Kinase inhibition and degradation

Abstract

Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of kinase activity and / or facilitators of the degradation of the kinases HCK and BTK are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including a proliferative disease, such as IgM gammopathy, mastocytosis, cancer.

Description

Federally Sponsored Research

[0001] This invention was made with government support under P50 CA100707 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0002] This application claims priority to U.S. Provisional Application No. 63 / 613,255, filed on December 21, 2023, and which is incorporated herein in its entirety by reference. Field

[0003] The present disclosure relates to degrader compounds having activity as against one or more, including two or more, target kinases, as well as methods of using the compounds for inhibiting kinase activity and / or facilitating degradation of kinases as well as methods for use in the treatment and / or prevention of a disease (e.g., a proliferative disease, such as IgM gammopathy, mastocytosis, and cancer). Background

[0001] Activating mutations in MYD88 are prevalent in many B-cell malignancies, including Waldenstrom Macroglobulinemia (95-97%), primary CNS lymphoma (70-80%), ABC DLBCL (40%), marginal zone lymphoma (5-10%), and CLL (5-15%). Mutated MYD88 transcriptionally upregulates the SRC family member HCK, which in turn serves as a master signal for triggering multiple pro-survival cascades in mutated MYD88 lymphoma cells including BTK / NFKB, SYK, and ERK. See Yang, G.; et. al. Blood 2016,127(25), 3237; Liu, X.; et. al. Blood Adv 2020, 4, 141; and Munshi, M.; et. al. Blood Adv 2022, 6(11), 3332 incorporated herein by reference. As an identified lead HCK kinase inhibitor, KIN-8194, blocked both HCK and BTK and was active both in vitro and in vivo in MYD88 mutated xenograft lymphoma models, including BTKCys481Ser ibrutinib resistant models. See Balsas, P.; et. al. Blood 2021,138(22), 1966 incorporated herein by reference.

[0002] Proteolysis targeting chimeras (PROTACs) represent a novel approach for blocking kinase based signaling and may provide an advantage over kinase inhibitors with greater selectivity and sustained target inhibition through degradation. Therefore, a need exists to - 1 - develop highly potent, selective, and bio-available HCK / BTK targeting PROTACS using KIN-8194 scaffold for the treatment of MYD88 driven lymphomas. Brief Summary of the Disclosure

[0004] In one embodiment, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein the dashed circle indicates the ring is aromatic; QI is N, S, or C; Q2 is N or C; Q3 is N or C; Ring A is absent or a heteroaryl ring; when Ring A is absent, two RA are present at the points of attachment for Ring A, RA is selected independently selected from the group consisting of H, NR’R”, C(O)R’R”, and NR’C(O)R” R’ and R” are independently H or Cl-3alkyl; LI is abend, C1-C3 alkyl, C(O)Cl-3alkyl, Cl-3alkyl-O, orCl-3alkyl-O-Cl-3alkyl; Ring B is a bond or selected from C4-6 cycloalkyl and 4-6 heterocyclyl ring; and RB is an E3 ligase-binding moiety.

[0005] In one aspect, QI is N.

[0006] In one aspect, QI is S.

[0007] In one aspect, QI and Q2 are N.

[0008] In one aspect, QI is N and Q2 are C.

[0009] In one aspect, QI is S and Q2 are C.

[0010] In one aspect, Q3 is C.

[0011] In one aspect, Q3 is N.

[0012] In one aspect, each of QI and Q2 is N, and Q3 is C.

[0013] In one aspect, Ring A is selected from the following: absent,

[0014] In one aspect, when Ring A is absent and RA is selected from NH2 and C(O)NH2.

[0015] In one aspect, RA is NH2.

[0016] In one aspect, Ring B is selected from:

[0017] In one aspect, RB is a cereblon E3 ligase-binding moiety.

[0018] In one aspect, RB is a VHL E3 ligase-binding moiety.

[0019] In one aspect, RB is selected from the group consisting of:

[0021] In one embodiment, the present disclosure includes a compound from Table B, or a pharmaceutically acceptable salt thereof.

[0022] Table B.

[0023] In one embodiment, the present disclosure includes a compound selected from or a pharmaceutically acceptable salt thereof.

[0024] In one embodiment, the present disclosure includes a compound selected from Compound 7, 10, 26, 27, 28, 29, 30, 31, or 33.

[0025] In one embodiment, the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0026] In one embodiment, the present disclosure includes a method for inhibiting the activity of one or more kinase in a subject comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure.

[0027] In one embodiment, the present disclosure includes a method for facilitating the degradation of one or more kinase in a subject comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure.

[0028] In one aspect, the one or more kinase is selected from the group consisting an SRC family of cytoplasmic tyrosine kinases (SFKs), a hemotopoietic cell kinase, a LYN protooncogene tyrosine kinase (LYN), a Tec family of cytoplasmic tyrosine kinases, and a Bruton’s tyrosine kinase (BTK).

[0029] In one aspect, the one or more kinase is a mutated kinase.

[0030] In one aspect, the one or more kinase is resistant to treatment. [0031 ] In one embodiment, the present disclosure includes a method of treating a proliferative disease associated with a mutation in a MYD88 protein in a subject in need thereof comprising administering to the subject the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure.

[0032] In one aspect, the disease is associated with aberrant activity of one or more of a hematopoietic cell kinase (HCK), of a LYN proto-oncogene tyrosine kinase (LYN), of Bruton’s tyrosine kinase (BTK), or a mutation in a BTK protein.

[0033] In one aspect, the disease is associated with a mutation in a BTK protein, wherein the mutated BTK protein is a C481S mutated BTK.

[0034] In one aspect, the proliferative disease is cancer, IgM gammopathy or mastocytosis.

[0035] In one aspect, the proliferative disease is cancer, and wherein the cancer is breast cancer, colon cancer, stomach cancer, testicular cancer, cancer of the central nervous system, lymphoma, leukemia, myeloma, or myeloproliferative disease.

[0036] In one aspect, the cancer is lymphoma, and wherein the lymphoma is a B-cell lymphoma.

[0037] In one aspect, the B-cell lymphoma is lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone B-cell lymphoma or small lymphocytic lymphoma.

[0038] In one aspect, the lymphoplasmacytic lymphoma is IgM secreting lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia, or non-IgM secreting lymphoplasmacytic lymphoma.

[0039] In one aspect, the diffuse large B-cell lymphoma is activated B-cell-like (ABC-DLBCL), or germinal center B-cell-like (GBC-DLBCL).

[0040] In one aspect, the small lymphocytic lymphoma is mantle cell lymphoma.

[0041] In one aspect, the cancer is leukemia, and wherein the leukemia is chronic lymphocytic leukemia, or myelogenous leukemia.

[0042] In one aspect, the myelogenous leukemia is chronic myelogenous leukemia, or acute myelogenous leukemia.

[0043] In one aspect, the acute myelogenous leukemia is mast cell leukemia.

[0044] In one aspect, the cancer is a myeloma, and the myeloma is an IgM myeloma.

[0045] In one aspect, the IgM myeloma is IgM multiple myeloma.

[0046] In one aspect, the cancer is a myeloproliferative disease, and wherein the myeloproliferative disease is myelodysplastic syndrome.

[0047] In one aspect, the proliferative disease is an IgM gammopathy and wherein the IgM gammopathy is an IgM Monoclonal gammopathy of undetermined significance (MGUS) or amyloid light chain (AL) amyloidosis.

[0048] In one aspect, the proliferative disease is mastocytosis and wherein the mastocytosis is systemic mastocytosis.

[0049] In one embodiment, the present disclosure includes a compound according to the present disclosure for use in inhibiting the activity of one or more kinase in a subject in need thereof.

[0050] In one embodiment, the present disclosure includes a compound according to the present disclosure for use in facilitating the degradation of one or more kinase in the subject in need thereof.

[0051] In one aspect, the kinase is an SRC cytoplasmic tyrosine kinase (SFK),

[0052] In one aspect, the SFK is hematopoietic cell kinase (HCK) or LYN proto-oncogene tyrosine kinase (LYN).

[0053] In one aspect, the kinase is a Tec cytoplasmic tyrosine kinase, and preferably a Bruton’s tyrosine kinase (BTK).

[0054] In one aspect, the kinase is one or more of HCK, LYN, and BTK. Preferably two or more of HCK, LYN, and BTK.

[0055] In one aspect, the BTK is a mutated BTK, preferably wherein the BTK is mutated at Cys481, more preferably wherein the BTK is a C481S mutated BTK.

[0056] In one aspect, the BTK is resistant to inhibition by ibrutinib.

[0057] In one aspect, the subject is resistant to treatment with one or more of ibrutinib, CC- 292, ONO-4059, evobrutinib, spebrutinib, BGB-3111, HM71224, and ACP-196, or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the present disclosure includes a method of treating, including lessening the severity of, one or more of breast cancer, colon cancer, stomach cancer, testicular cancer, cancer of the central nervous system, IgM secreting lymphoplasmacytic lymphoma, non-IgM secreting lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC-DLBCL), germinal center B-cell-like (GBC-DLBCL), follicular lymphoma, marginal zone B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, mast cell leukemia, IgM multiple myeloma, myelodysplastic syndrome, IgM Monoclonal gammopathy of undetermined significance (MGUS), amyloid light chain (AL) amyloidosis, or systemic mastocytosis comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure.

[0059] In one aspect, the subject is treated with one or more additional therapeutic agents or treatments, such as radiation, administered concurrently with, prior to, or subsequent to treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition of the present disclosure.

[0060] In one embodiment, the present disclosure includes the use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure, as a medicament.

[0061] In one aspect, the use is made in combination with one or more additional immunotherapy or oncologic treatment.

[0062] In one aspect, the additional immunotherapy comprises a chimeric antigen receptor (CAR).

[0063] In one aspect, the additional immunotherapy comprises a bispecific antibody. Brief Description of the Figures

[0064] Figure 1 illustrates that each of Compounds (7), (10), and (13) selectively targets HCK, BTK and LYN in MYD88 mutated WM and ABC DLBCL cells. Figure 1A shows the results of a KINOMEscan® of Compounds (7) and (10) and KIN-8194 against a panel of 468 kinases. Figure IB shows the impact of Compounds (7), (10), and (13) on HCK and BTK phosphorylation by western blotting in MYD88 mutated WM (BCWM.l, MWCL-1) and ABC DLBCL (TMD8, HBL-1) cell lines.

[0065] Figure 2 illustrates a mean plasma concentration-time profile of Compound 7 or a sulfate derivate thereof after an IV dose at 2 mg / kg and PO dose at 10 mg / kg, 30 mg / kg, and 60 mg / kg in male C57BL / 6 mice (N=9). No abnormal clinical signs were observed during the entire in-life phase. All BQL data (below quantifiable limit of 1.00 ng / mL for Compound 7 in mouse blood) was excluded from mean value concentration and graphing. Pharmacokinetics (PK) parameters were estimated by non-compartmental model using WinNonlin 8.2. If the adjusted rsq (linear regression coefficient of the concentration value on the terminal phase) is less than 0.9, Tl / 2 might not be accurately estimated. The F value was determined by the following equation: AUC,aqt            (AUC,nf fx x DOSEIV) AUCinf           (AUCinf ivxD0SEex) < 80% or AUCinf not available (NA): F = ^uci^-Exxdose,v) x 100% AUCjnf                                               (AuCiast-IvXDOSEEX)

[0066] Figure 3 illustrates a mean plasma concentration-time profile of Compound 10 after an IV dose at 2 mg / kg and PO dose at 10 mg / kg, 30 mg / kg and 60 mg / kg in male C57BL / 6 mice (N=9). No abnormal clinical signs were observed during the entire in-life phase. All BQL data -21 - (below quantifiable limit of 1.00 ng / mL for Compound 10 in mouse blood) was excluded from mean value concentration and graphing. Pharmacokinetics (PK) parameters were estimated by non-compartmental model using WinNonlin 8.2. If the adjusted rsq (linear regression coefficient of the concentration value on the terminal phase) is less than 0.9, Tl / 2 might not be accurately estimated. The F value was determined by the following equation: (AUCINF_FX x DOSEIV) --— > 80%: F = --------— x 100% AUCinf           (AUCinf_ivxDOSEex) < 80% or AUCinf not available (NA): F = ^uciast-ExxDosEIV) x w AUCinf                                   V 7 (AUClast_IVXDOSEEX)

[0067] Figure 4 depicts an ECso titration curve in a lymphoma cell line, TMD-8, established from cells of a patient with diffuse large B-cell lymphoma, where the Compounds (26), (27), and (30) dose titration was monitored as measured using relative light units (RLU) in comparison to a negative control (DMSO). The reduction in light was used to establish an ECso value for each of the respective compounds as compared with KIN-8194.

[0068] Figure 5 displays an ECso titration curve in two different cell lines. Figure 5A shows an ECso curve calculated for Compounds (28) and (30) in the lymphoma cell line, TMD-8, as compared with KIN-8194. Figure 5B shows the calculation of an ECso curve for Compounds (28) and (30) in a BCWM. 1 cell line, which was derived from the long-term culture of CD 19(+) selected bone marrow lymphoplasmacytic cells isolated from an untreated patient with Waldenstrom's macroglobulinemia.

[0069] Figure 6 shows an ECso titration curve in two different cell lines. Figure 6A exhibits the EC50 titration curve for Compounds (29), (30), (31), and (33) in the TMD-8 cell line, compared with KIN-8194. Figure 6B shows the ECso inhibition for Compounds (29), (30), (31), and (33) in the TMD-8 cell line, compared with KIN-8194. Detailed Description of the Disclosure

[0070] The present disclosure highlights the development and characterization of novel, dual HCK / BTK PROTACs that demonstrate potent and selective kinase inhibition and protein degradation of HCK and BTK. The HCK / BTK PROTACs showed enhanced apoptosis of MYD88 mutated WM and ABC DLBCL cells over the native kinase inhibitor KIN-8194 and sparing of healthy donor B- and T-cells with high levels of bioavailability.

[0071] Thus described herein is a compound of Formula (I): and methods of using the compound for inhibiting kinase activity and / or facilitating degradation of kinases as well as methods for use in the treatment and / or prevention of a disease (e.g., a proliferative disease, such as IgM gammopathy, mastocytosis, cancer) in a subject in need thereof as described herein. Definitions

[0072] The following definitions are meant to clarify, but not limit, the terms defined. If a particular term used herein is not specifically defined, such term should not be considered indefinite. Rather, terms arc used within their accepted meanings.

[0073] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modem Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0074] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by -23- methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0075] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “Ci-6 alkyl” encompasses Ci, C2, C3, C4, C5, Ce, Ci-6, C1-5, Cm, C1-3, Ci-2, C2-6, C2-5, C2m, C2-3, C3-6, C3-5, C3M, C4-6, C4-5, and C5-6 alkyl.

[0076] The term “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted Ci-12 alkyl (such as unsubstituted Ci-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (zi-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted .sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z-Bu)). In certain embodiments, the alkyl group is a substituted Ci-12 alkyl (such as substituted Ci^ alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0077] The term “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds. The one or more carbon-carbon double bonds can be internal (such as in 2-24- butenyl) or terminal (such as in 1-butenyl). Examples of C2 - alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2 4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., - CH=CHCH3 or         may be in the (E)- or (Z)-configuration.

[0078] The term “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2 20 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2 4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2 4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl.

[0079] Moreover, with regard to each of the foregoing, reference to an “alkylene,” “alkenylene,” or “alkynylene” group refers to divalent forms of these groups.

[0080] The term “cycloalkyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). Exemplary C3-6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 cycloalkyl groups include, without limitation, the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 cycloalkyl groups include, without limitation, the aforementioned C3-8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Unless otherwise specified, each instance of a cycloalkyl group is independently optionally substituted, i.e.. unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-10 cycloalkyl.

[0081] The term “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., -26- unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0082] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-onc. Exemplary 5-mcmbcrcd heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2--27- b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0083] The term “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce u aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Cearyl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Ci4 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted Ce-14 aryl. In certain embodiments, the aryl group is substituted Ce-14 aryl.

[0084] The term “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety. In certain embodiments, the aralkyl is optionally substituted benzyl. In certain embodiments, the aralkyl is benzyl. In certain embodiments, the aralkyl is optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl.

[0085] The term “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In hctcroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more cycloalkyl or -28- heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0086] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 -29- membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.

[0087] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azcpinyl, oxcpinyl, and thicpinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0088] The term “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the attachment is on the alkyl moiety.

[0089] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond. A “partially unsaturated” ring system is further intended to encompass rings having multiple sites of unsaturation but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as defined herein. Likewise, “saturated” refers to a group that does not contain a double or triple bond, i.e., contains all single bonds.

[0090] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which are divalent bridging groups are further referred to using the suffix -ene, e.g., alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, and heteroarylene. -30-

[0091] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted.

[0092] In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted”, “substituted” or “unsubstituted” cycloalkyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0093] Illustrative substituents, which with multiple substituents can be the same or different, include halogen, haloalkyl, R', OR', OH, SH, SR', NO2, CN, C(O)R', C(O)(alkyl substituted with one or more of halogen, haloalkyl, NH2, OH, SH, CN, and NO2), C(O)OR', OC(O)R', CON(R')2, OC(O)N(R')2, NH2, NHR', N(R')2, NHCOR', NHCOH, NHCONH2, NHCONHR', NHCON(R')2, NRCOR', NRCOH, NHCO2H, NHCO2R', NHC(S)NH2, NHC(S)NHR', NHC(S)N(R')2, CO2R', CO2H, CHO, CONH2, CONHR', CON(R')2, S(O)2H, S(O)2R', SO2NH2, S(O)H, S(O)R', SO2NHR', SO2N(R')2, NHS(O)2H, NR'S(O)2H, NHS(O)2R', NR'S(O)2R', Si(R')3, where each of the preceding may be linked through a divalent alkylene linker, (CH2)x, where x is 1, 2, or 3. In embodiments where a saturated carbon atom is optionally substituted with one or more -31- substituent groups, the substituents may be the same or different and also include =0, =S, =NNHR', =NNH2, =NN(R')2, =N-0R', =N-0H, =NNHCOR', =NNHC0H, =NNHCO2R', =NNHC02H, =NNHSO2R', =NNHS02H, =N-CN, =NH, or =NR'. For each of the preceding, each may be linked through an alkylene linker, (CH2)x, where x is 1,2, or 3, Each occurrence of R’ is the same or different and , in some embodiments, represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or, in some embodiments,when two R’ are each attached to a nitrogen atom, they may form a saturated or unsaturated heterocyclic ring containing from 4 to 6 ring atoms.

[0094] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F", Cl , Br , F), NO3 , CIO4 , OH , H2PO4 , HCOa-, HSO4 , sulfonate ions (e.g., mcthansulfonatc, trifluoromcthancsulfonatc, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BET, PF4 , PFe , AsFe , SbFe , B[3,5-(CF3)2C6H3]4F, BCCeFsF-, BPh4 , A1(OC(CF3)3)4-, and carborane anions (e.g., CBnHn" or (HCBnMesBre) ). Exemplary counterions which may be multivalent include COs2-, HPO42-, PO43-, B4O?2-, SO42-, SiOs2-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0095] “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0096] “Alkoxy” or “alkoxyl” refers to a radical of the formula: -O-alkyl.

[0097] As used herein, a “leaving group” (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in a heterolytic bond cleavage, wherein the molecular- fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not -32- limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups. Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, A^O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, amines, ammonia, alcohols, ether moieties, sulfurcontaining moictics, thiocthcr moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0098] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, WH, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, -33- malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tailrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci 4 alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0099] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. Compound (I) may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0100] The term “stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent molecules are an integral part of the crystal lattice, in which they interact strongly with the compound and each other. The removal of the solvent molecules will cause instability of the crystal network, which subsequently collapses into an amorphous phase or recrystallizes as a new crystalline form with reduced solvent content.

[0101] The term “non-stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent content may vary without major changes in the crystal structure. The amount of solvent in the crystal lattice only depends on the partial pressure of solvent in the surrounding atmosphere. In the fully solvated state, non-stoichiometric solvates may, but not necessarily have to, show an integer molar ratio of solvent to the compound. During diying of a non-stoichiometric solvate, a portion of the solvent may be removed without significantly disturbing the ciystal network, and the resulting solvate can -34- subsequently be resolvated to give the initial crystalline form. Unlike stoichiometric solvates, the desolvation and resolvation of non-stoichiometric solvates is not accompanied by a phase transition, and all solvation states represent the same crystal form.

[0102] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula Rx H2O, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (RO.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).

[0103]

[0104] The term “tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.

[0105] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0106] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

[0107] Stereoisomers that arc not mirror images of one another arc termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”

[0108] The term “prodrugs” refer to compounds, including derivatives of Compound (I), which have cleavable groups and become by solvolysis or under physiological conditions Compound (I) which are pharmaceutically active in vivo. Such examples include, but are not limited to, ester derivatives and the like. Other derivatives of the compounds of this disclosure have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds of this disclosure are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.

[0109] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys). In certain embodiments, the animal is a mammal. The animal may be a male or female and at any stage of development. A non-human animal may be a transgenic animal. A subject who is resistant to treatment with a BTK inhibitor is one who shows no or minimal response to the treatment. In some embodiments, response to a treatment is measured by reduction in tumor cells or tumor cell killing. In some embodiments, response to a treatment is measured by changes in symptoms of the -36- disease, condition or malignancy (e.g., a proliferative disease). It has been discovered that the compounds that block ATP binding to HCK as described herein are able to cause tumor cell killing even in cells that are derived from subjects who are resistant to a BTK inhibitor treatment.

[0110] The terms “administer,” “administering,” or “administration,” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound, or a pharmaceutical composition thereof.

[0111] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a “pathological condition” (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein. In some embodiments, treatment may be administered after one or more signs or symptoms have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0112] The terms “condition,” “disease,” and “disorder” are used interchangeably. The treatment may be therapeutic treatment (not including prevention or prophylactic treatment).

[0113] An “effective amount” of Compound (I) refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition. As will be appreciated by those of ordinary skill in this ait, the effective amount of Compound (I) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of a compound may reduce the tumor burden or stop the growth or spread of a tumor.

[0114] A “therapeutically effective amount” of Compound (I) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0115] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, stomach cancer, lymphoma (e.g., B-cell Lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM secreting (i.e., Waldenstrom’s Macroglobulinemia), non-IgM secreting)), Diffuse Large B-Cell Lymphoma (e.g., activated B-cell-like (ABC)- DLBCL, germinal center B-cell-like (GBC)-DLBCL)), Follicular Lymphoma, Marginal zone B-cell lymphoma, Small lymphocytic lymphoma (e.g. Chronic lymphocytic leukemia (CLL)), Mantle cell lymphoma), Leukemia (e.g., myelogenous leukemia (e.g., chronic myelogenous leukemia, acute myelogenous leukemia)), benign neoplasms, angiogenesis, inflammatory diseases, auto inflammatory diseases, and autoimmune diseases.

[0116] The terms “neoplasm” and “tumor” are used interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.

[0117] The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0118] The term “cancer” refers to a malignant neoplasm {Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). The cancer may be a solid tumor. The cancer may be a hematological malignancy. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangiocndothcliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL) (e.g., activated B-cell-like (ABC)- DLBCL, germinal center B-cell-like (GBC)-DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., IgM secreting lymphoplasmacytic lymphoma, i.e., Waldenstrom’s macroglobulinemia, and non-IgM secreting lymphoplasmacytic lymphoma), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, cxtranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrinetumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal -40- papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0119] The term “angiogenesis” refers to the formation and the growth of new blood vessels. Normal angiogenesis occurs in the healthy body of a subject for healing wounds and for restoring blood flow to tissues after injury. The healthy body controls angiogenesis through a number of means, e.g., angiogenesis-stimulating growth factors and angiogenesis inhibitors. Many disease states, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal or pathological angiogenesis refers to angiogenesis greater than that in a normal body, especially angiogenesis in an adult not related to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels that feed diseased tissues and / or destroy normal tissues, and in the case of cancer, the new vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases). In certain embodiments, the angiogenesis is pathological angiogenesis.

[0120] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary -41 - autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic poly angiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0121] The term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infcctious causes. Inflammatory diseases include atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, dermatitis (e.g., stasis dermatitis, allergic contact dermatitis, atopic dermatitis, irritant contact dermatitis, neurodermatitis perioral dermatitis, seborrheic dermatitis), hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic -42- cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, necrotizing enterocolitis, inflammatory rosacea. An ocular inflammatory disease includes post-surgical inflammation.

[0122] The term “kinase” refers to any enzyme that catalyzes the addition of phosphate groups to an amino acid residue of a protein. For example, a serine kinase catalyzes the addition of a phosphate group to serine residue in a protein. In certain embodiments, the kinase is a protein kinase. Examples of kinases include, but are not limited to, cytoplasmic tyrosine kinases (e.g., SRC family kinases (e.g., HCK, LYN, BLK, FRK), Tec family kinases (e.g., BTK)), a cyclin-dependent kinase (CDK, e.g., CDK1, CDK2, CDK2, CDK4, CDK5, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, CDK14, CDK16, CDK20)), a mitogen-activated protein kinase (MAPK, e.g., MAPK1 , MAPK3 , MAPK4 , MAPK6 , MAPK7 , MAPK8 , MAPK9 , MAPK10 , MAPK11 , MAPK12 , MAPK13 , MAPK14 , MAPK15), a glycogen synthase kinase 3 (GSK3, e.g., GSK3a, GSK30), a CDK-like kinase (CLK, e.g., CLK1, CLK2, CLK3, CLK4)), an AGC kinase (e.g., protein kinase A (PKA), protein kinase C (PKC), protein kinase G (PKG)), a Ca2+ / calmodulin-dependent protein kinase (CaM kinase, e.g., a specialized CaM kinase, a multifunctional CaM kinase), a casein kinase 1 (CK1, e.g., CK1 alpha, CKlbeta 1, CKlgamma 1, CKlgamma 2, CKlgamma 3, CKldelta, CKlepsilon), a STE kinase (e.g., a homolog of yeast Sterile 7, Sterile 11, or Sterile 20 kinase), a tyrosine kinase (TK, e.g., a receptor tyrosine kinase (RTK), a non-receptor tyrosine kinase (nRTK)), and a tyrosine-kinase-like kinase (TKL, e.g., a mixed lineage kinase (MLK), RAF, a serine threonine kinase receptor (STKR), a leucine rich repeat kinase (LRRK), a LIM domain kinase (LIMK), a testis expressed serine kinase (TESK), an IL1 receptor associated kinase (IRAK), a receptor interacting protein kinase (RIPK)).

[0123] Hematopoietic cell kinase (HCK) is a member of the src-family of protein tyrosine kinases, and is aberrantly up-regulated in WM cells. In myeloma cells, HCK is activated by interleukin 6 (IL6) through the IL6 co-receptor IL6ST (GP130).

[0124] Bruton’s tyrosine kinase (BTK) is a member of the src-related BTK / Tec family of cytoplasmic tyrosine kinases, is required for B cell receptor signaling, plays a key role in B-cell maturation, and exhibits increased activation in a number of B-cell malignancies.

[0125] LYN proto-oncogene (LYN) is a member of the src-family of protein tyrosine kinases, plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, is important for immune self-tolerance, and acts downstream of several immune receptors, including the B-cell receptor (BCR). Without wishing to be bound by theory, BCR signaling is thought to be involved in pro-growth and survival signaling in MYD88 mutated disease, as well as being involved in non-MYD88 mutated disease. For example, BCR signaling is thought to be active in Waldenstrom’s Macroglobulinemia, ABC subtype of diffuse large B-cell lymphoma, and chronic lymphocytic leukemia.

[0126] Proto-oncogene tyrosine-protein kinase SRC (SRC) is a protein tyrosine kinase, plays a central role in the regulation of a variety of biological processes, such as cell proliferation, migration, adhesion, and survival in solid tumors, and is overexpressed in Waldenstrom’s Macroglobulinemia.

[0127] As used herein “inhibition”, “inhibiting”, “inhibit” and “inhibitor”, and the like, refer to the ability of a compound to reduce, slow, halt, block, or prevent activity of a particular biological process (e.g., a kinase (e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec family kinases (e.g., BTK)) in a cell relative to vehicle.

[0128] The terms “block” or “blocking” refer to the ability of a compound to prevent a biological interaction (e.g., binding) in a cell relative to a negative control, e.g., vehicle. For example, a compound can block ATP from binding to the ATP binding pocket of a kinase. Such blocking may occur by direct binding of the compound to the ATP binding pocket itself, or indirect blocking. In some embodiments, the term refers to a reduction in the level of binding of ATP to a kinase, e.g., BTK and / or HCK, and / or LYN, and / or SRC, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of ATP binding. In some embodiments, the term refers to a reduction in the level of ATP binding to a kinase, e.g., BTK and / or HCK, and / or LYN, and / or SRC, to a level that is less than 75%, less than 50%, less than -44- 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of ATP binding. In some embodiments, blocking ATP binding leads to a reduction in the level of enzyme activity, e.g., BTK and / or HCK, and / or LYN, and / or SRC activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.

[0129] When a compound or pharmaceutical composition is referred to as “selectively,” “specifically,” or “competitively” binding a first protein, the compound binds the first protein, e.g., BTK or HCK or LYN or SRC, with a higher binding affinity (e.g., not less than about 2-fold, not less than about 5-fold, not less than about 10-fold, not less than about 30-fold, not less than about 100-fold, not less than about 1,000-fold, or not less than about 10,000-fold) than binding a second protein that is different from the first protein, e.g., BTK. In some embodiments, a compound blocks ATP binding to a first protein, e.g., HCK or LYN or SRC, at a lower concentration (e.g., not less than about 10-fold) than it blocks ATP binding a second protein that is different from the first protein, e.g., BTK.

[0130] Compounds which selectively block ATP binding to a kinase (e.g., BTK, HCK, LYN) provided herein can be identified and / or characterized by methods known in the art. Methods include purified enzyme and cell based biochemical and binding assays such as an HCK gatekeeper mutant rescue assay, an in vitro kinase assay, e.g., using HCK gatekeeper mutated kinase, competitive binding assays using KiNativ™ technology or biotin tagged inhibitors, e.g., HCK inhibitors. Suitable assays for determining selective inhibition of HCK by a compound include, but are not limited to, Life Technology Z-Lyte activity assays (e.g., including HCK gatekeeper mutants and GK+6 mutants); DiscoverX KINOMEscan® binding assays; MRC radioactivity assays; ACD Ba / F3 viability assays (e.g., including HCK gatekeeper mutants and GK+6 mutants); Yeast hybrid proliferation assays; Protein thermostability assays; and cancer cells with HCK gatekeeper mutants or GK+6 mutants proliferation-rescue assays. Such assays can also be used to determine selective inhibition of LYN and / or SRC by a compound.

[0131] The term “E3 Ubiquitin Ligase,” is used to describe a target enzyme(s) binding site of ubiquitin ligase moieties as described herein, e.g., in the bifunctional (chimeric) compounds as described herein. The E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome. E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to a lysine on a target protein. In general, the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added by the ubiquitin ligase to a substrate molecule. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin.

[0132] As used herein, the term “proteolysis targeting chimera” (“PROTAC”) refers to a compound comprising two functional moieties, a target (e.g., HCK / BTK) binding moiety and a degradation moiety, tethered together by a suitable linker. PROTACs bind to a target molecule (e.g., HCK / BTK) and signal for degradation of the target molecule (e.g., by recruitment of the E3 ligase, resulting in ubiquitination and subsequent degradation of the target protein by the proteasome). PROTACs may inhibit the activity of the taiget through their binding to the target active site (e.g., as with a conventional enzyme inhibitor) or may bind to the taiget without significant inhibition of activity. In some embodiments, the compounds described herein are PROTACs.

[0133] The term “chimeric antigen receptor” or “CAR,” as used herein, refers to an artificial T cell receptor that is engineered to be expressed on an immune effector cell and specifically bind an antigen. CARs may be used as a therapy with adoptive cell transfer. T cells are removed from a patient and modified so that they express the receptors specific to a particular form of antigen. In some embodiments, the CARs have been expressed with specificity to a tumor associated antigen, for example. CARs may also comprise an intracellular activation domain, a transmembrane domain and an extracellular domain comprising a tumor associated antigen binding region. In some aspects, CARs comprise fusions of single-chain variable fragments (scFv) derived monoclonal antibodies, fused to CD3zeta transmembrane and intracellular domain. The specificity of CAR designs may be derived from ligands of receptors (e.g., peptides). In some embodiments, a CAR can target cancers by redirecting the specificity of a T cell expressing the CAR specific for tumor associated antigens.

[0134] The term “MYD88 mutation” means any change or difference in the nucleic acid or protein sequence of MYD88 as compared to the wild type sequence that results in the activation of MYD88 which leads to the activation of NF-kB. Mutations include, but are not limited to, nonsense mutations, missense mutations, frameshift mutations, rearrangement mutations, insertion mutations and deletion mutations. In some embodiments, the mutation is a somatic mutation at position 38182641 in chromosome 3p22.2 which results in a single nucleotide change from T—>C in the myeloid differentiation primary response (MYD88) gene, and a predicted non-synonymous change at amino acid position 265 from leucine to proline (L265P). In some embodiments, the mutation is another activating mutation in MYD88, such as V217F, W218R, I220T, S222R, M232T, S243N, T294P. Signaling studies show that SU-DHL-2 lymphoma cells that express the serine to arginine mutation at amino acid position 222 also have upregulated HCK (Yang et al, Blood 2016). In some embodiments, Sanger sequencing, whole exome or whole genome sequencing can be used to identify somatic mutations in MYD88.

[0135] The term “MYD88 mutated disease” or “disease associated with mutated MYD88” means any disease in a subject that is related to a change or difference in the nucleic acid or protein sequence of MYD88 as compared to the wild type sequence that results in the activation of MYD88 which leads to the activation of NF-kB. In some embodiments, mutated MYD88 is associated with Waldenstrom’s Macroglobulinemia (IgM secreting lymphoplasmacytic lymphoma), non-IgM secreting lymphoplasmacytic lymphoma, ABC subtype of diffuse large B-cell lymphoma, primary central nervous system (CNS) lymphoma, immune privileged lymphomas that include testicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia. In some embodiments, mutated MYD88 is associated with susceptibility to infectious disease. In some embodiments, mutated MYD88 is associated with susceptibility to autoimmune disease. Detailed Description of Certain Embodiments of the Invention

[0136] In one embodiment of the present disclosure is a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein the dashed circle indicates the ring is aromatic; Q'isN, S,orC; Q2 is N or C; Q3 is N or C; Ring A is absent or a heteroaryl ring; when Ring A is absent, two RA are present at the points of attachment for Ring A, Ra is selected independently selected from the group consisting of H, -NR’R”, -C(0)NR’R”, and -NR’C(0)R”; R’ and R” are independently H or Ci-3alkyl; Li is a bond, C1-C3 alkyl, -C(O)Ci-3alkyl-, -Ci-3alkyl-O-, or -Ci-3alkyl-O-Ci-3alkyl-; Ring B is a bond (and RB is attached through Li) or selected from C4-6 cycloalkyl and 4-6 heterocyclyl, and Rb is E3 ligase-binding moiety.

[0137] In some embodiments, the disclosure relates to a compound of Formula (I), wherein Q1 is N, S, or C. In some embodiments, Q1 is N. In some embodiments, Q1 is C. In some embodiments, Q1 is S. In some embodiments, the disclosure relates to a compound of Formula (I), wherein Q1 is N, S, or C and Q2 is N or C. In some embodiments, Q1 and Q2 are N. In some embodiments, Q1 is N and Q2 is C. In some embodiments, Q1 is C and Q2 are N. In some embodiments, Q1 is S and Q2 is C.

[0138] In some embodiments, the disclosure relates to a compound of Formula (I), wherein Q3 is N or C. In some embodiments, Q3 is C. In some embodiments, Q3 is N.

[0139] In some embodiments, the disclosure relates to a compound of Formula (I), wherein Q1 and Q2 are N, and Q3 is C.

[0140] In some embodiments, the disclosure relates to a compound of Formula (I), wherein Ring A is absent or a heteroaryl ring. In some embodiments, Ring A is absent, N^. _N In some embodiments, Ring A is

[0141] In some embodiments, the disclosure relates to a compound of Formula (I), wherein Ring A is a heteroaryl ring and RA is selected independently selected from the group consisting of H, -NR’R”, -C(O)NR’R”, and -NR’C(O)R”. In some embodiments, RA is H. In some embodiments, RA is -NR’R”. In some embodiments, RA is -NH2.

[0142] In some embodiments, the disclosure relates to a compound of Formula (I), wherein Ring A is absent and RA is selected independently selected from the group consisting of H, -NR’R”, -C(O)NR’R”, and -NR’C(O)R”.. In some embodiments, RA is H and -NR’R”. In some embodiments, RA is H and -NFh. In some embodiments, RA is -NR’R” and -NR’C(O)R”. In some embodiments, RA is -NH2 and -NHC(O)CH3. In some embodiments, RA is -NR’R” and -C(O)NR’R”. In some embodiements, RA is -NH2 and -C(O)NH2.

[0143] In some embodiments, the disclosure relates to a compound of Formula (I), wherein Ring B is a bond (and and RB is attached through Li) or selected from C4-6 cycloalkyl and 4-6 heterocyclyl ring. In some embodiments, Ring B is a bond, . In some embodiments, Ring B is a bond. In some embodiments, Ring B is          . In some embodiments, Ring B is . In some embodiments, Ring B is JW1 6 N i JWV\

[0144] In some embodiments, the Ligase ligand is a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety (e.g., hydroxyproline, hydroxyproline derivatives, or binding moieties described in U.S. Patent Application Pub. No. 2014 / 03022523 (herein incorporated by reference in its entirety)), a cereblon E3 ubiquitin ligase binding moiety (e.g., thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, derivatives thereof, or binding moieties described in U.S. Patent Application Publication US 2015 / 0291562 (herein incorporated by reference in its entirety)), a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (e.g., binding moieties described in U.S. patent application Ser. No. 15 / 206,497 (herein incorporated by reference in its entirety)), or an IAP E3 ubiquitin ligase binding moiety. Suitable ligands for binding the aforementioned E3 ubiquitin ligases, as well as other known E3 ubiquitin ligases, are understood in the field and described in, for example, U.S. Pub. Nos. 2015 / 0291562, 2014 / 0356322, 2018 / 0256586, 2018 / 0228907, 2018 / 0193470, 2018 / 0179183, 2018 / 0134684; 2017 / 0327469; herein incorporated by reference in their entireties. The compounds and formulas within the scope of embodi ments herein are not limited to specific ligase ligand struc tures described herein, or incorporated by reference, but include ligase ligands understood in the field.

[0145] In some embodiments, the disclosure relates to a compound of Formula (I), wherein is Rb is an E3 ligase-binding moiety. In some embodiments, RB is a cereblon E3 ligase-binding moiety. In some embodiments, RB is a VHL E3 ligase-binding moiety. In some embodiments, RB is an E3 ligase-binding moiety selected from Table A. Table A. E3 Ligase-binding Moiety Structures.

[0146] In some embodiments, the disclosure relates to a compound of Formula (I), wherein RB

[0147] In some embodiments, the disclosure relates to a compound of formula (I) or any embodiment thereof, i.e., the compound in non-salt form.

[0148] In some embodiments, the disclosure relates to a compound selected from Table B, or a pharmaceutically acceptable salt thereof. In other embodiments, the disclosure relates to a compound selected from Table B, i.e., the compound in non-salt form.

[0149] A compound selected from Table B, or a pharmaceutically acceptable salt thereof. Table B: Compound Structures and Numbers.

[0150] In some embodiments, the disclosure relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the disclosure relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the disclosure,” as that term is used herein.

[0151] In some embodiments, the disclosure relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the disclosure,” as that term is used herein. Salts, Compositions, Uses, Fomulations, Administration, and Additional Agents Pharmaceutically acceptable salts and compositions

[0152] As discussed herein, the disclosure provides compounds, and pharmaceutically acceptable salts thereof, that inhibit the activity of one or more kinases and / or facilitate degradation of one or more kinases, and thus the present compounds, and pharmaceutically acceptable salts thereof, are useful for the treatment of diseases, disorders, and conditions including, but not limited to a proliferative disease (e.g., an IgM gammopathy (e.g., an IgM Monoclonal gammopathy of undetermined significance (MGUS), amyloid light chain (AL) amyloidosis), mastocytosis (e.g., systemic mastocytosis) cancer (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, stomach cancer, lymphoma (e.g., B-cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM secreting lymphoplasmacytic lymphoma (i.e., Waldenstrom’s Macroglobulinemia), non-IgM secreting lymphoplasmacytic lymphoma)), diffuse large B-cell lymphoma (e.g., activated B-cell-like (ABC)- DLBCL, germinal center B-cell-like (GBC)-DLBCL), follicular lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma), myeloma (e.g., IgM myelomas (e.g., IgM multiple myeloma)), and leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myelogenous leukemia (e.g., chronic myelogenous leukemia, acute myelogenous leukemia (e.g., mast cell leukemia) and myeloproliferative diseases (e.g., myelodysplastic syndrome). Accordingly, in another aspect of the disclosure, pharmaceutical compositions are provided, wherein these compositions comprise a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0153] Pharmaceutical preparations and compounds are administered to a subject by any suitable route. For example, compositions can be administered orally, including sublingually, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically and transdermally (as by powders, ointments, or drops), bucally, or nasally. The pharmaceutical preparations of the present disclosure may include or be diluted into a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier" as used herein means one or more compatible fillers, diluants or other such substances, which are suitable for administration to a human or other mammal such as a dog, cat, or horse. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The carriers are capable of being commingled with the preparations of the present disclosure, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability. Carriers suitable for oral, subcutaneous, intravenous, intramuscular, etc. formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. The present disclosure also provides pharmaceutical compositions comprising a compound described herein and optionally a pharmaceutically acceptable excipient.

[0154] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the ail and can be lower or the same as that administered to an adult.

[0155] In another aspect, the disclosure features a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0156] In another aspect, the disclosure features a pharmaceutical composition comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles. Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[0157] Provided herein are methods of treating a disease (e.g., a proliferative disease (e.g., an IgM gammopathy (e.g., an IgM Monoclonal gammopathy of undetermined significance (MGUS), amyloid light chain (AL) amyloidosis), mastocytosis (e.g., systemic mastocytosis) cancer (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, stomach cancer, lymphoma (e.g., B-cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM secreting lymphoplasmacytic lymphoma (i.e., Waldenstrom’s Macroglobulinemia), non-IgM secreting lymphoplasmacytic lymphoma)), diffuse large B-cell lymphoma (e.g., activated B-cell-like (ABC)- DLBCL, germinal center B-cell-like (GBC)-DLBCL), follicular lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma), myeloma (e.g., IgM myelomas (e.g., IgM multiple myeloma)), and leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myelogenous leukemia (e.g., chronic myelogenous leukemia, acute myelogenous leukemia (e.g., mast cell leukemia) myeloproliferative diseases (e.g., myelodysplastic syndrome))))) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically-labeled derivative, stereoisomer, or prodrug thereof. In certain embodiments, the method comprises administering a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In certain embodiments, the disease is associated with a mutated MYD88 protein. In certain embodiments, the disease is associated with a mutated BTK protein. In certain embodiments, the disease is associated with a C481 mutated BTK protein. In certain embodiments, the disease is associated with a C481S mutated BTK protein. In some embodiments, the diseases are associated with aberrant activity of a kinase (e.g., SRC Family kinases (e.g., HCK, LYN, BLK, FRK), Tec family kinases (e.g., BTK). In certain embodiments, the disease is resistant to inhibition by a BTK inhibitor (e.g., ibrutinib, CC-292, ONO-4059, evobrutinib, spebrutinib, BGB-3111, HM71224, or ACP-196). In certain embodiments, the disease is resistant to treatment with ibrutinib. In certain embodiments, the disease is associated with a mutated BTK protein (e.g., a C481S mutated BTK), and the disease is resistant to treatment with ibrutinib.

[0158] Further provided herein are methods of inhibiting the activity of one or more kinase in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically-labeled derivative, stereoisomer, or prodrug thereof. In certain embodiments, the one or more kinase is an SRC Family kinase (e.g., HCK, LYN, BLK, FRK). In other embodiments, the one or more kinase is a Tec family kinase (e.g., BTK). In certain embodiments, the BTK is resistant to inhibition by a BTK inhibitor (e.g., ibrutinib, CC-292, ONO-67- 4059, evobrutinib, spebrutinib, BGB-3111, HM71224, or ACP-196). In certain embodiments, the BTK is ibrutinib resistant.

[0159] Provided herein are methods of facilitating the degradation of one or more kinase in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically-labeled derivative, stereoisomer, or prodrug thereof. In certain embodiments, the one or more kinase is an SRC Family kinase (e.g., HCK, LYN, BLK, FRK). In other embodiments, the one or more kinase is a Tec family kinase (e.g., BTK). In certain embodiments, the BTK is resistant to inhibition by a BTK inhibitor (e.g., ibrutinib, CC-292, ONO-4059, evobrutinib, spebrutinib, BGB-3111, HM71224, or ACP-196). In certain embodiments, the BTK is ibrutinib resistant.

[0160] Provided herein is a method of treating a subject comprising administering to a subject with an MYD88 mutated disease. An MYD88 mutated disease can include, but is not limited to a proliferative disease (e.g., an IgM gammopathy (e.g., an IgM Monoclonal gammopathy of undetermined significance (MGUS), amyloid light chain (AL) amyloidosis), mastocytosis (e.g., systemic mastocytosis) cancer (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, stomach cancer, lymphoma (e.g., B-cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM secreting lymphoplasmacytic lymphoma (i.e., Waldenstrom’s Macroglobulinemia), non-IgM secreting lymphoplasmacytic lymphoma)), diffuse large B-cell lymphoma (e.g., activated B-cell-like (ABC)- DLBCL, germinal center B-cell-like (GBC)-DLBCL), follicular’ lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma), myeloma (e.g., IgM myelomas (e.g., IgM multiple myeloma)), and leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myelogenous leukemia (e.g., chronic myelogenous leukemia, acute myelogenous leukemia (e.g., mast cell leukemia) myeloproliferative diseases (e.g., myelodysplastic syndrome))))) a pharmaceutical composition comprising a compound of the disclosure as described herein. In certain embodiments, the subject being treated has previously undergone treatment with ibrutinib. In certain embodiments, the subject being treated has developed ibrutinib resistance.

[0161] In some embodiments, the provided methods include inhibiting and facilitating the degradation of LYN and / or SRC comprising the steps of administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable -68- salt, solvate, hydrate, polymorph, co-crystal, isotopically-labeled derivative, stereoisomer, or prodrug thereof. In some embodiments, the method further comprises administering an agent which inhibits and facilitates the degradation of LYN and / or SRC. For example, in some embodiments, a compound of the disclosure as described herein is administered to the subject in combination (e.g., concurrently or sequentially) with an agent which blocks ATP binding to SRC. In some embodiments, a compound of the disclosure as described herein is administered to the subject in combination (e.g., concurrently or sequentially) with an agent which blocks ATP binding to LYN. In some embodiments, a compound of the disclosure as described herein is administered to the subject in combination (e.g., concurrently or sequentially) with an agent which blocks ATP binding to HCK.

[0162] In some embodiments, the provided methods include inhibiting and facilitating the degradation of Tec family kinases comprising the steps of administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically-labclcd derivative, stereoisomer, or prodrug thereof. In some embodiments, the provided methods include inhibiting and facilitating the degradation of BTK comprising the steps of administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically-labeled derivative, stereoisomer, or prodrug thereof. In some embodiments, the method further comprises administering an agent which inhibits and facilitates the degradation of BTK and / or other Tec family kinases. For example, in some embodiments, a compound of the disclosure as described herein is administered to the subject in combination (e.g., concurrently or sequentially) with an agent which blocks ATP binding to a Tec family kinase. In some embodiments, a compound of the disclosure as described herein is administered to the subject in combination (e.g., concurrently or sequentially) with an agent which blocks ATP binding to BTK.

[0163] One skilled in the art will appreciate that many suitable methods, in addition to and including the ones discussed in the examples, can be used to detect mutations in the MYD88 gene. Detection methods that can be used include, but are not limited to, direct sequencing, DNA chip technologies, mass spectroscopy, polymerase chain reaction (PCR), allele specific polymerase chain reaction, real time polymerase chain reaction, reverse transcriptase PCR, electrophoretic mobility, nucleic acid hybridization, fluorescent in situ hybridization, and denaturing high -69- performance liquid chromatography. In some embodiments, mutations in the MYD88 gene may be detected by allele specific polymerase chain reaction (AS-PCR), e.g., as described in WO 2013 / 006443.

[0164] One or more symptoms or clinical features of LPL include anemia, hyper-viscosity, neuropathy, coagulopathies, splenomegaly, hepatomegaly, adenopathy, and an IgM serum paraprotein. In addition, the subject may also present one or more of the following clinical features or symptoms of other B cell neoplasms: asymptomatic localized or generalized peripheral lymphadenopathy, plasmacytic difference, bone marrow involvement, autoimmune thrombocytopenia, peripheral blood villous lymphocytes, end organ damage (hypercalcemia, renal insufficiency, bone lesions), recurrent infections, elevated creatine, hyperuricemia, and hypoalbunemia. A subject suspected of having one or more of Waldenstrom’s Macroglobulinemia (i.e., IgM secreting lymphoplasmacytic lymphoma), non-IgM secreting lymphoplasmacytic lymphoma, ABC subtype of diffuse large B-cell lymphoma, primary central nervous system (CNS) lymphoma, immune privileged lymphomas that include testicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia may be assessed for the presence of a mutation in the gene encoding MYD88, e.g., at position 38182641 in chromosome 3p22.2, as well as other activating mutations in MYD88 (including but not limited to V217F, W218R, I220T, S222R, M232T, S243N, and T294P).

[0165] Without wishing to be bound by any particular theory, in certain embodiments the compounds described herein are able to bind the one or more kinase being inhibited. In certain embodiments, a compound described herein is able to bind to the one or more kinase. In certain embodiments, the one or more kinase is an SFK (e.g., HCK, LYN, BLK, FRK). In certain embodiments, the one or more kinase is HCK. In certain embodiments, the onr or more kinase is LYN. In certain embodiments, the one or more kinase is a Tec family kinase (e.g., BTK). In certain embodiments, the one or more kinase is BTK.

[0166] In certain embodiments, provided are methods of decreasing the activity of a kinase (e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec family kinase (e.g., BTK)) in a subject by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In certain embodiments, the activity of a kinase in a subject is decreased by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at -70- least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the activity of a kinase in a subject is selectively inhibited by the method. In some embodiments, the activity of a kinase (e.g., HCK, LYN, BTK) in a subject is selectively decreased by a compound or pharmaceutical composition described herein.

[0167] A disease, including proliferative disease, may be associated with aberrant or undesired activity of a kinase, and / or overexpression of the kinase. Aberrant or undesired activity of a kinase may be an increased or a decreased level of activity of the kinase. Proliferative diseases are sometimes associate with abnormal levels of JAK activity, frequently through increased or decreased JAK activation. Inhibition of the activity of JAK2 would be expected to inhibit phosphorylation. In certain embodiments, JAK2 is not overexpressed, but the activity of JAK2 is increased. In certain embodiments, JAK2 is overexpressed, and the activity of JAK2 is increased. The compounds and pharmaceutical compositions described herein may inhibit the activity of JAK2 and be useful in treating and / or preventing diseases, such as diseases associated with the aberrant, increased, or undesired activity of a kinase, overactivation of the kinase, and / or overexpression of the kinase.

[0168] In certain embodiments, the disease (e.g., the disease to be treated or prevented by a method described herein) is associated with the increased activity of a kinase (e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec Family kinases (e.g., BTK)). In certain embodiments, the disease is associated with overexpression of a kinase (e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec Family kinases (e.g., BTK)). In certain embodiments, the disease is a proliferative disease. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is associated with a mutation in MYD88. In another embodiment, the cancer is associated with mutated BTK. In certain embodiments, the proliferative disease is mastocytosis. In certain embodiments, the mastocytosis is systemic mastocytosis. In certain embodiments, the proliferative disease is an IgM gammopathy. In certain embodiments, the IgM gammopathy is IgM monoclonal gammopathy with undetermined significance.

[0169] In certain embodiments, the disease is breast cancer. In certain embodiments, the disease is colon cancer. In certain embodiments, the disease is testicular cancer. In certain embodiments, the disease is cancer of the CNS. In certain embodiments, the disease is stomach cancer. In certain embodiments, the disease is lymphoma. In certain embodiments, the lymphoma -71 - is B-cell Lymphoma. In certain embodiments, B-cell lymphoma is lymphoplasmacytic lymphoma. In certain embodiments, the lymphoplasmacytic lymphoma is IgM secreting lymphoplasmacytic lymphoma (i.e., Waldenstrom’s Macroglobulinemia). In certain embodiments, the disease is Waldenstrom’s Macroglobulinemia. In certain embodiments, the lymphoplasmacytic lymphoma is non-IgM secreting lymphoplasmacytic lymphoma. In certain embodiments, the lymphoma is Diffuse Large B-Cell Lymphoma (DLBCL). In certain embodiments, the DLBCL is activated B-cell-like (ABC)-DLBCL. In certain embodiments, the DLBCL is germinal center B-celLlike (GBC)-DLBCL. In certain embodiments, the lymphoma is Follicular Lymphoma. In certain embodiments, the lymphoma is marginal zone B-cell lymphoma. In certain embodiments, the lymphoma is Small lymphocytic lymphoma. In certain embodiments, the small lymphocytic lymphoma is Mantle cell lymphoma. In certain embodiments, the cancer is leukemia. In certain embodiments, the leukemia is chronic lymphocytic leukemia (CLL). In certain embodiments, the leukemia is myelogenous leukemia. In certain embodiments, the myelogenous leukemia is chronic myelogenous leukemia. In certain embodiments, the myelogenous leukemia is acute myelogenous leukemia. In certain embodiments, the acute myelogenous leukemia is mast cell leukemia. In certain embodiments, the cancer is myeloma. In certain embodiments, the myeloma is IgM myeloma. In certain embodiments, the IgM myeloma is IgM multiple myeloma. In certain embodiments, the cancer is a myeloproliferative disease. In certain embodiments, the myeloproliferative disease is myelodysplastic syndrome.

[0170] In certain embodiments, the method described herein is superior (e.g., showing improved safety and / or therapeutic effects) or comparable to existing therapy (e.g., chemotherapy, treatment with a BTK inhibitor). In certain embodiments, the method described herein is associated with decreased toxicity when compared to existing therapy (e.g., chemotherapy, treatment with a BTK inhibitor).

[0171] In certain embodiments, the cell is a malignant cell (e.g., cancer cell). In certain embodiments, the cell is a malignant blood cell. In certain embodiments, the cell is a malignant bone marrow cell. In certain embodiments, the cell is an adenocarcinoma cell, blastoma cell, carcinoma cell, or sarcoma cell. In certain embodiments, the cell is a pre-malignant cell (e.g., pre-cancerous cell).

[0172] In certain embodiments, the method described herein further comprises administering to the subject in need thereof an additional therapy. In certain embodiments, the additional therapy -72- is a cytotoxic chemotherapy (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, 1-asparaginase, cyclophosphamide, or etoposide). In certain embodiments, the additional therapy is an epigenetic modifier (e.g., azacitidine or romidepsin). In certain embodiments, the additional therapy is a glucocorticoid. In certain embodiments, the additional therapy is an immunotherapy (e.g., an immunotherapeutic monoclonal antibody). In some embodiments, the additional pharmaceutical agent is etoposide, obatoclax, or navitoclax, and optionally the disease is breast cancer, e.g., triple-negative breast cancer, HER2 positive breast cancer, HER2 negative breast cancer, ER-positive breast cancer, ER-negative breast cancer, or ER / PR-positive breast cancer. In some embodiments, the additional pharmaceutical agent is etoposide, JIB04, or cisplatin, and optionally the disease is Ewing’s sarcoma. In some embodiments, the additional pharmaceutical agent is JQ1 or NVP2, and optionally the disease is leukemia, e.g., acute myelogenous leukemia, myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, monoblastic leukemia, or megakaryoblastic leukemia.

[0173] In yet another aspect, the present disclosure provides compounds and pharmaceutical compositions described herein for use in the treatment of a disease (e.g., a proliferative disease, such as an IgM gammopathy, mastocytosis, or cancer) in a subject in need thereof.

[0174] In yet another aspect, the present disclosure provides compounds and pharmaceutical compositions described herein for use in the prevention of a disease (e.g., a proliferative disease, such as an IgM gammopathy, mastocytosis, or cancer) in a subject in need thereof.

[0175] In another aspect, the present disclosure provides compounds and pharmaceutical compositions described herein for use in inhibiting the activity of a kinase in a subject in need thereof.

[0176] In another aspect, the present disclosure provides uses of compounds and pharmaceutical compositions described herein in the manufacture of a medicament for treating a disease in a subject in need thereof.

[0177] In another aspect, the present disclosure provides uses of compounds and pharmaceutical compositions described herein in the manufacture of a medicament for preventing a disease in a subject in need thereof.

[0178] The compounds, pharmaceutical compositions, and kits described herein may synergistically augment inhibition of a kinase (e.g., SFK (e.g., HCK, LYN, BLK, FRK), a TEC family kinase (e.g., BTK)) induced by the additional pharmaceutical agent(s) in the subject. Thus, -73- the combination of the compounds, pharmaceutical compositions, or kits with additional pharmaceutical agent(s) may be useful in treating diseases resistant to a treatment using the additional pharmaceutical agent(s) without the compounds, pharmaceutical compositions, or kits described herein. Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0179] In certain embodiments of the disclosure, an “effective amount” of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating or lessening the severity of one or more of the conditions recited above.

[0180] When administered to a subject, effective amounts of the therapeutic agent will depend on the particular disease being treated; the severity of the disease; individual patient parameters including age, physical condition, size and weight, concurrent treatment, frequency of treatment, and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. In some embodiments, a maximum dose is used, that is, the highest safe dose according to sound medical judgment.

[0181] An effective amount of a compound typically will vary from about 0.001 mg / kg to about 1000 mg / kg in one or more dose administrations, for one or several days (depending of course of the mode of administration and the factors discussed above).

[0182] Actual dosage levels of the therapeutic agent can be varied to obtain an amount that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level depends upon the activity of the particular compound, the route of administration, the tissue being treated, and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effort and to gradually increase the dosage until the desired effect is achieved

[0183] In the treatment of an MYD88 mutated disease, such as Waldenstrom’s Macroglobulinemia (IgM secreting lymphoplasmacytic lymphoma), non-IgM secreting lymphoplasmacytic lymphoma, ABC subtype of diffuse large B-cell lymphoma, primary central nervous system (CNS) lymphoma, immune privileged lymphomas that include testicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia, an effective amount of a selective HCK inhibitor is that amount which slows the progression of the disease, halts the progression of the disease, or reverses the progression of the disease. An effective amount includes, but is not limited to, that amount necessary to slow, reduce, inhibit, ameliorate or reverse one or more symptoms associated with the MYD88 mutated disease. In some embodiments, such terms refer to a reduction in the levels of IgM serum paraprotein, anemia, hyper-viscosity, neuropathy, coagulopathies, splenomegaly, hepatomegaly, and adenopathy.

[0184] In certain embodiments, the compound described herein is provided in an effective amount (e.g., effective for inhibiting kinase activity and facilitating the degradation of a kinase, such as a SRC family kinases (e.g., HCK, LYN, BLK, FRK), or Tec family kinases (e.g., BTK)) in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting a kinase. In certain embodiments, a therapeutically effective amount is an amount effective for degrading a kinase. In certain embodiments, a therapeutically effective amount is an amount effective for treating a disease (e.g., a disease associated with aberrant activity of a kinase (e.g., proliferative disease)). In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting the activity of a kinase and treating a disease (e.g., a disease associated with aberrant activity of a kinase (e.g., proliferative disease)). In certain embodiments, a therapeutically effective amount is an amount effective for degrading a kinase and treating a disease (e.g., a disease associated with aberrant activity of a kinase (e.g., proliferative disease)). In certain embodiments, a therapeutically effective amount is an amount effective for inducing apoptosis in a cell (e.g., malignant cell, premalignant cell).

[0185] In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a kinase by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a kinase by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%.

[0186] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human (e.g., an adult, juvenile, or child). In certain embodiments, the subject is a non-human -75- animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a dog. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the subject is a genetically engineered animal. In certain embodiments, the subject is a transgenic animal (e.g., transgenic mice, transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0187] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0188] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0189] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0190] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0191] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0192] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0193] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular' weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, -77- cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0194] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0195] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0196] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0197] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0198] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. -78-

[0199] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0200] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0201] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, NeoIone®, Kathon®, and Euxyl®.

[0202] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0203] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0204] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea -79- buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0205] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise 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 (e.g., 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 include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0206] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known ail using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can 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 can 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 di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0207] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0208] In order 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 -80- 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 may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0209] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein 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 ingredient.

[0210] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymcthylccllulosc, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0211] Solid compositions of a similar type can 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 solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain pail of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can 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.

[0212] The active ingredient can be in a 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 ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may 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 comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0213] Dosage forms for topical and / or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable earner or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0214] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to -82- accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0215] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0216] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions arc conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0217] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0218] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such -83- formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0219] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0220] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0221] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise -84- the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0222] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0223] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0224] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0225] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject, the frequency of administering the multiple doses to the subject is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject is three doses per day. In certain embodiments, when multiple doses are administered to a subject, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five year’s, seven years, ten year’s, fifteen years, twenty year’s, or the lifetime of the subject or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose -86- described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0226] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). In certain embodiments, the kit comprises a compound of the disclosure or a pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition. In certain embodiments, the kit comprises a first container, wherein the first container includes the compound or pharmaceutical composition. In some embodiments, the kit further comprises a second container. In certain embodiments, the second container includes an excipient (e.g., an excipient for dilution or suspension of the compound or pharmaceutical composition). In certain embodiments, the second container includes an additional pharmaceutical agent. In some embodiments, the kit further comprises a third container. In certain embodiments, the third container includes an additional pharmaceutical agent. In some embodiments, the compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form one unit dosage form. In some embodiments, the compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are combined to form one unit dosage form. In certain embodiments, each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.

[0227] In certain embodiments, the instructions are for administering the compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease described herein). In certain embodiments, the instructions comprise information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Agency for the Evaluation of Medicinal Products (EMA). In certain embodiments, the instructions comprise prescribing information.

[0228] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount (e.g., therapeutically effective amount) of a compound of the disclosure described herein or a pharmaceutical composition described herein.

[0229] In another aspect, the present disclosure provides methods of preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount (e.g., prophylactically effective amount) of a compound described herein or a pharmaceutical composition described herein.

[0230] In another aspect, the present disclosure provides methods of inhibiting the activity of a kinase in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound described herein or a pharmaceutical composition described herein. In another aspect, the present disclosure provides methods of degrading a kinase in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound described herein or a pharmaceutical composition described herein. Additional Therapeutic Agents

[0231] It will also be appreciated that the compounds, salts, and pharmaceutically acceptable compositions of the disclosure can be employed in combination therapies, that is, the compounds, salts, and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp &Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0232] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in inhibiting the activity of a kinase (e.g., SFK (e.g., LYN, HCK), Tec family kinases (e.g., BTK)) in a subject, improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

[0233] In some embodiments, treatment further includes administering to the subject an agent, e.g., an anti-cancer agent, in combination with a compound described herein. In some embodiments, treatment further includes administering to the subject one or more of bendamustine, fludarabine, bortezomib, or idelalisib. In some embodiments, treatment further includes administering to the subject one or more of a BCL-2 inhibitor (e.g., venetoclax, navitoclax, obatoclax), a BCL-2 / BCL-xL inhibitor (e.g., APG-1252, BM-1197), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib or oprozomib), a monoclonal antibody (e.g., rituximab, daratumumab, ofatumumab or obinituzumab), an alkylator drug (e.g., bendamustine, cyclophosphamide), a nucleoside analogue (e.g., fludarabine or cladribine), an MTOR inhibitor (e.g., everolimus), a BTK inhibitor (e.g., ibrutinib, acalabrutinib or BGB-3111), a BCR inhibitor (e.g., a SYK inhibitor) and / or an immunomodulating agent (e.g., thalidomide or lenalidomide). In some embodiments, the anti-cancer agent is a monoclonal antibody, e.g., rituximab. In some embodiments, the anti-cancer agent is a chemotherapeutic drug such as chlorambucil, cyclophosphamide, or vincristine or thalidomide. Corticosteroids, such as Prednisone, may also be used in combination. Plasmapheresis can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood. Autologous bone marrow transplantation may be used in combination with compounds described herein. In some embodiments, treatment further includes administering to the subject an agent that inhibits LYN and / or SRC.

[0234] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., -89- combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (e.g., proliferative disease, cancer, inflammatory disease, autoimmune disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) or premalignant condition. Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0235] The additional pharmaceutical agents include, but are not limited to, cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, antiproliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent (e.g., anti-cancer agent). In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (Asparaginase Erwinia Chrysanthemi), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposome), METHOTREXATE LPF (methorexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (Pegaspargase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxine mepesuccinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA (bcndamustinc hydrochloride), TRISENOX (arsenic trioxidc), VINCASAR PFS (vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I 131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferon alfa-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), Lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN -91- (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine ), VIDAZA (azacitidine ), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin ), CERUBIDINE (daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticle formulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX, CAPRELSA (vandctanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicin hydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), DOXORUBICIN HYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EV ACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV) quadrivalent vaccine), GEMCITABINECISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON -92- A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin hydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MITOXANTRONE HYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacitidine), NAVELBINE (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferon alfa-2b), PEMETREXED DISODIUM, PERJETA (pcrtuzumab), PLATINOL (cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide), prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE (sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR (temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VIDAZA (azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA (denosumab), XOFIGO (radium 223 dichloride), XTANDI (enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF (vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), ENMD-2076, PCL32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, -93- MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, and OSI-027), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,, aminopterin, and hexamethyl melamine, or a combination thereof. In certain embodiments, the additional pharmaceutical agent is a cytotoxic chemotherapeutic agent (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, 1-asparaginase, cyclophosphamide, or etoposide). In certain embodiments, the additional pharmaceutical agent is an epigenetic modifier such as azacitidine or romidepsin. In certain embodiments, the additional pharmaceutical agent is ruxolitinib, BBT594, CHZ868, CYT387, or BMS911543. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a tyrosine kinase. In some embodiments, the additional pharmaceutical agent is a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonji histone demethylase inhibitor, or a DNA damage inducer. In some embodiments, the additional pharmaceutical agent is etoposide, obatoclax, navitoclax, JQ1,4-(((5'-chloro-2'-(((lR,4R)-4-(((R)-l-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4'-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile, JIB04, or cisplatin. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a kinase (e.g., an SRC family kinase (e.g., HCK, LYN, BLK, FRK), A Tec family kinase (e.g., BTK)). In certain embodiments, the additional pharmaceutical agent is an antibody or a fragment thereof (e.g., monoclonal antibody). In certain embodiments, the additional pharmaceutical agent is a tyrosine kinase inhibitor. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine -94- protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the additional pharmaceutical agent is a glucocorticoid (e.g., cortisol, cortisone, prednisone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, or deoxycorticosterone acetate). In certain embodiments, the additional therapy is an immunotherapy (e.g., an immunotherapeutic monoclonal antibody). In certain embodiments, the additional pharmaceutical agent is an immunomodulator. In certain embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In certain embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein (PD-1) inhibitor. In certain embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor. In certain embodiments, the additional pharmaceutical agent is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. In certain embodiments, the additional pharmaceutical agent is a T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitor, lymphocyte activation gcnc-3 (LAG3) inhibitor, V-sct domain-containing T-cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitor, cluster of differentiation 276 (CD276 or B7-H3) inhibitor, B and T lymphocyte attenuator (BTLA) inhibitor, galectin-9 (GAL9) inhibitor, checkpoint kinase 1 (Chkl) inhibitor, adenosine A2A receptor (A2AR) inhibitor, indoleamine 2,3-dioxygenase (IDO) inhibitor, killer-cell immunoglobulin-like receptor (KIR) inhibitor, or V-domain Ig suppressor of T cell activation (VISTA) inhibitor. In certain embodiments, the PD-1 inhibitor is nivolumab, pidilizumab, pembrolizumab, MEDI-0680, REGN2810, or AMP-224. In certain embodiments, the PD-L1 inhibitor is atezolizumab, durvalumab, BMS-936559, avelumab, or CA-170. In certain embodiments, the CTLA-4 inhibitor is ipilimumab or tremelimumab. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, and transplantation (e.g., stem cell transplantation, bone marrow transplantation).

[0236] In certain embodiments, the additional pharmaceutical agent is a BCL-2 inhibitor (e.g., venetoclax, navitoclax, obatoclax), or a BCL-2 / BCL-xL inhibitor (e.g., APG-1252, BM-1197).

[0237] In certain embodiments, the additional pharmaceutical agent is venetoclax.

[0238] In some embodiments, the compounds of the disclosure are used in combination with one or more additional immunotherapies. In some embodiments, the additional immunotherapy -95- comprises a chimeric antigen receptor (CAR). In some embodiments, the additional immunotherapy comprises a bispecific antibody. Synthesis of the Compounds of the Disclosure

[0239] The compounds of the disclosure can be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to one skilled in the ait. As one skilled in the ait would appreciate, the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T.G.M. Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0240] The present disclosure is further illustrated by the following Examples, which in no way should be construed as further limiting. The entire contents of all of the references (including literature references, issued patents, published patent applications, and co pending patent applications) cited throughout this application are hereby expressly incorporated by reference. Examples Example 1: Synthesis of 1-(6-(3-((4-(( Ir,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l -yl)cyclohexyl)piperazin-l -yl)methyl)azetidin-l -yl )benzo[ d]isoxazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (Compound 2)

[0241] Compound (2) was synthesized according to the scheme below. (2)

[0242] Step 1: Synthesis of 6-bromobenzo[d]isoxazol-3-amine.

[0243] To a suspension of A-hydroxyacetamide (897 mg, 11.96 mmol) in DMF (40 mL) was added KOfBu (1.33 g, 11.96 mmol) at room temperature and stirred for 0.5 h. 4-bromo-2-fluorobenzonitrile (1.7 g, 8.54 mmol) was added, and the resulting mixture was stirred for 4 hs at room temperature. The reaction mixture was diluted with water (120 mL) and the aqueous phase was extracted with EtOAc (60 mL x 3), the combined organic phase was washed with brine, dried over anhydrous NasSCL, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-30% ethyl acetate in petroleum ether) to give 6-bromobenzo[ri]isoxazol-3-amine (1.1 g, 61% yield) as a white solid. LCMS: m / z 212.9 [M+H]+.

[0244] Step 2: Synthesis of 3-((6-bromobcnzo|d|isoxazol-3-yl)amino)propancnitrilc Br

[0245] To a mixture of 6-bromobenzo[ri]isoxazol-3-amine (1.1 g, 5.19 mmol) in CH3CN (10 mL) was added A-hydroxy acetamide (289 mg, 5.44 mmol) and CS2CO3 (2.5 g, 7.79 mmol). The resulting mixture was stirred at room temperature for 1 h and refluxed for 4 hs. The reaction mixture was cooled to room temperature and the orange suspension was filtered through the celite. The filtrate was concentrated, and the residue was purified by flash chromatography (silica, 40 g, 0-40% ethyl acetate in petroleum ether) to give 3-((6-bromobenzo[d]isoxazoL3-yl)amino)propanenitrile (1 g, 73% yield) as a white solid. LCMS: m / z 268.1 [M+H]+.

[0246] Step 3: Synthesis of 3-((6-bromobenzo[ri]isoxazol-3-yl)amino)propanamide ? V-NH A 0

[0247] To a solution of 3-((6-bromobenzo[ri]isoxazol-3-yl)amino)propanenitrile (1 g, 3.77 mmol) in TFA (20 mL) was added dropwise H2SO4 (4 mL) at 0°C. The resulting mixture was stirred at room temperature overnight, and poured into ice water. The precipitate was formed and collected, the solid was dried in vacuo to give 3-((6-bromobenzo[6?]isoxazol-3-yl)amino)propanamide (800 mg, 75% yield) as a white solid, which was used directly for the next step. LCMS: m / z 285.0 [M+H]+.

[0248] Step 4: Synthesis of l-(6-bromobenzo[<7]isoxazol-3-yl)dihydropyrimidine- 2,4( 1H, 3 / 0-dione

[0249] To a mixture of 3-((6-bromobenzo[< / ]isoxazol-3-yl)amino)propanamide (720 mg, 2,54 mmol) in CH3CN (10 mL) was added CDI (1.65 g, 10.18 mmol) and CS2CO3 (3.31mg, 10.18 mmol). The resulting mixture was stirred at 90°C overnight and filtered through the celite. The filtrate was concentrated and the residue was purified by flash chromatography (silica, 40 g, 010% MeOH in DCM) to give l-(6-bromobenzo[rf]isoxazol-3-yl)dihydropyrimidine-2,4(1 / / ,370-dione (750 mg, 96% yield) as a white solid. LCMS: m / z 312.0 [M+H]+.

[0250] Step 5:      Synthesis of l-(6-bromobenzo[( / ]isoxazol-3-yl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(l / / ,3H)-dione

[0251] To a solution of l-(6-bromobenzo[t / ]isoxazol-3-yl)dihydropyrimidine-2,4(1 / / ,3 / 0-dione (3.3 g, 10.7 mmol) and PMBC1 (2.51 g, 16.1 mmol) in DMF (40 mL) was added CS2CO3 (6.99 g, 21.4 mmol). The resulting mixture was stirred at room temperature overnight, diluted with water and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NhoSCL, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-80% ethyl acetate in petroleum ether) to give 1-(6-bromobenzo[< / ]isoxazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1 / / ,3H)-dione (1.9 g, 41% yield) as a white solid. LCMS: m / z 430.1 [M+H]+.

[0252] Step 6: Synthesis of tert-butyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidine-l-carboxylate. TBDPSO d BocN—1

[0253] To a solution of terf-butyl 3-(hydroxymethyl)azetidine-l-carboxylate (3.4 g, 18.2 mmol), imidazole (2.7 g, 39.7 mmol) and DMAP (222 mg, 1.82 mmol) in DCM (50 mL) was added dropwise TBDPSC1 (5.2 g, 19.0 mmol). The mixture was stirred at room temperature overnight and diluted with DCM, the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-5% ethyl acetate in petroleum ether) to give tert-butyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidine-l-carboxylate (3 g, 44% yield) as a white solid. HNMR (400 MHz, CDC13) 6 7.65 (dd, 7= 7.6, 1.6 Hz, 4H), 7.46 - 7.36 (m, 6H), 3.93 (t, J= 8.4 Hz, 2H), 3.78 - 3.70 (m, 4H), 2.72 - 2.63 (m, 1H), 1.43 (s, 9H), 1.05 (s, 9H).

[0254] Step 7: Synthesis of 3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidine TBDPSO / HN—1

[0255] To a solution of tert-butyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidine-l-carboxylate (1.0 g, 2.35 mmol) in DCM (10 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature overnight and concentrated. The residue was dissolved with DCM, and the organic phase was washed with saturated NaHCOs solution, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-5% MeOH in DCM) to give 3-(((t(?rt-butyldiphenylsilyl)oxy)methyl)azetidine (620 mg, 81% yield) as a white solid. LCMS: m / z 326.2 [M+H]+.

[0256] Step 8: Synthesis of l-(6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-l-yl)bcnzo[ / ]isoxazol-3-yl)-3-(4-mcthoxybcnzyl)dihydropyrimidinc-2,4(lZ / ,3H)-dionc TBDPSO VA XX? PMBN-V O

[0257] To a solution of 3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidine (1.73 g, 5.31 mmol) and l-(6-bromobenzo[d]isoxazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(l / f,3H)-dione (1.90 g, 4.43 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3 (324 mg, 0.35 mmol), t-BuxantPhos (330 mg, 0.66 mmol) and CsCOa (2.89 g, 8.86 mmol). The reaction mixture was stirred at 90°C overnight under nitrogen atmoshphere. The mixture was concentrated in vacuo, and the resdiue was purified by silica gel chromatography (silica, 80 g, 0-50% EtOAc in petroleum ether) to give l-(6-(3-(((rer / -butyldiphenylsilyl)oxy)methyl)azetidin-l-yl)benzo[<7]isoxazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (524 mg, 18% yield) as a yellow solid.. LCMS: m / z 675.5 [M+H]+. 10258] Step 9: Synthesis of i-(6-(3-(hydroxymethyl)azetidin-l-yl)benzo[< / ]isoxazol-3-yl)-3-(4-methoxybenzy l)dihy dropyrimidine-2,4( 1H, 3H) -dione

[0259] To a solution of l-(6-(3-(((terZ-butyldiphenylsilyl)oxy)methyl)azetidin-l-yl)benzo[6?]isoxazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1 / 7,3H)-dione (524 mg, 0.78 mmol) in THF (10 mL) was added TBAF (1 N in THF, 3 mL). The resulting mixture was stirred at room temperature overnight and concentrated. The residue was dissovled with DCM, and the organic phase was washed with water, brine, dried over anhydrous Na?SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, 20 g, 0-8% MeOH in DCM) to give l-(6-(3-(hydroxymethyl)azetidin-l-yl)benzo[t / ]isoxazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(177,377)-dione (120 mg, 35% yield) as a yellow solid. LCMS: m / z 437.3 [M+H]+.

[0260] Step 10: Synthesis of l-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2 / / )-yl)benzo[t / ]isoxazol-6-yl)azetidine-3-carbaldehyde

[0261] To a solution of l-(6-(3-(hydroxymethyl)azetidin-l-yl)benzo[t / ]isoxazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4( 1 H,3#)-dione (120 mg, 0.28 mmol) in DCM (5 mL) was added Dess-Martin reagent (234 mg, 0.55 mmol) at 0°C. The resulting mixture was stirred at room temperature overnight and quenched with a solution of Na2S2O3 : NaHCO3=l:l(5mL). The aqueous phase was extracted with DCM, and the organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give l-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin- l(2H)-yl)benzo[r / ]isoxazol-6-yl)azetidine-3-carbaldehyde (120 mg, crude) as a yellow solid, which was used directly for the next step. LCMS: m / z 435.2 [M+H]+.

[0262] Step 11: Synthesis of l-(6-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-( / ]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)benzo[r / ]isoxazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione

[0263] To a mixture of 3-(4-phenoxyphenyl)-l-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (120 mg, 0.26 mmol) in DCE (10 mL) was added 1-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)benzo[d]isoxazol-6-yl)azetidine-3-carbaldehyde (120 mg, crude) and CH3COOH (1 drop). The resulting mixture was stirred at room temperature for 30 min, and then NaBH(OAc)3 (117 mg, 0.55 mmol) was added, and the mixture was stirred at the room temperature overnight. The reaction mixture was diluted with H2O (20 ml), and the aqueous phase was extracted with DCM ( 20 mL X 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaiSO4, concentrated, and the residue was purified by flash chromatography (silica, 40 g, 0-8% MeOH in DCM) to give 1-(6-(3-((4-(( lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-17 / -pyrazolo[3,4-r / ]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)benzo[d]isoxazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine- 2,4( 1 H,3H)-dione (90 mg, 37% yield of 2 steps) as a yellow solid. LCMS: m / z 888.3 [M+H]+.

[0264] Step 12: Synthesis of 1-(6-(3-((4-(( 1 r,4r)-4-(4-amino-3-(4-phenoxyphenyl)- 1H- pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)benzo[d]isoxazol- 3-yl)dihydropyrimidine-2,4( 1 H,3H)-dione (2)

[0265] A solution of l-(6-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)benzo[d]isoxazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4( 1 / / ,3 / / )-dionc (90 mg, 0.10 mmol) in TfOH / TFA (1 / 10, 3 mL) was stirred at room temperature overnight and concentrated. The residue was dissolved with DCM, and the organic phase was washed with saturated NaHCOs solution, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 1(6-(3-((4-((1 r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4( 1 H,3H)-dione (2) (5 mg, 6.4% yield) as a yellow solid. LCMS: m / z 768.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 6 10.80 (s, 1H), 8.23 (s, 1H), 7.65 (d, J= 8.4 Hz, 2H), 7.61 - 7.39 (m, 4H), 7.27 - 7.07 (m, 5H), 6.46 (d, J = 8.8 Hz, 2H), 4.70 - 4.61 (m, 1H), 4.08 - 3.96 (m, 4H), 3.62 -3.54 (m, 2H), 3.02 - 2.90 (m, 1H), 2.76 (t, J = 6.4 Hz, 2H), 2.62 - 2.53 (m, 5H), 2.45 - 2.35 (m, 4H), 2.09 - 1.88 (m, 6H), 1.53 - 1.41 (m, 2H), 1.30 - 1.21 (m, 2H). Example 2: Synthesis of 5-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l -yl)cyclohexyl)piperazin-l -yl)methyl)azetidin-l -yl)-2-( 2,6-dioxopiperidin-3-yl)isoindoline-l ,3-dione (Compound 7)

[0092] Compound (7) was synthesized according the scheme below.

[0266] Step 1: Synthesis of 3-iodo-l-(l,4-dioxaspiro[4.5Jdecan-8-yl)-lH-pyrazolo[3,4- ( / ]pyrimidin-4- amine.

[0267] To a suspension of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (2.6 g, 10 mmol), l,4-dioxaspiro[4.5]decan-8-ol (3.2 g, 20 mmol) and PPh3 (3.9 g, 15 mmol) in THF (30 mL) was added dropwise DIAD (4.04 g, 20 mmol) over a period of 30 min at 0 °C. The reaction was stirred at room temperature for 12 hs under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was pulped with EtOAc (30 mL x 3), and the precipitate was dried in vacuo to give 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-<7]pyrimidin-4-amine (2.8 g, 70%) as a white solid. LCMS: m / z 402.0 [M+H]+.

[0268] Step 2: Synthesis of 4-(4-amino-3-iodo-177-pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexan-1 -one.

[0269] To a suspension of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-( / ]pyrimidin-4-amine (2.8 g, 6.9 mmol) in THF (10 mL) was added HC1 (6N, 3 mL). The reaction was stirred at 60 °C for 2 hs, and diluted with water. The aqueous phase was neutralized with saturated sodium carbonate solution to pH=6-8, the precipitate was formed. The precipitate was filtered and dried in vacuo to give 4-(4-arnino-3-iodo-177-pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexan-l-one (2 g, 83% yield) as a white solid, which was used directly for the next step. LCMS: m / z 358.0 [M+H]+.

[0270] Step 3: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate. I

[0271] To a mixture of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexan-l-one (1.8 g, 5.05 mmol) in DCM (20 mL) was added tert-butyl piperazine-1-carboxylate (1.87 g, 10.11 mmol) and CH3COOH (150 mg, 2.5 mmol). The resulting mixture was stirred at room temperature for 6 hs, and then NaHB(OAc)3 (2.14 g, 10.11 mmol) was added. The mixture was stirred at 50 °C overnight, and diluted with DCM (80 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash - 105- chromatography (silica, 40 g, 0-10% DCM\MeOH=10:l in DCM) to give tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-l / / -pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg) as a white solid. LCMS: m / z 528.0 [M+H]+.

[0272] Step 4: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-( / ]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate.

[0273] To a mixture of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg, 0.76 mmol) in dioxaneXthO (20X2 mL) was added 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (450 mg, 1.52mmol), Pd(dppf)Ch (55 mg, 0.076 mmol) and NaoCOs (161 mg, 1.52 mmol). The resulting mixture was stirred at 90 °C for 12 hs under nitrogen atmosphere and concentrated, and the residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in EtOAc) to give 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-<7]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 90% yield) as a white solid. LCMS: m / z 570.2 [M+H]+.

[0274] Step 5: Synthesis of 3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-t / ]pyrimidin-4-amine.

[0275] To a mixture of 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-< / ]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 0.68 mmol) in DCM (10 mL) was added HCIXdioxane (5 mL). The resulting mixture was stirred at room temperature overnight and diluted with DCM (40 mL). The organic phase was washed with saturated sodium hydrogen carbonate solution, brine, dried over anhydrous Na2SO4, filtered and concentrated to give 3-(4-phenoxypheny 1)-1-(( lr,4r)-4-(piperazin-l-yl)cyclohexyl)-l / / -pyrazolo[3,4-<7]pyrimidin-4-amine - 106- (270 mg, 85% yield) as a white solid, which was used directly for the next step. LCMS: m / z 470.2 [M+H]+.

[0276] Step 6: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-1,3-dione.

[0277] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (400 mg, 1.45 mmol), azetidin-3-ylmethanol (189 mg, 2.17 mmol) and DIPEA (461 mg, 4.35 mmol) in DMF (4 ml) was stirred at 100 °C for 16 hs. After cooling to room temperature, the mixture was diluted with H2O (20 ml), and the aqueous phase was extracted with EtOAc ( 20 ml X 3). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column (0-15% MeOH / CELCh) to give 240 mg of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-1,3-dione as yellow solid (48% yield). LCMS: m / z 344.1 [M+H]+.

[0278] Step 7: Synthesis of   1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)azetidine-3-carbaldehyde.

[0279] A mixture      of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1- yl)isoindoline-1,3-dione (240 mg, 0.70 mmol), Dess-Martin reagent (593 mg, 1.40 mmol) in DCM (5 ml) was stirred at 0°C for 2 hs. The mixture was quenched with a solution of NaHCOj and NaiSsOa, The aqueous phase was extracted with DCM, and the organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give 600 mg of 1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde as yellow solid (100% yield), which was used directly for the next step. LCMS: m / z 342.1 [M+H]+.

[0280] Step 8: Synthesis of 5-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (7) - 107-

[0281] A mixture of 1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (77 mg, 0.22 mmol),   3-(4-phenoxypheny 1)-1-((1 r,4r)-4-(piperazin-1- yl)cyclohexyl)-l / / -pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.15 mmol) and CH3COOH (5 drops) in DCM (3 ml). The mixture was stirred at room temperature for 0.5 h, and then NaBH(OAc)3 (95 mg, 0.45 mmol) was added, and the mixture was stirred at the room temperature overnight. The reaction mixture was diluted with H2O (20 ml), and the aqueous phase was extracted with DCM ( 20 ml X 3). The organic phases was washed with brine (20 ml), dried over anhydrous Na2SO4, concentrated, and the residue was purified by silica gel chromatography (020% MeOH / CHiCh) to give 23 mg of 5-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-17 / -pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (7) as yellow solid (19% yield). LCMS: m / z 795.1 [M+H]+. ’H NMR (400 MHz, MeOD- / 4) 8 8.24 (s, 1H), 7.65 (dd, J= 13.7, 8.5 Hz, 3H), 7.46 -7.35 (m, 2H), 7.26 - 7.05 (m, 5H), 6.80 (d, / = 2.1 Hz, 1H), 6.64 (d, / = 8.4 Hz, 1H), 5.13 - 4.99 (m, 2H), 4.30 - 4.09 (m, 2H), 3.85 - 3.65 (m, 2H), 3.21 - 2.56 (m, 14H), 2.30 - 2.06 (m, 8H), 1.76 -1.51 (m, 2H).

[0282] The sulfate salt of compound 7 was also prepared.

[0283] To a suspension of 5-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- / ]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (90 mg, 0.11 mmol) in l,4-dioxane(18 mL) was added - 108- a solution of H2SO4 (5 drops in 2 mL dioxane, 0.8 mL). The reaction was stirred at room temperature for 20 mins and centrifuged to give 5-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-t / ]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione sulfate (98.1 mg, 99% yield) as a yellow solid. LCMS: zn / z 795.3 [M+H]+. 'H NMR (400 MHz, DMSO-76) 6 11.09 (s, 1H), 8.45-8.33 (m, 1H), 7.73 - 7.59 (m, 3H), 7.46 (t, 7= 8.0 Hz, 2H), 7.26 - 7.09 (m, 5H), 6.82 (s, 1H), 6.68 (d, 7 = 7.0 Hz, 1H), 5.09-5.04 (m, 2H), 4.85-4.77 (m, 2H), 4.26-4.17 (m, 2H), 3.88-3.78 (m, 2H), 3.67 - 3.16 (m, 10H), 2.92-2.83 (m, 1H), 2.61-2.55 (m, 1H), 2.22-1.98 (m, 7H), 1.85-1.73 (m, 2H).

[0284] Similarly, additional compounds of the present disclosure may be made.

[0285] Synthesis of compounds containing a thieno[3,4-d]pyrimidin-4-amine are synsized according to the route below:

[0286] Following a similar procedure as described above, the following compounds were prepared. Cmpd No. Compound Structure / Name LCMS NMR (shifts in ppm) 8 A / Cnh rN^° ° h2n.           \          FT Y 1 W'N N^N       \— / 5-(3-((4-((1 r,4r)-4-(4-amino-5-(4- phenoxyphenyl)thieno[3,4-< / ]pyrimidin-7-yl)cyclohexyl)piperazin- l-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione LCMS: m / z 811.3 [M+H]+. 'H NMR (400 MHz, DMSO-do) 5 11.08 (s, lH),8.06(s, 1H),7.63 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.45 (dd, J= 8.4, 7.6 Hz, 2H), 7.23 - 7.11 (m, 6H), 6.77 (d, J = 2.0 Hz, 1H), 6.65 -6.63 (m, 1H), 5.08 - 5.03 (m, 1H), 4.13 (t, J= 8.0 Hz, 2H), 3.72 - 3.64 (m, 2H), 3.48 - 3.43 (m, 1H), 2.99 - 2.84 (m, 2H), 2.632.53 (m, 7H), 2.43 - 2.29 (m, 5H), 2.16 - 2.08 (m, 2H), 2.05 -1.86 (m, 4H), 1.62 - 1.52 (m, 2H), 1.47-1.40 (m, 2H) 9 S ,-n^o ° H,N.              \           F l YY W’" N^N 5-(3-((4-(( U4s)-4-(4-amino-5-(4- phenoxyphenyl)thieno [3,4-< / ]pyrimidin-7 - yl)cyclohexyl)piperazin- l-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione LCMS: m / z 811.0 [M+H]+. 'H NMR (400 MHz, DMSO-rie) 5 11.08 (s, 1H), 8.06 (s, 1H), 7.69-7.56 (m, 3H), 7.45 (dd, J = 8.4, 7.6 Hz, 2H), 7.23 - 7.11 (m, 5H), 6.76 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 8.4, 2.0 Hz, 1H), 5.12-5.06 (m, 1H), 4.12 (t, J = 8.0 Hz, 2H), 3.77 - 3.64 (m, 3H), 3.00 - 2.86 (m, 2H), 2.62 - 2.56 (m, 3H), 2.46 - 2.19 (m, 7H), 2.01 - 1.77 (m, 7H), 1.64- 1.57 (m, 2H) Example 3: Synthesis of4-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-rt{-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l ,3-dione (Compound 10)

[0092] Compound (10) was synthesized according the scheme below. DIAD, PPh3, THF 6N HCI NaHB(OAc)3 DCM, CH3COOH PdCI2(dppf), Na2CO3

[0287] Step 1: Synthesis of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-17 / -pyrazolo[3,4- d ] py rimidin-4- amine.

[0288] To a suspension of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (2.6 g, 10 mmol), l,4-dioxaspiro[4.5]decan-8-ol (3.2 g, 20 mmol) and PPhs (3.9 g, 15 mmol) in THF (30 mL) was added dropwise DIAD (4.04 g, 20 mmol) over a period of 30 min at 0 °C. The reaction was stirred at room temperature for 12 hs under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was pulped with EtOAc (30 mL x 3), and the precipitate was dried in vacuo to give 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-t / ]pyrimidin-4-amine (2.8 g, 70%) as a white solid. LCMS: m / z 402.0 [M+H]+.

[0289] Step 2: Synthesis of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-( / ]pyrimidin-l-yl)cyclohexan-1 -one.

[0290] To a suspension of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-<7]pyrimidin-4-amine (2.8 g, 6.9 mmol) in THF (10 mL) was added HC1 (6N, 3 mL). The reaction was stirred at 60 °C for 2 hs, and diluted with water. The aqueous phase was neutralized with saturated sodium carbonate solution to pH=6-8, the precipitate was formed. The precipitate was filtered and dried in vacuo to give 4-(4-amino-3-iodo-177-pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexan-l-one (2 g, 83% yield) as a white solid, which was used directly for the next step. LCMS: m / z 358.0 [M+H]+.

[0291] Step 3: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-1 -yl)cyclohexyl)piperazine-1 -carboxylate.

[0292] To a mixture of 4-(4-amino-3-iodo-l / / -pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexan-l-one (1.8 g, 5.05 mmol) in DCM (20 mL) was added tert-butyl piperazine-1-carboxylate (1.87 g, 10.11 mmol) and CH3COOH (150 mg, 2.5 mmol). The resulting mixture was stirred at room - 113- temperature for 6 hs, and then NaHB(OAc)3 (2.14 g, 10.11 mmol) was added. The mixture was stirred at 50 °C overnight, and diluted with DCM (80 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-10% DCM\MeOH=10:l in DCM) to give tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg) as a white solid. LCMS: m / z 528.0 [M+H]+.

[0293] Step 4: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate.

[0294] To a mixture of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg, 0.76 mmol) in dioxaneXthO (20X2 mL) was added 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (450 mg, 1.52mmol), Pd(dppf)Ch (55 mg, 0.076 mmol) and NaoCOs (161 mg, 1.52 mmol). The resulting mixture was stirred at 90 °C for 12 hs under nitrogen atmosphere and concentrated, and the residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in EtOAc) to give 4-((lr,4r)-4-(4-amino-3-(4-phcnoxyphcnyl )-1 / / -pyrazolo|3.4-c / |pyrimidin-1-yljcyclohcxyljpipcrazinc-1-carboxylate (390 mg, 90% yield) as a white solid. LCMS: m / z 570.2 [M+H]+.

[0295] Step 5: Synthesis of 3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-t / ]pyrimidin-4-amine.

[0296] To a mixture of 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-r / ]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 0.68 mmol) in DCM (10 mL) was added HCIXdioxane (5 mL). The resulting mixture was stirred at room temperature overnight and - 114- diluted with DCM (40 mL). The organic phase was washed with saturated sodium hydrogen carbonate solution, brine, dried over anhydrous Na2SO4, filtered and concentrated to give 3-(4-phenoxyphenyl)-1 -((1 r,4r)-4-(piperazin-1 -yl)cyclohexyl)-1 H-pyrazolo[3,4-<7]pyrimidin-4-amine (270 mg, 85% yield) as a white solid, which was used directly for the next step. LCMS: m / z 470.2 [M+H]+.

[0297] Step 6: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-l- yl)isoindoline-1,3-dione.

[0298] To a suspension of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (200 mg, 0.72 mmol) in DMF(5 mL) was added azetidin-3-ylmethanol (133 mg, 1.08 mmol) and DIPEA (279 mg, 2.16 mmol). The reaction was stirred at 100°C overnight and diluted with water (10 mL), the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous NazSCL, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in DCM) to give 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-1,3-dione (150 mg, 61% yield) as a yellow solid. LCMS: m / z 344.1 [M+H]+.

[0299] Step 7: Synthesis of   1 -(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)azetidine-3-carbaldehyde.

[0300] To a mixture of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione (100 mg, 0.29mmol) in DCM (10 mL) was added Dess-Martin reagent (247 mg, 0.58 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours and quenched with a solution of NaiSiOs : NaHCOs=l :1 (5mL). The aqueous phase was extracted with DCM, and the organic phase was washed with brine, dried over anhydrous Na2SO4, and - 115- concentrated io give   1 -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidine-3- carbaldehyde (100 mg, 67%) as a yellow solid. LCMS: m / z 342.0 [M+H]+.

[0301] Step 8: Synthesis of 4-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-( / ]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (10)

[0302] To a mixture of 3-(4-phenoxyphenyl)-l-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-177-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.13 mmol) in DCE (10 mL) was added 1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)azetidine-3-carbaldehyde (88 mg, 0.26 mmol) and CH3COOH (1 drop). The resulting mixture was stirred at room temperature for 30 min, , and then NaBH(OAc)3(55 mg, 0.26 mmol) was added, and the mixture was slimed at the room temperature overnight. The reaction mixture was diluted with H2O (20 ml), and the aqueous phase was extracted with DCM ( 20 ml X 3). The organic phases was washed with brine (20 ml), dried over anhydrous Na2SO4, concentrated, and the residue was purified by Prep-HPLC to give 4-(3-((4((1 r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-177-pyrazolo[3,4-r / ]pyrimidin-1 -yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (10) (51 mg, yield 49%) as a yellow solid. LCMS: m / z 795.1 [M+H]+. ’H NMR (400 MHz, DMSO-^6) 8 11.08 (s, 1H), 8.23 (s, 1H), 7.66-7.64 (m2H), 7.57-7.53 (m, 1H), 7.46-7.42 (m, 2H), 7.23 - 7.08 (m, 6H), 6.78 (d, J= 8.8 Hz, 1H), 5.05 (dd, J= 12.8, 5.6 Hz, 1H), 4.70-4.61 (m, 1H), 4.31-4.23 (m, 2H), 3.86-3.79 (m, 2H), 2.92-2.84(m, 2H), 2.60-2.51 (m, 8H), 2.43-2.33 (m, 5H), 2.10 - 1.89 (m, 7H), 1.52-1.42 (m 2H).

[0303] The sulfate salt of compound 10 was also prepared.

[0304] To a suspension of 4-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-ri]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (40 mg, 0.05 mmol) in 1,4-dioxane (8 mL) was added a solution of H2SO4 (5 drops in 2 mL dioxane, 0.8 mL) at 0 °C. The reaction was stirred at room temperature for 20 mins and centrifuged 4-(3-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-ri]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione sulfate (42 mg, 99% yield) as a yellow solid. LCMS: m / z 795.1 [M+H]+. 'H NMR (400 MHz, DMSO-J6) 8 11.09 (s, 1H), 8.56 (s, 1H), 7.69 - 7.59 (m, 3H), 7.46 (t, J= 7.9 Hz, 2H), 7.25 - 7.13 (m, 6H), 6.81 (d, J = 8.6 Hz, 1H), 5.08-5.04 (m, 2H), 4.86 - 4.81 (m, 2H), 4.44-4.40 (m, 2H), 4.04-3.96 (m, 2H), 3.89-3.71 (m, 4H), 3.61-3.53 (m, 2H), 3.44-3.34 (m, 3H), 3.27-3.18 (m, 1H), 2.94 - 2.81 (m, 1H), 2.61-2.56 (m, 1H), 2.27 - 1.99 (m, 7H), 1.88-1.79 (m, 2H).

[0305] Following a similar procedure as described above for compound 10, the following compounds, or hydrates or salts thereof, may be prepared. Cmpd Compound Structure / Name LCMS No. 11 4-(3-((4-(( 1 r,4r)-4-(4-amino-5-(4- phcnoxy phenyl) thicno [ 3,4 - < / ] pyrimidin-7 - y l)cyclohexyl)piperazin-1 -yl)methy l)azetidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione NMR (shifts in ppm) LCMS: m / z 811.0 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 11.08 (s, 1H), 8.06 (s, 1H), 7.63 - 7.52 (m, 3H), 7.49 - 7.42 (m, 2H), 7.297.04 (m, 6H), 6.78 (d, J= 8.8 Hz, 1H), 5.05 (dd, J = 12.4, 5.2 Hz, 1H), 4.35-4.21 (m, 2H), 3.89-3.77 (m, 2H), 3.53- 3.46 (m, 1H), 2.96-2.84 (m, 2H), 2.69 - 2.52 (m, 7H), 2.46-2.28 (m, 5H), 2.17-2.09 (m, 2H), 2.03-1.88 (m, 3H), 1.61-1.52 (m, 2H), 1.46-1.37 (m, 2H). 12 y-s                    y HI V / n 'N^j ( / N^N      '<7       OX / nA H O 4-(3-((4-((15,4^)-4-(4- amino-5-(4- phenoxyphenyl)thieno[3,4-7]pyrimidin-7- y l)cyclohexyl)piperazin-1 -yl)methy l)azetidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione LCMS:m / z 811.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 11.08 (s, 1H), 8.06 (s, 1H), 7.58-7.51 (m, 3H), 7.48 - 7.41 (m, 2H), 7.23-7.08 (m, 6H), 6.77 (d, 7= 8.4 Hz, 1H), 5.08-4.99 (m, 1H), 4.32-4.24 (m, 2H), 3.90-3.72 (m, 3H), 2.94-2.81 (m, 2H), 2.66-2.55 (m, 5H), 2.45-2.20 (m, 7H), 2.14-1.72 (m, 8H), 1.65-1.55 (m, 2H). Example 4: Synthesis of (lR,4S)-2-((R)-3-((((lR,4R)-4-((4-((lr,4R)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[ 3,4-d]pyrimidin-l -yl)cyclohexyl )piperazin-l - yl)methyl)cyclohexyl)methyl)thio )-2-(1 -fluorocyclopropane-1 -carboxamido )-3 -methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)cyclopentane-l-carboxamide (Compound 13)

[0092] Compound (13) was synthesized according the scheme below. DIAD, PPh3, THF

[0306] Step 1: Synthesis of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4- <71 p y rimidin-4- amine.

[0307] To a suspension of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (2.6 g, 10 mmol), l,4-dioxaspiro[4.5]decan-8-ol (3.2 g, 20 mmol) and PPha (3.9 g, 15 mmol) in THF (30 mL) was added dropwise DIAD (4.04 g, 20 mmol) over a period of 30 min at 0 °C. The reaction was stirred at room temperature for 12 hs under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was pulped with EtOAc (30 mL x 3), and the precipitate was dried in vacuo to give -119- 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-l / / -pyrazolo[3,4-( / ]pyrimidin-4-amine (2.8 g, 70%) as a white solid. LCMS: m / z 402.0 [M+H]+.

[0308] Step 2: Synthesis of 4-(4-amino-3-iodo-17 / -pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexan-l-one. I

[0309] To a suspension of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-17 / -pyrazolo[3,4-e / ]pyrimidin-4-amine (2.8 g, 6.9 mmol) in THF (10 mL) was added HC1 (6N, 3 mL). The reaction was stirred at 60 °C for 2 hs, and diluted with water. The aqueous phase was neutralized with saturated sodium carbonate solution to pH=6-8, the precipitate was formed. The precipitate was filtered and dried in vacuo to give 4-(4-amino-3-iodo-l / / -pyrazolo[3,4-<7]pyrimidin-l-yl)cyclohexan-l-one (2 g, 83% yield) as a white solid, which was used directly for the next step. LCMS: m / z 358.0 [M+H]+.

[0310] Step 3: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-1 -yl)cyclohexyl)piperazine-1 -carboxylate. I

[0311] To a mixture of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexan-l-one (1.8 g, 5.05 mmol) in DCM (20 mL) was added tert-butyl piperazine-1-carboxylate (1.87 g, 10.11 mmol) and CH3COOH (150 mg, 2.5 mmol). The resulting mixture was stirred at room temperature for 6 hs, and then NaHB(OAc)3 (2.14 g, 10.11 mmol) was added. The mixture was stirred at 50 °C overnight, and diluted with DCM (80 mL). The organic phase was washed with brine, dried over anhydrous NaiSO4, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-10% DCM\MeOH=10:l in DCM) to give tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg) as a white solid. LCMS: m / z 528.0 [M+H]+.

[0312] Step 4: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate.

[0313] To a mixture of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg, 0.76 mmol) in dioxaneMLO (20\2 mL) was added 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (450 mg, 1.52mmol), Pd(dppf)C12 (55 mg, 0.076 mmol) and NazCO s (161 mg, 1.52 mmol). The resulting mixture was stirred at 90 °C for 12 hs under nitrogen atmosphere and concentrated, and the residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in EtOAc) to give 4-((lr,4r)-4-(4-amino-3-(4-phcnoxyphcnylj-1 Z / -pyrazolo|3,4-<7|pyrimidin-1-yl)cyclohcxyl)pipcraziiie-1-carboxylate (390 mg, 90% yield) as a white solid. LCMS: m / z 570.2 [M+H]+.

[0314] Step 5: Synthesis of 3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(piperazin-1-yl)cyclohexy 1)-l / / -pyrazolo[3,4-t / ]pyrimidin-4-amine.

[0315] To a mixture of 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-£ / ]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 0.68 mmol) in DCM (10 mL) was added HCl\dioxane (5 mL). The resulting mixture was stirred at room temperature overnight and diluted with DCM (40 mL). The organic phase was washed with saturated sodium hydrogen carbonate solution, brine, dried over anhydrous Na2SCL, filtered and concentrated to give 3-(4-phenoxypheny 1)-1-(( lr,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-( / ]pyrimidin-4-amine (270 mg, 85% yield) as a white solid, which was used directly for the next step. LCMS: m / z 470.2 [M+H]+.

[0316] Step          6:          Synthesis          of          l-((17?,4r)-4-(4-(((lr,47?)-4- (bromomethyl)cyclohexyl)methyl)piperazin-1 -yl)cyclohexyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0317] To a mixture of 3-(4-phcnoxyphcnyl)-l-((lr,4r)-4-(pipcrazin-l-yl)cyclohcxyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.21 mmol) in acetone (10 mL) was added (lr,4r)-1,4-bis(bromomethyl)cyclohexane (173 mg, 0.64 mmol) and K2CO3 (174 mg, 1.26 mmol). The resulting mixture was stirred at 50 °C for 48 hs and concentrated, the residue was diluted with water (10 mL). The aqueous phase was extracted with DCM (10 mL x 3), the combined organic phase was washed with brine, dried over anhydrous Na2SCL, filtered and concentrated. The residue was purified by flash chromatography (silica, 15 g, 0-2% MeOH in DCM) to give l-((l / ?,4r)-4-(4-((( lr,47?)-4-(bromomethyl)cyclohexyl)methyl)piperazin-l-yl)cyclohexyl)-3-(4-phenoxyphenyl)-177-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 18% yield) as a white solid. LCMS: m / z 658.2 [M+H]+.

[0318] Step 7: Synthesis of (l / ?,4S)-2-(( / ?)-3-((((l / ?,4 / ?)-4-((4-((lr,4 / ?)-4-(4-amino-3-(4- phenoxyphenyl)-177-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l- yl)methyl)cyclohexyl)methyl)thio)-2-(l-fluorocyclopropane-l-carboxamido)-3-methylbutanoyl)- 4-hydroxy-A^-(4-(4-methylthiazol-5-yl)benzyl)cyclopentane-l-carboxamide (13)

[0319] To           a          mixture          of          l-((lR,4r)-4-(4-(((lr,4R)-4- (bromomethyl)cyclohexyl)methyl)piperazin-l-yl)cyclohexyl)-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 0.04 mmol) in THF (3 mL) was added (25,4R)-1-((R)-2-( 1-11 uorocyclopropanc- l-caiFoxamido)-3-mcrcap(o-3-mcthylbu(anoyl)-4-hydroxy- / V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (26 mg, 0.048 mmol) and DBU (36 mg, 0.24 mmol). The resulting mixture was stirred at room temperature overnight and concentrated. The residue was purified by Prep-HPLC to give (lR,45)-2-((R)-3-((((iR,4R)-4-((4-((lr,4R)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)cyclohexyl)methyl)thio)-2-(l-fluorocyclopropane-l-carboxamido)-3-methylbutanoyl)-4-hydroxy-A(-(4-(4-methylthiazol-5-yl)benzyl)cyclopentane-l-carboxamide (13) (36.1 mg, yield 49%) as a white solid. LCMS: m / z 556.8 [M+H\2]+. 'H NMR (400 MHz, DMSO-d6) 8 8.99 (s, 1H), 8.59 (t, J= 6.0 Hz, 1H), 8.23 (s, 1H), 7.65 (d, 7= 8.8 Hz, 2H), 7.52-7.35 (m, 7H), 7.20-7.11 (m, 5H), 5.20 (d, J = 3.6 Hz, 1H), 4.77 (d, 7= 9.2 Hz, 1H), 4.64-4.61 (mz, 1H), 4.51 - 4.33 (m, 3H), 4.26-4.21 (m, 1H), 3.77 - 3.61 (m, 2H), 3.34 (s, 3H), 2.45 (s, 3H), 2.43 - 2.17 (m, 7H), 2.13 - 1.81 (m, 11H), 1.76- 1.64 (m, 4H), 1.46-1.35 (m, 11H), 1.22-1.16 (m, 4H), 0.88 - 0.66 (m, 4H).

[0320] Following a similar procedure as described above for compound 13, the following compounds were prepared. Cmpd No. Compound Structure / Name LCMS NMR (shifts in ppm) 14 Qy Q o HO,          / = / \ HN— / . V o T □ (lR,45)-2-((R)-3-((((17?,4R)-4-((4-((lr,4R)-4-(4- amino-5-(4-phenoxyphenyl)thieno[3,4-( / ]pyrimidin- 7-yl)cyclohexy l)piperazin-1 - yl)methyl)cyclohexyl)methyl)thio)-2-(l- LCMS: m / z 564.7 [M / 2+H]+. ’H NMR (400 MHz, DMSO-d6)8 8.99(s, 1H), 8.61-8.55 (m, 1H), 8.06 (s, 1H), 7.54 (d, 7 = 8.5 Hz, 2H), 7.48 - 7.38 (m, 7H), 7.23 - 7.10 (m, 5H), 5.20 (s, 1H), 4.77 (d, 7 = 9.1 Hz, 1H), 4.50 - 4.35 (m, 3H), 4.26 -4.21(m, 1H), 3.73-3.63 (m, 2H), 3.53 - 3.45 (m, 2H), 3.26 - 3.20 (m, 1H), 2.45 (s, 3H), fluorocyclopropane-1 -carboxamido)-3-methylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzy l)cyclopentane-1 -carboxamide 2.42 - 2.37 (m, 3H), 2.33 - 2.23 (m, 4H), 2.15 - 2.07 (m, 3H), 2.02 - 1.96 (m, 2H), 1.92 - 1.89 (m, 3H), 1.75 - 1.66 (m, 5H), 1.61-1.51 (m, 4H), 1.39-1.34 (m, 9H), 1.23 - 1.19 (m, 4H), 0.87-0.72 (m, 4H). 15 0-o_ Q ys                     sP" N Jn < / N-. ho,        y= / hn-^ V / \ / k. '° k □ HN^-U (17?,45)-2-((7?)-3-(((( 17?,47?)-4-((4-(( 1s,45)-4-(4- amino-5-(4-phenoxyphenyl)thieno[3,4-( / ]pyrimidin- 7-yl)cyclohexy l)piperazin-1 - yl)methyl)cyclohexyl)methyl)thio)-2-(l-fluorocyclopropane-1 -carboxamido)-3-methylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzy l)cyclopentane-1 -carboxamide LCMS: m / z 565.3 [M / 2+H]+. ‘H NMR (400 MHz, DMSO-< / 6)8 8.98 (s, 1H), 8.59-8.56 (m, 1H), 8.06 (s, 1H), 7.58-7.56 (m, 2H), 7.48 - 7.40 (m, 7H), 7.217.11 (m, 5H), 5.19-5.18 (m, 1H), 4.78-4.76 (m, 1H), 4.484.37 (m, 3H), 4.26 - 4.20 (m, 1H), 3.78 - 3.63 (m, 3H), 2.45 (s, 4H), 2.41-2.38 (m, 3H), 2.33 -2.21 (m, 5H), 1.99- 1.86 (m, 9H), 1.79- 1.56 (m, 9H), 1.381.34 (m, 8H), 0.88 - 0.66 (m, 4H). Example 5: Synthesis of 4-(4-(3-(4-((h,4x)-4-(4-amino-3-(4-phenoxyphenyl)-l}3-pyrazolo[3,4-d]pyrimidin-l -yl )cyclohexyl )piperazin-l -yl )propyl )piperazin-l -yl)-2-( 2,6-dioxopiperidin-3-yl)isoindoline-l ,3-dione (Compound 16) and 5-(4-(3-(4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)propyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Compound 17)

[0092] Compound (17) was synthesized according the scheme below.

[0321] Step 1: Synthesis of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-l / / -pyrazolo[3,4- ( / ]pyrimidin-4- amine.

[0322] To a suspension of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (2.6 g, 10 mmol), l,4-dioxaspiro[4.5]decan-8-ol (3.2 g, 20 mmol) and PPh3 (3.9 g, 15 mmol) in THF (30 mL) was added dropwise DIAD (4.04 g, 20 mmol) over a period of 30 min at 0 °C. The reaction was stirred at room temperature for 12 hs under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was pulped with EtOAc (30 mL x 3), and the precipitate was dried in vacuo to give 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-<7]pyrimidin-4-amine (2.8 g, 70%) as a white solid. LCMS: m / z 402.0 [M+H]+.

[0323] Step 2: Synthesis of 4-(4-amino-3-iodo-177-pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexan-1 -one.

[0324] To a suspension of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-( / ]pyrimidin-4-amine (2.8 g, 6.9 mmol) in THF (10 mL) was added HC1 (6N, 3 mL). The reaction was stirred at 60 °C for 2 hs, and diluted with water. The aqueous phase was neutralized with saturated sodium carbonate solution to pH=6-8, the precipitate was formed. The precipitate was filtered and dried in vacuo to give 4-(4-amino-3-iodo-lH-pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexan-l-one (2 g, 83% yield) as a white solid, which was used directly for the next step. LCMS: m / z 358.0 [M+H]+.

[0325] Step 3: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate. I

[0326] To a mixture of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexan-l-one (1.8 g, 5.05 mmol) in DCM (20 mL) was added tert-butyl piperazine-1-carboxylate (1.87 g, 10.11 mmol) and CH3COOH (150 mg, 2.5 mmol). The resulting mixture was stirred at room temperature for 6 hs, and then NaHB(OAc)3 (2.14 g, 10.11 mmol) was added. The mixture was stirred at 50 °C overnight, and diluted with DCM (80 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash - 126- chromatography (silica, 40 g, 0-10% DCM\MeOH=10:l in DCM) to give tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-l / / -pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg) as a white solid. LCMS: m / z 528.0 [M+H]+.

[0327] Step 4: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-r / ]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate.

[0328] To a mixture of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg, 0.76 mmol) in dioxaneXthO (20X2 mL) was added 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (450 mg, 1.52mmol), Pd(dppf)Ch (55 mg, 0.076 mmol) and NaoCOs (161 mg, 1.52 mmol). The resulting mixture was stirred at 90 °C for 12 hs under nitrogen atmosphere and concentrated, and the residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in EtOAc) to give 4-((lr,4r)-4-(4-amino-3-(4-phcnoxyphcnyl )-1 / / -pyrazolo|3.4-<: / |pyrimidin-1-yl)cyclohcxyl)pipcrazmc-1-carboxylate (390 mg, 90% yield) as a white solid. LCMS: m / z 570.2 [M+H]+.

[0329] Step 5: Synthesis of 3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-t / ]pyrimidin-4-amine.

[0330] To a mixture of 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-r / ]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 0.68 mmol) in DCM (10 mL) was added HCIXdioxane (5 mL). The resulting mixture was stirred at room temperature overnight and diluted with DCM (40 mL). The organic phase was washed with saturated sodium hydrogen carbonate solution, brine, dried over anhydrous Na2SO4, filtered and concentrated to give 3-(4-phenoxypheny 1)-1-(( lr,4r)-4-(piperazin-l-yl)cyclohexyl)-l / / -pyrazolo[3,4-<7]pyrimidin-4-amine - 127- (270 mg, 85% yield) as a white solid, which was used directly for the next step. LCMS: m / z 470.2 [M+H]+.

[0331] Step 6: Synthesis of tert-butyl 4-(3-bromopropyl)piperidine-l-carboxylate. Br

[0332] To a solution of tert-butyl 4-(3-hydroxypropyl)piperidine-l-carboxylate (800 mg, 3.29 mmol) and CBr4 (1.7 g, 5.3 mmol) in DCM (7 mL) was added PPh3 (1 g, 3.95 mmol) It 0 °C. The resulting mixture was stirred at room temperature for 45 mins and concentretated. The residue was purified by flash chromatography (silica, 40 g, 0-30% ethyl acetate in petroleum ether) to give tertbutyl 4-(3-bromopropyl)piperidine-l-carboxylate (800 mg, 79% yield) as a white solid. LCMS: m / z 307.1 [M+H]+.

[0333] Step 7: Synthesis of tert-butyl 4-(3-(4-(( lr,4r)-4-(4-amino-3-(4-phcnoxyphenyl)-1 / / -pyrazolo[3,4-6?]pyrimidin- l-yl)cyclohexyl)piperazin- l-yl)propyl)piperazine-1-carboxylate.

[0334] To a mixture of tert-butyl 4-(3-bromopropyl)piperidine-l-carboxylate (100 mg, 0.33 mmol) and 3-(4-phenoxyphenyl)-l-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-l / / -pyrazolo[3,4-e / ]pyrimidin-4-amine (79 mg, 0.17 mmol) in CH3CN (4 mL) was added, K2CO3 (66 mg, 0.51 mmol). The resulting mixture was stirred at 50 °C overnight and then concentrated. The residue was purified by flash chromatography (silica, 25 g, 0-10% MeOH in DCM) to give tert-butyl 4-(3-(4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-£ / ]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)propyl)piperazine-l-carboxylate (80 mg, 68% yield) as a yellow solid. LCMS: m / z 696.1 [M+H]+.

[0335] Step 8: Synthesis of   3-(4-phenoxypheny 1)-1-((1 r, 4r)-4-(4-(3-(piperazin-1- yl)propyl)piperazin-1 -yl)cyclohexy 1)-1 H-pyrazolo [3,4-J] pyrimidin-4-amine.

[0336] To a solution of tert-butyl 4-(3-(4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-< / ]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)propyl)piperazine-l-carboxylate (80 mg, 0.11 mmol) in DCM (10 mL) was added HC1 (4 N in 1,4-dioxane, 2 mL). The reaction was stirred at room temperature overnight and concentrated. The residue was added water, and the aqueous phase was neutralized with sodium carbonate solution, extracted with DCM. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(4-(3-(piperazin- l-yl)propyl)piperazin-1-yl)cyclohexyl)-l / / -pyrazolo[3,4-rf]pyrimidin-4-amine (60 mg, 92% yield) as a yellow solid, which was used directly for the next step. LCMS: m / z 596.3 [M+H]+.

[0337] Step 9: Synthesis of 4-(4-(3-(4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)propyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (16)

[0338] To a solution of 3-(4-phenoxyphenyl)-l-((lr,4r)-4-(4-(3-(piperazin-l-yl)propyl)piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-t / ]pyrimidin-4-amine (30 mg, 0.05 mmol) in THF (4 mL) was added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (27 mg, 0.1 mmol) and DIPEA (19 mg, 0.15 mmol). The resulting mixture was stirred at 80 °C overnight and concentrated. The residue was purified by Prep-HPLC to give 4-(4-(3-(4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-17 / -pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)propyl)piperazin-1-y 1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (16) (40.5 mg, yield 45%) as a yellow solid. LCMS: m / z 852.1 [M+HJT ‘H NMR (400 MHz, DMSO-c?6) 8 11.10 (s, - 129- 1H), 8.23 (s, 1H), 7.72 - 7.63 (m, 3H), 7.47 - 7.40 (m, 2H), 7.37-7.33 (m, 2H), 7.21 - 7.10 (m, 5H), 5.12 - 5.06 (m, 1H), 4.66-4.61 (m, 1H), 3.31 - 3.24 (m, 4H), 2.92-2.82 (m, 1H), 2.61-2.53 (m, 9H), 2.41-2.26 (m, 9H), 2.04-1.91 (m, 8H), 1.65-1.58 (m, 2H), 1.51-1.43 (m, 2H).

[0339] Step 10: Synthesis of 5-(4-(3-(4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)propyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (17)

[0340] To a solution of    3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(4-(3-(piperazin-1- yl)propyl)piperazin-1 -yl)cyclohexyl)-1 H-pyrazolo[3,4-ri]pyrimidin-4-amine (60 mg, 0.13 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (71 mg, 0.26 mmol) in THF (4 mL) was added DIPEA (50 mg, 0.39 mmol). The resulting mixture was stirred at 80 °C overnight and concentrated. The residue was purified by Prep-HPLC to give 5-(4-(3-(4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo [3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1 -yl)propyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (17) (39.4 mg, yield 35%) as a yellow solid. LCMS: m / z 852.1 [M+H]+. NMR (400 MHz, DMSO-d6)8 11.09 (s, 1H), 8.23 (s, 1H), 7.68-7.64 (m, 3H), 7.46 - 7.41 (m, 2H), 7.35 - 7.24 (m, 2H), 7.21 - 7.11 (m, 5H), 5.11-5.05 (m, 1H), 4.69-4.62 (m, 1H), 3.46-3.42 (m, 4H), 2.91-2.84 (m, 1H), 2.61-2.55 (m, 8H), 2.40-2.28 (m, 10H), 2.09 - 1.90 (m, 8H), 1.65-1.58 (m, 2H), 1.51-1.43 (m, 2H).

[0341] Following a similar procedure as described above for compound 17, the following compounds were prepared. Cmpd No. Compound Structure / Name LCMS NMR (shifts in ppm) 18 O^N o r—\..>N J              / -4) U \                                \yNH h2nhH                ° 4-(4-(2-(4-(( If, 4r)-4-(4-amino-3-(4- phenoxyphenyl)- IH-pyrazolo [3,4-t / ]pyrimidin-1 -yl)cyclohexyl)piperazin-1 -yl)ethyl)piperazin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione LCMS: m / z 838.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 11.10 (s, 1H), 8.23 (s, 1H), 7.74 - 7.62 (m, 3H), 7.46-7.34 (m, 4H), 7.22 - 7.09 (m, 5H), 5.15 -5.06 (m, 1H), 4.71-4.61 (m, 1H), 3.59-3.41 (m, 7H), 2.91-2.84 (m, 2H), 2.81 - 2.51 (m, 14H), 2.10-1.91(m, 7H), 1.54-1.42 (m, 2H). 19 Q o O / NH 5-(4-(2-(4-((lr,4r)-4-(4-amino-3-(4- phenoxyphenyl)- IH-pyrazolo [3,4-c / ]pyrimidin-1 -yl)cyclohexyl)piperazin-1 -yl)ethyl)piperazin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione LCMS: m / z 838.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6)5 11.09 (s, 1H), 8.23 (s, 1H), 7.697.64 (m, 3H), 7.47 - 7.24 (m, 4H), 7.22 - 7.09 (m, 5H), 5.105.05 (m, 1H), 4.72-4.57 (m, 1H), 3.66-3.40 (m, 8H), 2.96-2.82 (m, 2H), 2.77-2.53 (m, 14H), 2.071.93 (m,7H), 1.57-1.41 (m, 2H). Example 6: Synthesis of5-(2-(4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)ethoxy )-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Compound 20)

[0092] Compound (20) was synthesized according the scheme below. (20)

[0342] Step 1: Synthesis of 5-(2-bromoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione. O O O

[0343] To a soluton of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (274 mg, 1.00 mmol), 2-bromoethan-l-ol (124 mg, 1.00 mmol) and PPhs (393 mg, 1.50 mmol) in THF (3 mL) was added dropwise DIAD (303 mg, 1.50 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 6 hs and concentrated, the residue was purified by silica gel chromatography (20-40% EtOAc / petroleum ether) to give 500 mg of 5-(2- bromoethoxy )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as yellow solid (100% yield). LCMS: m / z 381.0 [M+H]+.

[0344] Step 2: Synthesis of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4- <7]pyrimidin-4- amine.

[0345] To a suspension of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (2.6 g, 10 mmol), l,4-dioxaspiro[4.5]decan-8-ol (3.2 g, 20 mmol) and PPha (3.9 g, 15 mmol) in THF (30 mL) was added dropwise DIAD (4.04 g, 20 mmol) over a period of 30 min at 0 °C. The reaction was stirred at room temperature for 12 hs under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was pulped with EtOAc (30 mL x 3), and the precipitate was dried in vacuo to give 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-l / / -pyrazolo[3,4-( / ]pyrimidin-4-amine (2.8 g, 70%) as a white solid. LCMS: m / z 402.0 [M+H]+.

[0346] Step 3: Synthesis of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-t / ]pyrimidin-l-yl)cyclohexan-1 -one.

[0347] To a suspension of 3-iodo-l-(l,4-dioxaspiro[4.5]dccan-8-yl)-lH-pyrazolo[3,4-<7]pyrimidin-4-amine (2.8 g, 6.9 mmol) in THF (10 mL) was added HC1 (6N, 3 mL). The reaction was stirred at 60 °C for 2 hs, and diluted with water. The aqueous phase was neutralized with saturated sodium carbonate solution to pH-6-8, the precipitate was formed. The precipitate was filtered and dried in vacuo to give 4-(4-amino-3-iodo-lH-pyrazolo[3,4-< / ]pyrimidin-l-yl)cyclohexan-l-one (2 g, 83% yield) as a white solid, which was used directly for the next step. LCMS: m / z 358.0 [M+H]+.

[0348] Step 4: Synthesis of ferLbutyl 4-((lr,4r)-4-(4-amino-3-iodo-l / / -pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate. h2n "N NBoc

[0349] To a mixture of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexan-l-one (1.8 g, 5.05 mmol) in DCM (20 mL) was added tert-butyl piperazine-1-carboxylate (1.87 g, 10.11 mmol) and CH3COOH (150 mg, 2.5 mmol). The resulting mixture was stirred at room temperature for 6 hs, and then NaHB(OAc)3 (2.14 g, 10.11 mmol) was added. The mixture was stirred at 50 °C overnight, and diluted with DCM (80 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-10% DCM\MeOH=10:l in DCM) to give tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg) as a white solid. LCMS: m / z 528.0 [M+H]+.

[0350] Step 5: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-e?]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate.

[0351] To a mixture of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg, 0.76 mmol) in dioxanc\H2O (20\2 mL) was added 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (450 mg, 1.52mmol), Pd(dppf)C12 (55 mg, 0.076 mmol) and Na2CO3 (161 mg, 1.52 mmol). The resulting mixture was stirred at 90 °C for 12 hs under nitrogen atmosphere and concentrated, and the residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in EtOAc) to give 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-e / ]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 90% yield) as a white solid. LCMS: m / z. 570.2 [M+H]+.

[0352] Step 6: Synthesis of 3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-( / ]pyrimidin-4-amine.

[0353] To a mixture of 4-((lr,4r)-4-(4-amino-3-(4-phcnoxyphcnyl)-lH-pyrazolo[3,4-<7]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 0.68 mmol) in DCM (10 mL) was added HCl\dioxane (5 mL). The resulting mixture was stirred at room temperature overnight and diluted with DCM (40 mL). The organic phase was washed with saturated sodium hydrogen carbonate solution, brine, dried over anhydrous NaaSCU, filtered and concentrated to give 3-(4-phenoxyphenyl)-l-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-6?]pyrimidin-4-amine (270 mg, 85% yield) as a white solid, which was used directly for the next step. LCMS: m / z 470.2 [M+H]+.

[0354] Step 7: Synthesis of 5-(2-(4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20).

[0355] To a solution of 5-(2-bromoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (81 mg, 0.21 mmol), 3-(4-phenoxyphenyl)-l-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.21 mmol) in 2 mL of acetonitrile was added K2CO3 (88 mg, 0.64 mmol). The resulting mixture was stirred at 50°C overnight and concentrated. The residue was purified by silica gel column (0-15% MeOH / CHaCL) to give 25 mg of 5-(2-(4((1 r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)cyclohexyl)piperazin-l-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20) as white solid (21% yield). LCMS: m / z 770.0 [M+H]+. ’H NMR (400 MHz, DMSO-tfe) 6 11.12 (s, 1H), 8.23 (s, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.53 - 7.29 (m, 4H), 7.22 - 6.95 (m, 5H), 5.29 - 4.98 (m, 1H), 4.78 - 4.46 (m, 1H), 4.44 - 4.10 (m, 2H), 3.03 - 2.83 (m, 1H), 2.82 - 2.54 (m, 10H), 2.43 - 2.25 (m, 3H), 2.16 - 1.78 (m, 7H), 1.60 - 1.33 (m, 2H). Example 7: Synthesis 5-(3-(4-(( 1 r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-H3-pyrazolo[3,4- d]pyrimidin-l -yl )cyclohexyl )piperazin-l -yl )propoxy)-2-( 2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Compound 21)

[0092] Compound (21) was synthesized according the scheme below.

[0356] Step 1: Synthesis of 5-(3-bromopropoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione. O 0

[0357] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (137 mg, 0.50 mmol), 3-bromopropan-1 -ol (70 mg, 0.50 mmol) and PPh; (197 mg, 0.75 mmol) in THF (2 mL) was added dropwise DIAD (152 mg, 0.75 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 6 hs and concentrated, the residue was purified by silica gel chromatography (20-40% EtOAc / petroleum ether) to give 150 mg of 5-(3-bromopropoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as yellow solid (76% yield). LCMS: m / z 396.9 [M+H]+.

[0358] Step 2: Synthesis of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-17 / -pyrazolo[3,4-(Z]pyrimidin-4-amine. I

[0359] To a suspension of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (2.6 g, 10 mmol), l,4-dioxaspiro[4.5]decan-8-ol (3.2 g, 20 mmol) and PPh; (3.9 g, 15 mmol) in THF (30 mL) was added dropwise DIAD (4.04 g, 20 mmol) over a period of 30 min at 0 °C. The reaction was stirred at room temperature for 12 hs under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was pulped with EtOAc (30 mL x 3), and the precipitate was dried in vacuo to give 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-( / ]pyrimidin-4-amine (2.8 g, 70%) as a white solid. LCMS: m / z 402.0 [M+H]+.

[0360] Step 3: Synthesis of 4-(4-amino-3-iodo-17 / -pyrazolo[3,4-t / ]pyrimidin-l-yl)cyclohexan-1-one.

[0361] To a suspension of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4- ( / ]pyrimidin-4-amine (2.8 g, 6.9 mmol) in THF (10 mL) was added HC1 (6N, 3 mL). The reaction was stirred at 60 °C for 2 hs, and diluted with water. The aqueous phase was neutralized with saturated sodium carbonate solution to pH=6-8, the precipitate was formed. The precipitate was filtered and dried in vacuo to give 4-(4-amino-3-iodo-l / / -pyrazolo|3,4-d|pyrimidin-l-yl)cyclohexan-l-one (2 g, 83% yield) as a white solid, which was used directly for the next step. LCMS: m / z 358.0 [M+H]+.

[0362] Step 4: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-1-carboxylate. I

[0363] To a mixture of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexan-l-one (1.8 g, 5.05 mmol) in DCM (20 mL) was added tert-butyl piperazine-1-carboxylate (1.87 g, 10.11 mmol) and CH3COOH (150 mg, 2.5 mmol). The resulting mixture was stirred at room temperature for 6 hs, and then NaHB(OAc)3 (2.14 g, 10.11 mmol) was added. The mixture was stirred at 50 °C overnight, and diluted with DCM (80 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-10% DCM\MeOH=10:l in DCM) to give tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin- l-yl)cyclohexyl)piperazine- 1-carboxylate (400 mg) as a white solid. LCMS: m / z 528.0 [M+H]+.

[0364] Step 5: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-1-carboxylate.

[0365] To a mixture of tert-butyl 4-((1 r,4r)-4-(4-amino-3-iodo- l / / -pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-1-carboxylate (400 mg, 0.76 mmol) in dioxaneXHiO (20\2 mL) was added 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (450 mg, 1.52mmol), Pd(dppf)CL (55 mg, 0.076 mmol) and NaaCOs (161 mg, 1.52 mmol). The resulting mixture was stirred at 90 °C for 12 hs under nitrogen atmosphere and concentrated, and the residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in EtOAc) to give 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-t / ]pyrimidin-1 -yl)cyclohexyl)piperazine-1 -carboxylate (390 mg, 90% yield) as a white solid. LCMS: m / z 570.2 [M+H]+.

[0366] Step 6: Synthesis of 3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-t / ]pyrimidin-4-amine.

[0367] To a mixture of 4-((h',4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 0.68 mmol) in DCM (10 mL) was added HCl\dioxane (5 mL). The resulting mixture was stirred at room temperature overnight and diluted with DCM (40 mL). The organic phase was washed with saturated sodium hydrogen carbonate solution, brine, dried over anhydrous NaaSCU, filtered and concentrated to give 3-(4-phenoxypheny 1)-1-(( lr,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-<7]pyrimidin-4-amine (270 mg, 85% yield) as a white solid, which was used directly for the next step. LCMS: m / z 470.2 [M+H]+.

[0368] Step 7: Synthesis of   5-(3-(4-((1 / -,4 / ')-4-(4-amino-3-(4-phenoxyphenyl)-l / / - pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21).

[0369] To a solution of 5-(3-bromopropoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (40 mg, 0.10 mmol), 3-(4-phenoxyphenyl)-l-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (48 mg, 0.10 mmol) in 2 mL of acetonitrile was added K2CO3 (42 mg, 0.30 mmol). The resulting mixture was stirred at 50°C overnight and concentrated. The residue was purified by silica gel column (0-15% MeOH / CHoCh) to give 17 mg of 5-(3-(4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-177-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-1-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21) as yellow solid (21% yield). LCMS: m / z 392.6 [M / 2+H]+. JH NMR (400 MHz, DMSO-< / 6) 8 8.23 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.44 (t, J = 7.9 Hz, 2H), 7.27 - 7.04 (m, 8H), 5.29 - 5.06 (m, 1H), 4.81 - 4.51 (m, 1H), 3.78 - 3.59 (m, 2H), 3.04 - 2.87 (m, 1H), 2.83 -2.63 (m, 2H), 2.50 - 2.18 (m, 5H), 2.16 - 1.84 (m, 9H), 1.69 - 1.40 (m, 5H), 1.37-1.13 (m, 3H). Example 8: Synthesis of 4-(3-((4-((1 r,4r)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1 -f][l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l ,3-dione (Compound26) and 4-(3-((4-((Is,4s)-4-(4-amino-5-(4-phenoxyphenyl )pyrrolo[2,1 -f][l,2,4 ] triazin-7-yl)cyclohexyl )piperazin-l -yl )methyl )azetidin-l -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Compound 27).

[0370] Compounds (26 and 27) were synthesized according to the scheme below.

[0371] Step 1: Synthesis of 7-bromo-5-iodopyrrolo[2,l- / ][l,2,4]triazin-4-amine. Br

[0372] To a solution of 7-bromopyiTolo[2,l- / ][l,2,4]triazin-4-amine (4 g, 18.79 mmol) in DMF (50 mL) was added NIS (4.65 g, 20.67 mmol), the resulting mixture was stirred at room temperature for 16 h in the dark. The mixture was diluted with water (200 mL), and the precipitate was formed and filtered. The filter cake was triturated with DCM to give 7-bromo-5-iodopyrrolo[2,l- / ][l,2,4]triazin-4-amine (5 g, yield 79%) as a white solid. LCMS: m / z 393.2 [M+H]+.

[0373] Step 2: Synthesis of 7-bromo-5-(4-phenoxyphenyl)pyrrolo[2,!- / ][!,2,4]triazin-4-

[0374] To a solution of 7-bromo-5-iodopyrrolo[2,l- / ][l,2,4]triazin-4-amine (5 g, 23.5 mol) in l,4-dioxane / water(4 / l, 100 mL) was added 4-Phenoxyphenyl boric acid (5.5 g, 25.8 mmol), Pd(dppf)C12 (1.7 g, 2.35 mmol) and K2CO3 (9.7 g, 70.4 mmol). The resulting mixture was stirred at 100 °C for 5hs under nitrogen atmosphere, and then diluted with H2O (50 mL). The aqueous phase was extracted with EtOAc (100 ml*2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (eluting with DCM / MeOH = 50 / 1-15 / 1) to give 7-bromo-5-(4-phenoxyphenyl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (3.2 g, yield 36%) as brown solid. LCMS: m / z 381.3 [M+H]+.

[0375] Step 3: Synthesis of 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]dec-7-en-8- yl)pyrrolo[2,1- / ] [1,2,4]triazin-4-amine.

[0376] A mixture of 7-bromo-5-(4-phenoxyphenyl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (700 mg, 1.84 mmol), 4,4,5,5-tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (490 mg, 1.84 mmol), Pd(ddppf)C12 (135 mg, 0.184 mmol) and K2CO3 (508 mg,53.68 mmol) in l,4-dioxane / water(4 / l, 10 mL). The resulting mixture was stirrred at 100 °C for 2 hs under nitrogen atmosphere, and then concentrated. The residue was purified by flash chromatography (eluting with 0-50% EtOAc in Petroleum ether) to give 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine (600 mg, 74% yield)as a white solid. LCMS: m / z 441.0 [M+H]+.

[0377] Step 4: Synthesis of 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,I - / ] [ 1,2,4]triazin-4-amine.

[0378] To a solution of 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine (1.3 g, 2.95 mmol) in EtOAc (20 mL) was added Pd / C (350 mg). The resulting mixture was stirred at room temperature for 12 hs under hydrogen atmospere, and then filtered, the filtrate was concentrated to give 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,l- / |[L2,4]triazin-4-amine (920 mg, 70% yield) as a yellow oil, which was used directly for the next step. LCMS: m / z 443.2 [M+H]+.

[0379] Step 5: Synthesis of 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / ][l,2,4]triazin-7-yl)cyclohexan-1 -one.

[0380] To a suspension of 5-(4-phcnoxyphcnyl)-7-(l,4-dioxaspiro[4.5]dccan-8-yl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (920 mg, 2.08 mmol) in THF (10 mL) was added HC1 (6N, 3 mL). The reaction was stirred at 60 °C for 2 hs, and diluted with water. The aqueous phase was neutralized with saturated sodium carbonate solution to pH-6-8., the precipitate was formed. The precipitate was filtered and dried in vacuo to give 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / |[l,2,4]triazin-7-yl)cyclohexan-l-one (750 mg, 90% yield) as a white solid, which was used directly for the next step. LCMS: m / z 399.2 [M+H]+.

[0381] Step 6: Synthesis of cL-terZ-butyl 4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l-f\[ 1,2,4]triazin-7-yl)cyclohexyl)piperazine-1 -carboxylate and trans-fert-butyl 4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2, 1- / ] [ 1,2,4] triazin-7-yl)cy clohexy l)piperazine-1-carboxylate.

[0382] To a solution of 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / ][l,2,4]triazin-7-yl)cyclohexan-l-one (750 mg, 1.97 mmol) and / er / -butyl piperazine-1-carboxylate (350 mg, 1.97 mmol) in DCE (15 mL) was added CH3COOH (2 drops). The resulting mixture was stirred at room temperature for 0.5 h, and then added NaHB(OAc)3 (1.2 g, 5.91 mmol). The resulting mixture was stirred at 40 °C for 16 hs, and then quenched with water (40 mL). The aqueous phase was extracted with DCM (3 x 50 mL), the combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC (30%-60%ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give trans-tert-butyl 4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo [2,1 - / ] [ 1,2,4]triazin-7-yl)cyclohexyl)piperazine-1 -carboxylate (90 mg) and cA-tert-butyl 4-((15,45)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / ][l,2,4]triazin-7-yl)cyclohexyl)piperazine-1-carboxylate (100 mg) as a white solid. LCMS: m / z 573.4 [M+H]+.

[0383] Step 7: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-1,3-dione.

[0384] To a suspension of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (200 mg, 0.72 mmol) in DMF(5 mL) was added azetidin-3-ylmethanol (133 mg, 1.08 mmol) and DIPEA (279 mg, 2.16 mmol). The reaction was stirred at 100°C overnight and diluted with water (10 mL), the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in DCM) to give 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-1,3-dione (150 mg, 61% yield) as a yellow solid. LCMS: m / z 344.1 [M+H]+.

[0385] Step 8: Synthesis of   1 -(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)azetidine-3-carbaldehyde. O H

[0386] To a mixture of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hy droxymethyl)azetidin-1-yl)isoindoline-1,3-dione (100 mg, 0.29mmol) in DCM (10 mL) was added Dess-Martin reagent (247 mg, 0.58 mmol) at 0°C. The resulting mixture w'as stirred at room temperature for 3 hours and quenched with a solution of NaiSiOa: NaHCOs-l: l(5mL). The aqueous phase was extracted with DCM. and the organic phase was washed with brine, dried over anhydrous NaiSCL, and concentrated to give 1 -(2-(2,6-dioxopipcridin-3-yl)-1,3-dioxoisoindolin-4-yl)azctidinc-3-carbaldehyde (100 mg, 67%) as a yellow solid. LCMS: m / z 342.0 [M+H]+.

[0387] Step 9:     Synthesis of Zrans'-5-(4-phenoxyphenyl)-7-(4-(piperazin-l- yl)cyclohexyl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine.

[0388] To a solution of trans-tert-butyl 4-(4-(4-amino-5-(4-phcnoxyphcnyl)pyrrolo[2,l- / ][ 1,2,4] triazin-7-yl)cyclohexyl)piperazine-l-carboxy late (60 mg, 0.11 mmol) in DCM (3 mL )was added TFA (1 mL). The resulting mixture was stirred at room temperature for 12 hs. The resulting mixture was concentrated to give trans-5-(4-phenoxyphenyl)-7-(4-(piperazin-l-yl)cyclohexyl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine (40 mg, 81% yield) as a yellow oil, which was used directly for the next step. LCMS: m / z 469.2 [M+H]+.

[0389] Step 10: Synthesis of / raz7.y-4-(3-((4-(4-amino-5-(4-phcnoxyphcnyl / )pyiTolo|2,l- / ][l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (26).

[0390] To a mixture of rra«5-5-(4-phenoxyphenyl)-7-(4-(piperazin-l-yl)cyclohexyl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (50 mg, 0.11 mmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)azetidine-3-carbaldehyde (55 mg, 0.15 mmol) in DCM (5 mL) was added Et3N (30 mg, 0.33 mmol). The mixture was stirred at room temperature for 0.5 h, and then NaBH(OAc)3 (45 mg, 0.21 mmol) was added, and the mixture was stirred at the room temperature overnight. The reaction mixture was diluted with H2O (20 ml), and the aqueous phase was extracted with DCM (20 ml X 3). The organic phases was washed with brine (20 ml), dried over anhydrous Na2SO4, concentrated, and the residue was purified by Prep-HPLC (ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give Zraz75-4-(3-((4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1 -f\ [ 1,2,4]triazin-7-yl)cyclohexyl)piperazin-1 -yl)methyl)azetidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (36 mg, 42% yield) as a yellow solid. LCMS: m / z 794.1 [M+H]+.jH NMR (400 MHz, DMSO-t / 6) 8 11.05 (s, 1H), 7.88 (s, 1H), 7.57 - 7.52 (m, 1H), 7.51 -7.38 (m, 5H), 7.20 - 7.14 (m, 1H), 7.13-7.05 (m, 5H), 6.77 (d, J= 8.4 Hz, 1H), 6.54 (s, 1H), 5.03 (dd, J= 12.8, 5.6 Hz, 1H), 4.27 (s, 2H), 3.81 (s, 2H), 2.92 - 2.80 (m, 2H), 2.69 - 2.53 (m, 4H), 2.46 - 2.26 (m, 7H), 2.24 - 2.11 (m, 2H), 2.03 - 1.84 (m, 6H), 1.79 - 1.72 (m, 2H), 1.60 -1.53 (m, 2H).

[0391] Step 11: Synthesis of cz5-5-(4-phenoxyphenyl)-7-((15,4v)-4-(piperazin-l-yl)cyclohexyl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine.

[0392] To a solution of cis-tert-buty\ 4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1- / |[ 1,2,4]triazin-7-yl)cyclohexyl)piperazine-l-carboxylate (90 mg, 0.16 mmol) in DCM (3 mL )was added TFA (1 mL). The resulting mixture was stirred at room temperature for 12 hs. The resulting mixture was concentrated to give cA-5-(4-phcnoxyphcnyl)-7-(4-(pipcrazin-l-yl)cyclohexyl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine (60 mg, 81% yield) as a yellow oil, which was used directly for the next step. LCMS: m / z 469.3 [M+H]+.

[0393] Step 12: Synthesis of cL-4-(3-((4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / |[l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (27).

[0394] To a mixture of czs-5-(4-phenoxyphenyl)-7-(4-(piperazin-l-yl)cyclohexyl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (70 mg, 0.15 mmol) and  1 -(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)azetidine-3-carbaldehyde (76 mg, 0.23 mmol) in DCM (5 mL) was added Et3N (45 mg, 0.45 mmol). The mixture was stirred at room temperature for 0.5 h, and then NaBH(OAc)3 (62 mg, 0.29 mmol) was added, and the mixture was stirred at the room temperature overnight. The reaction mixture was diluted with H2O (20 ml), and the aqueous phase was extracted with DCM (20 ml X 3). The organic phases was washed with brine (20 ml), dried over anhydrous NaiSCL, concentrated, and the residue was purified by Prep-HPLC (30%-70% ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give cA-4-(3-((4-(4-amino-5-(4-- 148- phenoxypheny l)pyrrolo [ 2,1 - / ] [ 1,2,4] triazin-7-yl)cy clohexyl)piperazin-1 -yl)methyl)azetidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (16 mg, 14% yield) as a yellow solid. LCMS: m / z 794.1 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 5 11.05 (s, 1H), 7.88 (s, 1H), 7.57 - 7.52 (m, 1H), 7.51 - 7.38 (m, 5H), 7.20 - 7.14 (m, 1H), 7.13- 7.05 (m, 5H), 6.77 (d, J = 8.5 Hz, 1H), 6.54 (s, 1H), 5.03 (dd, J = 12.7, 5.5 Hz, 1H), 4.27 (s, 2H), 3.81 (s, 2H), 2.92 - 2.80 (m, 2H), 2.69 - 2.53 (m, 4H), 2.46-2.26 (m, 7H), 2.24-2.11 (m, 2H), 2.03- 1.84 (m, 6H), 1.79- 1.72 (m, 2H), 1.60 - 1.53 (m, 2H). Example 9: Synthesis of 5-(3-((4-((lr,4r)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- f][ 1,2,4] triazin-7-y I)cyclohexyl)piperazin-l -yl)methyl)azetidin-l -yl)-2-( 2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Compound 28) and 5-(3-((4-((ls,4s)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[ 2,1 -f][ 1,2,4 ] triazin-7-yl)cyclohexyl )piperazin-l -yl)methyl)azetidin-l -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Compound 29).

[0395] Compounds (28 and 29) were synthesized according to the scheme below.

[0396] Step 1: Synthesis of 7-bromo-5-iodopyrrolo[2,l- / |[l,2,4]triazin-4-amine. nh2 । MY Br

[0397] To a solution of 7-bromopyrrolo[2,l- / ][l,2,4]triazin-4-amine (4 g, 18.79 mmol) in DMF (50 mL) was added NIS (4.65 g, 20.67 mmol), the resulting mixture was stirred at room temperature for 16 h in the dark. The mixture was diluted with water (200 mL), and the precipitate was formed and filtered. The filter cake was triturated with DCM to give 7-bromo-5-iodopyrrolo[2,l- / ][l,2,4]triazin-4-amine (5 g, yield 79%) as a white solid. LCMS: m / z 393.2 [M+H]+.

[0398] Step 2: Synthesis of 7-bromo-5-(4-phenoxyphenyl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine. Q o A nh2 n^M\ ,n-< n \ Br

[0399] To a solution of 7-bromo-5-iodopyrrolo[2,l- / ][l,2,4]triazin-4-amine (5 g, 23.5 mol) in l,4-dioxane / water(4 / l, 100 mL) was added 4-Phenoxyphenyl boric acid (5.5 g, 25.8 mmol), Pd(dppf)C12 (1.7 g, 2.35 mmol) and K2CO3 (9.7 g, 70.4 mmol). The resulting mixture was stirred at 100 °C for 5hs under nitrogen atmosphere, and then diluted with H2O (50 mL). The aqueous phase was extracted with EtOAc (100 ml*2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (eluting with DCM / MeOH = 50 / 1-15 / 1) to give 7-bromo-5-(4-phenoxyphenyl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (3.2 g, yield 36%) as brown solid. LCMS: m / z 381.3 [M+H]+.

[0400] Step 3: Synthesis of 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,l- / ][l,2,4]triazin-4-aminc.

[0401] A mixture of 7-bromo-5-(4-phenoxyphenyl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (700 mg, 1.84 mmol), 4,4,5,5-tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (490 mg, 1.84 mmol), Pd(ddppf)Ch (135 mg, 0.184 mmol) and K2CO3 (508 mg,53.68 mmol) in l,4-dioxane / water(4 / l, 10 mL). The resulting mixture was stirrred at 100 °C for 2 hs under nitrogen atmosphere, and then concentrated. The residue was purified by flash chromatography (eluting with 0-50% EtOAc in Petroleum ether) to give 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine (600 mg, 74% yield)as a white solid. LCMS: m / z 441.0 [M+H]+.

[0402] Step 4: Synthesis of 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1- / ] [1,2,4]triazin-4-amine.

[0403] To a solution of 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (1.3 g, 2.95 mmol) in EtOAc (20mL) was added Pd / C (350 mg). The resulting mixture was stirred at room temperature for 12 hs under hydrogen atmospere, and then filtered, the filtrate was concentrated to give 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine (920 mg, 70% yield) as a yellow oil, which was used directly for the next step. LCMS: m / z 443.2 [M+H]+.

[0404] Step 5: Synthesis of 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / ][l,2,4]triazin-7-yl)cyclohexan-1 -one.

[0405] To a suspension of 5-(4-phcnoxyphcnyl)-7-(l,4-dioxaspiro[4.5]dccan-8-yl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (920 mg, 2.08 mmol) in THF (10 mL) was added HC1 (6N, 3 mL). The reaction was stirred at 60 °C for 2 hs, and diluted with water. The aqueous phase was neutralized with saturated sodium carbonate solution to pH-6-8., the precipitate was formed. The precipitate was filtered and dried in vacuo to give 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / |[l,2,4]triazin-7-yl)cyclohexan-l-one (750 mg, 90% yield) as a white solid, which was used directly for the next step. LCMS: m / z 399.2 [M+H]+.

[0406] Step 6: Synthesis of cL-terZ-butyl 4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l-f\[ 1,2,4]triazin-7-yl)cyclohexyl)piperazine-1 -carboxylate and trans-fert-butyl 4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2, 1- / ] [ 1,2,4] triazin-7-yl)cy clohexy l)piperazine-1-carboxylate.

[0407] To a solution of 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / ][l,2,4]triazin-7-yl)cyclohexan-l-one (750 mg, 1.97 mmol) and / er / -butyl piperazine-1-carboxylate (350 mg, 1.97 mmol) in DCE (15 mL) was added CH3COOH (2 drops). The resulting mixture was stirred at room temperature for 0.5 h, and then added NaHB(OAc)3 (1.2 g, 5.91 mmol). The resulting mixture was stirred at 40 °C for 16 hs, and then quenched with water (40 mL). The aqueous phase was extracted with DCM (3 x 50 mL), the combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC (30%-60%ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give trans-tert-butyl 4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo [2,1 - / ] [ 1,2,4]triazin-7-yl)cyclohexyl)piperazine-1 -carboxylate (90 mg) and cA-tert-butyl 4-((15,45)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / ][l,2,4]triazin-7-yl)cyclohexyl)piperazine-1-carboxylate (100 mg) as a white solid. LCMS: m / z 573.4 [M+H]+.

[0408] Step 7: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-1,3-dione.

[0409] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (400 mg, 1.45 mmol), azetidin-3-ylmethanol (189 mg, 2.17 mmol) and DIPEA (461 mg, 4.35 mmol) in DMF (4 ml) was stirred at 100 °C for 16 hs. After cooling to room temperature, the mixture was diluted with H2O (20 ml), and the aqueous phase was extracted with EtOAc ( 20 ml X 3). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column (0-15% MeOH / CH2Ch) to give 240 mg of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-1,3-dione as yellow solid (48% yield). LCMS: m / z 344.1 [M+H]+.

[0410] Step 8: Synthesis of   1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)azetidine-3-carbaldehyde.

[0411] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione (240 mg, 0.70 mmol), Dess-Martin reagent (593 mg, 1.40 mmol) in DCM (5 ml) was stirred at 0°C for 2 hs. The mixture was quenched with a solution of NaHCOs and NaiSsOs. The aqueous phase was extracted with DCM, and the organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give 600 mg of 1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde as yellow solid (100% yield), which was used directly for the next step. LCMS: m / z 342.1 [M+H]+.

[0412] Step 9:     Synthesis of traz?5-5-(4-phenoxyphenyl)-7-(4-(piperazin-l- yl)cyclohexyl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine.

[0413] To a solution of trans-tert-butyl 4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / ][ 1,2,4]triazin-7-yl)cyclohexyl)piperazine-l-carboxy late (60 mg, 0.11 mmol) in DCM (3 mL )was added TFA (1 mL). The resulting mixture was stirred at room temperature for 12 hs. The resulting mixture was concentrated to give trans-5-(4-phenoxyphenyl)-7-(4-(piperazin-l-yl)cyclohexyl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (40 mg, 81% yield) as a yellow oil, which was used directly for the next step. LCMS: m / z 469.2 [M+H]+.

[0414] Step 10: Synthesis of zrans-5-(3-(4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / ][l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0415] To a mixture of rra«s-5-(4-phenoxyphenyl)-7-(4-(piperazin-l-yl)cyclohexyl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (40 mg, 0.08 mmol) and 1-(2-(2,6-dioxopipcridin-3-yl)-l,3-dioxoisoindolin-4-yl)azctidinc-3-carbaldchydc (29 mg, 0.08 mmol) in DCM (5 mL) was added Et3N (24 mg, 0.24 mmol). The mixture was stirred at room temperature for 0.5 h, and then NaBH(OAc)s (36 mg, 0.16 mmol) was added, and the mixture was stirred at the room temperature overnight. The reaction mixture was diluted with H2O (20 ml), and the aqueous phase was extracted with DCM (20 ml X 3). The organic phases was washed with brine (20 ml), dried over anhydrous Na2SO4, concentrated, and the residue was purified by Prep-HPLC (30%-70% ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give trans-5-(3-(4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / |[l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (24 mg, 36% yield) as a yellow solid. LCMS: m / z 794.8 [M+Hf.jH NMR (400 MHz, DMSO-de) 8 11.07 (s, 1H), 7.89 (s, 1H), 7.63 (d, J= 8.3 Hz, 1H), 7.46 - 7.41 (m, 5H), 7.18 (d, J= 7.4 Hz, 1H), 7.10 (t, J= 8.3 Hz, 5H), 6.77 (d, J= 1.9 Hz, 1H), 6.64 (dd, J= 8.4, 1.9 Hz, 1H), 6.50 (s, 1H), 5.05 (dd, J= 12.9, 5.4 Hz, 1H), 4.12 (t, J= 8.1 Hz, 2H), 3.72 - 3.62 (m, 2H), 2.98-2.75 (m, 4H), 2.57-2.51 (m, 5H), 2.44 - 2.28 (m, 5H), 2.17-1.88 (m, 6H), 1.55 - 1.38 (m, 5H).

[0416] Step 11: Synthesis of cz3-5-(4-phenoxyphenyl)-7-((15,4v)-4-(piperazin-l-yl)cyclohexyl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine.

[0417] To a solution of czs-terZ-butyl 4-(4-(4-amino-5-(4-phenoxyphenyl)pyiTolo[2,l- / ][ 1,2,4]triazin-7-yl)cyclohexyl)piperazine-l -carboxylate (90 mg, 0.16 mmol) in DCM (3 mL )was added TFA (1 mL). The resulting mixture was stirred at room temperature for 12 hs. The resulting mixture was concentrated to give cA-5-(4-phenoxyphenyl)-7-(4-(piperazin-l-yl)cyclohexyl)pyrrolo[2,l- / |[l,2,4]triazin-4-amine (60 mg, 81% yield) as a yellow oil, which was used directly for the next step. LCMS: m / z 469.3 [M+H]+.

[0418] Step 12: Synthesis of czs-5-(3-((4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,l- / |[l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. Compound 29

[0419] To a mixture of czs-5-(4-phenoxyphenyl)-7-(4-(piperazin-l-yl)cyclohexyl)pyrrolo[2,l- / ][l,2,4]triazin-4-amine (60 mg, 0.13 mmol) and 1 -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidine-3-carbaldehyde (44 mg, 0.13 mmol) in DCM (5 mL) was added Et3N (39 mg, 0.45 mmol). The mixture was stirred at room temperature for 0.5 h, and then NaBH(OAc)3 (54 mg, 0.26 mmol) was added, and the mixture was stirred at the room temperature overnight. The reaction mixture was diluted with H2O (20 ml), and the aqueous phase was extracted with DCM (20 ml X 3). The organic phases was washed with brine (20 ml), dried over anhydrous Na2SCL, concentrated, and the residue was purified by Prep-HPLC (30%-70% ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give czs-5-(3-((4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1 - / ] 11,2,4]triazin-7-yl)cyclohexyl)piperazin-1 -yl)methyl)azetidin-1 - yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (44 mg, 43% yield) as a yellow solid. LCMS: m / z 794.8 [M+Hf.jH NMR (400 MHz, DMSO-J6) 8 11.07 (s, 1H), 7.89 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.46-7.41 (m, 5H), 7.18 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 8.3 Hz, 5H), 6.77 (d, J= 1.9 Hz, 1H), 6.64 (dd, 7=8.4, 1.9 Hz, 1H), 6.50 (s, 1H), 5.05 (dd, J = 12.9,5.4 Hz, 1H), 4.12 (t, J = 8.1 Hz, 2H), 3.72 - 3.62 (m, 2H), 2.98-2.75 (m, 4H), 2.57-2.51 (m, 5H), 2.44-2.28 (m, 5H), 2.17 - 1.88 (m, 6H), 1.55 - 1.38 (m, 5H). Example 10: Synthesis of4-(3-((4-((lr,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l-f][l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l ,3-dione (Compound30) and 4-(3-((4-((ls,4s)-4-(4-amino-5-(4- phenoxyphenyl)imidazo[5,1 -f] [1,2,4]triazin-7-yl)cyclohexyl)piperazin-1 -yl)methyl)azetidin-l -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Compound 31)

[0420] Compounds 30 and 31 were synthesized according to the scheme below.

[0421] Step 1: Synthesis of ethyl 2-( 1,4-dioxaspiro[4.5]decan-8-yl)-1 H-imidazole-5- carboxylate.

[0422] To a solution of hydroxylamine hydrochloride (5.27 g, 76.3 mmol) in H2O (30 mL) was added NaHCO3 (8.55 g, 101.8mmol). A solution of l,4-dioxaspiro[4.5]dccanc-8-carbonitrilc (8.5 g, 50.9 mmol) in EtOH (100 mL) was added, the mixture was stirred at room temperature for 1 hour, and then stirred at 80 °C overnight. It was then cooled to room temperature and concentrated. The residue was added H2O (50 mL), and the aqueous phase was extracted with EtOAc (50 mL * 3), the combined organic phase was concentrated. The residue was dissolved - 157- with EtOH (150 mL.), and ethyl propiolate (6.87 g, 76.3 mmol) was added. The resulting mixture was refluxed for 5 hours and concentrated, the residue was added H2O (50 mL), and the aqueous phase was extracted with EtOAc (50 mL * 3), the combined organic phase was concentrated. The residue was dissolved with Ph2O (85 g), and the resulting solution was stirred at 200 °C under nitrogen atmosphere for 2 hours, and then cooled to room temperature. The resulting mixture was diluted with Petroleum ether (45 mL), the mixture was filtered. The black crude product was purified by flash chromatography (eluting with Petroleum ether / EtOAc =10 / 1-1 / 100) to give ethyl 2-(l,4-dioxaspiro[4.5]decan-8-yl)-17 / -imidazole-5-carboxylate as a yellow solid (6.55 g, yield 46%). LCMS: m / z 281.3 [M+H]+.

[0423] Step 2: Synthesis of 7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / ][l,2,4]triazin-4-ol.

[0424] To a solution of ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)-lH-imidazole-5-carboxylate as a yellow solid (2.8 g, 10 mmol) in DMF (50 mL) was added drop-wisely LiHMDS (10 mL, 10 mmol) at 0 °C under nitrogen atmosphere, and the resulting solution was stirred at room temperature for 2 hours, and then (aminooxy)diphenylphosphine oxide (2.33 g, 10 mmol) was added, and the precipitate was formed immediately. The mixture was stirred at room temperature overnight, and diluted with DCM (100 mL) and filtered, the filtrate was concentrated to give a red liquid, which was added EtOH (50 mL) and formimidamide acetate (10.4 g, 0.1 mol). The resulting mixture was stirred at 85 °C under nitrogen atmosphere for 18 hours, and then heated to 110 °C for 4 hours. The mixture was concentrated, and the residue was purified by reverse phase chromatography (eluting with ACN and H2O with 0.05% NH4HCO3 as mobile phase, 0-50%) to give 7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / |[l,2,4]triazin-4-ol as a pale solid (2.0 g, yield 72%). LCMS: m / z 277.2 [M+H]+.

[0425] Step 3: Synthesis of 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / ] [ 1,2,4]triazin-4-ol.

[0426] To a solution of 7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / |[l,2,4]triazin-4-ol (2.0 g, 7.25 mmol) in DMF (20 mL) was added NBS (1.54 g, 8,70 mmol) portion wise, and the resulting solution was stirred at room temperature overnight. The precipitate was formed, and the mixture was diluted with water (50 mL), the precipitate was filtered and dried to give 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / |[l,2,4]triazin-4-ol as a white solid, which was used directly for the next step. (1.8 g, yield 70%). LCMS: m / z 355.0 [M+H]+.

[0427] Step 4: Synthesis of 5-bromo-7-(l,4-dioxaspiro[4.5]dccan-8-yl)-4-(lH-l,2,4-triazol-l-yl)imidazo[5,1 -f] [ 1,2,4] triazine.

[0428] To an ice bath cooled suspension of 1,2,4-triazole (6.04 g, 87.6 mmol) in anhydrous ACN (80 mL) was added POCh (3.99 g, 26.3 mmol) dropwise. Then EtsN (10.6 g, 1.05 mol) and 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / |[l,2,4]triazin-4-ol (3.1 g, 8.76 mmol) was added at room temperature. The reaction was stirred at room temperature for 18 hours and concentrated to give 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)-4-(l / / -l,2,4-triazol-l-yl)imidazo [5,1- / [1,2,4] triazine as a pale solid, which was used directly for the next step. (25 g, crude). LCMS: m / z 406.0 [M+H]+.

[0429] Step 5: Synthesis of 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / [1,2,4]triazin-4-amine.

[0430] A suspension of 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)-4-(17 / -l,2,4-triazol-l-yl)imidazo [5,1- / ] [1,2,4] triazine (25 g, crude) in NH3 (7N in MeOH, 30 mL) was stirred at 80 °C for 1 hours, then stirred at room temperature overnight, and filtered. The filter cake was washed with water (8 mL *3), and dried in vacuo to give 5-bromo-7-(l,4-dioxaspiro[4.5]dccan-8-yl)imidazo[5,l- / ][l,2,4]triazin-4-amine as a pale solid, which was used directly for the next step. (2.17 g, yield 70% of 2 steps). LCMS: m / z 354.1 [M+H]+.

[0431] Step 6: Synthesis of 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo [5,1 - / ] [ 1,2,4] triazin-4-amine.

[0432] To a mixture of 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / ][l,2,4]triazin-4-amine (2.30 g, 6.52 mmol), 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (1.67 g, 7.82 mmol) and Na2CO3 (1.38 g, 13.0mmol)in l,4-dioxane / H2O(10mL / 2 mL) was added Pd(dppf)C12 (477 mg, 0.65 mmol), and the mixture was stirred at 95°C under nitrogen atmosphere for 8 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and EtOAc (30 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (40 mL * 2), the combined organic phase was concentrated, and the residue was purified by flash chromatography (eluting with Petroleum ether / EtOAc =10 / 1-1 / 10) to give - 160- 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan- 8-y l)imidazo[5,1 -f\[ 1,2,4]triazin-4-amine as a light yellow solid (1.81 g, yield 61%). LCMS: m / z 444.3 [M+H]+.

[0433] Step 7: Synthesis of 4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][l,2,4]triazin-7- yl)cyclohexan-1-one.

[0434] To a solution of 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / ][l,2,4]triazin-4-amine (1.5 g, 3.39 mmol) in THF (25 mL) was added HC1 (6N in water, 5 mL), and the solution was stirred at 50 °C under nitrogen atmosphere for 5 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and EtOAc (50 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (50 mL * 2), the combined organic phase was concentrated, give 4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][l,2,4]triazin-7-yl)cyclohexan-l-one as a light yellow solid (1.1 g, crude), which was used directly for the next step. LCMS: m / z 400.3 [M+H]+.

[0435] Step 8:      Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-5-(4- phenoxyphenyl)imidazo[5,1 - / ] [1,2,4] triazin-7-yl)cyclohexyl)piperazine-1 -carboxylate (P1) and tert-butyl              4-(( I,y,4.s)-4-(4-amino-5-(4-phcnoxyphcnyl)imidazo|5, L / ][ 1,2,4]triazin-7- yl)cyclohexyl)piperazine-l-carboxylate. O            0 Boc              Boc

[0436] To a mixture of 4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][l,2,4]triazin-7-yl)cyclohexan-l-one (1.1 g, 2.76 mmol) in DCM (25 mL) was added tert-butyl piperazine-1-carboxylate (615 mg, 3.31 mmol) and AcOH (3 drops). The resulting mixture was stirred at room temperature for 0.5 h, NaHB(OAc)a (1.17 g, 5.51 mmol) was added. Then the mixture was stirred at room temperature overnight and diluted with water (30 mL), and the aqueous phase was extracted with DCM (50 ml x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (eluting with ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give tertbutyl                 4-((lF,4r)-4-(4-amino-5-(4-phcnoxyphcnyl)imidazo[5,l- / ][l,2,4]triazin-7- yl)cyclohexyl)piperazine-l-carboxylate as a white solid (200 mg yield 11%), and tert-butyl 4-((15',45')-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,!- / ][!,2,4]triazin-7 -yl)cyclohexyl)piperazine-l-carboxylate (550 mg, yield 30%).

[0437] Step 9: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-1,3-dione.

[0438] To a suspension of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (200 mg, 0.72 mmol) in DMF(5 mL) was added azetidin-3-ylmethanol (133 mg, 1.08 mmol) and DIPEA - 162- (279 mg, 2.16 mmol). The reaction was stirred at 100°C overnight and diluted with water (10 mL), the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na^SOa, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in DCM) to give 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-1,3-dione (150 mg, 61% yield) as a yellow solid. LCMS: m / z 344.1 [M+H]+.

[0439] Step 10: Synthesis of   1 -(2-(2,6-dioxopiperidin-3-yl)-i,3-dioxoisoindolin-4- yl)azetidine-3-carbaldehyde.

[0440] To a mixture of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hy droxymethyl)azetidin-1-yl)isoindoline-1,3-dione (100 mg, 0.29mmol) in DCM (10 mL) was added Dess-Martin reagent (247 mg, 0.58 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours and quenched with a solution of NaiSiOj : NaHCOj=l: 1 (5mL). The aqueous phase was extracted with DCM, and the organic phase was washed with brine, dried over anhydrous NaiSO4, and concentrated to give 1 -(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)azetidine-3-carbaldehyde (100 mg, 67%) as a yellow solid. LCMS: m / z 342.0 [M+H]+.

[0441] Step 11: Synthesis of 5-(4-phenoxyphenyl)-7-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)imidazo[5,1- / | [ 1,2,4]triazin-4-amine.

[0442] To a mixture of tert-butyl 4-((lr,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][ 1,2,4]triazin-7-yl)cyclohexyl)piperazine-l-carboxy late (300 mg, 0.53 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 12 hours and concentrated. The residue was dissolved with DCM (50 mL), and the organic phase was washed with NaHCO3 (30 mL*3), brine (30 mL) and water (30 mL), dried with anhydrous Na2SO4, filtered and concentrated to give 5-(4-phenoxyphenyl)-7-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)imidazo[5,l- / |[l,2,4]triazin-4-amine as a white solid (203 mg, yield 82%), which was used directly for the next step. LCMS: m / z 470.4 [M+H]+.

[0443] Step 11: Synthesis of 4-(3-((4-((lr,4r)-4-(4-amino-5-(4-phcnoxyphcnyl)imidazo[5,l-f\[ 1,2,4] triazin-7-yl)cyclohexyl)piperazin-1 -yl)methyl)azetidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (30).

[0444] To a mixture of 5-(4-phenoxyphenyl)-7-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)imidazo[5,l- / ][l,2,4]triazin-4-amine (100 mg, 0.21 mmol) in DCE (20 mL) was added 1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)azetidine-3-carbaldehyde (72.7 mg, 0.21 mmol) and AcOH (2 drops). The resulting mixture was stirred at room temperature for 0.5 hour, and then NaHB(OAc)3 (90.3 mg, 0.43 mmol) was added. The mixture was stirred at 50 °C overnight, and diluted with DCM (50 mL), The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give 4-(3-((4-((lr,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (30.6 mg, yield 19%) as a white solid. LCMS: m / z 794.8 [M+H]+. NMR (500 MHz, DMSO DMSO-^6) 8 11.14 - 10.98 (m, 1H), 7.89 (s, 1H), 7.61 (d, J= 8.4 Hz, 2H), 7.58-7.52 (m, 1H), 7.42 (t, J= 8.0 Hz, 2H), 7.17 (1,7 = 7.2 Hz, 1H), 7.10 (t, J= 7.2 Hz, 5H), 6.78 (d, J= 8.4 Hz, 1H), 5.04 (dd, J= 12.8, 5.5 Hz, 1H), 4.28 (s, 2H), 3.82 (s, 2H), 3.15 (s, 1H), 2.89 (s, 2H), 2.65 - 2.53 (m, 7H), 2.36 (s, 6H), 2.04 (s, 2H), 1.99 (s, 1H), 1.91 (s, 2H), 1.75 - 1.61 (m, 2H), 1.45 - 1.31 (m, 2H).

[0445] Step 12: Synthesis of 5-(4-phenoxyphenyl)-7-((15,4v)-4-(piperazin-l-yl)cyclohexy l)imidazo [5,1 - / ] [ 1,2,4] triazin-4-amine. H

[0446] To a mixture of tert-butyl 4-((ls,4.s)-4-(4-amino-5-(4-phenoxyphenyl)iniidazo[5,l- / ][ 1,2,4]triazin-7-yl)cyclohexyl)piperazine-l-carboxy late (300 mg, 0.53 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 12 hours and concentrated. The residue was dissolved with DCM (50 mL), and the organic phase was washed with NaHCO3 (30 mL*3), brine (30 mL) and water (30 mL), dried with anhydrous Na2SO4, filtered and concentrated to give 5-(4-phenoxypheny 1)-7-(( Ir, 4r)-4-(piperazin-1-yl)cyclohexyl)imidazo[5,17 / ][l,2,4]triazin-4-amine as a white solid (223 mg, yield 90%), which was used directly for the next step. LCMS: m / z 470.4 [M+H]+.

[0447] Step 13: Synthesis of 4-(3-((4-((ls,4s)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (31).

[0448] To a mixture        of5-(4-phenoxyphenyl)-7-(( 1 / -,4r)-4-(piperazin-1 - yl)cyclohexyl)imidazo[5,l- / ][l,2,4]triazin-4-amine (100 mg, 0.21 mmol) in DCM (5 mL) was added 1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)azetidine-3-carbaldehyde (87 mg, 0.26 mmol) and AcOH (2 drops). The resulting mixture was stirred at room temperature for 0.5 h, NaHB(OAc)3 (90 mg, 0.43 mmol) was added. The mixture was stirred at room temperature overnight and diluted with water (10 mL), and the aqueous phase was extracted with DCM (20 ml x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (eluting with ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give 4-(3-((4-(( Is,4s)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1 - / ] [ 1,2,4] triazin-7-y l)cyclohexyl)piperazin-1 -yl)methy l)azetidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (45 mg, yield 27%). LCMS: m / z 795.3 [M+H]+. 'H NMR (500 MHz, DMSO-d6) 8 11.05 (s, 1H), 7.89 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.57 - 7.50 (m, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.21 - 7.07 (m, 6H), 6.77 (d, J = 8.5 Hz, 1H), 5.05 - 5.01 (m, 1H), 4.27 (s, 2H), 3.81 (s, 2H), 3.40 (s, 1H), 2.95 - 2.80 (m, 2H), 2.65 - 2.54 (m, 4H), 2.48 - 2.38 (m, 8H), 2.22 (s, 1H), 2.07 (d, J = 8.5 Hz, 2H), 2.02 - 1.91 (m, 3H), 1.69 (s, 2H), 1.58 (s, 2H). Example 11: Synthesis of5-(3-((4-((lr,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l-f][l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-- 166- yl)isoindoline-l ,3-dione (Compound 32) and 5-(3-((4-((lr,4r)-4-(4-amino-5-(4- phenoxyphenyl)imidazo[5,l-f][l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Compound 33).

[0449] Compounds 32 and 33 were synthesized according to the scheme below. NBS DMF, 0 °C-rt PdCI2(dppf), Na2CO3 1.4-Dioxane / H2O, 100 DC Step 1: Synthesis of ethyl 2-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-imidazole-5-

[0450] carboxylate.

[0451] To a solution of hydroxylamine hydrochloride (5.27 g, 76.3 mmol) in H2O (30 mL) was added NaHCO3 (8.55 g, 101.8mmol). A solution of l,4-dioxaspiro[4.5]decane-8-carbonitrile (8.5 g, 50.9 mmol) in EtOH (100 mL) was added, the mixture was stirred at room temperature for 1 hour, and then stirred at 80 °C overnight. It was then cooled to room temperature and concentrated. The residue was added H2O (50 mL), and the aqueous phase was extracted with EtOAc (50 mL * 3), the combined organic phase was concentrated. The residue was dissolved with EtOH (150 mL.), and ethyl propiolate (6.87 g, 76.3 mmol) was added. The resulting mixture was refluxed for 5 hours and concentrated, the residue was added H2O (50 mL), and the aqueous phase was extracted with EtOAc (50 mL * 3), the combined organic phase was concentrated. The residue was dissolved with Ph20 (85 g), and the resulting solution was stirred at 200 °C under nitrogen atmosphere for 2 hours, and then cooled to room temperature. The resulting mixture was diluted with Petroleum ether (45 mL), the mixture was filtered. The black crude product was purified by flash chromatography (eluting with Petroleum ether / EtOAc =10 / 1-1 / 100) to give ethyl 2-(l,4-dioxaspiro[4.5]decan-8-yl)-17 / -imidazole-5-carboxylate as a yellow solid (6.55 g, yield 46%). LCMS: m / z 281.3 [M+H]+.

[0452] Step 2: Synthesis of 7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / |[l,2,4]triazin-4-ol.

[0453] To a solution of ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)-lH-imidazole-5-carboxylate as a yellow solid (2.8 g, 10 mmol) in DMF (50 mL) was added drop-wisely LiHMDS (10 mL, 10 mmol) at 0 °C under nitrogen atmosphere, and the resulting solution was stirred at room temperature for 2 hours, and then (aminooxy)diphenylphosphine oxide (2.33 g, 10 mmol) was added, and the precipitate was formed immediately. The mixture was stirred at room temperature overnight, and diluted with DCM (100 mL) and filtered, the filtrate was concentrated to give a red liquid, which was added EtOH (50 mL) and formimidamide acetate (10.4 g, 0.1 mol). The resulting mixture was stirred at 85 °C under nitrogen atmosphere for 18 hours, and then heated to 110 °C for 4 hours. The mixture was concentrated, and the residue was purified by reverse phase chromatography (eluting with ACN and H2O with 0.05% NH4HCO3 as mobile phase, 0-50%) to give 7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / |[l,2,4]triazin-4-ol as a pale solid (2.0 g, yield 72%). LCMS: m / z 277.2 [M+H]+.

[0454] Step 3: Synthesis of 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l-f\[ 1,2,4]triazin-4-ol.

[0455] To a solution of 7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / |[l,2,4]triazin-4-ol (2.0 g, 7.25 mmol) in DMF (20 mL) was added NBS (1.54 g, 8,70 mmol) portion wise, and the resulting solution was stirred at room temperature overnight. The precipitate was formed, and the mixture was diluted with water (50 mL), the precipitate was filtered and dried to give 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / |[l,2,4]triazin-4-ol as a white solid, which was used directly for the next step. (1.8 g, yield 70%). LCMS: m / z 355.0 [M+H]+.

[0456] Step 4: Synthesis of 5-bromo-7-(l,4-dioxaspiro[4.5]dccan-8-yl)-4-(lH-l,2,4-triazol-l-yl)imidazo[5,1 -f] [ 1,2,4] triazine.

[0457] To an ice bath cooled suspension of 1,2,4-triazole (6.04 g, 87.6 mmol) in anhydrous ACN (80 mL) was added POCh (3.99 g, 26.3 mmol) dropwise. Then EtsN (10.6 g, 1.05 mol) and 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / |[l,2,4]triazin-4-ol (3.1 g, 8.76 mmol) was added at room temperature. The reaction was stirred at room temperature for 18 hours and concentrated to give 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)-4-(l / / -l,2,4-triazol-l-yl)imidazo [5,1- / [1,2,4] triazine as a pale solid, which was used directly for the next step. (25 g, crude). LCMS: m / z 406.0 [M+H]+.

[0458] Step 5: Synthesis of 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / [1,2,4]triazin-4-amine.

[0459] A suspension of 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)-4-(17 / -l,2,4-triazol-l-yl)imidazo [5,1- / ] [1,2,4] triazine (25 g, crude) in NH3 (7N in MeOH, 30 mL) was stirred at 80 °C for 1 hours, then stirred at room temperature overnight, and filtered. The filter cake was washed with water (8 mL *3), and dried in vacuo to give 5-bromo-7-(l,4-dioxaspiro[4.5]dccan-8-yl)imidazo[5,l- / ][l,2,4]triazin-4-amine as a pale solid, which was used directly for the next step. (2.17 g, yield 70% of 2 steps). LCMS: m / z 354.1 [M+H]+.

[0460] Step 6: Synthesis of 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo [5,1 - / ] [ 1,2,4] triazin-4-amine.

[0461] To a mixture of 5-bromo-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / ][l,2,4]triazin-4-amine (2.30 g, 6.52 mmol), 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (1.67 g, 7.82 mmol) and Na2CO3 (1.38 g, 13.0mmol)in l,4-dioxane / H2O(10mL / 2 mL) was added Pd(dppf)C12 (477 mg, 0.65 mmol), and the mixture was stirred at 95°C under nitrogen atmosphere for 8 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and EtOAc (30 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (40 mL * 2), the combined organic phase was concentrated, and the residue was purified by flash chromatography (eluting with Petroleum ether / EtOAc =10 / 1-1 / 10) to give - 170- 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan- 8-y l)imidazo[5,1 -f\[ 1,2,4]triazin-4-amine as a light yellow solid (1.81 g, yield 61%). LCMS: m / z 444.3 [M+H]+.

[0462] Step 7: Synthesis of 4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][l,2,4]triazin-7- yl)cyclohexan-1-one.

[0463] To a solution of 5-(4-phenoxyphenyl)-7-(l,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,l- / ][l,2,4]triazin-4-amine (1.5 g, 3.39 mmol) in THF (25 mL) was added HC1 (6N in water, 5 mL), and the solution was stirred at 50 °C under nitrogen atmosphere for 5 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and EtOAc (50 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (50 mL * 2), the combined organic phase was concentrated, give 4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][l,2,4]triazin-7-yl)cyclohexan-l-one as a light yellow solid (1.1 g, crude), which was used directly for the next step. LCMS: m / z 400.3 [M+H]+.

[0464] Step 8:      Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-5-(4- phenoxyphenyl)imidazo[5,1 - / ] [1,2,4] triazin-7-yl)cyclohexyl)piperazine-1 -carboxylate (P1) and tert-butyl              4-(( I,y,4.s)-4-(4-amino-5-(4-phcnoxyphcnyl)imidazo|5, L / ][ 1,2,4]triazin-7- yl)cyclohexyl)piperazine-l-carboxylate.

[0465] To a mixture of 4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][l,2,4]triazin-7-yl)cyclohexan-l-one (1.1 g, 2.76 mmol) in DCM (25 mL) was added tert-butyl piperazine-1-carboxylate (615 mg, 3.31 mmol) and AcOH (3 drops). The resulting mixture was stirred at room temperature for 0.5 h, NaHB(OAc)a (1.17 g, 5.51 mmol) was added. Then the mixture was stirred at room temperature overnight and diluted with water (30 mL), and the aqueous phase was extracted with DCM (50 ml x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (eluting with ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give tertbutyl                 4-((lF,4r)-4-(4-amino-5-(4-phcnoxyphcnyl)imidazo[5,l- / ][l,2,4]triazin-7- yl)cyclohexyl)piperazine-l-carboxylate as a white solid (200 mg yield 11%), and tert-butyl 4-((15',45')-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,!- / ][!,2,4]triazin-7 -yl)cyclohexyl)piperazine-l-carboxylate (550 mg, yield 30%).

[0466] Step 9: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-1,3-dione.

[0467] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline- 1,3-dione (400 mg, 1.45 mmol), azetidin-3-ylmethanol (189 mg, 2.17 mmol) and DIPEA (461 mg, 4.35 mmol) in DMF (4 ml) was stirred at 100 °C for 16 hs. After cooling to room temperature, the mixture was diluted - 172- with H2O (20 ml), and the aqueous phase was extracted with EtOAc ( 20 ml X 3). The combined organic phase was washed with brine (30 ml), dried over anhydrous NaaSCU and concentrated. The residue was purified by silica gel column (0-15% MeOH / CtLCh) to give 240 mg of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-l-yl)isoindoline-l,3-dione as yellow solid (48% yield). LCMS: m / z 344.1 [M+H]+.

[0468] Step 10: Synthesis of   1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)azetidine-3-carbaldehyde. O

[0469] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione (240 mg, 0.70 mmol), Dess-Martin reagent (593 mg, 1.40 mmol) in DCM (5 ml) was stirred at 0°C for 2 hs. The mixture was quenched with a solution of NaHCOs and NaiSsOg. The aqueous phase was extracted with DCM, and the organic phase was washed with brine, dried over anhydrous NajSOw and concentrated to give 600 mg of 1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde as yellow solid (100% yield), which was used directly for the next step. LCMS: m / z 342.1 [M+H]+.

[0470] Step 11: Synthesis of 5-(4-phenoxyphenyl)-7-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)imidazo[5,1- / | [ 1,2,4]triazin-4-amine. H

[0471] To a mixture of tert-butyl 4-((lr,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][ 1,2,4]triazin-7-yl)cyclohexyl)piperazine-l-carboxylate (300 mg, 0.53 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 12 hours and concentrated. The residue was dissolved with DCM (50 mL), and the organic phase was washed with NaHCO3 (30 mL*3), brine (30 mL) and water (30 mL), dried with anhydrous Na2SO4, filtered and concentrated to give 5-(4-phenoxypheny 1)-7-(( Ir,4r)-4-(piperazin-1-yl)cyclohexyl)imidazo[5,l- / ][i,2,4]triazin-4-amine as a white solid (203 mg, yield 82%), which was used directly for the next step. LCMS: m / z A-1QA [M+H]+.

[0472] Step 12: Synthesis of 5-(3-((4-((lr,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][l,2,4]triazin-7-yl)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (32).

[0473] To a mixture of 5-(4-phenoxyphenyl)-7-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)imidazo[5,l- / ][l,2,4]triazin-4-amine (100 mg, 0.21 mmol) in DCM (5 mL) was added 1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (87 mg, 0.26 mmol) and AcOH (2 drops). The resulting mixture was stirred at room temperature for 0.5 h, NaHB(OAc)3 (90 mg, 0.43 mmol) was added. Then the mixture was stirred at room temperature overnight and diluted with water (10 mL), and the aqueous phase was extracted with DCM (20 ml x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (eluting with ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give 5-(3-((4-((lr,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5, 1 - / ] [ 1,2,4] triazin-7-yl)cyclohexyl)piperazin-1 -yl)methyl)azetidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (42 mg, yield 25%). LCMS: m / z 794.9 [M+H]+. ’H NMR (400 MHz, DMSO DMSO-d6) 5 11.07 (s, 1H), 8.47 - 7.98 (m, 1H), 7.90 (s, 1H), 7.71 - 7.55 (m, 3H), 7.50 - 7.37 (m, 2H), 7.26 - 7.06 (m, 5H), 6.77 (d, J= 2.0 Hz, 1H), 6.64 (dd, J= 8.4, 2.0 Hz, 1H), 6.54 - 6.10 (m, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.13 (t, J - 174- = 8.2 Hz, 2H), 3.77 - 3.58 (m, 2H), 3.16 (t, J= 11.9 Hz, 1H), 3.03-2.94 (m, 1H), 2.93 - 2.82 (m, 1H), 2.67 - 2.53 (m, 7H), 2.47 - 2.21 (m, 6H), 2.09 - 1.88 (m, 5H), 1.69 (dd, J= 23.7, 11.6 Hz, 2H), 1.48-1.31 (m, 2H).

[0474] Step 13: Synthesis of 5-(4-phenoxyphenyl)-7-((15’,4i’)-4-(piperazin-l- yl)cyclohexyl)imidazo[5,l- / ][l,2,4]triazin-4-amine.

[0475] To a mixture of tert-butyl 4-((15,45)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l- / ][ 1,2,4] triazin-7-yl)cyclohexyl)piperazine-l-carboxylate (300 mg, 0.53 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 12 hours and concentrated. The residue was dissolved with DCM (50 mL), and the organic phase was washed with NaHCO3 (30 mL*3), brine (30 mL) and water (30 mL), dried with anhydrous Na2SO4, filtered and concentrated to give 5-(4-phenoxyphenyl)-7-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)imidazo[5,l- / |[l,2,4]triazin-4-amine as a white solid (223 mg, yield 90%), which was used directly for the next step. LCMS: m / z A1QA [M+H]+.

[0476] Step 14: Synthesis of 5-(3-((4-((lr,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,l-f\[ 1,2,4] triazin-7-yl)cyclohexyl)piperazin-1 -yl)methyl)azetidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (33).

[0477] To a mixture of5-(4-phenoxyphenyl)-7-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)imidazo[5,l- / ][l,2,4]triazin-4-amine (100 mg, 0.21 mmol) in DCM (5 mL) was added 1-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (88 mg, 0.26 mmol) and AcOH (2 drops). The resulting mixture was stirred at room temperature for 0.5 h, NaHB(OAc)3 (90 mg, 0.43 mmol) was added. Then the mixture was stirred at room temperature overnight and diluted with water (10 mL), and the aqueous phase was extracted with DCM (20 ml x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (eluting with ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give 5-(3-((4-((lr,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5, 1 - / ] [ 1,2,4] triazin-7-yl)cyclohexyl)piperazin-1 -yl)methyl)azetidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (25 mg, yield 15%). LCMS: m / z 795.1 [M+H]+. H NMR (500 MHz, DMSO-< / 6) 5 11.06 (s, 1H), 7.89 (s, 1H), 7.62 (d, J = 8.5Hz, 3H), 7.42 (t, J = 8.0 Hz, 2H), 7.20 - 7.10 (dt, J = 17.3, 8.0 Hzm, 5H), 6.76 (d, J = 2.0 Hz, 1H), 6.63 (dd, / = 8.5, 2.0 Hz, 1H), 5.05 (dd, / = 12.5, 5.5 Hz, 1H), 4.11 (t, / = 8.0 Hz, 2H), 3.72 - 3.62 (m, 2H), 3.41 (s, 1H), 3.01 - 2.82 (m, 2H), 2.64 - 2.53 (m, 4H), 2.48 - 2.32 (m, 6H), 2.28 -2.15 (m, 2H), 2.13- 1.90 (m, 6H), 1.70 (s, 2H), 1.58 (s, 2H). Example 12: Synthesis of 4-(4-((4-(( Ir,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l -yl )cyclohexyl )piperazin-l -yl jmethyl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3 -yl)isoindoline-l,3-dione (Compound 34)

[0478] Compound 34 was synthesized according to the scheme below. NaHB(OAc)3 DCM, rt •"N NBoc PdCI2(dppf), Na2CO3 1.4-Dioxane / H2O, 90°C Compound 34

[0479] Step 1: Synthesis of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-< / ]py rimidin-4- amine.

[0480] To a suspension of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (2.6 g, 10 mmol), l,4-dioxaspiro[4.5]decan-8-ol (3.2 g, 20 mmol) and PPha (3.9 g, 15 mmol) in THF (30 mL) was added dropwise DIAD (4.04 g, 20 mmol) over a period of 30 min at 0 °C. The reaction was stirred at room temperature for 12 hs under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was pulped with EtOAc (30 mL x 3), and the precipitate was dried in vacuo to give 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-J|pyrimidin-4-amine (2.8 g, 70%) as a white solid. LCMS: m / z 402.0 [M+H]+.

[0481] Step 2: Synthesis of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-6?]pyrimidin-l- yl)cyclohexan-1 -one.

[0482] To a suspension of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-< / ]pyrimidin-4-amine (2.8 g, 6.9 mmol) in THF (10 mL) was added HC1 (6N, 3 mL). The reaction was stirred at 60 °C for 2 hs, and diluted with water. The aqueous phase was neutralized with saturated sodium carbonate solution to pH=6-8, the precipitate was formed. The precipitate was filtered and dried in vacuo to give 4-(4-amino-3-iodo-lH-pyrazolo[3,4-( / ]pyrimidin-l-yl)cyclohexan-l-one (2 g, 83% yield) as a white solid, which was used directly for the next step. LCMS: m / z 358.0 [M+H]+.

[0483] Step 3: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate.

[0484] To a mixture of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexan-l-one (1.8 g, 5.05 mmol) in DCM (20 mL) was added tert-butyl piperazine-1-carboxylate (1.87 g, 10.11 mmol) and CH3COOH (150 mg, 2.5 mmol). The resulting mixture was stirred at room temperature for 6 hs, and then NaHB(OAc)3 (2.14 g, 10.11 mmol) was added. The mixture was stirred at 50 °C overnight, and diluted with DCM (80 mL). The organic phase was washed with brine, dried over anhydrous NazSCL, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-10% DCM\MeOH=10:l in DCM) to give tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg) as a white solid. LCMS: m / z 528.0 [M+H]+.

[0485] Step 4: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate.

[0486] To a mixture of tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg, 0.76 mmol) in l,4-dioxane / H2O (20 / 2 mL) was added 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (450 mg, 1.52mmol), Pd(dppf)C12 (55 mg, 0.076 mmol) and Na2CO3 (161 mg, 1.52 mmol). The resulting mixture was stirred at 90 °C for 12 hs under nitrogen atmosphere and concentrated, and the residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in EtOAc) to give 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-( / ]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 90% yield) as a white solid. LCMS: m / z 570.2 [M+H]+.

[0487] Step 5: Synthesis of 3-(4-phcnoxyphcnyl)-1-((1 r,4r)-4-(pipcrazin-1-yl)cyclohcxy 1)-lH-pyrazolo[3,4-t / ]pyrimidin-4-amine.

[0488] To a mixture of 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-< / ]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 0.68 mmol) in DCM (10 mL) was added HCl\dioxane (5 mL). The resulting mixture was stirred at room temperature overnight and diluted with DCM (40 mL), The organic phase was washed with saturated sodium hydrogen carbonate solution, brine, dried over anhydrous Na2SCh, filtered and concentrated to give 3-(4-phenoxyphenyl)-1 -((1 r,4r)-4-(piperazin-1 -yl)cyclohexyl)-1 H-pyrazolo[3,4-<7]pyrimidin-4-amine (270 mg, 85% yield) as a white solid, which was used directly for the next step. LCMS: m / z 470.2 [M+H]+.

[0489] Step 6: Synthesis of tert-butyl 4-((4-(( Ir,4r)-4-(4-amino-3-(4-phenoxypheny 1)-1H-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)piperidine-l-carboxylate.

[0490] To a mixture of 3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(piperazin-1 -yl)cyclohexyl)-lH-pyrazolo[3,4-<7]pyrimidin-4-amine (500 mg, 1.06 mmol) in DCE (20 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (227 mg, 1.06 mmol) and DIPEA (275 mg, 2.13 mmol). The resulting mixture was stirred at room temperature for 0.5 hs, and then NaHB(OAc)3 (451 mg, 2.13 mmol) was added. The mixture was stirred at 50 °C overnight, and diluted with DCM (100 mL). The organic phase was washed with brine, dried over anhydrous Na?SO4, filtered and concentrated. The residue was purified by flash chromatography (eluting with 0-10% MeOH in DCM) to give tert-butyl 4-((4-(( lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-l / / -pyrazolo[3,4-6?]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)piperidine-l-carboxylate (270 mg, 38% yield) as a white solid. LCMS: m / z 667.3 [M+H]+.

[0491] Step 7: Synthesis of 3-(4-phenoxyphenyl)-l-((lr,4r)-4-(4-(piperidin-4-ylmethyl)piperazin-1 -yl)cyclohexyl)-1 H-pyrazolo [3,4-d]pyrimidin-4-amine. h2n

[0492] To a suspension of tert-butyl 4-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo [3,4-J|pyrimidin-1 -yl)cyclohexyl)piperazin-1 -yl)methyl)piperidine-1 -carboxylate (27 0 g, 0.40 mmol) in DCM (10 mL) was added TFA (3 mL). The reaction was stirred at room temperature overnight, and concentrated, the residue was dissolved with DCM (50 mL). The organic phase was washed with saturated sodium carbonate solution and brine, concentrated to give 3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(4-(piperidin-4-ylmethyl)piperazin-l-yl)cyclohexy 1)-1 / / -pyrazolo[3,4-r / ]pyrimidin-4-amine (200 mg, 87% yield) as a yellow solid, which was used directly for the next step. LCMS: m / z 567.0 [M+H]+.

[0493] Step 8: Synthesis of 4-(4-((4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (34).

[0494] To a solution of 3-(4-phenoxyphenyl)-l-((lr,4r)-4-(4-(piperidin-4-ylmethyl)piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-r / ]pyrimidin-4-amine (100 mg, 0.18 mmol) in DMF (5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (48.7 mg, 0.18 mmol) and K2CO3 (73.2 mg, 0.53 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 5hs. After cooling to room temperature, the reaction mixture was quenched with ice cold water (20 mL), and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC(ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give 4-(4-((4-((lr,4r)-4-(4-amino-3-(4-phcnoxyphcnyl)-lH-pyrazolo[3,4-- 181 - <7]pyrimidin-l-yl)cyclohexyl)piperazin-l-yl)methyl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (36) (50.2 mg, 35% yield) as a yellow solid. LCMS: m / z 823.3 [M+H]+. !H NMR (500 MHz, DMSO-d6) 6 11.09 (s, 1H), 8.23 (s, 1H), 7.73 - 7.59 (m, 3H), 7.44 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 8.4 Hz, 2H), 7.24 - 7.08 (m, 5H), 5.14 - 5.03 (m, 1H), 4.64 (s, 1H), 3.76 -3.62 (m, 2H), 2.94 - 2.79 (m, 3H), 2.64 - 2.51 (m, 6H), 2.44 - 2.31 (m, 4H), 2.19 - 2.12 (m, 2H), 2.09 - 1.91 (m, 7H), 1.85 - 1.76 (m, 2H), 1.71 (s, 1H), 1.54 - 1.41 (m, 2H), 1.37 - 1.23 (m, 2H). Example 13: Synthesis of 4-(4-((4-(( lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l -yl)cyclohexyl )piperazin-l -yl)methyl)piperidin-l-yl)-2-( 2,6-dioxopiperidin-3-yl)isoindoline-l ,3-dione (34).

[0495] Compound 34 was synthesized according to the scheme below. Compound 34

[0496] Step 1: Synthesis of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-< / ]py rimidin-4- amine.

[0497] To a suspension of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (2.6 g, 10 mmol), l,4-dioxaspiro[4.5]dccan-8-ol (3.2 g, 20 mmol) and PPhs (3.9 g, 15 mmol) in THF (30 mL) was added dropwise DIAD (4.04 g, 20 mmol) over a period of 30 min at 0 °C. The reaction was stirred at room temperature for 12 hs under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was pulped with EtOAc (30 mL x 3), and the precipitate was dried in vacuo to give 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazolo[3,4-( / ]pyrimidin-4-amine (2.8 g, 70%) as a white solid. LCMS: m / z 402.0 [M+H]+.

[0498] Step 2: Synthesis of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-<7]pyrimidin-l-yl)cyclohexan-1-one.

[0499] To a suspension of 3-iodo-l-(l,4-dioxaspiro[4.5]decan-8-yl)-l / / -pyrazolo[3,4-d]pyrimidin-4-amine (2.8 g, 6.9 mmol) in THF (10 mL) was added HC1 (6N, 3 mL). The reaction was stirred at 60 °C for 2 hs, and diluted with water. The aqueous phase was neutralized with saturated sodium carbonate solution to pH=6-8, the precipitate was formed. The precipitate was filtered and dried in vacuo to give 4-(4-amino-3-iodo-17 / -pyrazolo[3,4-<7]pyrimidin-l-yl)cyclohexan-l-one (2 g, 83% yield) as a white solid, which was used directly for the next step. LCMS: m / z 358.0 [M+H]+.

[0500] Step 3: Synthesis of Zer / -butyl 4-((lr,4r)-4-(4-amino-3-iodo-17 / -pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate.

[0501] To a mixture of 4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexan-l-one (1.8 g, 5.05 mmol) in DCM (20 mL) was added tert-butyl piperazine-1-carboxylate (1.87 g, 10.11 mmol) and CH3COOH (150 mg, 2.5 mmol). The resulting mixture was stirred at room temperature for 6 hs, and then NaHB(OAc)3 (2.14 g, 10.11 mmol) was added. The mixture was stirred at 50 °C overnight, and diluted with DCM (80 mL). The organic phase was washed with brine, dried over anhydrous NazSCL, filtered and concentrated. The residue was purified by flash chromatography (silica, 40 g, 0-10% DCM\MeOH=10:l in DCM) to give tert-butyl 4-((lr,4r)-4-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg) as a white solid. LCMS: m / z 528.0 [M+H]+.

[0502] Step 4: Synthesis of tert-butyl 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-e?]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate.

[0503] To a mixture of tert-butyl 4-(( 1 r,4r)-4-(4-amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (400 mg, 0.76 mmol) in l,4-dioxane / H2O (20 / 2 mL) was added 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (450 mg, 1.52mmol), Pd(dppf)C12 (55 mg, 0.076 mmol) and NaoCOs (161 mg, 1.52 mmol). The resulting mixture was stirred at 90 °C for 12 hs under nitrogen atmosphere and concentrated, and the residue was purified by flash chromatography (silica, 40 g, 0-10% MeOH in EtOAc) to give 4-((lr,4r)-4-(4-amino-3-(4-phenoxyphenyl)-l / / -pyrazolo[3,4-t / ]pyrimidin-l-yl)cyclohexyl)piperazine-l-carboxylate (390 mg, 90% yield) as a white solid. LCMS: m / z 570.2 [M+H]+.

[0504] Step 6: Synthesis of 3-(4-phenoxyphenyl)-1-((1 r,4r)-4-(piperazin-l-yl)cyclohexyl)-lH-pyrazolo[3,4-£ / ]pyrimidin-4-amine.

[0505] ...

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:whereinthe dashed circle indicates the ring is aromatic;Q1 is N, S, or C;Q2 is N or C;Q3 is N or C;Ring A is absent or a heteroaryl ring;when Ring A is absent, two RA are present at the depicted points of attachment for Ring A;Ra is independently selected from the group consisting of H, NR’R”, C(O)R’R”, and NR’C(0)R”each of R’ and R” are independently H or Ci-3alkyl;Li is a bond, C1-C3 alkylene, C(O)Ci-3alkylene, Ci-3alkylene-O, or Ci-3alkylene-O-Ci-3alkylene; Ring B is a bond or selected from a divalent C4-6 cycloalkyl ring and a divalent 4-6 heterocyclyl ring; andRb is an E3 ligase-binding moiety.

2. The compound of claim 1, wherein Q1 is N.

3. The compound of claim 1, wherein Q1 is S.

4. The compound of claims 1 and 2, wherein Q1 and Q2 are N.

5. The compound of claims 1 and 2, wherein Q1 is N and Q2 are C.

6. The compound of claims 1 and 3, wherein Q1 is S and Q2 are C.

7. The compound of any of the claims 1 to 6, wherein Q3 is C.

8. The compound of any of the claims 1 to 6, wherein Q3 is N.

9. The compound of any of claims 1, 2, 4, and 7 wherein Q1 and Q2 are N, and Q3 is C.

10. The compound of any of claims 1 to 9, wherein Ring A is selected from the group vMA            .AAA            .AAA                  .AAAXaconsisting of: absent, N<^N ,         ,         , and N<^N .

11. The compound of claims 1 and 10, wherein when Ring A is absent and RA is selected from NH2 and C(0)NH2.

12. The compound of any one of claims 1 to 11, wherein RA is NH2.

13. The compound of any one of claims 1 to 1, wherein Ring B is selected from the group14. The compound of any one of claims 1 to 13, wherein RB is a cereblon E3 ligase-binding moiety.

15. The compound of any one of claims 1 to 14, wherein RB is a VHL E3 ligase-binding moiety.

16. The compound of any one of claims 1 to 15, wherein RB is selected from the group consisting of:

17. The compound of anyone of claims 1 to 16, wherein RB is selected from the groupconsisting of:

18. A compound selected from Table B, or a pharmaceutically acceptable salt thereof.Table B.

19. A compound selected from20. A pharmaceutical composition comprising the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

21. A compound selected from Compound 7, 10, 26, 27, 28, 29, 30, 31, or 33.

22. A method of inhibiting the activity of one or more kinase in a subject comprising administering to the subject the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20.

23. A method of facilitating the degradation of one or more kinase in a subject comprising administering to the subject the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20.

24. The method of claim 22 or 23, wherein the one or more kinase is selected from the group consisting an SRC family of cytoplasmic tyrosine kinases (SFKs), a hemotopoietic cell kinase, a LYN proto-oncogene tyrosine kinase (LYN), a Tec family of cytoplasmic tyrosine kinases, and a Bruton’s tyrosine kinase (BTK).

25. The method of any one of claims 22 to 24, wherein the one or more kinase is a mutated kinase.

26. The method of any one of claims 22 to 25, wherein the one or more kinase is resistant to treatment.

27. A method of treating a proliferative disease associated with a mutation in a MYD88 protein in a subject in need thereof comprising administering to the subject the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20.

28. The method according to claim 27, wherein the disease is associated with aberrant activity of one or more of a hematopoietic cell kinase (HCK), of a LYN proto-oncogene tyrosine kinase (LYN), of Bruton’s tyrosine kinase (BTK), or a mutation in a BTK protein.

29. The method according to claim 28, wherein the disease is associated with a mutation in a BTK protein, wherein the mutated BTK protein is a C481S mutated BTK.

30. The method according to any one of claims 27 to 29, wherein the proliferative disease is cancer, IgM gammopathy or mastocytosis.

31. The method according to any one of claims 27 to 30, wherein the proliferative disease is cancer, and wherein the cancer is breast cancer, colon cancer, stomach cancer, testicular cancer, cancer of the central nervous system, lymphoma, leukemia, myeloma or myeloproliferative disease.

32. The method according to claim 31, wherein the cancer is lymphoma, and wherein the lymphoma is a B-cell lymphoma.

33. The method according to claim 32, wherein the B-cell lymphoma is lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone B-cell lymphoma or small lymphocytic lymphoma.

34. The method according to claim 33, wherein the lymphoplasmacytic lymphoma is IgM secreting lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia, or non-IgM secreting lymphoplasmacytic lymphoma.

35. The method according to claim 33, wherein the diffuse large B-cell lymphoma is activated B-cell-like (ABC-DLBCL), or germinal center B-cell-like (GBC-DLBCL).

36. The method according to claim 33, wherein the small lymphocytic lymphoma is mantle cell lymphoma.

37. The method according to claim 31, wherein the cancer is leukemia, and wherein the leukemia is chronic lymphocytic leukemia, or myelogenous leukemia.

38. The method according to claim 37, wherein the myelogenous leukemia is chronic myelogenous leukemia, or acute myelogenous leukemia.

39. The method according to claim 38, wherein the acute myelogenous leukemia is mast cell leukemia.

40. The method according to claim 31, wherein the cancer is a myeloma, and wherein the myeloma is an IgM myeloma.

41. The method according to claim 40, wherein the IgM myeloma is IgM multiple myeloma.

42. The method according to claim 31, wherein the cancer is a myeloproliferative disease, and wherein the myeloproliferative disease is myelodysplastic syndrome.

43. The method according to claim 30, wherein the proliferative disease is an IgM gammopathy and wherein the IgM gammopathy is an IgM Monoclonal gammopathy of undetermined significance (MGUS) or amyloid light chain (AL) amyloidosis.

44. The method according to claim 30, wherein the proliferative disease is mastocytosis and wherein the mastocytosis is systemic mastocytosis.

45. A compound according to any one of claims 1 to 19, for use in inhibiting the activity of one or more kinase in the subject.

46. A compound according to any one of claims 1 to 19, for use in facilitating the degradation of one or more kinase in the subject.

47. The compound for use according to claim 45 or 46, wherein the kinase is an SRC cytoplasmic tyrosine kinase (SFK),48. The compound for use according to claim 45 or 46, wherein the SFK is hematopoietic cell kinase (HCK) or LYN proto-oncogene tyrosine kinase (LYN).

49. The compound for use according to claim 45 or 46, wherein the kinase is a Tec cytoplasmic tyrosine kinase, preferably a Bruton’s tyrosine kinase (BTK).

50. The compound for use according to claim 45 or 46, wherein the kinase is selected from one or more of HCK, LYN, and BTK.

51. The compound for use according to claim 49, wherein the BTK is one or more of: (i) a mutated BTK, (ii) the BTK is mutated at Cys481, and (iii) the BTK is a C481S mutated BTK.

52. The compound for use according to claim 51, wherein the BTK is resistant to inhibition by ibrutinib.

53. The compound for use according to any one of claims 45 to 52, wherein the subject is resistant to treatment with one or more of ibrutinib, CC-292, ONO-4059, evobrutinib, spebrutinib, BGB-3111, HM71224, and ACP-196, or a pharmaceutically acceptable salt thereof.

54. A method of treating one or more of breast cancer, colon cancer, stomach cancer, testicular cancer, cancer of the central nervous system, IgM secreting lymphoplasmacytic lymphoma, non-IgM secreting lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC-DLBCL), germinal center B-cell-like (GBC-DLBCL), follicular lymphoma, marginal zone B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, mast cell leukemia, IgM multiple myeloma, myelodysplastic syndrome, IgM Monoclonal gammopathy of undetermined significance (MGUS), amyloid light chain (AL) amyloidosis, and systemic mastocytosis in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20.

55. The method of any one of claims 22 to 44 and 54, wherein said subject is treated with one or more additional therapeutic agents, or oncologic treatments administered concurrently with, prior to, or subsequent to treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

56. Use of the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20, as a medicament.

57. Use of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20 in combination with one or more additional immunotherapy.

58. The use of a compound or pharmaceutical composition according to claim 57, wherein the additional immunotherapy comprises a chimeric antigen receptor (CAR).

59. The use of a compound or pharmaceutical composition according to claim 57, wherein the additional immunotherapy comprises a bispecific antibody.

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