PYRAZOLOPYRIMIDINE DERIVATIVES AS HCK INHIBITORS FOR USE IN THE TREATMENT, PARTICULARLY IN MYD88 MUTANT DISEASES - Patent application

Abstract

Provided herein is a method for treating a disease (e.g., a proliferative disease (e.g., cancer (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, gastric 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 (i.e., Waldenstrom's macroglobulinemia)), a method for treating a disease (e.g., a proliferative disease (e.g., cancer (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, gastric cancer), lymphoma (e.g., B cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM-secreting lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia)), a ... and leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myeloid leukemia (e.g., chronic myeloid leukemia, acute myeloid leukemia)). Also provided are methods for treating diseases that are resistant to treatment with a BTK inhibitor (e.g., ibrutinib). TIFF2022551502000018.tif49157

Description

[Technical field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 912,474, filed October 8, 2019, which is incorporated by reference herein. [Background technology]

[0002] Transcription and activation of hematopoietic cell kinase (HCK), triggered by mutant myeloid differentiation primary response 88 (MYD88), has been found to be a key determinant of pro-survival signaling. It has also been found that inhibition of the kinase activity of HCK triggers apoptosis in mutant MYD88 cells. For example, expression of MYD88 mutations in Waldenström's macroglobulinemia (WM), where 95-97% of patients have MYD88 L265P , and non-L265P MYD88 mutations are extremely rare. WM is thought to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. Up to 30% of patients with diffuse large B-cell lymphoma of the activated B-cell (ABC) subtype (ABC DLBCL) also express MYD88 L265P These cells express activating MYD88 mutations, including those in the IL1 receptor-associated kinase (IRAK4 / IRAK1) and Bruton's tyrosine kinase (BTK), which promote the self-assembly of myosinosomes and can trigger NF-kB signaling in the absence of Toll (TLR) or IL1 (IL1R) receptor signaling.

[0003] Next-generation sequencing has revealed activated myeloid differentiation primary response 88 (MYD88) mutations in several B-cell malignancies, including immune-privileged lymphomas, including Waldenström macroglobulinemia (immunoglobulin M (IgM)-secreting lymphoplasmacytic lymphoma), non-IgM-secreting lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma of the ABC subtype, primary central nervous system (CNS) lymphoma, testicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia. Particularly striking was the expression of MYD88 mutations in Waldenström macroglobulinemia (WM), where 95–97% of patients have MYD88 mutations. L265P Waldenström's macroglobulinemia is thought to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. Up to 30% of patients with diffuse large B-cell lymphoma of the activated B-cell (ABC) subtype (ABC-DLBCL) also express MYD88 L265P These cells express activating MYD88 mutations, including those in the IL1 receptor-associated kinase (IRAK4 / IRAK1) and Bruton's tyrosine kinase (BTK), which promote the self-assembly of myosinosomes and can trigger NF-kB signaling in the absence of Toll (TLR) or IL1 (IL1R) receptor signaling.

[0004] Ibrutinib (IB) is an inhibitor of BTK that is highly active in WM, resulting in responses in 91% of pretreated patients. In WM patients, both the primary and overall responses to ibrutinib are higher in patients with MYD88 mutations. Ibrutinib also shows activity in pretreated patients with ABC DLBCL, especially among patients with MYD88 mutations. Ibrutinib is also active in other B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). BTK-mediated inhibition of sustained B-cell receptor (BCR) activity has been implicated as the mechanism underlying ibrutinib activity in non-WM B-cell disorders.

Prior technical literature

[0005]

Patent Document 1

Non-licensed literature

[0006] [Non-licensed document 1] Handbook of Chemistry and Physics, 75th edition

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[0007] Provided herein are methods for treating a disease (e.g., a proliferative disease (e.g., IgM gammopathy (e.g., 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, gastric cancer), lymphoma (e.g., B cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM-secreting lymphoplasmacytic lymphoma (i.e., Waldenström's macroglobulinemia), non-IgM-secreting lymphoplasmacytic lymphoma (i.e., Waldenström's macroglobulinemia), 26. A method for treating lymphomas (e.g., diffuse large B cell lymphomas (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), myelomas (e.g., IgM myelomas (e.g., IgM multiple myeloma)), and leukemias (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myeloid leukemias (e.g., chronic myelogenous leukemia, acute myeloid leukemia (e.g., mast cell leukemia)), myeloproliferative disorders (e.g., myelodysplastic syndromes)), comprising administering a therapeutically effective amount of a compound of the formula:

[0008] [ka]

[0009] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, stereoisomer, or prodrug thereof to a subject.

[0010] Compound (I) may be a kinase inhibitor (e.g., an SRC family kinase (i.e., SFK) (e.g., HCK, LYN, BLK, FRK), a Tec family kinase (e.g., BTK)), and in certain embodiments, the compound may be specific or selective for an SFK (e.g., HCK, LYN, BLK, FRK) or a Tec family kinase (e.g., BTK) over one or more other kinases. Also provided are pharmaceutical compositions and kits comprising Compound (I). The present disclosure relates to the use of the disclosed compounds, pharmaceutical compositions, and kits (e.g., for the treatment of a disease in a subject in need thereof (e.g., a proliferative disease (e.g., IgM gammopathy (e.g., 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, gastric cancer, lymphoma (e.g., B cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM-secreting lymphoplasmacytic lymphoma (i.e., Waldenström's macroglobulinemia), non-IgM-secreting lymphoplasmacytic lymphoma)), diffuse large B cell lymphoma (e.g., pulmonary arterial fibrosis (PBC ... Also provided are methods of using the compounds of the present invention to treat 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 myeloma (e.g., IgM multiple myeloma)), and leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myeloid leukemia (e.g., chronic myelogenous leukemia, acute myeloid leukemia (e.g., mast cell leukemia)), myeloproliferative disorders (e.g., myelodysplastic syndromes))) or to inhibit activity of a kinase in a subject, biological sample, or cell in need thereof.

[0011] In yet another aspect, the disclosure provides Compound (I), as well as pharma- ceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in the treatment and / or prevention of a disease (e.g., a proliferative disease, such as IgM gammopathy, mastocytosis, cancer, etc.) in a subject in need thereof.

[0012] In another aspect, the disclosure provides the use of Compound (I), as well as pharma- ceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, in the manufacture of a medicament for treating and / or preventing a disease in a subject in need thereof.

[0013] In another aspect, the disclosure provides a method for preparing Compound (I), or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0014] In one aspect, the disclosure provides a pharmaceutical composition comprising Compound (I) and, optionally, a pharma- ceutically acceptable excipient. In certain embodiments, the pharmaceutical composition further comprises an additional pharmaceutical agent. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of a chemotherapeutic agent, an epigenetic modifier, a glucocorticoid, a biologic, and an immunotherapeutic agent. In another aspect, the additional pharmaceutical agent is a BCL-2 inhibitor (e.g., venetoclax, navitoclax, obatoclax).

[0015] The pharmaceutical compositions may be useful for inhibiting activity of a kinase in a subject, biological sample, or cell in need thereof to treat a disease in a subject in need thereof. In certain embodiments, the disease is a proliferative disease (e.g., IgM gammopathy (e.g., 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, gastric 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 myeloma (e.g., IgM multiple myeloma)), and leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myeloid leukemia (e.g., chronic myelogenous leukemia, acute myeloid leukemia (e.g., mast cell leukemia)), myeloproliferative disorders (e.g., myelodysplastic syndromes)).

[0016] The present disclosure provides a method of treating a disease in a subject by administering to a subject in need thereof an effective amount of Compound (I), or a pharmaceutical composition thereof, as described herein. In certain embodiments, the disease is a proliferative disease (e.g., IgM gammopathy (e.g., 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, gastric cancer), lymphoma (e.g., B cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM-secreting lymphoplasmacytic lymphoma (i.e., Waldenström's macroglobulinemia), non-IgM-secreting lymphoplasmacytic lymphoma), or a combination of these. )), 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 myeloma (e.g., IgM multiple myeloma)), and leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myeloid leukemia (e.g., chronic myeloid leukemia, acute myeloid leukemia (e.g., mast cell leukemia)), myeloproliferative disorders (e.g., myelodysplastic syndromes)). Also described are methods for contacting a biological sample or cell with an effective amount of a compound, or a pharmaceutical composition thereof, as described herein. In certain embodiments, the methods described herein further comprise administering an additional pharmaceutical agent to a subject in need thereof. In certain embodiments, the methods described herein further comprise the step of contacting the biological sample or cells with an additional pharmaceutical agent.

[0017] In one embodiment, provided is a method for treating a disease in a subject that is resistant to treatment with a BTK inhibitor (e.g., ibrutinib, CC-292, ONO-4059, evobrutinib, spebrutinib, BGB-3111, HM71224, or ACP-196 (i.e., acalabrutinib)). In certain embodiments, the subject that is resistant to treatment with a BTK inhibitor has mutant BTK (e.g., C481S mutant BTK). In certain embodiments, the subject has C481S mutant BTK. In another embodiment, the subject that is resistant to treatment with a BTK inhibitor has C481S mutant BTK. In another embodiment, the subject that is resistant to treatment with a BTK inhibitor is diagnosed with a MYD88 mutant disease (e.g., a proliferative disease (e.g., IgM gammopathy, mastocytosis, or cancer)).

[0018] In another aspect, provided herein is a method of inhibiting a kinase (e.g., an SFK (e.g., HCK, LYN, BLK, FRK), a Tec family kinase (e.g., BTK)) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (I), or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, stereoisomer, or prodrug thereof. In a particular aspect, provided herein is a method for inhibiting mutant BTK (e.g., the C481S mutant) in a subject in need thereof.

[0019] In certain aspects, the method further comprises administering to the subject an anti-cancer agent. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In another aspect, the method further comprises administering to the subject one or more of a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or oprozomib), a monoclonal antibody (e.g., rituximab, daratumumab, ofatumumab, or obinutuzumab), an alkylating agent (e.g., bendamustine, cyclophosphamide), a nucleoside analog (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 immunomodulator (e.g., thalidomide or lenalidomide).

[0020] In another aspect, the disclosure provides a method for the preparation of a compound (I), or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof; Instructions for using the compound, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition; A kit comprising:

[0021] The details of one or more embodiments of the disclosure are described herein. Other features, objects, and advantages of the disclosure will become apparent from the detailed description, examples, figures, and claims.

[0022] definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, 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 Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0023] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by 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 synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions at page 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0024] When a range of values ​​("range") is described, this includes each value and subrange within the range. A range includes both ends of the range unless otherwise specified. For example, "C 1~6 Alkyl" is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Including alkyl.

[0025] "Hydrocarbon chain" refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group. The hydrocarbon chain includes (1) one or more chains of carbon atoms directly between the two groups of the hydrocarbon chain; (2) optionally one or more hydrogen atoms on the chain of carbon atoms; and (3) optionally one or more substituents ("non-chain substituents" that are not hydrogen) on the chain of carbon atoms. The chain of carbon atoms consists of carbon atoms connected in succession ("chain atoms") and does not include hydrogen atoms or heteroatoms. However, the non-chain substituents of the hydrocarbon chain may include any atom including hydrogen atoms, carbon atoms, and heteroatoms. For example, the hydrocarbon chain -C A H(C B H2C C H3)- is one chain atom C A , C A One hydrogen atom on the chain and a non-chain substituent -(C B H2C C H3) is included. x The term "hydrocarbon chain" (where x is a positive integer) refers to a hydrocarbon chain that contains x chain atoms between two groups of the hydrocarbon chain. If there is more than one possible value of x, the smallest possible value of x is used to define the hydrocarbon chain. For example, -CH(C2H5)- is a C1 hydrocarbon chain;

[0026] [ka]

[0027] is a C3 hydrocarbon chain. When a range of values ​​is used, the meaning of the range is as described herein. For example, C 3~10A hydrocarbon chain refers to a hydrocarbon chain in which the number of chain atoms in the shortest chain of carbon atoms between two groups of the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. The hydrocarbon chain may be saturated (e.g., -C≡C- or -(CH2)4-). The hydrocarbon chain may not be saturated and may contain one or more C=C bonds and / or C≡C bonds anywhere in the hydrocarbon chain. For example, -CH=CH-(CH2)2-, -CH2-C≡C-CH2-, and -C≡C-CH=CH- are all examples of unsubstituted, unsaturated hydrocarbon chains. In certain embodiments, the hydrocarbon chain is unsubstituted (e.g., -(CH2)4-). In certain embodiments, the hydrocarbon chain is substituted (e.g., -CH(C2H5)- and -CF2-). Any two substituents on the hydrocarbon chain may be combined to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl ring. For example,

[0028] [ka]

[0029] are all examples of hydrocarbon chains. In contrast, in certain embodiments

[0030] [ka]

[0031] is not within the scope of the hydrocarbon chains described herein. x When a chain atom of a hydrocarbon chain is replaced with a heteroatom, the resulting group is C x-1 In contrast to hydrocarbon chains, C x They are called hydrocarbon chains. For example,

[0032] [ka]

[0033] is a C3 hydrocarbon chain in which one chain atom has been replaced by an oxygen atom.

[0034] The term "alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, an alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2~6 "Alkyl"). C 1~6Examples of alkyl groups include methyl (C1), 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 (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C9), n-hexyl (C10), n-hexyl (C11), n-hexyl (C12), n-hexyl (C13), n-hexyl (C14), n-hexyl (C15), n-hexyl (C16), n-hexyl (C17), n-hexyl (C18), n-hexyl (C19), n-hexyl (C20), n-hexyl (C21), n-hexyl (C22), n-hexyl (C23), n-hexyl (C24), n-hexyl (C25), n-hexyl (C26), n-hexyl (C27), n-hexyl (C28), n-hexyl (C29), n-hexyl (C30), n-hexyl (C31), n-hexyl (C32), n-hexyl (C33), n-hexyl (C34), n-hexyl (C35), n-hexyl (C36), n-hexyl (C37), n-hexyl (C38), n-hexyl (C39), n-hexyl (C31), n-hexyl (C32), n-hexyl (C33), n-hexyl (C34), n-hexyl (C35), n-hexyl (C36), n-hexyl (C37), n-hexyl (C38 12 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, an alkyl group is an unsubstituted C 1~12 Alkyl (unsubstituted C 1~6 Alkyl, for example, -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr), unsubstituted butyl (Bu, for example, unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu), etc.). In certain embodiments, the alkyl group is a substituted C 1~12 Alkyl (substituted C 1~6 alkyl, for example, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn), etc.

[0035] The term "alkenyl" refers to a group of straight-chain or branched hydrocarbon groups having 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms ("C 2~20 In some embodiments, the alkenyl group has 2 to 12 carbon atoms ("C 2~12 In some embodiments, the alkenyl group has 2 to 11 carbon atoms ("C2~11 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The carbon-carbon double bond or bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 In an alkenyl group, a C=C double bond where no stereochemistry is specified (e.g., -CH=CHCH3 or

[0036] [ka]

[0037] may be in the (E)- or (Z)-configuration).

[0038] The term "alkynyl" refers to a group of straight-chain or branched hydrocarbon groups having 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (see "C 2~20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2~5In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The carbon-carbon triple bond(s) can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0039] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3~8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~6 Included are carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~8 Carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the preceding examples illustrate, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or includes fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclic ring is fused with one or more aryl or heteroaryl groups, as defined above, where the point of attachment is on the carbocyclic ring, and in such instances the number of carbons continues to indicate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0040] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 "Cycloalkyl"). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). 3~6 Examples of cycloalkyl groups include the aforementioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8Examples of cycloalkyl groups include the aforementioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 In certain embodiments, a carbocyclyl contains, where valence allows, 0, 1, or 2 C=C double bonds in the carbocyclic ring system.

[0041] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), which may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclic ring is fused to one or more carbocyclyl groups, as defined above, at the point of attachment on the carbocyclyl ring or heterocyclic ring, or a heterocyclic ring is fused to one or more aryl or heteroaryl groups, as defined above, at the point of attachment on the heterocyclic ring, in which case the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, where one, two, or three atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valences permit.

[0042] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0043] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4 -b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0044] The term "aryl" refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms in a given aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement). 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the group or point of attachment is on the aryl ring, and in such instances the number of carbon atoms continues to indicate 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 ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0045] The term "aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl portion. In certain embodiments, an aralkyl is an optionally substituted benzyl. In certain embodiments, an aralkyl is benzyl. In certain embodiments, an aralkyl is an optionally substituted phenethyl. In certain embodiments, an aralkyl is phenethyl.

[0046] The term "heteroaryl" refers to a group of 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having a given ring carbon atom and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the point of attachment is on the heteroaryl ring, and in such instances the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring is fused with one or more aryl groups, as defined above, where the point of attachment is on the aryl or heteroaryl ring, and in such instances, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which 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 with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, where one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl, where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0047] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a given ring carbon atom and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a given ring carbon atom and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a given ring carbon atom and 1-4 ring heteroatoms in the aromatic ring system, where 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 ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0048] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0049] The term "heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the attachment is on the alkyl portion.

[0050] The term "unsaturated" or "partially unsaturated" refers to a moiety that contains at least one double or triple bond. A "partially unsaturated" ring system is further intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as defined herein. Similarly, "saturated" refers to a group that does not contain any double or triple bonds, i.e., all single bonds.

[0051] The divalent bridging groups alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are further referred to using the suffix -ene, e.g., alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.

[0052] Groups are optionally substituted unless expressly stated otherwise. The term "optionally substituted" refers to either substituted or unsubstituted.

[0053] In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a heteroalkyl group, a "substituted" or "unsubstituted" heteroalkenyl group, a "substituted" or "unsubstituted" heteroalkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on the group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise stated, 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 substituents may be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein that result in the formation of stable compounds. The present disclosure contemplates any and all such combinations to arrive at stable compounds. For purposes of the present disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0054] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSRcc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(Raa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc ) 4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc ) 4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, wherein X - is the counterion, Or two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc has been replaced by R aa Each instance of 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa and the groups taken together form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd is independently substituted with R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2Raa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bb and the groups taken together form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd groups, wherein X - is the counterion, R cc Each instance of is independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc and the groups taken together form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd is independently substituted with R dd Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee, -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd The substituents together may form =O or =S, where X - is the counterion, R ee Each instance of 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from 0, 1, 2, 3, 4, or 5 R gg is independently substituted with R ff Each instance of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5-10 membered heteroaryl, or two R ff and the groups taken together form a 3- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of 0, 1, 2, 3, 4, or 5 R gg is independently substituted with R gg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 Alkyl)2 + X - , -NH2(C 1~6 Alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C 1~6 Alkyl)2, -SO2NH(C 1~6 Alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 Alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6alkyl), C(=S)NH2, -C(=O)S(C 1~6 Alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 Alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal R gg The substituents together may form =O or =S, where X - is the counter ion.

[0055] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., contain one formal negative charge). Anionic counterions can also be multivalent (i.e., contain more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 -, sulfonates (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, and the like), carboxylates (e.g., acetic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid, and the like), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4 - , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, gluconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylic acid, phthalates, aspartic acid, glutamic acid, and the like), and carboranes.

[0056] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0057] The term "acyl" refers to a group having the general formula -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SRX1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 , or -C(=NR X1 )N(R X1 )2, wherein each R X1 are independently hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic substituted or unsubstituted branched or unbranched aliphatic; cyclic or acyclic substituted or unsubstituted branched or unbranched heteroaliphatic; cyclic or acyclic substituted or unsubstituted branched or unbranched alkyl; cyclic or acyclic substituted or unsubstituted branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1The groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0058] "Alkoxy" or "alkoxyl" refers to a group of the formula: --O-alkyl.

[0059] Nitrogen atoms may be substituted or unsubstituted where valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa, -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 or two R bonded to an N atom, including, but not limited to, aryl, and 5-14 membered heteroaryl. cc and the groups taken together form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd groups, wherein R aa , R bb , R cc and R dd is as defined above.

[0060] In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb)2, or a nitrogen protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 alkyl, or an oxygen protecting group when attached to an oxygen atom, bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 It is an alkyl or nitrogen protecting group.

[0061] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also called an amino protecting group). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 Rdd groups, wherein R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0062] For example, an amide group (e.g., -C(=O)R aa Nitrogen protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0063] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthy]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate, (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (DB-t-BOC), carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate mate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate (nitobenzyl carbamate), p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolyl methyl carbamate, 2-(trifluoromethyl)-6-chromonyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanyl methyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate carbamate), isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,Examples include, but are not limited to, 4,6-trimethylbenzyl carbamate.

[0064] Sulfonamide groups (e.g., -S(=O)R aa Nitrogen protecting groups such as p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2 ,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0065] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilylazacyclopentadiene. Tandem adducts (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamines, N-allylamines, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrolin-3 -yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethyl Thiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,These include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In some embodiments, two examples of nitrogen protecting groups together with the nitrogen atom to which the nitrogen protecting group is attached are N,N'-isopropylidenediamine.

[0066] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0067] In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or an oxygen protecting group, where R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10alkyl, or an oxygen protecting group when attached to an oxygen atom, bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 It is an alkyl or oxygen protecting group.

[0068] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, including, but not limited to, wherein X - , R aa , R bb , and R ccis as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0069] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-Trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methyl 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethoxyethyl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethoxyethyl , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl silyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropyl Silyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxy Acetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzene Dimethyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-napthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzyl carbonate, benzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2 Examples of suitable alkyl groups include, but are not limited to, alkyl 2-butenoates, o-(methoxyacyl)benzoates, α-naphthoates, nitrates, alkyl N,N,N',N'-tetramethylphosphorodiamidates, alkyl N-phenylcarbamates, borates, dimethylphosphinothioyls, alkyl 2,4-dinitrophenylsulfenates, sulfates, methanesulfonates (mesylates), benzylsulfonates, and tosylates (Ts).

[0070] In certain embodiments, the at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0071] In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 alkyl, or an oxygen protecting group when attached to an oxygen atom, bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 It is an alkyl or sulfur protecting group.

[0072] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called a "thiol protecting group"). In some embodiments, each sulfur protecting group is -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(Rcc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb 2) 2) selected from the group consisting of: aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0073] As used herein, "leaving group" (LG) is a term understood in the art to refer to a molecular fragment that leaves with an electron pair in a heterolytic bond cleavage, where the molecular fragment is an anion or a neutral molecule. As used herein, a leaving group can be an atom or group displaceable by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry, 6th Edition (501-502). Exemplary leaving groups include halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc) 3, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(NR bb )2(wherein, R aa , R bb , and R cc are as defined herein). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonate 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 be a phosphine oxide (e.g., generated during the Mitsunobu reaction), or an internal leaving group such as an epoxide or a cyclic sulfate. Other non-limiting examples of leaving groups are water, amines, ammonia, alcohols, ether moieties, sulfur-containing moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0074] The term "pharmaceutically acceptable salt" refers to a salt that is, 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 responses, and the like, 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, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups 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 pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lauryl sulfate ...cyclopentanepropionate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, lauryl sulfate, cyclopentanepropionate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, lauryl sulfate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, lauryl sulfate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, lauryl sulfate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, lauryl sulfate, cyclopentanepropionate, dodecyl sulfate, ethanesulf Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and the like. + (C 1~4 Alkyl)4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0075] The term "solvate" refers to a compound or its salt form that is combined with a solvent, usually by solvolysis. This physical association may include hydrogen bonds. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. Compound (I) may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharma- ceutically acceptable solvates, further including both stoichiometric and non-stoichiometric solvates. In certain instances, solvates are capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0076] The term "stoichiometric solvate" refers to a solvate comprising a compound (e.g., a compound disclosed herein) and a solvent, in which the solvent molecules are an integral part of the crystal lattice and in which they strongly interact with the compound and with each other. Removal of the solvent molecules will cause instability of the crystalline network, which subsequently collapses into an amorphous phase or recrystallizes as a new crystalline form with reduced solvent content.

[0077] The term "non-stoichiometric solvate" refers to a solvate comprising a compound (e.g., a compound disclosed herein) and a solvent, in which the solvent content can change without significant change in the crystal structure. The amount of solvent in the crystal lattice depends only on the partial pressure of the solvent in the surrounding atmosphere. In a fully solvated state, a non-stoichiometric solvate may, but need not, exhibit an integer molar ratio of solvent to compound. During drying of a non-stoichiometric solvate, a portion of the solvent can be removed without significantly disturbing the crystal network, and the resulting solvate can be subsequently resolvated to obtain the initial crystalline form. Unlike stoichiometric solvates, desolvation and resolvation of non-stoichiometric solvates does not involve a phase transition, and all solvation states result in the same crystalline form.

[0078] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is a compound and x is a number greater than 0. A given compound may form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0079] The term "tautomers" refers to compounds that are interchangeable forms of a particular compound structure and differ in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the movement of pi electrons and atoms (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, which are also produced by treatment with acid or base.

[0080] Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that gives the tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerizations.

[0081] It should also 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."

[0082] Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, e.g., is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light and is called dextrorotatory or levorotatory (i.e., (+) or (-)-isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0083] The term "crystalline" or "crystalline form" refers to a solid form that exhibits substantial three-dimensional order. In certain embodiments, a solid crystalline form is a solid form that is not substantially amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form comprises one or more distinct peaks.

[0084] The term "amorphous" or "amorphous form" refers to a solid form ("solid form") that is substantially devoid of three-dimensional order. In certain embodiments, a solid amorphous form is a solid form that is substantially not crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of the amorphous form includes a broad scattering band, e.g., having peaks at 2θ between 20 and 70°, inclusive, using CuKα radiation. In certain embodiments, the XRPD pattern of the amorphous form further includes one or more peaks attributable to a crystalline structure. In certain embodiments, the maximum intensity of any one of the one or more peaks attributable to a crystalline structure observed at 2θ between 20 and 70°, inclusive, is 300 times or less, 100 times or less, 30 times or less, 10 times or less, or 3 times or less than the maximum intensity of the broad scattering band. In certain embodiments, the XRPD pattern of the amorphous form does not include a peak attributable to a crystalline structure.

[0085] The term "co-crystal" refers to a crystalline structure that includes at least two different components (e.g., a compound disclosed herein and an acid), each of which is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound disclosed herein and an acid differs from a salt formed from a compound disclosed herein and an acid. In a salt, the compound disclosed herein is complexed with an acid such that proton transfer (e.g., complete proton transfer) from the acid to the compound disclosed herein occurs readily at room temperature. However, in a co-crystal, the compound disclosed herein is complexed with an acid such that proton transfer from the acid to the compound disclosed herein does not occur readily at room temperature. In certain embodiments, in a co-crystal, there is no proton transfer from the acid to the compound disclosed herein. In certain embodiments, in a co-crystal, there is partial proton transfer from the acid to the compound disclosed herein. Co-crystals can be useful for improving the properties (e.g., solubility, stability, and ease of formulation) of the compounds disclosed herein.

[0086] The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0087] The term "prodrug" refers to compounds including derivatives of compound (I) that have a cleavable group and become pharma- ceutically active compound (I) by solvolysis or under physiological conditions in vivo. Such examples include, but are not limited to, ester derivatives and the like. Other derivatives of the compounds of the present disclosure are active in both their acid and acid derivative forms, but the acid-sensitive forms often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in 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 anhydride, or mixed anhydride. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant to the compounds of the present disclosure are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.

[0088] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cows, 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 male or female and at any stage of development. The non-human animal may be a transgenic animal. A subject that is resistant to treatment with a BTK inhibitor is one that does not respond or shows a minimal response to the treatment. In some embodiments, the response to the treatment is measured by a reduction in tumor cells or death of tumor cells. In some embodiments, response to treatment is measured by a change in symptoms of a disease, condition, or malignancy (e.g., a proliferative disease). It has been discovered that compounds that block ATP binding to HCK as described herein can kill tumor cells, even in cells derived from subjects that are resistant to BTK inhibitor treatment.

[0089] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound, or a pharmaceutical composition thereof.

[0090] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the occurrence of, or inhibiting the progression of, a "pathological state" as described herein (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof). In some embodiments, treatment may be administered after one or more signs or symptoms have occurred or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a 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 be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0091] The terms "condition," "disease," and "disorder" are used interchangeably. Treatment can be a therapeutic treatment (not including preventative or prophylactic treatment).

[0092] "Effective amount" of compound (I) refers to an amount sufficient to induce a desired biological response, i.e., to treat a condition. As will be understood by those skilled in the art, the effective amount of compound (I) may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition to be treated, the mode of administration, and the age and health of the subject. Effective amounts include therapeutic and prophylactic treatments. For example, in the treatment of cancer, an effective amount of the compound may reduce tumor burden or stop tumor growth or spread.

[0093] 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 a condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0094] A "prophylactically effective amount" of Compound (I) is an amount sufficient to prevent a condition, or one or more symptoms associated with a condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0095] "Proliferative disorder" refers to a disorder arising due to the abnormal growth or extension of cells by proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders may involve: 1) pathological proliferation of normally quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as in proliferative retinopathies and tumor metastasis. Exemplary proliferative diseases include cancer (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, gastric 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., myeloid leukemia (e.g., chronic myeloid leukemia, acute myeloid leukemia)), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0096] The terms "neoplasm" and "tumor" are used interchangeably and refer to an abnormal mass of tissue in which the growth of the mass exceeds and is out of step with the growth of normal tissue. A neoplasm or tumor can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. "Benign neoplasms" are generally well differentiated, characteristically grow slower than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms do not have the ability to infiltrate, invasive, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratosis, lentigines, and sebaceous hyperplasia. In some cases, certain "benign" tumors may later give rise to malignant neoplasms, which may be the result of additional genetic changes in a subpopulation of neoplastic cells of the tumor, and these tumors are referred to as "premalignant neoplasms." An exemplary pre-malignant neoplasm is a teratoma. In contrast, a "malignant neoplasm" is generally poorly differentiated (anaplastic) and characteristically fast growing, with progressive infiltration, invasion, and destruction of surrounding tissue. Moreover, malignant neoplasms generally have the ability to metastasize to distant sites.

[0097] The terms "metastasis," "metastatic," or "metastasizing" refer to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue, and are typically identifiable by the presence of a "secondary tumor" or "secondary cell mass" of the primary or original tumor of a tissue type other than that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to bone is said to be metastatic prostate cancer, which contains cancerous prostate cancer cells growing in the bone tissue.

[0098] The term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Ed. Hensyl; Williams & Wilkins: Philadelphia, 1990). Cancer can be a solid tumor. Cancer can be a hematological malignancy. Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; bile duct cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast carcinoma, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); edema esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g., gastric 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 cancer (e.g., leukemia such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's 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 lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, etc.) lymphomas such as splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (e.g., IgM-secreting lymphoplasmacytic lymphoma, i.e., Waldenström'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 precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) ( and anaplastic large cell lymphoma); mixed leukemia / lymphomas such as one or more of the above; and multiple myeloma (MM); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., for example, hepatocellular carcinoma (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 carcinoma; myelodysplastic syndromes (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), myeloid metaplasia of unknown etiology (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES));Neuroblastoma; Neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); Neuroendocrine cancer (e.g., gastrointestinal pancreatic neuroendocrine tumor (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 adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); Penile cancer (e.g., Paget's disease of the penis and scrotum); Pinealoma; Primitive neuroectodermal tumor (PNT); Plasma cell neoplasm; Paraneoplastic syndromes; Intraepithelial neoplasm; Prostate cancer (e.g., prostatic 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 (small bowel These include, but are not limited to, 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; synovium; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0099] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in healthy subjects to heal wounds and restore blood flow to tissues after injury. A healthy body controls angiogenesis through several means, for example, angiogenic stimulatory growth factors and angiogenic 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. Aberrant or pathological angiogenesis refers to angiogenesis that is greater than normal in the body, especially angiogenesis in adults that is not associated with normal angiogenesis (e.g., menstruation or wound healing). Aberrant angiogenesis can provide new blood vessels to nourish diseased tissues and / or destroy normal tissues; in the case of cancer, the new blood vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastasis). In certain embodiments, the angiogenesis is pathological angiogenesis.

[0100] "Autoimmune disease" refers to a disease caused by an inappropriate immune response of a subject's body against substances and tissues normally present in the body. In other words, the immune system mistakes a part of the body as pathogenic and attacks its own cells. This may be limited to an organ (e.g., in autoimmune thyroiditis) or may involve specific tissues in different locations (e.g., Goodpasture's disease, which can affect the basement membrane in both the lungs and kidneys). Treatment of autoimmune diseases is typically by immunosuppression, e.g., drugs that reduce the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0101] 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 response that causes an excessive response by macrophages, granulocytes, and / or T lymphocytes, resulting in abnormal tissue damage and / or cell death. Inflammatory diseases can be either acute or chronic inflammatory conditions and can result from infectious or non-infectious causes.Inflammatory diseases include atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, osteoarthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, osteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes mellitus (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, and cholangitis. vasculitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, usual interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, beryllium poisoning, talc, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (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, erythroderma ... Rheumatoid dermatitis), hepatitis, delayed hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, airway inflammation, adult respiratory distress syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hay fever, allergy, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic 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, These include epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, ovariitis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis (urocystitis), uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, necrotizing enteritis, and inflammatory rosacea. Inflammatory diseases of the eye include postoperative inflammation.

[0102] The term "kinase" refers to any enzyme that catalyzes the addition of a phosphate group to an amino acid residue in a protein. For example, a serine kinase catalyzes the addition of a phosphate group to a serine residue in a protein. In certain embodiments, the kinase is a protein kinase. Examples of kinases include cytoplasmic tyrosine kinases (e.g., SRC family kinases (e.g., HCK, LYN, BLK, FRK), Tec family kinases (e.g., BTK)), cyclin-dependent kinases (CDKs, e.g., CDK1, CDK2, CDK2, CDK4, CDK5, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, CDK14, CDK16, CDK20), mitogen-activated protein kinases (MAPKs, e.g., MAPK1, MAPK2, CDK3, CDK4, CDK5, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, CDK14, CDK16, CDK20), and the like. , MAPK3, MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK15), glycogen synthase kinase 3 (GSK3, e.g., GSK3α, GSK3β), CDK-like kinases (CLKs, e.g., CLK1, CLK2, CLK3, CLK4), AGC kinases (e.g., protein kinase A (PKA), protein kinase C (PKC), protein kinase G (PKG)), Ca 2+ / Calmodulin-dependent protein kinase (CaM kinase, e.g., specific CaM kinase, multifunctional CaM kinase), casein kinase 1 (CK1, e.g., CK1 alpha, CK1 beta 1, CK1 gamma 1, CK1 gamma 2, CK1 gamma 3, CK1 delta, CK1 epsilon), STE kinase (e.g., homologs of yeast Sterile 7, Sterile 11, or Sterile 20 kinase), tyrosine kinase (TK, e.g., receptor tyrosine kinase (RTK), non-receptor tyrosine kinase (nRTK)), and tyrosine kinase-like kinase (TKL, e.g., mixed lineage kinase (MLK), RAF, serine threonine kinase receptor (STKR), leucine-rich repeat kinase (LRRK), LIM domain kinase (LIMK), testis-expressed serine kinase (TESK), IL1 receptor-associated kinase (IRAK), receptor-coupled protein kinase (RIPK)).

[0103] Hematopoietic cell kinase (HCK) is a member of the src-family of protein tyrosine kinases and is aberrantly upregulated in WM cells. In myeloma cells, HCK is activated by interleukin 6 (IL6) via the IL6 coreceptor IL6ST (GP130).

[0104] Bruton's tyrosine kinase (BTK) is a member of the src-related BTK / Tec family of cytoplasmic tyrosine kinases that is required for B cell receptor signaling, plays a key role in B cell maturation, and shows increased activation in several B cell malignancies.

[0105] LYN proto-oncogene (LYN) is a member of the src-family of protein tyrosine kinases, plays a key role in controlling 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 limited by theory, BCR signaling is thought to be involved in growth-promoting and survival signaling in MYD88 mutant diseases, as well as in non-MYD88 mutant diseases. For example, BCR signaling is thought to be active in Waldenstrom's macroglobulinemia, diffuse large B cell lymphoma of the ABC subtype, and chronic lymphocytic leukemia.

[0106] The proto-oncogene tyrosine-protein kinase SRC (SRC) is a protein tyrosine kinase that plays a central role in the regulation of various biological processes, such as cell proliferation, migration, adhesion, and survival in solid tumors, and is overexpressed in Waldenström's macroglobulinemia.

[0107] As used herein, "inhibition," "inhibiting," "inhibit," and "inhibitor," and the like, refer to the ability of a compound to reduce, slow, stop, block, or prevent the activity of a particular biological process in a cell (e.g., a kinase (e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec family kinase (e.g., BTK)) relative to a vehicle.

[0108] The term "block" or "blocking" refers to the ability of a compound to prevent a biological interaction (e.g., binding) in a cell compared to a negative control, e.g., vehicle. For example, a compound can block ATP binding to the ATP-binding pocket of a kinase. Such blocking can occur by direct binding of the compound to the ATP-binding pocket itself, or by indirect blocking. 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 statistically significantly lower than an initial level, which can be, for example, a baseline level of ATP binding. In some embodiments, the term refers to a decrease 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 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 the initial level, which may be, for example, a baseline level of ATP binding. In some embodiments, blocking ATP binding leads to a decrease 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 the initial level, which may be, for example, a baseline level of enzyme activity.

[0109] When a compound or pharmaceutical composition is said to bind "selectively," "specifically," or "competitively" to a first protein, the compound binds to the first protein, e.g., BTK or HCK or LYN or SRC, with a higher binding affinity (e.g., about 2-fold or more, about 5-fold or more, about 10-fold or more, about 30-fold or more, about 100-fold or more, about 1,000-fold or more, or about 10,000-fold or more) than it binds to a second protein that is different from the first protein, e.g., BTK. In some embodiments, the compound blocks ATP binding to the first protein, e.g., HCK or LYN or SRC, at a lower concentration (e.g., about 2-fold or more, about 5-fold or more, about 10-fold or more, about 30-fold or more, about 100-fold or more, about 1,000-fold or more, or about 10,000-fold or more) than the compound blocks ATP binding to the second protein that is different from the first protein, e.g., BTK.

[0110] Compounds provided herein that selectively block ATP binding to kinases (e.g., BTK, HCK, LYN) 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 HCK gatekeeper mutant rescue assays, in vitro kinase assays (e.g., using HCK gatekeeper mutant kinases), KiNativ™ technology, or competitive binding assays using biotin-tagged inhibitors, e.g., HCK inhibitors. Suitable assays for determining selective inhibition of HCK by a compound include the Life Technology Z-Lyte activity assay (e.g., using HCK gatekeeper mutant and GK inhibitors), and the like. + 6 mutants); DiscoverX KINOMEscan® binding assay; MRC radioactivity assay; ACD Ba / F3 viability assay (e.g., HCK gatekeeper mutants and GK + 6 mutants); yeast hybrid growth assay; protein thermostability assay; and HCK gatekeeper mutants or GK +Such assays can also be used to determine the selective inhibition of LYN and / or SRC by compounds, including, but not limited to, proliferation-rescue assays of cancer cells containing the 6 mutant.

[0111] The term "MYD88 mutation" refers to any change or difference in the nucleic acid or protein sequence of MYD88 compared to the wild-type sequence that results in activation of MYD88 leading to activation of NF-κB. 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 on chromosome 3p22.2 that results in a single nucleotide change of T to C in the myeloid differentiation primary response (MYD88) gene and a predicted nonsynonymous change of leucine to proline at amino acid position 265 (L265P). In some embodiments, the mutation is another activating mutation in MYD88, such as V217F, W218R, I220T, S222R, M232T, S243N, T294P, etc. Signal transduction studies show that SU-DHL-2 lymphoma cells, which express a serine to arginine mutation at amino acid position 222, also have upregulated HCK (Yang et al., Blood 2016). In some embodiments, somatic mutations in MYD88 can be identified using Sanger sequencing, whole-exome or whole-genome sequencing.

[0112] The term "MYD88 mutant disease" or "disease associated with mutant MYD88" refers to any disease in a subject that is associated with a change or difference in the nucleic acid or protein sequence of MYD88 compared to the wild-type sequence that results in activation of MYD88 leading to activation of NF-κB. In some embodiments, mutant MYD88 is associated with immune privileged lymphomas, including Waldenstrom's macroglobulinemia (IgM-secreting lymphoplasmacytic lymphoma), non-IgM-secreting lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma of the ABC subtype, primary central nervous system (CNS) lymphoma, testicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia. In some embodiments, mutant MYD88 is associated with susceptibility to infectious disease. In some embodiments, mutant MYD88 is associated with susceptibility to autoimmune disease. [Brief description of the drawings]

[0113] [Figure 1] FIG. 1 shows potential kinases targeted by compound (I). [Figure 2A] Figure 1 shows that compound (I) selectively targets HCK, BTK and LYN in MYD88 mutant WM and ABC DLBCL cells.Figure 2 shows KINOMEscan® results of compound (I) and A419259 against a panel of 464 kinases. [Figure 2B] Figure 1 shows that Compound (I) selectively targets HCK, BTK and LYN in MYD88 mutant WM and ABC DLBCL cells. Figure 2 shows the KiNativ™ cell target binding profile of Compound (I). Kinases bound by 1.0 μM Compound (I) treatment in TMD8 cells are shown to be greater than 50%. [Figure 2C]Figure 1 shows that Compound (I) selectively targets HCK, BTK and LYN in MYD88 mutant WM and ABC DLBCL cells. Figure 2 shows activated kinases enriched by pull-down assays using desthiobiotin-ATP probes following 90 min pretreatment of live BCWM.1 and TMD8 cells with the indicated concentrations of Compound (I) or ibrutinib, and ATP-bound HCK, BTK and LYN were resolved by Western blot. [Figure 3A] FIG. 1 shows the effects of Compound (I) and ibrutinib on HCK phosphorylation (N=3) by PhosFlow analysis. [Figure 3B] FIG. 1 shows the effect of Compound (I) and ibrutinib on BTK phosphorylation by Western blot in MYD88 mutant WM (BCWM.1, MWCL-1) and ABC DLBCL (TMD8, HBL-1) cell lines. [Figure 3C] FIG. 1 shows the effects of compound (I) and ibrutinib on HCK and BTK phosphorylation (N=4) by PhosFlow analysis in MYD88 mutant WM patient bone marrow tumor cells. [Figure 4A] Figure 1 shows the cellular efficacy of Compound (I) in MYD88 wild-type (MYD88WT) and MYD88 mutant (MYD88L265P) B-cell lymphoma cells.Figure 2 shows the dose-response of MYD88WT and MYD88L265P cell lines following 72 hour treatment with serially diluted Compound (I), A419259 and ibrutinib. [Figure 4B] Figure 1 shows the cellular efficacy of Compound (I) in MYD88 wild type (MYD88WT) and MYD88 mutant (MYD88L265P) B cell lymphoma cells. Figure 2 shows the apoptotic activity of primary BM lymphoplasmocytic cells from CD19+ B cells of six MYD88 mutant patients and six healthy donors after 16 hours of ibrutinib or Compound (I) treatment at the indicated concentrations. *p<0.05; **p<0.01; ****p<0.0001. [Figure 5A]Figure 1 shows that HCK gatekeeper mutant (HCKT333M) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in BCWM.1 WM cells. Figure 2 shows dose-response of vector only, or HCKWT or HCKT333M transduced BCWM.1 cells after 72 hours of compound (I) treatment. [Figure 5B] Figure 1 shows that HCK gatekeeper mutant (HCKT333M) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in BCWM.1 WM cells. Figure 2 shows relative pHCKY411 levels resolved by PhosFlow analysis after 1.0 hour treatment with the indicated concentrations of compound (I) in vector-only, HCKWT or HCKT333M-transduced MYD88 mutant BCWM.1 cells. [Figure 5C] Figure 1 shows that HCK gatekeeper mutant (HCKT333M) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in BCWM.1 WM cells. Figure 2 shows pBTKY223, pSYKY525 / 526, p-AKTS473, p-ERK1 / 2T202 / Y204 expression by Western blot analysis in HCKWT or HCKT333M-transduced BCWM.1 cells after 1.0 hour treatment with the indicated concentrations of compound (I). Also shown are the expression levels of BTK, SYK, AKT and ERK1 / 2 total in these cells, as well as the protein loading control GAPDH. [Figure 6A] Figure 1 shows that HCK gatekeeper mutant (HCKT333M) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in MWCL-1 WM cells.Figure 2 shows dose-response of vector only, or HCKWT or HCKT333M transduced BCWM.1 cells after 72 hours of compound (I) treatment. [Figure 6B]Figure 1 shows that HCK gatekeeper mutant (HCKT333M) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in MWCL-1 WM cells. Figure 2 shows relative pHCKY411 levels resolved by PhosFlow analysis after 1.0 hour treatment with the indicated concentrations of compound (I) in vector-only, HCKWT or HCKT333M-transduced MYD88 mutant BCWM.1 cells. [Figure 6C] Figure 1 shows that HCK gatekeeper mutant (HCKT333M) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in MWCL-1 WM cells. Figure 2 shows pBTKY223, pSYKY525 / 526, p-AKTS473, p-ERK1 / 2T202 / Y204 expression by Western blot analysis in HCKWT or HCKT333M-transduced BCWM.1 cells after 1.0 hour treatment with the indicated concentrations of compound (I). Also shown are the expression levels of BTK, SYK, AKT and ERK1 / 2 total in these cells, as well as the protein loading control GAPDH. [Figure 7A] Figure 1 shows that HCK gatekeeper mutant (HCKT333M) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in TMD8 ABC DLBCL cells.Figure 2 shows the dose-response of vector only, or HCKWT or HCKT333M transduced BCWM.1 cells after 72 hours of compound (I) treatment. [Figure 7B] Figure 1 shows that HCK gatekeeper mutant (HCKT333M) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in TMD8 ABC DLBCL cells.Figure 2 shows relative pHCKY411 levels resolved by PhosFlow analysis after 1.0 hour treatment with the indicated concentrations of compound (I) in vector-only, HCKWT or HCKT333M-transduced MYD88 mutant BCWM.1 cells. [Figure 7C]Figure 1 shows that HCK gatekeeper mutant (HCKT333M) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in TMD8 ABC DLBCL cells. Figure 2 shows pBTKY223, pSYKY525 / 526, p-AKTS473, p-ERK1 / 2T202 / Y204 expression by Western blot analysis in HCKWT or HCKT333M-transduced BCWM.1 cells after 1.0 hour treatment with the indicated concentrations of compound (I). Also shown are the expression levels of BTK, SYK, AKT and ERK1 / 2 total in these cells, as well as the protein loading control GAPDH. [Figure 8] FIG. 1 shows the in vitro and in vivo pharmacokinetic properties of Compound (I). [Figure 9] FIG. 1 shows the in vitro and in vivo pharmacokinetic properties of A419259. [Figure 10A] Figure 1 shows a pharmacodynamic study demonstrating the activity of HCK and BTK following oral administration of compound (I) in NOD-SCID mice xenografted subcutaneously with ibrutinib-sensitive BTKWT TMD8 ABC-DLBCL cells. Figure 2 shows a PhosFlow plot of pHCKY411 (n=3 per group) in excised GFP+ TMD8 tumor cells 6 and 24 hours after oral administration of the indicated doses of compound (I). ****p<0.0001. [Figure 10B] Figure 1 shows a pharmacodynamic study demonstrating HCK and BTK activity following oral administration of compound (I) in NOD-SCID mice xenografted subcutaneously with ibrutinib-sensitive BTKWT TMD8 ABC-DLBCL cells. Figure 2 shows a PhosFlow plot of pBTKY223 in excised GFP+ TMD8 tumor cells (n=3 per group) 6 and 24 hours after oral administration of the indicated doses of compound (I). ****p<0.0001. [Figure 11A]Figure 1 shows the effect of Compound (I) on tumor volume and survival in a BTKWT TMD8 ABC DLBCL xenograft mouse model. Efficacy study in NOD-SCID mice (n=8 per cohort) bearing ibrutinib-sensitive BTKWT TMD8 cells following daily oral administration of vehicle control, ibrutinib or Compound (I) at 50 mg / kg. Tumor volumes (mm3) were measured twice weekly and reported as mean volume ± SEM. Treatment was stopped on day 42 (indicated by green arrow) and tumor volumes were monitored until day 113. [Figure 11B] FIG. 1 shows the effect of Compound (I) on tumor volume and survival in a BTKWT TMD8 ABC DLBCL xenograft mouse model. Efficacy study in NOD-SCID mice (n=8 per cohort) bearing ibrutinib-sensitive BTKWT TMD8 cells following daily oral administration of vehicle control, ibrutinib or Compound (I) at 50 mg / kg. Tumor volume comparison at day 33. p-values ​​for cohort comparisons are shown. [Figure 11C] FIG. 1 shows the effect of Compound (I) on tumor volume and survival in a BTKWT TMD8 ABC DLBCL xenograft mouse model. Survival curve estimation using Kaplan-Meier method. Median survival times (days) of cohorts are shown using Prism software. Efficacy study in NOD-SCID mice (n=8 per cohort) bearing ibrutinib-sensitive BTKWT TMD8 cells following daily oral administration of vehicle control, ibrutinib or Compound (I) at 50 mg / kg. P<.0001 for log-rank comparison between cohorts. [Figure 12A] Figure 1 shows the in vitro cellular efficacy (drug dose-response) of ibrutinib or Compound (I).Drug dose-response was measured by CellTiter-Glo™ cell viability assay in vector only, BTKWT or BTKC481S expressing lentiviral vector transduced TMD8 ABC-DLBCL or BCWM.1 WM cells. [Figure 12B]Figure 1 shows the in vitro cellular efficacy (drug dose-response) of Ibrutinib or Compound (I). Apoptosis analysis measured by the inventors by flow cytometry using Annexin-V / PI staining, the percentage of apoptotic cells is shown. [Figure 13A] Figure 1 shows that Compound (I) blocks activation of HCK, BTK and downstream ERK1 / 2 in BTK Cys481 mutant BCWM.1 WM and TMD8 ABC DLBCL cell lines.Figure 2 shows relative pHCKY411 levels resolved by PhosFlow analysis following 1.0 hour treatment with the indicated concentrations of ibrutinib or Compound (I) in vector only, BTKWT or BTKC481S transduced BCWM.1 and TMD8 cells. [Figure 13B] Figure 1 shows that Compound (I) blocks activation of HCK, BTK and downstream ERK1 / 2 in BTK Cys481 mutant BCWM.1 WM and TMD8 ABC DLBCL cell lines. Figure 2 shows pBTKY223 and p-ERK1 / 2T202 / Y204 expression by Western blot analysis after 1.0 hour treatment with the indicated concentrations of ibrutinib or Compound (I) in vector only, BTKWT or BTKC481S transduced BCWM.1 and TMD8 cells. Total BTK and ERK1 / 2 expression levels in these cells, as well as protein loading control GAPDH, are also shown. [Figure 14A] Figure 1 shows a pharmacodynamic study demonstrating HCK and BTK activity following oral administration of compound (I) in NOD-SCID mice xenografted subcutaneously with ibrutinib-resistant BTKC481S TMD8 ABC-DLBCL cells. Figure 2 shows a PhosFlow plot of pHCKY411 (n=3 per group) in excised GFP+ TMD8 tumor cells 6 and 24 hours after oral administration of the indicated doses of compound (I). *p<0.05; **p<0.01; ***p<0.005; ****p<0.0001. [Figure 14B]Figure 1 shows a pharmacodynamic study demonstrating HCK and BTK activity following oral administration of compound (I) in NOD-SCID mice xenografted subcutaneously with ibrutinib-resistant BTKC481S TMD8 ABC-DLBCL cells. Figure 2 shows a PhosFlow plot of pBTKY223 (n=3 per group) in excised GFP+ TMD8 tumor cells 6 and 24 hours after oral administration of the indicated doses of compound (I). *p<0.05; **p<0.01; ***p<0.005; ****p<0.0001. [Figure 15A] Figure 1 shows the effect of Compound (I) on tumor volume and survival in an ibrutinib-resistant BTKC481S TMD8 ABC DLBCL xenograft mouse model. Efficacy study in NOD-SCID mice (n=8 per cohort) harboring ibrutinib-resistant BTKC481S-expressing TMD8 cells following daily oral administration of vehicle control, ibrutinib (50 mg / kg) or Compound (I) (50 or 75 mg / kg). Tumor volumes (mm3) were measured twice weekly and reported as mean volume ± SEM. [Figure 15B] Figure 1 shows the effect of Compound (I) on tumor volume and survival in an ibrutinib-resistant BTKC481S TMD8 ABC DLBCL xenograft mouse model. Efficacy study in NOD-SCID mice (n=8 per cohort) harboring ibrutinib-resistant BTKC481S-expressing TMD8 cells following daily oral administration of vehicle control, ibrutinib (50 mg / kg) or Compound (I) (50 or 75 mg / kg). Tumor volume comparison at day 29. p-values ​​for cohort comparisons are shown. [Figure 15C]Figure 1 shows the effect of Compound (I) on tumor volume and survival in an ibrutinib-resistant BTKC481S TMD8 ABC DLBCL xenograft mouse model. Survival curve estimation using Kaplan-Meier method. Median survival times (days) of cohorts are shown using Prism software. Efficacy study in NOD-SCID mice (n=8 per cohort) harboring ibrutinib-resistant BTKC481S-expressing TMD8 cells following daily oral administration of vehicle control, ibrutinib (50 mg / kg) or Compound (I) (50 or 75 mg / kg). P<.0007 for log-rank comparison between cohorts. [Figure 16A] Figure 1 shows the effect of Compound (I) on tumor volume and survival in an ibrutinib-resistant BTKC481S TMD8 ABC DLBCL xenograft mouse model. Efficacy study in NOD-SCID mice (n=8 per cohort) harboring ibrutinib-resistant BTKC481S-expressing TMD8 cells following daily oral administration of vehicle control, ibrutinib (50 mg / kg), A419259 (50 mg / kg) or Compound (I) (50 mg / kg). Tumor volumes (mm3) were measured twice weekly and reported as mean volume ± SEM. [Figure 16B] Figure 1 shows the effect of Compound (I) on tumor volume and survival in an ibrutinib-resistant BTKC481S TMD8 ABC DLBCL xenograft mouse model. Efficacy study in NOD-SCID mice (n=8 per cohort) harboring ibrutinib-resistant BTKC481S-expressing TMD8 cells following daily oral administration of vehicle control, ibrutinib (50 mg / kg), A419259 (50 mg / kg) or Compound (I) (50 mg / kg). Tumor volume comparison at day 33. p-values ​​for cohort comparisons are shown. [Figure 16C]Figure 1 shows the effect of Compound (I) on tumor volume and survival in an ibrutinib-resistant BTKC481S TMD8 ABC DLBCL xenograft mouse model. Survival curve estimation using Kaplan-Meier method. Median survival times (days) of cohorts are shown using Prism software. Efficacy study in NOD-SCID mice (n=8 per cohort) harboring ibrutinib-resistant BTKC481S-expressing TMD8 cells following daily oral administration of vehicle control, ibrutinib (50 mg / kg), A419259 (50 mg / kg) or Compound (I) (50 mg / kg). P<0.0001 for log-rank comparison between cohorts. [Figure 17] FIG. 1 shows an in vitro study evaluating the synergistic interaction of compound (I) and venetoclax in native (non-transduced) BTKWT and BTKC481S expressing MYD88 mutant BCWM.1 WM and TMD8 ABC DLBCL cells. Combination index (CI) and normalized isobologram analysis are shown. CI<1 (indicated by red shade) or points below the diagonal line in the isobologram plot indicate synergistic effect of the combination. [Figure 18A] Figure 1 shows the effect of the combination of Compound (I) and venetoclax on tumor volume and survival in an ibrutinib-resistant BTKC481S TMD8 ABC DLBCL xenograft mouse model. Efficacy study in NOD-SCID mice (n=8 per cohort) harboring ibrutinib-resistant BTKC481S-expressing TMD8 cells following daily oral administration of vehicle control, venetoclax (50 mg / kg), Compound (I) (30 mg / kg), or a combination of venetoclax (50 mg / kg) and Compound (I) (30 mg / kg). Tumor volumes (mm3) were measured twice weekly and reported as mean volume ± SEM. [Figure 18B]Figure 1 shows the effect of combination of Compound (I) and venetoclax on tumor volume and survival in an ibrutinib-resistant BTKC481S TMD8 ABC DLBCL xenograft mouse model. Efficacy study in NOD-SCID mice (n=8 per cohort) harboring ibrutinib-resistant BTKC481S-expressing TMD8 cells following daily oral administration of vehicle control, venetoclax (50 mg / kg), Compound (I) (30 mg / kg), or a combination of venetoclax (50 mg / kg) and Compound (I) (30 mg / kg). Tumor volume comparison at day 22. p-values ​​for cohort comparisons are shown. [Figure 18C] Figure 1 shows the combination of Compound (I) and venetoclax on tumor volume and survival in an ibrutinib-resistant BTKC481S TMD8 ABC DLBCL xenograft mouse model. Survival curve estimation using Kaplan-Meier method. Median survival times (days) of the cohorts are shown using Prism software. Efficacy study in NOD-SCID mice (n=8 per cohort) harboring ibrutinib-resistant BTKC481S-expressing TMD8 cells following daily oral administration of vehicle control, venetoclax (50 mg / kg), Compound (I) (30 mg / kg), or a combination of venetoclax (50 mg / kg) and Compound (I) (30 mg / kg). P=0.0020 for log-rank comparison between cohorts. [Figure 19] FIG. 1 shows that HCK activation status in CLL patients was assessed in primary tumor cells from peripheral blood mononuclear cells (PBMCs) of pretreated or untreated patients. [Figure 20] FIG. 1 shows Annexin V-PI (propidium iodide) assay of freshly isolated tumor cells harboring the BTKC481S mutation in peripheral blood mononuclear cells (PBMCs) from ibrutinib-relapsed CLL patients treated with either ibrutinib or compound (I). [Figure 21]FIG. 1 shows western blot analysis of phosphorylation levels of BTK, LYN, and ERK1 / ERK2 after 1 hour incubation with ibrutinib, dasatinib, A419259, and compound (I) in BTK wild-type and BTKC481S mutant-expressing BCWM.1 cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0114] The present disclosure is based, in part, on the surprising finding that subjects treated with compound (I) showed increased survival rates compared to subjects treated with other BTK inhibitors (e.g., ibrutinib, A419259). Without wishing to be limited by any theory, the increased survival rates may be the result of a shorter half-life in vivo of compound (I) compared to other BTK inhibitors (e.g., A419259). The shorter half-life of compound (I) compared to other BTK inhibitors (e.g., A419259) may lead to reduced toxicity of the compound. In certain embodiments, the half-life of compound (I) is less than 20% of the half-life of other BTK inhibitors (e.g., A419259) in vivo. In certain embodiments, the half-life of compound (I) is less than 10% of the half-life of other BTK inhibitors (e.g., A419259) in-vivo.

[0115] Provided herein are methods for treating a disease (e.g., a proliferative disease (e.g., IgM gammopathy (e.g., 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, gastric cancer), lymphoma (e.g., B cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM-secreting lymphoplasmacytic lymphoma (i.e., Waldenström's macroglobulinemia), non-IgM-secreting lymphoplasmacytic lymphoma (i.e., Waldenström's macroglobulinemia), 26. A method for treating lymphomas (e.g., diffuse large B cell lymphomas (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), myelomas (e.g., IgM myelomas (e.g., IgM multiple myeloma)), and leukemias (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myeloid leukemias (e.g., chronic myelogenous leukemia, acute myeloid leukemia (e.g., mast cell leukemia)), myeloproliferative disorders (e.g., myelodysplastic syndromes)), comprising administering a therapeutically effective amount of a compound of the formula:

[0116] [ka]

[0117] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, stereoisomer, or prodrug thereof to a subject. In certain embodiments, the method comprises administering Compound (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the disease is associated with a mutant MYD88 protein. In certain embodiments, the disease is associated with a mutant BTK protein. In certain embodiments, the disease is associated with a C481 mutant BTK protein. In certain embodiments, the disease is associated with a C481S mutant BTK protein. In some embodiments, the disease is associated with abnormal activity 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 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 mutant BTK protein (e.g., C481S mutant BTK) and the disease is resistant to treatment with ibrutinib.

[0118] Further provided herein is a therapeutically effective amount of a compound of the formula:

[0119] [ka]

[0120] A method for inhibiting the activity of a kinase in a subject, comprising administering to the subject Compound (I) of the formula (I) or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, isotopically labeled derivative, stereoisomer, or prodrug thereof. In certain embodiments, the kinase is an SRC family kinase (e.g., HCK, LYN, BLK, FRK). In other embodiments, the kinase is a Tec family kinase (e.g., BTK). In certain embodiments, 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, BTK is ibrutinib-resistant.

[0121] Provided herein is a method of treating a subject having a MYD88 mutant disease, comprising administering to the subject a MYD88 mutant disease. MYD88 mutant diseases include proliferative diseases (e.g., IgM gammopathy (e.g., 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, gastric 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 myeloma (e.g., IgM multiple myeloma)), and leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myeloid leukemia (e.g., chronic myelogenous leukemia, acute myeloid leukemia (e.g., mast cell leukemia)), myeloproliferative disorders (e.g., myelodysplastic syndrome) ...

[0122] In some embodiments, the provided method includes inhibiting LYN and / or SRC, comprising administering to a subject a therapeutically effective amount of compound (I), or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, isotopically labeled derivative, stereoisomer, or prodrug thereof. In some embodiments, the method further includes administering an agent that inhibits LYN and / or SRC. For example, in some embodiments, compound (I) as described herein is administered to a subject in combination (e.g., simultaneously or sequentially) with an agent that blocks ATP binding to SRC. In some embodiments, compound (I) as described herein is administered to a subject in combination (e.g., simultaneously or sequentially) with an agent that blocks ATP binding to LYN. In some embodiments, compound (I) as described herein is administered to a subject in combination (e.g., simultaneously or sequentially) with an agent that blocks ATP binding to HCK.

[0123] In some embodiments, the methods provided include inhibiting a Tec family kinase, comprising administering to a subject a therapeutically effective amount of compound (I), or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, stereoisomer, or prodrug thereof. In some embodiments, the methods provided include inhibiting BTK, comprising administering to a subject a therapeutically effective amount of compound (I), or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, stereoisomer, or prodrug thereof. In some embodiments, the methods further include administering an agent that inhibits BTK and / or other Tec family kinases. For example, in some embodiments, compound (I) as described herein is administered to a subject in combination (e.g., simultaneously or sequentially) with an agent that blocks ATP binding to a Tec family kinase. In some embodiments, compound (I) as described herein is administered to a subject in combination (e.g., simultaneously or sequentially) with an agent that blocks ATP binding to BTK.

[0124] In some embodiments, the selective inhibition of HCK and / or LYN and / or SRC by a compound can be determined by a native protein kinase activity profiling assay, such as KiNativ™ profiling. As described in the Examples, in some embodiments, the ability of an inhibitor to protect a kinase from subsequent labeling with a reactive ATP-biotin probe can be determined. Live cells can be treated with Compound (I), followed by lysis with ATP-biotin, and Western blotted for BTK and HCK and / or LYN and / or SRC. It can be determined whether the compound being tested blocks ATP binding to one or more specific concentrations of HCK and / or LYN and / or SRC, and whether the compound being tested blocks ATP binding to one or more concentrations of BTK. In such an assay, the blockade of binding to ATP can be determined by the absence of a detectable band in a Western blot when performed under the conditions described in Example 1. In some embodiments, the compound blocks ATP binding to HCK and / or LYN and / or SRC at a concentration that is at least 10-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 150-fold, at least 200-fold, at least 250-fold, at least 300-fold, at least 350-fold, at least 400-fold, at least 450-fold, at least 500-fold, at least 750-fold, or at least 1000-fold lower than the concentration at which it blocks ATP binding to BTK under comparable conditions. In some embodiments, the compound blocks ATP binding to HCK and / or LYN and / or SRC at a concentration that is at least 10-fold lower than the concentration at which it blocks ATP binding to Bruton's tyrosine kinase (BTK) under comparable conditions.

[0125] Those skilled in the art will understand that many suitable methods can be used to detect mutations in MYD88 gene, including those discussed in the examples.Detection methods that can be used include, but are not limited to, direct sequencing, DNA chip technology, mass spectrometry, 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 performance liquid chromatography.In some embodiments, mutations in MYD88 gene can be detected by allele-specific polymerase chain reaction (AS-PCR), for example, as described in WO2013 / 006443.

[0126] One or more symptoms or clinical features of LPL include anemia, hyperviscosity, neuropathy, coagulopathy, splenomegaly, hepatomegaly, adenopathy, and IgM serum paraprotein. In addition, subjects may also present with one or more of the following clinical features or symptoms of other B-cell neoplasms: asymptomatic localized or generalized peripheral lymphadenopathy, plasma cell differentials, bone marrow involvement, autoimmune thrombocytopenia, peripheral blood trophoblastic lymphocytes, end-organ damage (hypercalcemia, renal insufficiency, bone lesions), recurrent infections, hypercreatine, hyperuricemia, and hypoalbuminemia. Subjects suspected of having one or more of immune-privileged lymphomas, including Waldenstrom's macroglobulinemia (i.e., IgM-secreting lymphoplasmacytic lymphoma), non-IgM-secreting lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma of the ABC subtype, primary central nervous system (CNS) lymphoma, testicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia, may be evaluated for the presence of mutations in the gene encoding MYD88, e.g., at position 38182641 on chromosome 3p22.2, as well as other activating mutations in MYD88 (including, but not limited to, V217F, W218R, I220T, S222R, M232T, S243N, and T294P).

[0127] In some embodiments, the treatment further comprises administering to the subject an agent, e.g., an anti-cancer agent, in combination with a compound described herein. In some embodiments, the treatment further comprises administering to the subject one or more of bendamustine, fludarabine, bortezomib, or idelalisib. In some embodiments, the treatment further comprises 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 alveolar sarcoma, or a combination thereof. The method further comprises administering to the subject one or more of the following: a killer drug (e.g., bendamustine, cyclophosphamide), a nucleoside analog (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 immunomodulator (e.g., thalidomide or lenalidomide). In some embodiments, the anti-cancer drug is a monoclonal antibody, e.g., rituximab. In some embodiments, the anti-cancer drug is a chemotherapeutic drug, such as chlorambucil, cyclophosphamide, or vincristine or thalidomide. Corticosteroids, such as prednisone, may also be used in combination. Plasma exchange therapy may be used to treat hyperviscosity syndrome by removing paraproteins from the blood. Autologous bone marrow transplantation may be used in combination with the compounds described herein. In some embodiments, the treatment further comprises administering to the subject an agent that inhibits LYN and / or SRC.

[0128] When administered to a subject, the effective amount of the therapeutic agent will depend on the specific disease being treated; the severity of the disease; individual patient parameters including age, physical condition, size and weight, concurrent treatments, frequency of treatment, and mode of administration. These factors are well known to those skilled in the art and can be addressed with only routine experimentation. In some embodiments, a maximum dose is used, i.e., the highest dose that is safe according to sound medical judgment.

[0129] An effective amount of the compound will typically vary from about 0.001 mg / kg to about 1000 mg / kg in one or more doses administered over a period of one or several days (depending on the course of the mode of administration and the factors discussed above).

[0130] The actual dosage level of the therapeutic agent can be varied to obtain an amount that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. The dosage level selected will depend on the activity of the particular compound, the route of administration, the tissue being treated, and the previous medical history of the patient being treated. However, it is within the skill of the art to start the dose of the compound at a level lower than required to achieve the desired therapeutic effort, and gradually increase the dosage until the desired effect is achieved.

[0131] In the treatment of MYD88 mutated diseases, such as immune privileged lymphomas, including Waldenstrom's macroglobulinemia (IgM-secreting lymphoplasmacytic lymphoma), non-IgM-secreting lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma of the ABC subtype, primary central nervous system (CNS) lymphoma, testicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia, an effective amount of a selective HCK inhibitor is an amount that slows down, stops, or reverses the progression of the disease. Effective amounts include, but are not limited to, the amount required to slow down, reduce, inhibit, ameliorate, or reverse one or more symptoms associated with MYD88 mutated diseases. In some embodiments, such terms refer to a reduction in the levels of IgM serum paraprotein, anemia, hyperviscosity, neuropathy, coagulopathy, splenomegaly, hepatomegaly, and adenopathy.

[0132] The pharmaceutical preparations and compounds are administered to a subject by any suitable route. For example, the compositions can be administered orally, including sublingually, rectally, parenterally, intracisternally, vaginally, intraperitoneally, topically, and transdermally (as by powders, ointments, or drops), bucally, or nasally. The pharmaceutical preparations of the present disclosure may contain or be diluted in a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" refers to one or more compatible fillers, diluents, or other such substances that are suitable for administration to humans or other mammals, such as dogs, cats, or horses. The term "carrier" refers to a natural or synthetic organic or inorganic component with which the active ingredient is combined to facilitate application. The carriers can be mixed with the preparations of the present disclosure, and with each other, in such a way that there is no interaction that 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 disclosure also provides pharmaceutical compositions comprising the compounds described herein and, optionally, a pharma- ceutically acceptable excipient.

[0133] The dosage ranges as described herein provide guidance for administration of the provided pharmaceutical compositions to adults. For example, the amount to be administered to a child or adolescent can be determined by a physician or person skilled in the art and may be less than or the same as the amount administered to an adult.

[0134] The compounds or compositions may be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutic and / or prophylactic active agents) as described herein. The compounds or compositions may be administered in combination with additional pharmaceutical agents that improve their 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 kinase (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 understood that the treatments used may achieve the desired effect on the same disorder and / or may achieve different effects. In certain embodiments, the pharmaceutical compositions described herein that include the compounds described herein and the additional pharmaceutical agents exhibit synergistic effects that are not present in pharmaceutical compositions that include one of the compounds and the additional pharmaceutical agents but not both.

[0135] The compound or composition may be administered simultaneously with, prior to, or subsequent to one or more additional pharmaceutical agents that may be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration, as described 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, DNA, RNA, 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., a proliferative disease, a cancer, an inflammatory disease, an autoimmune disease, a genetic disease, a hematological disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder) or a pre-malignant condition. Each additional pharmaceutical agent may be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may be administered in a single dose together with each other and / or the compounds or compositions described herein, or may be administered separately in different doses. The particular combination to use in the regimen will take into consideration the compatibility of the compounds described herein with the additional pharmaceutical agents and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents of the combination will 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 the levels utilized individually.

[0136] The additional pharmaceutical agent includes, but is not limited to, a cytotoxic chemotherapeutic agent, an epigenetic modifier, a glucocorticoid, an immunotherapeutic agent, an anti-proliferative agent, an anti-cancer agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunosuppressant, an anti-bacterial agent, an anti-viral agent, a cardiovascular agent, a cholesterol-lowering agent, an anti-diabetic agent, an anti-allergy agent, a contraceptive agent, an analgesic agent, and combinations thereof. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent (e.g., an anti-cancer agent). In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of 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 (methotrexate), 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 (bendamustine hydrochloride), TRISENOX (arsenic trioxide), 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), AMBOCHLORIN (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 (Praratrexate), HYPER-CVAD, ICE, IMBRUVICA (Ibrutinib), INTRON A (Recombinant Interferon Alpha-2b), ISTODAX (Romidepsin), LEUKERAN (Chlorambucil), LINFOLIZIN (Chlorambucil), Lomustine, MATULANE (Procarbazine Hydrochloride), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plelixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab),STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (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 (vandetanib) , 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), EVACET (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), GEMCITABINE-CISPLATIN, 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 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 liposomal), 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 (plelixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacytidine), 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 (pertuzumab), 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, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992(TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, 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), rifabutinib (RIBA ... Daforolimus, AP23573 (Ariad), AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, and OSI-027), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase,Aminopterin, methopterin, porfiromycin, melphalan, leurocidin, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine, or combinations thereof. In certain embodiments, the additional pharmaceutical agent is a cytotoxic chemotherapeutic agent (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, l-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 tyrosine kinase. In some embodiments, the additional pharmaceutical agent is a topoisomerase inhibitor, an MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, a BRCA2 inhibitor, a HER1 inhibitor, a 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'-(((1R,4R)-4-(((R)-1-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), an A Tec family kinase (e.g., BTK)). In certain embodiments, the additional pharmaceutical agent is an antibody or fragment thereof (e.g., a 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 agents (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 protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, 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 immunomodulatory agent. 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, a lymphocyte activation gene-3 (LAG3) inhibitor, a V-set domain-containing T cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitor, a cluster of differentiation 276 (CD276 or B7-H3) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a galectin-9 (GAL9) inhibitor, a checkpoint kinase 1 (Chk1) inhibitor, an adenosine A2A receptor (A2AR) inhibitor, an indoleamine 2,3-dioxygenase (IDO) inhibitor, a killer cell immunoglobulin-like receptor (KIR) inhibitor, or a 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 or pharmaceutical compositions described herein may be administered in combination with anti-cancer treatments, including, but not limited to, surgery, radiation therapy, and transplantation (e.g., stem cell transplantation, bone marrow transplantation).

[0137] In certain embodiments, the additional pharmaceutical agent is a BCL-2 inhibitor (e.g., venetoclax, navitoclax, obatoclax), a BCL-2 / BCL-xL inhibitor (e.g., APG-1252, BM-1197).

[0138] In certain embodiments, the additional pharmaceutical agent is venetoclax.

[0139] In certain embodiments, the compounds described herein are provided in an effective amount (e.g., effective to inhibit a kinase, such as an SRC family kinase (e.g., HCK, LYN, BLK, FRK) or a Tec family kinase (e.g., BTK) in a pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, a therapeutically effective amount is an amount effective to inhibit a kinase. In certain embodiments, a therapeutically effective amount is an amount effective to treat a disease (e.g., a disease associated with aberrant activity of a kinase (e.g., a proliferative disease)). In certain embodiments, a therapeutically effective amount is an amount effective to inhibit activity of a kinase and treat a disease (e.g., a disease associated with aberrant activity of a kinase (e.g., a proliferative disease)). In certain embodiments, a therapeutically effective amount is an amount effective to induce apoptosis in a cell (e.g., a malignant cell, a pre-malignant cell).

[0140] In certain embodiments, an effective amount is an amount effective to inhibit activity of the 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, an effective amount is an amount effective to inhibit activity of the kinase by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, or no more than 98%.

[0141] In certain embodiments, the subject is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject described herein is a human (e.g., adult, juvenile, or child). In certain embodiments, the subject is a non-human 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 modified animal. In certain embodiments, the subject is a transgenic animal (e.g., a transgenic mouse, a transgenic pig). In certain embodiments, the subject is a fish or a reptile.

[0142] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparation methods include bringing into association a compound described herein (i.e., the "active ingredient") with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single-dose or multi-dose unit.

[0143] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as single unit doses, and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that 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.

[0144] The relative amounts of the active ingredient, pharma- ceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is to be administered. The compositions may contain between 0.1% and 100% (w / w) active ingredient.

[0145] Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may also be present in the composition.

[0146] 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, corn starch, powdered sugar, and mixtures thereof.

[0147] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, 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(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0148] Exemplary surfactants 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., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenans, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene cellulose, polyvinyl alcohol ... Ethylene 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(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate,Potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0149] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), 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.

[0150] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal 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.

[0151] 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.

[0152] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. 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.

[0153] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0154] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0155] 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.

[0156] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (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, Neolone®, Kathon®, and Euxyl®.

[0157] Exemplary buffering agents include citrate buffer solution, acetate buffer solution, phosphate buffer solution, 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.

[0158] Exemplary lubricants 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.

[0159] Exemplary natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, black current seed oil, borage oil, cade oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter oil, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, gourd oil, grape seed oil, hazelnut oil, hyssop oil, isopropyl myristate oil, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, litsea cubeba oil, macadamia nut oil, and the like. nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, sabryonia oil, sea buckthorn oil, sesame oil, shea butter oil, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. 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.

[0160] Liquid dosage forms for oral and parenteral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers 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 oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may contain auxiliary agents, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with a solubilizing agent such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0161] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any brand of fixed oil can be used, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0162] 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.

[0163] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0164] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing a conjugate described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at room temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active ingredient.

[0165] 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 pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) humectants, such as glycerol; (d) agar, calcium carbonate, potato, or other suitable saccharides; They are mixed with disintegrating agents such as potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarders such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as 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 contain buffering agents.

[0166] Similar types of solid compositions can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and 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 can optionally contain opacifying agents and can be of a composition that releases the active ingredient only, or preferentially in a certain part of the intestinal tract, optionally delayed. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

[0167] The active ingredient may be in microencapsulated form with one or more excipients as mentioned 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 art of pharmaceutical formulation. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may contain additional substances other than the inert diluent, as is common practice, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially in a certain part of the intestinal tract, optionally with a delay. Examples of encapsulating agents that can be used include polymeric substances and waxes.

[0168] Dosage forms for topical and / or transdermal administration of the compounds described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. In general, the active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier or excipient and / or any necessary preservatives and / or buffers as may be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of the active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in a suitable medium. Alternatively or additionally, the rate can be controlled by providing a rate-controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0169] Devices suitable for use in delivering the intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices that limit the effective penetration length of the needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical Mantoux method of intradermal administration. Jet injection devices are suitable that deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle that penetrates the stratum corneum and creates a jet that reaches the dermis. Ballistic powder / particle delivery devices are suitable that use compressed gas to accelerate the compound in powder form through the outer layer of the skin to the dermis.

[0170] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as oil-in-water and / or water-in-oil emulsions, such as liniments, lotions, creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may contain, for example, about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further include one or more of the additional ingredients described herein.

[0171] The pharmaceutical compositions described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such formulations may comprise dry particles comprising the active ingredient and having a diameter in the range of about 0.5 to about 7 nanometers, or about 1 to about 6 nanometers. Such compositions are conveniently in the form of a dry powder for administration using a device with a dry powder reservoir capable of directing a flow of propellant to disperse the powder, and / or using a self-propelling solvent / powder dispensing container, such as a device containing the active ingredient dissolved and / or suspended in a low boiling point propellant in a sealed container. Such powders comprise particles in which at least 98% of the particles by mass 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 mass 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.

[0172] Low boiling propellants generally include liquid propellants having a boiling point below 65° F. at atmospheric pressure. Generally, the propellant may comprise 50-99.9% (w / w) of the composition and the active ingredient may comprise 0.1-20% (w / w) of the composition. The propellant may further comprise additional ingredients such as liquid non-ionic and / or solid anionic surfactants and / or solid diluents (which may have a particle size similar to that of the particles containing the active ingredient).

[0173] The 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 formulations may be prepared, packaged, and / or sold as optionally sterile, aqueous and / or dilute alcoholic solutions and / or suspensions containing the active ingredient, and may be conveniently administered using any nebulizing and / or atomizing device. Such formulations may further comprise one or more additional ingredients, including, but not limited to, flavoring agents such as sodium saccharin, volatile oils, buffering agents, surfactants, and / or preservatives such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range of about 0.1 to about 200 nanometers.

[0174] The formulations described herein as useful for pulmonary delivery are useful for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle size of about 0.2 to 500 micrometers. Such formulations are administered by rapid inhalation through the nasal passages from a container of the powder held close to the nostrils.

[0175] Formulations for nasal administration may, for example, contain from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may include one or more of the additional ingredients described herein. The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in formulations 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) of the active ingredient, the remainder comprising an orally dissolvable and / or degradable composition, and optionally one or more of the additional ingredients described herein. Alternatively, 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 size and / or droplet size in the range of about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0176] Pharmaceutical compositions described herein may be prepared, packaged, and / or sold in a formulation for ocular administration. Such formulations may be in the form of, for example, eye drops comprising a 0.1 to 1.0% (w / w) solution and / or suspension of the active ingredient in, for example, an aqueous or oily liquid carrier or excipient. Such drops may further comprise a buffering agent, a salt, and / or one or more other additional ingredients described herein. Other ophthalmically administrable formulations that are useful include those which comprise 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 the present disclosure.

[0177] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to animals of all kinds. Modifications of pharmaceutical compositions suitable for administration to humans to provide compositions suitable for administration to a variety of animals are well understood and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications with routine experimentation.

[0178] The compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage.However, it will be understood that the total daily use amount of the compositions described herein will be determined by a physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism will depend on various factors, including the severity of the disease and disorder being treated; the activity of the specific active ingredient used; the specific composition being used; the age, weight, general health, sex and diet of the subject; the time of administration, the route of administration and the excretion rate of the specific active ingredient used; the duration of treatment; the drug used in combination with or simultaneously with the specific active ingredient used; and similar factors well known in the medical technology field.

[0179] The compounds and compositions provided herein may be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intracerebroventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (such as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), local administration via the blood and / or lymphatic supply, and / or direct administration to the affected area. In general, the most appropriate route of administration will depend on 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 can tolerate oral administration). In certain embodiments, the compounds or pharmaceutical compositions described herein are suitable for topical administration to the subject's eye.

[0180] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the species, age, and general condition of the subject, the severity of side effects or disorders, the identity of the particular compound, the mode of administration, and the like. An effective amount can be contained in a single dose (e.g., a 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 contain different or substantially the same amount of the compound described herein. In certain embodiments, when multiple doses are administered to a subject, the frequency with which the multiple doses are administered to a subject is three doses per day, two doses per day, one dose per 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 with which the multiple doses are administered to a subject is one dose per day. In certain embodiments, the frequency with which the multiple doses are administered to a subject is two doses per day. In certain embodiments, the frequency of administering multiple doses to the subject is 3 doses per day.In certain embodiments, when multiple doses are administered to the subject, the period between the first administration and the last administration of multiple doses is 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years, 15 years, 20 years, or the lifespan of the subject or cell.In certain embodiments, the period between the first administration and the last administration of multiple doses is 3 months, 6 months, or 1 year.In certain embodiments, the period between the first administration and the last administration of multiple doses is the lifespan of the subject. In certain embodiments, a dose described herein (e.g., either a single dose, or multiple doses) independently comprises between 0.1 μg and 1 μg, 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, the doses described herein independently comprise between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, the doses described herein independently comprise between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, the doses described herein independently comprise between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, the doses described herein independently comprise between 30 mg and 100 mg, inclusive, of a compound described herein.

[0181] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). In certain embodiments, the kits include a compound (I) or pharmaceutical composition described herein and instructions for using the compound or pharmaceutical composition. In certain embodiments, the kits include a first container that includes the compound or pharmaceutical composition. In some embodiments, the kits further include a second container. In certain embodiments, the second container includes an excipient (e.g., an excipient for diluting or suspending the compound or pharmaceutical composition). In certain embodiments, the second container includes an additional pharmaceutical agent. In some embodiments, the kits further include 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 produce 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 produce one unit dosage form. In certain embodiments, each of the first, second, and third containers is independently a vial, an ampoule, a bottle, a syringe, a dispenser package, a tube, or an inhaler.

[0182] 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 include information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). In certain embodiments, the instructions include prescribing information.

[0183] In another aspect, the disclosure provides a method of treating a disease in a subject in need thereof, comprising administering to a subject in need thereof an effective amount (e.g., a therapeutically effective amount) of a compound (I) described herein or a pharmaceutical composition described herein.

[0184] In another aspect, the disclosure provides a method of preventing a disease in a subject in need thereof, comprising administering to a subject in need thereof an effective amount (e.g., a prophylactically effective amount) of a compound described herein or a pharmaceutical composition described herein.

[0185] In another aspect, the disclosure provides a method of inhibiting activity of a kinase in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound described herein or a pharmaceutical composition described herein.

[0186] Without wishing to be limited by any particular theory, in certain embodiments, the compounds described herein can bind the kinase to be inhibited. In certain embodiments, the compounds described herein can bind to the kinase. In certain embodiments, the kinase is an SFK (e.g., HCK, LYN, BLK, FRK). In certain embodiments, the kinase is HCK. In certain embodiments, the kinase is LYN. In certain embodiments, the kinase is a Tec family kinase (e.g., BTK). In certain embodiments, the kinase is BTK.

[0187] In certain embodiments, provided are methods of reducing 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, activity of the kinase in the subject is reduced 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 some embodiments, activity of the kinase in the subject is selectively inhibited by the method. In some embodiments, activity of the kinase (e.g., HCK, LYN, BTK) in a subject is selectively reduced by a compound or pharmaceutical composition described herein.

[0188] Diseases, including proliferative diseases, may be associated with abnormal or unwanted activity of kinases and / or overexpression of kinases. The abnormal or unwanted activity of kinases may be increased or decreased levels of activity of kinases. Proliferative diseases are sometimes associated with abnormal levels of JAK activity, often through increased or decreased JAK activation. Inhibition of JAK2 activity is expected to inhibit phosphorylation. In certain embodiments, JAK2 is not overexpressed, but activity of JAK2 is increased. In certain embodiments, JAK2 is overexpressed and activity of JAK2 is increased. The compounds and pharmaceutical compositions described herein can inhibit the activity of JAK2 and may be useful in treating and / or preventing diseases, such as diseases associated with abnormal, increased, or unwanted activity of kinases, overactivation of kinases, and / or overexpression of kinases.

[0189] In certain embodiments, the disease (e.g., a disease to be treated or prevented by the methods described herein) is associated with increased activity of a kinase (e.g., an SFK (e.g., HCK, LYN, BLK, FRK), a Tec family kinase (e.g., BTK)). In certain embodiments, the disease is associated with overexpression of a kinase (e.g., an SFK (e.g., HCK, LYN, BLK, FRK), a Tec family kinase (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 a mutant 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 an IgM monoclonal gammopathy of undetermined significance.

[0190] 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 gastric cancer. In certain embodiments, the disease is lymphoma. In certain embodiments, the lymphoma is B-cell lymphoma. In certain embodiments, the 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 cell-like (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 myeloid leukemia. In certain embodiments, the myeloid leukemia is chronic myeloid leukemia. In certain embodiments, the myeloid leukemia is acute myeloid leukemia. In certain embodiments, the acute myeloid 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 disorder. In certain embodiments, the myeloproliferative disorder is a myelodysplastic syndrome.

[0191] In certain embodiments, the methods described herein are superior (e.g., exhibit improved safety and / or therapeutic efficacy) to or comparable to existing therapies (e.g., chemotherapy, treatment with a BTK inhibitor). In certain embodiments, the methods described herein are associated with reduced toxicity when compared to existing therapies (e.g., chemotherapy, treatment with a BTK inhibitor).

[0192] In certain embodiments, the cell is a malignant cell (e.g., a 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, a blastoma cell, a carcinoma cell, or a sarcoma cell. In certain embodiments, the cell is a pre-malignant cell (e.g., a pre-cancerous cell).

[0193] In certain embodiments, the methods described herein further comprise administering an additional treatment to a subject in need thereof. In certain embodiments, the additional treatment is a cytotoxic chemotherapy (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, l-asparaginase, cyclophosphamide, or etoposide). In certain embodiments, the additional treatment is an epigenetic modifier (e.g., azacytidine or romidepsin). In certain embodiments, the additional treatment is a glucocorticoid. In certain embodiments, the additional treatment 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 myeloid leukemia, myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, monoblastic leukemia, or megakaryoblastic leukemia.

[0194] In yet another aspect, the disclosure provides compounds and pharmaceutical compositions described herein for use in treating a disease (e.g., a proliferative disease such as IgM gammopathy, mastocytosis, or cancer) in a subject in need thereof.

[0195] In yet another aspect, the disclosure provides compounds and pharmaceutical compositions described herein for use in preventing a disease (e.g., a proliferative disease such as IgM gammopathy, mastocytosis, or cancer) in a subject in need thereof.

[0196] In another aspect, the disclosure provides compounds and pharmaceutical compositions described herein for use in inhibiting the activity of a kinase in a subject in need thereof.

[0197] In another aspect, the disclosure provides for the use of the compounds and pharmaceutical compositions described herein in the manufacture of a medicament for treating a disease in a subject in need thereof.

[0198] In another aspect, the disclosure provides for the use of the compounds and pharmaceutical compositions described herein in the manufacture of a medicament for preventing a disease in a subject in need thereof.

[0199] The compounds, pharmaceutical compositions, and kits described herein can synergistically enhance the inhibition of kinases (e.g., SFKs (e.g., HCK, LYN, BLK, FRK), TEC family kinases (e.g., BTK)) induced by additional pharmaceutical agents in a subject. Thus, the combination of the compounds, pharmaceutical compositions, or kits with additional pharmaceutical agents can be useful in treating diseases that are resistant to treatment using the additional pharmaceutical agents without the compounds, pharmaceutical compositions, or kits described herein.

[0200] The present disclosure is further illustrated by the following examples, which should not be construed as further limiting in any way. The entire contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are expressly incorporated herein by reference. EXAMPLES

[0201] Example 1 Compound (I) selectively targets HCK and BTK in MYD88 mutant WM and ABC DLBCL cells. Figure 2 shows the KINOMEscan® kinase selectivity profiles of compound (I) and A419259. The compounds were profiled by DiscoverX against a panel of over 460 kinases at a concentration of 1.0 μM. Compound (I) and A419259 have nearly identical selectivity with an S(10) score of 0.13 and an S(1) score of 0.07. Enzyme assays were also performed (SelectScreen, Life Technologies) for potential targets HCK, BTK, and LYN, which showed that compound (I) showed potent inhibition of HCK, BTK, and LYN with single-digit nanomolar IC50s, while A419259 was 10-fold less potent against BTK.

[0202] Biochemical kinase assays demonstrated that compound (I) inhibits HCK (IC 50 <0.495 nM) and BTK (IC 50 = 0.915 nM). In comparison, ibrutinib showed similar BTK inhibition (IC 50 = 0.614 nM), and 100-fold less potent HCK inhibition (IC 50=49 nM). To evaluate the kinase target selectivity of compound (I), KINOMEscan® against a panel of 464 kinases was performed. Compound (I) showed highly selective activity (S10=0.07; S35=0.13) that was comparable to the selectivity of ibrutinib (S10=0.04; S35=0.12). The kinases targeted by compound (I) were primarily limited to the Src-family kinases HCK, BLK, LYN, and FRK, and the Tec-family kinase BTK (Figure 2A). To further evaluate the kinome selectivity of compound (I) and to verify its target binding in live cells, KiNativ™ profiling was performed to measure the ability of compound (I) to block kinase binding to a desthiobiotin-ATP probe. KiNativ™ screening confirmed that compound (I) strongly targets both HCK and BTK in TMD8 ABC DLBCL cells treated at 1.0 μM. These experiments show that compound (I) also has nanomolar activity against SRC-family kinases (e.g., HCK, BLK, LYN, FRK), Tec-family kinases (e.g., BTK), ACK-family kinases (e.g., ACK (i.e., TNK2)), CSK, ErbB2, and ABL (Figure 2B). To further confirm HCK and BTK targeting by compound (I), ATP-competition assays were also performed using the Pierce™ Kinase Enrichment Kit with ActivX desthiobiotin-ATP probe after live cell pretreatment with compound (I) in MYD88 mutant BCWM.1 WM cells and TMD8 ABC DLBCL cells. The enriched kinases were separated by Western blot, showing strong binding of compound (I) to HCK and a similar level of BTK inhibition as ibrutinib (Figure 2C). Compound (I) binds efficiently to BTK in live BCWM.1 and TMD8 cells and binds very tightly to HCK and LYN.

[0203] Example 2 Inhibition of HCK and BTK by Compound (I). In MYD88 mutant WM and ABC DLBCL cells, the known functional site, i.e., Thr on HCK by PhosFlow, was identified. 209 Phosphorylation levels of HCK; and BTK by Western blotting Tyr223 The inhibition of HCK and BTK by compound (I) was evaluated by changes in Thr. Comparisons were made to ibrutinib for both HCK and BTK, and the findings were that ibrutinib moderately inhibited HCK phosphorylation, while compound (I) inhibited Thr. 209 We showed that Tyr1 inhibited HCK phosphorylation in 10% of the control mice (Fig. 3A). 223 Similar levels of BTK inhibition in WM were observed for ibrutinib and compound (I) (Figure 3B). The effects of compound (I) and ibrutinib were also determined on HCK and BTK phosphorylation by PhosFlow analysis in MYD88 mutant WM patient bone marrow tumor cells in the presence of bone marrow microenvironment mononuclear cells (N=4) (Figure 3C). Whole bone marrow mononuclear cells were treated with the indicated concentrations of ibrutinib, A419259, or Compound (I) for 2.0 hours, fixed with BD PhosFlow™ Fix Buffer I (BD biosciences) for 10 minutes at 37°C, permeabilized with BD Perm / Wash™ Buffer I (BD biosciences), and then stained with mouse anti-human CD20 (APC-cy7) specific antibody (BD biosciences) and rabbit anti-human p-HCK specific antibody followed by donkey anti-rabbit IgG (Alexa Fluor® 647) secondary antibody, or PE-labeled p-BTK antibody. p-HCK or p-BTK levels were measured using CD20 + Analyzed against the LPC population.

[0204] Example 3 Cellular efficacy of compound (I) in MYD88 wild-type (MYD88WT) and MYD88 mutated (MYD88L265P) B-cell lymphoma cells. The antitumor effect of compound (I) was also evaluated in MYD88 mutant WM and ABC DLBCL cell lines, as well as MYD88 wild-type GCB DLBCL, Burkitt's lymphoma, and multiple myeloma cell lines. Compound (I) showed targeted antitumor activity against MYD88 mutant cell lines versus wild-type cell lines (Figure 28A). The antitumor activity of compound (I) was also evaluated using primary MYD88 mutant bone marrow-derived CD19-positive lymphoplasmocytic cells (LPCs) from WM patients, and the effect was compared against CD19+ B cells from healthy donors. The activity of compound (I) was compared to ibrutinib in these experiments. While ibrutinib showed a moderate apoptotic effect on primary LPCs, compound (I) caused robust apoptosis of MYD88 mutant WM patient LPCs (Figure 4B). Compound (I) showed no apoptotic effect on CD19+ B cells from healthy donors (Figure 4B). The anti-apoptotic effect of compound (I) was confirmed by PhosFlow analysis of p-HCK(T209) and p-BTK in LPCs of WM patients. Y223 This corresponded to a decrease in (Figure 3C).

[0205] In vitro cellular efficacy (drug dose-response) was measured by CellTiter-Glo™ cell viability assay in MYD88 mutant or wild-type B-cell lymphoma or multiple myeloma cell lines under 72-hour treatment with serially diluted Compound (I) or A419259. The blue line crossing the Y-axis at 50 indicates the EC50 level of each cell line at the corresponding drug concentration on the X-axis (Figure 4A).

[0206] Example 4 HCK T333M Compound (I) resistance to gatekeeper mutants indicates that HCK is an important target of compound (I) in MYD88 mutant WM cells. HCK gatekeeper mutant HCK T333M and rescue experiments were performed in MYD88 mutant BCWM.1 cells. T333M Expression of HCK increased resistance to compound (I) by more than 20-fold over vector- or wild-type HCK-transduced BCWM.1 cells ( FIG. 5A ). In addition, HCKWT Not HCK T333M Expression of HCK1 led to sustained activation of HCK in the presence of compound (I) (Figure 5B). WT or HCK T333M BCWM.1 cells expressing HCK were further evaluated with Compound (I) and the activation status was found to include BTK, AKT, ERK1 / 2, and SYK. Compound (I) inhibited HCK WT In HCK-expressing cells, it blocked the expression of pBTK, pAKT, pERK1 / 2, and p-SYK in a dose-dependent manner (Figure 5C). Conversely, the attenuation of pBTK, pAKT, pERK1 / 2, and pSYK was suppressed by HCK- T333M pBTK was abrogated in BCWM.1 cells expressing HCK, consistent with its role as a direct inhibitor of BTK activity. T333M The results continued to show reduced activity by Compound (I) in expressing BCWM.1 cells (Figure 5C). Collectively, the above data indicate that HCK and BTK are on-target and have biologically important consequences in response to Compound (I) activity, including inhibition of multiple downstream pro-survival signaling pathways associated with HCK and BTK.

[0207] Figure 6 shows the HCK gatekeeper mutant (HCK T333M ) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in MWCL-1 WM cells. WT Or HCK T333M Dose-response of transduced MWCL-1 cells (Figure 6A). Vector only, HCK WT or HCK T333M Relative pHCK resolved by PhosFlow analysis following 1.0 hour treatment with the indicated concentrations of compound (I) in transduced MYD88 mutant BCWM.1 cells. Y411 Levels (FIG. 6B). HCK after 1.0 hour treatment with the indicated concentrations of Compound (I). WT or HCK T333M pBTK by Western blot analysis in transduced BCWM.1 cells Y223 , pSYK Y525 / 526 , p-AKTS473 , p-ERK1 / 2 T202 / Y204 Expression (FIG. 6C). The expression levels of BTK, SYK, AKT and ERK1 / 2 overall in these cells, as well as the protein loading control GAPDH, are also shown.

[0208] FIG. 7 shows the HCK gatekeeper mutant (HCK T333M ) rescues compound (I)-induced cell death and blocks HCK activation and its downstream signaling in TMD8 ABC DLBCL cells. WT Or HCK T333M Dose-response of transduced TMD7 cells (Figure 7A). Vector only, HCK WT or HCK T333M Relative pHCK resolved by PhosFlow analysis following 1.0 hour treatment with the indicated concentrations of compound (I) in transduced MYD88 mutant BCWM.1 cells. Y411 Levels (FIG. 7B). HCK after 1.0 hour treatment with the indicated concentrations of Compound (I). WT or HCK T333M pBTK by Western blot analysis in transduced BCWM.1 cells Y223 , pSYK Y525 / 526 , p-AKT S473 , p-ERK1 / 2 T202 / Y204 Expression (FIG. 7C). The expression levels of BTK, SYK, AKT and ERK1 / 2 overall in these cells, as well as the protein loading control GAPDH, are also shown.

[0209] Example 5 In vitro and in vivo profile of the pharmacokinetic properties of Compound (I). FIG. 8 shows that Compound (I) was further profiled for its in vitro and in vivo pharmacokinetic properties. Incubation in liver microsomes demonstrated excellent stability (T of approximately 60 minutes or longer) across multiple species, including human, mouse, and rat. 1 / 2Incubation in liver microsomes demonstrated excellent stability (T of approximately 60 minutes or longer) across multiple species, including human, mouse, and rat. 1 / 2 ) are shown. Mouse pharmacokinetic parameters are shown for compound (I) after dosing at 2 mg / kg i.v., and at 10 mg / kg and 25 mg / kg. Consistent with the long microsomal stability for compound (I), mouse pharmacokinetic studies showed a bioavailability of 49%-55% after oral dosing at 10 mg / kg and 25 mg / kg, respectively. Serum half-lives were 11.5 hours after intravenous dosing, and 15.1 and 16.9 hours after oral dosing at 10 mg / kg and 25 mg / kg, respectively. In vitro metabolism studies of CYP inhibition (% at 10 μM) were as follows: -27.9 (1A), 64.5 (2B6), -3.8 (2C8), -10.9 (2C9), 0.8 (2C19), 24.9 (2D6), -22.7 / -4.9 (3A). Ames genotoxicity tests were negative for four Salmonella typhimurium test strains (TA98, TA100, TA1535, and TA1537) up to 50 μM with and without metabolic activation with rat liver S9 fraction. hERG tests (patch clamp) for cardiotoxicity were negative at 16 μM. Tolerance studies showed that Compound (I) was well tolerated at daily oral doses of up to 75 mg / kg in NOD-SCID mice dosed for over 6 weeks, with no adverse events observed. Plasma protein binding showed comparable levels across species as follows: mouse (97.7%); rat (95.5%); dog (95.0%); and human (95.7%).

[0210] Consistent with the observed low metabolic rate in microsomal assays, Compound (I) was metabolized at 17.4 mL / min in mice. -1 kg -1When administered orally at 10 mg / kg and 25 mg / kg, Compound (I) provided excellent exposure (AUC = 5.2 and 11.4 μM h, respectively), high bioavailability (%F = 55% and 49%, respectively), and ideal drug clearance (T 1 / 2 =15.1~16.9 hours) and is well absorbed.

[0211] When incubated with purified microsomes, compound (I) exhibited t 1 / 2 = 106.4 min (mouse), t 1 / 2 ≥ 120 min (rats), t 1 / 2 = 60 min (dog), and t 1 / 2 = 49.5 min (human). In contrast, A419259 showed an extremely long T 1 / 2 (176.0 hours) (FIG. 9), which may pose problems for clinical development.

[0212] Example 6 Mean tumor volume and survival curves of NOD-SCID mice implanted with wild-type BTK-expressing TMD8 ABC DLBCL tumor cells treated with ibrutinib, A419259, or compound (I). Figure 11 shows the mean tumor volume curves (Figure 11A), tumor volume statistics at day 33 (Figure 11B) and survival curves (Figure 11C). TMD8 tumor cells were implanted subcutaneously into NOD-SCID mice with 8 mice per cohort. After tumors were established and reached approximately 200 cubic millimeters, mice were orally treated on a once-daily schedule with either vehicle control or ibrutinib or A419259 or compound (I) at the indicated concentrations. Tumors were measured twice weekly with electronic calipers (Figure 11A). Tumor volumes in all treatment groups were significantly smaller than those in mice at day 33 that received vehicle control (P<0.005 by Wilcoxon rank sum test and P<0.0001 by Tukey multiple comparison test) (Figure 11B). Treatment was stopped after completing the 6th week of treatment and tumor volume assessments continued for all surviving mice until week 16. Mouse survival was also followed by Kaplan-Meier survival curves until the study was terminated at 16 weeks.

[0213] Example 7 Compound (I) inhibited the in vitro BTK signaling in BCWM.1 WM and TMD8 ABC DLBCL cell models. C481S Overcome mutation-driven ibrutinib resistance. FIG. 12 shows the drug dose-response for vector alone, BTK WT Or BTK C481S Expression of BTK in lentiviral vector-transduced TMD8 ABC-DLBCL or BCWM.1 WM cells as measured by CellTiter-Glo™ cell viability assay. C481S Unlike ibrutinib, which shows resistance due to mutations, compound (I) does not show any effect on vector alone, BTKWT or BTK C481S Compound (I) gives similar cellular efficacy in BCWM.1 and TMD8 cells expressing BTK (Figure 12A). Apoptosis analysis measured by the inventors by flow cytometry using Annexin-V / PI staining, percentage of apoptotic cells is shown. Compound (I) inhibited the vector alone, BTK WT or BTK C481SExpressing BCWM.1 and TMD8 cells confers similar cellular efficacy (Figure 12B).

[0214] Example 8 Compound (I) inhibits ibrutinib-resistant BTK C481S Blocks activation of HCK, BTK and downstream ERK1 / 2 in mutant BCWM.1 WM and TMD8 ABC DLBCL cell lines. FIG. 13A shows the results of the lentiviral vector alone or BTK WT Or BTK C481S BCWM.1 or TMD8 cells transduced with lentiviral vectors expressing mutants, PhosFlow analysis of the effect of Compound (I) on HCK phosphorylation levels in TMD8 cells. Cells were treated with the indicated concentrations of ibrutinib, A419259, or Compound (I) for 1.0 hour, fixed with BD PhosFlow™ Fix Buffer I (BD biosciences) for 10 minutes at 37°C, permeabilized with BD Perm / Wash™ Buffer I (BD biosciences), and then stained with rabbit anti-human p-HCK specific antibody (Abcam) followed by donkey anti-rabbit IgG (Alexa Fluor® 647) secondary antibody (Abcam). Vector alone, BTK WT , or BTK C481S Compound (I) and A419259 effectively blocked HCK phosphorylation in transduced BCWM.1 or TMD8 cells, whereas ibrutinib only modestly reduced HCK phosphorylation.

[0215] FIG. 13B shows lentiviral vector alone, BTK WT or BTK C481S Western blot analysis of the effect of Compound (I) on BTK phosphorylation levels in BCWM.1 or TMD8 cells transduced with lentiviral vectors expressing mutants. Cells were treated with the indicated concentrations of ibrutinib or Compound (I) for 1.0 hour and lysed in protein lysis buffer. Both Compound (I) and ibrutinib inhibited BTK phosphorylation levels compared to vector alone and BTK. WTCompound (I) effectively blocked BTK and ERK 1 / 2 phosphorylation in transduced BCWM.1 or TMD8 cells. However, only compound (I) inhibited BTK C481S whereas ibrutinib did not potently block BTK and ERK 1 / 2 phosphorylation in transduced BCWM.1 or TMD8 cells.

[0216] Example 9 Ibrutinib-resistant BTK C481S Pharmacodynamic study showing activity of HCK and BTK in NOD-SCID mice xenografted subcutaneously with TMD8 ABC-DLBCL cells. Ibrutinib-resistant TMD8-BTK C481S Tumor cells were implanted subcutaneously into NOD-SCID mice, 8 mice per cohort. After tumors were established and reached approximately 300 cubic millimeters, mice were orally treated on a once-daily schedule with either vehicle control, ibrutinib, A419259, or compound (I) at the indicated concentrations. Tumors were measured twice weekly with electronic calipers (Figure 14). PhosFlow plots of pHCKY411 (Figure 14A) and pBTKY223 (Figure 14B) in excised GFP+ TMD8 tumor cells 6 and 24 hours after oral administration of the indicated doses of compound (I) (n=3 per group). *p<0.05; **p<0.01; ***p<0.005; ****p<0.0001.

[0217] Example 10 Ibrutinib-resistant TMD8-BTK C481S Mean tumor volume curves for compound (I) in xenograft models. Ibrutinib-resistant TMD8-BTK C481S Tumor cells were implanted subcutaneously into NOD-SCID mice, 8 mice per cohort. After tumors were established and reached approximately 200 cubic millimeters, mice were orally treated on a once daily schedule with either vehicle control, ibrutinib (50 mg / kg), or Compound (I) (50 mg / kg or 75 mg / kg). Ibrutinib-resistant BTK following daily oral administration of vehicle control, ibrutinib (50 mg / kg), or Compound (I) (50 or 75 mg / kg) C481SEfficacy study in NOD-SCID mice (n=8 per cohort) bearing TMD8 expressing cells. Tumor volume (mm 3 ) were measured twice weekly and reported as mean volume ± SEM (Figure 15A). Tumor volume comparison at day 29. p values ​​for cohort comparisons are shown (Figure 15B). Survival curve estimation using the Kaplan-Meier method. Median survival times (days) for the cohorts are shown using Prism software. P=0.0007 for log-rank comparison between cohorts (Figure 15C).

[0218] Ibrutinib-resistant BTK following daily oral administration of vehicle control, ibrutinib (50 mg / kg), A419259 (50 mg / kg) or Compound (I) (50 mg / kg) C481S Efficacy study in NOD-SCID mice (n=8 per cohort) bearing TMD8 expressing cells. Tumor volume (mm 3 ) were measured twice weekly and reported as mean volume ± SEM (Figure 16A). Tumor volume comparison at day 33. p values ​​for cohort comparisons are shown (Figure 16B). Survival curve estimation using the Kaplan-Meier method. Median survival times (days) for the cohorts are shown using Prism software. P<0.0001 for log-rank comparison between cohorts (Figure 16C).

[0219] Example 11 Combination index (CI) of compound (I) and venetoclax (a BCL-2 inhibitor) in MYD88 mutant Waldenström's macroglobulinemia (BCWM.1) cells. Native (non-transduced) BTKWT and BTK C481S In vitro studies evaluated the synergistic interaction of compound (I) and venetoclax in expressing MYD88 mutant BCWM.1 WM and TMD8 ABC DLBCL cells. Combination index (CI) and normalized isobologram analysis are shown. CI<1 (indicated by red shade) or points below the diagonal line in the isobologram plot indicate synergistic effects of the combination (Figure 17).

[0220] Example 12 In non-transduced naturally MYD88-mutated Waldenström's macroglobulinemia (BCWM.1) and ABC DLBCL (TMD8) cells, and in BTK WT Or BTK C481S Combination index (CI) of compound (I) and venetoclax (a BCL-2 inhibitor) in transduced BCWM.1 or TMD8 cells. Figure 18 shows ibrutinib-resistant BTK. C481S Figure 1 shows the effect of the combination of Compound (I) and venetoclax on tumor volume and survival in a TMD8 ABC DLBCL xenograft mouse model. Ibrutinib-resistant BTK following daily oral administration of vehicle control, venetoclax (50 mg / kg), Compound (I) (30 mg / kg), or a combination of venetoclax (50 mg / kg) and Compound (I) (30 mg / kg). C481S Efficacy study in NOD-SCID mice (n=8 per cohort) bearing TMD8 expressing cells. Tumor volume (mm 3 ) were measured twice weekly and reported as mean volume ± SEM (Figure 18A). Tumor volume comparison at day 22. p values ​​for cohort comparisons are shown (Figure 18B). Survival curve estimation using the Kaplan-Meier method. Median survival times (days) for the cohorts are shown using Prism software. P=0.0020 for log-rank comparison between cohorts (Figure 18C).

[0221] As demonstrated above, the combination of Compound (I) and venetoclax produces synthetic lethality in MYD88 mutant lymphoma cells.

[0222] (Example 13) HCK activation status in patients with chronic lymphocytic leukemia. Figure 19 shows that HCK activation status in CLL patients was assessed in primary tumor cells from peripheral blood mononuclear cells (PBMCs) of pretreated or untreated patients. PBMCs were isolated by Ficoll-Paque, fixed with BD PhosFlow™ Fix Buffer I (BD biosciences) for 10 min at 37°C, permeabilized with BD Perm / Wash™ Buffer I (BD biosciences), and then stained with mouse anti-human CD20 (APC-cy7) and CD5 (BV421) specific antibodies (BD biosciences) and rabbit anti-human p-HCK specific antibody followed by donkey anti-rabbit IgG (Alexa Fluor® 647) secondary antibody, or PE-labeled p-BTK antibody. p-HCK or p-BTK levels were assessed by CD20 staining. + CD5 + The analysis was performed for the population.

[0223] Example 14 In vitro studies of peripheral blood mononuclear cells isolated from ibrutinib-relapsed CLL patients using ibrutinib or compound (I). Figure 20 shows that PBMCs from ibrutinib-treated relapsed CLL patients were isolated using Ficoll-Paque and were positive for CD19 + Cells were isolated using magnetic beads and analyzed by Sanger sequencing to identify BTK C481S The genotype for the mutation was later shown to be approximately 70% CD19 + BTK in cells C481S It was shown to carry the mutation (T>A).

[0224] Freshly isolated PBMCs were treated overnight with either ibrutinib or compound (I) in cell culture medium supplemented with 10% FBS. After drug treatment, PBMCs were stained with Annexin V-FITC and PI and mouse anti-human CD19 (APC-cy7) and CD5 (BV421) specific antibodies (BD biosciences). Apoptotic cells were identified by flow cytometry as CD19 + CD5 + Measured for the population.

[0225] Example 15 BTK WT or BTK C481S Western blot analysis of BTK, LYN, ERK1, and ERK2 following treatment with ibrutinib, dasatinib, A419259, or compound (I) in BCWM.1 cells. Figure 21 shows BTK WT or BTK C481S Western blot analysis of BTK, LYN and ERK1 / 2 phosphorylation levels after 1 hour treatment with the indicated concentrations of ibrutinib, dasatinib, A419259, and compound (I) in transduced BCWM.1 cells. Total protein of each kinase and GAPDH were used for protein expression and loading controls. Compound (I) inhibited the phosphorylation of BTK. WT and BTK C481S Both mutants effectively blocked BTK, LYN and ERK1 / ERK2 phosphorylation in BCWM.1 cells.

[0226] Example 16 Synthesis of compound (I). Compound (I) was synthesized according to the following scheme.

[0227] [ka]

[0228] (1s,4s)-4-(4-benzylpiperazin-1-yl)cyclohexanol (SM1) A mixture of cis-4-aminocyclohexanol hydrochloride (2.0 g, 17.3 mmol), N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine (5.5 g, 20.76 mmol) and NaHCO3 (5.7 g, 69.2 mmol) in EtOH (30 mL) was stirred at 90 °C for 5 h. The mixture was then concentrated in vacuum and the residue was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic phase was then washed with brine (50 mL x 2), dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give SM1 as a yellow oil (2.8 g, 57% yield). LCMS (m / z): 275.2 [M + H] + .

[0229] (1s,4s)-4-(piperazin-1-yl)cyclohexanol (SM2) A mixture of SM1 (2.7 g, 9.85 mmol), CH3COOH (0.5 mL) and Pd / C (10%, 270 mg) in i-PrOH (20 mL) was stirred under H2 (1 atm) at room temperature for 24 h. After this time, the mixture was filtered and the filtrate was concentrated to leave crude SM2 as a yellow oil (1.5 g, 83% yield). LCMS (m / z): 185.1 [M + H] + .

[0230] tert-Butyl 4-((1s,4s)-4-hydroxycyclohexyl)piperazine-1-carboxylate (SM3) A mixture of SM2 (1.5 g, 8.1 mmol), (Boc)2O (4.0 mL, 16.2 mmol) and DIPEA (4.0 mL) in THF (20 mL) was stirred at room temperature for 2 h. After this time, the mixture was concentrated to leave crude SM3 as a brown oil (2.5 g, 80% yield). LCMS (m / z): 285.2 [M + H] + .

[0231] tert-Butyl 4-((1s,4s)-4-(methylsulfonyloxy)cyclohexyl)piperazine-1-carboxylate (SM4) To a mixture of SM3 (2.5 g, 8.1 mmol) and DIPEA (4.0 mL) in DCM (20 mL) was added MsCl (1.0 mL) dropwise at 0° C. The mixture was then stirred at room temperature for 4 h, concentrated to remove the solvent, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (150 mL×2). The combined organic extracts were then washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to leave crude SM4 as a brown oil (600 mg, 20% yield). LCMS (m / z): 363.0 [M + H] + .

[0232] tert-Butyl 4-((1r,4r)-4-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate (SM5) A mixture of 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (353 mg, 1.65 mmol), SM4 (600 mg, 1.65 mmol), and Cs2CO3 (1.0 g, 3.3 mmol) in DMF (15 mL) was stirred at 100 °C for 16 h. After this time, the reaction mixture was cooled to room temperature, diluted with brine (100 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give SM5 as a yellow solid (300 mg, 38% yield). LCMS (m / z): 480.0 [M + H] + .

[0233] tert-Butyl 4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate (SM6) A mixture of SM5 (60 mg, 0.12 mmol), 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-1,3,2-dioxaborolane (56 mg, 0.18 mmol), Pd(PPh3)2Cl2 (9.0 mg, 0.012 mmol), and K3PO4 (51 mg, 0.24 mmol) in THF (2.0 mL) and H2O (0.5 mL) was stirred at 60 °C for 16 h. After this time, the mixture was filtered and the filtrate was diluted with brine (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were then dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give SM6 as a brown oil (40 mg, 58% yield). LCMS (m / z): 570.4 [M + H] + .

[0234] 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (SM7) To a solution of SM6 (40 mg, 0.07 mmol) in DCM (5.0 mL) was added a solution of HCl in 1,4-dioxane (4 M, 2.0 mL) and the mixture was stirred at room temperature for 2 h. After this time, the reaction mixture was concentrated in vacuo and the residue was diluted with DCM (30 mL). The pH was adjusted to pH 8 with saturated Na2CO3 solution, filtered, and the filtrate was concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O with 0.05% TFA) to give SM7 as a white solid (15.2 mg, 47.5% yield). LCMS (m / z): 470.1 [M + H] +; 1H NMR (400 MHz, DMSO-d6): δ 8.23 ​​(s, 1 H), 7.64 (d, J = 8.8 Hz, 2 H), 7.45-7.41 (m, 2 H), 7.20-7.11 (m, 5 H), 4.64-4.63 (m, 1 H), 2.85-2.81 (m, 4 H), 2.57 (s, 2 H), 2.49-2.39 (m, 2 H), 2.04-1.90 (m, 6 H), 1.50-1.47 (m, 2 H). 1-((1r,4r)-4-(4-methylpiperazin-1-yl)cyclohexyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (I)

[0235] SM7 (400 mg, 0.85 mmol) in MeOH (10.0 mL), (CHO) n A mixture of (76 mg, 0.85 mmol) and CH3COOH (0.5 mL) was stirred at room temperature for 3 h, then NaBH4 (97 mg, 2.55 mmol) was added, the mixture was stirred at room temperature for 16 h, concentrated in vacuo, the residue was diluted with brine (100 mL), extracted with ethyl acetate (150 mL x 2), the combined organics were dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC to give compound (I) as a white solid (150 mg, 36% yield). LCMS (m / z): 484.1 [M + H] + ; 1 H-NMR (400 MHz, DMSO-d6): δ 8.23 ​​(s, 1 H), 7.64 (d, J = 8.8 Hz, 2 H), 7.43 (t, J = 8.0 Hz, 2 H), 7.20-7.11 (m, 5 H), 4.63 (m, 1 H), 2.52 (m, 3 H), 2.37-2.30 (m, 6 H), 2.13 (s, 3 H), 2.03-1.91 (m, 6 H), 1.47-1.43 (m, 2 H).

[0236] Equivalents and Scope In the claims, articles such as "a", "an" and "the" can mean one or more, unless indicated otherwise or clear from the context. A claim or description containing "or" between one or more members of a group is considered to be satisfied if one, more than one, or all of the group members are present in, used in, or otherwise relevant to a given product or process, unless indicated otherwise or clear from the context. The present disclosure includes embodiments in which exactly one member of a group is present in, used in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, used in, or otherwise relevant to a given product or process.

[0237] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the claims set forth are introduced into another claim. For example, any claim that is dependent on another claim can be amended to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element can be removed from the group. In general, when the disclosure, or aspects described herein, are referred to as comprising certain elements and / or features, it should be understood that the particular embodiment described herein or aspects described herein consist of or consist essentially of such elements and / or features. For simplicity, those embodiments have not been specifically described in these terms herein. It should also be noted that the terms "comprising" and "containing" are intended to be open and permit the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Additionally, unless otherwise stated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can contemplate any specific value or subrange within the stated range of the different embodiments described herein, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0238] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, since they are deemed known to those of ordinary skill in the art. Any particular embodiment described herein may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0239] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to the description can be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

1. The following formula: 【Chemistry 1】 or a pharma- ceutical composition for treating a proliferative disease associated with a mutation in MYD88 protein, comprising compound (I) of the formula (I) or a pharma- ceutical acceptable salt thereof (provided that the proliferative disease associated with a mutation in MYD88 protein does not include leukemia).

2. The following formula: 【Chemistry 2】 or a pharma- ceutical composition for treating a proliferative disease in a subject having a mutation in MYD88 protein, comprising compound (I) of the formula (I) or a pharma- ceutical acceptable salt thereof (provided that the proliferative disease in a subject having a mutation in MYD88 protein does not include leukemia).

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the disease is associated with abnormal activity of hematopoietic cell kinase (HCK), abnormal activity of LYN proto-oncogene tyrosine kinase (LYN), abnormal activity of Bruton's tyrosine kinase (BTK), or a mutation in the BTK protein.

4. 4. The pharmaceutical composition of claim 3, wherein the disease is associated with a mutation in the BTK protein, and the mutant BTK protein is a C481S mutant BTK.

5. 5. The pharmaceutical composition of claim 1, wherein the proliferative disease is cancer, IgM gammopathy, or mastocytosis.

6. 6. The pharmaceutical composition of claim 5, wherein the proliferative disease is cancer, and the cancer is breast cancer, colon cancer, gastric cancer, testicular cancer, cancer of the central nervous system, lymphoma, myeloma, or a myeloproliferative disease.

7. 6. The pharmaceutical composition of claim 5, wherein the cancer is lymphoma, and the lymphoma is B-cell lymphoma.

8. 8. The pharmaceutical composition of claim 7, 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.

9. 9. The pharmaceutical composition of claim 8, wherein the lymphoplasmacytic lymphoma is IgM-secreting lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, or non-IgM-secreting lymphoplasmacytic lymphoma.

10. 9. The pharmaceutical composition of claim 8, wherein the diffuse large B-cell lymphoma is activated B-cell-like (ABC-DLBCL) or germinal center B-cell-like (GBC-DLBCL).

11. The pharmaceutical composition of claim 8, wherein the small lymphocytic lymphoma is mantle cell lymphoma.

12. The pharmaceutical composition of claim 6, wherein the cancer is myeloma, and the myeloma is IgM myeloma.

13. The pharmaceutical composition of claim 12, wherein the IgM myeloma is IgM multiple myeloma.

14. The pharmaceutical composition of claim 6, wherein the cancer is a myeloproliferative disorder, and the myeloproliferative disorder is a myelodysplastic syndrome.

15. 6. The pharmaceutical composition of claim 5, wherein the proliferative disease is an IgM gammopathy, and the IgM gammopathy is IgM monoclonal gammopathy of undetermined significance (MGUS) or amyloid light chain (AL) amyloidosis.

16. The pharmaceutical composition according to claim 5, wherein the proliferative disease is mastocytosis, and the mastocytosis is systemic mastocytosis.

17. 17. The pharmaceutical composition of any one of claims 1 to 16, capable of inhibiting kinase activity in a subject.

18. 18. The pharmaceutical composition of claim 17, wherein the kinase is an SRC cytoplasmic tyrosine kinase (SFK).

19. 18. The pharmaceutical composition of claim 17, wherein the kinase is Tec cytoplasmic tyrosine kinase.

20. 18. The pharmaceutical composition of claim 17, wherein the kinases are HCK, LYN and BTK.

21. 20. The pharmaceutical composition of claim 19, wherein the BTK is a mutant BTK, preferably wherein the BTK is mutated at Cys481, more preferably wherein the BTK is a C481S mutant BTK.

22. 21. The pharmaceutical composition of claim 20, wherein the BTK is resistant to inhibition by ibrutinib, or a pharma- ceutical acceptable salt thereof.

23. 22. The pharmaceutical composition of any one of claims 1 to 21, wherein the subject is resistant to treatment with ibrutinib, CC-292, ONO-4059, evobrutinib, spebrutinib, BGB-3111, HM71224, or ACP-196, or a pharmaceutically acceptable salt thereof.

24. The pharmaceutical composition according to claim 1 or 2, wherein the disease is Waldenstrom's Macroglobulinemia (WM).

25. 3. The pharmaceutical composition according to claim 1 or 2, wherein the disease is activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL).

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