Pyrazine compounds as inhibitors of FLT3

Abstract

Disclosed herein are heterocyclic compounds that inhibit the activity of FLT3. Specific covalent inhibitors of FLT3 are also described. Pharmaceutical compositions containing the compounds are also disclosed. Disclosed are methods of using FLT3 inhibitors, alone or in combination with other therapeutic agents, for the treatment of proliferative diseases or conditions, including hematological malignancies and other diseases or conditions that depend on FLT3 activity.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 295,494, filed December 30, 2021, U.S. Provisional Patent Application No. 63 / 316,939, filed March 4, 2022, U.S. Provisional Patent Application No. 63 / 364,860, filed May 17, 2022, and U.S. Provisional Patent Application No. 63 / 386,772, filed December 9, 2022, and International Patent Application No. PCT / US2022 / 40953, filed August 19, 2022, the contents of which are incorporated herein by reference in their entireties.

[0002] Field

[0002] Described herein are compounds, methods for making such compounds, pharmaceutical compositions and drugs containing such compounds, and methods for using such compounds and compositions to inhibit the activity of FLT3. [Background technology]

[0003] background

[0003] FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed in normal hematopoietic stem / progenitor cells. Upon activation by FLT3 ligand (FL), FLT3 dimerizes and induces multiple signaling pathways associated with hematopoietic cell survival and proliferation.

[0004] FLT3 is also frequently overexpressed in many acute leukemia cells, and mutations in the FLT3 gene are the most common genetic alteration in acute myeloid leukemia. Activating mutations in the FLT3 gene account for approximately one-third of newly diagnosed adult AML patients (Papaemmanuil et al., 2016, N Engl J Med. 374:2209), in which these mutations trigger a constitutive FLT3 signaling cascade. Genetic alterations in FLT3 have also been identified in other myeloid malignancies, such as myelodysplastic syndrome (MDS) and acute lymphocytic leukemia (ALL). Activating FLT3 mutations are either internal tandem duplications (ITDs) or point mutations in the tyrosine kinase domain, or sometimes a combination of both. FLT3-ITD mutations are present in approximately 20% of AML patients, and point mutations are present in approximately 5% to 10% of AML patients. Both mutations constitutively activate FLT3 through ligand-independent autophosphorylation, leading to increased signaling and cell proliferation, potentially resulting in leukemia cell survival (Kennedy et al., 2020, Front. Oncol. 10:612-880; Kiyoi et al., 2020, Cancer Science 111:312). FLT3-ITD mutations, in particular, are associated with poor prognosis and high relapse rates, and ITD mutations can be acquired or lost during disease progression and / or relapse. Therefore, testing for FLT3-ITD in patients with AML is recommended by both the European Leukemia Net and Cancer Network Guidelines.

[0005]

[0005] Early FLT3 inhibitors, referred to as first-generation FLT3 inhibitors, included the multikinase inhibitors sorafenib, midostaurin, lestaurtinib, sunitinib, and tandutinib. These first-generation inhibitors lacked efficacy as monotherapy, most likely due in part to nonspecific effects. While many of these first-generation inhibitors are no longer used as monotherapy or in combination with chemotherapy for the treatment of AML, midostaurin (Rydapt) in combination with chemotherapy was approved by the FDA in 2017 for adults with newly diagnosed FTL3-mutated AML.

[0006]

[0006] Second-generation FLT3 inhibitors have higher specificity for FLT3 and are more potent. Second-generation inhibitors include gilteritinib, crenolanib, and quizartinib. Gilteritinib and crenolanib are both type I inhibitors, meaning they can bind to both the inactive and active conformations of FLT3, while quizartinib is a type II inhibitor that can only bind to the inactive conformation. In 2018, the FDA approved gilteritinib for relapsed or refractory AML in patients with FLT3 mutations. In a phase III study testing the efficacy of quizartinib in combination with induction or consolidation chemotherapy (Quantum-R) in patients with relapsed or refractory FLT3-ITD AML, quizartinib demonstrated survival benefit and a manageable safety profile (Cortes et al., 2019, Lancet Oncol., 20:984). Crenolanib is currently being tested in a Phase III clinical trial for the treatment of relapsed or refractory AML in patients with FLT3 mutations.

[0007]

[0007] Additional inhibitors of FLT3 include the covalent FLT3 inhibitor FF-10101, which has shown activity against quizartinib-resistant AML (Yamaura et al., 2018, Blood, 131:426) and is currently being tested in clinical trials for relapsed or refractory hematological malignancies, including AML. FF-10101 and other N-phenylpyrimidine-2-amine compounds are described in PCT Application WO 2013 / 157540 and U.S. Patent No. 9,145,415, both assigned to Fujifilm Corporation. PCT Application WO 2015 / 056683 and U.S. Patent No. 9,701,644, also assigned to Fujifilm Corporation, describe crystalline forms of FF-10101. Additional patents and patent applications assigned to Fujifilm Corporation that describe FF-10101 and its use for certain types of cancer include PCT Application WO 2016 / 027904; WO 2020 / 075838; WO 2020 / 175629; and U.S. Patent No. 9,987,278.

[0008] Hanmi Pharmaceutical Co., Ltd. has described pyrimidine-containing compounds and their use in FLT3-mutant cancers in PCT applications WO 2020 / 022600; WO 2020 / 171646; WO 2020 / 171649; and WO 2020 / 262974. The pyrimidine-containing FLT3 inhibitor HM43239 is currently being tested in a Phase 1 / 2 clinical trial for patients with relapsed or refractory AML (Daver et al. 2019, Blood, 134:1331).

[0009] Genosco and Oscotec, Inc., in PCT Application WO 2013 / 142382 and U.S. Patent No. 8,877,763, describe pyridopyrimidine compounds and their use for the treatment of hematological malignancies. A crystalline form of the specific FLT3 inhibitor G-749 is described in WO 2020 / 040467, also assigned to Oscotec, Inc., and an oral pharmaceutical composition of G-749 is described in WO 2020 / 159117, also assigned to Oscotec, Inc.

[0010]

[0010] Biochemically, these inhibitors are reported to block the autophosphorylation of FLT3 and downstream signaling mediators signal transducer and activator of transcription 5 (STAT5) and extracellular signal-related kinase (ERK) in TYR-589 / 591 (Wang et al., 2021, J. Med. Chem. 64(8):4870-4890). Resistance to FLT3 inhibitors has been reported in clinical settings due to secondary mutations in FLT3, including mutations in the tyrosine kinase domain, in previous ITD-only mutant tumors (Heidel et al., 2006, Blood 107(1):293-300, Smith et al., 2012, Nature 485(7397):260-263).

[0011]

[0011] Despite research in this field, there remains a need to deliver effective compounds for inhibiting FLT3. Therefore, the object of the present invention is to provide an inhibitor of FLT3, a pharmaceutical composition thereof, and a method for inhibiting FLT3. It is also of great importance to develop an inhibitor that overcomes the known resistance mechanism of co-mutation of the ITD that restores the autophosphorylation ability of FLT3. Summary of the Invention [Means for solving the problem]

[0012] overview

[0012] In one aspect, inhibitors of FLT3 are described herein. Specific heterocyclic inhibitors of FLT3 are also described herein. In some embodiments, the inhibitors of FLT3 are covalent inhibitors. In some embodiments, the inhibitors of FLT3 are non-covalent inhibitors.

[0013] In another aspect, described herein are methods for synthesizing such covalent inhibitors, and methods for using such covalent inhibitors in the treatment of diseases, including diseases in which inhibition of FLT3 provides a therapeutic benefit to patients suffering from the disease. Further described are pharmaceutical compositions comprising an inhibitor of FLT3 and one or more pharmaceutically acceptable carriers, excipients, or diluents. Also described herein are compounds and methods of their use for inhibiting FLT3. In certain embodiments, the compounds and pharmaceutical compositions described herein are used to treat hematological malignancies, including, but not limited to, acute myeloid leukemia.

[0014] In one embodiment, a compound represented by formula (P6-I) having the following structure: [ka] (In the formula, each A 1 , A 2 , A 3 , and A 4 However, independently, -C(R 7 )= or -N=; provided that A 1 , A 2 , A 3 , and A 4 Not more than two of are N; Each L 1 and L 3 are independently substituted or unsubstituted C1-C4 alkylene; R 1 H, halo, CN, substituted or unsubstituted C 1~6alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R 2b are independently H or C1-C4 alkyl; R 4 i)-C(O)-C(R 6a )=C(R 6b )(R 6c ), ii)-S(O)-C(R 6a )=C(R 6b )(R 6c ), iii) -S(O)2-C(R 6a )=C(R 6b )(R 6c ), or iv) a substituted or unsubstituted epoxide; R 5 is H, Cy, CN, halo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted C 1~6 alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkylamino; Cy is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; 6a and R 6b are independently H, halo, CN, or C 1~6 alkyl; or R 6a and R 6b are joined together to form a bond; R 6c is H, halo, CN, or C 1~6 alkyl, where C 1~6 alkyl is unsubstituted or substituted with one or more groups selected from substituted or unsubstituted amino, substituted or unsubstituted hydroxy, and substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7 are independently H, halo, CN, substituted or unsubstituted C 1~6alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heterocycloalkyl) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, are provided herein.

[0015] In one embodiment, a compound represented by formula (P6-IIa) or (P6-IIb): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, are provided herein.

[0016] In one embodiment, a compound represented by formula (P6-IIIa), (P6-IIIb), (P6-IIIc) or (P6-IIId): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, are provided herein.

[0017] In certain embodiments, with respect to a compound of any of the formulae described herein, R 5 H, Cy, CN, Halo, C 1~6 Alkyl, C 1~6 Alkoxy or C 1~6 Cy is cycloalkyl or heterocycloalkyl; and each of Cy, alkyl, alkoxy, and alkylamino is unsubstituted or contains one or more of halo, CN, C 1~4 alkyl, hydroxy, amino, alkylamino, or dialkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C 1~4 Substituted with alkoxy.

[0018] In certain embodiments, with respect to a compound of any of the formulae described herein, R 5 is Me, Et, n-Pr, i-Pr, i-Bu, cyclopropyl, N,N-dimethyl, N-ethyl-N-methyl, N-isopropylamino, N-isopropyl-N-methylamino, methoxy, ethoxy, or i-propyloxy.

[0019] In certain embodiments, with respect to a compound of any of the formulae described herein, R 4 -C(O)-BC(R 6a )=C(R 6b )-C(O)-R 6c , -S(O)-BC(R 6a )=C(R 6b )-C(O)-R 6c , -S(O)2-BC(R 6a )=C(R 6b )-C(O)-R 6c , -BC(R 6a )=C(R 6b )-C(O)-R 6c , -BC(R 6a )=C(R 6b )-S(O)-R 6c , -BC(R 6a )=C(R 6b )-S(O)2-R 6c , -BC(R 6a )=C(R 6b )-P(O)-R 6a R 6b ; or -BC(R 6a )=C(R 6b )-P(O)-OR 6a OR 6b and B is a substituted or unsubstituted C 1~4 alkylene, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R 6c is substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4is —CH—CH═CH—C(O)—N(CH). In some embodiments, R 4 is -CH2-C≡CH-C(O)-N(CH3)2.

[0020] In certain embodiments, the compound is capable of covalently binding to FLT3. In certain embodiments, the compound is, for example, R 4 In certain embodiments, the compounds include a linker that facilitates covalent binding to FLT3. While not intending to be bound by any theory of operation, it is believed that the right side of structure P6-I (to the right of L1) forms a functional group that can bind to the binding pocket of FLT3. The linker in the compounds provided herein is linked to a site on FLT3, e.g., R to Cys12. 4 In certain embodiments, the linker is of sufficient length and composition to provide a covalent bond of L 1 In certain embodiments, the linker comprises L 3 In certain embodiments, the linker comprises L 1 and L 3 In certain embodiments, the linker comprises -L 1 -N(H)-C(O)-L 3 In certain embodiments, the linker facilitates covalent binding that distinguishes the present compounds from compounds known to those of skill in the art that have linkers of sufficient length or composition to facilitate either covalent binding of FLT3, or both, insufficient to facilitate covalent binding.

[0021] In certain embodiments, the compound is not any of compounds 1-41, or any salt thereof.

[0022] [Table 1]

[0023] [Table 2]

[0024] [Table 3]

[0025] In certain embodiments, the compound is not any of compounds 14-P19, or any salt thereof.

[0026] [Table 4]

[0027]

[0023] Any combination of the groups described above for the various variables is contemplated herein. It is understood that the substituents and substitution patterns in the compounds provided herein can be selected by those skilled in the art to provide chemically stable compounds that can be synthesized by techniques known in the art and described herein.

[0028]

[0024] In certain embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of at least one of any of the compounds herein, or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof. In certain embodiments, the pharmaceutical composition provided herein further comprises a pharmaceutically acceptable carrier, excipient, and / or diluent.

[0029]

[0025] Provided are pharmaceutical compositions formulated for administration by a suitable route and means containing an effective concentration of one or more of the compounds provided herein, or pharmaceutically effective derivatives thereof, that deliver an amount effective to treat, prevent, or ameliorate one or more symptoms of a disease, disorder, or condition that is regulated or otherwise affected by, involves, or is characterized by mutations in the FLT3 gene. The effective amount and concentration is effective to ameliorate any of the symptoms of any of the diseases, disorders, or conditions disclosed herein.

[0030]

[0026] In certain embodiments, provided herein is a pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier, diluent, and / or excipient; and ii) one or more compounds provided herein.

[0031]

[0027] In certain embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), and a pharmaceutically acceptable carrier, excipient, or diluent. In certain embodiments, the pharmaceutical composition comprising a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId) is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, and rectal administration.

[0032]

[0028] In one embodiment, provided herein is a method for preventing, treating, or ameliorating a disease or condition associated with abnormal FLT3 activity in a mammal, comprising administering to the mammal an effective disease- or condition-treating amount of a compound selected from Formulae (P2-I), (P4-I) to (P4-Vb), (P5-I') to (P5-Vd), and (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof. In another embodiment, provided herein is a method for preventing, treating, or ameliorating a disease or condition associated with a mutation in the FLT3 gene in a mammal, comprising administering to the mammal an effective disease- or condition-treating amount of a compound selected from Formulae (P2-I), (P4-I) to (P4-Vb), (P5-I') to (P5-Vd), and (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof. In certain embodiments, the FLT3 mutation is an internal tandem mutation (FLT3-ITD). In certain embodiments, the FLT3 mutation is a point mutation in the tyrosine kinase domain (FLT3-TKD).

[0033] In certain embodiments, the disease or condition is a hematological malignancy, including, but not limited to, leukemia, lymphoma, or multiple myeloma. In particular embodiments, the disease or condition is a leukemia, including, but not limited to, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), prolymphocytic leukemia (PLL), large granular lymphocytic (LGL), hairy cell leukemia (HCL), mast cell leukemia (MCL), or myelodysplastic syndrome (MDS).

[0034]

[0030] In certain embodiments, the disease or condition is acute myeloid leukemia (AML). In certain embodiments, the AML is FLT3 mutation positive. In certain embodiments, the AML is newly diagnosed. In certain embodiments, the AML is FLT3 mutation positive and newly diagnosed. In certain embodiments, the AML is relapsed or refractory. In certain embodiments, the AML is relapsed or refractory and FLT3 mutation positive. In certain embodiments, the patient has an NPM1 mutation.

[0035] In certain embodiments, the disease or condition is lymphoma, including but not limited to non-Hodgkin's lymphoma or Hodgkin's lymphoma. In certain embodiments, the disease or condition is multiple myeloma.

[0036]

[0032] In certain embodiments, provided herein is a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof, for use in therapy. In certain embodiments, provided herein is a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with abnormal activity of FLT3 in vivo. In one embodiment, provided herein is a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof, for use in therapy. In one embodiment, provided herein is a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with a mutation in the FLT3 gene in vivo. In one embodiment, provided herein is a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating. In one embodiment, provided herein is a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease or condition associated with abnormal activity of FLT3 or associated with a mutation in the FLT3 gene. Useful diseases and conditions are described herein.

[0037]

[0033] In certain embodiments, provided herein is a pharmaceutical composition comprising a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof, for use in therapy. In certain embodiments, provided herein is a pharmaceutical composition comprising a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with abnormal activity of FLT3 or associated with a mutation in the FLT3 gene. In certain embodiments, provided herein is a pharmaceutical composition comprising a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating. In certain embodiments, provided herein is a pharmaceutical composition comprising a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease or condition associated with abnormal activity of FLT3 in vivo or associated with a mutation in the FLT3 gene. Useful diseases and conditions are described herein.

[0038]

[0034] In any of the above embodiments, there are certain embodiments in which administration is enteral, parenteral, or both, wherein (a) an effective amount of a provided compound is administered systemically to a mammal; (b) an effective amount of a provided compound is administered orally to a mammal; (c) an effective amount of a provided compound is administered intravenously to a mammal; (d) an effective amount of a provided compound is administered by inhalation; (e) an effective amount of a provided compound is administered by intranasal administration; or (f) an effective amount of a provided compound is administered by injection to a mammal; (g) an effective amount of a provided compound is administered topically (transdermally) to a mammal; (h) an effective amount of a provided compound is administered by intraocular administration; or (i) an effective amount of a provided compound is administered rectally to a mammal.

[0039]

[0035] In any of the above embodiments, certain embodiments include a single administration of an effective amount of a provided compound, including certain embodiments in which (i) the provided compound is administered once; (ii) the provided compound is administered multiple times over a daily period; (iii) continuously; or (iv) continuously to a mammal.

[0040]

[0036] In any of the above embodiments, certain embodiments include multiple administrations of an effective amount of a provided compound, including certain embodiments in which: (i) the provided compound is administered in a single dose; (ii) the time between the multiple administrations is 6 hours apart; or (iii) the provided compound is administered to the mammal every 8 hours. In certain embodiments, the method includes a drug holiday, during which administration of the compound is temporarily stopped or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. The length of the drug holiday can vary from 2 days to 1 year.

[0041]

[0037] In any of the above embodiments involving the treatment of a proliferative disease including cancer, e.g., a hematological cancer, one embodiment includes administering at least one additional agent selected from the group consisting of alemtuzumab, azacitidine, bortezomib, decitabine, everolimus, malademetan, palbocyclib, ponatinib, venetoclax, and vorinostat. In other embodiments, the treatment of proliferative disorders, including cancer, e.g., hematological cancers, is by chemotherapy with arsenic trioxide, asparaginase (PEGylated or non-PEGylated), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin / doxorubicin / idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel™, taxol, temozolomide, thioguanine, or a class of drugs containing hormones (anti-estrogens, anti-androgens, or gonadotropin-releasing hormone analogs), alpha-interferon, or steroids. The present invention further comprises the administration of at least one further active agent selected from an interferon such as interferon, a nitrogen mustard such as busulfan or melphalan or mechlorethamine, a retinoid such as tretinoin, an irreversible topoisomerase inhibitor such as irinotecan or topotecan, an irreversible tyrosine kinase inhibitor such as gefitinib or imatinib, or an agent for treating signs or symptoms induced by such treatment, including allopurinol, filgrastim, granisetron / ondansetron / palonosetron, dronabinol.

[0042]

[0038] In certain embodiments, provided herein is a product comprising packaging material, a compound provided herein or a composition thereof within the packaging material, and a label indicating that the compound or composition is administered to treat a disease or condition.

[0043] In certain embodiments, the compounds of Formula (P2-I), Formula (P4-I) through (P4-Vb), Formula (P5-I') through (P5-Vd), and Formula (P6-I) through (P6-IIId) are covalent inhibitors of FLT3 activity. In certain embodiments, such covalent inhibitors have an IC of less than 10 microM in an enzyme assay. 50 In certain embodiments, the FLT3 inhibitor has an IC of less than 1 microM, and in certain embodiments, less than 0.25 microM or even less than 0.025 microM. 50 It has.

[0044]

[0040] Other objects, features, and advantages of the methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various modifications and variations within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, papers, books, manuals, and articles, are expressly incorporated herein by reference in their entirety for all purposes. [Brief explanation of the drawings]

[0045] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0041] Figure 1 shows the cell-based activity of compounds 506, C-1, C-2, and C-3 in the MV-4:11 cell line. [Figure 2]

[0042] Figure 1 shows the cell-based and biochemical activities of compounds 506, C-1, C-2, and C-3 in (2a) MOLM-13 and (2b) K-562 cell lines, and (2c) FLT3-WT and (2d) FLT3-ITD enzymes. [Figure 3]

[0043] Figure 1 shows the cell-based and biochemical activities of compounds 204, 205, 307, and 232 in (3a) MOLM-13 and (3b) K-562 cell lines, and (3c) FLT3-WT and (3d) FLT3-ITD enzymes. [Figure 4]

[0044] Figure 1 shows the cell-based and biochemical activities of compounds 250, 252, 507, and 516 in (4a) MOLM-13 and (4b) K-562 cell lines, and (4c) FLT3-WT and (4d) FLT3-ITD enzymes. [Figure 5]

[0045] Figure 1 shows the cell-based and biochemical activities of compounds 516A, 602, 603, and 605 in (5a) MOLM-13 and (5b) K-562 cell lines, and (5c) FLT3-WT and (5d) FLT3-ITD enzymes. DETAILED DESCRIPTION OF THE INVENTION

[0046] Detailed Description of the Preferred Embodiments 1. Specific Terminology

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In the event of multiple definitions of terms herein, those in this section prevail. When a URL or other such identifier or address is referenced, it is understood that such identifiers may change and particular information on the Internet may appear and disappear, but that equivalent information may be found by an Internet search. Reference thereto confirms the availability and public dissemination of such information.

[0047]

[0047] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The use of the term "including" and other forms such as "include," "includes," and "included" is open-ended. Standard definitions of chemistry terms are found in Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology, within the skill of one of ordinary skill in the art, will be used. Unless specific definitions are given, the nomenclature used in connection with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein, and the laboratory methods and techniques thereof, are those known in the art. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques may be performed, for example, using manufacturer's specification kits, or as commonly accomplished in the art, or as described herein. The techniques and procedures described above may generally be performed in a conventional manner known in the art and as described in various general and more specific references cited and described throughout this specification.

[0048] It should be understood that the methods and compositions described herein are not limited to the particular methods, protocols, cell lines, constructs, and reagents described herein, and as such may vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods and compositions described herein, which will be limited only by the scope of the appended claims.

[0049]

[0049] All publications and patents mentioned herein are incorporated herein by reference in their entirety to describe and disclose, for example, the constructs and methods described therein that may be used in conjunction with the methods, compositions, and compounds described herein. The publications described herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the inventors described herein are not entitled to antedate such disclosure by prior invention or for any other reason.

[0050] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, alkyl comprises 1 to 13 carbon atoms (e.g., C1 to C 13 In certain embodiments, alkyl comprises 1 to 8 carbon atoms (e.g., C1 to C8 alkyl). In some embodiments, alkyl comprises 5 to 15 carbon atoms (e.g., C5 to C 15In certain embodiments, an alkyl comprises 5 to 8 carbon atoms (e.g., a C5-C8 alkyl). An alkyl is attached to the remainder of the molecule by a single bond, and is, for example, methyl (Me), ethyl (Et), n-propyl (n-pr), 1-methylethyl (iso-propyl or i-Pr), n-butyl (n-Bu), n-pentyl, 1,1-dimethylethyl (t-butyl, or t-Bu), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise in the specification, an alkyl group is optionally substituted as defined and described below and herein.

[0051] An "alkyl" group may also be a "lower alkyl" having 1 to 6 carbon atoms.

[0052] As used herein, C1-C x are C1~C2, C1~C3...C1~C x Includes.

[0053] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms containing at least one double bond and having 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains 2 to 8 carbon atoms. In some embodiments, an alkenyl contains 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise in this specification, an alkenyl group is optionally substituted as defined and described below and herein.

[0054] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms containing at least one triple bond and having 2 to 12 carbon atoms. In certain embodiments, an alkynyl contains 2 to 8 carbon atoms. In some embodiments, an alkynyl has 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise herein, an alkynyl group is optionally substituted as defined and described below and herein.

[0055] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, without unsaturation, having 1 to 12 carbon atoms, linking the rest of the molecule to a radical group, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon within the alkylene chain or any two carbons within the chain. Unless stated otherwise in this specification, an alkylene chain is optionally substituted as defined and described below and herein.

[0056]

[0056] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one double bond and having 2 to 12 carbon atoms, linking the rest of the molecule to a radical group, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in this specification, an alkenylene chain is optionally substituted as defined and described below and herein.

[0057]

[0057] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one triple bond and having 2 to 12 carbon atoms, linking the rest of the molecule to a radical group, e.g., ethyne, propyne, butyne, and the like. The alkenylene chain is attached to the rest of the molecule through a triple bond or a single bond and to the radical group through a triple bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in the specification, the alkynylene chain is optionally substituted as defined and described below and herein.

[0058]

[0058] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms from 6 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Aryl groups include, but are not limited to, groups such as phenyl (Ph), fluorenyl, and naphthyl. Unless otherwise stated herein, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is intended to include aryl groups that are optionally substituted as defined and described below and herein.

[0059] "Aralkyl" refers to a group of the formula -R c -aryl (wherein R c is an alkylene chain as defined above, e.g., benzyl, diphenylmethyl, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for an alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for an aryl group.

[0060] "Aralkenyl" refers to a group of the formula -R d-aryl (wherein R d is an alkenylene chain as defined above. The aryl part of the aralkenyl group is optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl group is optionally substituted as defined above for an alkenylene group.

[0061] "Aralkynyl" refers to a group of the formula -R e -aryl (wherein R e is an alkynylene chain as defined above. The aryl part of the aralkynyl group is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl group is optionally substituted as defined above for an alkynylene chain.

[0062] "Carbocyclyl" or "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having 3 to 15 carbon atoms, including fused or bridged ring systems. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In some embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the remainder of the molecule by a single bond. A carbocyclyl is optionally saturated (i.e., contains only one C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclyl group is also referred to as a "cycloalkyl." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as a "cycloalkenyl." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated herein, the term "carbocyclyl" is intended to include carbocyclyl groups that are optionally substituted as defined and described below and herein.

[0063] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0064] The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures in which at least one hydrogen has been replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are not all the same as one another. In certain embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are not all the same as one another.

[0065] "Fluoroalkyl" refers to an alkyl group as defined above that is substituted with one or more fluoro groups as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl group is optionally substituted as defined above for an alkyl group.

[0066] As used herein, the terms "non-aromatic heterocycle", "heterocycloalkyl" or "heteroalicyclic" refer to non-aromatic rings in which one or more of the atoms forming the ring are heteroatoms. A "non-aromatic heterocycle" or "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur. This group may be fused to an aryl or heteroaryl. The heterocycloalkyl ring may be formed by 3 to 14 ring atoms such as 3, 4, 5, 6, 7, 8, 9, or 10 or more atoms. The heterocycloalkyl ring may be optionally substituted. In certain embodiments, the non-aromatic heterocycle contains one or more carbonyl or thiocarbonyl groups such as, for example, oxo-containing groups and thio-containing groups. Examples of heterocycloalkyl include, but are not limited to, lactam, lactone, cyclic imide, cyclic thioimide, cyclic carbamate, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidinone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxol, 1,3-dioxolane, 1,3-dithiol, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. Exemplary examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, are [Chemical Formula] and the like. The term heteroalicyclic also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).

[0067]

[0067] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. In some embodiments, a heteroaryl ring has 5, 6, 7, 8, 9, or 10 or more ring atoms. Heteroatoms in a heteroaryl group are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is bonded to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyri diphenyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl,Isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4 -d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in this specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, optionally substituted as defined and described below and herein.

[0068] "N-heteroaryl" refers to a heteroaryl group, as defined above, containing at least one nitrogen, where the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group. The N-heteroaryl group is optionally substituted as described above for heteroaryl groups.

[0069] "C-heteroaryl" refers to a heteroaryl group as defined above, where the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. The C-heteroaryl group is optionally substituted as described above for heteroaryl groups.

[0070]

[0070] "Epoxide" refers to a three-membered cyclic ether, which is optionally substituted as defined and described below and herein.

[0071] "Heteroarylalkyl" refers to a group of the formula -R c heteroaryl (wherein R c refers to the group: (wherein R is an alkylene chain as defined above). If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl group is optionally substituted as defined above for a heteroaryl group.

[0072] "Sulfanyl" refers to the group --S--.

[0073] "Sulfinyl" refers to the group -S(=O)-.

[0074] "Sulfonyl" refers to the group -S(=O)2-.

[0075] "Amino" refers to the group --NH.sub.2.

[0076] "Cyano" refers to the group --CN.

[0077] "Nitro" refers to the group --NO.sub.2.

[0078] "Oxa" refers to the group --O--.

[0079] "Oxo" refers to the group =O.

[0080] "Imino" refers to the group =NH.

[0081] "Thioxo" refers to the group ═S.

[0082] An "alkoxy" group refers to an (alkyl)O- group, where alkyl is as defined herein.

[0083] An "aryloxy" group refers to an (aryl)O- group, where aryl is as defined herein.

[0084] "Carbocyclylalkyl" means an alkyl group, as defined herein, substituted with a carbocyclyl group. "Cycloalkylalkyl" means an alkyl group, as defined herein, substituted with a cycloalkyl group. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0085] As used herein, the terms "heteroalkyl," "heteroalkenyl," and "heteroalkynyl" include optionally substituted alkyl, alkenyl, and alkynyl groups in which one or more skeletal atoms is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof. The heteroatom may be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Additionally, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0086] The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from among oxygen, sulfur, nitrogen, silicon, and phosphorus, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be different from the others.

[0087]

[0087] The terms "bond," "direct bond," or "single bond" refer to a chemical bond between two atoms or two moieties when the atoms joined by the bond are considered to be part of a larger substructure.

[0088] An "isocyanato" group refers to a --NCO group.

[0089] An "isothiocyanato" group refers to a --NCS group.

[0090]

[0090] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded in or attached to a molecule.

[0091] A "thioalkoxy" or "alkylthio" group refers to an --S-alkyl group.

[0092] An "alkylthioalkyl" group refers to an alkyl group substituted with an --S-alkyl group.

[0093] As used herein, the term "acyloxy" refers to a group of formula RC(=O)O-.

[0094] "Carboxy" means the radical --C(O)OH.

[0095] As used herein, the term "acetyl" refers to a group of formula -C(=O)CH3.

[0096] "Acyl" refers to the group --C(O)R.

[0097] As used herein, the term "trihalomethanesulfonyl" refers to a group of formula X3CS(=O)2-, where X is a halogen.

[0098] "Cyanoalkyl" means an alkyl group, as defined herein, that is substituted with at least one cyano group.

[0099] As used herein, the term "N-sulfonamido" or "sulfonylamino" refers to a group of formula RS(=O)2NH-.

[0100] As used herein, the term "O-carbamyl" refers to a group of formula -OC(=O)NR2.

[0101] As used herein, the term "N-carbamyl" refers to a group of formula ROC(=O)NH-.

[0102] As used herein, the term "O-thiocarbamyl" refers to a group of formula -OC(=S)NR2.

[0103] As used herein, "N-thiocarbamyl" refers to a group of formula ROC(=S)NH-.

[0104] As used herein, the term "C-amido" refers to a group of formula -C(=O)NR2.

[0105] "Aminocarbonyl" refers to the radical -CONH2.

[0106] As used herein, the term "N-amido" refers to a group of formula RC(=O)NH-.

[0107]

[0107] "Hydroxyalkyl" refers to an alkyl group, as defined herein, substituted with at least one hydroxy group. Non-limiting examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl.

[0108]

[0108] "Alkoxyalkyl" refers to an alkyl group, as defined herein, substituted with an alkoxy group, as defined herein.

[0109]

[0109] An "alkenyloxy" group refers to an (alkenyl)O- group, where alkenyl is as defined herein.

[0110] The term "alkylamine" refers to an amine that is an -N(alkyl) x H y refers to a group where x and y are selected from among x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, together with the N atom to which they are attached, can optionally form a cyclic ring system.

[0111]

[0111] "Alkylaminoalkyl" refers to an alkyl group, as defined herein, substituted with an alkylamine, as defined herein.

[0112]

[0112] An "amide" is a chemical moiety represented by the formula -C(O)NHR or -NHC(O)R, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon). The amide moiety forms a linkage between an amino acid or peptide molecule and a compound described herein, thereby forming a prodrug. Any amine or carboxyl side chain on a compound described herein can be amidated. Procedures and specific groups for making such amides are known to those of skill in the art and are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3, pp. 111-114, which is incorporated herein by reference in its entirety. rd Ed., John Wiley & Sons, New York, NY, 1999.

[0113] The term "ester" refers to a chemical moiety of the formula -COOR, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon). Any hydroxy or carboxyl side chain on the compounds described herein can be esterified. Procedures and specific groups for making such esters are known to those skilled in the art and are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3, incorporated herein by reference in its entirety. rd Ed., John Wiley & Sons, New York, NY, 1999.

[0114]

[0114] As used herein, the term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings can be optionally substituted. Rings can be monocyclic or polycyclic.

[0115] As used herein, the term "ring system" refers to one or more rings.

[0116] The term "membered ring" can encompass any cyclic structure. The term "membered" is intended to indicate the number of skeletal atoms that make up the ring. Thus, for example, cyclohexyl, pyridine, pyran, and thiopyran are six-membered rings, and cyclopentyl, pyrrole, furan, and thiophene are five-membered rings.

[0117]

[0117] The term "fused" refers to a structure in which two or more rings share one or more bonds.

[0118] As described herein, the compounds provided herein can be "optionally substituted." In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be the same or different at all positions. Combinations of substituents provided herein preferably result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0119] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 R o , -O-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 CH(OR°)2;-(CH2) 0~4 SR°; may be substituted with R° -(CH2) 0~4 Ph; R° may be substituted with -(CH2) 0~4 O(CH2) 0~1 Ph; may be substituted with R° -CH=CHPh; may be substituted with R° -(CH 0~4 O(CH2) 0~1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0~4 N(R°)2;-(CH2) 0~4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0~4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0~4N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0~4 C(O)R°;-C(S)R°;-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 C(O)SR°;-(CH2) 0~4 C(O)OSiR°3;-(CH2) 0~4 OC(O)R°;-OC(O)(CH2) 0~4 SR-, -SC(S)SR°;-(CH2) 0~4 SC(O)R°;-(CH2) 0~4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2) 0~4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0~4 SSR°;-(CH2) 0~4 S(O)2R°;-(CH2) 0~4 S(O)2OR°;-(CH2) 0~4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0~4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1~4 linear or branched alkylene)ON(R°)2; or -(C 1~4 linear or branched alkylene)C(O)ON(R°)2, where each R° may be substituted as defined below and independently represents hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independent occurrences of R° together with their intervening atoms form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0120] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R°, together with their intervening atoms) are independently halogen, —(CH 2 ), 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1~4Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include ═O and ═S.

[0121] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O- or -S(C(R * 2)) 2~3 S-, where R * Each independent occurrence of may be substituted as defined below with hydrogen, C 1~6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of may be substituted as defined below with hydrogen, C 1~6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0122]

[0122] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0123] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, R † two independent occurrences of together with their intervening atoms form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0124]

[0124] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ●), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0125]

[0125] The term "nucleophile" or "nucleophilic" refers to an electron-rich compound or portion thereof.

[0126]

[0126] The terms "electrophile" or "electrophilic" refer to an electron-deficient or electron-deficient molecule or portion thereof. Examples of electrophiles include, but are in no way limited to, Michael acceptor moieties.

[0127]

[0127] As used herein, the term "acceptable" or "pharmaceutically acceptable" with respect to a formulation, composition, or ingredient means that it does not have a lasting adverse effect on the overall health of the subject being treated or inhibit the biological activity or properties of the compound, and is relatively non-toxic.

[0128]

[0128] As used herein, "amelioration" of the symptoms of a particular disease, disorder, or condition by the administration of a particular compound or pharmaceutical composition refers to a reduction in severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, long-term or short-term, that can result from or be associated with the administration of the compound or composition.

[0129] "Bioavailability" refers to the percentage of the weight of an administered compound disclosed herein, such as any of the compounds of Formula (P2-I), Formula (P4-I) through (P4-Vb), Formula (P5-I') through (P5-Vd), and Formula (P6-I) through (P6-IIId), that is delivered to the systemic circulation of the animal or human being tested. The total exposure (AUC (0-∞) ) is typically defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which a compound disclosed herein, such as any of the compounds of Formula (P2-I), Formulas (P4-I) through (P4-Vb), Formulas (P5-I') through (P5-Vd), and Formulas (P6-I) through (P6-IIId), is absorbed into the systemic circulation when the pharmaceutical composition is taken orally, as compared to intravenous injection.

[0130] "Plasma concentration" refers to the concentration of a compound disclosed herein, such as any of the compounds of Formula (P2-I), Formulas (P4-I) through (P4-Vb), Formulas (P5-I') through (P5-Vd), and Formulas (P6-I) through (P6-IIId), in the plasma component of a subject's blood. It is understood that the plasma concentration of any of the compounds of Formula (P2-I), Formulas (P4-I) through (P4-Vb), Formulas (P5-I') through (P5-Vd), and Formulas (P6-I) through (P6-IIId) may vary considerably between subjects due to variability in metabolism and / or possible interactions with other therapeutic agents. According to certain embodiments disclosed herein, the plasma concentration of any of the compounds of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId) may vary between subjects. Similarly, the maximum plasma concentration (C max ) or time to reach maximum plasma concentration (T max ), or the total area under the plasma concentration-time curve (AUC (0-∞) ) may vary between subjects. Because of this variability, the amount necessary to constitute a "therapeutically effective amount" of any of the compounds of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId) may vary between subjects.

[0131]

[0131] As used herein, terms such as "co-administration" are intended to encompass the administration of selected therapeutic agents to a single patient and include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0132] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient quantity of an agent or compound being administered to relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the quantity of a composition comprising a compound disclosed herein that is required to achieve a clinically significant reduction in disease symptoms without producing undue adverse side effects. An appropriate "effective amount" in any individual case can be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective to achieve a desired pharmacological effect or therapeutic improvement without producing undue adverse side effects. It is understood that an "effective amount" or "therapeutically effective amount" may vary from subject to subject, depending on variability in metabolism of any of the compounds of Formula (PI), Formulas (I) through (LXIIIb), Formula (P2-I), Formulas (P4-I) through (P4-Vb), or Formulas (P5-I') through (P5-Vd), the subject's age, weight, general condition, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, a therapeutically effective amount may be determined by routine experimentation, including, but not limited to, a dose escalation clinical trial.

[0133] The terms "enhance" or "enhancing" mean to increase or prolong, in either potency or duration, a desired effect. By way of example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong, in either potency or duration, the effect of the therapeutic agent in treating a disease, disorder, or condition. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of the therapeutic agent in treating a disease, disorder, or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drug, and the judgment of the treating physician.

[0134] As used herein, the term "identical" refers to two or more sequences or subsequences that are the same. Furthermore, the term "substantially identical" refers to two or more sequences that have the same percentage of sequence units when compared and aligned for maximum correspondence over a comparison window or designated region, as measured using a comparison algorithm or by manual alignment and visual inspection. By way of example only, two or more sequences may be "substantially identical" if the sequence units are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over the designated region. Such percentages are intended to describe the "percent identity" of two or more sequences. Sequence identity can exist over a region that is at least about 75-100 sequence units in length, over a region that is about 50 sequence units in length, or, if not specified, over the entire sequence. This definition also refers to the complement of a test sequence. By way of example only, two or more polypeptide sequences are identical if the amino acid residues are the same, whereas two or more polypeptide sequences are "substantially identical" if the amino acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a designated region. Identity can exist over a region that is at least about 75-100 amino acids in length, over a region that is about 50 amino acids in length, or, if not specified, over the entire sequence of the polypeptide sequence. Further, by way of example only, two or more polynucleotide sequences are identical if the nucleic acid residues are the same, whereas two or more polynucleotide sequences are "substantially identical" if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a designated region. Identity can exist over a region that is at least about 75-100 nucleic acids in length, over a region that is about 50 nucleic acids in length, or, if not specified, over the entire sequence of the polynucleotide sequence.

[0135] As used herein, the term "isolated" refers to the separation and removal of a component of interest from components that are not of interest. An isolated material can be in a dry or semi-dry state, or in a solution, including but not limited to, an aqueous solution. An isolated component can be in a homogenous state, or the isolated component can be part of a pharmaceutical composition that includes an additional pharmaceutically acceptable carrier and / or excipient. By way of example only, a nucleic acid or protein is "isolated" when such nucleic acid or protein is free from at least some of the cellular components with which it is naturally associated, or when the nucleic acid or protein is concentrated to a level greater than its in vivo or in vitro production concentration. Also by way of example, a gene is isolated when it is separated from open reading frames adjacent to it and encoding proteins other than the gene of interest.

[0136]

[0136] A "metabolite" of a compound disclosed herein is a derivative of the compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the entire process by which a particular substance is transformed by an organism (including, but not limited to, enzyme-catalyzed reactions such as hydrolysis and oxidation). Thus, enzymes can produce specific structural changes to a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information regarding metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by either administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are well known in the art. In some embodiments, metabolites of the compounds are formed by oxidation processes and correspond to the corresponding hydroxy-containing compounds. In some embodiments, the compounds are metabolized to pharmacologically active metabolites.

[0137]

[0137] As used herein, the term "modulate" means to interact directly or indirectly with a target to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0138] As used herein, the term "modulator" refers to a compound that alters the activity of a molecule. For example, a modulator may increase or decrease the magnitude of a particular activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments, the presence of a modulator results in an activity that does not occur in the absence of the modulator.

[0139] As used herein, the term "covalent inhibitor" refers to a compound that, upon contact with a target protein (e.g., FLT3), causes the formation of a new covalent bond with or within the protein, thereby reducing or eliminating one or more of the target protein's biological activities (e.g., phosphotransferase activity), regardless of the subsequent presence or absence of the covalent inhibitor. In contrast, a non-covalent inhibitor compound, upon contact with a target protein, does not cause the formation of a new covalent bond with or within the protein, and thus can bind to and disengage from the target protein. In certain embodiments, a covalent inhibitor is irreversible. In certain embodiments, a non-covalent inhibitor is reversible.

[0140] As used herein, the term "covalent inhibitor of FLT3 protein-protein interaction" refers to an inhibitor of FLT3 that can form a covalent bond with an amino acid residue of FLT3. In one embodiment, the covalent inhibitor of FLT3 can form a covalent bond with a Cys residue of FLT3; in a specific embodiment, the covalent inhibitor can form a covalent bond with the Cys 12 residue (or a homolog thereof) of FLT3.

[0141]

[0141] As used herein, the term "prophylactically effective amount" refers to an amount of a composition applied to a patient that will relieve to some extent one or more of the symptoms of the disease, disorder, or condition being treated. In such prophylactic applications, such amount may depend on the patient's health status, weight, and the like. It is considered well within the skill of one in the art for one to determine such prophylactically effective amounts by routine experimentation, including but not limited to, dose escalation clinical trials.

[0142] As used herein, the term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target proteins.

[0143] As used herein, the term "selectively binds" refers to the ability of a selective binding compound to bind to a target protein, such as FLT3, with higher affinity than it binds to a non-target protein. In certain embodiments, specific binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, 1000, or more times higher than the affinity for a non-target.

[0144] As used herein, the term "selective modulator" refers to a compound that selectively modulates a target activity relative to a non-target activity. In certain embodiments, a specific modulator refers to modulating a target activity at least 10, 50, 100, 250, 500, 1000 times more than a non-target activity.

[0145] As used herein, the term "substantially purified" refers to a component of interest that may be substantially or essentially free from other components that normally accompany or interact with the component of interest prior to purification. By way of example only, a component of interest may be "substantially purified" when a preparation of the component of interest contains less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of contaminating components. Thus, a "substantially purified" component of interest may have a purification level of about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or greater.

[0146]

[0146] The term "subject" or "patient" as used herein refers to an animal that is the object of treatment, observation, or experiment. By way of example only, a subject may be a mammal, including, but not limited to, a human.

[0147] As used herein, the term "target activity" refers to a biological activity that can be modulated by a selective modulator. Specific exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.

[0148]

[0148] As used herein, the term "target protein" refers to a molecule or portion of a protein that can be bound by a selective binding compound. In certain embodiments, the target protein is FLT3.

[0149] The terms "treat," "treating," or "treatment" as used herein include alleviating, alleviating, or ameliorating the symptoms of a disease or condition, preventing further symptoms, ameliorating or preventing the underlying metabolic cause of the symptoms, inhibiting the disease or condition, for example, arresting the progression of the disease or condition, relieving the disease or condition, causing the disease or condition to regress, alleviating the conditions caused by the disease or condition, or halting the symptoms of the disease or condition. The terms "treat," "treating," or "treatment" include, but are not limited to, prophylactic and / or therapeutic treatment.

[0150] As used herein, the term "FLT3" or "FLT3" refers to FMS-like tyrosine kinase 3, gene, or protein. Synonyms include CD135, CD135 antigen, fetal liver kinase 2, FL cytokine receptor, FLK-2, FLK2, FLT3_HUMAN, fms-related tyrosine kinase 3, growth factor receptor tyrosine kinase type III, receptor tyrosine-protein kinase FLT3, stem cell tyrosine kinase 1, STK-1, and STK1. Human sequences include NM_004119 and NM_004119.2 (mRNA), and NP_004110 and NP_004110.2 (protein). Mouse sequences include NM_010229 and NM_010229.2 (mRNA), and NP_034359 and NP_034359.2 (protein).

[0151] As used herein, IC 50 refers to the amount, concentration, or dosage of a particular test compound that achieves 50% inhibition of a maximal response, such as inhibition of FLT3, in an assay that measures the maximal response.

[0152] As used herein, EC 50refers to the dose, concentration, or amount of a particular test compound that induces a dose-dependent response at 50% of the maximal expression of a particular response induced, caused, or enhanced by the particular test compound.

[0153]

[0153] The methods described herein include administering to a subject in need thereof a therapeutically effective amount of a composition containing one or more FLT3 inhibitor compounds described herein.

[0154] In certain embodiments, the methods described herein may be used to treat cancer, such as a B-cell proliferative disorder, including, but not limited to, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, and lymphomatoid granulomatosis.

[0155] Symptoms, diagnostic tests, and prognostic tests for each of the above conditions are known in the art. See, e.g., Harrison's Principles of Internal Medicine (Copyright), 16th ed., 2004, The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal 3(24), and the "Revised European American Lymphoma" (REAL) classification system (see, e.g., the website maintained by the National Cancer Institute).

[0156]

[0156] A number of animal models are useful for establishing therapeutically effective dose ranges of FLT3 inhibitor compounds for treating any of the above-mentioned diseases.

[0157]

[0157] Animal models for the treatment of thromboembolic disorders are also known.

[0158] The therapeutic effect of the provided compounds for one of the above diseases can be optimized during the course of treatment. For example, the treated subject can undergo a diagnostic evaluation to correlate the alleviation of the symptoms or pathology of the disease with the inhibition of in vivo FLT3 activity achieved by administering a given dose of a FLT3 inhibitor.

[0159] 2.Compound In the following description of FLT3 inhibitor compounds suitable for use in the methods described herein, definitions of standard chemical terms referred to can be found in references, including Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vols. A (2000) and B (2001), Plenum Press, New York (unless defined herein). Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the skill of those skilled in the art will be used. Unless specific definitions are given, the nomenclatures used in conjunction with analytical chemistry, synthetic organic chemistry, and medicinal chemistry and pharmaceutical chemistry described herein, as well as their testing methods and techniques, are known in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and patient treatment.

[0160]

[0160] The FLT3 inhibitor compounds may be used in the manufacture of a medicament for treating any of the conditions described above (eg, hematological malignancies).

[0161] In certain embodiments, the FLT3 inhibitor compound used in the methods described herein has a concentration of less than about 10 μM (e.g., less than about 1 μM, less than about 0.5 μM, less than about 0.4 μM, less than about 0.3 μM, less than about 0.1 μM, less than about 0.08 μM, less than about 0.06 μM, less than about 0.05 μM, less than about 0.04 μM, less than about 0.03 μM, less than about 0.02 μM, less than about 0.01 μM, less than about 0.008 μM, less than about 0.006 μM, an in vitro IC of less than about 0.005 μM, less than about 0.004 μM, less than about 0.003 μM, less than about 0.002 μM, less than about 0.001 μM, less than about 0.00099 μM, less than about 0.00098 μM, less than about 0.00097 μM, less than about 0.00096 μM, less than about 0.00095 μM, less than about 0.00094 μM, less than about 0.00093 μM, less than about 0.00092 μM, or less than about 0.00090 μM 50 In one embodiment, the FLT3 inhibitor is selective for FLT3 over cKit.

[0162] Also described herein are methods for synthesizing such covalent inhibitors, and methods for using such covalent inhibitors in the treatment of diseases, including diseases in which inhibition of FLT3 provides a therapeutic benefit to patients suffering from the disease. Pharmaceutical compositions comprising inhibitors of FLT3 are further described.

[0163]

[0163] Particularly described herein are covalent inhibitors of FLT3 that form a covalent bond with a cysteine ​​residue in FLT3. Further described herein are covalent inhibitors of FLT3 that form a covalent bond with a Cys12 residue in FLT3. The covalent inhibitor compounds described herein include a Michael acceptor moiety. Pharmaceutical formulations containing covalent inhibitors of FLT3 are also described.

[0164] Generally, the non-covalent or covalent inhibitor compounds of FLT3 used in the methods described herein are identified or characterized in an in vitro assay, such as a cell-free biochemical assay or a cellular functional assay. Such assays include in vitro IC for non-covalent or covalent FLT3 inhibitor compounds. 50 This is useful for determining

[0165] Furthermore, the covalent complex formation between FLT3 and candidate covalent FLT3 inhibitor is a useful indicator of the covalent inhibition of FLT3, which can be easily determined by some methods known in the art (for example, mass spectrometry).For example, some covalent FLT3-inhibitor compounds can form a covalent bond with Cys 12 of FLT3 GC12 (for example, via Michael reaction).See S. Xu et al. Angewandte Chemie International Ed. 57(6),1601-1605(2017) (the whole is incorporated by reference).

[0166] Compounds of any of Formula (PI), Formula (I) to Formula (LXIIIb), Formula (P2-I), Formula (P4-I) to (P4-Vb), and Formula (P5-I') to (P5-Vd) are described herein. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds are also described herein. Pharmaceutical compositions comprising at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite, or pharmaceutically acceptable prodrug of such a compound are provided. In certain embodiments, when a compound disclosed herein contains an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. In certain embodiments, isomers and chemically protected forms of compounds having a structure represented by any of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId) are also provided.

[0167]

[0167] In one embodiment, provided herein is a FLT3 covalent inhibitor according to the compound of formula (P6-I). In one embodiment, the compound of formula (P6-I) has the following structure: [ka] (In the formula, each A 1 , A 2 , A 3 , and A 4 However, independently, -C(R 7 )= or -N=; provided that A 1 , A 2 , A 3 , and A 4 Not more than two of are N; Each L 1 and L 3 are independently substituted or unsubstituted C1-C4 alkylene; R 1 H, halo, CN, substituted or unsubstituted C 1~6alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R 2b are independently H or C1-C4 alkyl; R 4 i)-C(O)-C(R 6a )=C(R 6b )(R 6c ), ii)-S(O)-C(R 6a )=C(R 6b )(R 6c ), iii) -S(O)2-C(R 6a )=C(R 6b )(R 6c ), or iv) a substituted or unsubstituted epoxide; R 5 is H, Cy, CN, halo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted C 1~6 alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkylamino; Cy is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; 6a and R 6b are independently H, halo, CN, or C 1~6 alkyl; or R 6a and R 6b are joined together to form a bond; R 6c is H, halo, CN, or C 1~6 alkyl, where C 1~6 alkyl is unsubstituted or substituted with one or more groups selected from substituted or unsubstituted amino, substituted or unsubstituted hydroxy, and substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7 are independently H, halo, CN, substituted or unsubstituted C 1~6alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heterocycloalkyl) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, are provided herein.

[0168] In certain embodiments, the compounds provided herein are compounds C-1, C-2, or C-3: [ka] or any salt thereof. In certain embodiments, one or more compounds provided herein exhibit superior properties compared to one or more of C-1, C-2, and C-3. In certain embodiments, one or more compounds provided herein exhibit superior IC compared to C-1, C-2, and / or C-3 in cells harboring a FLT3-ITD mutation, e.g., MOLM-13 cells. 50 In certain embodiments, one or more compounds provided herein exhibit superior IC values ​​compared to C-1, C-2, and / or C-3 in cells harboring a FLT3-ITD mutation, e.g., MV4-11 cells. 50 In certain embodiments, one or more compounds provided herein exhibit fewer off-target effects compared to C-1, C-2, and / or C-3. In certain embodiments, one or more compounds provided herein exhibit more inhibition than compound C-2 in cells that do not have an FLT-3 mutation, e.g., K562 cells. In certain embodiments, compound C-1 exhibits an IC of >100 nM in MOLM-13 cells. 50 and 0% Ymax, IC of >100 nM in MV4-11 cells 50 and 9.7% Ymax, and an IC of >100 nM in K562 cells 50 and 0% Ymax. In certain embodiments, compound C-2 exhibited an IC of 19.2 nM in MOLM-13 cells. 50 and 98.6% Ymax, IC of 5 nM in MV4-11 cells50 and 99.1% Ymax, and an IC of 44 nM in K562 cells 50 and a Ymax of 95.8%. The K562 results for compound C-2 demonstrate its effect in cells without FLT3 mutations. In certain embodiments, compound C-3 exhibits an IC of >100 nM in MOLM-13 cells. 50 and 0% Ymax, IC of >100 nM in MV4-11 cells 50 and Ymax of 6.8%, and IC of >100 nM in K562 cells 50 and 0% Ymax. These results are comparable to those in Table 2A of the Examples herein.

[0169] In certain embodiments, R 5 is Cy. In certain embodiments, R 5 is substituted or unsubstituted C 1~6 In certain embodiments, R 5 is unsubstituted or is halo, CN, OH, substituted or unsubstituted C 1~6 Alkoxy-substituted C 1~6 In certain embodiments, R 5 is substituted with F, CN, OMe, or OEt 1~6 In certain embodiments, R 5 is unsubstituted or is halo, CN, OH, substituted or unsubstituted C 1~6 Alkoxy-substituted C 1~6 In certain embodiments, R 5 is substituted with F, CN, OMe, or OEt 1~6 In certain embodiments, R 5 is unsubstituted or is halo, CN, OH, substituted or unsubstituted C 1~6 In certain embodiments, R is alkylamino substituted with alkoxy. 5 is alkylamino substituted with F, CN, OMe, or OEt. 5is N(H)(Me), N(H)(Et), or N(H)(iPr). In certain embodiments, R 5 is unsubstituted or is halo, CN, OH, substituted or unsubstituted C 1~6 In certain embodiments, R is a dialkylamino substituted with alkoxy. 5 is dialkylamino substituted with F, CN, OMe, or OEt.

[0170] In certain embodiments, R 5 is N(Me)2.

[0171] In certain embodiments, R 5 is Cy. In certain embodiments, R 5 is cyclopropyl, cyclobutyl or cyclopentyl.

[0172] In certain embodiments, R 1 is Me. In certain embodiments, R 1 is Et. In certain embodiments, R 7 is F, Cl, Me, Et, or OMe. 7 is H.

[0173] In certain embodiments, R 4 is —C(O)—CH═CH. In certain embodiments, R 4 is -C(O)-CH=CH-CH2-NMe2.

[0174]

[0174] In certain embodiments, with respect to compounds of any of the formulae described herein, R 4 -C(O)-BC(R 6a )=C(R 6b )-C(O)-R 6c , -S(O)-BC(R 6a )=C(R6b )-C(O)-R 6c , -S(O)2-BC(R 6a )=C(R 6b )-C(O)-R 6c , -BC(R 6a )=C(R 6b )-C(O)-R 6c , -BC(R 6a )=C(R 6b )-S(O)-R 6c , -BC(R 6a )=C(R 6b )-S(O)2-R 6c , -BC(R 6a )=C(R 6b )-P(O)-R 6a R 6b ; or -BC(R 6a )=C(R 6b )-P(O)-OR 6a OR 6b and B is a substituted or unsubstituted C 1~4 alkylene, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R 6c is substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 is —CH—CH═CH—C(O)—N(CH). In some embodiments, R 4 is -CH2-C≡CH-C(O)-N(CH3)2.

[0175] In certain embodiments, A 1 , A 2 , A 3 , and A 4 is N. In certain embodiments, A 1 , A 2 , A 3 , and A 4 Two of them are N.

[0176] In certain embodiments, A 1, A 2 , and A 3 each independently represents -C(R 7 )=;A 4 However, C(R 7 )= or N.

[0177] In certain embodiments, A 4 In certain embodiments, A 4 -C(R 7 )=;R 7 is H, alkyl, or alkoxy. 4 -C(R 7 )=;R 7 is substituted or unsubstituted heterocycloalkyl. 4 -C(R 7 )=;R 7 is substituted or unsubstituted pyrrolidinyl, or piperidinyl. 4 -C(R 7 )=;R 7 is piperidinyl that is unsubstituted or substituted with alkyl, or heterocycloalkyl. 3 -C(R 7 )=;R 7 is H, alkyl, or alkoxy.

[0178] In certain embodiments, Y is —C(R 2e R 2f )-. In certain embodiments, Y is -CH2-, -C(Me)H, CMe2, CHF, or CF2. In certain embodiments, Y is -O-. In certain embodiments, Y is -NR 2g In certain embodiments, Y is -NMe-. In certain embodiments, Y is -NH-.

[0179] In certain embodiments, each R 2c and R 2dis independently H or alkyl. In certain embodiments, each R 2c and R 2d is independently H or Me. In certain embodiments, R 2c is H;R 2d is Me. In certain embodiments, R 2c and R 2d may be joined together to form a 4- to 6-membered heterocycloalkyl. In certain embodiments, each R 2c and R 2d is H.

[0180] In certain embodiments, L 1 is a substituted or unsubstituted C2-C4 alkylene. 1 is a C2-C4 alkylene that is unsubstituted or substituted with halo, hydroxy, or alkyl.

[0181] In certain embodiments, L 1 is an unsubstituted C2-C4 alkylene. 1 is -CH-CH-, -CH-CH-CH-, or -CH-CH-CH-CH-CH-. In certain embodiments, L 1 is -CH-CH-. In certain embodiments, L 1 is -CH-CH-CH-. In certain embodiments, L 1 is -CH2-CH2-CH2-CH2-.

[0182] In certain embodiments, L 2 is a single bond. 2 But -C(O)-L 3 -NR 2b In certain embodiments, L 2 But -C(O)-L 3 In certain embodiments, L 2 But -C(O)-L 3 -N(CH3)-.

[0183] In certain embodiments, L 1 is an unsubstituted C2-C4 alkylene, and L 2 But -C(O)-L 3 -NR 2b In certain embodiments, L 1 is an unsubstituted C2-C4 alkylene, and L 2 But -C(O)-L 3 -NR 2b In certain embodiments, L 1 is -CH2-CH2-, -CH2-CH2-CH2-, or -CH2-CH2-CH2-CH2-, and L 2 is -C(O)-CH(CH3)-NH-.

[0184] In certain embodiments, the compound has the formula (P5-I'): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0185] In certain embodiments, A 1 , A 2 , and A 4 Each of the is CH, and A 4 is CR 7 and the compound has the formula (P4-I): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0186] In certain embodiments, the compounds have the formula (P5-Ia) and (P5-Ib): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0187] In certain embodiments, L 1 is substituted or unsubstituted ethylene. In certain embodiments, L 1 is unsubstituted ethylene.

[0188] In certain embodiments, the compound has the formula (P4-II): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0189] In certain embodiments, the compound has the formula (P5-IIa) or (P5-IIb): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0190] In certain embodiments, L 1 is ethylene substituted with Me, Et, i-Pr, dimethyl, OH, or methoxy.

[0191] In certain embodiments, the compound is (P4-IIIa) or (P4-IIIb): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0192] In certain embodiments, the compound is (P5-IIIa), (P5-IIIb), (P5-IIIc) or (P5-IIId): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0193] In certain embodiments, L 3 is -CH2-.

[0194] In certain embodiments, the compound has the formula (P4-IVa) or (P4-IVb): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0195] In certain embodiments, the compound has formula (P5-IVa), (P5-IVb), (P5-IVc) or (P5-IVd): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0196] In certain embodiments, L 3 is —CH(Me)— or C(Me)—.

[0197] In certain embodiments, the compound has the formula (P4-Va) or (P4-Vb): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0198] In certain embodiments, the compound has the formula (P5-Va), (P5-Vb), (P5-Vc) or (P5-Vd): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0199] In certain embodiments, R 2b is H or Me.

[0200] In certain embodiments, the compound has the formula (P2-I): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0201] In certain embodiments, R 7 is H, Me, Et, Cl, F, or OMe. 7 is H.

[0202] In certain embodiments, R 1 is Me or Et. In certain embodiments, R 5 is cyclopropyl, Me, Et, N(Me)2, or N(i-Pr)(Me). In certain embodiments, R 1 is Me or Et, and R 5 is cyclopropyl, Me, Et, N(Me)2, or N(i-Pr)(Me). In certain embodiments, R 1 is Me or Et, and R 5 is cyclopropyl, Me, Et, N(Me)2, or N(i-Pr)(Me), and R 7 is H.

[0203] In certain embodiments, the compound has formula (XLIIIa), (XLIIIb), (XLIIIc) or (XLIIId): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0204] In certain embodiments, the compound has formula (XLIVa), (XLIVb), (XLIVc), or (XLIVd): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0205] In certain embodiments, the compound has formula (XLVIa), (XLVIb), (XLVIc), (XLVId), (XLVIe) or (XLVIf): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0206] In certain embodiments, the compound has formula (XLVIm), (XLVIn), (XLVIo), (XLVIp), (XLVIq) or (XLVIr): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0207] In certain embodiments, the compound has formula (XLVIIa) or (XLVIIb): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0208] In certain embodiments, the compound has formula (XLVIIIa), (XLVIIIb), (XLVIIIc), or (XLVIIId): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0209] In certain embodiments, the compound has formula (XLVIIIe), (XLVIIIf), (XLVIIIg), or (XLVIIIh): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0210]

[0210] In certain embodiments relating to formula Va-LIIf, Et groups, if present, are replaced with Me.

[0211] In certain embodiments, the compound has formula (LXa), (LXb), (LXc), (LXd), (LXe) or (LXf): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0212] In certain embodiments, the compound has formula (LXIa), (LXIb), (LXIc), or (LXId): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0213] In certain embodiments, the compound has formula (LXIIa), (LXIIb), (LXIIc), or (LXIId): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0214] In certain embodiments, the compound has the formula (LXIIIa) or (LXIIIb): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0215] In certain embodiments, R 5 is as described for formula P6-I. In certain embodiments, R 5 is cyclopropyl, Me, Et, N(Me)2, or N(i-Pr)(Me). In certain embodiments, R 5 is NHMe, NH(CH(CH2CH3)2), or NH(cycloalkyl), where the cycloalkyl is substituted with one or two fluoro groups.

[0216]

[0216] In certain embodiments of Formulae (PI), (P2-I), (I) through (LXIIIb), (P4-I) through (P4-Vb), and (P5-I') through (P5-Vd), the -CONH2 group is replaced with -CON(H)Me.

[0217]

[0217] Each of the following embodiments described herein may independently correspond to each of the above formulas (PI), (P2-I), (I) to (LXIIIb), (P4-I) to (P4-Vb), and (P5-I') to (P5-Vd), unless otherwise specified.

[0218] In certain embodiments, X is O. In certain embodiments, X is —NR 2a In certain embodiments, X is -NR 2a - and;R 2a is H, Me, Et, or i-Pr. In certain embodiments, X is -NR 2a - and;R 2a is H. In certain embodiments, X is a single bond.

[0219] In certain embodiments, L 1 is a substituted or unsubstituted C1-C4 alkylene. 1 is a C2-C4 alkylene that is unsubstituted or substituted with halo, hydroxy, or alkyl. 1 is unsubstituted C1-C4 alkylene. 1 is an unsubstituted C2-C4 alkylene. 1 is -CH-CH-, -CH-CH-CH-, or -CH-CH-CH-CH-CH-. In certain embodiments, L 1 is -CH-CH-. In certain embodiments, L 1 is -CH-CH-CH-. In certain embodiments, L 1 is -CH2-CH2-CH2-CH2-.

[0220] In certain embodiments, L 2 is a single bond. In certain embodiments, L 2 But -C(O)-L 3 -NR 2b In certain embodiments, L 2 But -C(O)-L 3 In certain embodiments, L 2 But -C(O)-L 3 -N(CH3)-.

[0221] In certain embodiments, L 3 is a substituted or unsubstituted C1-C4 alkylene; and the substituents on each alkylene are independently one or more of halo, CN, C 1~4 Alkyl, hydroxy, and C 1~4 In certain embodiments, L is selected from alkoxy. 3 is unsubstituted C1-C4 alkylene. 3 is an unsubstituted C2-C4 alkylene. 3 is an unsubstituted C alkylene. 3 is an unsubstituted C alkylene. 3 is an unsubstituted C3 alkylene.

[0222] In certain embodiments, R 2b is C1-C4 alkyl. In certain embodiments, R 2b is methyl.

[0223] In certain embodiments, R 4 But -C(O)-C(R 6a )=C(R 6b )(R 6c In certain embodiments, R 4 is —C(O)—CH═CH. In certain embodiments, R 4 But -S(O)-C(R 6a )=C(R 6b )(R 6c ), or -S(O)2-C(R 6a )=C(R 6b )(R 6c In certain embodiments, R 4 is -S(O)-CH=CH. In certain embodiments, R 4 But -C(O)-C(R 6a )=C(R 6b )(R 6c )

[0224] In certain embodiments, R 4 is —C(O)—CH═CH. In certain embodiments, R 4 But -S(O)2-C(R 6a )=C(R 6b )(R 6c In certain embodiments, R 4 is -S(O)2-CH=CH2.

[0225] In certain embodiments, R 7 is hydrogen.

[0226] In certain embodiments, R 6a , R 6b , and R 6c is H. In certain embodiments, R 6a and R 6b each of which is H or F; R 6c is substituted or unsubstituted alkyl. In certain embodiments, R 6a and R 6b one of which is CN and the other is H; R 6c is H, or substituted or unsubstituted alkyl. In certain embodiments, R 6a and R 6b Each of the is H; R 6c is unsubstituted alkyl. In certain embodiments, R 6a and R 6b Each of the is H; R 6c is Me, or Et. In certain embodiments, R 6a and R 6b Each of the is H; R 6c is alkyl substituted with amino, alkylamino, or dialkylamino. In certain embodiments, R 6a and R 6b Each of the is H; R 6c is alkyl substituted with NH, NHCH, or N(CH). In certain embodiments, R 6a and R 6b Each of the is H; R 6cis alkyl substituted with dimethylamino. In certain embodiments, R 6a and R 6b Each of the is H; R 6c is —CHNMe. In certain embodiments, R 6a and R 6b forms a bond (thereby forming a triple bond); R 6c is H or substituted or unsubstituted alkyl. In certain embodiments, R 6a and R 6b forms a bond (thereby forming a triple bond); R 6c is Me. In certain embodiments, R 6a and R 6b Each of the is H; R 6c But -(CH2) q -heterocycloalkyl; and q is 1, 2, 3, or 4. In certain embodiments, R 6a and R 6b Each of the is H; R 6c But -(CH2) q -heterocycloalkyl; and q is 1. In certain embodiments, R 6a and R 6b Each of the is H; R 6c But -(CH2) q -heterocycloalkyl; and q is 2. In certain embodiments, R 6a and R 6b Each of the is H; R 6c But -(CH2) q -heterocycloalkyl; and q is 3. In certain embodiments, heterocycloalkyl is substituted or unsubstituted azetidinyl, pyrrolidinyl, piperidinyl, or azepinyl. In certain embodiments, heterocycloalkyl is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or azepin-1-yl. In certain embodiments, heterocycloalkyl is substituted azetidin-1-yl substituted with one or two fluoro groups. In certain embodiments, R 6a and R 6b each of which is H or Me; R6c is -CH2-azetidin-1-yl, -CH2-pyrrolidin-1-yl, or -CH2-piperidin-1-yl. 6a and R 6b each of which is H or Me; R 6c is —CH-azetidin-1-yl, where the azetidin-1-yl is substituted with one or two fluoro groups. 6a , and R 6b One of the two is F;R 6c is H or unsubstituted alkyl. In certain embodiments, R 6a , and R 6b One of the two is F;R 6c is Me, or Et. In certain embodiments, R 6a , and R 6b One of the two is F;R 6c is alkyl substituted with amino, alkylamino, or dialkylamino. In certain embodiments, R 6a , and R 6b One of them is F; the other is H; R 6c is H. In certain embodiments, R 6c is alkyl substituted with a substituted amino, where the substitution on the amino is selected from alkyl, cycloalkyl, or heterocycloalkyl. 6c is alkyl substituted with N-cycloalkyl-N-alkyl-amino. In certain embodiments, R 6c is alkyl substituted with N-heterocycloalkyl-N-alkyl-amino. In certain embodiments, R 6c is alkyl substituted with N-cyclopropyl-N-alkyl-amino. 6c is alkyl substituted with N-cyclopropyl-N-methyl-amino. In certain embodiments, R 6c is alkyl substituted with N-cyclopropyl-N-ethyl-amino. 6cIn certain embodiments, alkyl is methyl or ethyl. 6c is a methyl substituted with N-cyclopropyl-N-methyl-amino.

[0227] In certain embodiments, R 4 is -C(O)-CH=CH2, -C(O)-C(F)=CH2, or -S(O)2-CH=CH2.

[0228] In certain embodiments, R 1a is Me, Et, or i-Pr. 1a is Me.

[0229] In certain embodiments, R 4 is an unsubstituted epoxide. In certain embodiments, R 4 is an alkyl-substituted epoxide. In certain embodiments, R 4 is an epoxide substituted with Me, Et, i-Pr, or n-Pr.

[0230] In certain embodiments, R 6a is H. In certain embodiments, R 6a is F. In certain embodiments, R 6a is CN.

[0231] In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 But -C(O)-CR a =C(R b )R 6c In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 -C(O)-CH=C(H)R 6cIn certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 But -C(O)-CF=C(R b )R 6c In certain embodiments, R 4 is —C(O)—CF═CH2. In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 is —C(O)—CH═CH2. In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 But -C(O)-C≡CR 6c In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 is —C(O)—C≡CH. In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 is —C(O)—C≡C—CH3. In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 is —C(O)—CH═CH—CH—NMe. In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 is —C(O)—CH═CH—CH—NHMe. In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4is —C(O)—CH═CH—CH2-heterocycloalkyl, where heterocycloalkyl has one nitrogen and is optionally substituted. In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 is —C(O)—CH═CH—CH2-heterocycloalkyl, where heterocycloalkyl is N-linked and optionally substituted. In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 is —C(O)—CH═CH—CH2-heterocycloalkyl having one nitrogen. In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 but, [ka] In certain embodiments of Formula (PI), (P2-I), (I), (LXIa) through (LXIIIb), (P4-I) through (P4-Vb), or (P5-I′) through (P5-Vd), R 4 but, [ka] In certain embodiments, R 4 but, [ka] is.

[0232] In certain embodiments, R 6c is H. In certain embodiments, R 6c is substituted or unsubstituted alkyl. In certain embodiments, R 6cis H, or substituted or unsubstituted alkyl. In certain embodiments, R 6c is unsubstituted alkyl. In certain embodiments, R 6c is Me or Et.

[0233] In certain embodiments, R 6c In certain embodiments, R is alkyl substituted with amino, alkylamino, or dialkylamino. In certain embodiments, R is alkyl substituted with dimethylamino. In certain embodiments, R is alkyl substituted with dimethylamino. 6c is —CH—NMe. In certain embodiments, R 6c is H or substituted or unsubstituted alkyl. In certain embodiments, R 6c is Me. In certain embodiments, R 6c But -(CH2) q -heterocycloalkyl; and q is 1, 2, 3, or 4. In certain embodiments, R 6c But -(CH2) q -heterocycloalkyl; and q is 1. In certain embodiments, R 6c But -(CH2) q -heterocycloalkyl; and q is 2. In certain embodiments, R 6c But -(CH2) q -heterocycloalkyl; and q is 3.

[0234] In certain embodiments, the compound has formula (XLIVa) or (XLIVc). In certain embodiments, the compound has formula (XLVIe) or (XLVIq). In certain embodiments, the compound has formula (XLVIIIa) or (XLVIIIc). In certain embodiments, the compound has formula (XLIIIa) or (XLIIIc). In certain embodiments, the compound has formula (XLIVa) or (XLIVc); R 4 is -C(O)-CH=CH2. In certain embodiments, the compound is represented by formula (XLIVa) or (XLIVc); 4-C(O)-CH=CHR 6c In certain embodiments of formula (XLIVa) or (XLIVc), R 4 is -C(O)-CH=CH-CH2-NMe2.

[0235] In certain embodiments, the compound has formula (XLVIe) or (XLVIq); R 4 is -C(O)-CH=CH2. In certain embodiments, the compound is represented by formula (XLVIe) or (XLVIq); 4 -C(O)-CH=CHR 6c In certain embodiments of formula (XLVIe) or (XLVIq), R 4 is -C(O)-CH=CH-CH2-NMe2. In certain embodiments, the compound is represented by formula (XLVIIIa) or (XLVIIIc); 4 is -C(O)-CH=CH2. In certain embodiments, the compound is represented by formula (XLVIIIa) or (XLVIIIc); 4 -C(O)-CH=CHR 6c In certain embodiments of formula (XLVIIIa) or (XLVIIIc), R 4 is -C(O)-CH=CH-CH2-NMe2. In certain embodiments, the compound is represented by formula (XLIIIa) or (XLIIIc); R 4 is —C(O)—CH═CH. In certain embodiments, the compound is represented by formula (XLIIIa) or (XLIIIc); R 4 -C(O)-CH=CHR 6c In certain embodiments of formula (XLIIIa) or (XLIIIc), R 4 is -C(O)-CH=CH-CH2-NMe2.

[0236]

[0236] Formula (PI), (P4-I), (P2-I), (XLIIIa), (XLIIIb), (XLIIIc), (XLIIId), (XLIVa), (XLIVb), (XLIVc), (XLIVd), Formula ( XLVIa), (XLVIb), (XLVIc), (XLVId), (XLVIe), (XLVIf), (XLVIm), (XLVIn), (XLVIo), (XLVIp), (XLVIq), (XL In certain embodiments of compounds of Formula (VIr), (XLVIIIa), (XLVIIIc), (XLVIIIe), (XLVIIIg), (LXa), (LXb), (LXc), (LXd), (LXe), (LXf), (LXIa), (LXIb), (LXIc), (LXId), (LXIIa), (LXIIb), (LXIIc), (LXIId), (LXIIIa), or (LXIIIb), R 4 -C(O)-BC(R 6a )=C(R 6b )-C(O)-R 6c , -S(O)-BC(R 6a )=C(R 6b )-C(O)-R 6c , -S(O)2-BC(R 6a )=C(R 6b )-C(O)-R 6c , -BC(R 6a )=C(R 6b )-C(O)-R 6c , -BC(R 6a )=C(R 6b )-S(O)-R 6c , -BC(R 6a )=C(R 6b )-S(O)2-R 6c , -BC(R 6a )=C(R 6b )-P(O)-R 6a R 6b ; or -BC(R 6a )=C(R 6b )-P(O)-OR 6a OR 6b and B is a substituted or unsubstituted C 1~4 alkylene, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R 6cis substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 -C(O)-BC(R 6a )=C(R 6b )-C(O)-R 6c , -S(O)-BC(R 6a )=C(R 6b )-C(O)-R 6c , or -S(O)2-BC(R 6a )=C(R 6b )-C(O)-R 6c In certain embodiments, R 4 But -BC(R 6a )=C(R 6b )-C(O)-R 6c , -BC(R 6a )=C(R 6b )-S(O)-R 6c , -BC(R 6a )=C(R 6b )-S(O)2-R 6c In certain embodiments, R 4 But -BC(R 6a )=C(R 6b )-P(O)-R 6a R 6b ; or -BC(R 6a )=C(R 6b )-P(O)-OR 6a OR 6b In certain embodiments, R 4 But -BC(R 6a )=C(R 6b )-C(O)-R 6c In certain embodiments, R 4 is —C(O)—CH═CH—CH—NMe. In certain embodiments, R 4 is —C(O)—CH═CH—CH—NHMe. In certain embodiments, R 6c is substituted or unsubstituted alkoxy. In certain embodiments, R 6cis substituted or unsubstituted OMe, OEt, Oi-Pr, or Ot-Bu. 6c is OMe, OEt, Oi-Pr, or Ot-Bu. 6c is substituted or unsubstituted heterocycloalkyl. In certain embodiments, R 6c is substituted or unsubstituted azetidinyl, pyrrolidinyl, piperidinyl, or azepinyl. 6c is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or azepin-1-yl. 6c is piperidin-1-yl. In certain embodiments, R 6c is substituted or unsubstituted amino. In certain embodiments, R 6c is a substituted amino. In certain embodiments, R 6c is dialkylamino. In certain embodiments, R 6c is dimethylamino, diethylamino, N-isopropyl-N-methylamino, or N-isopropyl-N-ethylamino. 6c is dimethylamino.

[0237]

[0237] In one preferred embodiment, a compound represented by formula (P6-I) has the following structure (P6-I): [ka] (In the formula, each A 1 , A 2 , A 3 , and A 4 But independently, -C(R 7 )= or -N=; provided that A 1 , A 2 , A 3 , and A 4 Not more than two of are N; Each L 1 and L 3are independently substituted or unsubstituted C1-C4 alkylene; R 1 H, halo, CN, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R 2b are independently H or C1-C4 alkyl; R 4 i)-C(O)-C(R 6a )=C(R 6b )(R 6c ), ii)-S(O)-C(R 6a )=C(R 6b )(R 6c ), iii) -S(O)2-C(R 6a )=C(R 6b )(R 6c ), or iv) a substituted or unsubstituted epoxide; R 5 is H, Cy, CN, halo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted C 1~6 alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkylamino; Cy is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; Each R 6a and R 6b are independently H, halo, CN, or C 1~6 alkyl; or R 6a and R 6b are joined together to form a bond; R 6c is H, halo, CN, or C 1~6 alkyl, where C 1~6 alkyl is unsubstituted or substituted with one or more groups selected from substituted or unsubstituted amino, substituted or unsubstituted hydroxy, and substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7 are independently H, halo, CN, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heterocycloalkyl) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, are provided herein.

[0238] In certain embodiments, with respect to compounds of any of the formulae described herein, R 5 H, Cy, CN, Halo, C 1~6 Alkyl, C 1~6 Alkoxy or C 1~6 Cy is cycloalkyl or heterocycloalkyl; and each of Cy, alkyl, alkoxy, and alkylamino is unsubstituted or contains one or more of halo, CN, C 1~4 alkyl, hydroxy, amino, alkylamino, or dialkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C 1~4 In certain embodiments, the substituents on each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more of halo, CN, C 1~4 Alkyl, hydroxy, and C 1~4 Alkoxy is selected from:

[0239] In certain embodiments, R 5 But substitution C 1~6 Alkyl, substituted C 1~6 alkoxy, or substituted alkylamino; the substitution being other than substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. In certain embodiments, R 5 is unsubstituted cycloalkyl. In certain embodiments, R 5 is cycloalkyl and is substituted with hydroxy, alkoxy, halo, or C1-C6 alkyl. 5is unsubstituted cycloalkyl. In certain embodiments, R 5 is heterocycloalkyl and is substituted with hydroxy, alkoxy, halo, or C1-C6 alkyl.

[0240] In certain embodiments, R 5 is -NHC(O)R; and R is C1-C6 alkyl.

[0241] In certain embodiments, A 1 , A 2 , and A 4 Each of the is CH, and A 3 is CR 7 In certain embodiments, A 1 , and A 2 Each of the is CH; A 3 is CR 7 and A 4 is N. In certain embodiments, A 1 , A 2 , and A 3 Each of the is CH, and A 4 is CR 7 In certain embodiments, A 4 is CR 7 and;R 7 is H, halo, alkyl, haloalkyl, or alkoxy. 4 is CR 7 and;R 7 is H, F, Me, Et, Cl, CF3, or OMe. 3 is CR 7 and;R 7 is H, halo, alkyl, haloalkyl, or alkoxy. 3 is CR 7 and;R 7 is H, F, Me, Et, Cl, CF3, or OMe.

[0242] In certain embodiments, the compound has the formula (P6-IIa) or (P6-IIb): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0243] In certain embodiments, L 1 is a substituted or unsubstituted C1-C4 alkylene. In certain embodiments, the substituents on each of the alkylenes are independently one or more of halo, CN, C 1~4 Alkyl, hydroxy, and C 1~4 In certain embodiments, L is selected from alkoxy. 1 is —CH—CH—, —C(Me)H—CH—, or —CH—C(Me)H—. In certain embodiments, L 1 is -CH2-C(Me)H-.

[0244] In certain embodiments, the compound has formula (P6-IIIa), (P6-IIIb), (P6-IIIc) or (P6-IIId): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0245] In certain embodiments, R 1 H, halo, CN, substituted or unsubstituted C 1~6 In certain embodiments, the substituents on each of the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are one or more of halo, CN, C, C, D, E, E, F, H, H, I, I, I, II, I, III, I, III, I, IV ... 1~4 Alkyl, hydroxy, and C 1~4In certain embodiments, R 1 is H, Me, or Et.

[0246] In certain embodiments, the compound has formula (P6-IVa), (P6-IVb), (P6-IVc) or (P6-IVd): [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0247] In certain embodiments, L 3 is a substituted or unsubstituted C1-C4 alkylene. In certain embodiments, the substituents on each of the alkylenes are independently one or more of halo, CN, C 1~4 Alkyl, hydroxy, and C 1~4 In certain embodiments, L is selected from alkoxy. 3 is —CH—, or —C(Me)H—. In certain embodiments, L 3 is -C(Me)2-, -CH2-CH2-, -C(Me)H-CH2-, -CH2-C(Me)H-, or [ka] is.

[0248] In certain embodiments, R 2b is H or Me.

[0249] In certain embodiments, each R 7 are independently H, halo, CN, substituted or unsubstituted C 1~6In certain embodiments, the substituents on each of the alkyl, alkoxy, and heterocycloalkyl are one or more of halo, CN, C, OH ... 1~4 Alkyl, hydroxy, and C 1~4 Alkoxy is selected from:

[0250] In certain embodiments, R 7 is H, F, Me, Et, Cl, CF3, or OMe.

[0251] In certain embodiments, R 5 H, Cy, CN, Halo, C 1~6 Alkyl, C 1~6 Alkoxy or C 1~6 and each of Cy, alkyl, alkoxy, and alkylamino is unsubstituted or selected from one or more of halo, CN, C 1~4 alkyl, hydroxy, amino, alkylamino, dialkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C 1~4 In certain embodiments, the substituents on each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more of halo, CN, C 1~4 Alkyl, hydroxy, and C 1~4 In certain embodiments, Cy is selected from alkoxy. In certain embodiments, Cy is cycloalkyl. In certain embodiments, Cy is heterocycloalkyl.

[0252] In certain embodiments, R 5 is unsubstituted or contains one or more halo, CN, C 1~4alkyl, hydroxy, amino, alkylamino, dialkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C 1~4 In certain embodiments, the substituents on each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more of halo, CN, C 1~4 Alkyl, hydroxy, and C 1~4 alkoxy; and Cy is cycloalkyl, or heterocycloalkyl.

[0253] In certain embodiments, R 5 is unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 1~6 In certain embodiments, each of the alkyl, alkoxy, and alkylamino is unsubstituted or substituted with one or more of halo, CN, C 1~4 alkyl, hydroxy, amino, alkylamino, dialkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C 1~4 In certain embodiments, the substituents on each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more of halo, CN, C 1~4 Alkyl, hydroxy, and C 1~4 Alkoxy is selected from:

[0254] In certain embodiments, R 5 Cy, CN, halo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted haloalkoxy, or substituted or unsubstituted alkylamino.

[0255] In certain embodiments, R 5 is Me, Et, i-Pr, n-Pr, n-Bu, i-Bu, t-Bu, sec-Bu, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, Cl, F, CN, CF3, OMe, OEt, Oi-Pr, -OCF3, N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-iso-propyl-N-methylamino, N-iso-propyl-N-ethylamino, N-isopropylamino, N-ethylamino, N-methylamino, Nn-propylamino, substituted or unsubstituted 1-azetidinyl, substituted or unsubstituted 1-pyrrolidinyl, substituted or unsubstituted 1-piperidinyl, or substituted or unsubstituted 1-morpholinyl. In certain embodiments, the substituents on each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are one or more of halo, CN, C 1~4 Alkyl, hydroxy, and C 1~4 Alkoxy is selected from:

[0256] In certain embodiments, R 5 is Me, Et, n-Pr, i-Pr, i-Bu, cyclopropyl, N,N-dimethyl, N-ethyl-N-methyl, N-isopropylamino, N-isopropyl-N-methylamino, methoxy, ethoxy, or i-propyloxy. 5 is cyclopropyl. In certain embodiments, R 5 is Me. In certain embodiments, R 5 is N-isopropyl-N-methylamino.

[0257] In certain embodiments, R 4 But -C(O)-C(R 6a )=C(R 6b )(R 6c )

[0258] In certain embodiments, each R6a and R 6b are independently H, halo, CN, or C 1~6 alkyl; or R 6a and R 6b are joined together to form a bond; R 6c is H, halo, CN, or C 1~6 alkyl, where C 1~6 The alkyl is unsubstituted or substituted or unsubstituted amino, hydroxy, substituted or unsubstituted C 1~6 In certain embodiments, the substituents on each of the amino, alkoxy, and heterocycloalkyl are one or more groups selected from halo, CN, C ... 1~4 Alkyl, hydroxy, and C 1~4 Alkoxy is selected from:

[0259] In certain embodiments, R 6a , R 6b , and R 6c Each of these is H.

[0260] In certain embodiments, R 6c is alkyl substituted with amino, alkylamino, or dialkylamino. In certain embodiments, R 6a and R 6b Each of the is H; R 6c is alkyl substituted with amino, alkylamino or dialkylamino.

[0261] In certain embodiments, R 6a and R 6b forms a bond; R 6c is H or substituted or unsubstituted alkyl. In certain embodiments, the substituents on the alkyl are one or more of halo, CN, C 1~4 Alkyl, hydroxy, C 1~4alkoxy, and heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6a and R 6b forms a bond; R 6c is Me.

[0262] In certain embodiments, R 6a and R 6b Each of the is H; R 6c But -(CH2) q -heterocycloalkyl; and q is 1.

[0263] In certain embodiments, heterocycloalkyl is substituted or unsubstituted azetidin-1-yl, substituted or unsubstituted pyrrolidin-1-yl, substituted or unsubstituted piperidin-1-yl, substituted or unsubstituted morpholin-1-yl, or substituted or unsubstituted azepin-1-yl. In certain embodiments, the substituents on each of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and azepinyl are one or more of halo, CN, C 1~4 Alkyl, hydroxy, and C 1~4 Alkoxy is selected from:

[0264] In certain embodiments, R 6a and R 6b each of which is H or Me; R 6c is -CH2-azetidin-1-yl, -CH2-pyrrolidin-1-yl, or -CH2-piperidin-1-yl.

[0265] In certain embodiments, R 4is —C(O)—CH≡CH, —C(O)—CH≡CH—CH—NHMe, —C(O)—CH≡CH—CH—NMe, —C(O)—CH≡CH—CH—azetidin-1-yl, —C(O)—CH≡CH—CH—(3-fluoroazetidin-1-yl), —C(O)—CH≡CH—CH—(3,3-difluoroazetidin-1-yl), —C(O)—C≡CH, —C(O)—C≡C-Me, or —C(O)—C≡C—CH—NMe.

[0266]

[0266] In certain embodiments, the compound is selected from any one of the compounds listed in Table 2A, or a pharmaceutically acceptable stereoisomer, salt, or solvate.

[0267]

[0267] In certain embodiments, the compound is any compound selected from compounds #163, 164, 202, 203, 204, 213, 224, 226, 227, 228, 230, 232, 233, 241, 247, 252, 308, 310, 315, 501-506, 507, 508, 509, 511, 512, 513, 516A, 517, 518, 520, and 605, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0268]

[0268] In certain embodiments, the compound is any compound selected from compounds #204, 252, 310, 501-506, 507, 508, 509, 511, 512, 513, 516A, 517, 518, 520, and 605.

[0269] In certain embodiments, the compound is selected from compound IDs 204, 252, 310, 509, 511, and 516A.

[0270] In certain embodiments, the compound is selected from compound IDs 308, 315, 506, 507, 508, 513, 512, 513, 517, and 520.

[0271] In certain embodiments, the compound is selected from compounds IDs 515 and 516.

[0272]

[0272] In certain embodiments, the compound is any compound selected from compounds #156, 158, 159, and 160, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

[0273] In certain embodiments, the compound is any compound selected from compounds #142A, 204, 219, 221, 228, 232, and 246, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain embodiments, the compound is any compound selected from compounds #142A, 204, 228, and 232, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0274] In certain embodiments, the compound is compound #142A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain embodiments, the compound is compound 228, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain embodiments, the compound is compound 204. In certain embodiments, the compound is compound 506. In certain embodiments, the compound is compound 516A. In certain embodiments, the compound is compound ID 252. In certain embodiments, the compound is compound ID 509. In certain embodiments, the compound is compound 511.

[0275]

[0275] In certain embodiments, the compound is any compound selected from Table 2A or Table 2B, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

[0276]

[0276] In certain embodiments, the compound is any of the compounds listed below in Table 1, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

[0277] [Table 5]

[0278] [Table 6]

[0279] [Table 7]

[0280] [Table 8]

[0281] [Table 9]

[0282] [Table 10]

[0283] [Table 11]

[0284] [Table 12]

[0285] [Table 13]

[0286] [Table 14]

[0287]

[0277] In certain embodiments, the compound is any compound selected from compound #204, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

[0288]

[0278] In certain embodiments, the compound is any compound selected from compound #232, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

[0289]

[0279] In certain embodiments, the compound is any one compound selected from the following: [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0290]

[0280] In certain embodiments, the compound is any one compound selected from the following: [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0291] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0292] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0293] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0294] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0295] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0296] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0297] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0298] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0299] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0300] Certain embodiments of the compounds of Formula (P2-I), Formula (P4-I) to (P4-Vb), Formula (P5-I') to (P5-Vd), and Formula (P6-I) to (P6-IIId) have IC values ​​of less than 1 nM or less than 0.1 nM when administered in vivo (e.g., to rats) at low doses of less than 5 mg / kg (e.g., 3 mg / kg or less). 50 values ​​showed improved potency against FLT3 and / or high occupancy of the active site of FLT3 (e.g., greater than 50%, 70% or 90% occupancy).

[0301]

[0291] In one embodiment, provided herein is a pharmaceutical composition comprising a compound selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof.

[0302]

[0292] In one embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (PI), Formula (I) to Formula (LXIIIb), Formula (P2-I), Formula (P4-I) to Formula (P4-Vb), and Formula (P5-I') to Formula (P5-Vd), and a pharmaceutically acceptable excipient.

[0303]

[0293] In certain embodiments, the pharmaceutical composition is formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration.

[0304]

[0294] In one embodiment, provided herein is a method for treating a proliferative disease or condition, comprising administering to a patient in need thereof a pharmaceutical composition provided herein.

[0305] In certain embodiments, the patient has one or more FLT3 mutations. In certain embodiments, the FLT3 mutation is selected from N676K, F691L, D835H, D835V, D835Y, Y842C, and combinations thereof. In certain embodiments, the FLT3 mutation is N676K. In certain embodiments, the FLT3 mutation is F691L. In certain embodiments, the FLT3 mutation is D835H. In certain embodiments, the FLT3 mutation is D835V. In certain embodiments, the FLT3 mutation is D835Y. In certain embodiments, the FLT3 mutation is Y842C. In certain embodiments, the patient has an NPM1 mutation.

[0306] In certain embodiments, the autoimmune disease is selected from a hematological malignancy.

[0307]

[0297] In one embodiment, provided herein is a method for treating a heteroimmune disease or condition, comprising administering to a patient in need thereof a pharmaceutical composition provided herein.

[0308]

[0298] In one embodiment, provided herein is a method for treating cancer, comprising administering to a patient in need thereof a pharmaceutical composition provided herein.

[0309] In certain embodiments, the cancer has an ALK (anaplastic lymphoma kinase) mutation. In certain embodiments, the cancer is positive for ALK fusion. In certain embodiments, the cancer is resistant to an ALK inhibitor. In certain embodiments, the cancer has an ALK mutation selected from the group consisting of T1151K, I1171N, I1171S, I1171T, F1174I, F1174L, F1174V, V1180L, L1196M, L1196Q, L1198F, L1198H, C1156Y, C1159Y, G1202R, D1203N, F1245V, L1256F, G1269A, and combinations thereof.

[0310]

[0300] In some embodiments, the cancer is a hematological malignancy.

[0311] In certain embodiments, the disease or condition is leukemia, lymphoma, or multiple myeloma. In particular embodiments, the disease or condition is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), prolymphocytic leukemia (PLL), large granular lymphocytic (LGL), hairy cell leukemia (HCL), mast cell leukemia (MCL), or myelodysplastic syndrome (MDS).

[0312] In certain embodiments, the disease or condition is acute myeloid leukemia (AML). In certain embodiments, the AML is FLT3 mutation-positive. In certain embodiments, the AML is newly diagnosed. In certain embodiments, the AML is FLT3 mutation-positive and newly diagnosed. In certain embodiments, the AML is relapsed or refractory. In certain embodiments, the AML is relapsed or refractory and FLT3 mutation-positive. In certain embodiments, the FLT3 mutation is a FLT3-ITD mutation. In certain embodiments, the FLT3 mutation is selected from N676K, F691L, D835H, D835V, D835Y, Y842C, and combinations thereof. In certain embodiments, the FLT3 mutation is N676K. In certain embodiments, the FLT3 mutation is F691L. In certain embodiments, the FLT3 mutation is D835H. In certain embodiments, the FLT3 mutation is D835V. In certain embodiments, the FLT3 mutation is D835Y. In certain embodiments, the FLT3 mutation is Y842C. In certain embodiments, the patient has an NPM1 mutation.

[0313] In certain embodiments, the AML is resistant to chemotherapy. In certain embodiments, the AML is resistant to chemotherapy and has developed a FLT3-IND mutation, including at least one mutation selected from, but not limited to, N676K, F691L, D835H, D835V, D835Y, Y842C, and combinations thereof.

[0314] In certain embodiments, the AML is resistant to a previously administered FLT3 inhibitor. In certain embodiments, the AML is resistant to gilteritinib. In certain embodiments, the AML is resistant to midostaurin.

[0315]

[0305] In one embodiment, provided herein is a method for treating mastocytosis, comprising administering to a patient in need thereof a pharmaceutical composition provided herein.

[0316]

[0306] In one embodiment, provided herein is a method for treating osteoporosis or a bone resorption disorder, comprising administering to a patient in need thereof a pharmaceutical composition provided herein.

[0317]

[0307] In one embodiment, provided herein is a method for treating an inflammatory disease or condition, comprising administering to a patient in need thereof a pharmaceutical composition provided herein.

[0318]

[0308] In one embodiment, provided herein is a method for treating lupus erythematosus, comprising administering to a subject in need thereof a therapeutically effective amount of a composition containing a compound that is an inhibitor of FLT3 selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof.

[0319]

[0309] In one embodiment, provided herein is a method for treating a heteroimmune disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a composition containing a compound that is an inhibitor of FLT3 selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof.

[0320]

[0310] In one embodiment, provided herein is a method for treating diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia, comprising administering to a subject in need thereof a therapeutically effective amount of a composition containing a compound that is an inhibitor of FLT3 selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof.

[0321]

[0311] In one embodiment, provided herein is a method for treating mastocytosis, comprising administering to a subject in need thereof a therapeutically effective amount of a composition containing a compound that is an inhibitor of FLT3 selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof.

[0322]

[0312] In one embodiment, provided herein is a method for treating osteoporosis or a bone resorption disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a composition containing a compound that is an inhibitor of FLT3 selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof.

[0323]

[0313] In one embodiment, provided herein is a method for treating an inflammatory disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a composition containing a compound that is an inhibitor of FLT3 selected from Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), or a pharmaceutically acceptable salt thereof.

[0324]

[0314] In some embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound represented by any one of the formulae described herein. In some embodiments, the compound is represented by any one of Formulas (PI), (I) to (LXIIIb), (P2-I), (P4-I) to (P4-Vb), and (P5-I') to (P5-Vd).

[0325]

[0315] In certain embodiments, the pharmaceutical composition is formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration.

[0326] In some embodiments, the carrier is a parenteral carrier. In some embodiments, the carrier is an oral carrier. In some embodiments, the carrier is a topical carrier.

[0327]

[0317] Any combination of the groups described above for the various variables is contemplated herein. It is understood that the substituents and substitution patterns in the compounds provided herein can be selected by one skilled in the art to provide chemically stable compounds that can be synthesized by techniques known in the art and described herein.

[0328]

[0318] Further representative embodiments of compounds of Formula (I) include the compounds listed in Table 2A and Table 2B, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

[0329]

[0319] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the art to provide stable moieties and compounds.

[0330] In certain embodiments, compounds of Formula (P2-I), Formulas (P4-I) through (P4-Vb), Formulas (P5-I') through (P5-Vd), and Formulas (P6-I) through (P6-IIId) inhibit FLT3. In certain embodiments, compounds of Formula (P2-I), Formulas (P4-I) through (P4-Vb), Formulas (P5-I') through (P5-Vd), and Formulas (P6-I) through (P6-IIId) are used to treat patients suffering from FLT3-dependent or FLT3-mediated conditions or diseases, including, but not limited to, proliferative diseases such as hematological malignancies.

[0331]

[0321] In certain embodiments, compounds of Formula (P2-I), Formula (P4-I) to (P4-Vb), Formula (P5-I') to (P5-Vd), and Formula (P6-I) to (P6-IIId) are used to treat patients suffering from FLT-dependent or FLT3-mediated conditions or diseases, including, but not limited to, cancer, e.g., hematological malignancies.

[0332] 3. Compound Preparation

[0322] Compounds of any of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId) can be synthesized using standard synthetic reactions known to those skilled in the art or using methods known in the art. The reactions can be used in linear sequences to provide compounds, or they may be used to synthesize fragments that are subsequently coupled by methods known in the art. Exemplary methods are shown in the Examples herein.

[0333]

[0323] Described herein are compounds that inhibit the activity of FLT3, and methods for their preparation. Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds. Pharmaceutical compositions comprising at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite, or pharmaceutically acceptable prodrug of such a compound are provided.

[0334] The starting materials used in the synthesis of the compounds described herein may be synthesized or obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein, and other related compounds with different substituents, may be synthesized or obtained from commercial sources such as, for example, March, ADVANCED ORGANIC CHEMISTRY 4 th Ed.,(Wiley 1992);Carey and Sundberg,ADVANCED ORGANIC CHEMISTRY4 th Ed.,Vols. A and B(Plenum 2000,2001);Green and Wuts,PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rdEd., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), all of which are incorporated by reference in their entireties. Further methods for the synthesis of the compounds described herein can be found in International Patent Publication No. WO 01 / 01982901, Arnold et al. Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170; Burchat et al. Bioorganic & Medicinal Chemistry Letters 12 (2002) 1687-1690. General methods for the preparation of the compounds disclosed herein may be derived from reactions known in the art, which may be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulas provided herein, as will be recognized by those skilled in the art.

[0335]

[0325] The products of the reactions may be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0336]

[0326] The compounds described herein may be prepared as a single isomer or a mixture of isomers.

[0337]

[0327] In certain embodiments, representative compounds of formula (P6-I) are prepared according to the synthetic schemes set forth herein.

[0338] 4. Further Forms of the Compound

[0328] The compounds disclosed herein have a structure of Formula (PI), Formulas (I) to (LXIIIb), Formula (P2-I), Formulas (P4-I) to (P4-Vb), or Formulas (P5-I') to (P5-Vd). When a compound described herein is referred to, it is understood that unless otherwise indicated, it is intended to include any compound of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), as well as all specific compounds within these general formulas.

[0339] The compounds described herein may have one or more stereocenters, and each center may exist in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms and the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art, such as, for example, the separation of stereoisomers by chiral chromatographic columns.

[0340] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by known methods, such as, for example, chromatography and / or fractional crystallization. In certain embodiments, enantiomers can be separated by chiral chromatography columns. In certain embodiments, enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., alcohol), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis). All such isomers, including diastereomers, enantiomers, and mixtures thereof, are considered to be part of the compositions described herein.

[0341] The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds that have the same type of activity. In certain situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds described herein. Additionally, the compounds described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds described herein are also considered to be disclosed herein.

[0342]

[0332] The unoxidized forms of any of the compounds of Formula (P2-I), Formula (P4-I) to (P4-Vb), Formula (P5-I') to (P5-Vd), and Formula (P6-I) to (P6-IIId) can be prepared from the N-oxide of any of the compounds of Formula (P2-I), Formula (P4-I) to (P4-Vb), Formula (P5-I') to (P5-Vd), and Formula (P6-I) to (P6-IIId) by treating with a reducing agent such as, but not limited to, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like, in a suitable inert organic solvent such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, and the like, at 0 to 80°C.

[0343] In certain embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in certain situations, they may be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, while the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug is a compound described herein that is administered as an ester ("prodrug") to facilitate transport across cell membranes where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the carboxylic acid, the active form, once inside the cell, where water solubility is beneficial. A further example of a prodrug may be a short-chain peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, after in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes into a biologically, pharmaceutically, or therapeutically active form of the compound. To generate a prodrug, a pharmaceutically active compound is modified so that the active compound is regenerated after in vivo administration. Prodrugs can be designed to alter the metabolic stability or transport properties of a drug, mask side effects or toxicity, improve the flavor of a drug, or change other characteristics or properties of a drug. With knowledge of pharmacodynamic processes and in vivo drug metabolism, one skilled in the art can design a prodrug of a compound once a pharmaceutically active compound is known.(For example, Nogrady (1985), Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry (See Letters, Vol. 4, p. 1985).

[0344]

[0334] Prodrug forms of the compounds described herein, where the prodrug is metabolized in vivo to produce a derivative described herein, are included within the scope of the claims. In some cases, some of the compounds described herein may be a prodrug for another derivative or active compound.

[0345] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration, whereas the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives for use as modifiers to enhance drug transport to site-specific tissues. In certain embodiments, the design of the prodrug increases effective water solubility. For example, Fedorak et al.,Am. Pharmaceutics,37,87(1987);J. Larsen et al.,Int. J. Pharmaceutics,47,103(1988);Sinkula et al.,J. Pharm. Sci.,64:181-210(1975);T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems,Vol. 14 of the ACS Symposium Series; and Edward B. Roche, Bioreversible See Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference in their entirety.

[0346] Sites on the aromatic ring portion of any of the compounds of Formula (P2-I), Formulas (P4-I) through (P4-Vb), Formulas (P5-I') through (P5-Vd), and Formulas (P6-I) through (P6-IIId) may be susceptible to various metabolic reactions, and therefore, incorporation of appropriate substituents on the aromatic ring structure, such as, by way of example only, halogens, can reduce, minimize, or eliminate this metabolic pathway.

[0347]

[0337] The compounds described herein include isotopically labeled compounds, which are identical to those depicted in the various formulas and structures set forth herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds are, respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Certain isotopically labeled compounds described herein, e.g., 3 H and 14 Those in which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. Additionally, deuterium, i.e., 2 Substitution with isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0348]

[0338] In further or certain embodiments, the compounds described herein are metabolized after administration to an organism in need thereof to produce metabolic products that are subsequently used to bring about a desired effect, including a desired therapeutic effect.

[0349] The compounds described herein can be formed as and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) salts of the free base form of the compound with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or salts of acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2 (2) Acid addition salts formed by reacting with organic acids such as oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; (3) salts formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, or potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion, or coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0350]

[0340] The corresponding counter ions of pharmaceutically acceptable salts may be analyzed and identified using various methods, including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any combination thereof.

[0351]

[0341] The salts are recovered by using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.

[0352]

[0342] Reference to a pharmaceutically acceptable salt should be understood to include solvent addition forms or crystalline forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and can be formed during the process of crystallization with a pharmaceutically acceptable solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0353]

[0343] Reference to a salt should be understood to include solvent addition forms or crystalline forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are often formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystalline shapes, optical and electrical properties, stability, and solubility. Various factors, such as the recrystallization solvent, crystallization rate, and storage temperature, can result in a predominant single crystalline form.

[0354] The compounds described herein may be in various forms, including, but not limited to, amorphous, milled, and nanoparticulate forms. Furthermore, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability, and solubility. Various factors, such as the recrystallization solvent, crystallization rate, and storage temperature, can result in a predominantly single crystal.

[0355] Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be performed using a variety of techniques, including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods address thermochemical decomposition or thermal physical processes, including, but not limited to, polymorphic transformations, and such methods are used to analyze relationships between polymorphs, determine weight loss, find glass transition temperatures, or for excipient compatibility studies. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetry and infrared spectroscopy (TG / IR). X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron light sources. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy with EDX (in a gas or water vapor atmosphere), IR microscopy, and Raman microscopy.

[0356]

[0346] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the art to provide stable moieties and compounds.

[0357] 5. Pharmaceutical Compositions / Formulations

[0347] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, which facilitate the processing of active compounds into pharmaceutically usable preparations. The appropriate formulation depends on the selected route of administration. Any of the well-known techniques, carriers, and excipients can be used as appropriate and as understood in the art. Comprehensive descriptions of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entireties.

[0358] As used herein, a pharmaceutical composition refers to a mixture of a compound described herein, such as any of the compounds of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. A pharmaceutical composition facilitates administration of a compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a mammal having the disease, disorder, or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound may be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0359] In certain embodiments, the composition may also include one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0360] In some embodiments, the composition may also contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0361] As used herein, the term "pharmaceutical combination" refers to a product resulting from mixing or combining two or more active ingredients, and includes both fixed and inconsistent combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound described herein and a co-agent, are both administered to a patient simultaneously in a single entity or dosage form. The term "inconsistent combination" means that the active ingredients, e.g., a compound described herein and a co-agent, are administered to a patient simultaneously, in parallel, or sequentially as separate entities without a specific intervening time limit, where such administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0362] The pharmaceutical compositions described herein can be administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Pharmaceutical compositions described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast-dissolve formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and combined immediate and controlled release formulations.

[0363]

[0353] Pharmaceutical compositions containing the compounds described herein may be manufactured in a conventional manner, such as by way of example only, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, enveloping or compressing processes.

[0364] Pharmaceutical compositions comprise at least one compound described herein, such as any one of the compounds of Formula (P2-I), Formula (P4-I) to (P4-Vb), Formula (P5-I') to (P5-Vd), and Formula (P6-I) to (P6-IIId), as an active ingredient, in free acid or free base form or a pharmaceutically acceptable salt form. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds that have the same type of activity. In certain situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds described herein. Furthermore, the compounds described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Solvated forms of the compounds described herein are also considered to be disclosed herein.

[0365]

[0355] "Anti-foaming agents" reduce foaming during processing, which can cause flocculation of the aqueous dispersion, air bubbles in the finished film, or generally impair processing. Exemplary anti-foaming agents include silicone emulsion or sorbitan sesquioleate.

[0366]

[0356] "Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and tocopherol. In certain embodiments, antioxidants enhance chemical stability where needed.

[0367]

[0357] In certain embodiments, the compositions provided herein may also contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0368]

[0358] The formulations described herein may benefit from antioxidants, metal chelators, thiol-containing compounds and other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0369] "Binders" impart adhesive properties and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; acidic polysaccharides; acid); bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; sugars such as tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; natural or synthetic gums such as acacia, tragacanth, ghatti gum, isapol husk mucilage, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, and sodium alginate.

[0370]

[0360] "Carriers" or "carrier materials" include any excipients commonly used in pharmaceuticals and should be selected based on their compatibility with the compounds disclosed herein, such as the compounds of any one of Formulas (P2-I), (P4-I) to (P4-Vb), (P5-I') to (P5-Vd), and (P6-I) to (P6-IIId), and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, etc. "Pharmaceutically compatible carrier materials" may include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sodium sugar stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0371] "Dispersing agents" and / or "viscosity modifiers" include materials that control the diffusion and homogeneity of a drug through a liquid medium or a granulation or mixing method. In certain embodiments, these agents also facilitate the eroding effect of a coating or matrix. Exemplary diffusion enhancers / dispersing agents include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and carbohydrate-based dispersing agents, such as hydroxypropylcellulose (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), amorphous cellulose, etc.), magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer obtained from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ).)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gum (e.g., Examples of suitable dispersing agents include gum tragacanth and acacia, guar gum, xanthan, including xanthan gum, sugars, cellulose compounds (e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, etc.), polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginates, chitosan, and combinations thereof. Plasticizers such as cellulose or triethylcellulose may also be used as dispersing agents. Particularly useful dispersing agents for liposomal and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural egg-derived phosphatidylcholine, natural egg-derived phosphatidylglycerol, cholesterol, and isopropyl myristate.

[0372]

[0362] Combinations of one or more erosion facilitators and one or more diffusion facilitators may also be used in the present compositions.

[0373] The term "diluent" refers to a chemical compound used to dilute a compound of interest prior to delivery. Diluents can also be used to stabilize a compound because they can provide a more stable environment. Salts dissolved in buffers (which can also provide pH control or maintenance) are used as diluents in the art, and diluents include, but are not limited to, phosphate buffered saline solutions. In certain embodiments, diluents increase the volume of a composition to facilitate compression or to generate sufficient volume for homogeneous mixing for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; dibasic calcium phosphate, calcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars such as Di-Pac® (Amstar); mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, powdered sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed grain solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

[0374] The term "disintegrate" includes both dissolution and dispersion of the dosage form when in contact with gastrointestinal fluids. A "disintegration agent or disintegrant" promotes the breakdown or disintegration of a substance. Examples of disintegrants include starches, e.g., natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, celluloses, e.g., wood products, methyl crystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable excipients include Tia® and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose (e.g., crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose), crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0375]

[0365] "Drug absorption" or "absorption" typically refers to the process of movement of a drug from the site of drug administration across a barrier to the blood vessels or site of action, for example, movement of a drug from the gastrointestinal tract to the portal vein or lymphatic system.

[0376] An "enteric coating" is a material that remains substantially intact in the stomach but dissolves and releases a drug in the small intestine or colon. Generally, enteric coatings comprise polymeric materials that prevent release in the low pH environment of the stomach, but ionize at higher pHs, typically between 6 and 7, and therefore dissolve sufficiently in the small intestine or colon to release the active drug therein.

[0377] "Erosion enhancers" include materials that control the erosion of a particular material in gastrointestinal fluids. Erosion enhancers are generally known to those skilled in the art. Exemplary erosion enhancers include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0378]

[0368] Examples of "fillers" include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, and polyethylene glycol.

[0379]

[0369] "Flavors" and / or "sweeteners" useful in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, and cinnamon. Cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neote Ice cream, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talc, sylitol, sucralose, sorbitol, sugar Cream, tagatose, tangerine, thaumatin, tutti-frutti, vanilla, walnut, watermelon, sweet cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0380] "Lubricants" and "gliding agents" are compounds that prevent, reduce, or inhibit adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons such as mineral oil, or hydrogenated vegetable oils such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali metal and alkaline earth metal salts, for example, aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000) or methoxypolyethylene glycol such as Carbowax™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid™, starch such as Cab-O-Sil®, corn starch, silicone oil, surfactants, and the like.

[0381] "Measurable serum concentration" or "measurable plasma concentration" refers to the serum or plasma concentration, typically measured in mg, μg, or ng of therapeutic agent per ml, dl, or 1 of serum, absorbed into the bloodstream after administration. As used herein, measurable plasma concentration is typically measured in ng / ml or μg / ml.

[0382]

[0372] "Pharmacodynamics" refers to the factors that determine the biological response observed in relation to the concentration of a drug at a site of action.

[0383]

[0373] "Pharmacokinetics" refers to the factors that determine the achievement and maintenance of an adequate concentration of a drug at a site of action.

[0384] "Plasticizers" are compounds used to soften microencapsulation materials or film coatings, making them less brittle. Suitable plasticizers include, for example, polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, triethylcellulose, and triacetin. In some embodiments, plasticizers can also function as dispersing or wetting agents.

[0385]

[0375] Examples of "solubilizers" include compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, docusate sodium, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.

[0386]

[0376] "Stabilizers" include compounds such as any antioxidants, buffers, acids, preservatives, and the like.

[0387]

[0377] As used herein, "steady state" is when the amount of drug administered is equal to the amount of drug removed within one dosing interval resulting in a steady or constant plasma drug exposure.

[0388]

[0378] Examples of "suspending agents" include polyvinylpyrrolidone, for example, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol (for example, the polyethylene glycol may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, Examples of suitable cellulose compounds include cellulose acetate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums (e.g., tragacanth gum and acacia gum, guar gum, xanthan including xanthan gum), sugars, cellulose compounds (e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose), hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, and povidone.

[0389]

[0379] "Surfactants" include sodium lauryl sulfate, docusate sodium, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as Octoxynol 10 and Octoxynol 40. In certain embodiments, surfactants may be included to enhance physical stability or for other purposes.

[0390]

[0380] Examples of "viscosity enhancers" include methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof.

[0391]

[0381] Examples of "humectants" include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, docusate sodium, sodium oleate, sodium lauryl sulfate, docusate sodium, triacetin, Tween 80, vitamin E TPGS, and ammonium salts.

[0392] 5.1 Dosage Form The compositions described herein can be formulated for administration to a subject by any conventional means, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably.

[0393]

[0383] Furthermore, the pharmaceutical compositions described herein comprising any one of the compounds of Formula (P2-I), Formula (P4-I) to (P4-Vb), Formula (P5-I') to (P5-Vd), and Formula (P6-I) to (P6-IIId) may be formulated into any suitable dosage form for oral ingestion by a patient to be treated, including, but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, etc., solid oral dosage forms, aerosols, controlled release formulations, fast-dissolve formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate-release and controlled-release formulations.

[0394] Oral pharmaceutical preparations can be prepared by mixing one or more solid excipients with one or more of the compounds described herein, optionally milling the resulting mixture, and processing the resulting granules, after adding suitable excipients, if necessary, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants, such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, can be added.

[0395]

[0385] The dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0396]

[0386] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All preparations for oral administration should be in dosages suitable for such administration.

[0397] In certain embodiments, the solid dosage forms disclosed herein can be in the form of a tablet (including a suspension tablet, a fast-dissolving tablet, a bite-disintegrating tablet, a quick-disintegrating tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile-packaged powder, a dispensable powder, or an effervescent powder), a capsule (including a soft or hard capsule, e.g., a capsule made from animal-derived gelatin or plant-derived HPMC, or a "sprinkle capsule"), a solid dispersion, a solid solution, a bioerodible dosage form, a controlled-release formulation, a pulsed-release dosage form, a multiparticulate dosage form, a pellet, a granule, or an aerosol. In certain embodiments, the pharmaceutical composition is in the form of a powder. In certain embodiments, the pharmaceutical composition is in the form of a tablet, including, but not limited to, a fast-dissolving tablet. Furthermore, the pharmaceutical compositions described herein can be administered in the form of a single capsule or multiple capsules. In certain embodiments, the pharmaceutical composition is administered in two, three, or four capsules or tablets.

[0398] In certain embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by blending particles of any one of the compounds of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId) with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is meant that the particles of any one of the compounds of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId) are evenly dispersed throughout the composition so that the composition can be easily divided into similarly effective unit dosage forms, such as tablets, pills, and capsules. Individual unit dosages may also include a film coating that disintegrates after oral ingestion or contact with a diluent. These formulations may be manufactured by conventional pharmaceutical techniques.

[0399] Conventional pharmaceutical techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Worcester coating), tangential coating, top spraying, tabletting, extrusion, etc.

[0400] The pharmaceutical solid dosage forms described herein can comprise a compound described herein and one or more pharmaceutically acceptable excipients, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, wetting agent, plasticizer, stabilizer, penetration enhancer, humectant, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. In certain embodiments, a film coating, such as that described in Remington's Pharmaceutical Sciences, 20th Edition (2000), is provided around a formulation of a compound of Formula (PI), Formulas (I) to (LXIIIb), Formulas (P2-I), Formulas (P4-I) to (P4-Vb), or Formulas (P5-I') to (P5-Vd) using standard coating procedures. In some embodiments, some or all of the particles of the compound of Formula (PI), Formulas (I) through (LXIIIb), Formula (P2-I), Formulas (P4-I) through (P4-Vb), or Formulas (P5-I') through (P5-Vd) are coated. In some embodiments, some or all of the particles of the compound of Formula (PI), Formulas (I) through (LXIIIb), Formula (P2-I), Formulas (P4-I) through (P4-Vb), or Formulas (P5-I') through (P5-Vd) are microencapsulated. In further embodiments, the particles of the compound of Formula (PI), Formulas (I) through (LXIIIb), Formula (P2-I), Formulas (P4-I) through (P4-Vb), or Formulas (P5-I') through (P5-Vd) are neither microencapsulated nor coated.

[0401]

[0391] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0402]

[0392] Fillers suitable for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0403]

[0393] To release the compound of Formula (PI), Formulas (I) to (LXIIIb), Formula (P2-I), Formulas (P4-I) to (P4-Vb), or Formulas (P5-I') to (P5-Vd) or a pharmaceutically acceptable salt thereof from the solid dosage form matrix as efficiently as possible, a disintegrant is often used in the formulation, particularly when the dosage form is compressed with a binder. The disintegrant helps to rupture the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Disintegrants suitable for use in the solid dosage forms described herein include, but are not limited to, natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methyl crystalline celluloses such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable excipients include Tia® and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose (e.g., crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose), crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0404] Binders provide cohesiveness to solid oral dosage form formulations: for powder-filled capsule formulations, they aid in the formation of a plug that can be filled into soft or hard shell capsules, and for tablet formulations, they help ensure the tablet remains intact after compression and ensure blend uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603), hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, acid polysaccharides, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrin, Sugars such as sucrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, natural or synthetic gums such as acacia, tragacanth, ghatti gum, and mucilage of isapol husk, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabinogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

[0405]

[0395] Generally, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage levels in tablet formulations vary depending on whether the formulation is direct compression, wet granulation, roller compaction, or the use of other excipients such as fillers that may themselves act as moderate binders. A formulator skilled in the art can determine the binder level for a formulation, but binder usage levels of up to 70% are common in tablet formulations.

[0406]

[0396] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol (such as Carbowax™, PEG 4000, PEG 5000, PEG 6000), propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.

[0407]

[0397] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0408]

[0398] The term "water-insoluble diluents" includes calcium phosphate, calcium sulfate, starch, modified starch, and microcrystalline cellulose, and finely divided cellulose (e.g., about 0.45 g / cm 3and represents compounds typically used in pharmaceutical formulations, such as Avicel, powdered cellulose, and talc.

[0409]

[0399] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10 (registered trademark)), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

[0410]

[0400] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), and the like.

[0411] Suitable suspending agents for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400), vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, methylcellulose, methylcellulose copolymer (S630), ... Examples of suitable cellulose derivatives include methylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums (e.g., tragacanth gum and acacia gum, guar gum, xanthan including xanthan gum), sugars, cellulose compounds (e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose), hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0412]

[0402] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0413] It should be understood that there is a considerable overlap between the additives used in the solid dosage forms described herein.Therefore, the additives listed above should be regarded as merely exemplary, but not limited to, the types of additives that can be included in the solid dosage forms described herein.The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0414] In some embodiments, one or more layers of the pharmaceutical composition are plasticized. Illustratively, plasticizers are generally high-boiling solids or liquids. Suitable plasticizers may be added at about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0415] Compressed tablets are solid dosage forms prepared by compressing bulk mixtures of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth contain one or more flavoring agents. In some embodiments, compressed tablets contain a film surrounding the final compressed tablet. In some embodiments, the film coating can provide delayed release of the compound of Formula (PI), Formula (I) through Formula (LXIIIb), Formula (P2-I), Formula (P4-I) through Formula (P4-Vb), or Formula (P5-I') through Formula (P5-Vd) from the formulation. In some embodiments, the film coating aids in patient compliance (e.g., Opadry® coating or sugar coating). Film coatings, including Opadry®, typically range from about 1% to about 3% of the tablet weight. In some embodiments, the compressed tablet contains one or more excipients.

[0416]

[0406] Capsules can be prepared, for example, by placing a bulk mixture of a formulation of a compound of Formula (PI), Formula (I) to Formula (LXIIIb), Formula (P2-I), Formula (P4-I) to (P4-Vb), or Formula (P5-I') to (P5-Vd) above inside a capsule. In some embodiments, the formulation (non-aqueous suspension and solution) is placed in a soft gelatin capsule. In some embodiments, the formulation is placed in a standard gelatin capsule or a non-gelatin capsule, such as a capsule containing HPMC. In some embodiments, the formulation is placed in a sprinkle capsule, where the capsule may be taken whole or the capsule may be opened and the contents sprinkled on food before a meal. In some embodiments, a therapeutic dose is divided into multiple (e.g., 2, 3, or 4) capsules. In some embodiments, the entire dose of the formulation is delivered in capsule form.

[0417] In various embodiments, particles of a compound of Formula (PI), Formula (I) through Formula (LXIIIb), Formula (P2-I), Formula (P4-I) through (P4-Vb), or Formula (P5-I') through (P5-Vd) and one or more excipients are dry blended and compressed into a mass, such as a tablet, that has sufficient hardness to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation into gastrointestinal fluids.

[0418]

[0408] In some embodiments, the dosage form may contain a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH adjusters, erosion promoters, antifoaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0419] Materials useful for microencapsulation as described herein include materials that are compatible with a compound of Formula (PI), Formula (I) through Formula (LXIIIb), Formula (P2-I), Formula (P4-I) through Formula (P4-Vb), or Formula (P5-I') through Formula (P5-Vd), which sufficiently isolate the compound of Formula (PI), Formula (I) through Formula (LXIIIb), Formula (P2-I), Formula (P4-I) through Formula (P4-Vb), or Formula (P5-I') through Formula (P5-Vd) from other incompatible excipients. Materials compatible with the compounds of Formula (PI), Formulas (I) to (LXIIIb), Formula (P2-I), Formulas (P4-I) to (P4-Vb), or Formulas (P5-I') to (P5-Vd) slow the release of the compounds of Formula (PI), Formulas (I) to (LXIIIb), Formula (P2-I), Formulas (P4-I) to (P4-Vb), or Formulas (P5-I') to (P5-Vd) in vivo.

[0420] Exemplary microencapsulation materials useful for delaying the release of formulations comprising the compounds described herein include, but are not limited to, hydroxypropyl cellulose ethers (HPC) (such as Klucel® or Nisso HPC), low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methylcellulose ethers (HPMC) (such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843), methylcellulose polymers (such as Methocel®-A, hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS), and Metolose®), ethylcellulose (EC) and mixtures thereof (such as E461, Ethocel®, Aqualon®-EC, Surelease®), polyvinyl alcohol (PVA) (such as Opadry®), and mixtures thereof (such as E461, Ethocel®, Aqualon®-EC, Surelease®). AMB, etc.), hydroxyethylcellulose (such as Natrosol®), carboxymethylcellulose and salts of carboxymethylcellulose (CMC) (such as Aqualon®-CMC), polyvinyl alcohol and polyethylene glycol copolymers (such as Kollicoat IR®), monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers (Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.Examples of suitable cellulose acetates include cellulose acetate phthalate, cellulose acetate phthalate (such as a mixture of HPMC and stearic acid), cyclodextrin, and mixtures of these materials.

[0421] In some embodiments, plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In some embodiments, microencapsulation materials useful for delaying release of pharmaceutical compositions are from the USP or the National Formulary (NF). In some embodiments, the microencapsulation material is Klucel. In some embodiments, the microencapsulation material is methocel.

[0422]

[0412] The microencapsulated compounds of any one of Formulas (P2-I), (P4-I) to (P4-Vb), (P5-I') to (P5-Vd), and (P6-I) to (P6-IIId) can be formulated by methods known to those skilled in the art. Such known methods include, for example, spray-drying, spinning disk-solvent, hot-melt, spray-cooling, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at a liquid-gas or solid-gas interface, pressure extrusion, or spray-solvent extraction bath. In addition, several chemical techniques, such as complex coacervation, melt evaporation, polymer-polymer incompatibility, interfacial polymerization in a liquid medium, in situ polymerization, submerged drying, and desolvation in a liquid medium, can also be used. Furthermore, other methods, such as roller compaction, extrusion / spheronization, coacervation, or nanoparticle coating, can also be used.

[0423] In certain embodiments, particles of a compound of any one of Formula (P2-I), Formulas (P4-I) through (P4-Vb), Formulas (P5-I') through (P5-Vd), and Formulas (P6-I) through (P6-IIId) are microencapsulated before being formulated into one of the above forms. In further embodiments, some or most of the particles are coated before being further formulated by using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

[0424] In some embodiments, a solid dosage formulation of a compound of any one of Formulae (P2-I), (P4-I) to (P4-Vb), (P5-I') to (P5-Vd), and (P6-I) to (P6-IIId) is plasticized (coated) with one or more layers. Exemplarily, plasticizers are generally high-boiling solids or liquids. Suitable plasticizers may be added at about 0.01% to about 50% by weight (w / w) of the coating composition. Examples of plasticizers include, but are not limited to, diethyl phthalate, citric acid esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0425] In certain embodiments, powders containing formulations comprising any one of the compounds of Formula (P2-I), Formulae (P4-I) to (P4-Vb), Formulae (P5-I') to (P5-Vd), and Formulae (P6-I) to (P6-IIId) described herein can be formulated to include one or more pharmaceutical excipients and flavoring agents. Such powders can be prepared, for example, by mixing the formulation and any pharmaceutical excipients to form a bulk blend composition. Further embodiments also include a suspending agent and / or a wetting agent. This bulk blend is then uniformly divided into unit-dose packages or multi-dose packaging units.

[0426]

[0416] In further embodiments, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse drugs in water for oral administration. Effervescent salts are granules or coarse powders containing a drug in a dry mixture, typically composed of sodium bicarbonate, citric acid, and / or tartaric acid. When the salt of the compositions described herein is added to water, the acid and base react to liberate carbon dioxide gas, thereby causing "effervescence." Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric acid and tartaric acid, as long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or greater.

[0427] In certain embodiments, the formulations described herein comprising a compound of Formula (PI), Formula (I) to Formula (LXIIIb), Formula (P2-I), Formula (P4-I) to (P4-Vb), or Formula (P5-I') to (P5-Vd) are solid dispersions. Methods for producing such solid dispersions are known in the art and include, but are not limited to, U.S. Patent Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Patent Application Publication No. 2004 / 0013734, each of which is expressly incorporated by reference. In certain embodiments, the formulations described herein are solid solutions. A solid solution incorporates a substance with an active agent and other excipients, whereby heating the mixture causes the agent to dissolve, and the resulting composition is then cooled to obtain a solid mixture that can be further formulated or added directly to capsules or compressed into tablets. Methods for producing such solid solutions are known in the art and include, but are not limited to, U.S. Patent Nos. 4,151,273, 5,281,420, and 6,083,518, each of which is expressly incorporated by reference.

[0428]

[0418] Pharmaceutical solid oral dosage forms, including the formulations described herein comprising any one of the compounds of Formula (PI), Formulas (I) to (LXIIIb), Formula (P2-I), Formulas (P4-I) to (P4-Vb), and Formulas (P5-I') to (P5-Vd), can be further formulated to provide controlled release of the compound of Formula (PI), Formulas (I) to (LXIIIb), Formula (P2-I), Formulas (P4-I) to (P4-Vb), or Formulas (P5-I') to (P5-Vd). Controlled release refers to the release of any one of the compounds of Formulas (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId) from a dosage form into which it is incorporated according to desired characteristics over an extended period of time. Controlled release characteristics include, for example, sustained release, extended release, pulsed release, and delayed release characteristics.In contrast to immediate release compositions, controlled release compositions allow the delivery of drugs to subjects over a long period of time according to predetermined characteristics.This release rate provides a therapeutically effective level of drug over a long period of time, thereby providing a longer-term pharmacological response with minimal side effects compared to conventional rapid-release dosage forms.This long-term response provides many inherent benefits that cannot be achieved by corresponding short-acting immediate-release formulations.

[0429] In certain embodiments, the solid dosage forms described herein can be formulated as enterically coated delayed-release oral dosage forms, i.e., oral dosage forms of the pharmaceutical compositions described herein that use an enteric coating to affect release in the small intestine of the gastrointestinal tract. The enterically coated dosage form can be a compressed, molded, or extruded tablet / formation (coated or uncoated) containing granules, powders, pellets, beads, or particles (themselves coated or uncoated) of the active ingredient(s) and / or other composition ingredients. The enterically coated oral dosage form can also be a capsule (coated or uncoated) containing pellets, beads, or granules (themselves coated or uncoated) of the solid carrier or composition.

[0430] As used herein, the term "delayed release" refers to delivery such that release can be achieved at some generally predictable location in the gastrointestinal tract distal to that which would be achieved if the delayed-release modification were not present. In certain embodiments, the method for delayed release is a coating. Any coating should be applied to a sufficient thickness such that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, but dissolves at a pH above about 5. It is anticipated that any anionic polymer that exhibits pH-dependent solubility characteristics can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In certain embodiments, the polymer described herein is an anionic carboxylic acid polymer. In certain embodiments, polymers and compatible mixtures thereof, as well as specific examples thereof, include, but are not limited to, the following:

[0431]

[0421] Shellac, also known as purified lac, is a purified product obtained from the resinous secretions of insects. This coating dissolves in media with a pH >7.

[0432] Acrylic Polymers. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available solubilized in organic solvents, aqueous dispersions, or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but permeable and are primarily used for colonic targeting. The Eudragit series E dissolves in the stomach. The Eudragit series L, L-30D, and S are insoluble in the stomach and dissolve in the intestine.

[0433] Cellulose Derivatives. Examples of suitable cellulose derivatives are ethyl cellulose; a reaction mixture of a partial acetate ester of cellulose with phthalic anhydride. Performance may vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH >6. Aquateric (FMC) is an aqueous system and is a spray-dried CAP pseudolatex containing particles <1 μm. Other components in Aquateric may include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). Performance may vary based on the degree and type of substitution. For example, HPMCP grades such as HP-50, HP-55, HP-55S, and HP-55F are suitable. Performance may vary based on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pHs. These polymers are provided as granules for aqueous dispersion or as fine powders.

[0434] Polyvinyl acetate phthalate (PVAP) PVAP dissolves at pH >5 and has fairly low permeability to water vapor and gastric juices.

[0435] In some embodiments, the coating may contain, and typically does contain, a plasticizer and, optionally, other coating excipients such as colorants, talc, and / or magnesium stearate, as are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyltriethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers typically contain 10 to 25% by weight of a plasticizer, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques, such as spray or pan coating, are used to apply the coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired site of topical delivery in the gastrointestinal tract.

[0436]

[0426] Colorants, anti-blocking agents, surfactants, anti-foaming agents, lubricants (e.g., carnauba wax or PEG) may be added to the coating in addition to plasticizers to solubilize or disperse the coating materials and to improve coating performance and the coated product.

[0437] In certain embodiments, formulations described herein comprising a compound of Formula (PI), Formulas (I) to (LXIIIb), Formula (P2-I), Formulas (P4-I) to (P4-Vb), or Formulas (P5-I') to (P5-Vd) are delivered using a pulsatile dosage form. Pulsatile dosage forms can provide one or more immediate release pulses at predetermined times or at specific sites after a controlled delay time. Pulsatile dosage forms, including formulations described herein comprising any one of compounds of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), can be administered using various pulsatile dosage forms known in the art. For example, such formulations include, but are not limited to, those described in U.S. Patent Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329 (each of which is expressly incorporated by reference).Other pulsed release dosage forms suitable for use with the present formulations include, but are not limited to, U.S. Patent Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441, and 5,837,284, all of which are expressly incorporated by reference.In some embodiments, the controlled release dosage form is a pulsed release solid oral dosage form comprising at least two groups of particles (i.e., multiparticulates), each containing a formulation described herein. The first group of particles provides substantially immediate administration of a compound of Formula (PI), Formulas (I) through (LXIIIb), Formula (P2-I), Formulas (P4-I) through (P4-Vb), or Formulas (P5-I') through (P5-Vd) after ingestion by a mammal. The first group of particles can be either uncoated or include a coating and / or sealant. The second group of particles includes coated particles and, in admixture with one or more binders, comprises about 2% to about 75%, about 2.5% to about 70%, or about 40% to about 70% by weight of the total dose of any one of the compounds of Formula (P2-I), Formulas (P4-I) through (P4-Vb), Formulas (P5-I') through (P5-Vd), and Formulas (P6-I) through (P6-IIId) in the formulation.The coating comprises a pharmaceutically acceptable component in an amount sufficient to provide a delay of about 2 to about 7 hours after ingestion prior to release of the second dose. Suitable coatings include, by way of example only, acrylic resins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS), alone or in admixture with a cellulose derivative, e.g., ethylcellulose, or a non-enteric coating of variable thickness to provide a staggered release of a formulation comprising a compound of any one of Formula (PI), Formulas (I) to (LXIIIb), Formulas (P2-I), Formulas (P4-I) to (P4-Vb), and Formulas (P5-I') to (P5-Vd). 30D, Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, and pH-sensitive coatings (enteric coatings) such as Eudragit® NE30D, Eudragit® NE 40D®).

[0438] Many other types of controlled release systems are known to those skilled in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include polymer-based systems such as polylactic acid and polyglycolic acid, polyanhydrides, and polycaprolactone; porous matrices, non-polymer-based systems, including sterols, such as cholesterol, cholesterol esters, and fatty acids, or lipids, including monoglycerides, diglycerides, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, biodegradable dosage forms, compressed tablets with conventional binders, and the like. For example, Liberman et al., Pharmaceutical Dosage Forms, 2nd Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2 nd Ed., pp. 751-753 (2002); U.S. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983, each of which is expressly incorporated by reference.

[0439]

[0429] In certain embodiments, there is provided a pharmaceutical composition comprising particles of a compound of any one of Formulae (P2-I), (P4-I) to (P4-Vb), (P5-I') to (P5-Vd), and (P6-I) to (P6-IIId) described herein and at least one dispersing or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, which, when mixed with water, provides a substantially uniform suspension.

[0440]

[0430] The liquid pharmaceutical dosage form for oral administration may be an aqueous suspension selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2000. nd Ed., pp. 754-757 (2002). In addition to particles of the compound of Formula (PI), Formula (I) to Formula (LXIIIb), Formula (P2-I), Formula (P4-I) to (P4-Vb), or Formula (P5-I') to (P5-Vd), the liquid dosage form may include additives such as (a) a disintegrant; (b) a dispersant; (c) a wetting agent; (d) at least one preservative, (e) a viscosity enhancer, (f) at least one sweetener, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersion may further include a crystallization inhibitor.

[0441] The aqueous suspensions and dispersions described herein can remain homogeneous for at least 4 hours, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905). Homogeneity should be determined by consistent sampling methods for determining the homogeneity of the entire composition. In certain embodiments, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 1 minute. In certain embodiments, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 45 seconds. In still certain embodiments, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 30 seconds. In still certain embodiments, agitation is not required to maintain a homogeneous aqueous dispersion.

[0442] Examples of disintegrants for use in aqueous suspensions and dispersions include, but are not limited to, starches, for example, natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®; celluloses, for example, wood products; methyl crystalline cellulose, for example, Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable surfactants include Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose (e.g., crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose); crosslinked starches such as sodium starch glycolate; crosslinked polymers such as crospovidone; crosslinked polyvinylpyrrolidone; alginates such as alginic acid or salts of alginic acid such as sodium alginate; clays such as Veegum® HV (magnesium aluminum silicate); gums such as agar, guar, locust bean, karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; natural sponges; surfactants; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination with starch.

[0443] In certain embodiments, dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and carbohydrate-based dispersing agents, such as hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100). K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate, amorphous cellulose, etc.), magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymers (Plasdone®, e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer obtained from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ).In certain embodiments, the dispersing agent is selected from the group that does not include one of the following agents: hydrophilic polymers; electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); sodium carboxymethylcellulose; methylcellulose; hydroxyethylcellulose; hydroxypropyl methylcellulose phthalate; hydroxypropyl methylcellulose acetate stearate; amorphous cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymers with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide; or poloxamine (e.g., Tetronic 908®, also known as Poloxamine 908®).

[0444] Suitable humectants for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available Tweens®, such as Tween 20® and Tween 80® (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowaxs 3350® and 1450®, and Carbopol 934® (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphatidylcholine, and the like.

[0445] Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. As used herein, preservatives are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

[0446]

[0436] Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Plasdon® S-630, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof. The concentration of the viscosity enhancing agent will depend on the agent selected and the desired viscosity.

[0447]

[0437] Examples of sweeteners suitable for aqueous suspensions or dispersions include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus fruits, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, silamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, Orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talc, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, sweet cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. In some embodiments, the aqueous liquid dispersion may include a sweetener or flavoring agent at a concentration ranging from about 0.001% to about 1.0% by volume of the aqueous dispersion, hi some embodiments, the aqueous liquid dispersion may include a sweetener or flavoring agent at a concentration ranging from about 0.005% to about 0.5% by volume of the aqueous dispersion.Additionally, in certain embodiments, the aqueous liquid dispersion may include a sweetener or flavoring agent at a concentration ranging from about 0.01% to about 1.0% by volume of the aqueous dispersion.

[0448] In addition to the additives listed above, the liquid formulation may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers. Exemplary emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, cholesterol esters, taurocholic acid, phosphatidylcholine, oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, or mixtures of these substances.

[0449] In certain embodiments, the pharmaceutical compositions described herein may be self-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase, usually in the form of droplets, in another form. Generally, emulsions are created by vigorous mechanical dispersion. In contrast to emulsions or microemulsions, SEDDS spontaneously form emulsions when added to excess water without any external mechanical dispersion or agitation. The advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. Furthermore, water or an aqueous phase can be added immediately before administration, thereby ensuring the stability of unstable or hydrophobic active ingredients. Therefore, SEDDS provide an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS may provide improved bioavailability of hydrophobic active ingredients. Methods for producing self-emulsifying dosage forms are known in the art and include, but are not limited to, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, each of which is expressly incorporated by reference.

[0450]

[0440] It should be understood that there is overlap between the additives listed above that are used in the aqueous dispersions or suspensions described herein, because a given additive is often classified differently by different practitioners in the art or is commonly used for any of several different functions.Therefore, the additives listed above should be considered merely as examples and, without limitation, as examples of the types of additives that can be included in the formulations described herein.The amount of such additives can be easily determined by those skilled in the art depending on the specific properties desired.

[0451] 5.2 Intranasal formulations Intranasal formulations are known in the art and are described, for example, in U.S. Patent Nos. 4,476,116, 5,116,817, and 6,391,452, each of which is expressly incorporated by reference. Formulations containing any one of compounds of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), prepared according to these and other techniques known in the art, are prepared as solutions in saline using benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared using suitable non-toxic, pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the art of preparing nasal dosage forms, and some of them can be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, a standard reference in the art. The selection of suitable carriers depends heavily on the exact nature of the desired nasal dosage form, e.g., solution, suspension, ointment, or gel. Nasal dosage forms generally contain a large amount of water in addition to the active ingredient. Small amounts of other ingredients, such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling agents, or buffers and other stabilizers and solubilizers, may also be present. The nasal dosage form should be isotonic with nasal secretions.

[0452] For administration by inhalation, the compounds of any one of Formulae (P2-I), (P4-I) to (P4-Vb), (P5-I') to (P5-Vd), and (P6-I) to (P6-IIId) described herein may be in the form of an aerosol, mist, or powder. The pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges, by way of example only, made of gelatin or the like, for use in an inhaler or insufflator can be formulated containing a powder mix of the compounds described herein and a suitable powder base, such as lactose or starch.

[0453] 5.3 Oral preparations Oral formulations containing any one of the compounds of Formula (P2-I), Formula (P4-I) to (P4-Vb), Formula (P5-I') to (P5-Vd), and Formula (P6-I) to (P6-IIId) can be administered using various formulations known in the art. For example, such formulations include, but are not limited to, those described in U.S. Patent Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of which is expressly incorporated by reference. Furthermore, the oral dosage forms described herein may further include a biodegradable (hydrolyzable) polymeric carrier that also serves to adhere the dosage form to the oral mucosa. The oral dosage form is designed to slowly erode over a predetermined period of time, providing delivery of any one of the compounds of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId) throughout. As will be appreciated by those skilled in the art, oral drug delivery avoids drawbacks encountered with oral drug administration, such as slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract, and / or first-pass inactivation in the liver. With regard to the biodegradable (hydrolyzable) polymeric carrier, it is understood that virtually any such carrier may be used so long as the desired drug release characteristics are not compromised, and that the carrier is compatible with any one of the compounds of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId), and any other ingredients that may be present in the oral dosage unit. Generally, the polymeric carrier comprises a hydrophilic (water-soluble and water-swellable) polymer that adheres to the moist surface of the oral mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and copolymers (co), including those known as "carbomers" (Carbopol®, available from BF Goodrich, is one such polymer). Other ingredients may also be incorporated into the oral dosage forms described herein, including, but not limited to, disintegrants, diluents, binders, lubricants, flavoring agents, coloring agents, preservatives, etc. For buccal or sublingual administration, the composition may take the form of a tablet, lozenge, or gel, which is formulated in a conventional manner.

[0454] 5.4 Transdermal preparations The transdermal formulations described herein can be administered using various devices described in the art.For example, such devices are described in but not limited to United States Patent No. 3,598,122, United States Patent No. 3,598,123, United States Patent No. 3,710,795, United States Patent No. 3,731,683, United States Patent No. 3,742,951, United States Patent No. 3,814,097, United States Patent No. 3,921,636, United States Patent No. 3,972,995, United States Patent No. 3,993,072, United States Patent No. 3,993,073, United States Patent No. 3,996,934, United States Patent No. 4,031,894, United States Patent No. 4,060,084, United States Patent No. Nos. 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801, and 6,946,144, each of which is expressly incorporated by reference in its entirety.

[0455] The transdermal dosage forms described herein may incorporate certain pharmaceutically acceptable excipients conventional in the art. In certain embodiments, the transdermal formulations described herein comprise at least three components: (1) a formulation of any one of the compounds of Formula (P2-I), Formulas (P4-I) to (P4-Vb), Formulas (P5-I') to (P5-Vd), and Formulas (P6-I) to (P6-IIId); (2) a penetration enhancer; and (3) an aqueous adjuvant. Additionally, the transdermal formulations may contain additional components, such as, but not limited to, gelling agents, cream and ointment bases. In certain embodiments, the transdermal formulations may further comprise a woven or nonwoven backing material to promote absorption and prevent removal of the transdermal formulation from the skin. In certain embodiments, the transdermal formulations described herein may maintain a saturated or supersaturated state to promote diffusion into the skin.

[0456] Formulations suitable for transdermal administration of the compounds described herein may use transdermal delivery devices and patches, and may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives. Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. Furthermore, transdermal delivery of the compounds described herein may be achieved by iontophoretic patches and the like. Furthermore, transdermal patches may provide controlled delivery of any one of the compounds of Formula (PI), Formulas (I) to (LXIIIb), Formulas (P2-I), Formulas (P4-I) to (P4-Vb), and Formulas (P5-I') to (P5-Vd). The absorption rate can be slowed by using rate-limiting membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. The absorption enhancer or carrier may include absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, a transdermal device is in the form of a bandage that includes a backing member, a reservoir containing the compound, optionally with a carrier, optionally a rate-limiting barrier for delivering the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0457] 5.5 Injectable preparations Formulations containing any one of the compounds of Formula (P2-I), Formula (P4-I) to (P4-Vb), Formula (P5-I') to (P5-Vd), and Formula (P6-I) to (P6-IIId) suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifying agents, and dispensing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars and sodium chloride. Prolonged absorption of injectable pharmaceutical forms can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[0458] For intravenous injection, the compounds described herein can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, suitable formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.

[0459] Parenteral injections may include bolus injection or continuous infusion. Preparations for injection may be provided in unit dosage form, for example, in ampoules or in multi-dose containers with added preservatives. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compound in water-soluble form. Additionally, suspensions of the active compound may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use.

[0460] 6. Preparation In certain embodiments, delivery systems for pharmaceutical compounds such as, for example, liposomes and emulsions may be used. In certain embodiments, the compositions provided herein may also include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0461] In certain embodiments, the compounds described herein may be administered topically and may be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0462]

[0452] The compounds described herein can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In suppository forms of the composition, a low-melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally combined with cocoa butter, is first melted.

[0463] 7. Examples of administration methods and treatment regimens The compounds described herein can be used in the preparation of a medicament for the inhibition of FLT3 or a homolog thereof, or for the treatment of a disease or condition that would benefit, at least in part, from the inhibition of FLT3 or a homolog thereof. Additionally, a method for treating any of the diseases or conditions described herein in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition containing at least one compound of any of Formulas (P2-I), (P4-I) to (P4-Vb), (P5-I') to (P5-Vd), and (P6-I) to (P6-IIId) described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

[0464] Compositions containing the compounds described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. It is considered well within the skill of one in the art for one to determine such therapeutically effective amounts by routine experimentation, including, but not limited to, dose escalation clinical trials.

[0465] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amount will also depend on the patient's health, weight, and the like. It is considered well within the skill of one in the art for one to determine such prophylactically effective amounts by routine experimentation (e.g., a dose escalation clinical trial). When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0466]

[0456] If the patient's condition does not improve, after a physician's judgment, administration of the compound may be administered long-term, i.e., for an extended period of time (including the patient's lifetime), to improve or otherwise control or suppress the symptoms of the patient's disease or condition.

[0467] If the patient's condition improves, after the physician's judgment, administration of the compound may be given continuously; alternatively, the dose of the administered drug may be temporarily reduced or temporarily stopped for a specified period of time (i.e., a "drug holiday"). The length of the drug holiday may vary from 2 days to 1 year (including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days). Dose reductions during drug holidays can be from 10% to 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0468]

[0458] Once improvement of the patient's condition occurs, a maintenance dose is administered as needed. Thereafter, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, to a level at which improvement of the disease, disorder, or condition is maintained. However, the patient may require intermittent treatment on a long-term basis upon recurrence of symptoms.

[0469] The amount of a given agent corresponding to such an amount will vary depending on factors such as the particular compound, the disease or condition and its severity, the attributes of the subject or host requiring treatment (e.g., body weight), and the like, but may nevertheless be routinely determined by methods known in the art according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult treatment will typically range from 0.02 to 5000 mg per day, or from about 1 to 1500 mg per day. The desired dose may conveniently be provided in a single administration or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, e.g., two, three, four or more subdoses per day.

[0470]

[0460] The pharmaceutical compositions described herein may be in unit dosage forms suitable for single administration of precise dosage amounts. In unit dosage forms, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dosages may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers may be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be provided in unit dosage forms, including, but not limited to, ampoules, or in multi-dose containers with added preservatives.

[0471]

[0461] Due to the many variables involved in any particular treatment regimen, the above ranges are only suggestive, and significant deviations from these recommendations are not uncommon. Such dosages may vary depending on many variables, including, but not limited to, the activity of the compound being used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0472] The toxicity and therapeutic efficacy of such a treatment regimen are 50 (50% lethal dose in the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD50. 50 and ED 50 Therapeutic indices can be expressed as a ratio between ED and ED. Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds preferably is such that ED is achieved with minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0473] 8. Treatment Methods

[0463] In certain embodiments, provided herein are methods for treating, ameliorating, or preventing a disease or condition in a patient in need thereof, comprising administering an amount of a compound described herein to treat, ameliorate, or prevent the disease or condition. In certain embodiments, provided herein are methods for treating, ameliorating, or preventing a disease or condition in a patient in need thereof, comprising administering an amount of a pharmaceutical composition described herein to treat, ameliorate, or prevent the disease or condition. In certain embodiments, provided herein are any of the compounds described herein for use in therapy. In certain embodiments, provided herein are any of the pharmaceutical compositions described herein for use in treating, ameliorating, or preventing a disease or condition in a patient in need thereof. In certain embodiments, provided herein are any of the pharmaceutical compositions described herein for use in treating, ameliorating, or preventing a disease or condition in a patient in need thereof. In certain embodiments, provided herein are any of the compounds described herein for use in the manufacture of a medicament for therapy. In certain embodiments, provided herein are any of the pharmaceutical compositions described herein for treatment. In certain embodiments, provided herein are any of the compounds described herein for use in the manufacture of a medicament for treating, ameliorating, or preventing a disease or condition in a patient in need thereof. In certain embodiments, provided herein are any of the pharmaceutical compositions described herein for the manufacture of a medicament for treating, ameliorating, or preventing a disease or condition in a patient in need thereof. Useful conditions and disorders are described herein.

[0474] In certain embodiments, the disease or condition is associated with impaired FLT3 function. In certain embodiments, the disease or condition is associated with unwanted FLT3 expression. In certain embodiments, the disease or condition is associated with excessive FLT3 expression. In certain embodiments, the disease or condition is associated with unwanted FLT3 levels. In certain embodiments, the disease or condition is associated with excessive FLT3 levels. In certain embodiments, the disease or condition is associated with unwanted FLT3 activity. In certain embodiments, the disease or condition is associated with excessive FLT3 activity. In certain embodiments, the disease or condition is associated with unwanted FLT3-MLL interaction. In certain embodiments, the disease or condition is treatable by inhibiting FLT3 expression. In certain embodiments, the disease or condition is treatable by inhibiting excessive FLT3 expression. In certain embodiments, the disease or condition is treatable by inhibiting FLT3 levels. In certain embodiments, a disease or condition is treatable by inhibiting excessive FLT3 levels. In certain embodiments, a disease or condition is treatable by inhibiting unwanted FLT3 activity. In certain embodiments, a disease or condition is treatable by inhibiting excessive FLT3 activity. In certain embodiments, a disease or condition is treatable by inhibiting FLT3-MLL interaction. In certain embodiments, a disease or condition is treatable by inhibiting excessive FLT3-MLL interaction.

[0475] In certain embodiments, the disease or condition is associated with a mutation in the FLT3 gene. In certain embodiments, the mutation in the FLT3 gene is an internal tandem duplication mutation (FLT3-IND). In certain embodiments, the FLT3-IND mutation is a D835 mutation. In one embodiment, the FLT3-IND mutation is D835V. In certain embodiments, the FLT3-IND mutation is D835Y. In certain embodiments, the mutation is a point mutation in the tyrosine kinase domain (FLT3-TKD). In certain embodiments, the FLT3 mutation is selected from N676K, F691L, D835H, D835V, D835Y, Y842C, and combinations thereof. In certain embodiments, the FLT3 mutation is N676K. In certain embodiments, the FLT3 mutation is F691L. In certain embodiments, the FLT3 mutation is D835H. In certain embodiments, the FLT3 mutation is D835V. In certain embodiments, the FLT3 mutation is D835Y. In certain embodiments, the FLT3 mutation is Y842C. In certain embodiments, the patient has an NPM1 mutation.

[0476]

[0466] In certain embodiments, the compounds provided herein are administered to a human.

[0477]

[0467] In certain embodiments, the compounds provided herein are administered orally.

[0478]

[0468] In certain embodiments, the disease or condition is a hematological malignancy, including but not limited to leukemia, lymphoma, or multiple myeloma. In certain embodiments, the disease or condition is a leukemia, including, but not limited to, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), prolymphocytic leukemia (PLL), acute prolymphocytic leukemia (APL), large granular lymphocytic (LGL), hairy cell leukemia (HCL), chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, or myeloproliferative disorders (MPD), mast cell lymphoma (MCC), or myelodysplastic syndromes (MDS). In certain embodiments, the disease or condition is acute myeloid leukemia (AML). In certain embodiments, the disease or condition is relapsed or refractory AML.

[0479] In certain embodiments, the disease or condition is a lymphoma, including but not limited to non-Hodgkin's lymphoma or Hodgkin's lymphoma. In certain embodiments, the disease or condition is a non-Hodgkin's lymphoma, including but not limited to B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma (FL), mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, or Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma). In certain embodiments, the disease or condition is a Hodgkin's lymphoma, including but not limited to lymphopenic Hodgkin's disease, lymphocyte-rich Hodgkin's disease, mixed cytology Hodgkin's lymphoma, nodular lymphocyte-predominant Hodgkin's disease, or nodular sclerosing Hodgkin's lymphoma.

[0480]

[0470] In certain embodiments, the disease or condition is multiple myeloma. In one embodiment, the multiple myeloma is hyperdiploid. In one embodiment, the multiple myeloma is hypodiploid.

[0481] In certain embodiments, the disease or condition is relapsed or refractory. In one embodiment, the disease or condition is relapsed or refractory acute myeloid leukemia (AML). In certain embodiments, the disease or condition is newly diagnosed. In one embodiment, the disease or condition is newly diagnosed AML.

[0482] 9. Combination therapy The FLT3 inhibitor compositions described herein may also be used in combination with other well-known therapeutic agents selected for their therapeutic value for the condition being treated. Generally, in embodiments in which the compositions described herein and combination therapies are used, the other agents need not be administered in the same pharmaceutical composition and may need to be administered by different routes due to different physical and chemical properties. Determination of the method of administration and advisability of administration, where possible in the same pharmaceutical composition, is well within the knowledge of a skilled clinician. Initial administration may be performed according to established protocols known in the art, and thereafter, dosage, method of administration, and time of administration may be adjusted by a skilled clinician based on the observed effects.

[0483] In certain instances, it may be appropriate to administer at least one FLT3 inhibitor compound described herein in combination with another therapeutic agent. By way of example only, if nausea is one of the side effects experienced by a patient administered one of the FLT3 inhibitor compounds described herein, it may be appropriate to administer an antiemetic in combination with the first therapeutic agent. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by the administration of an adjunct agent (i.e., the adjunct agent itself may provide minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein with another therapeutic agent (including a treatment regimen) that also has a therapeutic benefit. In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be simply the additive effect of the two therapeutic agents, or the patient may experience a synergistic effect.

[0484] The particular choice of compounds to be used will depend on the diagnosis and judgment of the attending physician regarding the patient's condition and the appropriate treatment protocol. Compounds may be administered concurrently (e.g., simultaneously, substantially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder, or condition, the patient's condition, and the actual choice of compounds to be used. The determination of the order of administration of each therapeutic agent in a treatment protocol, and the number of repeated administrations, is well within the knowledge of a skilled physician after evaluation of the disease being treated and the patient's condition.

[0485]

[0475] Those skilled in the art know that therapeutically effective dosages can vary when drugs are used in combination therapy. Methods for experimentally determining therapeutically effective dosages of drugs and other drugs for use in combination therapy regimens are described in the literature. For example, the use of metered administration, i.e., providing smaller doses more frequently to minimize toxic side effects, is extensively described in the literature. Combination therapy also includes periodic therapy, starting and ending at various times to aid in the clinical management of patients.

[0486] For the combination therapies described herein, the dosage of the co-administered compound will, of course, vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. Furthermore, when co-administered with one or more biologically active agents, the compounds provided herein can be administered simultaneously with the biologically active agents or sequentially. If administered sequentially, the attending physician will determine the appropriate sequence for administering the protein in combination with the biologically active agent(s).

[0487] In either case, the multiple therapeutic agents (one of which is a compound of Formula (PI), Formula (I)-(LXIIIb), Formula (P2-I), Formula (P4-I)-(P4-Vb), or Formula (P5-I')-(P5-Vd) described herein) can be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form or in multiple forms (by way of example only, as a single pill or two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneously, the timing between the multiple doses can vary from more than zero weeks to less than four weeks. Furthermore, the combination methods, compositions, and formulations are not limited to the use of only two agents; the use of multiple therapeutic combinations is also envisioned.

[0488] It is understood that the dosage regimen for treating, preventing, or ameliorating the condition for which relief is sought can be adjusted depending on various factors. These factors include the disorder from which the subject suffers, as well as the subject's age, weight, sex, diet, and medical condition. Therefore, the dosage regimen actually used may vary widely and may therefore deviate from the dosage regimen described herein.

[0489] The pharmaceutical agents constituting the combination therapy disclosed herein may be in a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents constituting the combination therapy may also be administered sequentially, where the therapeutic compounds are administered by a regimen requiring two-step administration. A two-step administration regimen may require sequential administration of the active agents or spaced-apart administration of the separate active agents. The period between multiple administration steps may range from minutes to hours, depending on the properties of each pharmaceutical agent, such as its potency, solubility, bioavailability, plasma half-life, and kinetics. Daily fluctuations in target molecule concentrations may also determine the optimal administration interval.

[0490]

[0480] Additionally, the compounds described herein can also be used in combination with procedures that may provide an additive or synergistic benefit to a patient. By way of example only, a patient is expected to derive therapeutic and / or prophylactic benefit from the methods described herein, where a pharmaceutical composition of a compound disclosed herein and / or combination with other therapies is combined with genetic testing to determine whether the individual is a carrier of a mutant gene known to be correlated with a particular disease or condition.

[0491] The compounds and combination therapies described herein can be administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound can vary. Thus, for example, the compounds can be used as prophylactics and administered continuously to a subject prone to developing a condition or disease to prevent the onset of the disease or condition. The compounds and compositions can be administered to a subject during or as soon as possible after the onset of symptoms. Administration of the compound can begin within the first 48 hours of the onset of symptoms, within the first 6 hours of the onset of symptoms, or within 3 hours of the onset of symptoms. The initial administration can be via any practical route, such as intravenous injection, bolus injection, infusion over 5 minutes to about 5 hours, pill, capsule, transdermal patch, buccal delivery, or the like, or a combination thereof. The compound should be administered as soon as practicable after the onset of the disease or condition is detected or suspected, for the period necessary to treat the disease, such as about 1 month to about 3 months. The length of treatment can vary from subject to subject, and can be determined using known criteria. For example, the compound or a formulation containing the compound can be administered over a period of at least two weeks, for about one month to about five years, or for about one month to about three years.

[0492] 10. Exemplary Therapeutic Agents for Use in Combination with FLT3 Inhibitor Compounds Other anticancer drugs that may be used in combination with the FLT3 inhibitor compounds include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamine Do;Bisantrene hydrochloride;Visnafide dimesylate;Bizelesin;Bleomycin sulfate;Brequinar sodium;Bropirimine;Busulfan;Cactinomycin;Calsterone;Caracemide;Carbetimer;Carboplatin;Carmustine;Carubicin hydrochloride;Carzelesin;Cedefingol;Chlorambucil;Ciloremycin;Cladribine;Crisnatol mesylate;Cyclophosphamide;Cytarabine;Dacarbazine;Daunorubicin hydrochloride;Decitabine;Dexormaplatin;Dezaguanine;Dezaguanine mesylate;Diaziquone;Do Xorubicin; Doxorubicin hydrochloride; Droloxifene; Droloxifene citrate; Dromostanolone propionate; Duazomycin; Edatrexate; Eflornithine hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropizine; Epirubicin hydrochloride; Elbrozole; Esorubicin hydrochloride; Estramustine; Estramustine phosphate sodium; Etanidazole; Etoposide; Etoposide phosphate; Etoprine; Fadrozole hydrochloride; Fazarabine; Fenretinide; Floxacin Lysine; Fludarabine phosphate; Fluorouracil; Flurocitabine; Foskidone; Fostrietine sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Iimofosine; Interleukin II (including recombinant interleukin II, or rlL2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-la; interferon gamma-lb; Iproplatin; Irinotecan hydrochloride;Lanreotide acetate; Letrozole; Leuprolide acetate; Liarozole hydrochloride; Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcin; Mitochromin; Mitogillin; Mitomarcin; Mitomycin; Mitospel; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Pegaspargase; Periomycin; Pentamustine; Peplomycin sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone hydrochloride; Plicamycin; Promestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pirazofurin; Ribopurin; Rogreti Mido; Safingol; Safingol hydrochloride; Semustine; Simtrazene; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Surofenur; Tallysomycin; Tecogalan sodium; Tegafur; Teloxantrone hydrochloride; Temoporfin; Teniposide; Teloxylon; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Toremifenic acid Examples of antihistamines include: threstrone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tuburozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglisinate sulfate; vinleucosine sulfate; vinorelbine tartrate; vinrocidin sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

[0493] Other anticancer agents that may be used in combination with FLT3 inhibitor compounds include 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adzelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; irreversible angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; antiandrogens, prostate cancer; antiestrogens; antineoplastons; antisense oligonucleotides; aphidicolin glycinate; apoptotic gene modulators; apoptosis regulators; apurinic acid; ar a-CDP-DL-PTBA;Arginine deaminase;Asulaculin;Atamestane;Atrimustine;Axinastatin 1;Axinastatin 2;Axinastatin 3;Azasetron;Azatoxin;Azatyrosine;Baccatin III derivatives;Balanol;Batimastat;BCR / ABL antagonists;Benzochlorins;Benzoylstaurosporine;β-Lactam derivatives;β-Aretin;Betaclamycin B;Betulinic acid;bFGF inhibitors;Bicalutamide;Bisantrene;Bisaziridinylspermine;Bisnafide;Bistraten A;Bizelesin;Brefurate;Bropirimine;Budotitanium;Buthionine sulfoximine;Calcpotriol;Calphostin C;Camptothecin derivatives;Canarypox IL-2;Capecitabine;Carboxamido-amino-triazole;Carboxamido-aminotriazole;CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; irreversible casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorln; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analogs; conagenin; clambecidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;Cyclopentasiloxane; Cycloplatin; Sipemycin; Cytarabine ocphosphate; Cytolytic factors; Cytostatin; Dacliximab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexphosphamide; Dexrazoxane; Dexverapamil; Diaziquone; Didemnin B; Didox; Diethylnorspermine; Dihydro-5-azacytidine; 9-dioxamycin; Diphenylspiromustine; Docosanol; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; Duocarmycin SA; Eb Selenium;Ecomustine;Edelfosine;Edrecolomab;Eflornithine;Elemene;Emiteflu;Epirubicin;Epristeride;Estramustine analogues;Estrogen agonists;Estrogen antagonists;Etanidazole;Etoposide phosphate;Exemestane;Fadrozole;Fazarabine;Fenretinide;Filgrastim;Finasteride;Flavopiridol;Flezelastine;Fluasterone;Fludarabine;Fluorodaunornithine hydrochloride;Forfenimex;Formestane;Fostriesine;Fotemustine;Gadolinium tetrachloride Sapphyrin; Gallium nitrate; Galocitabine; Ganirelix; Irreversible gelatinase inhibitors; Gemcitabine; Irreversible glutathione inhibitors; Hepsulfam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Idramanton; Ilmofosine; Ilomastat; Imidazoacridone; Imiquimod; Immunostimulating peptides; Insulin-like growth factor-1 receptor inhibitors; Interferon agonists; Interferons; Interleukins; Iobenguane; Iododoxorubicin; Ipomeanol, 4-; Ilopract; Irsogladine; Isobengazole; Isohomohalichondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreotide; Leinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprolide + estrogen + progesterone; Leuprorelin; Levamisole; Liarozole; Linear polyamine analogs; Lipophilic disaccharide peptides; Lipophilic platinum compounds; Lysocrinamide 7; Lobaplatin; Lombricin; Lometrexol;Lonidamine; losoxantrone; lovastatin; loxoribine; raltotecan; lutetium texaphyrin; lisofylline; lytic peptides; maytansine; mannostatin A; marimastat; massoprocol; maspin; irreversible matrilysin inhibitors; irreversible matrix metalloproteinase inhibitors; menogaril; mervalone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; millimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitona Fido; myotoxin fibroblast growth factor-saporin; mitoxantrone; mofalotene; molgramostim; monoclonal antibodies, human chorionic gonadotropin; monophosphoryl lipid A + mycobacterial cell wall sk; mopidamol; multidrug resistance gene inhibitors; multiple tumor suppressor 1-based therapy; mustard anticancer drugs; mycaperoxide; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagressip; naloxone + pentazocine; napavine; naphterpine; nartograstim; nedapra cin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidants; nitrulline; O6-benzylguanine; octreotide; oxenon; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; ormaplatin; osateron; oxaliplatin; oxaunomycin; paralaumine; palmitoylrhizoxin; pamidronate; panaxytriol; panomyphen; parabactin; pazelliptin; pegaspargase ;Perdecine;Pentosan polysulfate sodium;Pentostatin;Pentrozole;Perflubron;Perfosfamide;Perillyl alcohol;Phenazinomycin;Phenyl acetate;Irreversible phosphatase inhibitors;Picibanil;Pilocarpine hydrochloride;Pirarubicin;Piritrexim;Prasetin A;Prasetin B;Plasminogen activator inhibitors;Platinum complexes;Platinum compounds;Platinum-triamine complexes;Porfimer sodium;Porfiromycin;Prednisone;Propylbis-acridone;Prostaglandin J2;Irreversible proteasome inhibitors;Protein A-based immunomodulators; protein kinase C inhibitors; protein kinase C irreversible inhibitors, microalgae; protein tyrosine phosphatase irreversible inhibitors; purpurins; pyrazoloacridines; pyridoxylated hemoglobin polyoxyethylene conjugates; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase irreversible inhibitors; ras irreversible inhibitors; ras-GAP inhibitors; demethylated leteriptin; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukin; romurtide; roquinimex; rubiginone B1; ruboxil; safingol; saintpin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetic drugs; semustine; senescence-derived inhibitor 1; sense oligonucleotides; irreversible inhibitors of signal transduction; signal transduction modulators; single-chain antigen-binding proteins; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; sorberol; somatomedin-binding proteins; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitors; irreversible inhibitors of stem cell division; stipiamide; irreversible inhibitors of stromelysin; sulfinosine; superactive vasoactive intestinal peptide antagonists; sulagist; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide ;Tauromustine;Tazarotene;Tecogalan sodium;Tegafur;Terlapyrylium;Telomerase irreversible inhibitors;Temoporfin;Temozolomide;Teniposide;Tetrachlorodecaoxide;Tetrazomine;Taliblastine;Thiocoraline;Thrombopoietin;Thrombopoietin mimetics;Thymalfasin;Thymopoietin receptor agonists;Thymotrin;Thyroid-stimulating hormone;Tin ethyl etiopurpurin;Tirapazamine;Titanocene dichloride;Topsentin;Toremifene;Totipotent stem cell factor;Irreversible translation inhibitors;Tretinoin;Triacetyluridine;Triciribine;Trimetrexate;Triptorelin;Tropisetron;Turosteride;Irreversible tyrosine kinase inhibitors;Tyrphostin;These include irreversible inhibitors of UBC; ubenimex; urogenital sinus-derived growth inhibitor; urokinase receptor antagonists; vapreotide; variolin B; vector-based, red blood cell gene therapy; veraresol; veramine; verudin; verteporfin; vinorelbine; vinxartin; vitaxin; vorozole; zanoteron; zeniplatin; zilascorub; and zinostatin stimalamer.

[0494]

[0484] Still other anticancer agents that can be used in combination with FLT3 inhibitor compounds include alkylating agents, antimetabolites, natural products, or hormones, such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, etc.), or triazenes (e.g., dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0495]

[0485] Still other anti-cancer agents that may be used in combination with the FLT3 inhibitor compounds described herein include menin inhibitors.

[0496]

[0486] Anti-cancer agents that may be used in combination with the FLT3 inhibitor compounds described herein include WDR5 inhibitors.

[0497]

[0487] Anti-cancer agents that may be used in combination with the FLT3 inhibitor compounds described herein include KRAS inhibitors.

[0498]

[0488] Still other anti-cancer agents that can be used in combination with the FLT3 inhibitor compounds described herein include MEK inhibitors. In one embodiment, the MEK inhibitor is trametinib.

[0499]

[0489] Still other anticancer agents that can be used in combination with the FLT3 inhibitor compounds described herein include BCL2 inhibitors. In one embodiment, the BCL2 inhibitor is venetoclax.

[0500]

[0490] Examples of natural products that are effective in combination with the FLT3 inhibitor compounds described herein include, but are not limited to, vinca alkaloids (e.g., vinblastine, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).

[0501] Examples of alkylating agents that may be used in combination with the FLT3 inhibitor compounds described herein include, but are not limited to, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (e.g., dacarbazine). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0502]

[0492] Examples of hormones and antagonists effective in combination with the FLT3 inhibitor compounds described herein include, but are not limited to, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), and gonadotropin-releasing hormone analogs (e.g., leuprolide). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide).

[0503] Examples of anti-cancer agents that act by arresting cells in the G2-M phase by stabilized microtubules and that may be used in combination with the FLT3 inhibitor compounds described herein include, but are not limited to, the following marketed and investigational agents: elbrozole (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mibobulin isethionate (also known as CI-980), vincristine, NSC-639829, discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altrilutins (such as altriltin A and altriltin C), spongistatins (such as spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), epothilones (epothilone A, epothilone B, epothilone C (also known as desoxyepothilone A or dEpoA), epothilone D (also known as KOS-862, dEpoB, and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone AN-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as desoxyepothilone F and dEpoF), 26-fluoroepothilone, etc.), auristatin PE (also known as NSC-654663), sobridotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), (Pharmacia), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A), bitilebumid, tublysin A, canadensol, centaureydin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16(Kansas StateUniversity), oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), physianolide B, laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, inanosin (also known as NSC-698666), 3-lAABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), eleutherobin (such as desmethyleleutherobin, desacetyleleutherobin, isoeluterobin A, and Z-eleutherobin), caribeoside, caribeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahistine (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (AstaMedica), myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (SPA-110, also known as trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resbellastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0504]

[0494] The FLT3 inhibitors described herein may also be administered in combination with other FLT3 inhibitors, including, but not limited to, sorafenib, midostaurin, lestaurtinib, sunitinib, tandutinib, gilteritinib, crenolanib, quizartinib, FF-10101, and HM43239.

[0505] 11. Kits / Products

[0495] Kits and articles of manufacture are also described herein for use in the therapeutic applications described herein. Such kits may include a carrier, package, or container partitioned to accommodate one or more containers, such as vials, tubes, etc., each of which contains one of the separate elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials, such as glass or plastic.

[0506] The products provided herein include packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging suitable for the selected formulation and the intended mode of administration and treatment. A wide variety of formulations of the compounds and compositions provided herein are contemplated as various treatments for any disease, disorder, or condition that would benefit from FLT3 inhibition or in which FLT3 is a mediator or contributing factor to the symptoms or causation.

[0507] For example, a container can contain one or more compounds described herein, optionally in a composition or in combination with another agent disclosed herein. The container optionally has a sterile access port (e.g., the container can be an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally contain a compound with an identifying description or label or instructions for its use in the methods described herein.

[0508]

[0498] The kits typically include one or more additional containers, each containing one or more of a variety of materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; labels for carriers, packages, containers, vials, and / or tubes that list the contents and / or instructions for use, and inserts containing instructions for use. A set of instructions is also typically included.

[0509]

[0499] A label can be on or associated with a container. A label can be on a container if letters, numbers, or other indicia forming the label are affixed to, molded into, or engraved into the container itself; a label can be associated with a container if the label is present in a receptacle or carrier that also holds the container, for example, as a package insert. A label can be used to indicate that the contents are to be used for a particular therapeutic application. A label can also indicate instructions for using the contents, such as in the methods described herein.

[0510] In certain embodiments, pharmaceutical compositions may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing a compound provided herein. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for administration to humans or animals. Such notice may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved package insert. Compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [Example]

[0511] Example

[0501] The following specific and non-limiting examples should be construed as merely illustrative and in no way limit the present disclosure. Without further elaboration, it is believed that one skilled in the art can utilize the present disclosure to its fullest extent based on the description herein. All publications cited herein are incorporated by reference in their entirety. When a URL or other such identifier or address is mentioned, it is understood that such identifiers may change and particular information on the Internet may appear and disappear, but that equivalent information may be found by an Internet search. Reference thereto acknowledges the availability and public dissemination of such information.

[0512]

[0502] In the examples below, as well as throughout this application, the following abbreviations have the following meanings: If not defined, terms have their generally accepted meanings.

[0513] [Table 15]

[0514] [Table 16]

[0515] General synthetic scheme I [ka] In the formula, L 3 , R 1 , R 4 , R 5 , and R 7 as described herein.

[0516] Synthesis of intermediates Intermediate 6 tert-Butyl (S)-(1-((3-((3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino)-5-methoxyphenethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate Step 1: tert-butyl (3-amino-5-methoxyphenethyl)carbamate [ka] To a solution of Ni (723.77 mg, 12.33 mmol, 1 equiv) in THF (50 mL) at 25° C. was added 2-(3-amino-5-methoxyphenyl)acetonitrile (2 g, 12.33 mmol, 1 equiv), (Boc)O (2.69 g, 12.33 mmol, 2.83 mL, 1 equiv), and DIPEA (3.19 g, 24.66 mmol, 4.30 mL, 2 equiv). The mixture was stirred at 25° C. under 50 psi of H for 2 h. TLC showed that one major new spot with high polarity was detected. The crude mixture was concentrated under reduced pressure. The crude product was purified by chromatography on silica thiol gel (petroleum ether / EtOAc=3 / 1) to give tert-butyl (3-amino-5-methoxyphenethyl)carbamate (1.3 g, 4.88 mmol, 39.58% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=6.81(br t,J=5.4Hz, 1H), 6.00-5.96(m,2H), 5.92(s,1H), 4.98(s,2H), 3.63(s,3H), 3.11-3.01(m,2H), 2.49-2.45(m,2H), 1.38(s,9H).

[0517] Step 2: tert-butyl (3-((3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino)-5-methoxyphenethyl)carbamate [ka] To a solution of tert-butyl (3-amino-5-methoxyphenethyl)carbamate (1.65 g, 7.51 mmol, 1 equiv.), 3,5-dichloro-6-ethylpyrazine-2-carboxamide (2 g, 7.51 mmol, 1 equiv.) in 872-50-4 (5 mL) was added DIPEA (19.41 g, 150.19 mmol, 26.16 mL, 20 equiv.). The mixture was stirred at 140° C. under N for 24 hours. LCMS showed the reaction was complete. The reaction was poured into water (30 mL) and EtOAc (20 mL) was added. * The organic layers were combined and extracted with water (50 mL * 2), washed with saturated brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was purified by chromatography on silica thiol gel (petroleum ether / ethyl acetate / dichloromethane=2 / 1 / 1) to give tert-butyl (3-((3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino)-5-methoxyphenethyl)carbamate (1.93 g, 4.01 mmol, 53.40% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ=11.27(s,1H), 8.33(s,1H), 8.11(s,1H), 7.42(s,1H), 6.92(br t,J=5.3Hz, 1H), 6.86(s,1H), 6.54(s,1H), 3.81(s,3H), 3.21(q,J=6.6Hz, 2H), 3.30- 3.26(m,2H), 2.81-2.79(m,2H)2.50-2.48(m,2H), 1.42(s,9H), 1.32(t,J=7.5Hz, 4H). LC-MS(ES+, m / z):351.4[(M+H) + ];Rt=0.824 minutes.

[0518] Step 3: 3-((3-(2-aminoethyl)-5-methoxyphenyl)amino)-5-chloro-6-ethylpyrazine-2-carboxamide [ka] To a solution of tert-butyl (3-((3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino)-5-methoxyphenethyl)carbamate (1.93 g, 3.43 mmol, 80% purity, 1 equiv.) in HCl / EtOAc (100 mL). The mixture was stirred at 25° C. for 2 h. LCMS showed the reaction was complete. The crude mixture was worked up by filtration. The crude product was purified by recrystallization from EtOAc (20 mL) at 25° C. to give 3-((3-(2-aminoethyl)-5-methoxyphenyl)amino)-5-chloro-6-ethylpyrazine-2-carboxamide (1.3 g, 3.30 mmol, 96.11% yield, HCl) as a yellow solid. LC-MS (ES+, m / z): 350.1 [(M+H) + ];Rt=0.698 minutes. Note: HCl / EtOAc (4M): HCl was bubbled into the solution EtOAc for 0.5 h at 0° C. The solution was then weighed to give HCl / EtOAc (4M).

[0519] Step 4: tert-butyl (S)-(1-((3-((3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino)-5-methoxyphenethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate [ka] To a solution of 3-((3-(2-aminoethyl)-5-methoxyphenyl)amino)-5-chloro-6-ethylpyrazine-2-carboxamide (1.3 g, 3.65 mmol, 98.2% purity, 1 equiv), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (1.11 g, 5.47 mmol, 1.5 equiv) in DMF (10 mL) was added BOP (1.54 g, 5.47 mmol, 1.5 equiv), DIPEA (3.00 g, 36.49 mmol, 2.91 mL, 10 equiv). The mixture was stirred at 25° C. under N for 10 h. LCMS showed the reaction was complete. The crude product was purified by chromatography on silica thiol gel (petroleum ether / EtOAc=1 / 2) to give tert-butyl (S)-(1-((3-((3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino)-5-methoxyphenethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (1.84 g, 2.48 mmol, 67.85% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ=11.22(s,1H), 8.28(s,1H), 8.06(s,1H), 7.81(br s,1H), 7.34(s,1H), 6.85(s,1H), 6.50(s,1H), 4.55-4.52(m,1H), 3.76( s,3H), 3.30-3.24(m,2H), 2.90-2.78(m,2H), 2.74-2.66(m,5H), 1.36(br s,9H), 1.28-1.11(m,6H). LC-MS(ES+, m / z):435.2[(M+H) + ];Rt=0.884 min;HRMS:435.1911.

[0520] Intermediate 7 tert-Butyl (S)-(1-((3-((3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino)phenethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate Step 1: tert-butyl (3-((3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino)phenethyl)carbamate [ka] To a solution of tert-butyl (3-aminophenethyl)carbamate (2.25 g, 9.52 mmol, 1 equiv.) 3,5-dichloro-6-ethylpyrazine-2-carboxamide (2.10 g, 9.52 mmol, 1 equiv.) in dioxane (20 mL) at 25° C. was added DIPEA (12.31 g, 95.21 mmol, 16.58 mL, 10 equiv.). The mixture was stirred at 130° C. for 10 h. LCMS showed the reaction was complete. The mixture was poured into water (40 mL) and EtOAc (20 mL) was added. * The organic layer was extracted with water (40 mL * 2), saturated salt water (80 mL * The crude product was purified by chromatography on silica gel (petroleum ether / EtOAc = 1:1) to give tert-butyl (3-((3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino)phenethyl)carbamate (3 g, 4.79 mmol, 50.27% yield) as a yellow oil. LC-MS (ES + , m / z): 420.2 [(M + H) + ];Rt=0.939 minutes.

[0521] Step 2: 3-((3-(2-aminoethyl)phenyl)amino)-5-chloro-6-ethylpyrazine-2-carboxamide [ka] A mixture of tert-butyl N-[2-[3-[(3-carbamoyl-6-chloro-5-ethyl-pyrazin-2-yl)amino]phenyl]ethyl]carbamate (2 g, 4.76 mmol, 1 equiv) and HCl / EtOAc (4 M, 50 mL, 41.99 equiv) was stirred at 25° C. for 2 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by chromatography on silica gel (petroleum ether / EtOAc=1:1) to give 3-((3-(2-aminoethyl)phenyl)amino)-5-chloro-6-ethylpyrazine-2-carboxamide (1.38 g, 4.32 mmol, 90.60% yield) as a yellow solid. LC-MS (ES + , m / z): 320.2 [(M + H) + ];Rt=0.671 minutes. Note: HCl / EtOAc (4M): HCl was bubbled into the solution EtOAc for 0.5 h at 0° C. The solution was then weighed to give HCl / EtOAc (4M).

[0522] Step 3: tert-butyl (S)-(1-((3-((3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino)phenethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate [ka] To a solution of 3-((3-(2-aminoethyl)phenyl)amino)-5-chloro-6-ethylpyrazine-2-carboxamide (1.38 g, 4.32 mmol, 1 equiv.), TCFH (1.82 g, 6.47 mmol, 1.5 equiv.), and NMI (3.54 g, 43.15 mmol, 10 equiv.) in DMF (15 mL) at...

Claims

1. Compound represented by formula (P6-I): 【Chemistry 1】 (In the formula, each A １ , A ２ , A ３ , and A ４ are independently -C(R ７ ) = and Each L １ and L ３ are independently substituted or unsubstituted C １ ~C ４ alkylene; and the substituents on each C 1-4 alkylene are independently one or more of halo, CN, C １～４ Alkyl, hydroxy, and C １～４ alkoxy; R １ is H, halo, CN, substituted or unsubstituted C １～６ alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and the substituents on each of the C 1-6 alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are one or more of halo, CN, C １～４ Alkyl, hydroxy, and C １～４ alkoxy; R ２ｂ are independently H or C １ ~C ４ is alkyl; R ４ is -C(O)-C(R ６ａ ) = C(R ６ｂ ) (R ６ｃ ) and R ５ is H, cycloalkyl, heterocycloalkyl, CN, halo, C １～６ Alkyl, C １～６ Alkoxy, or C １～６ alkylamino; Each of cycloalkyl, heterocycloalkyl, C 1-6 alkyl, alkoxy, and alkylamino is unsubstituted or contains one or more of halo, CN, C １～４ alkyl, hydroxy, amino, alkylamino, dialkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C １～４ substituted with alkoxy; The substituents on each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more of halo, CN, C １～４ Alkyl, hydroxy, and C １～４ alkoxy; Each R ６ａ and R ６ｂ are independently H, halo, CN, or C １～６ alkyl; or R ６ａ and R ６ｂ are joined together to form a bond; R ６ｃ is H, halo, CN, or C １～６ alkyl, wherein said C １～６ Alkyl is unsubstituted or substituted or unsubstituted amino, hydroxy, substituted or unsubstituted C １～６ and substituted with one or more groups selected from alkoxy and substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and the substituents on each of amino, alkoxy, and heterocycloalkyl are one or more of halo, CN, C １～４ Alkyl, hydroxy, and C １～４ alkoxy; Each R ７ are independently H, halo, CN, substituted or unsubstituted C １～６ alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heterocycloalkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and the substituents in each of the C 1-6 alkyl, alkoxy, and heterocycloalkyl are one or more of halo, CN, C １～４ Alkyl, hydroxy, and C １～４ alkoxy) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

2. The compound has the formula (P6-IIa) or (P6-IIb): 【Chemistry 2】 2. The compound of claim 1, wherein the compound is represented by:

3. The compound has the formula (P6-IIIa), (P6-IIIb), (P6-IIIc) or (P6-IIId): 【Transformation 3】 2. The compound of claim 1, wherein the compound is represented by:

4. The compound has formula (P6-IVa), (P6-IVb), (P6-IVc) or (P6-IVd): 【Chemistry 4】 2. The compound of claim 1, wherein the compound is represented by:

5. R ５ is Me, Et, n-Pr, i-Pr, i-Bu, cyclopropyl, N,N-dimethyl, N-ethyl-N-methyl, N-isopropylamino, N-isopropyl-N-methylamino, methoxy, ethoxy, or i-propyloxy.

6. R ６ａ , R ６ｂ , and R ６ｃ are each H, or each of R 6a and R 6b is H; and R 6c is alkyl substituted with amino, alkylamino, or dialkylamino; or R 6a and R 6b form a bond; and R 6c is Me; The compound of claim 1.

7. R ６ａ and R ６ｂ each of which is H; ６ｃ But -(CH ２ ) ｑ -heterocycloalkyl; and q is 1.

8. R ４ is -C(O)-CH=CH ２ , -C(O)-CH=CH-CH ２ -NHMe, -C(O)-CH=CH-CH ２ -NMe ２ , -C(O)-CH=CH-CH ２ -azetidin-1-yl, -C(O)-CH=CH-CH ２ -(3-fluoroazetidin-1-yl), -C(O)-CH=CH-CH ２ -(3,3-difluoroazetidin-1-yl), -C(O)-C≡CH, -C(O)-C≡C-Me, or -C(O)-C≡C-CH ２ -NMe ２ 2. The compound of claim 1, wherein:

9. 2. The compound of claim 1, wherein the compound is selected from compound IDs 137, 138, 142A, 143, 144, 156, 158-160, 162-164, 202-205, 207-209, 211, 213-228, 230-234, 236-255, 301-328, 501-513, 515, 516, 516A, 517-520, 601-607; or a pharmaceutically acceptable salt or stereoisomer thereof.

10. 2. The compound of claim 1, wherein the compound is selected from compound IDs 204, 252, 310, 509, 511, and 516A; or a pharmaceutically acceptable salt or stereoisomer thereof.

11. 2. The compound of claim 1, wherein the compound is selected from compound IDs 308, 315, 506, 507, 508, 513, 512, 513, 517, and 520; or a pharmaceutically acceptable salt or stereoisomer thereof.

12. 2. The compound of claim 1, wherein the compound is selected from compound IDs 506 and 516; or a pharmaceutically acceptable salt or stereoisomer thereof.

13. 2. The compound of claim 1, wherein the compound is Compound ID 204; or a pharmaceutically acceptable salt or stereoisomer thereof.

14. 2. The compound of claim 1, wherein the compound is compound ID516A; or a pharmaceutically acceptable salt or stereoisomer thereof.

15. 2. The compound of claim 1, wherein the compound is Compound ID 252; or a pharmaceutically acceptable salt or stereoisomer thereof.

16. 2. The compound of claim 1, wherein the compound is Compound ID 506; or a pharmaceutically acceptable salt or stereoisomer thereof.

17. 2. The compound of claim 1, wherein the compound is Compound ID 511; or a pharmaceutically acceptable salt or stereoisomer thereof.

18. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1; or a pharmaceutically acceptable stereoisomer, salt, solvate, or prodrug thereof; and a pharmaceutically acceptable excipient.

19. 20. The pharmaceutical composition of claim 18, formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration.

20. Use of a compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 18 or 19, in the manufacture of a medicament for the treatment of cancer.

21. 10. Use of a compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a medicament for the treatment of a hematological malignancy.

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