 mL × 3), and dried to afford tert-butyl 4-(2-(5-bromo-2- imino-4-isopropoxypyridin-1(2H)-yl)acetyl)piperazine-1-carbo xylate (4.5 g, 9.84 mmol, 87% yield) as a white solid which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.31 (s, 1H), 8.26 (br s, 2H), 6.59 (s, 1H), 5.12 (s, 2H), 4.83 - 4.72 (m, 1H), 3.54 - 3.37 (m, 8H), 1.42 (s, 9H), 1.39 (d, J = 6.0 Hz, 6H). Step 2: 1-(4-(6-bromo-7-isopropoxyimidazo[1,2-a]pyridin-2-yl)piperaz in-1-yl)-2,2,2- trifluoroethanone To a solution of tert-butyl 4-(2-(5-bromo-2-imino-4-isopropoxypyridin-1(2H)- yl)acetyl)piperazine-1-carboxylate (4 g, 8.75 mmol, 1 eq) in 1,2-dichloroethane (160 mL) was added trifluoroacetic anhydride (18.12 g, 86.27 mmol, 12.00 mL, 9.86 eq) and the mixture was stirred at 100 °C for 3 h. The reaction mixture was poured into 100 mL of ice water and the pH was adjusted to 8 and further diluted with 1,2-dichloroethane (200 mL). The organic phase was separated, washed with brine (45 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was stirred with methanol (50 mL) at 25 °C for 0.5 h and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250*70mm,10 mm); mobile phase: [water (0.225% formic acid) - acetonitrile]; B%: 15-45%) to afford 1-(4-(6-bromo-7-isopropoxyimidazo[1,2-a]pyridin-2-yl)piperaz in-1-yl)-2,2,2- trifluoroethanone (3.0 g, 6.89 mmol, 79% yield) as a white solid. MS (ESI) m/z: 182.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.09 (s, 1H), 6.76 (s, 1H), 6.67 (s, 1H), 4.63 - 4.52 (m, 1H), 3.85 (t, J = 4.8 Hz, 2H), 3.76 (t, J = 4.8 Hz, 2H), 3.35 (td, J = 4.8, 12.8 Hz, 4H), 1.42 (d, J = 6.0 Hz, 6H). Step 3: N-(7-isopropoxy-2-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)i midazo[1,2-a]pyridin-6- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide To a solution of 1-(4-(6-bromo-7-isopropoxyimidazo[1,2-a]pyridin-2-yl)piperaz in-1-yl)- 2,2,2-trifluoroethanone (3 g, 6.89 mmol, 1 eq) and pyrazolo[1,5-a]pyrimidine-3-carboxamide (2.25 g, 13.88 mmol, 2.01 eq) in dioxane (105 mL) was added potassium carbonate (2 g, 14.47 mmol, 2.10 eq) and BrettPhos Pd G4 (650 mg, 706.12 mmol, 1.02e-1 eq). The reaction mixture was stirred at 90 °C for 12 h under an atmosphere of nitrogen and then quenched by the addition of water (100 mL) at 25 °C. The mixture was then extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 (250*70mm,10 μm); mobile phase: [water (0.225% formic acid) -acetonitrile]; B%: 15-45%) to afford N-(7-isopropoxy-2-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)i midazo[1,2-a]pyridin-6- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.2 g, 2.32 mmol, 34% yield) as a yellow solid. MS (ESI) m/z: 517.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.42 (s, 1H), 9.46 - 9.29 (m, 2H), 8.86 (dd, J = 1.6, 4.4 Hz, 1H), 8.71 (s, 1H), 7.34 (dd, J = 4.4, 6.8 Hz, 1H), 7.20 (s, 1H), 6.99 (s, 1H), 4.90 - 4.79 (m, 1H), 3.76 - 3.67 (m, 4H), 3.26 (br s, 4H), 1.45 (d, J = 6.0 Hz, 6H). Step 4: N-(7-isopropoxy-2-(piperazin-1-yl)imidazo[1,2-a]pyridin-6-yl )pyrazolo[1,5- a]pyrimidine-3-carboxamide To a solution of N-(7-isopropoxy-2-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)i midazo[1,2- a]pyridin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (400 mg, 774.48 μmol, 1 eq) in methanol (16 mL), water (4 mL) was added potassium carbonate (600.0 mg, 4.34 mmol, 5.61 eq) and stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was washed with a 10:1 solution of dichloromethane:methanol (25 mL × 2), filtered and concentrated under reduced pressure to afford N-(7-isopropoxy-2- (piperazin-1-yl)imidazo[1,2-a]pyridin-6-yl)pyrazolo[1,5-a]py rimidine-3-carboxamide (325 mg, 772.95 mmol, 100% yield) as a yellow solid which was used in the next step without further purification. MS (ESI) m/z: 421.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.42 (s, 1H), 9.43 - 9.33 (m, 2H), 8.90 - 8.84 (m, 1H), 8.71 (s, 1H), 7.35 (dd, J = 4.0, 6.8 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.97 (s, 1H), 4.90 - 4.80 (m, 1H), 4.18 - 4.10 (m, 1H), 3.41 - 3.38 (m, 2H), 3.18 - 3.15 (m, 2H), 3.06 - 2.99 (m, 4H), 2.80 (br s, 1H), 1.45 (d, J = 6.0 Hz, 6H). Step 5: tert-butyl 5-bromo-2-fluorobenzoate A solution of N,N'-methanediylidenedicyclohexanamine (8.3 g, 40.23 mmol, 8.14 mL, 1.1 eq) in tetrahydrofuran (80 mL) was added dropwise to a stirred solution of 5-bromo-2- fluorobenzoic acid (8 g, 36.53 mmol, 1 eq) and dimethylaminopyridine (4.5 g, 36.83 mmol, 1.01 eq) in tert-butanol (200 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with a gradient from 20:1 to 5:1 petroleum ether:ethyl acetate to afford tert-butyl 5-bromo-2-fluorobenzoate (7.6 g, 27.62 mmol, 76% yield) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.91 (dd, J = 2.4, 6.4 Hz, 1H), 7.87 - 7.79 (m, 1H), 7.32 (dd, J = 8.8, 10.4 Hz, 1H), 1.53 (s, 9H). Step 6: (3-fluoroazetidin-3-yl)methanol To a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (5.0 g, 24.36 mmol, 1 eq) in dichloromethane (50 mL) was added trifluoroacetic acid (38.50 g, 337.65 mmol, 25 mL, 13.86 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford (3-fluoroazetidin-3-yl)methanol (8 g, 24.01 mmol, 99% yield, 2 trifluoroacetic acid) as a yellow oil which was used in the next step without further purification. Step 7: tert-butyl 2-fluoro-5-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzoate Cesium carbonate (35.21 g, 108.06 mmol, 5 eq), (3-fluoroazetidin-3-yl)methanol (7.2 g, 21.61 mmol, 1 eq, 2 trifluoroacetic acid), tert-butyl 5-bromo-2-fluorobenzoate (5.95 g, 21.61 mmol, 1 eq), and (2-dicyclohexylphosphino-2,6-dimethoxybiphenyl)[2-(2-amino-1 ,1- biphenyl)]palladium(ii)methanesulfonate (1.80 g, 2.31 mmol, 1.07e-1 eq) in 2-methylbutan-2- ol (200 mL) was de-gassed and then heated to 90 °C for 12 h under an atmosphere of nitrogen. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate= 6:1 to 1:1) to afford tert-butyl 2-fluoro-5-(3-fluoro-3- (hydroxymethyl)azetidin-1-yl)benzoate (4.5 g, 15.03 mmol, 70% yield) as a yellow oil. MS (ESI) m/z: 300.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.13 (dd, J = 8.8, 10.4 Hz, 1H), 6.77 (dd, J = 3.2, 5.6 Hz, 1H), 6.72 (td, J = 3.6, 8.8 Hz, 1H), 5.30 (t, J = 6.0 Hz, 1H), 4.07 - 3.93 (m, 2H), 3.91 - 3.78 (m, 2H), 3.76 - 3.64 (m, 2H), 1.52 (s, 9H). Step 8: tert-butyl 2-fluoro-5-(3-fluoro-3-formylazetidin-1-yl)benzoate Dimethyl sulfoxide (2.00 g, 25.60 mmol, 2.00 mL, 3.83 eq) was slowly added to a solution of oxalyl chloride (2.90 g, 22.85 mmol, 2.00 mL, 3.42 eq) in distilled methylene chloride (30 mL) at -78 °C, and the mixture was stirred at -78 °C for 0.5 h. Then, tert-butyl 2- fluoro-5-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzoate (2 g, 6.68 mmol, 1 eq) was added and the mixture was stirred at -78 °C for 1 h. Triethylamine (7.27 g, 71.85 mmol, 10.00 mL, 10.75 eq) was slowly added at -78 °C, and the mixture was stirred for 1 h. The reaction mixture was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate=4/1 to 1/1) to afford tert-butyl 2- fluoro-5-(3-fluoro-3-formylazetidin-1-yl)benzoate (1.5 g, 5.05 mmol, 76% yield) as a light yellow oil. MS (ESI) m/z: 316.0 [M+H ₂ O] ^+. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.20 - 7.10 (m, 1H), 6.96 - 6.57 (m, 2H), 4.30 - 3.72 (m, 4H), 1.51 (s, 9H). Step 9: tert-butyl 2-fluoro-5-(3-fluoro-3-((4-(7-isopropoxy-6-(pyrazolo[1,5-a]p yrimidine-3- carboxamido)imidazo[1,2-a]pyridin-2-yl)piperazin-1-yl)methyl )azetidin-1-yl)benzoate To a solution of tert-butyl 2-fluoro-5-(3-fluoro-3-formylazetidin-1-yl)benzoate (500 mg, 1.68 mmol, 4.42 eq), N-(7-isopropoxy-2-(piperazin-1-yl)imidazo[1,2-a]pyridin-6- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (160 mg, 380.53 μmol, 1 eq) in dimethylsulfoxide (5 mL) and 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (500 mg, 2.36 mmol, 6.20 eq). The mixture was stirred at 25 °C for 30 min and then 4-methylmorpholine (368.0 mg, 3.64 mmol, 400 μL, 9.56 eq) was added into the mixture. The mixture was stirred at 25 °C for 9.5 h. The reaction mixture was quenched by addition of water (10 mL) and basified with saturated aqueous solution of sodium bicarbonate (pH=8), extracted with dichloromethane (20 mL × 3), The orange phase was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (eluted with dichloromethane: methanol = 12:1) to afford tert-butyl 2-fluoro-5-(3-fluoro-3-((4-(7- isopropoxy-6-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)imidaz o[1,2-a]pyridin-2-yl)piperazin- 1-yl)methyl)azetidin-1-yl)benzoate (167 mg, 237.97 mmol, 63% yield) as a yellow gum. MS (ESI) m/z: 702.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.41 (s, 1H), 9.45 (br s, 1H), 8.85 (dd, J = 1.6, 6.8 Hz, 1H), 8.78 - 8.73 (m, 1H), 8.72 - 8.65 (m, 1H), 7.09 (dd, J = 4.0, 6.8 Hz, 1H), 7.02 - 6.89 (m, 3H), 6.57 (td, J = 3.6, 8.8 Hz, 1H), 4.81 - 4.70 (m, 1H), 4.04 (dd, J = 8.8, 15.2 Hz, 2H), 3.96 - 3.87 (m, 2H), 3.42 - 3.21 (m, 4H), 2.97 (s, 1H), 2.90 (s, 1H), 2.78 (br s, 4H), 1.59 (s, 9H), 1.54 (d, J = 6.0 Hz, 6H). Step 10: 2-fluoro-5-(3-fluoro-3-((4-(7-isopropoxy-6-(pyrazolo[1,5-a]p yrimidine-3- carboxamido)imidazo[1,2-a]pyridin-2-yl)piperazin-1-yl)methyl )azetidin-1-yl)benzoic acid To a solution of tert-butyl 2-fluoro-5-(3-fluoro-3-((4-(7-isopropoxy-6-(pyrazolo[1,5- a]pyrimidine-3-carboxamido)imidazo[1,2-a]pyridin-2-yl)pipera zin-1-yl)methyl)azetidin-1- yl)benzoate (330 mg, 470.24 μmol, 1 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 57.44 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to yield 2-fluoro-5- (3-fluoro-3-((4-(7-isopropoxy-6-(pyrazolo[1,5-a]pyrimidine-3 -carboxamido)imidazo[1,2- a]pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)benzoic acid (350 mg, 460.7 mmol, 98% yield, trifluoroacetic acid) as a yellow solid which was used without further purification in the subsequent reaction. MS (ESI) m/z: 646.1 [M+H] ⁺ . Step 11: N-(2-(4-((1-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-fluoro phenyl)-3-fluoroazetidin- 3-yl)methyl)piperazin-1-yl)-7-isopropoxyimidazo[1,2-a]pyridi n-6-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide To a solution of 2-fluoro-5-(3-fluoro-3-((4-(7-isopropoxy-6-(pyrazolo[1,5-a]p yrimidine- 3-carboxamido)imidazo[1,2-a]pyridin-2-yl)piperazin-1-yl)meth yl)azetidin-1-yl)benzoic acid (340 mg, 447.56 μmol, 1 eq, trifluoroacetic acid) and 3-aminopiperidine-2,6-dione (288.97 mg, 1.76 mmol, 3.92 eq, hydrochloride) in N,N-dimethylformamide (5 mL) was added O-(7- azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (346.76 mg, 911.98 μmol, 2.04 eq) and diisopropylethylamine (428.83 mg, 3.32 mmol, 577.94 μL, 7.41 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with dichloromethane (200 mL × 3). The orange phase was washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*25mm* 10μm; mobile phase: [water (formic acid) - acetonitrile]; B%: 10%-40%, 10 min) to afford N-(2-(4-((1-(3-((2,6- dioxopiperidin-3-yl)carbamoyl)-4-fluorophenyl)-3-fluoroazeti din-3-yl)methyl)piperazin-1-yl)-7- isopropoxyimidazo[1,2-a]pyridin-6-yl)pyrazolo[1,5-a]pyrimidi ne-3-carboxamide (49.7 mg, 62.47 μmol, 14% yield, 95% purity) as a yellow solid. MS (ESI) m/z: 756.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.86 (s, 1H), 10.43 (s, 1H), 9.39 (dd, J = 1.6, 7.2 Hz, 1H), 9.37 (s, 1H), 8.88 (dd, J = 1.6, 4.4 Hz, 1H), 8.72 (s, 1H), 8.46 (dd, J = 3.2, 8.0 Hz, 1H), 7.35 (dd, J = 4.0, 6.8 Hz, 1H), 7.19 - 7.11 (m, 2H), 6.98 (s, 1H), 6.73 (dd, J = 2.8, 5.6 Hz, 1H), 6.67 (td, J = 3.6, 8.8 Hz, 1H), 4.89 - 4.81 (m, 1H), 4.78 - 4.71 (m, 1H), 4.04 (dd, J = 9.2, 18.0 Hz, 2H), 3.91 (dd, J = 8.8, 20.8 Hz, 2H), 3.16 (br s, 4H), 2.95 - 2.86 (m, 2H), 2.84 - 2.73 (m, 1H), 2.69 - 2.62 (m, 4H), 2.57 - 2.53 (m, 1H), 2.16 - 1.96 (m, 2H), 1.46 (d, J = 6.0 Hz, 6H). Scheme 2. A compound of formula INT-VI, where Y and n will be defined herein, can be readily prepared using standard reaction conditions to one skilled in the art as exemplified by the sequence described in Scheme B. A compound of formula INT-VI may be reacted with a reagent INT-VII, wherein G is C(O), N, or CH ₂ and Z is N or CH, to afford compounds of formula CMPD-VIII through N-alkylation where Y is an appropriate leaving group (e.g. OMs, OTs, Cl, etc.) or through reductive amination where Y is an aldehyde or ketone. When Y is a leaving group, suitable reaction conditions are those for an alkylation reaction, e.g. diisopropylethylamine, potassium iodide, DMSO or acetonitrile, 80 °C. When Y is a carbonyl, suitable reaction conditions are those for a reductive amination reaction, e.g. sodium cyanoborohydride, methanol, dichloromethane, acetic acid, room temperature. Scheme B: Synthetic sequence for the preparation of 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3- yl)piperidine-4-carbaldehyde (INT-2), an example of generic intermediate INT-VI in Scheme 2. Analogous synthetic intermediates can be prepared by commencing with alternative coupling partners in Step 1.

Synthesis of example INT-2. Step 1: 2-chloro-5-(4-(dimethoxymethyl)piperidin-1-yl)pyridine A mixture of 5-bromo-2-chloro-pyridine (1.21 g, 6.3 mmol), 4- (dimethoxymethyl)piperidine (1 g, 6.3 mmol), sodium tert-butoxide (905 mg, 9.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (575 mg, 628 μmol) and Xantphos (1.09 g, 1.9 mmol) in toluene (40 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 1/1) to afford 2-chloro-5-(4- (dimethoxymethyl)piperidin-1-yl)pyridine (0.5 g, 29 %) as a yellow solid.MS (ESI) m/z: 270.8 [M+H] ⁺ . Step 2: 2',6'-bis(benzyloxy)-5-(4-(dimethoxymethyl)piperidin-1-yl)-2 ,3'-bipyridine A mixture of 2-chloro-5-(4-(dimethoxymethyl)piperidin-1-yl)pyridine (300 mg, 1.1 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (554 mg, 1.3 mmol), potassium phosphate (1.5 M, 1.48 mL), Mesylate[(di(1-adamantyl)-n- butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) (80 mg, 110 μmol) in N,N- dimethylacetamide (15 mL) was degassed and purged with nitrogen 3 times, then the mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. To the reaction mixture was added water (50 mL) and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 20/1 to 1/1) to afford 2',6'-bis(benzyloxy)-5- (4-(dimethoxymethyl)piperidin-1-yl)-2,3'-bipyridine (380 mg, 65%) as a white solid. MS (ESI) m/z: 526.3 [M+H] ⁺ . Step 3: 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-2-yl)piperid ine-2,6-dione To a solution of 2',6'-bis(benzyloxy)-5-(4-(dimethoxymethyl)piperidin-1-yl)-2 ,3'- bipyridine (200 mg, 380 μmol) in ethyl acetate (10 mL) was added 10% palladium/carbon (200 mg, 606 μmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25°C for 12 h. The mixture was filtered, concentrated in vacuo to afford 3-(5-(4- (dimethoxymethyl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6- dione (90 mg, crude) as a white solid. MS (ESI) m/z: 348.1 [M+1] ⁺ . Step 4: 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carb aldehyde To a solution of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-2-yl)piperid ine-2,6- dione (90 mg, 259 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (8.66 g, 75 mmol, 5.63 mL). The mixture was stirred at 25 °C for 0.5 h, then concentrated in vacuo to afford 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carb aldehyde (78 mg, crude) as a white solid. Scheme C. Synthetic sequence for the preparation of N-[7-isopropoxy-2-(4- piperidyl)imidazo[1,2-a]pyridin-6-yl]pyrazolo[1,5-a]pyrimidi ne-3-carboxamide (INT-3), an example of generic intermediate INT-VII in Scheme 2. Synthesis of example INT-3. Step 1: methyl 5-hydroxy-2-methylbenzoate 5-hydroxy-2-methylbenzoic acid (5.0 g, 32.9 mmol, 1 eq) and hydrogen chloride/methanol (4 M, 40 mL, 4.87 eq) were stirred at 40 °C for 12 h. The reaction mixture was then concentrated under reduced pressure to afford methyl 5-hydroxy-2- methylbenzoate (5.0 g, 30.1 mmol, 92% yield) as a yellow solid which was used in the next step without further purification. MS (ESI) m/z: 167.2 [M+H] ⁺ . Step 2: methyl 5-hydroxy-2-methyl-4-nitrobenzoate To an ice-cooled solution of methyl 5-hydroxy-2-methylbenzoate (8.0 g, 48.1 mmol, 1 eq) in HOAc (30 mL) and acetic anhydride (60 mL) was added copper (II) nitrate, trihydrate (17.60 g, 72.85 mmol, 1.51 eq). The reaction mixture was allowed to stir at 0 °C for 1.5 h. The reaction mixture was poured into ice water (1000 mL) and extracted with ethyl acetate (400 mL × 3). To the combined organic phase was added a saturated aqueous solution of sodium bicarbonate (600 mL) and the mixture was stirred at 25 °C for 12 h. The organic phase was then separated, and the aqueous phase was extracted with ethyl acetate (200 mL × 2). The combined organic phase was washed with water and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluted with petroleum ether/ethyl acetate = 20:1 to 10:1) to afford methyl 5-hydroxy-2-methyl-4-nitrobenzoate (1.3 g, 6.16 mmol, 13% yield) as a yellow solid. Step 3: methyl 5-acetoxy-2-methyl-4-nitrobenzoate To a solution of methyl 5-hydroxy-2-methyl-4-nitrobenzoate (2.5 g, 11.8 mmol, 1 eq) in dichloromethane (15 mL) was added triethylamine (4.79 g, 47.3 mmol, 6.59 mL, 4 eq) and acetic anhydride (3.02 g, 29.6 mmol, 2.77 mL, 2.5 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with water (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, eluted with petroleum ether/ethyl acetate = 20:1 to 10:1) to afford methyl 5-acetoxy-2-methyl-4- nitrobenzoate (2.8 g, 11.1 mmol, 93% yield) as a yellow solid. Step 4: methyl 5-acetoxy-2-(bromomethyl)-4-nitrobenzoate To a stirred solution of methyl 5-acetoxy-2-methyl-4-nitrobenzoate (2.4 g, 9.5 mmol, 1 eq) in carbon tetrachloride (40 mL) was added NBS (3.37 g, 18.96 mmol, 2 eq) and benzoyl peroxide (344.4 mg, 1.42 mmol, 0.15 eq). The mixture was stirred at 95 °C for 12 h under an atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluted with petroleum ether/ ethyl acetate = 20:1 to 5:1) to afford methyl 5-acetoxy-2-(bromomethyl)-4- nitrobenzoate (3.1 g, 9.3 mmol, 98% yield) as a yellow solid. Step 5: tert-butyl 4-(6-hydroxy-5-nitro-1-oxoisoindolin-2-yl)piperidine-1-carbo xylate To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (7.48 g, 37.3 mmol, 4 eq) in tetrahydrofuran (20 mL) was added diisopropylethylamine (2.41 g, 18.7 mmol, 3.25 mL, 2 eq), followed by the slow addition of a solution of methyl 5-acetoxy-2-(bromomethyl)-4- nitrobenzoate (3.1 g, 9.3 mmol, 1 eq) in tetrahydrofuran (10 mL) over a period of 30 min at 40 °C. The mixture was then allowed to stir at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250 × 50 mm × 10 μm; mobile phase: [water (0.225% formic acid) - acetonitrile]; B%: 30%-60%) to afford tert-butyl 4-(6- hydroxy-5-nitro-1-oxoisoindolin-2-yl)piperidine-1-carboxylat e (1.0 g, 2.6 mmol, 28% yield) as a yellow solid. MS (ESI) m/z: 322.2 [M-tBu+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.67 (s, 1H), 8.24 (s, 1H), 7.63 (s, 1H), 4.48 - 4.38 (m, 1H), 4.37 (s, 2H), 4.34 - 4.21 (m, 2H), 2.88 (br t, J = 12.0 Hz, 2H), 1.86 (br dd, J = 2.0, 12.0 Hz, 2H), 1.69 (br dd, J = 4.0, 12.4 Hz, 2H), 1.49 (s, 9H). Step 6: tert-butyl 4-(6-isopropoxy-5-nitro-1-oxoisoindolin-2-yl)piperidine-1-ca rboxylate To a solution of tert-butyl 4-(6-hydroxy-5-nitro-1-oxoisoindolin-2-yl)piperidine-1- carboxylate (900 mg, 2.38 mmol, 1 eq) and 2-bromopropane (15.0 g, 121.96 mmol, 11.45 mL, 51.14 eq) in acetonitrile (40 mL) was added potassium carbonate (1.65 g, 11.92 mmol, 5 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, eluted with petroleum ether/ethyl acetate = 5:1 to 1:1) to afford tert-butyl 4-(6-isopropoxy-5-nitro-1-oxoisoindolin-2-yl)piperidine-1- carboxylate (700 mg, 1.67 mmol, 70% yield) as a yellow solid. MS (ESI) m/z: 364.2 [M- tBu+H] ⁺ . Step 7: tert-butyl 4-(5-amino-6-isopropoxy-1-oxoisoindolin-2-yl)piperidine-1-ca rboxylate To a solution of tert-butyl 4-(6-isopropoxy-5-nitro-1-oxoisoindolin-2-yl)piperidine-1- carboxylate (700 mg, 1.67 mmol, 1 eq) in 2,2,2-trifluoroethanol (15 mL) was added palladium on carbon (100 mg, 93.97 mmol, 10% purity, 0.0563 eq) under an atmosphere of nitrogen. The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was stirred under hydrogen (15 psi) at 25 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product tert-butyl 4-(5-amino-6-isopropoxy-1-oxoisoindolin-2-yl)piperidine-1- carboxylate (649.5 mg, 1.67 mmol, >98% yield) afforded as a yellow solid was used in the subsequent reaction without further purification. MS (ESI) m/z: 334.2 [M-tBu+H] ⁺ . Step 8: tert-butyl 4-(6-isopropoxy-1-oxo-5-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)isoindolin-2-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(5-amino-6-isopropoxy-1-oxoisoindolin-2-yl)piperidine-1- carboxylate (300 mg, 770.2 mmol, 1 eq) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (200 mg, 1.23 mmol, 1.59 eq) in DMF (10 mL) was added diisopropylethylamine (300.0 mg, 2.32 mmol, 404.3 μL, 3.01 eq), followed by the addition of HATU (500 mg, 1.31 mmol, 1.71 eq) to the mixture. The mixture was allowed to stir at 70 °C for 12 h. The reaction mixture was poured into cold water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: methanol=0:1 to 10:1) to afford tert-butyl 4-(6-isopropoxy-1-oxo-5-(pyrazolo[1,5- a]pyrimidine-3-carboxamido)isoindolin-2-yl)piperidine-1-carb oxylate (410 mg, 766.9 mmol, >98% yield) as a yellow solid. MS (ESI) m/z: 479.2 [M-tBu+H] ⁺ . Step 9: N-(6-isopropoxy-1-oxo-2-(piperidin-4-yl)isoindolin-5-yl)pyra zolo[1,5-a]pyrimidine-3- carboxamide To a solution of tert-butyl 4-(6-isopropoxy-1-oxo-5-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)isoindolin-2-yl)piperidine-1-carboxylate (410 mg, 766.9 mmol, 1 eq) in methanol (4 mL) was added a solution of hydrogen chloride in methanol (4 M, 8.0 mL, 41.7 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the remaining residue was dissolved in 50 mL of methanol. The pH of the solution was then adjusted to 7-8 with the addition of a saturated aqueous solution of sodium bicarbonate solution. The mixture was then concentrated under reduced pressure to remove methanol, and the resulting residue was dissolved in ethanol (20 mL), filtered, and the filtrate was concentrated under reduced pressure to afford crude N-(6-isopropoxy-1-oxo- 2-(piperidin-4-yl)isoindolin-5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide (330 mg, 759.5 mmol, 99% yield) as a yellow solid which used in a subsequent transformation without further purification. MS (ESI) m/z: 435.3 [M+H] ⁺ . Scheme D. Synthetic sequence for preparation of N-(2-isopropoxy-7-oxo-6-(piperidin-4-yl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)pyrazolo[1,5-a]pyr imidine-3-carboxamide (INT-4), an example of generic intermediate INT-VII in Scheme 2.

Synthesis of example INT-4. Step 1: methyl 3-methyl-5-nitropicolinate To a solution of methyl 3-methylpicolinate (6.5 g, 43.0 mmol, 1 eq) and tetrabutylammonium nitrate (14.40 g, 47.30 mmol, 1.1 eq) in DCM (100 mL) was added trifluoroacetic anhydride (19.87 g, 94.60 mmol, 13.16 mL, 2.2 eq) at 0 °C and stirred at 25 °C for 12 h. The reaction mixture was quenched with water (100 mL), adjusted to pH =8 with a saturated solution of sodium carbonate at 0 °C, and extracted with dichloromethane (80 mL × 3). The combined organic layers were washed with brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5/1 to 3/1) to afford methyl 3-methyl-5-nitropicolinate (7.2 g, 36.70 mmol, 85% yield) as a light yellow solid. MS (ESI) m/z: 197.1 [M+H] ⁺ . Step 2: 2-(methoxycarbonyl)-3-methyl-5-nitropyridine 1-oxide To a solution of methyl 3-methyl-5-nitropicolinate (7.2 g, 36.70 mmol, 1 eq) in DCM (80 mL) was added m-chloroperbenzoic acid (11.18 g, 55.06 mmol, 85% purity, 1.5 eq) at 0 °C and stirred at 50 °C for 12 h. The reaction mixture was quenched with water (60 mL), the pH was adjusted to 8 with a saturated aqueous solution of sodium bicarbonate at 0 °C, and extracted with dichloromethane (80 mL × 4). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) to afford 2-(methoxycarbonyl)-3-methyl-5-nitropyridine 1- oxide (4 g, 18.85 mmol, 51% yield) as a light yellow solid. MS (ESI) m/z: 213.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ= 8.89 (d, J=1.2 Hz, 1 H) 7.87 - 7.93 (m, 1 H) 4.06 (s, 3 H) 2.43 (s, 3 H). Step 3: methyl 6-hydroxy-3-methyl-5-nitropicolinate To a solution of 2-(methoxycarbonyl)-3-methyl-5-nitropyridine 1-oxide (4 g, 18.85 mmol, 1 eq) in N,N-dimethylformamide (40 mL) was added trifluoroacetic anhydride (31.68 g, 150.83 mmol, 20.98 mL, 8 eq) at 0 °C and stirred at 50 °C for 12 h. The mixture was poured into ice-water (80 mL). The aqueous phase was extracted with ethyl acetate (80 mL × 6). The combined organic phase was washed with brine (30 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was triturated with petroleum ether (100 mL) at 25 °C for 0.5 h. Methyl 6-hydroxy-3-methyl-5-nitropicolinate (2.5 g, 11.78 mmol, 62% yield) was obtained as a yellow solid. MS (ESI) m/z: 213.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.80 (s, 1 H) 8.40 (s, 1 H) 3.88 (s, 3 H) 2.30 (s, 3 H). Step 4: methyl 6-isopropoxy-3-methyl-5-nitropicolinate To a solution of methyl 6-hydroxy-3-methyl-5-nitropicolinate (0.9 g, 4.24 mmol, 1 eq) and 2-iodopropane (1.44 g, 8.48 mmol, 848.38 μL, 2 eq) in DMF (10 mL) was drop-wise added silver carbonate (1.75 g, 6.36 mmol, 288.59 μL, 1.5 eq). The mixture was allowed to stir at 70 °C for 12 h. The mixture was poured into ice-water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to afford methyl 6-isopropoxy-3-methyl-5-nitropicolinate (0.7 g, 2.75 mmol, 64% yield) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.08 (s, 1 H) 5.51 (m, 1 H) 3.97 (s, 3 H) 2.49 (s, 3 H) 1.41 (d, J=6.0 Hz, 6 H). Step 5: methyl 3-(bromomethyl)-6-isopropoxy-5-nitropicolinate To a solution of methyl 6-isopropoxy-3-methyl-5-nitropicolinate (1.3 g, 5.11 mmol, 1 eq) and NBS (910.1 mg, 5.11 mmol, 1 eq) in carbon tetrachloride (10 mL) was added azobisisobutyronitrile (71.37 mg, 434.63 μmol, 0.085 eq). The mixture was allowed to stir at 80 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 20/1) to afford methyl 3-(bromomethyl)-6-isopropoxy-5-nitropicolinate (0.8 g, 2.40 mmol, 46% yield) as a light yellow solid. Step 6: tert-butyl 4-(2-isopropoxy-3-nitro-7-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H) -yl)piperidine- 1-carboxylate To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (1.44 g, 7.20 mmol, 3 eq) and N,N-diisopropylethylamine (1.55 g, 12.01 mmol, 2.09 mL, 5 eq) in THF (10 mL) was added dropwise a solution of methyl 3-(bromomethyl)-6-isopropoxy-5-nitropicolinate (0.8 g, 2.40 mmol, 1 eq) in tetrahydrofuran (5 mL) at 40 °C. The mixture was then stirred at 60 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1 to 2/1) to afford tert-butyl 4- (2-isopropoxy-3-nitro-7-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-y l)piperidine-1-carboxylate (0.55 g, 1.31 mmol, 54% yield) as a light yellow solid. MS (ESI) m/z: 365.1 [M-OtBu] ⁺ . Step 7: tert-butyl 4-(3-amino-2-isopropoxy-7-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H) - yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-isopropoxy-3-nitro-7-oxo-5H-pyrrolo[3,4-b]pyridin- 6(7H)-yl)piperidine-1-carboxylate (0.5 g, 1.19 mmol, 1 eq) in trifluoroethanol (10 mL) was added palladium on carbon (10%, 500 mg) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen 3 times. The mixture was stirred under hydrogen (15 psi) at 25 °C for 2 h. The reaction mixture was filtered and washed with ethanol (20 mL × 2). The collected filtrate was concentrated to give tert-butyl 4-(3-amino-2-isopropoxy-7-oxo- 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)piperidine-1-carboxylate (0.4 g, 1.02 mmol, 86% yield) as a light yellow solid which was used without further purification. MS (ESI) m/z: 391.2 [M+H] ⁺ . Step 8: tert-butyl 4-(2-isopropoxy-7-oxo-3-(pyrazolo[1,5-a]pyrimidine-3-carboxa mido)-5H- pyrrolo[3,4-b]pyridin-6(7H)-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(3-amino-2-isopropoxy-7-oxo-5H-pyrrolo[3,4-b]pyridin- 6(7H)-yl)piperidine-1-carboxylate (370 mg, 947.56 μmol, 1 eq) and pyrazolo[1,5- a]pyrimidine-3-carboxylic acid (463.74 mg, 2.84 mmol, 3 eq) in pyridine (10 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (908.25 mg, 4.74 mmol, 5 eq). The mixture was stirred at 70 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by preparative TLC (petroleum ether/ethyl acetate =0/1) to afford tert-butyl 4-(2-isopropoxy-7-oxo-3-(pyrazolo[1,5-a]pyrimidine-3-carboxa mido)-5H-pyrrolo[3,4- b]pyridin-6(7H)-yl)piperidine-1-carboxylate (0.27 g, 504.11 μmol, 53% yield) as a yellow solid. MS (ESI) m/z: 536.3 [M+H] ⁺ . Step 9: N-(2-isopropoxy-7-oxo-6-(piperidin-4-yl)-6,7-dihydro-5H-pyrr olo[3,4-b]pyridin-3- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide To a solution of tert-butyl 4-(2-isopropoxy-7-oxo-3-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)piperidine-1- carboxylate (0.25 g, 466.77 μmol, 1 eq) in DCM (3 mL) was added a solution of hydrochloric acid in methanol (4 M, 10 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to give a residue. The residue was diluted with dichloromethane/methyl alcohol =10/1 (30 mL), then the pH was adjusted to 8 with ammonium hydroxide (33%) at 0 °C, dried over anhydrous sodium sulfate, filtered and concentrated to give N-(2-isopropoxy-7-oxo-6-(piperidin-4-yl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)pyrazolo[1,5-a]pyr imidine-3-carboxamide (0.2 g, 459.27 μmol, 98% yield) as a yellow solid which was used without further purification. MS (ESI) m/z: 436.2 [M+H] ⁺ . Scheme E. Synthetic sequence for preparation of N-(6-(cyclopropylmethoxy)-2-(piperidin-4- yl)-2H-indazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (INT-5), an example of generic intermediate INT-VI in Scheme 2. Synthesis of example INT-5. Step 1: 2-fluoro-4-hydroxy-5-nitrobenzaldehyde To a solution of 2-fluoro-4-hydroxybenzaldehyde (10.0 g, 71.4 mmol, 1 eq) in sulfuric acid (60 mL) cooled to -15 °C was slowly added a mixture of nitric acid (6 mL) and sulfuric acid (14 mL). The mixture was stirred at -15 °C for 1 h then it was poured into water (500 mL) at 0 °C and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over anhydrous sodium sulfate, concentrated in vacuo to give a residue. The crude product 2-fluoro-4-hydroxy-5-nitrobenzaldehyde (13.2 g, 71.3 mmol, >98% yield) was obtained as a yellow solid and used in subsequent transformations without further purification. Step 2: 4-(cyclopropylmethoxy)-2-fluoro-5-nitrobenzaldehyde To a solution of 2-fluoro-4-hydroxy-5-nitrobenzaldehyde (15.0 g, 81.03 mmol, 1 eq) in N,N-dimethylformamide (100 mL) was added potassium carbonate (34 g, 246.0 mmol, 3.04 eq) and (bromomethyl)cyclopropane (15 g, 111.1 mmol, 10.64 mL, 1.37 eq). The mixture was stirred at 60 °C for 12 h. The reaction mixture was poured into water (300 mL) at 0 °C, and then extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluted with petroleum ether/ethyl acetate = 20:1 to 3:1) to afford 4-(cyclopropylmethoxy)-2- fluoro-5-nitrobenzaldehyde (6.5 g, 27.17 mmol, 34% yield) as a yellow solid. MS (ESI) m/z: 240.1 [M+H] ⁺ . Step 3: 2-azido-4-(cyclopropylmethoxy)-5-nitrobenzaldehyde To a solution of 4-(cyclopropylmethoxy)-2-fluoro-5-nitrobenzaldehyde (6.5 g, 27.2 mmol, 1 eq) in dimethyl sulfoxide (40 mL) was added sodium azide (3.6 g, 55.4 mmol, 2.04 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (50 mL) at 0 °C, and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue. The crude product 2-azido-4-(cyclopropylmethoxy)- 5-nitrobenzaldehyde (7 g, 26.70 mmol, 98% yield) obtained as a yellow oil was used in the next step without further purification. MS (ESI) m/z: 263.1 [M+H] ⁺ . Step 4: tert-butyl 4-(6-(cyclopropylmethoxy)-5-nitro-2H-indazol-2-yl)piperidine -1-carboxylate To a solution of 2-azido-4-(cyclopropylmethoxy)-5-nitrobenzaldehyde (7.0 g, 26.7 mmol, 1 eq) in toluene (70 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (5.5 g, 27.5 mmol, 1.03 eq). The mixture was stirred at 120 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide, eluted with petroleum ether/ethyl acetate = 10:1 to 0.5:1) to afford tert-butyl 4-(6-(cyclopropylmethoxy)-5-nitro-2H-indazol-2-yl)piperidine -1-carboxylate (10.5 g, 25.21 mmol, 94% yield) as a yellow solid. MS (ESI) m/z: 417.2 [M+H] ⁺ . Step 5: tert-butyl 4-(5-amino-6-(cyclopropylmethoxy)-2H-indazol-2-yl)piperidine -1- carboxylate To a solution of tert-butyl 4-(6-(cyclopropylmethoxy)-5-nitro-2H-indazol-2- yl)piperidine-1-carboxylate (10.5 g, 25.2 mmol, 1 eq) in methanol (150 mL) was added palladium on carbon (11.00 g, 10.34 mmol, 10% purity, 0.41 eq) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250 × 80 mm × 10 mm; mobile phase: [water (10 mM ammonium hydrogen carbonate) -acetonitrile]; B%: 40%-65%, 18 min) yielding tert-butyl 4-(5-amino-6-(cyclopropylmethoxy)-2H-indazol-2-yl)piperidine -1-carboxylate (7 g, 18.1 mmol, 72% yield) as a yellow solid. MS (ESI) m/z: 387.3 [M+H] ⁺ . Step 6: tert-butyl 4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine-3-car boxamido)- 2H-indazol-2-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(5-amino-6-(cyclopropylmethoxy)-2H-indazol-2- yl)piperidine-1-carboxylate (500 mg, 1.29 mmol, 1 eq) and pyrazolo[1,5-a]pyrimidine-3- carboxylic acid (220 mg, 1.35 mmol, 1.04 eq) in N,N-dimethylformamide (5 mL) was added diisopropylethylamine (500 mg, 3.87 mmol, 673.8 μL, 2.99 eq), followed by the addition of HATU (740 mg, 1.95 mmol, 1.5 eq) to the mixture. The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (500 mL) at 0 °C, and then extracted with ethyl acetate (250 mL × 3). The combined organic layers were washed with brine (250 mL × 3), dried over anhydrous sodium sulfate, concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate=4:1 to 1:4) to afford tert-butyl 4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5- a]pyrimidine-3-carboxamido)-2H-indazol-2-yl)piperidine-1-car boxylate (300 mg, 564.33 µmol, 44% yield) as a yellow solid. MS (ESI) m/z: 532.5 [M+H] ⁺ . Step 7: N-(6-(cyclopropylmethoxy)-2-(piperidin-4-yl)-2H-indazol-5-yl )pyrazolo[1,5- a]pyrimidine-3-carboxamide To a solution of tert-butyl 4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)-2H-indazol-2-yl)piperidine-1-carboxylate (300 mg, 564.33 mmol, 1 eq) in dioxane (2 mL) was added a solution of hydrogen chloride in dioxane (4 M, 4 mL, 28.35 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with tetrahydrofuran and the pH was adjusted to 7-8 with ammonium hydroxide. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product N-(6- (cyclopropylmethoxy)-2-(piperidin-4-yl)-2H-indazol-5-yl)pyra zolo[1,5-a]pyrimidine-3- carboxamide (240 mg, 556.21 mmol, 99% yield) obtained as a yellow solid was used in subsequent reactions without further purification. MS (ESI) m/z: 432.3 [M+H] ⁺ . Scheme F. Synthetic sequence for preparation of N-(6-(4-(azetidin-1-yl)piperidin-1-yl)-1-oxo- 2-(piperidin-4-yl)isoindolin-5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide (INT-6), an example of generic intermediate INT-VII in Scheme 2. Synthesis of example INT-6. Step 1: 4-(azetidin-1-yl)-1-benzylpiperidine A solution of azetidine hydrochloride (10 g, 106.89 mmol, 1 eq) and acetic acid (5.25 g, 87.42 mmol, 5.00 mL, 8.18e-1 eq) in methanol (50 mL) and DCM (50 mL) was added 1- benzylpiperidin-4-one (20.23 g, 106.89 mmol, 19.83 mL, 1 eq) was allowed to stir for 1 h. Sodium cyanoborohydride (13.00 g, 206.87 mmol, 1.94 eq) was then added and the mixture was stirred at 25 °C for 11 h. The reaction mixture was quenched by addition water 100 mL at 0 °C, and then diluted with ethyl acetate (300 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10/1 to 0/1 and then DCM:Methanol=10:1 to 5/1) and further purified by preparative HPLC to afford 4-(azetidin-1-yl)-1-benzylpiperidine (20 g, 86.83 mmol, 81% yield) as a colorless oil. MS (ESI) m/z: 231.2 [M+H] ⁺ . Step 2: 4-(azetidin-1-yl)piperidine To a solution of 4-(azetidin-1-yl)-1-benzylpiperidine (5.5 g, 23.88 mmol, 1 eq) in trifluoroethanol (100 mL) was added palladium on carbon (400 mg, 10% purity) and palladium hydroxide (550.0 mg, 391.64 μmol, 10% purity, 1.64e-2 eq). The mixture was stirred under hydrogen (15 psi) at 25 °C for 12 h. The reaction mixture was and concentrated under reduced pressure to afford 4-(azetidin-1-yl)piperidine (3.3 g, 23.53 mmol, 98% yield) as a colorless oil. Step 3: tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-5-nitro-1-oxoisoindol in-2-yl)piperidine- 1-carboxylate To a solution of tert-butyl 4-(6-chloro-5-nitro-1-oxoisoindolin-2-yl)piperidine-1- carboxylate (1.1 g, 2.78 mmol, 1 eq), 4-(azetidin-1-yl)piperidine (779.35 mg, 5.56 mmol, 2 eq) in DMSO (1 mL) was added diisopropylethylamine (1.08 g, 8.34 mmol, 1.45 mL, 3 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by addition water 10 mL at 0 °C, and then diluted with ethyl acetate (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (dichloromethane:methanol = 10:1) to afford tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-5-nitro-1-oxoisoindol in-2- yl)piperidine-1-carboxylate (750 mg, 1.50 mmol, 54% yield) as a brown oil. MS (ESI) m/z: 500.5 [M+H] ⁺ . Step 4: tert-butyl 4-(5-amino-6-(4-(azetidin-1-yl)piperidin-1-yl)-1-oxoisoindol in-2- yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-5-nitro-1-oxoisoindol in- 2-yl)piperidine-1-carboxylate (750 mg, 1.50 mmol, 1 eq) in ethanol (3 mL) was added ammonium chloride (1.20 g, 22.52 mmol, 15 eq) and zinc powder (1.47 g, 22.52 mmol, 15 eq). The mixture was stirred at 50 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Then the reaction mixture was quenched by addition of an aqueous solution of sodium bicarbonate (10 mL) at 0 °C, and then diluted with ethyl acetate (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (dichloromethane: methanol = 6:1) to afford tert-butyl 4-(5- amino-6-(4-(azetidin-1-yl)piperidin-1-yl)-1-oxoisoindolin-2- yl)piperidine-1-carboxylate (550 mg, 1.17 mmol, 78% yield) as a yellow solid. MS (ESI) m/z: 470.1 [M+H] ⁺ . Step 5: tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-1-oxo-5-(pyrazolo[1,5 -a]pyrimidine-3- carboxamido)isoindolin-2-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(5-amino-6-(4-(azetidin-1-yl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-1-carboxylate (200 mg, 425.88 μmol, 1 eq), pyrazolo[1,5- a]pyrimidine-3-carboxylic acid (138.95 mg, 851.76 μmol, 2 eq) in pyridine (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (326.57 mg, 1.70 mmol, 4 eq). The mixture was stirred at 50 °C for 0.5 h. The reaction mixture was quenched by addition of water (10 mL) at 0 °C, and then diluted with dichloromethane (30 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparativeTLC (dichloromethane: methanol = 6:1) to afford tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-1-oxo-5-(pyrazolo[1,5 - a]pyrimidine-3-carboxamido)isoindolin-2-yl)piperidine-1-carb oxylate (170 mg, 276.54 μmol, 64% yield) as a light yellow solid. MS (ESI) m/z: 615.2 [M+H] ⁺ . Step 6: N-(6-(4-(azetidin-1-yl)piperidin-1-yl)-1-oxo-2-(piperidin-4- yl)isoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide To a solution of tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-1-oxo-5-(pyrazolo[1,5 - a]pyrimidine-3-carboxamido)isoindolin-2-yl)piperidine-1-carb oxylate (170 mg, 276.54 μmol, 1 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (6.55 g, 57.40 mmol, 4.25 mL, 207.57 eq). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated in vacuo, then the reaction was diluted with dichloromethane (10 mL), and ammonium hydroxide was added until the pH reached between 7-8. The mixture was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-(6- (4-(azetidin-1-yl)piperidin-1-yl)-1-oxo-2-(piperidin-4-yl)is oindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide (140 mg, 272.05 μmol, 98% yield) as a yellow oil. Synthetic sequence for preparation of N-(6-(4-(azetidin-1-yl)piperidin-1-yl)-2-(piperidin-4-yl)- 2H-indazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, an example of generic intermediate INT-IX in Scheme 2. Synthesis of example INT-7. Step 1: 2-azido-4-hydroxy-5-nitrobenzaldehyde To a solution of 2-fluoro-4-hydroxy-5-nitrobenzaldehyde (2 g, 10.80 mmol, 1 eq) in DMSO (130 mL) was added sodium azide (1.05 g, 16.21 mmol, 1.5 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was separated, washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-azido-4-hydroxy-5-nitrobenzaldehyde (2.2 g, 10.57 mmol, 98% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 11.12 (br s, 1H), 10.18 (s, 1H), 8.69 (s, 1H), 6.97 (s, 1H). Step 2: tert-butyl 4-(6-hydroxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylat e To a solution of 2-azido-4-hydroxy-5-nitrobenzaldehyde (1.1 g, 5.29 mmol, 1 eq) in toluene (30 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (1.06 g, 5.29 mmol, 1 eq). The mixture was stirred at 120 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water 100 mL and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) to give tert-butyl 4-(6-hydroxy-5-nitro-2H-indazol-2-yl)piperidine-1- carboxylate (0.6 g, 1.66 mmol, 31% yield) as a yellow solid. MS (ESI) m/z: 363.1 [M+H] ⁺ . Step 3: tert-butyl 4-(5-nitro-6-(((trifluoromethyl)sulfonyl)oxy)-2H-indazol-2-y l)piperidine-1- carboxylate To a solution of tert-butyl 4-(6-hydroxy-5-nitro-2H-indazol-2-yl)piperidine-1- carboxylate (1 g, 2.76 mmol, 1 eq) in DCM (20 mL) was added pyridine (1.31 g, 16.56 mmol, 1.34 mL, 6 eq) and trifluoromethanesulfonic anhydride (2.34 g, 8.28 mmol, 1.37 mL, 3 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give tert-butyl 4-(5-nitro-6-(((trifluoromethyl)sulfonyl)oxy)- 2H-indazol-2-yl)piperidine-1-carboxylate (1.3 g, 2.63 mmol, 95.3% yield) as a white solid. MS (ESI) m/z: 439.0 [M-OtBu] ⁺ Step 4: tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-5-nitro-2H-indazol-2- yl)piperidine-1-car boxylate To a solution of tert-butyl 4-(5-nitro-6-(((perfluorobutyl)sulfonyl)oxy)-2H-indazol-2- yl)piperidine-1-carboxylate (14 g, 21.72 mmol, 1 eq) and 4-(azetidin-1-yl)piperidine (8 g, 57.05 mmol, 2.63 eq) in dioxane (150 mL) was added cesium carbonate (14.16 g, 43.45 mmol, 2 eq) and SPhos Pd G3 (1.4 g, 1.79 mmol, 8.26e-2 eq) under nitrogen atmosphere. The suspension was degassed and purged with nitrogen for 3 times. The mixture was stirred under nitrogen at 90 °C for 12 h. The reaction mixture was filtered and washed with dichloromethane (20 mL x 3). The collected filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (dichloromethane /methyl alcohol=10/1) to give tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-5-nitro-2H-indazol-2- yl)piperidine-1-carboxylate (6 g, 12.38 mmol, 57% yield) as a black brown solid. MS (ESI) m/z: 485.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ )δ: 8.10 (s, 1 H) 8.03 (s, 1 H) 7.23 (s, 1 H) 4.51 (tt, J=11.2, 3.6 Hz, 1 H) 4.31 (br s, 2 H) 3.22 (br t, J=6.8 Hz, 6 H) 2.84 - 3.02 (m, 3 H) 2.72 (br t, J=10.4 Hz, 2 H) 2.21 (br d, J=12.4 Hz, 2 H) 2.11 - 2.17 (m, 1 H) 2.04 - 2.09 (m, 3 H) 1.77 (br d, J=10.4 Hz, 2 H) 1.49 - 1.55 (m, 2 H) 1.47 (s, 9 H). Step 5: tert-butyl 4-(5-amino-6-(4-(azetidin-1-yl)piperidin-1-yl)-2H-indazol-2- yl)piperidine-1- carboxylate To a solution of tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-5-nitro-2H-indazol-2- yl)piperidine-1-carboxylate (1 g, 2.06 mmol, 1 eq) in trifluoroethanol (15 mL) was added palladium on carbon (10%, 0.5 g) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen 3 times. The mixture was stirred under hydrogen (15 psi) at 25 °C for 2 h. The reaction mixture was filtered and washed with a 5:1 solution of dichloromethane\methyl alcohol (30 mL x 3). The collected filtrate was concentrated to give tert-butyl 4-(5-amino-6-(4-(azetidin-1-yl)piperidin-1-yl)-2H-indazol-2- yl)piperidine-1- carboxylate (0.9 g, 1.98 mmol, 95% yield) obtained as a black brown solid which was used without further purification. MS (ESI) m/z: 455.3 [M+H] ⁺ . Step 6: tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-5-(pyrazolo[1,5-a]pyr imidine-3-carboxa mido)-2H-indazol-2-yl)piperidine-1-carboxylate To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (322.96 mg, 1.98 mmol, 1 eq) in pyridine (10 mL) was added tert-butyl 4-(5-amino-6-(4-(azetidin-1-yl)piperidin-1-yl)-2H- indazol-2-yl)piperidine-1-carboxylate (0.9 g, 1.98 mmol, 1 eq) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.14 g, 5.94 mmol, 3 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to give a residue which was purified by silica gel column chromatography (dichloromethane /methyl alcohol=10/1) to give tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-5-(pyrazolo[1,5- a]pyrimidine-3-carboxamido)-2H-indazol-2-yl)piperidine-1-car boxylate (1 g, 1.67 mmol, 84% yield) as a black brown solid. MS (ESI) m/z: 600.2 [M+H] ⁺ . Step 7: N-(6-(4-(azetidin-1-yl)piperidin-1-yl)-2-(piperidin-4-yl)-2H -indazol-5-yl)pyrazolo[1,5-a] pyrimidine-3-carboxamide To a solution of tert-butyl 4-(6-(4-(azetidin-1-yl)piperidin-1-yl)-5-(pyrazolo[1,5- a]pyrimidine-3-carboxamido)-2H-indazol-2-yl)piperidine-1-car boxylate (0.2 g, 333.49 μmol, 1 eq) in dichloromethane (6 mL) was added trifluoroacetic acid (9.24 g, 81.04 mmol, 6.00 mL, 243.0 eq). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated to give N-(6-(4-(azetidin-1-yl)piperidin-1-yl)-2-(piperidin-4-yl)-2H -indazol-5- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.2 g, crude, trifluoroacetate) as a brown oil. MS (ESI) m/z: 500.4 [M+H] ⁺ . Example 10: N-[2-[1-[[7-[4-(2,6-dioxo-3-piperidyl)-3-fluoro-phenyl]-7-az aspiro[3.5]nonan-2- yl]methyl]-4-piperidyl]-6-isopropoxy-1-oxo-isoindolin-5-yl]p yrazolo[1,5-a]pyrimidine-3- carboxamide Step 1: 7-azaspiro[3.5]nonan-2-ylmethanol To a solution of tert-butyl 2-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (2.5 g, 9.8 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.23 g, 19.6 mmol, 1.45 mL). The reaction mixture was stirred at 25 °C for 0.5 h, then concentrated under reduced pressure to afford 7-azaspiro[3.5]nonan-2-ylmethanol trifluoroacetic acid (2.6 g, crude) as yellow oil, which was used in the next step without further purification. Step 2: benzyl 2-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate To a solution of 7-azaspiro[3.5]nonan-2-ylmethanol (2.6 g, 16.8 mmol) and sodium carbonate (5.33 g, 50.3 mmol) in tetrahydrofuran (25 mL) and water (25 mL) was added p- toluenesulfonyl chloride (3.14 g, 18.4 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h, then quenched by water (10 mL). Diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient from 0 to 50% ethyl acetate in petroleum ether gradient to afford benzyl 2-(hydroxymethyl)-7- azaspiro[3.5]nonane-7-carboxylate (2.6 g, 53%) as colorless oil. MS (ESI) m/z: 290.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.41 - 7.29 (m, 5H), 5.12 (s, 2H), 3.61 (d, J = 6.4 Hz, 2H), 3.49 - 3.41 (m, 2H), 3.39 - 3.32 (m, 2H), 2.64 - 2.38 (m, 1H), 1.97 - 1.83 (m, 2H), 1.65 - 1.43 (m, 8H). Step 3: benzyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate To a solution of benzyl 2-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (2.6 g, 9.0 mmol) in dichloromethane (30 mL) was added Dess-Martin periodinane (7.62 g, 18.0 mmol, 5.56 mL) and sodium bicarbonate (4.53 g, 53.9 mmol). The reaction mixture was stirred at 25 °C for 1 h, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to afford benzyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (1.77 g, 68%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) = 9.76 (s, 1H), 7.44 - 7.28 (m, 5H), 5.13 (s, 2H), 3.49 - 3.42 (m, 2H), 3.41 - 3.35 (m, 2H), 3.23 - 3.11 (m, 1H), 2.15 - 1.96 (m, 5H), 1.64 (s, 2H). Step 4: benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate To a solution of benzyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (1.77 g, 6.2 mmol) and p-toluene sulfonic acid (1.17 g, 6.2 mmol) in methanol (20 mL) was added trimethoxymethane (1.31 g, 12.3 mmol). The reaction mixture was stirred at 25 °C for 12 h, then quenched by sodium bicarbonate (50 mL), diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to afford benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7- carboxylate (1.7 g, 82%) as colorless oil. MS (ESI) m/z: 334.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.50 - 7.28 (m, 5H), 5.12 (s, 2H), 4.29 (d, J = 6.8 Hz, 1H), 3.57 - 3.23 (m, 11H), 2.69 - 2.51 (m, 1H), 1.88 (t, J = 10.0 Hz, 2H), 1.74 - 1.56 (m, 5H). Step 5: 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane To a solution of benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.7 g, 5.1 mmol) in trifluoroethanol (20 mL) was added 10% palladium on carbon (500 mg). The reaction mixture was stirred at 25 °C for 2 h with hydrogen (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to afford 2- (dimethoxymethyl)-7-azaspiro[3.5]nonane (1 g, crude) as a colorless oil. Step 6: 7-[4-(2,6-dibenzyloxy-3-pyridyl)-3-fluoro-phenyl]-2-(dimetho xymethyl)-7- azaspiro[3.5]nonane To a solution of 2,6-dibenzyloxy-3-(4-bromo-2-fluoro-phenyl)pyridine (500 mg, 1.1 mmol) and 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (322 mg, 1.6 mmol) in dioxane (20 mL) was added tris(dibenzylideneacetone)dipalladium(0) (49 mg, 0.05 mmol), dicyclohexyl- [2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane (101 mg, 0.2 mmol) and sodium tert- butoxide (2 M, 1.6 mL). The reaction mixture was stirred at 110 °C for 2 h. The reaction was quenched by water (20 mL), diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a gradient of ethyl acetate:petroleum ether to afford 7-[4-(2,6-dibenzyloxy-3-pyridyl)-3-fluoro-phenyl]-2-(dimetho xymethyl)-7- azaspiro[3.5]nonane (500 mg, 79%) as yellow oil. MS (ESI) m/z: 583.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.52 (dd, J = 1.2, 8.0 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.40 - 7.29 (m, 7H), 7.27 - 7.18 (m, 2H), 6.78 - 6.61 (m, 2H), 6.44 (d, J = 8.0 Hz, 1H), 5.40 (s, 2H), 5.34 (s, 2H), 4.33 (d, J = 7.2 Hz, 1H), 3.34 (s, 6H), 3.23 - 3.16 (m, 2H), 3.14 - 3.07 (m, 2H), 2.70 - 2.53 (m, 1H), 1.98 - 1.87 (m, 2H), 1.81 - 1.63 (m, 6H). Step 7: 3-[4-[2-(dimethoxymethyl)-7-azaspiro[3.5]nonan-7-yl]-2-fluor o-phenyl]piperidine-2,6- dione To a solution of 7-[4-(2,6-dibenzyloxy-3-pyridyl)-3-fluoro-phenyl]-2- (dimethoxymethyl)-7-azaspiro[3.5]nonane (540 mg, 0.9 mmol) in trifluoroethanol (10 mL) was added 10% palladium on carbon (200 mg). The reaction mixture was stirred at 25 °C with hydrogen (15 psi) for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to afford 3-[4-[2-(dimethoxymethyl)-7-azaspiro[3.5]nonan-7-yl]-2-fluor o- phenyl]piperidine-2,6-dione (330 mg, 88%) as a blue solid. MS (ESI) m/z: 405.2 [M+H] ⁺ . Step 8: 7-[4-(2,6-dioxo-3-piperidyl)-3-fluoro-phenyl]-7-azaspiro[3.5 ]nonane-2-carbaldehyde To a stirred solution of 3-[4-[2-(dimethoxymethyl)-7-azaspiro[3.5]nonan-7-yl]-2-fluor o- phenyl]piperidine-2,6-dione (200 mg, 0.5 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (56 mg, 0.5 mmol). The reaction mixture was stirred at 25 °C for 0.15 h, then concentrated under reduced pressure to afford 7-[4-(2,6-dioxo-3-piperidyl)-3-fluoro- phenyl]-7-azaspiro[3.5]nonane-2-carbaldehyde (180 mg, crude) as a yellow oil, which was used in the next step without further purification. MS (ESI) m/z: 359.0 [M+H] ⁺ . Step 9: N-[2-[1-[[7-[4-(2,6-dioxo-3-piperidyl)-3-fluoro-phenyl]-7-az aspiro[3.5]nonan-2- yl]methyl]-4-piperidyl]-6-isopropoxy-1-oxo-isoindolin-5-yl]p yrazolo[1,5-a]pyrimidine-3- carboxamide To a solution of 7-[4-(2,6-dioxo-3-piperidyl)-3-fluoro-phenyl]-7-azaspiro[3.5 ]nonane-2- carbaldehyde (90 mg, 0.3 mmol) and N-methylmorpholine (127 mg, 1.3 mmol) in dichloromethane (2 mL) and dimethyl sulfoxide (2 mL) was added N-[6-isopropoxy-1-oxo-2- (4-piperidyl)isoindolin-5-yl]pyrazolo[1,5-a]pyrimidine-3-car boxamide hydrochloride (118 mg, 0.3 mmol). After 2 h, sodium triacetoxyborohydride (266 mg, 1.3 mmol) was added. The reaction mixture was stirred at 25 °C for 10 h. The reaction was quenched by water (10 mL), diluted with water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm*10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 13-43%,) to afford N-[2-[1-[[7-[4-(2,6-dioxo-3-piperidyl)-3-fluoro- phenyl]-7-azaspiro[3.5]nonan-2-yl]methyl]-4-piperidyl]-6-iso propoxy-1-oxo-isoindolin-5- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (74.8 mg, 38%) as a white solid. MS (ESI) m/z: 777.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.77 (d, J = 20.0 Hz, 2H), 9.39 (d, J = 7.2 Hz, 1H), 8.98 - 8.84 (m, 1H), 8.73 (s, 2H), 7.44 - 7.26 (m, 2H), 7.05 (t, J = 8.4 Hz, 1H), 6.82 - 6.62 (m, 2H), 4.99 - 4.78 (m, 1H), 4.40 (s, 2H), 3.97 (t, J = 11.2 Hz, 1H), 3.86 (dd, J = 4.0, 11.6 Hz, 1H), 3.14 (s, 2H), 3.05 (s, 2H), 2.92 (d, J = 10.2 Hz, 2H), 2.79 - 2.64 (m, 2H), 2.46 - 2.36 (m, 3H), 2.17 - 2.00 (m, 3H), 1.95 (d, J = 8.0 Hz, 3H), 1.84 - 1.73 (m, 2H), 1.65 (s, 4H), 1.53 (s, 2H), 1.43 (d, J = 4.8 Hz, 8H). Table 2. The following compounds may be prepared in an analogous fashion as described for the synthesis of Example 10 and as described in the general synthetic route Scheme 2. Scheme 3. A compound of formula INT-IX, where Y and n will be defined herein, can be readily prepared using standard reaction conditions to one skilled in the art as exemplified by the sequence described in Scheme G. A compound of formula INT-IX may be reacted with a reagent of general formula INT-VII to afford compounds of formula CMPD-X through N- alkylation where Y is an appropriate leaving group (e.g. OMs, OTs, Cl, etc.) or through reductive amination where Y is an aldehyde or ketone. When Y is a leaving group, suitable reaction conditions are those for an alkylation reaction, e.g. diisopropylethylamine, potassium iodide, DMSO or acetonitrile, 80 °C. When Y is a carbonyl, suitable reaction conditions are those for a reductive amination reaction, e.g. sodium cyanoborohydride, methanol, dichloromethane, acetic acid, room temperature. Scheme G: Synthetic sequence for the preparation of 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3- yl)piperidine-4-carbaldehyde (INT-8), an example of generic intermediate INT-IX in Scheme 3. Analogous synthetic intermediates can be prepared by commencing with alternative anilines in Step 1. Synthesis of example INT-8. Step 1: 3-((4-bromophenyl)amino)propanoic acid A mixture of 4-bromoaniline (10 g, 58.1 mmol), acrylic acid (4.19 g, 58.1 mmol, 3.99 mL) in acetic acid (20 mL) and water (100 mL) was stirred at 100 °C for 12 h under a nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure and then diluted with water (100 mL) at 0 °C, and ethyl acetate (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 3/1) to afford 3-((4-bromophenyl)amino)propanoic acid (9.7 g, 68%) as a pink solid. MS (ESI) m/z: 244.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.47 - 7.35 (m, 1 H), 7.29 - 7.27 (m, 1 H), 7.27 - 7.24 (m, 1 H), 6.53 - 6.51 (m, 1 H), 6.51 - 6.49 (m, 1 H), 3.43 (t, J = 6.0 Hz, 2 H), 2.66 (t, J = 6.4 Hz, 2 H). Step 2: 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of 3-((4-bromophenyl)amino)propanoic acid (8 g, 32.8 mmol) in acetic acid (80 mL) was added urea (19.68 g, 327.7 mmol, 17.57 mL). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched with water (100 mL) at 0 °C, diluted with ethyl acetate (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluted with a gradient of petroleum ether:ethyl acetate from 10:1 to 1:1) to afford 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (4.6 g, 52%) as a white solid. MS (ESI) m/z: 269.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.42 (s, 1 H), 7.62 - 7.52 (m, 2 H), 7.35 - 7.23 (m, 2 H), 3.78 (t, J = 6.4 Hz, 2 H), 2.70 (t, J = 6.8 Hz, 2 H). Step 3: 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)dihydropyrimi dine-2,4(1H,3H)-dione To a stirred solution of 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (0.9 g, 3.3 mmol) and 4-(dimethoxymethyl)piperidine (798.81 mg, 5.0 mmol) in dioxane (2 mL) was added [2-(2-aminophenyl)phenyl]palladium(1+);2-(2-dicyclohexylphos phanylphenyl)- N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine;methanesulfonate (269.69 mg, 334.5 mmol). Under an inert atmosphere, a solution of sodium tert-butoxide (2 M, 5.02 mL) was added. The mixture was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 90 °C for 12 h. The reaction mixture was quenched by water (10 mL) at 0 °C, diluted with ethyl acetate (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluted with ethyl acetate) to afford 1-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (0.5 g, 43%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.54 (s, 1 H), 7.16 (d, J = 9.2 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 4.09 (d, J = 7.2 Hz, 1 H), 3.81 (t, J = 6.8 Hz, 2 H), 3.71 (d, J = 12.4 Hz, 2 H), 3.38 (s, 6 H), 2.81 (t, J = 6.4 Hz, 2 H), 2.76 - 2.63 (m, 2 H), 1.85 (d, J = 13.6 Hz, 2 H), 1.80 - 1.70 (m, 1 H), 1.45 (m, 2 H). Step 4: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin e-4-carbaldehyde To a solution of 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)dihydropyrimi dine- 2,4(1H,3H)-dione (0.07 g, 201.5 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol, 2 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure to afford 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)piperidine-4-carbaldehyde trifluoroacetic acid (60 mg, crude) as a yellow oil. MS (ESI) m/z: 302.2 [M+H] ⁺ . Example 26: N-{6-[4-(azetidin-1-yl)piperidin-1-yl]-2-[1-({1-[4-(2,4-diox o-1,3-diazinan-1- yl)phenyl]piperidin-4-yl}methyl)piperidin-4-yl]-1-oxo-2,3-di hydro-1H-isoindol-5- yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide To a stirred solution of 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin e- 4-carbaldehyde (35.13 mg, 116.6 mmol) and N-(6-(4-(azetidin-1-yl)piperidin-1-yl)-1-oxo-2- (piperidin-4-yl)isoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide (60 mg, 116.6 mmol) in dimethylsulfoxide (1 mL) and dichloroethane (1 mL) was added 4-methylmorpholine (58.96 mg, 582.9 μmol, 64.09 mL), The mixture was stirred at 25 °C for 0.5 h, then added sodium borohydride acetate (74.13 mg, 349.8 mmol). The mixture was stirred at 25 °C for 11.5 h, quenched by water (10 mL) at 0 °C, diluted with ethyl acetate (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 column 150×25mm×10mm; mobile phase: [water(formic acid)-acetonitrile]; B%: 1-30%) to afford N- (6-(4-(azetidin-1-yl)piperidin-1-yl)-2-(1-((1-(4-(2,4-dioxot etrahydropyrimidin-1(2H)- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindo lin-5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide (32.5 mg, 34%) as a white solid. MS (ESI) m/z: 800.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1 H), 10.25 (s, 1 H), 9.41 (dd, J = 1.2, 6.8 Hz, 1 H), 8.93 (dd, J = 1.6, 4.4 Hz, 1 H), 8.76 (s, 1 H), 8.74 (s, 1 H), 7.54 (s, 1 H), 7.45 (dd, J = 4.4, 7.2 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 9.2 Hz, 2 H), 4.45 (s, 2 H), 4.06 - 3.91 (m, 1 H), 3.69 (m, 3 H), 3.17 (m, 4 H), 2.96 (m, 4 H), 2.78 - 2.70 (m, 2 H), 2.70 - 2.65 (m, 4 H), 2.25 - 2.17 (m, 3 H), 2.05 - 1.96 (m, 4 H), 1.80 (m, 6 H), 1.72 - 1.54 (m, 6 H), 1.26 - 1.17 (m, 2 H). Table 3. The following compounds may be prepared in an analogous fashion as described for the synthesis of Example 26 and as described in the general synthetic route Scheme 3. Example 30: N-[6-(cyclopropylmethoxy)-2-[(1r,4r)-4-({4-[4-(2,6-dioxopipe ridin-3-yl)-3- oxopiperazin-1-yl]piperidin-1-yl}methyl)cyclohexyl]-2H-indaz ol-5-yl]pyrazolo[1,5-a]pyrimidine- 3-carboxamide Step 1: tert-butyl 4-(2,6-dioxopiperidin-3-yl)-3-oxopiperazine-1-carboxylate To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (5.21 g, 26.0 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (1.04 g, 26.0 mmol, 60%) at 0 °C. The reaction mixture was heated at 60 °C for 30 min before its drop wise addition into a solution of 3-bromopiperidine-2,6-dione (2.5 g, 13.0 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 60 °C for 9.5 h, then quenched by 10% ammonium chloride solution (50 mL) at 0 °C and extracted with ethyl acetate (5 x 100 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by preparative TLC eluted with 4:1 solution of ethyl acetate:THF to afford tert-butyl 4-(2,6-dioxopiperidin-3-yl)-3-oxopiperazine-1-carboxylate (0.7 g, 17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.89 (s, 1H), 5.12 - 4.93 (m, 1H), 3.97 (br s, 2H), 3.67 - 3.56 (m, 1H), 3.51 - 3.42 (m, 1H), 3.32 - 3.28 (m, 1H), 3.27 - 3.19 (m, 1H), 2.85 - 2.71 (m, 1H), 2.54 (br s, 1H), 2.36 - 2.22 (m, 1H), 1.91 - 1.80 (m, 1H), 1.42 (s, 9H). Step 2: 3-(2-oxopiperazin-1-yl)piperidine-2,6-dione To a solution of tert-butyl 4-(2,6-dioxopiperidin-3-yl)-3-oxopiperazine-1-carboxylate (0.5 g, 1.6 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (7.70 g, 40.5 mmol, 5 mL). The reaction mixture was stirred at 25 °C for 1 h, then concentrated under reduced pressure to afford 3-(2-oxopiperazin-1-yl)piperidine-2,6-dione trifluoroacetic acid (0.52 g, crude) as a yellow solid, which was used in the next step without further purification. Step 3: benzyl 4-(4-(2,6-dioxopiperidin-3-yl)-3-oxopiperazin-1-yl)piperidin e-1-carboxylate To a solution of benzyl 4-oxopiperidine-1-carboxylate (7.52 g, 32.3 mmol, 6.43 mL) in dichloromethane (50 mL) was added acetic acid (5.49 g, 91.4 mmol, 5.23 mL) and 3-(2- oxopiperazin-1-yl)piperidine-2,6-dione trifluoroacetic acid (10.45 g, 32.1 mmol), stirred at 25 °C for 0.5 h, then added sodium triacetoxyborohydride (17.02 g, 80.3 mmol) to the mixture. The reaction was stirred at 25 °C for 9.5 h, then quenched by water (100 mL) and basified with saturated sodium bicarbonate solution (pH 8), extracted with dichloromethane (3 x 200 mL). The orange phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 (250*70mm, 10 um); mobile phase: [water (formic acid)- acetonitrile]; B%: 10-35%) to afford benzyl 4-(4-(2,6-dioxopiperidin-3-yl)-3-oxopiperazin-1- yl)piperidine-1-carboxylate (2 g, 15%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ =10.84 (s, 1H), 7.43 - 7.25 (m, 5H), 5.06 (s, 2H), 4.97 - 4.85 (m, 1H), 4.07 - 3.95 (m, 2H), 3.26 - 3.07 (m, 4H), 2.91 - 2.57 (m, 5H), 2.55 - 2.52 (m, 1H), 2.47 - 2.41 (m, 1H), 2.36 - 2.22 (m, 1H), 1.87 - 1.71 (m, 3H), 1.36 - 1.22 (m, 2H). Step 4: 3-(2-oxo-4-(piperidin-4-yl) piperazin-1-yl)piperidine-2,6-dione To a solution of benzyl 4-(4-(2,6-dioxopiperidin-3-yl)-3-oxopiperazin-1-yl)piperidin e-1- carboxylate (1 g, 2.3 mmol) in 2,2,2-trifluoroethanol (20 mL) was added 10% palladium on carbon (1 g, 939.7 μmol) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen balloon several times. The mixture was stirred under hydrogen balloon (15 psi) at 25 °C for 2 h, then filtered and concentrated under reduced pressure to afford 3-(2-oxo-4-(piperidin-4-yl)piperazin-1-yl)piperidine-2,6-dio ne (0.5 g, 73%) as a white gum, which was used in the next step without further purification. Step 3: N-(6-(cyclopropylmethoxy)-2-((1r,4r)-4-formylcyclohexyl)-2H- indazol-5- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide To a solution of N-(6-(cyclopropylmethoxy)-2-((1r,4r)-4-(hydroxymethyl)cycloh exyl)- 2H-indazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 434.28 μmol, 1 eq) in dichloromethane (15 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)- one (552.59 mg, 1.30 mmol, 403.35 μL, 3 eq). The mixture was stirred at 25 °C for 2 h. The mixture was filtered. The residue was purified by silica gel chromatography (0-5% methanol in dichloromethane) to give N-(6-(cyclopropylmethoxy)-2-((1r,4r)-4-formylcyclohexyl)-2H- indazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (190 mg, 414.38 μmol, 95% yield) as a yellow solid. MS (ESI) m/z: 459.2 [M+H] ⁺ . Step 4: N-(6-(cyclopropylmethoxy)-2-((1r,4r)-4-((4-(4-(2,6-dioxopipe ridin-3-yl)-3- oxopiperazin-1-yl)piperidin-1-yl)methyl)cyclohexyl)-2H-indaz ol-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide To a solution of N-(6-(cyclopropylmethoxy)-2-((1r,4r)-4-formylcyclohexyl)-2H- indazol- 5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (120 mg, 261.72 μmol, 1 eq), 3-(2-oxo-4- (piperidin-4-yl)piperazin-1-yl)piperidine-2,6-dione (120 mg, 407.68 μmol, 1.56 eq) in THF (4 mL) and DMF (1 mL) was added acetic acid (36.75 mg, 611.97 μmol, 35 μL, 2.34 eq) and sodium triacetoxyborohydride (138.67 mg, 654.29 μmol, 2.5 eq). The mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched by addition water 300 mL at 0°C, and then extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Synergi C18150*25mm* 10μm; mobile phase: [water(formic acid)-acetonitrile]; B%: 12-32%) to afford N-(6-(cyclopropylmethoxy)-2-((1r,4r)-4-((4-(4-(2,6-dioxopipe ridin-3-yl)-3-oxopiperazin- 1-yl)piperidin-1-yl)methyl)cyclohexyl)-2H-indazol-5-yl)pyraz olo[1,5-a]pyrimidine-3- carboxamide (46.8 mg, 55.0 μmol, 21% yield, 92% purity, formic acid) as a yellow solid. MS (ESI) m/z: 737.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.86 (s, 1H), 10.64 (s, 1H), 9.37 (dd, J = 1.6, 7.2 Hz, 1H), 8.86 (dd, J = 1.6, 4.4 Hz, 1H), 8.72 (d, J = 10.4 Hz, 2H), 8.24 (s, 1H), 8.18 (s, 1H), 7.31 (dd, J = 4.0, 6.8 Hz, 1H), 7.02 (s, 1H), 4.93 (br d, J = 1.2 Hz, 1H), 4.37 - 4.25 (m, 1H), 4.01 (d, J = 6.8 Hz, 2H), 3.25 - 3.09 (m, 4H), 2.91 (br d, J = 10.8 Hz, 2H), 2.83 - 2.70 (m, 2H), 2.69 - 2.63 (m, 1H), 2.29 - 2.05 (m, 6H), 2.02 - 1.66 (m, 10H), 1.63 - 1.34 (m, 4H), 1.07 (q, J = 12.0 Hz, 2H), 0.74 - 0.67 (m, 2H), 0.45 (q, J = 4.8 Hz, 2H). Example 31: N-(2-((1r,4r)-4-((4-(4-(2,6-dioxopiperidin-3-yl)-3-oxopipera zin-1-yl)piperidin-1- yl)methyl)cyclohexyl)-6-isopropoxy-1-oxoisoindolin-5-yl)pyra zolo[1,5-a]pyrimidine-3- carboxamide Step 1: N-(2-((1r,4r)-4-formylcyclohexyl)-6-isopropoxy-1-oxoisoindol in-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide To a solution of N-[2-[4-(hydroxymethyl)cyclohexyl]-6-isopropoxy-1-oxo-isoind olin-5- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.68 g, 1.47 mmol, 1 eq) in DCM (6 mL) was added (1,1-diacetoxy-3-oxo-1λ ⁵ ,2-benziodoxol-1-yl) acetate (1.87 g, 4.40 mmol, 1.36 mL, 3 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=50/1 to 0/1) to give N-[2-(4- formylcyclohexyl)-6-isopropoxy-1-oxo-isoindolin-5-yl]pyrazol o[1,5-a]pyrimidine-3- carboxamide (0.3 g, 650 μmol, 44% yield) as a yellow solid. MS (ESI) m/z: 462.2 [M+H] ⁺ . Step 2: N-(2-((1r,4r)-4-((4-(4-(2,6-dioxopiperidin-3-yl)-3-oxopipera zin-1-yl)piperidin-1- yl)methyl)cyclohexyl)-6-isopropoxy-1-oxoisoindolin-5-yl)pyra zolo[1,5-a]pyrimidine-3- carboxamide To a solution of N-(2-((1r,4r)-4-formylcyclohexyl)-6-isopropoxy-1-oxoisoindol in-5- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (170.00 mg, 368.4 μmol) and 3-(2-oxo-4- (piperidin-4-yl)piperazin-1-yl)piperidine-2,6-dione (170.23 mg, 578.3 μmol) in tetrahydrofuran (4.8 mL) and N,N-dimethylformamide (1.2 mL) was added acetic acid (52.50 mg, 874.3 μmol, 50.00 μL) at 0 °C and stirred at 0 °C for 0.5 h. Then sodium triacetoxyborohydride (195 mg, 920.1 μmol) was added and mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by water (100 mL) and basified with saturated sodium bicarbonate solution (pH 8), extracted with dichloromethane (3 x 200 mL). The orange phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Synergi C18150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 11%-31%, 10 min) to give 55 mg white solid. The white solid was further purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 11%-31%, 10 min) to afford N-(2-((1r,4r)-4-((4-(4-(2,6-dioxopiperidin-3-yl)-3- oxopiperazin-1-yl)piperidin-1-yl)methyl)cyclohexyl)-6-isopro poxy-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (23.5 mg, 8%) as a white solid. MS (ESI) m/z: 740.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.85 (s, 1H), 10.75 (s, 1H), 9.40 (dd, J = 1.6, 6.8 Hz, 1H), 8.89 (dd, J = 1.6, 4.4 Hz, 1H), 8.76 - 8.71 (m, 2H), 7.36 (dd, J = 4.0, 6.8 Hz, 1H), 7.32 (s, 1H), 4.98 - 4.84 (m, 2H), 4.39 (s, 2H), 3.98 (br s, 1H), 3.25 - 3.13 (m, 4H), 2.90 (br d, J = 10.8 Hz, 2H), 2.82 - 2.71 (m, 2H), 2.70 - 2.64 (m, 1H), 2.29 - 2.19 (m, 2H), 2.14 (br d, J = 6.0 Hz, 2H), 1.94 - 1.72 (m, 9H), 1.66 - 1.32 (m, 12H), 1.09 - 0.95 (m, 2H). Example 32: N-[6-(cyclopropylmethoxy)-2-[(1r,4r)-4-({1-[4-(2,6-dioxopipe ridin-3-yl)-3- fluorophenyl]piperidin-4-yl}(methyl)amino)cyclohexyl]-2H-ind azol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide Step 1: N-(2-(1-((1-(2-chloroethyl)-3-fluoroazetidin-3-yl)methyl)pip eridin-4-yl)-6- (cyclopropylmethoxy)-2H-indazol-5-yl)pyrazolo[1,5-a]pyrimidi ne-3-carboxamide To a solution of 2-chloroacetaldehyde (366.0 mg, 1.87 mmol, 300.0 mL, 40% purity, 3.22 eq), N-(6-(cyclopropylmethoxy)-2-(1-((3-fluoroazetidin-3-yl)methy l)piperidin-4-yl)-2H- indazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.3 g, 578.50 mmol, 1 eq) in DMSO (4 mL) and 1,2-dichloroethane (4 mL) was added acetic acid (126.0 mg, 2.10 mmol, 120.0 mL, 3.63 eq). The mixture was stirred at 25 °C for 30 min, followed by the addition of sodium triacetoxyborohydride (600.0 mg, 2.83 mmol, 4.89 eq). The mixture was stirred at 25 °C for 9.5 h. The reaction mixture was quenched by the addition of a 10% aqueous solution of sodium bicarbonate (25 mL) at 0 °C and then extracted with dichloromethane (250 mL × 5), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford N-(2-(1-((1-(2-chloroethyl)-3-fluoroazetidin-3-yl)methyl)pip eridin-4-yl)-6- (cyclopropylmethoxy)-2H-indazol-5-yl)pyrazolo[1,5-a]pyrimidi ne-3-carboxamide (165 mg, 283.95 mmol, 49% yield) as a yellow solid. MS (ESI) m/z: 581.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.63 (s, 1H), 9.36 (d, J = 7.2 Hz, 1H), 8.94 - 8.83 (m, 1H), 8.72 (d, J = 10.0 Hz, 2H), 8.29 (s, 1H), 7.31 (dd, J = 4.4, 7.2 Hz, 1H), 7.03 (s, 1H), 4.45 - 4.26 (m, 1H), 4.02 (d, J = 7.2 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.49 (br dd, J = 8.8, 14.8 Hz, 2H), 3.21 (dd, J = 8.8, 22.0 Hz, 2H), 2.98 (br d, J = 11.6 Hz, 2H), 2.85 - 2.73 (m, 4H), 2.38 - 2.28 (m, 2H), 2.15 - 2.01 (m, 4H), 1.54 - 1.44 (m, 1H), 0.74 - 0.66 (m, 2H), 0.45 (q, J = 4.8 Hz, 2H). Step 2: N-(6-(cyclopropylmethoxy)-2-(1-((1-(2-(4-(2,6-dioxopiperidin -3-yl)-3-oxopiperazin-1- yl)ethyl)-3-fluoroazetidin-3-yl)methyl)piperidin-4-yl)-2H-in dazol-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide To a solution of N-(2-(1-((1-(2-chloroethyl)-3-fluoroazetidin-3-yl)methyl)pip eridin-4-yl)- 6-(cyclopropylmethoxy)-2H-indazol-5-yl)pyrazolo[1,5-a]pyrimi dine-3-carboxamide (165 mg, 283.95 μmol, 1 eq), 3-(2-oxopiperazin-1-yl)piperidine-2,6-dione (200 mg, 614.93 mmol, 2.17 eq, Trifluoroacetic acid) in dimethylsulfoxide (5 mL) was added diisopropylethylamine (742.00 mg, 5.74 mmol, 1 mL, 20.22 eq) and potassium iodide (100 mg, 602.4 mmol, 2.12 eq). The mixture was stirred at 100 °C for 9.5 h. The reaction mixture was quenched by addition water 50 mL and extracted with dichloromethane (100 mL × 3), The orange phase was washed with brine 100 mL, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give residue. The residue was purified by preparative HPLC (Phenomenex Synergi C18150*25mm* 10um; mobile phase: [water (formic acid)- acetonitrile]; B%: 1-31%) to afford N-(6-(cyclopropylmethoxy)-2-(1-((1-(2-(4-(2,6- dioxopiperidin-3-yl)-3-oxopiperazin-1-yl)ethyl)-3-fluoroazet idin-3-yl)methyl)piperidin-4-yl)-2H- indazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (16.5 mg, 20.37 mmol, 7% yield, 99% purity, formic acid) as a yellow solid. MS (ESI) m/z: 756.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.84 (s, 1H), 10.65 (s, 1H), 9.36 (dd, J = 1.6, 7.2 Hz, 1H), 8.86 (dd, J = 1.6, 4.0 Hz, 1H), 8.72 (d, J = 8.4 Hz, 2H), 8.30 (s, 1H), 8.20 (s, 1H), 7.31 (dd, J = 4.4, 7.2 Hz, 1H), 7.03 (s, 1H), 5.00 - 4.83 (m, 1H), 4.43 - 4.28 (m, 1H), 4.01 (d, J = 7.2 Hz, 2H), 3.18 - 3.08 (m, 6H), 3.01 - 2.97 (m, 2H), 2.83 - 2.70 (m, 5H), 2.65 - 2.59 (m, 4H), 2.41 - 2.27 (m, 6H), 2.13 - 2.04 (m, 4H), 1.86 - 1.77 (m, 1H), 1.55 - 1.43 (m, 1H), 0.74 - 0.67 (m, 2H), 0.48 - 0.42(m, 2H). Example 33: N-[6-(cyclopropylmethoxy)-2-[(1r,4r)-4-({1-[4-(2,6-dioxopipe ridin-3-yl)-3- fluorophenyl]piperidin-4-yl}(methyl)amino)cyclohexyl]-2H-ind azol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide Step 1: tert-butyl 4-(((1r,4r)-4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyri midine-3- carboxamido)-2H-indazol-2-yl)cyclohexyl)amino)piperidine-1-c arboxylate To a solution of N-[2-(4-aminocyclohexyl)-6-(cyclopropylmethoxy)indazol-5- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.3 g, 673.4 mmol), tert-butyl 4-oxopiperidine-1- carboxylate (134.17 mg, 673.4 mmol) in 1,2-dichloroethane (3 mL) was added N-methyl morphine (204.34 mg, 2.0 mmol, 222.10 mL). The mixture was stirred for 0.5 h prior to the addition of sodium triacetoxyborohydride (428.15 mg, 2.0 mmol). The mixture was allowed to stir at 0 °C for 0.5 h, after which tert-butyl 4-oxopiperidine-1-carboxylate (134.17 mg, 673.4 mmol) was added and stirred for 0.5 h. Additional sodium triacetoxyborohydride (428.15 mg, 2.0 mmol) was added and stirring continued 0 °C for 0.5 h. The reaction mixture was used in the next step directly. Step 2: tert-butyl 4-(((1r,4r)-4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyri midine-3- carboxamido)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)piperi dine-1-carboxylate A solution of tert-butyl 4-[[4-[6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine-3 - carbonylamino)indazol-2-yl]cyclohexyl]amino]piperidine-1-car boxylate (0.42 g, 668.0 mmol, 981.6 mL) and formaldehyde (200.57 mg, 6.7 mmol, 184.01 mL) in 1,2-dichloroethane (3 mL) was allowed to stir for 10 min followed by the addition of sodium triacetoxyborohydride (424.71 mg, 2.0 mmol). The mixture was stirred at 25 °C for 20 min, and then diluted with water, and extracted with dichloromethane (3 x 30 mL). The combined organic phase was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane/methyl alcohol = 50/1 to 30/1) to afford tert-butyl 4-[[4-[6- (cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine-3-carbonyl amino)indazol-2-yl]cyclohexyl]- methyl-amino]piperidine-1-carboxylate (0.42 g, 97%) as yellow solid. MS (ESI) m/z: 643.3 [M+H] ⁺ . Step 3: N-(6-(cyclopropylmethoxy)-2-((1r,4r)-4-(methyl(piperidin-4-y l)amino)cyclohexyl)-2H- indazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide To a solution of tert-butyl 4-[[4-[6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine- 3-carbonylamino)indazol-2-yl]cyclohexyl]-methyl-amino]piperi dine-1-carboxylate (0.42 g, 653.4 μmol) in dichloromethane (4 mL) was added a solution of hydrochloric acid in methanol (4 M, 163.35 mL). The mixture was stirred at 25 °C for 0.5 h, then concentrated under vacuum to afford N-[6-(cyclopropylmethoxy)-2-[4-[methyl(4- piperidyl)amino]cyclohexyl]indazol-5-yl]pyrazolo[1,5-a]pyrim idine-3-carboxamide hydrochloride (0.37 g, crude) as a yellow solid. Step 4: N-(6-(cyclopropylmethoxy)-2-((1r,4r)-4-((1-(4-(2,6-dioxopipe ridin-3-yl)-3- fluorophenyl)piperidin-4-yl)(methyl)amino)cyclohexyl)-2H-ind azol-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide A mixture of N-[6-(cyclopropylmethoxy)-2-[4-[methyl(4- piperidyl)amino]cyclohexyl]indazol-5-yl]pyrazolo[1,5-a]pyrim idine-3-carboxamide hydrochloride (0.2 g, 345.3 mmol), 3-(4-bromo-2-fluoro-phenyl)piperidine-2,6-dione (98.80 mg, 345.3 mmol), cesium carbonate (281.3 mg, 863.4 μmol) in N,N-dimethylformamide (1 mL) was added 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-2H-imidazole;3- chloropyridine;dichloropalladium (8.22 mg, 10.4 mmol) was degassed and purged with nitrogen 3 times, then the mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane/methyl alcohol = 10/1) then by semi-preparative reverse phase HPLC (column: Phenomenex Synergi C18150*25mm* 10mm; mobile phase: [water(formic acid)- acetonitrile]; B%: 15%-45%) to afford N-[6-(cyclopropylmethoxy)-2-[4-[[1-[4-(2,6-dioxo-3- piperidyl)-3-fluoro-phenyl]-4-piperidyl]-methyl-amino]cycloh exyl]indazol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (22.7 mg, 8%) as an off-white solid. MS (ESI) m/z: 748.3 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 10.82 (s, 1 H) 10.65 (s, 1 H) 9.38 (dd, J=6.80, 1.60 Hz, 1 H) 8.87 (dd, J=4.40, 1.20 Hz, 1 H) 8.73 (s, 1 H) 8.71 (s, 1 H) 8.25 (s, 1 H) 7.29 - 7.34 (m, 1 H) 7.07 (t, J=8.80 Hz, 1 H) 7.02 (s, 1 H) 6.74 (br d, J=2.80 Hz, 1 H) 6.71 (s, 1 H) 4.28 - 4.39 (m, 1 H) 4.01 (d, J=7.20 Hz, 2 H) 3.88 (dd, J=12.40, 5.20 Hz, 1 H) 3.75 (br d, J=12.00 Hz, 2 H) 2.62 - 2.79 (m, 6 H) 2.23 (s, 3 H) 2.11 - 2.20 (m, 3 H) 1.92 - 2.01 (m, 3 H) 1.76 - 1.91 (m, 5 H) 1.51 - 1.61 (m, 4 H) 0.70 (br d, J=8.00 Hz, 2 H) 0.45 (d, J=5.20 Hz, 2 H). Table 4. The following compounds may be prepared in an analogous fashion as described for the synthesis of Example 33. Example 36: N-[1-oxo-6-(propan-2-yloxy)-2-[(1r,4r)-4-({1-[4-(2,6-dioxopi peridin-3-yl)-3- fluorophenyl]azetidin-3-yl}(methyl)amino)cyclohexyl]-2,3-dih ydro-1H-isoindol-5- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Step 1: 2-((1r,4r)-4-((1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3-fluor ophenyl)azetidin-3- yl)(methyl)amino)cyclohexyl)-6-isopropoxy-5-nitroisoindolin- 1-one To a solution of 2-[4-[azetidin-3-yl(methyl)amino]cyclohexyl]-6-isopropoxy-5- nitro- isoindolin-1-one (0.35 g, 869.6 mmol) and 2,6-bis(benzyloxy)-3-(4-bromo-2- fluorophenyl)pyridine (403.78 mg, 869.6 mmol) in dioxane (8 mL) was added cesium carbonate (1.13 g, 3.5 mmol) and [(2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)- 1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate (70.12 mg, 87.0 mmol). The reaction mixture was stirred at 90 °C for 12 h under nitrogen, then concentrated under reduced pressure. The residue was purified by semi-preparative reverse phase HPLC (Phenomenex Luna C18 (250*70mm,10 um) column; mobile phase: [water(formic acid)- acetonitrile]; B%: 40 to 70%) to afford 2-((1r,4r)-4-((1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3- fluorophenyl)azetidin-3-yl)(methyl)amino)cyclohexyl)-6-isopr opoxy-5-nitroisoindolin-1-one (0.45 g, 66%) as a brown solid. MS (ESI) m/z: 786.2 [M+H] ⁺ . Step 2: 3-(4-(3-(((1r,4r)-4-(5-amino-6-isopropoxy-1-oxoisoindolin-2- yl)cyclohexyl)(methyl)amino)azetidin-1-yl)-2-fluorophenyl)pi peridine-2,6-dione To a solution of 2-((1r,4r)-4-((1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3- fluorophenyl)azetidin-3-yl)(methyl)amino)cyclohexyl)-6-isopr opoxy-5-nitroisoindolin-1-one (0.4 g, 509.0 μmol) in ethyl acetate (15 mL) was added 10% palladium on carbon (1 g) under a nitrogen atmosphere. The suspension was degassed and purged with H ₂ 3 times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 12 h. The reaction mixture was filtered and washed with ethanol (2 x 20 mL). The collected filtrate was concentrated. The residue was purified by preparative TLC (dichloromethane /methyl alcohol=10/1) to afford 3-(4-(3- (((1r,4r)-4-(5-amino-6-isopropoxy-1-oxoisoindolin-2-yl)cyclo hexyl)(methyl)amino)azetidin-1- yl)-2-fluorophenyl)piperidine-2,6-dione (140 mg, 48%) as a brown solid. MS (ESI) m/z: 578.3 [M+H] ⁺ . Step 3: N-(2-((1r,4r)-4-((1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophe nyl)azetidin-3- yl)(methyl)amino)cyclohexyl)-6-isopropoxy-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (110.13 mg, 675.1 mmol) in pyridine (15 mL) was added 3-(4-(3-(((1r,4r)-4-(5-amino-6-isopropoxy-1-oxoisoindolin-2- yl)cyclohexyl)(methyl)amino)azetidin-1-yl)-2-fluorophenyl)pi peridine-2,6-dione (130 mg, 225.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130.0 mg, 678.1 mmol). The reaction was stirred at 50 °C for 12 h. The mixture was poured into ice- water (40 mL). The aqueous phase was extracted with dichloromethane (3 x 20 mL). The combined organic phase was washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane /methyl alcohol=10/1) then by semi-preparative reverse phase HPLC (Phenomenex Synergi C18150*25mm* 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 12-42%) to afford N-(2-((1r,4r)-4-((1-(4-(2,6-dioxopiperidin-3-yl)-3- fluorophenyl)azetidin-3-yl)(methyl)amino)cyclohexyl)-6-isopr opoxy-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (105.1 mg, 64%) as a purple solid. MS (ESI) m/z: 723.2 [M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.79 (s, 1 H) 10.75 (s, 1 H) 9.40 (dd, J=7.2, 1.6 Hz, 1 H) 8.89 (dd, J=4.0, 1.6 Hz, 1 H) 8.73 (s, 2 H) 8.02 - 8.23 (m, 1 H) 7.29 - 7.38 (m, 2 H) 7.05 (t, J=8.4 Hz, 1 H) 6.19 - 6.27 (m, 2 H) 4.89 (dt, J=12.0, 6.0 Hz, 1 H) 4.38 (s, 2 H) 3.96 - 4.03 (m, 1 H) 3.93 (br t, J=6.8 Hz, 2 H) 3.86 (dd, J=12.4, 5.2 Hz, 1 H) 3.77 (quin, J=6.0 Hz, 1 H) 3.59 (m, 2 H) 2.67 - 2.78 (m, 1 H) 2.44 (br s, 2 H) 2.17 (s, 3 H) 2.06 - 2.15 (m, 1 H) 1.90 - 1.99 (m, 1 H) 1.70 - 1.81 (m, 4 H) 1.58 - 1.68 (m, 2 H) 1.45 - 1.53 (m, 2 H) 1.44 (d, J=6.0 Hz, 6 H). Example 37: N-[6-(cyclopropylmethoxy)-2-(1-{2-[6-(2,6-dioxopiperidin-3-y l)-1,2,3,4- tetrahydroisoquinolin-2-yl]-2-oxoethyl}piperidin-4-yl)-2H-in dazol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide Step 1: tert-butyl 6-(2,6-bis(benzyloxy)pyridin-3-yl)-3,4-dihydroisoquinoline-2 (1H)- carboxylate A flask charged with 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2- yl)pyridine (6.50 g, 15.6 mmol,), potassium phosphate (9.60 g, 45.2 mmol), tert-butyl 6- bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (4.80 g, 15.4 mmol), and [1,1’- bis(diphenylphosphino) ferrocene]dichloropalladium(II)dichloromethane (2.40 g, 3.3 mmol) in dioxane (150 mL) and water (15 mL) was de-gassed and then heated to 100 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched by water (50 mL) at 0 °C, and then diluted with ethyl acetate (50 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 5/1) to afford tert-butyl 6- (2,6-bis(benzyloxy)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (6.6 g, 82%) as a yellow gum. MS (ESI) m/z: 523.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (d, J = 8.0 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.41 - 7.29 (m, 10H), 7.17 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 5.38 (d, J = 5.2 Hz, 4H), 4.50 (br s, 2H), 3.59 - 3.53 (m, 2H), 2.77 (br t, J = 5.6 Hz, 2H), 1.43 (s, 9H). Step 2: tert-butyl 6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinoline-2(1H)-ca rboxylate To a solution of tert-butyl 6-(2,6-bis(benzyloxy)pyridin-3-yl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate (3.0 g, 5.7 mmol) in ethyl acetate (300 mL) was added 10% palladium on carbon (5 g, 4.7 mmol) under an atmosphere of nitrogen. The suspension was degassed under vacuum and purged with hydrogen balloon several times. The mixture was stirred under hydrogen balloon (15 psi) at 25 °C for 10 h, then filtered and concentrated under reduced pressure to afford tert-butyl 6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate (1.98 g, crude) as a white solid, which was used in the next step without further purification. MS (ESI) m/z: 245.0 [M-Boc] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.88 (s, 1H), 7.18 (br d, J = 8.0 Hz, 1H), 7.12 - 7.05 (m, 2H), 4.54 (br s, 2H), 3.86 (br dd, J = 4.8, 11.2 Hz, 1H), 3.60 (br t, J = 5.6 Hz, 2H), 2.81 (br t, J = 5.6 Hz, 2H), 2.77 - 2.65 (m, 2H), 2.32 - 2.17 (m, 1H), 2.13 - 2.03 (m, 1H), 1.49 (s, 9H). Step 3: 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-2,6-dione To a solution of tert-butyl 6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinoline-2(1H)- carboxylate (1.98 g, 5.7 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (30.80 g, 27.0 mmol, 20 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford 3-(1,2,3,4-tetrahydroisoquinolin- 6-yl)piperidine-2,6-dione trifluoroacetic acid (2.06 g, 100%) as a white solid, which was used in the next step without further purification. MS (ESI) m/z: 245.1 [M+H] ⁺ . Step 4: tert-butyl 2-(4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)- 2H-indazol-2-yl)piperidin-1-yl)acetate To a solution of N-(6-(cyclopropylmethoxy)-2-(piperidin-4-yl)-2H-indazol-5- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.3 g, 695.3 mmol), tert-butyl 2-bromoacetate (145.20 mg, 744.4 μmol, 110 mL) in DMSO (4 mL) was added diisopropylethylamine (296.80 mg, 2.3 mmol, 400 mL) and the mixture was stirred at 60 °C for 12 h. The reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (3 x 100 mL), the organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluted with a 10:1 solution of dichloromethane:methanol) to afford tert-butyl 2-(4-(6- (cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine-3-carboxam ido)-2H-indazol-2-yl)piperidin- 1-yl)acetate (250 mg, 66%) as a white solid. MS (ESI) m/z: 546.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 9.38 (br d, J = 6.8 Hz, 1H), 8.87 (br d, J = 3.6 Hz, 1H), 8.78 - 8.69 (m, 2H), 8.31 (s, 1H), 7.31 (br d, J = 4.0 Hz, 1H), 7.04 (s, 1H), 4.40 - 4.28 (m, 1H), 4.02 (br d, J = 6.8 Hz, 2H), 3.64 - 3.55 (m, 2H), 3.18 (s, 2H), 2.97 (br d, J = 11.6 Hz, 2H), 2.07 (br s, 2H), 1.79 - 1.73 (m, 2H), 1.51 - 1.42 (m, 11H), 0.74 - 0.67 (m, 2H), 0.48 - 0.43 (m, 2H). Step 5: 2-(4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)-2H- indazol-2-yl)piperidin-1-yl)acetic acid To a solution of tert-butyl 2-(4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine- 3-carboxamido)-2H-indazol-2-yl)piperidin-1-yl)acetate (120 mg, 219.9 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1 mL) and the mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford 2-(4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)-2H-indazol-2-yl)piperidin-1-yl)acetic acid (107 mg, 99%) as a yellow gum, which was used in the next step without further purification. MS (ESI) m/z: 490.2 [M+H] ⁺ . Step 6: N-(6-(cyclopropylmethoxy)-2-(1-(2-(6-(2,6-dioxopiperidin-3-y l)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidin-4-yl)-2H-i ndazol-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide To a solution of 2-(4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)-2H-indazol-2-yl)piperidin-1-yl)acetic acid (107 mg, 218.6 mmol) and 3- (1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-2,6-dione trifluoroacetic acid (150 mg, 418.6 mmol) in N,N-dimethylformamide (3 mL) was added diisopropylethylamine (222.60 mg, 1.7 mmol, 300 mL) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (170 mg, 447.1 μmol). The mixture was stirred at 25 °C for 1 h, then quenched by water (50 mL) and extracted with ethyl acetate (3 x 100 mL), the organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Synergi C18150*25mm* 10μm column; mobile phase: [water (formic acid)-acetonitrile]; B%: 13-49%) to afford N-[6-(cyclopropylmethoxy)-2-[1-[2-[6-(2,6-dioxo-3-piperidyl) -3,4-dihydro- 1H-isoquinolin-2-yl]-2-oxo-ethyl]-4-piperidyl]indazol-5-yl]p yrazolo[1,5-a]pyrimidine-3- carboxamide (73 mg, 43%) as an off-white solid. MS (ESI) m/z: 716.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 10.66 (s, 1H), 9.38 (d, J = 7.2 Hz, 1H), 8.90 - 8.84 (m, 1H), 8.77 (s, 1H), 8.71 (s, 1H), 8.37 - 8.27 (m, 1H), 7.32 (dd, J = 4.4, 6.8 Hz, 1H), 7.22 - 7.14 (m, 1H), 7.11 - 7.04 (m, 3H), 4.66 (br s, 2H), 4.03 (br d, J = 6.8 Hz, 2H), 3.89 - 3.58 (m, 5H), 2.92 (br s, 2H), 2.85 - 2.57 (m, 6H), 2.46 - 2.13 (m, 6H), 2.06 - 1.97 (m, 1H), 1.55 - 1.43 (m, 1H), 0.75 - 0.67 (m, 2H), 0.49 - 0.43 (m, 2H). Example 38: N-[1-oxo-6-(propan-2-yloxy)-2-[(1r,4r)-4-{[6-(2,6-dioxopiper idin-3-yl)-1,2,3,4- tetrahydroisoquinolin-2-yl]methyl}cyclohexyl]-2,3-dihydro-1H -isoindol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide A solution of 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-2,6-dione formic acid (0.062 g, 213.6 mmol), triethylamine (47.54 mg, 469.8 mmol, 65.4 mL), N-[2-(4- formylcyclohexyl)-6-isopropoxy-1-oxo-isoindolin-5-yl]pyrazol o[1,5-a]pyrimidine-3- carboxamide (98.56 mg, 213.6 mmol) and in tetrahydrofuran (0.4 mL) and N,N- dimethylformamide (0.1 mL) was stirred at 0°C for 0.5 h followed by the addition of sodium triacetoxyborohydride (135.79 mg, 640.7 mmol). The mixture was stirred at 25 °C for 11.5 h. The residue was concentrated under vacuum and triethylamine was added to adjust the pH to between 7 and 8. The mixture was extracted with dichloromethane (3 x 20 mL). The combined organic phase was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane/methyl alcohol = 50/1 to 32.3/1) then semi-preparative reverse phase HPLC (column: Phenomenex Synergi C18150 × 25mm × 10μm; mobile phase: [(formic acid)-acetonitrile]; B%: 13%-43%, 10min) to afford N-[2-[4-[[6-(2,6-dioxo-3-piperidyl)-3,4- dihydro-1H-isoquinolin-2-yl]methyl]cyclohexyl]-6-isopropoxy- 1-oxo-isoindolin-5- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (58.5 mg, 38%) as a yellow solid. MS (ESI) m/z: 690.4 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 10.80 (s, 1 H) 10.74 (s, 1 H) 9.40 (dd, J=7.20, 1.20 Hz, 1 H) 8.86 - 8.92 (m, 1 H) 8.73 (s, 2 H) 7.35 (dd, J=6.80, 4.40 Hz, 1 H) 7.32 (s, 1 H) 7.00 - 7.06 (m, 1 H) 6.93 - 6.99 (m, 2 H) 4.83 - 4.95 (m, 1 H) 4.40 (s, 2 H) 3.96 - 4.04 (m, 1 H) 3.77 (br dd, J=11.20, 4.80 Hz, 1 H) 3.56 (br s, 3 H) 2.81 (br s, 3 H) 2.64 (br d, J=5.60 Hz, 1 H) 2.13 - 2.22 (m, 1 H) 1.97 - 2.09 (m, 2 H) 1.92 (br d, J=11.60 Hz, 2 H) 1.77 (br d, J=10.00 Hz, 3 H) 1.56 - 1.70 (m, 4 H) 1.44 (s, 3 H) 1.43 (s, 3 H) 1.05 - 1.16 (m, 2 H). Example 39: N-[2-(1-{2-[6-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydrois oquinolin-2-yl]-2- oxoethyl}piperidin-4-yl)-1-oxo-6-(propan-2-yloxy)-2,3-dihydr o-1H-isoindol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide Step 1: tert-butyl 2-(4-(6-isopropoxy-1-oxo-5-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)isoindolin-2-yl)piperidin-1-yl)acetate To a solution of N-(6-isopropoxy-1-oxo-2-(piperidin-4-yl)isoindolin-5-yl)pyra zolo[1,5- a]pyrimidine-3-carboxamide (0.15 g, 345.2 mmol) and tert-butyl 2-bromoacetate (67.34 mg, 345.2 mmol, 51.0 mL) in dimethyl sulfoxide (6 mL) was added N,N-diisopropylethylamine (133.86 mg, 1.0 mmol, 180.40 mL) and stirred at 60 °C for 12 h. The mixture was poured into ice-water (50 mL). The aqueous phase was extracted with dichloromethane (3 x 30 mL). The combined organic phase was washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane /methyl alcohol=20/1) to afford tert-butyl 2-(4-(6- isopropoxy-1-oxo-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido) isoindolin-2-yl)piperidin-1- yl)acetate (0.18 g, 95%) as a light brown solid. MS (ESI) m/z: 549.3 [M+H] ⁺ . Step 2: 2-(4-(6-isopropoxy-1-oxo-5-(pyrazolo[1,5-a]pyrimidine-3-carb oxamido)isoindolin-2- yl)piperidin-1-yl)acetic acid To a solution of tert-butyl 2-(4-(6-isopropoxy-1-oxo-5-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)isoindolin-2-yl)piperidin-1-yl)acetate (0.18 g, 328.1 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (9.24 g, 81.0 mmol, 6 mL) and stirred at 25 °C for 3 h. The reaction was concentrated to afford 2-(4-(6-isopropoxy-1-oxo-5-(pyrazolo[1,5- a]pyrimidine-3-carboxamido)isoindolin-2-yl)piperidin-1-yl)ac etic acid trifluoroacetate (0.15 g, 92%) as an off-white solid. MS (ESI) m/z: 493.2[M+H] ⁺ . Step 3: N-(2-(1-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinol in-2(1H)-yl)-2- oxoethyl)piperidin-4-yl)-6-isopropoxy-1-oxoisoindolin-5-yl)p yrazolo[1,5-a]pyrimidine-3- carboxamide To a solution of 2-(4-(6-isopropoxy-1-oxo-5-(pyrazolo[1,5-a]pyrimidine-3- carboxamido)isoindolin-2-yl)piperidin-1-yl)acetic acid trifluoroacetate (70 mg, 115.4 mmol) and 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-2,6-dione trifluoroacetate (82.70 mg, 230.8 mmol) in N,N-dimethylformamide (6 mL) was added N,N-diisopropylethylamine (44.75 mg, 346.2 mmol, 60.31 mL) and (dimethylamino(triazolo(4,5-b)pyridin-3-yloxy)methylene)- dimethyl)-ammonium; hexafluorophosphate (140.0 mg, 368.2 mmol). The reaction mixture was stirred at 25 °C for 12 h. The mixture was poured into ice-water (30 mL). The aqueous phase was extracted with dichloromethane (3 x 20 mL). The combined organic phase was washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by semi-preparative reverse phase HPLC (Phenomenex Synergi C18150*25mm* 10µm; mobile phase: [water(formic acid)- acetonitrile]; B%: 12-42%) to afford N-(2-(1-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidin-4-yl)-6-is opropoxy-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (28.2 mg, 31%) as an off-white solid. MS (ESI) m/z: 719.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.83 (s, 1 H) 10.77 (s, 1 H) 9.54 - 9.76 (m, 1 H) 9.41 (dd, J=6.8, 1.6 Hz, 1 H) 8.90 (dd, J=4.0, 1.6 Hz, 1 H) 8.78 (s, 1 H) 8.74 (s, 1 H) 7.34 - 7.39 (m, 2 H) 7.19 (m, 1 H) 7.05 - 7.13 (m, 2 H) 4.91 (dt, J=12.0, 6.0 Hz, 1 H) 4.56 - 4.71 (m, 2 H) 4.50 (br s, 5 H) 3.50 - 3.90 (m, 5 H) 3.06 - 3.28 (m, 2 H) 2.91 - 2.95 (m, 1 H) 2.82 (m, 1 H) 2.60 - 2.73 (m, 2 H) 2.14 - 2.25 (m, 2 H) 1.79 - 2.10 (m, 4 H) 1.44 (d, J=6.0 Hz, 6 H). Example 40: N-[1-oxo-6-(propan-2-yloxy)-2-[(1r,4r)-4-{[6-(2,4-dioxo-1,3- diazinan-1-yl)- 1,2,3,4-tetrahydroisoquinolin-2-yl]methyl}cyclohexyl]-2,3-di hydro-1H-isoindol-5- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Step 1: 6-bromo-1,2,3,4-tetrahydroisoquinoline To a solution of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (3 g, 9.6 mmol) in dichloromethane (30 mL) was added Trifluoroacetic acid (15.40 g, 135.1 mmol, 10 mL). The mixture was stirred at 25 °C for 1 h. To the mixture was added sodium bicarbonate until pH 7. The mixture was concentrated under reduced pressure to afford 6- bromo-1,2,3,4-tetrahydroisoquinoline (3 g, crude) as a yellow oil. Step 2: benzyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate To a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (2 g, 9.4 mmol) in tetrahydrofuran (20 mL) and water (20 mL) was added sodium carbonate (4.00 g, 37.7 mmol) and N-N dimethyl chlorosilane (2.41 g, 14.2 mmol, 2.01 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h, then filtered and concentrated under reduced pressure. Diluted with water (50 mL) and ethyl acetate (50 mL) at 0 °C, extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 5/1) to afford benzyl 6- bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.2 g, 98%) as a yellow oil. MS (ESI) m/z: 347.9 [M+H] ⁺ . Step 3: benzyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate To a stirred of benzyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (3 g, 8.7 mmol) and diphenylmethanimine (1.80 g, 9.9 mmol, 1.67 mL) in toluene (30 mL) was added BINAP (540.00 mg, 867.2 μmol), tris(dibenzylideneacetone)dipalladium(0) (793.47 mg, 866.5 mmol) under nitrogen atmosphere, then to the mixture was added a solution of sodium tert-butoxide (2 M, 6.07 mL). The mixture was degassed and purged with nitrogen atmosphere 3 times, and then the mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered, quenched by water (50 mL) at 0 °C, diluted with ethyl acetate (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then to the residue was added 10% hydrogen chloride: tetrahydrofuran = 1:1 (40 mL), the mixture was stirred at 25 °C for 1 h. Ammonium hydroxide was added to adjust the pH to 7, then diluted with ethyl acetate (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to 2/1) to afford benzyl 6-amino-3,4-dihydroisoquinoline-2(1H)- carboxylate (1.7 g, 69%) as a yellow oil. MS (ESI) m/z: 283.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 - 7.29 (m, 5 H), 6.90 (dd, J = 7.2, 18.8 Hz, 1 H), 6.55 (dd, J = 2.0, 8.0 Hz, 1 H), 6.48 (s, 1 H), 5.18 (s, 2 H), 4.55 (s, 2 H), 3.79 - 3.50 (m, 4 H), 2.76 (s, 2 H). Step 4: 3-((2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)propanoic acid To a solution of benzyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.7 g, 2.5 mmol) in acetic acid (4 mL) and water (20 mL) was added acrylic acid (178.67 mg, 2.5 mmol, 170.16 mL). The mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. Then quenched by water (10 mL) at 0 °C, diluted with ethyl acetate (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 0/1) to afford 3-((2- ((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ami no)propanoic acid (0.4 g, 45%) as a white solid. MS (ESI) m/z: 355.1 [M+H] ⁺ . Step 5: benzyl 6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,4-dihydroisoquin oline-2(1H)- carboxylate To a solution of 3-((2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)propanoic acid (0.4 g, 1.1 mmol) in acetic acid (4 mL) was added urea (677.83 mg, 11.3 mmol, 605.20 mL). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by water (10 mL) at 0 °C, diluted with ethyl acetate (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 1:1) to afford benzyl 6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,4-dihydroisoquin oline-2(1H)- carboxylate (0.1 g, 23%) as a white solid. MS (ESI) m/z: 380.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1 H), 7.41 - 7.29 (m, 5 H), 7.23 - 7.19 (m, 1 H), 7.17 - 7.12 (m, 2 H), 5.13 (s, 2 H), 4.57 (d, J = 14.8 Hz, 2 H), 3.75 (t, J = 6.8 Hz, 2 H), 3.63 (s, 2 H), 3.32 (s, 2 H), 2.80 (t, J = 5.6 Hz, 2 H). Step 6: 1-(1,2,3,4-tetrahydroisoquinolin-6-yl)dihydropyrimidine-2,4( 1H,3H)-dione A mixture of benzyl 6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (0.1 g, 263.6 μmol) and 10% palladium on carbon (0.01 g) in trifluoroethanol (4 mL) was degassed and purged with hydrogen for 3 times, and then the mixture was stirred at 25 °C for 0.5 h under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford 1-(1,2,3,4- tetrahydroisoquinolin-6-yl)dihydropyrimidine-2,4(1H,3H)-dion e (60 mg, 92%) as a white solid. Step 7: N-(2-((1r,4r)-4-((6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 3,4-dihydroisoquinolin- 2(1H)-yl)methyl)cyclohexyl)-6-isopropoxy-1-oxoisoindolin-5-y l)pyrazolo[1,5-a]pyrimidine-3- carboxamide To a solution of N-(2-((1r,4r)-4-formylcyclohexyl)-6-isopropoxy-1-oxoisoindol in-5- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (113 mg, 244.9 mmol) in tetrahydrofuran (4 mL) and N,N-dimethylformamide (1 mL) at 0 °C was added 1-(1,2,3,4-tetrahydroisoquinolin-6- yl)dihydropyrimidine-2,4(1H,3H)-dione (60 mg, 244.6 mmol) and acetic acid (58.76 mg, 978.5 μmol, 55.96 mL) at 0 °C, The mixture was stirred at 0 °C for 0.5 h, followed by the addition of sodium borohydride acetate (155.5 mg, 733.9 mmol). The mixture was allowed to stir at 0 °C for 2 h and was then quenched by water (10 mL) at 0 °C, diluted with ethyl acetate (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm* 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 12-42%) to afford N-(2-((1r,4r)-4-((6-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)cyclohexyl)-6-iso propoxy-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (9.3 mg, 5%) as a white solid. MS (ESI) m/z: 691.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.75 (s, 1 H), 10.32 (s, 1 H), 9.41 (dd, J = 1.6, 7.2 Hz, 1 H), 8.89 (dd, J = 1.6, 4.4 Hz, 1 H), 8.74 (s, 2 H), 7.42 - 7.28 (m, 2 H), 7.13 - 7.00 (m, 3 H), 4.90 (m, 1 H), 4.41 (s, 2 H), 4.06 - 3.93 (m, 1 H), 3.74 (t, J = 6.8 Hz, 2 H), 3.53 (s, 2 H), 2.73 - 2.60 (m, 5 H), 2.32 (m, 2 H), 1.99 - 1.85 (m, 2 H), 1.76 (m, 2 H), 1.70 - 1.54 (m, 3 H), 1.44 (d, J = 6.0 Hz, 6 H), 1.19 - 0.96 (m, 2 H). Example 41: Preparation of 6-(cyclopropylmethoxy)-2-(1-((1-(2-(2,6-dioxopiperidin-3-yl) -1,3- dioxoisoindolin-5-yl)-3-fluoroazetidin-3-yl)methyl)piperidin -4-yl)-N-(pyrazolo[1,5-a]pyrimidin- 3-yl)-2H-indazole-5-carboxamide. Step 1: 5-bromo-4-fluoro-2-nitrobenzaldehyde To a mixture of nitric acid (42.85 g, 442.01 mmol, 30.61 mL, 65% purity, 1.79 eq) in sulfuric acid (200 mL) was added 3-bromo-4-fluorobenzaldehyde (50 g, 246.30 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was poured into ice-water (800 mL). The aqueous phase was extracted with ethyl acetate (800 mL × 2). The combined organic phase was washed with brine (700 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (0 to 2% ethyl acetate in petroleum ether) to afford 5-bromo-4-fluoro-2- nitrobenzaldehyde (50 g, 201.61 mmol, 82% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.32 (s, 1H), 8.16 (d, J = 6.8 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H). Step 2: 5-bromo-4-hydroxy-2-nitrobenzaldehyde To a solution of 5-bromo-4-fluoro-2-nitrobenzaldehyde (10 g, 40.32 mmol, 1 eq) in dimethylacetamide (200 mL) was added sodium acetate (13.23 g, 161.29 mmol, 4 eq). The mixture was stirred at 70 °C for 12 h. The mixture was treated with hydrochloric acid (1 M) and extracted with ethyl acetate (400 mL × 2). The combined organic phase was washed with brine (400 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum to yield 5-bromo-4-hydroxy-2-nitrobenzaldehyde (9 g, crude) as a yellow solid. MS (ESI) m/z: 243.8 [M-H]-. Step 3: 5-bromo-4-(cyclopropylmethoxy)-2-nitrobenzaldehyde To a solution of 5-bromo-4-hydroxy-2-nitrobenzaldehyde (9 g, 36.58 mmol, 1 eq) in N,N-dimethylformamide (100 mL) was added potassium carbonate (15.17 g, 109.75 mmol, 3 eq) and (bromomethyl)cyclopropane (19.76 g, 146.33 mmol, 14.01 mL, 4 eq). The mixture was stirred at 80 °C for 3 h. The mixture was poured into water (300 mL). The aqueous phase was extracted with ethyl acetate (300 mL × 2). The combined organic phase was washed with brine (300 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (0-8% ethyl acetate in petroleum ether) to afford 5-bromo-4-(cyclopropylmethoxy)-2-nitrobenzaldehyde (10.3 g, 34.32 mmol, 94% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.04 (s, 1H), 8.17 (s, 1H), 7.76 (s, 1H), 4.17 (d, J = 7.2 Hz, 2H), 1.36-1.25 (m, 1H), 0.66-0.60 (m, 2H), 0.43-0.38 (m, 2H). Step 4: tert-butyl 4-(5-bromo-6-(cyclopropylmethoxy)-2H-indazol-2-yl)piperidine -1- carboxylate. To a solution of 5-bromo-4-(cyclopropylmethoxy)-2-nitrobenzaldehyde (10.3 g, 34.32 mmol, 1 eq) in isopropanol (150 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (6.87 g, 34.32 mmol, 1 eq) and the mixture was stirred at 80 °C for 12 h under nitrogen. The mixture was allowed to cool to 25 °C prior to the addition of tributylphosphane (20.83 g, 102.96 mmol, 25.40 mL, 3 eq). The reaction mixture was then stirred at 80 °C for another 20 h under an inert atmosphere. Once cooled, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-bromo-6-(cyclopropylmethoxy)-2H-indazol-2- yl)piperidine-1-carboxylate (11.44 g, 25.40 mmol, 74% yield) as a yellow solid. MS (ESI) m/z: 450.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.31 (s, 1H), 7.96 (s, 1H), 7.06 (s, 1H), 4.63 (tt, J = 4.0, 11.6 Hz, 1H), 4.08 (br d, J = 13.2 Hz, 2H), 3.93 (d, J = 6.8 Hz, 2H), 2.95 (br s, 2H), 2.08 (br dd, J = 2.4, 12.4 Hz, 2H), 1.91 (dq, J = 4.4, 12.4 Hz, 2H), 1.43 (s, 9H), 1.33- 1.24 (m, 1H), 0.63-0.57 (m, 2H), 0.42-0.36 (m, 2H). Step 4: 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-(cyclopropylmeth oxy)-2H-indazole-5-carbo xylic acid To a solution of tert-butyl 4-(5-bromo-6-(cyclopropylmethoxy)-2H-indazol-2- yl)piperidine-1-carboxylate (1 g, 2.22 mmol, 1 eq) and potassium acetate (446.73 mg, 4.55 mmol, 2.05 eq) in dimethyl sulfoxide (20 mL) and water (4 mL) was added DPPF (246.19 mg, 444.08 mmol, 0.2 eq) and palladium acetate (49.85 mg, 222.0 mmol, 0.1 eq) under an atmosphere of N ₂ . The suspension was degassed and purged with carbon monoxide 3 times. The mixture was stirred under carbon monoxide (50 psi) at 80 °C for 12 h. The mixture was poured into ice-water (100 mL) and the pH was adjusted to 5 with acetic acid. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with brine (50 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with a gradient from 2:1 to 1:1 petroleum ether:ethyl acetate) to afford 2-(1-(tert- butoxycarbonyl)piperidin-4-yl)-6-(cyclopropylmethoxy)-2H-ind azole-5-carboxylic acid (0.7 g, 1.68 mmol, 75% yield) as a light yellow solid.MS (ESI) m/z: 416.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 11.21 - 11.60 (m, 1 H) 8.72 (s, 1 H) 8.08 (s, 1 H) 7.07 (s, 1 H) 4.53 (tt, J=11.6, 4.0 Hz, 1 H) 4.23 - 4.43 (m, 2 H) 4.07 - 4.12 (m, 2 H) 2.88 - 3.02 (m, 2 H) 2.21 - 2.29 (m, 2 H) 2.06 - 2.16 (m, 2 H) 1.49 (s, 9 H) 1.43 (m, 1 H) 0.76 - 0.81 (m, 2 H) 0.47 (q, J=4.8 Hz, 2 H). Step 5: tert-butyl 4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidin-3-ylca rbamoyl)-2H- indazol-2-yl)piperidine-1-carboxylate To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-(cyclopropylmeth oxy)-2H- indazole-5-carboxylic acid (0.65 g, 1.56 mmol, 1 eq) and pyrazolo[1,5-a]pyrimidin-3-amine (230.84 mg, 1.72 mmol, 1.1 eq) in pyridine (10 mL) was added 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (899.72 mg, 4.69 mmol, 3 eq). The reaction was stirred at 50 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography eluted with a gradient from 1:1 to 1:4 petroleum ether:ethyl acetate to afford tert-butyl 4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidin-3- ylcarbamoyl)-2H-indazol-2-yl)piperidine-1-carboxylate (0.8 g, 1.49 mmol, 95% yield) as a yellow solid. MS (ESI) m/z: 532.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ =10.82 (s, 1 H) 9.04 (s, 1 H) 8.82 (s, 1 H) 8.60 (dd, J=7.2, 1.6 Hz, 1 H) 8.33 (dd, J=3.6, 1.6 Hz, 1 H) 8.06 (s, 1 H) 7.07 (s, 1 H) 6.77 (dd, J=7.2, 3.6 Hz, 1 H) 4.53 (tt, J=11.6, 4.0 Hz, 1 H) 4.33 (br d, J=6.0 Hz, 2 H) 4.08 - 4.12 (m, 2 H) 2.95 (br s, 2 H) 2.26 (m, 2 H) 2.06 - 2.17 (m, 2 H) 1.66 (td, J=7.2, 4.8 Hz, 1 H) 1.49 (s, 9 H) 0.76 - 0.82 (m, 2 H) 0.51 (q, J=4.8 Hz, 2 H). Step 6: 6-(cyclopropylmethoxy)-2-(piperidin-4-yl)-N-(pyrazolo[1,5-a] pyrimidin-3-yl)-2H- indazole-5-carboxamide To a solution of tert-butyl 4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidin-3- ylcarbamoyl)-2H-indazol-2-yl)piperidine-1-carboxylate (0.3 g, 564.33 mmol, 1 eq) in dichloromethane (3 mL) was added a 4M solution of hydrochloric acid in methanol (6 mL). The reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated to give a residue. The residue was dissolved in dichloromethane /methyl alcohol =10/1 (20 mL) and stirred at 25 °C until homogeneous, then ammonium hydroxide (3 mL) and water (5 mL) were added and the mixture was allowed to stir at 25 °C for 10 min. The resulting mixture was concentrated under reduced pressure and the resulting suspension was filtered and washed with water (5 mL x 3) and acetonitrile (8 mL x 3). The collected cake was dried yielding 6-(cyclopropylmethoxy)-2-(piperidin-4-yl)-N-(pyrazolo[1,5-a] pyrimidin-3-yl)-2H- indazole-5-carboxamide (210 mg, 486.69 μmol, 86% yield) as a yellow solid which was used in the next step without further purification. MS (ESI) m/z: 432.2 [M+H] ⁺ . Step 7: tert-butyl 3-((4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidin-3- ylcarbamoyl)- 2H-indazol-2-yl)piperidin-1-yl)methyl)-3-fluoroazetidine-1-c arboxylate To a solution of 6-(cyclopropylmethoxy)-2-(piperidin-4-yl)-N-(pyrazolo[1,5-a] pyrimidin- 3-yl)-2H-indazole-5-carboxamide (160 mg, 370.81 mmol, 1 eq) and tert-butyl 3- (bromomethyl)-3-fluoro-azetidine-1-carboxylate (198.84 mg, 741.62 mmol, 2 eq) in dimethyl sulfoxide (5 mL) was added N,N-diisopropylethylamine (143.77 mg, 1.11 mmol, 193.76 mL, 3 eq). The reaction was stirred at 90 °C for 12 h. The mixture was poured into ice-water (30 mL). The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with brine (30 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative TLC (eluted with a 10:1 solution of dichloromethane:methyl alcohol) to afford tert-butyl 3-((4-(6- (cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamo yl)-2H-indazol-2-yl)piperidin-1- yl)methyl)-3-fluoroazetidine-1-carboxylate (170 mg, 274.77 mmol, 74% yield) as a brown solid. MS (ESI) m/z: 619.3 [M+H] ⁺ . Step 8: 6-(cyclopropylmethoxy)-2-(1-((3-fluoroazetidin-3-yl)methyl)p iperidin-4-yl)-N- (pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide To a solution of tert-butyl 3-((4-(6-(cyclopropylmethoxy)-5-(pyrazolo[1,5-a]pyrimidin- 3-ylcarbamoyl)-2H-indazol-2-yl)piperidin-1-yl)methyl)-3-fluo roazetidine-1-carboxylate (150 mg, 242.44 mmol, 1 eq) in dichloromethane (4 mL) was added trifluoroacetic acid (6.16 g, 54.02 mmol, 4 mL, 222.83 eq). The reaction was stirred at 25 °C for 1 h. The mixture was concentrated to yield 6-(cyclopropylmethoxy)-2-(1-((3-fluoroazetidin-3-yl)methyl)p iperidin-4- yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxam ide (150 mg, crude, trifluoroacetate) as a brown gum which was used in subsequent reactions without further purification. MS (ESI) m/z: 519.2 [M+H] ⁺ . Step 9: 6-(cyclopropylmethoxy)-2-(1-((1-(2-(2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5- yl)-3-fluoroazetidin-3-yl)methyl)piperidin-4-yl)-N-(pyrazolo [1,5-a]pyrimidin-3-yl)-2H-indazole- 5-carboxamide To a solution of 6-(cyclopropylmethoxy)-2-(1-((3-fluoroazetidin-3-yl)methyl)p iperidin- 4-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carbox amide (150 mg, 237.11 mmol, 1 eq, trifluoroacetate, crude) in dimethyl sulfoxide (6 mL) was added N,N- diisopropylethylamine (91.94 mg, 711.34 mmol, 123.90 mL, 3 eq) and 2-(2,6-dioxo-3- piperidyl)-5-fluoro-isoindoline-1,3-dione (98.24 mg, 355.67 mmol, 1.5 eq). The reaction was stirred at 80°C for 12 h. The mixture was poured into ice-water (40 mL). The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-TLC (dichloromethane /methyl alcohol=10/1) to give the crude product. The crude product was further purified by semi-preparative reverse phase HPLC (column: Phenomenex Synergi C18150*25mm* 10μm;mobile phase: [water(formic acid)-acetonitrile]; B%: 14-44% to afford 6-(cyclopropylmethoxy)-2-(1-((1-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoro azetidin-3-yl)methyl)piperidin-4-yl)- N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (85.4 mg, 109.12 mmol, 46.0% yield, 99% purity as a yellow solid. MS (ESI) m/z: 775.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ =11.08 (s, 1 H) 10.72 (s, 1 H) 9.07 (dd, J=7.2, 1.6 Hz, 1 H) 8.80 (s, 1 H) 8.59 (d, J=4.4 Hz, 2 H) 8.45 - 8.52 (m, 1 H) 7.69 (d, J=8.4 Hz, 1 H) 7.17 (s, 1 H) 7.03 (dd, J=7.2, 4.0 Hz, 1 H) 6.92 (d, J=2.0 Hz, 1 H) 6.78 (dd, J=8.4, 2.0 Hz, 1 H) 5.07 (dd, J=12.8, 5.6 Hz, 1 H) 4.40 - 4.54 (m, 1 H) 4.18 - 4.29 (m, 3 H) 4.14 (d, J=7.2 Hz, 3 H) 3.03 - 3.11 (m, 2 H) 3.00 (s, 1 H) 2.82 - 2.95 (m, 2 H) 2.55 - 2.62 (m, 2 H) 2.40 - 2.45 (m, 2 H) 2.08 - 2.18 (m, 4 H) 1.97 - 2.04 (m, 1 H) 1.52 - 1.62 (m, 1 H) 0.68 - 0.75 (m, 2 H) 0.48 (m, 2 H). Table 5. The following compound may be prepared in an analogous fashion as described for the synthesis of Example 41. Biological Activity of Exemplary Compounds IRAK4 ELISA Protocol Reagents: Human IRAK4 Matched Antibody Pair Kit (Abcam ab218182) and ELISA Accessory Pack (Abcam ab210905). Cell treatment and lysis: 800,000 PBMC cells were seeded at 2×10 ⁶ /ml in 96-well U- bottom deep-well plates, 400 μL per well, and treated with compound the same day. Incubation proceeded overnight. Cell lysate was collected and analyzed by ELISA for IRAK4 levels. Table 6. PBMC Degradation Data. PBMC DC ₉₀ : A, B, C, or D. According to the code, A represents a DC ₉₀ value <10.0 nM; B represents a DC ₉₀ value ≥10.0 nM and <25.0 nM; C represents a DC ₉₀ value ≥25.0 nM and <50 nM; D represents a DC ₉₀ value ≥50 nM. PBMC DC ₅₀ : A, B, C, or D. According to the code, A represents a DC ₅₀ value <1.0 nM; B represents a DC ₅₀ value ≥1.0 nM and <5.0 nM; C represents a DC ₅₀ value ≥5.0 nM and <10 nM; D represents a DC ₅₀ value ≥10 nM. PBMC D _max : A, B, C, or D. According to the code, A represents a D _max value ≥90; B represents a Dmax value ≥80 and <90; C represents a Dmax value ≥70 and <80; D represents a Dmax value <70. IL-1β, LPS, or R848 stimulated IL6 inhibition and IL-1β stimulated IL8 inhibition assay Human PBMC cells were seeded at 2.5x10 ⁶ cells/mL, treated with compound overnight, and stimulated with the EC50 concentration of each stimulant (either IL-1B, LPS, or R848) determined for each donor. After 24hrs, media was collected and analyzed by MSD for IL6 and/or IL8 levels. Table 7. Inhibition of IL6 in PBMCs after stimulation with LPS and R848 LPS stimulated IL6 inhibition/ R848 stimulated IL6 inhibition IC ₅₀ : A, B, C, or D. According to the code, A represents an IC ₅₀ value <10.0 nM; B represents an IC ₅₀ value ≥10.0 nM and <50.0 nM; C represents an IC ₅₀ value ≥50.0 nM and <100 nM; D represents an IC ₅₀ value ≥100 nM. LPS stimulated IL6 inhibition/ R848 stimulated IL6 inhibition Y _max : A, B, C, or D. According to the code, A represents a Y _max value ≥90; B represents a Y _max value ≥80 and <90; C represents a Y _max value ≥70 and <80; D represents a Y _max value <70.