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WO2025137500A1 - Inhibition et dégradation de kinase - Google Patents

Inhibition et dégradation de kinase Download PDF

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Publication number
WO2025137500A1
WO2025137500A1 PCT/US2024/061364 US2024061364W WO2025137500A1 WO 2025137500 A1 WO2025137500 A1 WO 2025137500A1 US 2024061364 W US2024061364 W US 2024061364W WO 2025137500 A1 WO2025137500 A1 WO 2025137500A1
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Prior art keywords
compound
kinase
cancer
mmol
lymphoma
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Steven Peter TREON
John Michael HATCHER
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Dana Farber Cancer Institute Inc
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Dana Farber Cancer Institute Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to degrader compounds having activity as against one or more, including two or more, target kinases, as well as methods of using the compounds for inhibiting kinase activity and/or facilitating degradation of kinases as well as methods for use in the treatment and/or prevention of a disease (e.g., a proliferative disease, such as IgM gammopathy, mastocytosis, and cancer).
  • a disease e.g., a proliferative disease, such as IgM gammopathy, mastocytosis, and cancer.
  • MYD88 Activating mutations in MYD88 are prevalent in many B-cell malignancies, including Waldenström Macroglobulinemia (95-97%), primary CNS lymphoma (70-80%), ABC DLBCL (40%), marginal zone lymphoma (5-10%), and CLL (5-15%).
  • Proteolysis targeting chimeras represent a novel approach for blocking kinase based signaling and may provide an advantage over kinase inhibitors with greater selectivity and sustained target inhibition through degradation. Therefore, a need exists to develop highly potent, selective, and bio-available HCK/BTK targeting PROTACS using KIN- 8194 scaffold for the treatment of MYD88 driven lymphomas.
  • the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein the dashed circle indicates the ring is aromatic; Q1 is N, S, or C; Q2 is N or C; Q3 is N or C; Ring A is absent or a heteroaryl ring; when Ring A is absent, two RA are present at the points of attachment for Ring A, RA is selected independently selected from the group consisting of H, NR’R”, C(O)R’R”, and NR’C(O)R” R’ and R” are independently H or C1-3alkyl; L1 is a bond, C1-C3 alkyl, C(O)C1-3alkyl, C1-3alkyl-O, or C1-3alkyl-O-C1-3alkyl; Ring B is a bond or selected from C4-6 cycloalkyl and 4-6 heterocyclyl ring; and RB is an E3 ligase-bind
  • Q1 is N. [0006] In one aspect, Q1 is S. [0007] In one aspect, Q1 and Q2 are N. [0008] In one aspect, Q1 is N and Q2 are C. [0009] In one aspect, Q1 is S and Q2 are C. [0010] In one aspect, Q3 is C. [0011] In one aspect, Q3 is N. [0012] In one aspect, each of Q1 and Q2 is N, and Q3 is C. [0013] In one aspect, Ring A is selected from the following: absent, [0014] In one aspect, when Ring A is absent and RA is selected from NH 2 and C(O)NH 2 . [0015] In one aspect, RA is NH2.
  • Ring B is selected from: [0017]
  • RB is a cereblon E3 ligase-binding moiety.
  • RB is a VHL E3 ligase-binding moiety.
  • RB is selected from the group consisting of:
  • the present disclosure includes a compound from Table B, or a pharmaceutically acceptable salt thereof. [0022] Table B.
  • the present disclosure includes a compound selected from or a pharmaceutically acceptable salt thereof.
  • the present disclosure includes a compound selected from Compound 7, 10, 26, 27, 28, 29, 30, 31, or 33.
  • the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
  • the present disclosure includes a method for inhibiting the activity of one or more kinase in a subject comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure.
  • the present disclosure includes a method for facilitating the degradation of one or more kinase in a subject comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure.
  • the one or more kinase is selected from the group consisting an SRC family of cytoplasmic tyrosine kinases (SFKs), a hemotopoietic cell kinase, a LYN proto- oncogene tyrosine kinase (LYN), a Tec family of cytoplasmic tyrosine kinases, and a Bruton’s tyrosine kinase (BTK).
  • SFKs cytoplasmic tyrosine kinases
  • LYN LYN proto- oncogene tyrosine kinase
  • BTK Tec family of cytoplasmic tyrosine kinases
  • BTK Bruton’s tyrosine kinase
  • the one or more kinase is a mutated kinase.
  • the one or more kinase is resistant to treatment.
  • the present disclosure includes a method of treating a proliferative disease associated with a mutation in a MYD88 protein in a subject in need thereof comprising administering to the subject the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure.
  • the disease is associated with aberrant activity of one or more of a hematopoietic cell kinase (HCK), of a LYN proto-oncogene tyrosine kinase (LYN), of Bruton’s tyrosine kinase (BTK), or a mutation in a BTK protein.
  • HCK hematopoietic cell kinase
  • LYN LYN proto-oncogene tyrosine kinase
  • BTK Bruton’s tyrosine kinase
  • the disease is associated with a mutation in a BTK protein, wherein the mutated BTK protein is a C481S mutated BTK.
  • the proliferative disease is cancer, IgM gammopathy or mastocytosis.
  • the proliferative disease is cancer, and wherein the cancer is breast cancer, colon cancer, stomach cancer, testicular cancer, cancer of the central nervous system, lymphoma, leukemia, myeloma, or myeloproliferative disease.
  • the cancer is lymphoma, and wherein the lymphoma is a B-cell lymphoma.
  • the B-cell lymphoma is lymphoplasmacytic lymphoma, diffuse large B- cell lymphoma (DLBCL), follicular lymphoma, marginal zone B-cell lymphoma or small lymphocytic lymphoma.
  • the lymphoplasmacytic lymphoma is IgM secreting lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia, or non-IgM secreting lymphoplasmacytic lymphoma.
  • the diffuse large B-cell lymphoma is activated B-cell-like (ABC- DLBCL), or germinal center B-cell-like (GBC-DLBCL).
  • the small lymphocytic lymphoma is mantle cell lymphoma.
  • the cancer is leukemia, and wherein the leukemia is chronic lymphocytic leukemia, or myelogenous leukemia.
  • the myelogenous leukemia is chronic myelogenous leukemia, or acute myelogenous leukemia.
  • the acute myelogenous leukemia is mast cell leukemia.
  • the cancer is a myeloma, and the myeloma is an IgM myeloma.
  • the IgM myeloma is IgM multiple myeloma.
  • the cancer is a myeloproliferative disease, and wherein the myeloproliferative disease is myelodysplastic syndrome.
  • the proliferative disease is an IgM gammopathy and wherein the IgM gammopathy is an IgM Monoclonal gammopathy of undetermined significance (MGUS) or amyloid light chain (AL) amyloidosis.
  • the proliferative disease is mastocytosis and wherein the mastocytosis is systemic mastocytosis.
  • the present disclosure includes a compound according to the present disclosure for use in inhibiting the activity of one or more kinase in a subject in need thereof.
  • the present disclosure includes a compound according to the present disclosure for use in facilitating the degradation of one or more kinase in the subject in need thereof.
  • the kinase is an SRC cytoplasmic tyrosine kinase (SFK)
  • SFK SRC cytoplasmic tyrosine kinase
  • the SFK is hematopoietic cell kinase (HCK) or LYN proto-oncogene tyrosine kinase (LYN).
  • the kinase is a Tec cytoplasmic tyrosine kinase, and preferably a Bruton’s tyrosine kinase (BTK).
  • the kinase is one or more of HCK, LYN, and BTK. Preferably two or more of HCK, LYN, and BTK.
  • the BTK is a mutated BTK, preferably wherein the BTK is mutated at Cys481, more preferably wherein the BTK is a C481S mutated BTK.
  • the BTK is resistant to inhibition by ibrutinib.
  • the subject is resistant to treatment with one or more of ibrutinib, CC- 292, ONO-4059, evobrutinib, spebrutinib, BGB-3111, HM71224, and ACP-196, or a pharmaceutically acceptable salt thereof.
  • the present disclosure includes a method of treating, including lessening the severity of, one or more of breast cancer, colon cancer, stomach cancer, testicular cancer, cancer of the central nervous system, IgM secreting lymphoplasmacytic lymphoma, non- IgM secreting lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC-DLBCL), germinal center B-cell-like (GBC-DLBCL), follicular lymphoma, marginal zone B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, mast cell leukemia, IgM multiple myeloma, myelodysplastic syndrome, IgM Monoclonal gammopathy of undetermined significance (MGUS), amyloid light chain (AL) amyloidosis, or systemic mastocytosis comprising
  • the subject is treated with one or more additional therapeutic agents or treatments, such as radiation, administered concurrently with, prior to, or subsequent to treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition of the present disclosure.
  • the present disclosure includes the use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure, as a medicament.
  • the use is made in combination with one or more additional immunotherapy or oncologic treatment.
  • the additional immunotherapy comprises a chimeric antigen receptor (CAR).
  • the additional immunotherapy comprises a bispecific antibody.
  • Figure 1 illustrates that each of Compounds (7), (10), and (13) selectively targets HCK, BTK and LYN in MYD88 mutated WM and ABC DLBCL cells.
  • Figure 1A shows the results of a KINOMEscan ® of Compounds (7) and (10) and KIN-8194 against a panel of 468 kinases.
  • Figure 1B shows the impact of Compounds (7), (10), and (13) on HCK and BTK phosphorylation by western blotting in MYD88 mutated WM (BCWM.1, MWCL-1) and ABC DLBCL (TMD8, HBL- 1) cell lines.
  • PK Pharmacokinetics
  • PK Pharmacokinetics
  • FIG. 4 depicts an EC50 titration curve in a lymphoma cell line, TMD-8, established from cells of a patient with diffuse large B-cell lymphoma, where the Compounds (26), (27), and (30) dose titration was monitored as measured using relative light units (RLU) in comparison to a negative control (DMSO). The reduction in light was used to establish an EC50 value for each of the respective compounds as compared with KIN-8194.
  • Figure 5 displays an EC 50 titration curve in two different cell lines.
  • Figure 5A shows an EC 50 curve calculated for Compounds (28) and (30) in the lymphoma cell line, TMD-8, as compared with KIN-8194.
  • Figure 5B shows the calculation of an EC50 curve for Compounds (28) and (30) in a BCWM.1 cell line, which was derived from the long-term culture of CD19(+) selected bone marrow lymphoplasmacytic cells isolated from an untreated patient with Waldenstrom's macroglobulinemia.
  • Figure 6 shows an EC50 titration curve in two different cell lines.
  • Figure 6A exhibits the EC50 titration curve for Compounds (29), (30), (31), and (33) in the TMD-8 cell line, compared with KIN-8194.
  • Figure 6B shows the EC50 inhibition for Compounds (29), (30), (31), and (33) in the TMD-8 cell line, compared with KIN-8194.
  • DETAILED DESCRIPTION OF THE DISCLOSURE [0070] The present disclosure highlights the development and characterization of novel, dual HCK/BTK PROTACs that demonstrate potent and selective kinase inhibition and protein degradation of HCK and BTK.
  • the HCK/BTK PROTACs showed enhanced apoptosis of MYD88 mutated WM and ABC DLBCL cells over the native kinase inhibitor KIN-8194 and sparing of healthy donor B- and T-cells with high levels of bioavailability.
  • a compound of Formula (I) and methods of using the compound for inhibiting kinase activity and/or facilitating degradation of kinases as well as methods for use in the treatment and/or prevention of a disease (e.g., a proliferative disease, such as IgM gammopathy, mastocytosis, cancer) in a subject in need thereof as described herein.
  • a disease e.g., a proliferative disease, such as IgM gammopathy, mastocytosis, cancer
  • a disease e.g., a proliferative disease, such as IgM gammopathy, mastocytosis, cancer
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • range encompasses each value and sub–range within the range.
  • a range is inclusive of the values at the two ends of the range unless otherwise provided.
  • C 1–6 alkyl encompasses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1– 2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl.
  • alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1–20 alkyl”).
  • C 1–6 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 (C 6 ) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), n-dodecyl (C 12 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1–12 alkyl (such as unsubstituted C 1–6 alkyl, e.g., –CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., 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)).
  • unsubstituted C 1–12 alkyl such as unsubstituted C 1–6 alkyl, e.g.
  • the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).
  • alkyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 double bonds. The one or more carbon–carbon double bonds can be internal (such as in 2– butenyl) or terminal (such as in 1–butenyl).
  • Examples of C2–4 alkenyl groups include ethenyl (C2), 1–propenyl (C 3 ), 2–propenyl (C 3 ), 1–butenyl (C 4 ), 2–butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C2–6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is unsubstituted C 2–10 alkenyl.
  • the alkenyl group is substituted C 2–10 alkenyl.
  • Alkynyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, and one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2–20 alkynyl”).
  • the one or more carbon–carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl).
  • C2–4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1–propynyl (C 3 ), 2–propynyl (C 3 ), 1–butynyl (C 4 ), 2–butynyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.
  • each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.
  • the alkynyl group is unsubstituted C2–10 alkynyl.
  • the alkynyl group is substituted C 2–10 alkynyl.
  • cycloalkyl refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3–10 cycloalkyl”).
  • exemplary C 3–6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3–8 cycloalkyl groups include, without limitation, the aforementioned C3–6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3–10 cycloalkyl groups include, without limitation, the aforementioned C3–8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated.
  • Cycloalkyl also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system.
  • each instance of a cycloalkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C 3–10 cycloalkyl.
  • the cycloalkyl group is a substituted C3–10 cycloalkyl.
  • Heterocyclyl refers to a radical of a 3– to 10–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl.
  • the heterocyclyl group is substituted 3–10 membered heterocyclyl.
  • the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
  • Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl.
  • Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione.
  • Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinyl.
  • Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-d
  • each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted C6–14 aryl.
  • the aryl group is substituted C 6–14 aryl.
  • the term “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety. In certain embodiments, the aralkyl is optionally substituted benzyl.
  • the aralkyl is benzyl. In certain embodiments, the aralkyl is optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl.
  • Heteroaryl refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”).
  • heteroaryl groups that contain one or more nitrogen atoms
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).
  • the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”).
  • a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”).
  • a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”).
  • the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • 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.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5–14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5–14 membered heteroaryl.
  • Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6– membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • Heteroaralkyl is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the attachment is on the alkyl moiety.
  • the term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
  • a “partially unsaturated” ring system is further intended to encompass rings having multiple sites of unsaturation but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as defined herein.
  • saturated refers to a group that does not contain a double or triple bond, i.e., contains all single bonds.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which are divalent bridging groups are further referred to using the suffix –ene, e.g., alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, and heteroarylene.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted”, “substituted” or “unsubstituted” cycloalkyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • Illustrative substituents which with multiple substituents can be the same or different, include halogen, haloalkyl, R', OR', OH, SH, SR', NO2, CN, C(O)R', C(O)(alkyl substituted with one or more of halogen, haloalkyl, NH2, OH, SH, CN, and NO2), C(O)OR', OC(O)R', CON(R')2, OC(O)N(R')2, NH2, NHR', N(R')2, NHCOR', NHCOH, NHCONH2, NHCONHR', NHCON(R')2, NRCOR', NRCOH, NHCO2H, NHCO2R', NHC(S)NH2, NHC(S)NHR', NHC(S)N(R')2, CO2R', CO2H, CHO, CONH2, CONHR', CON(R')2, S(O)2, S(
  • each may be linked through an alkylene linker, (CH2)x, where x is 1, 2, or 3,
  • R’ is the same or different and , in some embodiments, represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or, in some embodiments,when two R’ are each attached to a nitrogen atom, they may form a saturated or unsaturated heterocyclic ring containing from 4 to 6 ring atoms.
  • a “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F – , Cl – , Br – , I – ), NO3 – , ClO4 – , OH – , H2PO4 – , HCO ⁇ 3 , HSO4 – , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid
  • Exemplary counterions which may be multivalent include CO3 2 ⁇ , HPO4 2 ⁇ , PO 3 ⁇ 4 , B4O7 2 ⁇ , SO4 2 ⁇ , S2O3 2 ⁇ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, mal
  • Halo or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), or iodine (iodo, –I).
  • Alkoxy or “alkoxyl” refers to a radical of the formula: –O–alkyl.
  • a “leaving group” LG is an art-understood term referring to a molecular fragment that departs with a pair of electrons in a heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
  • a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
  • exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups.
  • 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.
  • halogen such as F, Cl, Br, or I (iodine)
  • alkoxycarbonyloxy such as F, Cl, Br, or I (iodine)
  • alkanesulfonyloxy alkanesulfonyloxy
  • arenesulfonyloxy alkyl- carbonyloxy (e.g., acetoxy)
  • alkyl- carbonyloxy e.g., acetoxy
  • the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, –OTs), methanesulfonate (mesylate, –OMs), p- bromobenzenesulfonyloxy (brosylate, –OBs), or trifluoromethanesulfonate (triflate, –OTf).
  • the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
  • the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy.
  • the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group.
  • the leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.
  • Other non-limiting examples of leaving groups are water, amines, ammonia, alcohols, ether moieties, sulfur- containing moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • 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.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 - salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • Compound (I) may be prepared, e.g., in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
  • the term “stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent molecules are an integral part of the crystal lattice, in which they interact strongly with the compound and each other.
  • non-stoichiometric solvate refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent content may vary without major changes in the crystal structure.
  • the amount of solvent in the crystal lattice only depends on the partial pressure of solvent in the surrounding atmosphere. In the fully solvated state, non- stoichiometric solvates may, but not necessarily have to, show an integer molar ratio of solvent to the compound.
  • hydrate refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate.
  • a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H2O, wherein R is the compound and wherein x is a number greater than 0.
  • a given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)).
  • tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. [0105] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • Tautomerizations i.e., the reaction providing a tautomeric pair
  • exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • prodrugs refer to compounds, including derivatives of Compound (I), which have cleavable groups and become by solvolysis or under physiological conditions Compound (I) which are pharmaceutically active in vivo. Such examples include, but are not limited to, ester derivatives and the like. Other derivatives of the compounds of this disclosure have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds of this disclosure are particular prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult, or senior adult)) and/or other non–human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys).
  • mammals e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (
  • the animal is a mammal.
  • the animal may be a male or female and at any stage of development.
  • a non–human animal may be a transgenic animal.
  • a subject who is resistant to treatment with a BTK inhibitor is one who shows no or minimal response to the treatment.
  • response to a treatment is measured by reduction in tumor cells or tumor cell killing.
  • response to a treatment is measured by changes in symptoms of the disease, condition or malignancy (e.g., a proliferative disease). It has been discovered that the compounds that block ATP binding to HCK as described herein are able to cause tumor cell killing even in cells that are derived from subjects who are resistant to a BTK inhibitor treatment.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound, or a pharmaceutical composition thereof.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a “pathological condition” (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein.
  • pathological condition e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof
  • treatment may be administered after one or more signs or symptoms have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • condition e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors.
  • Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • the terms “condition,” “disease,” and “disorder” are used interchangeably.
  • the treatment may be therapeutic treatment (not including prevention or prophylactic treatment).
  • An “effective amount” of Compound (I) refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition.
  • the effective amount of Compound (I) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • an effective amount of a compound may reduce the tumor burden or stop the growth or spread of a tumor.
  • a “therapeutically effective amount” of Compound (I) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • terapéuticaally effective amount can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases)
  • the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, stomach cancer, lymphoma (e.g., B-cell Lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM secreting (i.e., Waldenström’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.
  • B-cell Lymphoma e.g., lymphoplasmacytic lymphoma (e.g., IgM secreting (i.e., Waldenström’s Macroglobulinemia), non-IgM secreting)
  • Chronic lymphocytic leukemia CLL
  • Mantle cell lymphoma Leukemia
  • Leukemia e.g., myelogenous leukemia (e.g., chronic myelogenous leukemia, acute myelogenous leukemia)
  • benign neoplasms angiogenesis, inflammatory diseases, auto inflammatory diseases, and autoimmune diseases.
  • neoplasm and “tumor” are used interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue.
  • a neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis.
  • a “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin.
  • a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.
  • Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
  • certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.”
  • An exemplary pre-malignant neoplasm is a teratoma.
  • a malignant neoplasm is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.
  • the term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.
  • a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.
  • cancer refers to a malignant neoplasm (Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990).
  • the cancer may be a solid tumor.
  • the cancer may be a hematological malignancy.
  • Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocar
  • Wilms tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendocrinetumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma pancreatic cancer
  • pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • angiogenesis refers to the formation and the growth of new blood vessels. Normal angiogenesis occurs in the healthy body of a subject for healing wounds and for restoring blood flow to tissues after injury. The healthy body controls angiogenesis through a number of means, e.g., angiogenesis-stimulating growth factors and angiogenesis inhibitors. Many disease states, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis.
  • Abnormal or pathological angiogenesis refers to angiogenesis greater than that in a normal body, especially angiogenesis in an adult not related to normal angiogenesis (e.g., menstruation or wound healing).
  • Abnormal angiogenesis can provide new blood vessels that feed diseased tissues and/or destroy normal tissues, and in the case of cancer, the new vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).
  • the angiogenesis is pathological angiogenesis.
  • An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells.
  • autoimmune thyroiditis This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney).
  • the treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response.
  • Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardio
  • inflammatory disease refers to a disease caused by, resulting from, or resulting in inflammation.
  • inflammatory disease may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death.
  • An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non- infectious causes.
  • Inflammatory diseases include atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia
  • kinase refers to any enzyme that catalyzes the addition of phosphate groups to an amino acid residue of a protein.
  • a serine kinase catalyzes the addition of a phosphate group to serine residue in a protein.
  • the kinase is a protein kinase.
  • kinases include, but are not limited to, cytoplasmic tyrosine kinases (e.g., SRC family kinases (e.g., HCK, LYN, BLK, FRK), Tec family kinases (e.g., BTK)), a cyclin- dependent kinase (CDK, e.g., CDK1, CDK2, CDK2, CDK4, CDK5, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, CDK14, CDK16, CDK20)), a mitogen-activated protein kinase (MAPK, e.g., MAPK1 , MAPK3 , MAPK4 , MAPK6 , MAPK7 , MAPK8 , MAPK9 , MAPK10 , MAPK11 , MAPK12 , MAPK13 , MAPK14 , MAPK15), a glycogen synthase kinase 3
  • HCK Hematopoietic cell kinase
  • IL6 interleukin 6
  • GP130 IL6 co-receptor IL6ST
  • Bruton’s tyrosine kinase is a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is required for B cell receptor signaling, plays a key role in B-cell maturation, and exhibits increased activation in a number of B-cell malignancies.
  • LYN proto-oncogene is a member of the src-family of protein tyrosine kinases, plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, is important for immune self-tolerance, and acts downstream of several immune receptors, including the B-cell receptor (BCR).
  • BCR signaling is thought to be involved in pro-growth and survival signaling in MYD88 mutated disease, as well as being involved in non-MYD88 mutated disease.
  • BCR signaling is thought to be active in Waldenström’s Macroglobulinemia, ABC subtype of diffuse large B-cell lymphoma, and chronic lymphocytic leukemia.
  • Proto-oncogene tyrosine-protein kinase SRC is a protein tyrosine kinase, plays a central role in the regulation of a variety of biological processes, such as cell proliferation, migration, adhesion, and survival in solid tumors, and is overexpressed in Waldenström’s Macroglobulinemia.
  • inhibitors refer to the ability of a compound to reduce, slow, halt, block, or prevent activity of a particular biological process (e.g., a kinase (e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec family kinases (e.g., BTK)) in a cell relative to vehicle.
  • a kinase e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec family kinases (e.g., BTK)
  • block or blocking refer to the ability of a compound to prevent a biological interaction (e.g., binding) in a cell relative to a negative control, e.g., vehicle.
  • a compound can block ATP from binding to the ATP binding pocket of a kinase. Such blocking may occur by direct binding of the compound to the ATP binding pocket itself, or indirect blocking.
  • the term refers to a reduction in the level of binding of ATP to a kinase, e.g., BTK and/or HCK, and/or LYN, and/or SRC, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of ATP binding.
  • the term refers to a reduction in the level of ATP binding to a kinase, e.g., BTK and/or HCK, and/or LYN, and/or SRC, to a level that is less than 75%, less than 50%, less than
  • an initial level which may, for example, be a baseline level of ATP binding.
  • the compound binds the first protein, e.g., BTK or HCK or LYN or SRC, with a higher binding affinity (e.g., not less than about 2-fold, not less than about 5-fold, not less than about 10-fold, not less than about 30-fold, not less than about 100-fold, not less than about 1,000-fold, or not less than about 10,000-fold) than binding a second protein that is different from the first protein, e.g., BTK.
  • a higher binding affinity e.g., not less than about 2-fold, not less than about 5-fold, not less than about 10-fold, not less than about 30-fold, not less than about 100-fold, not less than about 1,000-fold, or not less than about 10,000-fold
  • a compound blocks ATP binding to a first protein, e.g., HCK or LYN or SRC, at a lower concentration (e.g., not less than about 10-fold) than it blocks ATP binding a second protein that is different from the first protein, e.g., BTK.
  • a first protein e.g., HCK or LYN or SRC
  • a second protein that is different from the first protein, e.g., BTK.
  • Methods include purified enzyme and cell based biochemical and binding assays such as an HCK gatekeeper mutant rescue assay, an in vitro kinase assay, e.g., using HCK gatekeeper mutated kinase, competitive binding assays using KiNativTM technology or biotin tagged inhibitors, e.g., HCK inhibitors.
  • Suitable assays for determining selective inhibition of HCK by a compound include, but are not limited to, Life Technology Z-Lyte activity assays (e.g., including HCK gatekeeper mutants and GK + 6 mutants); DiscoverX KINOMEscan ® binding assays; MRC radioactivity assays; ACD Ba/F3 viability assays (e.g., including HCK gatekeeper mutants and GK + 6 mutants); Yeast hybrid proliferation assays; Protein thermostability assays; and cancer cells with HCK gatekeeper mutants or GK + 6 mutants proliferation-rescue assays. Such assays can also be used to determine selective inhibition of LYN and/or SRC by a compound.
  • Life Technology Z-Lyte activity assays e.g., including HCK gatekeeper mutants and GK + 6 mutants
  • DiscoverX KINOMEscan ® binding assays MRC radioactivity assays
  • ACD Ba/F3 viability assays e
  • E3 Ubiquitin Ligase is used to describe a target enzyme(s) binding site of ubiquitin ligase moieties as described herein, e.g., in the bifunctional (chimeric) compounds as described herein.
  • the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome.
  • E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to a lysine on a target protein.
  • the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth.
  • PROTAC proteolysis targeting chimera
  • a target e.g., HCK/BTK
  • a degradation moiety tethered together by a suitable linker.
  • PROTACs bind to a target molecule (e.g., HCK/BTK) and signal for degradation of the target molecule (e.g., by recruitment of the E3 ligase, resulting in ubiquitination and subsequent degradation of the target protein by the protea- some).
  • PROTACs may inhibit the activity of the taiget through their binding to the target active site (e.g., as with a conventional enzyme inhibitor) or may bind to the taiget without significant inhibition of activity.
  • the compounds described herein are PROTACs.
  • the term “chimeric antigen receptor” or “CAR,” as used herein, refers to an artificial T cell receptor that is engineered to be expressed on an immune effector cell and specifically bind an antigen. CARs may be used as a therapy with adoptive cell transfer. T cells are removed from a patient and modified so that they express the receptors specific to a particular form of antigen. In some embodiments, the CARs have been expressed with specificity to a tumor associated antigen, for example.
  • CARs may also comprise an intracellular activation domain, a transmembrane domain and an extracellular domain comprising a tumor associated antigen binding region.
  • CARs comprise fusions of single-chain variable fragments (scFv) derived monoclonal antibodies, fused to CD3zeta transmembrane and intracellular domain.
  • the specificity of CAR designs may be derived from ligands of receptors (e.g., peptides).
  • a CAR can target cancers by redirecting the specificity of a T cell expressing the CAR specific for tumor associated antigens.
  • MYD88 mutation means any change or difference in the nucleic acid or protein sequence of MYD88 as compared to the wild type sequence that results in the activation of MYD88 which leads to the activation of NF- ⁇ B. Mutations include, but are not limited to, nonsense mutations, missense mutations, frameshift mutations, rearrangement mutations, insertion mutations and deletion mutations.
  • the mutation is a somatic mutation at position 38182641 in chromosome 3p22.2 which results in a single nucleotide change from T ⁇ C in the myeloid differentiation primary response (MYD88) gene, and a predicted non-synonymous change at amino acid position 265 from leucine to proline (L265P).
  • the mutation is another activating mutation in MYD88, such as V217F, W218R, I220T, S222R, M232T, S243N, T294P.
  • MYD88 mutated disease or “disease associated with mutated MYD88” means any disease in a subject that is related to a change or difference in the nucleic acid or protein sequence of MYD88 as compared to the wild type sequence that results in the activation of MYD88 which leads to the activation of NF- ⁇ B.
  • mutated MYD88 is associated with Waldenström’s Macroglobulinemia (IgM secreting lymphoplasmacytic lymphoma), non-IgM secreting lymphoplasmacytic lymphoma, ABC subtype of diffuse large B-cell lymphoma, primary central nervous system (CNS) lymphoma, immune privileged lymphomas that include testicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia.
  • mutated MYD88 is associated with susceptibility to infectious disease.
  • mutated MYD88 is associated with susceptibility to autoimmune disease.
  • Ring A is absent or a heteroaryl ring; when Ring A is absent, two R A are present at the points of attachment for Ring A, R A is selected independently selected from the group consisting of H, –NR’R”, –C(O)NR’R”, and –NR’C(O)R”; R’ and R” are independently H or C 1-3 alkyl; L1 is a bond, C1-C3 alkyl, –C(O)C1-3alkyl–, –C1-3alkyl-O–, or –C1-3alkyl-O-C1-3alkyl–; Ring B is a bond (and R B is attached through L1) or selected from C4-6 cycloalkyl and 4-6 heterocyclyl, and R B is E3 ligase-binding moiety.
  • the disclosure relates to a compound of Formula (I), wherein Q 1 is N, S, or C. In some embodiments, Q 1 is N. In some embodiments, Q 1 is C. In some embodiments, Q 1 is S. In some embodiments, the disclosure relates to a compound of Formula (I), wherein Q 1 is N, S, or C and Q 2 is N or C. In some embodiments, Q 1 and Q 2 are N. In some embodiments, Q 1 is N and Q 2 is C. In some embodiments, Q 1 is C and Q 2 are N. In some embodiments, Q 1 is S and Q 2 is C. [0138] In some embodiments, the disclosure relates to a compound of Formula (I), wherein Q 3 is N or C.
  • Q 3 is C. In some embodiments, Q 3 is N. [0139] In some embodiments, the disclosure relates to a compound of Formula (I), wherein Q 1 and Q 2 are N, and Q 3 is C. [0140] In some embodiments, the disclosure relates to a compound of Formula (I), wherein Ring A is absent or a heteroaryl ring. In some embodiments, Ring A is absent, In some embodiments, Ring A is absent.
  • Ring A is I [0141]
  • the disclosure relates to a compound of Formula (I), wherein Ring A is a heteroaryl ring and R A is selected independently selected from the group consisting of H, –NR’R”, –C(O)NR’R”, and –NR’C(O)R”.
  • R A is H.
  • R A is –NR’R”.
  • R A is –NH 2 .
  • the disclosure relates to a compound of Formula (I), wherein Ring A is absent and R A is selected independently selected from the group consisting of H, –NR’R”, –C(O)NR’R”, and –NR’C(O)R”.
  • R A is H and –NR’R”.
  • R A is H and –NH 2 .
  • R A is –NR’R” and –NR’C(O)R”.
  • R A is –NH2 and –NHC(O)CH3.
  • R A is –NR’R” and –C(O)NR’R”.
  • R A is –NH2 and –C(O)NH2.
  • the disclosure relates to a compound of Formula (I), wherein Ring B is a bond (and and R B is attached through L1) or selected from C4-6 cycloalkyl and 4-6 heterocyclyl ring.
  • Ring B is a bond
  • Ring B some embodiments
  • Ring B is [0144]
  • the Ligase ligand is a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety (e.g., hydroxyproline, hydroxyproline derivatives, or binding moieties described in U.S. Patent Application Pub. No.
  • VHL Von Hippel-Lindau
  • a cereblon E3 ubiquitin ligase binding moiety e.g., thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, derivatives thereof, or binding moieties described in U.S. Patent Application Publication US 2015/0291562 (herein incorporated by reference in its entirety)
  • MDM2 mouse double minute 2 homolog
  • E3 ubiquitin ligase binding moiety e.g., binding moieties described in U.S. patent application Ser. No. 15/206,497 (herein incorporated by reference in its entirety)
  • IAP E3 ubiquitin ligase binding moiety e.g., IAP E3 ubiquitin ligase binding moiety.
  • Suitable ligands for binding the aforementioned E3 ubiquitin ligases, as well as other known E3 ubiquitin ligases, are understood in the field and described in, for example, U.S. Pub. Nos.2015/ 0291562, 2014/0356322, 2018/0256586, 2018/0228907, 2018/0193470, 2018/0179183, 2018/0134684; 2017/ 0327469; herein incorporated by reference in their entireties.
  • the compounds and formulas within the scope of embodi ments herein are not limited to specific ligase ligand struc tures described herein, or incorporated by reference, but include ligase ligands understood in the field.
  • the disclosure relates to a compound of Formula (I), wherein R B is selected from the group consisting of
  • the disclosure relates to a compound of formula or a pharmaceutically acceptable salt thereof. In other embodiments, the disclosure relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the disclosure,” as that term is used herein. [0151] In some embodiments, the disclosure relates to the foregoing compound in non-salt form. Such compound is considered to be a “compound of the disclosure,” as that term is used herein.
  • compositions that inhibit the activity of one or more kinases and/or facilitate degradation of one or more kinases, and thus the present compounds, and pharmaceutically acceptable salts thereof, are useful for the treatment of diseases, disorders, and conditions including, but not limited to a proliferative disease (e.g., an IgM gammopathy (e.g., an IgM Monoclonal gammopathy of undetermined significance (MGUS), amyloid light chain (AL) amyloidosis), mastocytosis (e.g., systemic mastocytosis) cancer (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, stomach cancer, lymphoma (e.g., B-cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM
  • a proliferative disease e.g., an IgM gammopathy (e.g., an IgM Monoclonal gammopathy of undetermined significance (MG
  • pharmaceutically-acceptable carrier means one or more compatible fillers, diluants or other such substances, which are suitable for administration to a human or other mammal such as a dog, cat, or horse.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the carriers are capable of being commingled with the preparations of the present disclosure, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability.
  • Carriers suitable for oral, subcutaneous, intravenous, intramuscular, etc. formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
  • the present disclosure also provides pharmaceutical compositions comprising a compound described herein and optionally a pharmaceutically acceptable excipient.
  • Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • the disclosure features a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the disclosure features a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
  • a proliferative disease e.g., an IgM gammopathy (e.g., an IgM Monoclonal gammopathy of undetermined significance (MGUS), amyloid light chain (AL) amyloidosis), mastocytosis (e.g., systemic mastocytosis) cancer (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, stomach cancer, lymphoma (e.g., B- cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM secreting lymphoplasmacytic lymphoma (i.e., Waldenström’s
  • a proliferative disease e.g., an IgM gammopathy (e.g., an IgM Monoclonal
  • the method comprises administering a compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • the disease is associated with a mutated MYD88 protein.
  • the disease is associated with a mutated BTK protein.
  • the disease is associated with a C481 mutated BTK protein.
  • the disease is associated with a C481S mutated BTK protein.
  • the diseases are associated with aberrant activity of a kinase (e.g., SRC Family kinases (e.g., HCK, LYN, BLK, FRK), Tec family kinases (e.g., BTK).
  • 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).
  • a BTK inhibitor e.g., ibrutinib, CC-292, ONO-4059, evobrutinib, spebrutinib, BGB-3111, HM71224, or ACP-196.
  • the disease is resistant to treatment with ibrutinib.
  • the disease is associated with a mutated BTK protein (e.g., a C481S mutated BTK), and the disease is resistant to treatment with ibrutinib.
  • the one or more kinase is an SRC Family kinase (e.g., HCK, LYN, BLK, FRK).
  • the one or more kinase is a Tec family kinase (e.g., BTK).
  • the one or more kinase is an SRC Family kinase (e.g., HCK, LYN, BLK, FRK). In other embodiments, the one or more kinase is a Tec family kinase (e.g., BTK). In certain embodiments, the BTK is resistant to inhibition by a BTK inhibitor (e.g., ibrutinib, CC-292, ONO-4059, evobrutinib, spebrutinib, BGB-3111, HM71224, or ACP-196). In certain embodiments, the BTK is ibrutinib resistant.
  • a BTK inhibitor e.g., ibrutinib, CC-292, ONO-4059, evobrutinib, spebrutinib, BGB-3111, HM71224, or ACP-196. In certain embodiments, the BTK is ibrutinib resistant.
  • An MYD88 mutated disease can include, but is not limited to a proliferative disease (e.g., an IgM gammopathy (e.g., an IgM Monoclonal gammopathy of undetermined significance (MGUS), amyloid light chain (AL) amyloidosis), mastocytosis (e.g., systemic mastocytosis) cancer (e.g., breast cancer, colon cancer, testicular cancer, CNS cancer, stomach cancer, lymphoma (e.g., B-cell lymphoma (e.g., lymphoplasmacytic lymphoma (e.g., IgM secreting lymphoplasmacytic lymphoma (i.e., Waldenström’s Macroglobulinemia), non-IgM secreting lymphoplasmacytic lymphoma)), diffuse large B-cell lymphom
  • the subject being treated has previously undergone treatment with ibrutinib. In certain embodiments, the subject being treated has developed ibrutinib resistance.
  • the provided methods include inhibiting and facilitating the degradation of LYN and/or SRC comprising the steps of administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically-labeled derivative, stereoisomer, or prodrug thereof.
  • the method further comprises administering an agent which inhibits and facilitates the degradation of LYN and/or SRC.
  • a compound of the disclosure as described herein is administered to the subject in combination (e.g., concurrently or sequentially) with an agent which blocks ATP binding to SRC.
  • a compound of the disclosure as described herein is administered to the subject in combination (e.g., concurrently or sequentially) with an agent which blocks ATP binding to LYN.
  • a compound of the disclosure as described herein is administered to the subject in combination (e.g., concurrently or sequentially) with an agent which blocks ATP binding to HCK.
  • the provided methods include inhibiting and facilitating the degradation of Tec family kinases comprising the steps of administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically-labeled derivative, stereoisomer, or prodrug thereof.
  • the provided methods include inhibiting and facilitating the degradation of BTK comprising the steps of administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically-labeled derivative, stereoisomer, or prodrug thereof.
  • Detection methods include, but are not limited to, direct sequencing, DNA chip technologies, mass spectroscopy, polymerase chain reaction (PCR), allele specific polymerase chain reaction, real time polymerase chain reaction, reverse transcriptase PCR, electrophoretic mobility, nucleic acid hybridization, fluorescent in situ hybridization, and denaturing high performance liquid chromatography.
  • PCR polymerase chain reaction
  • allele specific polymerase chain reaction e.g., as described in WO 2013/006443.
  • LPL LPL
  • the subject may also present one or more of the following clinical features or symptoms of other B cell neoplasms: asymptomatic localized or generalized peripheral lymphadenopathy, plasmacytic difference, bone marrow involvement, autoimmune thrombocytopenia, peripheral blood villous lymphocytes, end organ damage (hypercalcemia, renal insufficiency, bone lesions), recurrent infections, elevated creatine, hyperuricemia, and hypoalbunemia.
  • a subject suspected of having one or more of Waldenström’s Macroglobulinemia i.e., IgM secreting lymphoplasmacytic lymphoma), non-IgM secreting lymphoplasmacytic lymphoma, ABC subtype of diffuse large B-cell lymphoma, primary central nervous system (CNS) lymphoma, immune privileged lymphomas that include testicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia may be assessed for the presence of a mutation in the gene encoding MYD88, e.g., at position 38182641 in chromosome 3p22.2, as well as other activating mutations in MYD88 (including but not limited to V217F, W218R, I220T, S222R, M232T, S243N, and T294P).
  • MYD88 e.g., at position 38182641 in chromosome 3p22.2
  • the compounds described herein are able to bind the one or more kinase being inhibited.
  • a compound described herein is able to bind to the one or more kinase.
  • the one or more kinase is an SFK (e.g., HCK, LYN, BLK, FRK).
  • the one or more kinase is HCK.
  • the onr or more kinase is LYN.
  • the one or more kinase is a Tec family kinase (e.g., BTK).
  • the one or more kinase is BTK.
  • a kinase e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec family kinase (e.g., BTK)
  • SFK e.g., HCK, LYN, BLK, FRK
  • Tec family kinase e.g., BTK
  • the activity of a kinase in a subject is decreased by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.
  • the activity of a kinase in a subject is selectively inhibited by the method.
  • the activity of a kinase (e.g., HCK, LYN, BTK) in a subject is selectively decreased by a compound or pharmaceutical composition described herein.
  • a disease including proliferative disease, may be associated with aberrant or undesired activity of a kinase, and/or overexpression of the kinase.
  • Aberrant or undesired activity of a kinase may be an increased or a decreased level of activity of the kinase.
  • Proliferative diseases are sometimes associate with abnormal levels of JAK activity, frequently through increased or decreased JAK activation. Inhibition of the activity of JAK2 would be expected to inhibit phosphorylation.
  • JAK2 is not overexpressed, but the activity of JAK2 is increased.
  • JAK2 is overexpressed, and the activity of JAK2 is increased.
  • the compounds and pharmaceutical compositions described herein may inhibit the activity of JAK2 and be useful in treating and/or preventing diseases, such as diseases associated with the aberrant, increased, or undesired activity of a kinase, overactivation of the kinase, and/or overexpression of the kinase.
  • the disease e.g., the disease to be treated or prevented by a method described herein
  • a kinase e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec Family kinases (e.g., BTK)).
  • the disease is associated with overexpression of a kinase (e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec Family kinases (e.g., BTK)).
  • a kinase e.g., SFK (e.g., HCK, LYN, BLK, FRK), Tec Family kinases (e.g., BTK)
  • the disease is a proliferative disease.
  • the proliferative disease is cancer.
  • the cancer is associated with a mutation in MYD88.
  • the cancer is associated with mutated BTK.
  • the proliferative disease is mastocytosis.
  • the mastocytosis is systemic mastocytosis.
  • the proliferative disease is an IgM gammopathy.
  • the IgM gammopathy is IgM monoclonal gammopathy with undetermined significance.
  • the disease is breast cancer. In certain embodiments, the disease is colon cancer. In certain embodiments, the disease is testicular cancer. In certain embodiments, the disease is cancer of the CNS. In certain embodiments, the disease is stomach cancer. In certain embodiments, the disease is lymphoma. In certain embodiments, the lymphoma is B-cell Lymphoma. In certain embodiments, B-cell lymphoma is lymphoplasmacytic lymphoma.
  • the lymphoplasmacytic lymphoma is IgM secreting lymphoplasmacytic lymphoma (i.e., Waldenström’s Macroglobulinemia). In certain embodiments, the disease is Waldenström’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.
  • BCC B-cell-like
  • the lymphoma is Follicular Lymphoma. In certain embodiments, the lymphoma is marginal zone B-cell lymphoma. In certain embodiments, the lymphoma is Small lymphocytic lymphoma. In certain embodiments, the small lymphocytic lymphoma is Mantle cell lymphoma. In certain embodiments, the cancer is leukemia. In certain embodiments, the leukemia is chronic lymphocytic leukemia (CLL). In certain embodiments, the leukemia is myelogenous leukemia. In certain embodiments, the myelogenous leukemia is chronic myelogenous leukemia. In certain embodiments, the myelogenous leukemia is acute myelogenous leukemia.
  • CLL chronic lymphocytic leukemia
  • the acute myelogenous leukemia is mast cell leukemia.
  • the cancer is myeloma.
  • the myeloma is IgM myeloma.
  • the IgM myeloma is IgM multiple myeloma.
  • the cancer is a myeloproliferative disease.
  • the myeloproliferative disease is myelodysplastic syndrome.
  • the method described herein is superior (e.g., showing improved safety and/or therapeutic effects) or comparable to existing therapy (e.g., chemotherapy, treatment with a BTK inhibitor).
  • the additional therapy is a cytotoxic chemotherapy (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, l-asparaginase, cyclophosphamide, or etoposide).
  • the additional therapy is an epigenetic modifier (e.g., azacitidine or romidepsin).
  • the additional therapy is a glucocorticoid.
  • the additional therapy is an immunotherapy (e.g., an immunotherapeutic monoclonal antibody).
  • 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.
  • the additional pharmaceutical agent is etoposide, JIB04, or cisplatin, and optionally the disease is Ewing’s sarcoma.
  • an “effective amount” of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating or lessening the severity of one or more of the conditions recited above.
  • effective amounts of the therapeutic agent will depend on the particular disease being treated; the severity of the disease; individual patient parameters including age, physical condition, size and weight, concurrent treatment, frequency of treatment, and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation.
  • a maximum dose is used, that is, the highest safe dose according to sound medical judgment.
  • An effective amount of a compound typically will vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations, for one or several days (depending of course of the mode of administration and the factors discussed above).
  • Actual dosage levels of the therapeutic agent can be varied to obtain an amount that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level depends upon the activity of the particular compound, the route of administration, the tissue being treated, and prior medical history of the patient being treated.
  • An effective amount includes, but is not limited to, that amount necessary to slow, reduce, inhibit, ameliorate or reverse one or more symptoms associated with the MYD88 mutated disease.
  • such terms refer to a reduction in the levels of IgM serum paraprotein, anemia, hyper-viscosity, neuropathy, coagulopathies, splenomegaly, hepatomegaly, and adenopathy.
  • the effective amount is an amount effective for inhibiting the activity of a kinase by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%.
  • the subject is an animal. The animal may be of either sex and may be at any stage of development.
  • the subject described herein is a human (e.g., an adult, juvenile, or child).
  • the subject is a non-human animal.
  • the subject is a mammal.
  • the subject is a non-human mammal.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a dog.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • the subject is a genetically engineered animal.
  • a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cell
  • Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol,
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • 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.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • 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.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • 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.
  • Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ® Plus, Phenonip ® , methylparaben, Germall ® 115, Germaben ® II, Neolone ® , Kathon ® , and Euxyl ® .
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • 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.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as Cremophor ® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • solubilizing agents such as Cremophor ® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • 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.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (a) fillers or
  • the dosage form may include a buffering agent.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • 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 can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • a flavoring agent such as saccharin sodium
  • a volatile oil such as a liquid oil
  • a buffering agent such as a liquid oil
  • a surface active agent such as methylhydroxybenzoate
  • a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • kits e.g., pharmaceutical packs.
  • the kit comprises a compound of the disclosure or a pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition.
  • the kit comprises a first container, wherein the first container includes the compound or pharmaceutical composition.
  • the kit further comprises a second container.
  • the present disclosure provides methods of inhibiting the activity of a kinase in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound described herein or a pharmaceutical composition described herein.
  • the present disclosure provides methods of degrading a kinase in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound described herein or a pharmaceutical composition described herein.
  • the compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in inhibiting the activity of a kinase (e.g., SFK (e.g., LYN, HCK), Tec family kinases (e.g., BTK)) in a subject, improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject.
  • a kinase e.g., SFK (e.g., LYN, HCK), Tec family kinases (e.g., BTK)
  • a kinase e.g., SFK (e.g., LYN, HCK), Tec family kinases (e.g., BTK)
  • treatment further includes administering to the subject one or more of a BCL-2 inhibitor (e.g., venetoclax, navitoclax, obatoclax), a BCL-2/BCL-xL inhibitor (e.g., APG-1252, BM-1197), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib or oprozomib), a monoclonal antibody (e.g., rituximab, daratumumab, ofatumumab or obinituzumab), an alkylator drug (e.g., bendamustine, cyclophosphamide), a nucleoside analogue (e.g., fludarabine or cladribine), an MTOR inhibitor (e.g., everolimus), a BTK inhibitor (e.g., ibrutinib, acalabrutini
  • the anti-cancer agent is a monoclonal antibody, e.g., rituximab.
  • the anti-cancer agent is a chemotherapeutic drug such as chlorambucil, cyclophosphamide, or vincristine or thalidomide.
  • Corticosteroids such as Prednisone, may also be used in combination.
  • Plasmapheresis can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood.
  • Autologous bone marrow transplantation may be used in combination with compounds described herein.
  • treatment further includes administering to the subject an agent that inhibits LYN and/or SRC.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
  • CFR Code of Federal Regulations
  • proteins proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • CFR Code of Federal Regulations
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease, cancer, inflammatory disease, autoimmune disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) or premalignant condition.
  • a disease e.g., proliferative disease, cancer, inflammatory disease, autoimmune disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses.
  • the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • the additional pharmaceutical agents include, but are not limited to, cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, anti- proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol- lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof.
  • the additional pharmaceutical agent is an anti-proliferative agent (e.g., anti-cancer agent). In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (Asparaginase Erase Er
  • the additional pharmaceutical agent is an anti-lymphoma agent.
  • the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I 131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP- ABV,
  • 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.
  • REVLIMID lacalidomide
  • DACOGEN decitabine
  • VIDAZA azacitidine
  • CYTOSAR-U cytarabine
  • IDAMYCIN idarubicin
  • CERUBIDINE dounorubicin
  • LEUKERAN chlorambucil
  • NEOSAR cyclophosphamide
  • FLUDARA fludarabine
  • LEUSTATIN cladribine
  • the additional pharmaceutical agent is a cytotoxic chemotherapeutic agent (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, l- asparaginase, cyclophosphamide, or etoposide).
  • the additional pharmaceutical agent is an epigenetic modifier such as azacitidine or romidepsin.
  • the additional pharmaceutical agent is ruxolitinib, BBT594, CHZ868, CYT387, or BMS911543.
  • the additional pharmaceutical agent is an inhibitor of a tyrosine kinase.
  • the additional pharmaceutical agent is a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonji histone demethylase inhibitor, or a DNA damage inducer.
  • 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.
  • the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation.
  • epigenetic or transcriptional modulators e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors
  • antimitotic drugs e.g., taxanes and vinca
  • the additional pharmaceutical agent is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor.
  • the additional pharmaceutical agent is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor.
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • the additional pharmaceutical agent is a T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitor, lymphocyte activation gene-3 (LAG3) inhibitor, V-set domain-containing T-cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitor, cluster of differentiation 276 (CD276 or B7- H3) inhibitor, B and T lymphocyte attenuator (BTLA) inhibitor, galectin-9 (GAL9) inhibitor, checkpoint kinase 1 (Chk1) inhibitor, adenosine A2A receptor (A2AR) inhibitor, indoleamine 2,3- dioxygenase (IDO) inhibitor, killer-cell immunoglobulin-like receptor (KIR) inhibitor, or V- domain Ig suppressor of T
  • the additional pharmaceutical agent is a BCL-2 inhibitor (e.g., venetoclax, navitoclax, obatoclax), or a BCL-2/BCL-xL inhibitor (e.g., APG-1252, BM-1197).
  • the additional pharmaceutical agent is venetoclax.
  • the compounds of the disclosure are used in combination with one or more additional immunotherapies.
  • the additional immunotherapy comprises a chimeric antigen receptor (CAR).
  • the additional immunotherapy comprises a bispecific antibody.
  • the compounds of the disclosure can be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to one skilled in the art.
  • the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups.
  • Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed.2006).
  • the present disclosure is further illustrated by the following Examples, which in no way should be construed as further limiting.
  • Step 1 Synthesis of 6-bromobenzo[d]isoxazol-3-amine.
  • N-hydroxyacetamide 897 mg, 11.96 mmol
  • DMF 40 mL
  • KOt-Bu 1.33 g, 11.96 mmol
  • 4-bromo-2- fluorobenzonitrile 1.7 g, 8.54 mmol
  • Step 2 Synthesis of 3-((6-bromobenzo[d]isoxazol-3-yl)amino)propanenitrile
  • Step 3 Synthesis of 3-((6-bromobenzo[d]isoxazol-3-yl)amino)propanamide
  • Step 5 Synthesis of 1-(6-bromobenzo[d]isoxazol-3-yl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione [0251] To a solution of 1-(6-bromobenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)- dione (3.3 g, 10.7 mmol) and PMBCl (2.51 g, 16.1 mmol) in DMF (40 mL) was added Cs2CO3 (6.99 g, 21.4 mmol).
  • Step 8 Synthesis of 1-(6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1- yl)benzo[d]isoxazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 10 Synthesis of 1-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin- 1(2H)-yl)benzo[d]isoxazol-6-yl)azetidine-3-carbaldehyde [0261] To a solution of 1-(6-(3-(hydroxymethyl)azetidin-1-yl)benzo[d]isoxazol-3-yl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (120 mg, 0.28 mmol) in DCM (5 mL) was added Dess-Martin reagent (234 mg, 0.55 mmol) at 0 o C.
  • Step 11 Synthesis of 1-(6-(3-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)benzo[d]isoxazol- 3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione [0263] To a mixture of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine (120 mg, 0.26 mmol) in DCE (10 mL) was added 1-(3-(3-(4- methoxybenzyl)-2,4-di
  • Step 12 Synthesis of 1-(6-(3-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)benzo[d]isoxazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2) [0265] A solution of 1-(6-(3-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)benzo[d]iso
  • Example 2 Synthesis of 5-(3-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 7) [0092] Compound (7) was synthesized according the scheme below.
  • Step 1 Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2.6 g, 10 mmol
  • 1,4-dioxaspiro[4.5]decan-8-ol 3.2 g, 20 mmol
  • PPh 3 3.9 g, 15 mmol
  • Step 3 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 4 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 5 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 7 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)azetidine-3-carbaldehyde.
  • Step 1 Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2.6 g, 10 mmol
  • 1,4-dioxaspiro[4.5]decan-8-ol 3.2 g, 20 mmol
  • PPh 3 3.9 g, 15 mmol
  • Step 3 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 6 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-1- yl)isoindoline-1,3-dione.
  • azetidin-3-ylmethanol 133 mg, 1.08 mmol
  • DIPEA 279 mg, 2.16 mmol
  • Step 7 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)azetidine-3-carbaldehyde.
  • 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-1- yl)isoindoline-1,3-dione 100 mg, 0.29mmol
  • DCM 10 mL
  • Dess-Martin reagent 247 mg, 0.58 mmol
  • Step 4 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 5 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 6 Synthesis of 1-((1R,4r)-4-(4-(((1r,4R)-4- (bromomethyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl)-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine [0317] To a mixture of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.21 mmol) in acetone (10 mL) was added (1r,4r)- 1,4-bis(bromomethyl)cyclohexane (173 mg, 0.64 mmol) and K2CO3 (174 mg, 1.26 mmol).
  • Step 7 Synthesis of (1R,4S)-2-((R)-3-((((1R,4R)-4-((4-((1r,4R)-4-(4-amino-3-(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1- yl)methyl)cyclohexyl)methyl)thio)-2-(1-fluorocyclopropane-1-carboxamido)-3-methylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)cyclopentane-1-carboxamide (13) [0319] To a mixture of 1-((1R,4r)-4-(4-(((1r,4R)-4- (bromomethyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl)-3-(4-
  • Step 1 Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2.6 g, 10 mmol
  • 1,4-dioxaspiro[4.5]decan-8-ol 3.2 g, 20 mmol
  • PPh 3 3.9 g, 15 mmol
  • Step 3 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 5 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 6 Synthesis of tert-butyl 4-(3-bromopropyl)piperidine-1-carboxylate.
  • tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate 800 mg, 3.29 mmol
  • CBr4 1.7 g, 5.3 mmol
  • PPh3 1,3 g, 3.95 mmol
  • Step 8 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(4-(3-(piperazin-1- yl)propyl)piperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 10 Synthesis of 5-(4-(3-(4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)propyl)piperazin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione.
  • Step 1 Synthesis of 5-(2-bromoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione.
  • 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (274 mg, 1.00 mmol)
  • 2-bromoethan-1-ol 124 mg, 1.00 mmol
  • PPh3 PPh3
  • DIAD 303 mg, 1.50 mmol
  • Step 4 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Example 7 Synthesis 5-(3-(4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (Compound 21) [0092] Compound (21) was synthesized according the scheme below. [0356] Step 1: Synthesis of 5-(3-bromopropoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione.
  • Step 2 Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • Step 4 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 5 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 7 Synthesis of 5-(3-(4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)propoxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (21).
  • Example 8 Synthesis of 4-(3-((4-((1r,4r)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 26) and 4-(3-((4-((1s,4s)-4-(4-amino-5-(4- phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 27). [0370] Com
  • Step 1 Synthesis of 7-bromo-5-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine.
  • 141 To a solution of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (4 g, 18.79 mmol) in DMF (50 mL) was added NIS (4.65 g, 20.67 mmol), the resulting mixture was stirred at room temperature for 16 h in the dark. The mixture was diluted with water (200 mL), and the precipitate was formed and filtered.
  • Step 4 Synthesis of 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8- yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine.
  • Step 6 Synthesis of cis-tert-butyl 4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazine-1-carboxylate and trans-tert-butyl 4-(4-(4-amino-5-(4- phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 7 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-1- yl)isoindoline-1,3-dione.
  • 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione 200 mg, 0.72 mmol
  • azetidin-3-ylmethanol 133 mg, 1.08 mmol
  • DIPEA 279 mg, 2.16 mmol
  • Step 8 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)azetidine-3-carbaldehyde.
  • 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-1- yl)isoindoline-1,3-dione 100 mg, 0.29mmol
  • DCM 10 mL
  • Dess-Martin reagent 247 mg, 0.58 mmol
  • Step 9 Synthesis of trans-5-(4-phenoxyphenyl)-7-(4-(piperazin-1- yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine.
  • Step 10 Synthesis of trans-4-(3-((4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (26).
  • Step 11 Synthesis of cis-5-(4-phenoxyphenyl)-7-((1s,4s)-4-(piperazin-1- yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine.
  • Example 9 Synthesis of 5-(3-((4-((1r,4r)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 28) and 5-(3-((4-((1s,4s)-4-(4-amino-5-(4- phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 29).
  • Step 4 Synthesis of 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8- yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine.
  • Step 6 Synthesis of cis-tert-butyl 4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazine-1-carboxylate and trans-tert-butyl 4-(4-(4-amino-5-(4- phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 7 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1- yl)isoindoline-1,3-dione.
  • Step 8 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)azetidine-3-carbaldehyde.
  • Step 10 Synthesis of trans-5-(3-(4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione.
  • Step 11 Synthesis of cis-5-(4-phenoxyphenyl)-7-((1s,4s)-4-(piperazin-1- yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine.
  • Step 12 Synthesis of cis-5-(3-((4-(4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione.
  • Example 10 Synthesis of 4-(3-((4-((1r,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 30) and 4-(3-((4-((1s,4s)-4-(4-amino-5-(4- phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1- yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 31) [0420]
  • Step 1 Synthesis of ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-imidazole-5- carboxylate.
  • hydroxylamine hydrochloride 5.27 g, 76.3 mmol
  • NaHCO3 8.55 g, 101.8mmol
  • Step 4 Synthesis of 5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(1H-1,2,4-triazol- 1-yl)imidazo[5,1-f][1,2,4]triazine.
  • POCl 3 3.99 g, 26.3 mmol
  • Step 5 Synthesis of 5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,1- f][1,2,4]triazin-4-amine.
  • Step 7 Synthesis of 4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7- yl)cyclohexan-1-one.
  • Step 8 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-5-(4- phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexyl)piperazine-1-carboxylate (P1) and tert-butyl 4-((1s,4s)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7- yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 10 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)azetidine-3-carbaldehyde.
  • 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-1- yl)isoindoline-1,3-dione 100 mg, 0.29mmol
  • DCM 10 mL
  • Dess-Martin reagent 247 mg, 0.58 mmol
  • Step 11 Synthesis of 5-(4-phenoxyphenyl)-7-((1r,4r)-4-(piperazin-1- yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine.
  • Step 11 Synthesis of 4-(3-((4-((1r,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (30).
  • Step 12 Synthesis of 5-(4-phenoxyphenyl)-7-((1s,4s)-4-(piperazin-1- yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine.
  • Step 13 Synthesis of 4-(3-((4-((1s,4s)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (31).
  • Step 1 Synthesis of ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-imidazole-5- carboxylate.
  • hydroxylamine hydrochloride 5.27 g, 76.3 mmol
  • NaHCO3 8.55 g, 101.8mmol
  • Step 4 Synthesis of 5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(1H-1,2,4-triazol- 1-yl)imidazo[5,1-f][1,2,4]triazine.
  • POCl 3 3.99 g, 26.3 mmol
  • Step 5 Synthesis of 5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,1- f][1,2,4]triazin-4-amine.
  • Step 7 Synthesis of 4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7- yl)cyclohexan-1-one.
  • Step 8 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-5-(4- phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexyl)piperazine-1-carboxylate (P1) and tert-butyl 4-((1s,4s)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7- yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 10 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)azetidine-3-carbaldehyde.
  • Step 11 Synthesis of 5-(4-phenoxyphenyl)-7-((1r,4r)-4-(piperazin-1- yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine.
  • Step 12 Synthesis of 5-(3-((4-((1r,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (32).
  • Step 13 Synthesis of 5-(4-phenoxyphenyl)-7-((1s,4s)-4-(piperazin-1- yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine.
  • Step 14 Synthesis of 5-(3-((4-((1r,4r)-4-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1- f][1,2,4]triazin-7-yl)cyclohexyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (33).
  • Example 12 Synthesis of 4-(4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 34) [0478] Compound 34 was synthesized according to the scheme below.
  • Step 1 Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2.6 g, 10 mmol
  • 1,4-dioxaspiro[4.5]decan-8-ol 3.2 g, 20 mmol
  • PPh3 3.9 g, 15 mmol
  • Step 3 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 4 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 5 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 6 Synthesis of tert-butyl 4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.
  • Step 8 Synthesis of 4-(4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (34).
  • reaction mixture was quenched with ice cold water (20 mL), and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated.
  • Example 13 Synthesis of 4-(4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (34). [0495] Compound 34 was synthesized according to the scheme below.
  • Step 1 Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • Step 1 To a suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.6 g, 10 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (3.2 g, 20 mmol) and PPh3 (3.9 g, 15 mmol) in THF (30 mL) was added dropwise DIAD (4.04 g, 20 mmol) over a period of 30 min at 0 o C.
  • Step 4 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 6 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 7 Synthesis of tert-butyl 4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.
  • Step 8 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(4-(piperidin-4- ylmethyl)piperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 9 Synthesis of 4-(4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (34).
  • reaction mixture was quenched with ice cold water (20 mL), and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated.
  • Example 14 Synthesis of 5-(4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (35). [0512] Compound 35 was synthesized according to the scheme below.
  • Step 1 Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • Step 1 To a suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.6 g, 10 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (3.2 g, 20 mmol) and PPh 3 (3.9 g, 15 mmol) in THF (30 mL) was added dropwise DIAD (4.04 g, 20 mmol) over a period of 30 min at 0 o C.
  • Step 4 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 5 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 6 Synthesis of tert-butyl 4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.
  • Step 7 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(4-(piperidin-4- ylmethyl)piperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 8 Synthesis of 5-(4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (35).
  • reaction mixture was quenched with ice cold water (20 mL), and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with water, brine, dried over anhydrous Na 2 SO 4 and concentrated.
  • Example 15 Synthesis of 3-(4-(4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)-2,6- difluorophenyl)piperidine-2,6-dione (36). [0529] Compound 36 was synthesized according to the scheme below.
  • Step 1 Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2.6 g, 10 mmol
  • 1,4-dioxaspiro[4.5]decan-8-ol 3.2 g, 20 mmol
  • PPh3 3.9 g, 15 mmol
  • DIAD 4.04 g, 20 mmol
  • Step 3 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 4 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 5 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 6 Synthesis of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine.
  • Step 8 Synthesis of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)- 2,6-difluorophenyl)pyridine.
  • Step 10 Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidine-4- carbaldehyde.
  • Step 11 Synthesis of 3-(4-(4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)-2,6- difluorophenyl)piperidine-2,6-dione (36).
  • Example 16 Synthesis of 4-(3-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 37) [0552] Compound 37 was synthesized according to the scheme below.
  • Step 1 Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2.6 g, 10 mmol
  • 1,4-dioxaspiro[4.5]decan-8-ol 3.2 g, 20 mmol
  • PPh 3 3.9 g, 15 mmol
  • Step 3 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 6 Synthesis of tert-butyl 3-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)pyrrolidine-1-carboxylate.
  • Step 7 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(4-(pyrrolidin-3- ylmethyl)piperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 8 Synthesis of 4-(3-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 37).
  • Example 17 Synthesis of 5-(3-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dionee (Compound 38) [0569] Compound 38 was synthesized according to the scheme below.
  • Step 1 Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2.6 g, 10 mmol
  • 1,4-dioxaspiro[4.5]decan-8-ol 3.2 g, 20 mmol
  • PPh3 3.9 g, 15 mmol
  • DIAD 4.04 g, 20 mmol
  • Step 3 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 4 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 6 Synthesis of tert-butyl 3-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)pyrrolidine-1-carboxylate.
  • Step 7 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(4-(pyrrolidin-3- ylmethyl)piperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 8 Synthesis of 5-(3-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione.
  • Example 18 Synthesis of 1-(4-(4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione (Compound 39) [0585] Step 1: Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine.
  • Step 3 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 4 Synthesis of tert-butyl 4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 5 Synthesis of 3-(4-phenoxyphenyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine.
  • Step 6 Synthesis of 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione [0596] To a mixture of dihydropyrimidine-2,4(1H,3H)-dione (5.0 g, 43.9 mmol) and Cs 2 CO 3 (21.4 g, 65.8 mmol) in DMF (50 mL) was added 1-(chloromethyl)-4-methoxybenzene (6.84 g, 43.9 mmol). The resulting mixture was stirred at 50 o C overnight and diluted with H2O (200 mL).
  • Step 8 Synthesis of 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione [0600] To a mixture of 1-(4-bromophenyl)-3-(4-methoxybenzyl)dihydropyrimidine- 2,4(1H,3H)-dione (1.52 g, 3.92 mmol), 4-(dimethoxymethyl)piperidine (940 mg, 5.88 mmol), RuPhos (366 mg, 0.78 mmol) and Pd 2 (dba) 3 (360 mg, 0.39 mmol) in 1,4-dioxane (20 mL) was added K2CO3 (1.09 g, 7.84 mmol).
  • Step 9 Synthesis of 1-(4-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)piperidine-4-carbaldehyde
  • a mixture of 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (550 mg, 0.68 mmol) in TFA (5 mL) was stirred at 50 o C for 5hs, and the resulting mixture was concentrated to give 1-(4-(3-(4- methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (520 mg, crude) as brown oil, which was used directly for the next step.
  • Step 10 Synthesis of 1-(4-(4-((4-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example 20 Selective Inhibition of HCK and BTK in MYD88 mutated WM and ABC DLBCL cells
  • the Z ⁇ -LYTE biochemical assay employs a fluorescence-based, coupled-enzyme format and is based on the differential sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage.
  • the peptide substrate is labeled with two fluorophores—one at each end—that make up a FRET pair.
  • the Adapta universal kinase assay is a homogenous, fluorescent based immunoassay for the detection of ADP.
  • FIG. 1A shows the KINOMEscan ® kinase selectivity profiles of Compounds (7) and (10) with KIN-8194 as a comparison.
  • Example 21 Inhibition in TMD-8 and BCWM.1 cell lines
  • the dose-response and EC 50 values were determined. Mammalian cells in culture medium optimized for experimental conditions were prepared in multiwell plates. Control wells were prepared without cells, and used to determine background luminescence. The Compounds to be tested were added to the experimental wells. The multiwell plates were then incubated at 37 °C, 5% CO2 for 72 hours. [0612] Following incubation, the multiwell plates were allowed to equilibrate to room temperature for approximately 30 minutes.
  • Figures 4, 5A-5B, and 6A-6B graphically represent the signmoidal curves used to calculated the EC50 values generated.
  • Table 1 Results 215 ⁇
  • Example 20 Pharmacokinetic Study of Compounds of the Present Disclosure Following Single Intravenous and Oral Administrations to Male C57BL/6 Mice
  • Compound 7 or a sulfate thereof a study was made to determine a PK profile of a compound of the present disclosure after IV and PO administrations to male C57BL/6 mice.
  • Stocks of the compound were made in 5% DMSO, 5% Solutol® HS15, and 90% saline.
  • Blood was collected by restraining the animals at the designated time points. Approximately 110 ⁇ L of blood were taken from the animals via facial vein for semi-serial bleeding into K 2 EDTA tubes.
  • Blood was collected by restraining the animals at the designated time points. Approximately 110 ⁇ L of blood were taken from the animals via facial vein for semi-serial bleeding into K 2 EDTA tubes. Blood samples were put on ice and centrifuged to obtain plasma samples (2000 g, 5 min under 4°C) within 15 minutes. [0620] The study design is summarized below in Table 7 with the results summarized in Tables 6, 7, and 9 as well as Figure 3. Table 6: Study Design.
  • Table 7 Summary of PK Profile.
  • Table 8 Summary of PK Data for IV Administration.
  • Table 9 Summary of PK Data for PO Administration.

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Abstract

L'invention concerne des composés et des sels pharmaceutiquement acceptables de ceux-ci, utiles en tant qu'inhibiteurs de l'activité kinase et/ou des faciliteurs de la dégradation des kinases HCK et BTK. L'invention concerne également des compositions pharmaceutiques contenant les composés ou des sels pharmaceutiquement acceptables et des méthodes d'utilisation des composés, des sels pharmaceutiquement acceptables et des compositions pharmaceutiques dans le traitement de divers troubles, y compris une maladie proliférative, telle que la gammapathie à IgM, la mastocytose, le cancer.
PCT/US2024/061364 2023-12-21 2024-12-20 Inhibition et dégradation de kinase Pending WO2025137500A1 (fr)

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