CSF1r inhibitor dendrimer conjugates and uses thereof

Abstract

Provided herein are dendrimer conjugates of Formula (I), as well as compositions comprising the same. Further provided are methods of using the dendrimer conjugates and compositions, including methods of treating a disease or disorder in a subject.

Description

CSF1R INHIBITOR DENDRIMER CONJUGATES AND USES THEREOF RELATEDAPPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application U.S.S.N.63 / 637,601, filed April 23, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Advancements in the field of nanotechnology have resulted in the creation of many new materials and devices with a vast range of applications. Nanotechnology manifests in a wide range of materials and particles, such as fullerenes and dendrimers. However, in vivo application of dendrimers is challenged by their stability and physical properties at physiological conditions and in plasma. Alternative strategies in dendrimer development could allow for more effective utilization of dendrimers in the context of therapeutic, diagnostic, and research applications. SUMMARY

[0003] Provided herein are dendrimer conjugates with improved physical properties, including aqueous solubility, which are stable in vivo. The utility of the dendrimer conjugates in compositions, methods, and kits are also disclosed herein.

[0004] In one aspect, provided herein are dendrimer conjugates of Formula (I): ,or a pharmaceutically acceptable salt thereof, wherein D is a dendrimer, Z is a linker comprising a polyethylene glycol (e.g.,, ,), R1is colony stimulating factor-1 receptor (CSF1R) inhibitor, and each of q, p, m, f, g, and n are integers as defined herein. In some embodiments, R1is 1 / 75 13870760pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580, or a derivative or analog thereof.

[0005] In some embodiments, the dendrimer conjugate of Formula (I) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0006] Also provided herein are dendrimer conjugates of the formula:, or a pharmaceutically acceptable salt thereof.

[0007] In another aspect, provided herein are compositions comprising a dendrimer conjugate as disclosed herein (e.g., of Formula (I), or otherwise provided), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient.

[0008] In a further aspect, provided herein are methods of modulating CSF1R in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a dendrimer conjugate disclosed herein, or pharmaceutically acceptable salt thereof, or composition disclosed herein. 2 / 75 13870760

[0009] In an additional aspect, provided herein are methods of modulating CSF1R in a subject, the method comprising administering to the subject an effective amount of a dendrimer conjugate disclosed herein, or pharmaceutically acceptable salt thereof, or composition disclosed herein.

[0010] In another aspect, provided herein are methods of treating a disease or disorder in a subject, the method comprising administering to the subject an effective amount of a dendrimer conjugate disclosed herein, or pharmaceutically acceptable salt thereof, or composition disclosed herein. In some embodiments, the disease or disorder is a neurological disorder, an inflammatory disease, an autoimmune disorder, a cancer, a central nervous system disease, a painful condition, a bone disease, or a tumor.

[0011] In a further aspect, provided herein are kits comprising: a dendrimer conjugate described herein, or a pharmaceutically acceptable salt thereof, or a composition described herein; and instructions for using the dendrimer conjugate, or pharmaceutically acceptable salt thereof, or the composition. BRIEFDESCRIPTION OF THEDRAWINGS

[0012] FIG.1 shows release of thiol-dasatinib with 10 mM glutathione (GSH).

[0013] FIGs.2A-2C show D4-45113 stability at 37 °C in mouse plasma (FIG.2A), rat plasma (FIG.2B), and human plasma (FIG.2C).

[0014] FIG.3 shows clinical scores for sham control (no EAE induction) and either daily ip vehicle or D4-45113 administered from day 14 to 28.

[0015] FIGs.4A-4B show first generation CSF1 RTKi small molecule linkers and HDTs (D4 = generation 4 PAMAM hydroxyl dendrimers; D6 = generation 6 PAMAM hydroxyl dendrimers).

[0016] FIGs.5A-5D show dasatinib linker and HDT compounds (D4 = generation 4 PAMAM hydroxyl dendrimers; D6 = generation 6 PAMAM hydroxyl dendrimers).

[0017] FIGs.6A-6F show pexidartinib (or pexidartinib2) linker and HDT compounds (D4 = generation 4 PAMAM hydroxyl dendrimers; D6 = generation 6 PAMAM hydroxyl dendrimers).

[0018] FIGs.7A-7C show third generation HDTs with CSF1 RTKi (D4 = generation 4 PAMAM hydroxyl dendrimers; D6 = generation 6 PAMAM hydroxyl dendrimers).

[0019] FIGs.8A-8B show macrophage phenotype switch. Peripheral blood mononuclear cells (PBMCs) differentiated into M1 (FIG.8A) or M2 (FIG.8B) macrophages, which were 3 / 75 13870760treated with 0.5, 5 and 20 µM of ASH41020, dasatinib or masitinib for 24 hours then analyzed by FACS.

[0020] FIG.9 shows body weights in EAE mouse model. EAE-induced mice were treated with ASH41020 at 20, 60 or 200 mg / kg daily (IP); dasatinib at 30 mg / kg daily (PO), masitinib at 50 mg / kg daily (PO); Fingolimod at 3 mg / kg daily (PO) for 14 days after mean clinical scores reached 1.5 on day 11. Body weights were measured starting from day 0. n=15 / group. Data are mean + / - SEM, analyzed by 2-way ANOVA, treatment vs vehicle, ** p<0.01, **** p<0.0001.

[0021] FIGs.10A-10C show effects of ASH41020 on EAE clinical scores. EAE-induced mice were treated for 14 days after mean clinical scores reached 1.5 on Day 11. FIG.10A shows EAE scores for ASH41020 daily at 20, 60 or 200 mg / kg; dasatinib at 30 mg / kg and masitinib at 50 mg / kg daily; Fingolimod at 3 mg / kg daily. FIG.10B shows cumulative scores over the course of 14 days of treatment. FIG.10C shows peak scores over the course of 14 days of treatment. n=15 / group; Data are mean + / - SEM, analyzed by 2-way ANOVA or two- tailed t-test, treatment vs vehicle, *p<0.05, **p<0.01, ***p<0.001, ****<0.0001.

[0022] FIGs.11A-11B show effects of ASH41020 on macrophage phenotypes in the EAE model. After 14 days of ASH41020 treatment, spinal cords were collected for FACS analysis. FIG.11A shows the percentage of CD86+CD80+ M1 macrophages. FIG.11B shows the percentage of CD206+CD163+ M2 macrophages. n=15 / group. Data are mean + / -SEM, analyzed by One-way ANOVA, treatment vs vehicle.

[0023] FIGs.12A-12C show results of cell proliferation in mouse microglial BV2 cells. BV2 cells were plated in serum-free DMEM supplemented with 100 ng / mL mouse MCSF, treated with H74DS3M8 ranging from 5 nM to 10 uM, and placed in an Incucyte S3 for 60 hours with well scanning every 2 hours. FIG.12A shows brightfield images obtained in one of four field-views per well at 10x magnification, 52 hours post-plating. FIG.12B shows confluence values plotted against time. FIG.12C shows IC50 was obtained by plotting confluence at each drug concentration and fitting the data to log(inhibitor)-vs- response (4-parameter fit) using Graphpad Prism. Data represents the average ± SD confluence from 3 wells for each drug concentration. IC50 = 343 ± 64 nM (n=2).

[0024] FIGS.13A and 13B show results of macrophage phenotype switch assay. M0 macrophages from freshly isolated human PBMCs were differentiated into M1 macrophages using GMCSF polarizing agent or M2 macrophages using MCSF polarizing agent. M1 or M2 cells were treated with 2 μM of H74DS3M8 or dasatinib for 24 hours and analyzed by flow cytometry. Live cells were gated for CD14+ then CD86+ cells for M1 phenotype, or CD163+ 4 / 75 13870760CD206+ cells for M2 phenotype. FIG.13A shows the effect on M1 and M2 cells by H74DS3M8 (H74) or Dasatinib (Das) in the M1 polarized environment. FIG.13B shows the effect on M1 and M2 cells by H74DS3M8 (H74) or Dasatinib (Das) in the M2 polarized environment. n=2. Data are mean + / - SEM, 2-way ANOVA treatment vs vehicle, ***p<0.001, ****p<0.0001.

[0025] FIGs.14A and 14B show the efficacy of oral H74DS3M8 in an EAE model. Eight- week-old female C57Bl / 6 mice were injected subcutaneously (s.c.) with MOG35-55 peptide emulsified in the Complete Freund’s Adjuvant (CFA) containing 6 mg / mL H37R (Mycobacterium tuberculosis) on day 0 at Redoxis, Sweden. Booster injections of pertussis toxin (PTX) were administered on day 0 (2hr post-MOG immunization) and again on day 2. On day 11, treatment was initiated with vehicle (daily p.o.), 3 mg / kg fingolimod (daily p.o.) or 20 mg / kg H74DS3M8 (twice per week p.o.) and continued throughout the study. FIG.14A shows disease severity scores were evaluated from day 5 until the end of the study. Treatment started on Day 11. FIG.14B shows area under the curve (AUC) of disease scores from study day 12 to day 25. Data are presented as mean + / - SEM and analyzed using a mixed-effects model (A) and one-way ANOVA (B). *p<0.05, **p<0.01, ****<0.0001.

[0026] FIG.15 shows H74DS3M8 effect on inhibiting cell proliferation. BV2 cells were grown in DMEM supplemented with 100 ng / ml murine MCSF and 1% Penicillin- Streptomycin and treated with varying concentrations of H74DS3M8 for 52 hours in serum- free DMEM. Cells were washed with warm PBS, fixed with 4% paraformaldehyde, permeabilized in PBS-T (Triton-100) buffer and stained with a rabbit anti-Ki67 antibody. A secondary anti-rabbit antibody conjugated to Alexa Fluor 647 was used to detect Ki67 staining, Hoechst-33742 was used to stain the nuclei, and cells were imaged using the 10x objective on a Cytation5 plate imager. Plotted is the percentage of Hoechst-positive BV2 nuclei that were positive for Ki67. *p<0.05, ***<0.001 by ANOVA with Holm-Sidak's multiple comparison test. DEFINITIONS

[0027] Definitions of specific terms are described in more detail below. These and other exemplary terms are described in more detail in the Detailed Description, Examples, and Claims.

[0028] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless 5 / 75 13870760otherwise provided. For example “C1-6alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl.

[0029] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and, in some embodiments, are saturated or contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is 6 / 75 13870760on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0030] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0031] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and, in some embodiments, is saturated or contains one or more carbon-carbon double or triple bonds. In some embodiments, heterocyclyl polycyclic ring systems include one or more heteroatoms in one or both rings. 7 / 75 13870760“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7- membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0032] In some embodiments, a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0033] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5- dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- 8 / 75 13870760membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetra- hydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6- dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0034] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl. 9 / 75 13870760

[0035] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, in some embodiments the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, heteroaryl polycyclic ring systems include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment is on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6- membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. “Heterobiaryl” refers to an instance of two aryl rings being fused together, wherein at least one of the aryl rings is heteroaryl.

[0036] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms 10 / 75 13870760provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5- 6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0037] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0038] The term “unsaturated bond” refers to a double or triple bond.

[0039] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0040] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds. 11 / 75 13870760

[0041] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0042] The term “dendrimer” refers to a compound having a molecular architecture with an interior core and layers (or “generations”) of repeating units which are attached to and extend from this interior core, each layer having one or more branching points, and the outermost generation having terminal functional groups. In some embodiments, terminal functional groups of a dendrimer include one or more hydroxyl groups, one or more amine groups, and / or one or more carboxyl groups. In some embodiments, the terminal functional groups of a dendrimer provide attachment sites through which the at least one agent is conjugated to form the dendrimer conjugate. In some embodiments, the at least one agent is conjugated to the dendrimer through an ether bond, an amide bond, or an ester bond formed by conjugation to a terminal functional group of the dendrimer. In some embodiments, the at least one agent is conjugated to the dendrimer through an ether bond or an amide bond. In some embodiments, the at least one agent is conjugated to the dendrimer through an ether bond.

[0043] The term “dendrimer conjugate” refers to a compound, specifically, a dendrimer that comprises at least one agent, such as an active agent, imaging agent, or therapeutic agent described herein. In some embodiments, the dendrimer is conjugated to the at least one agent through a covalent or non-covalent linkage.

[0044] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, 12 / 75 13870760camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0045] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. 13 / 75 13870760Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0046] The terms “CSF1R” and “colony stimulating factor 1 receptor” are used herein to refer to a cell-surface protein encoded by the human CSF1R gene. CSF1R is a tyrosine kinase transmembrane receptor and member of the CSF1 / PDGF receptor family of tyrosine-protein kinases. CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R signaling is involved in the survival, proliferation, and differentiation of many myeloid cells. CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.

[0047] The term “modulate,” “modulating,” “modulation,” or “modulator” refers to the ability of a compound to reduce / increase, slow / speed up, halt / initiate, inhibit / stimulate, or prevent / cause activity of a particular biological target (e.g., CSF1R) in a cell relative to vehicle.

[0048] The term “inhibition,” “inhibiting,” “inhibit,” or “inhibitor” refer to the ability of a compound to reduce, slow, halt or prevent activity of a particular biological target (e.g., CSF1R) in a cell relative to vehicle. As used herein the term “inhibit” or “inhibition” in the context of, for example, CSF1R, refers to a reduction in the activity of CSF1R. In some embodiments, the term refers to a reduction of the level of activity, e.g., CSF1R activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of activity. In some embodiments, the term refers to a reduction of the level of activity, e.g., CSF1R activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of activity.

[0049] The terms “composition” and “formulation” are used interchangeably.

[0050] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In 14 / 75 13870760certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0051] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0052] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound, particle, and / or composition of the present disclosure is delivered. A target tissue may be an abnormal or unhealthy tissue, which may need to be treated. A target tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the target tissue is the liver. In certain embodiments, the target tissue is the lung. A “non-target tissue” is any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is not a target tissue.

[0053] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0054] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in 15 / 75 13870760the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0055] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0056] In certain embodiments, the effective amount is an amount effective for inhibiting the activity of CSF1R by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of CSF1R by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of CSF1R by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0057] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to 16 / 75 13870760about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0058] In certain embodiments, the compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0059] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0060] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting CSF1R. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease or disorder (e.g., a neurological disorder, an inflammatory disease, an autoimmune disorder, a cancer, a central nervous system disease, a painful condition, a bone disease, or a tumor). In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting CSF1R and treating a disease or disorder (e.g., a neurological disorder, an inflammatory disease, an autoimmune disorder, a cancer, a central nervous system disease, a painful condition, a bone disease, or a tumor).

[0061] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0062] The terms “neurological disease” and “neurological disorder” are used interchangeably herein and refer to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous 17 / 75 13870760system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease.

[0063] Examples of neurological diseases and disorders include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; bbrain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie- Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine- Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; 18 / 75 13870760epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert- Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus- Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and 19 / 75 13870760neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0064] Exemplary central nervous system (CNS) diseases and disorders include, but are not limited to, neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, drug addiction, transient ischemic attack (TIA), subarachnoid hemorrhage, subdural hemorrhage and hematoma, extradural hemorrhage, meningitis, encephalitis, polio, epidural abscess, brain injury, Bell’s palsy, cervical spondylosis, carpal tunnel syndrome, brain tumor, spinal cord tumor, peripheral neuropathy, Charcot-Marie-Tooth disease type 1, Guillain-Barré syndrome, dizziness, neuralgia, Parkinson disease, multiple sclerosis, Huntington chorea. In certain embodiments, the CNS disorder is neurotoxicity and / or neurotrauma, e.g., for example, as a result of acute neuronal injury (e.g., traumatic brain injury (TBI), stroke, epilepsy) or a chronic neurodegenerative disorder (e.g., multiple sclerosis, Parkinson’s disease, 20 / 75 13870760Huntington’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease). In certain embodiments, the CNS disorder is a movement disorder, e.g., basal ganglia disorders, such as, for example, Parkinson’s disease, levodopa-induced dyskinesia, Huntington’s disease, Gilles de Ia Tourette’s syndrome, tardive dyskinesia, or dystonia.

[0065] The terms “inflammatory disease” and “inflammatory condition” are used interchangeably herein and refer to a disease or condition caused by, resulting from, or resulting in inflammation. Inflammatory diseases and conditions include those diseases, disorders or conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and / or loss of function (functio laesa, which can be partial or complete, temporary or permanent. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), 21 / 75 13870760inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus- graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0066] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate 22 / 75 13870760colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener’s granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. The compounds disclosed herein may also be useful in treating inflammation associated with cancer.

[0067] The terms “autoimmune disease” and “autoimmune disorder” are used interchangeably herein and refer to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, , psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardiomyopathy. 23 / 75 13870760

[0068] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non- Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, 24 / 75 13870760peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0069] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated 25 / 75 13870760with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0070] A “painful condition” includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post–operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre–operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre–term labor, pain associated with withdrawl symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter’s arthritis), lumbosacral pain, musculo– skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, 26 / 75 13870760dental / maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g. nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[0071] In certain embodiments, the painful condition is neuropathic pain. The term "neuropathic pain" refers to pain resulting from injury to a nerve. Neuropathic pain is distinguished from nociceptive pain, which is the pain caused by acute tissue injury involving small cutaneous nerves or small nerves in muscle or connective tissue. Neuropathic pain typically is long-lasting or chronic and often develops days or months following an initial acute tissue injury. Neuropathic pain can involve persistent, spontaneous pain as well as allodynia, which is a painful response to a stimulus that normally is not painful. Neuropathic pain also can be characterized by hyperalgesia, in which there is an accentuated response to a painful stimulus that usually is trivial, such as a pin prick. Neuropathic pain conditions can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain conditions include, but are not limited to, diabetic neuropathy (e.g., peripheral diabetic neuropathy); sciatica; non-specific lower back pain; multiple sclerosis pain; carpal tunnel syndrome, fibromyalgia; HIV-related neuropathy; neuralgia (e.g., post-herpetic neuralgia, trigeminal neuralgia); pain resulting from physical trauma (e.g., amputation; surgery, invasive medical procedures, toxins, burns, infection), pain resulting from cancer or chemotherapy (e.g., chemotherapy- induced pain such as chemotherapy- induced peripheral neuropathy), and pain resulting from an inflammatory condition (e.g., a chronic inflammatory condition). Neuropathic pain can result from a peripheral nerve disorder such as neuroma; nerve compression; nerve crush, nerve stretch or incomplete nerve transsection; mononeuropathy or polyneuropathy. Neuropathic pain can also result from a disorder such as dorsal root ganglion compression; inflammation of the spinal cord; contusion, tumor or hemisection of the spinal cord; tumors of the brainstem, thalamus or cortex; or trauma to the brainstem, thalamus or cortex.

[0072] The symptoms of neuropathic pain are heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" 27 / 75 13870760(paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia). In certain embodiments, the painful condition is non-inflammatory pain. The types of non-inflammatory pain include, without limitation, peripheral neuropathic pain (e.g., pain caused by a lesion or dysfunction in the peripheral nervous system), central pain (e.g., pain caused by a lesion or dysfunction of the central nervous system), deafferentation pain (e.g., pain due to loss of sensory input to the central nervous system), chronic nociceptive pain (e.g., certain types of cancer pain), noxious stimulus of nociceptive receptors (e.g., pain felt in response to tissue damage or impending tissue damage), phantom pain (e.g., pain felt in a part of the body that no longer exists, such as a limb that has been amputated), pain felt by psychiatric subjects (e.g., pain where no physical cause may exist), and wandering pain (e.g., wherein the pain repeatedly changes location in the body).

[0073] In certain embodiments, the painful condition is inflammatory pain. In certain embodiments, the painful condition (e.g., inflammatory pain) is associated with an inflammatory condition and / or an immune disorder.

[0074] The term “bone disease” refers to an injury, pain, or condition in the subject’s bones. Examples include, without limitation, achondroplasia, acromegaly, bone callus, bone demineralization, bone fracture, bone marrow disease, bone marrow neoplasm, dyskeratosis congenita, leukemia (e.g., hairy cell leukemia, lymphocytic leukemia, myeloid leukemia, Philadelphia chromosome-positive leukemia, plasma cell leukemia, stem cell leukemia), systemic mastocytosis, myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, myeloid sarcoma, myeloproliferative disorders, multiple myeloma, polycythemia vera, pearson marrow-pancreas syndrome, bone neoplasm, bone marrow neoplasm, Ewing sarcoma, osteochondroma, osteoclastoma, osteosarcoma, brachydactyly, Camurati- Engelmann syndrome, Craniosynostosis, Crouzon craniofacial dysostosis, dwarfism, achondroplasia, bloom syndrome, Cockayne syndrome, Ellis-van Creveld syndrome, Seckel syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, Werner syndrome, hyperostosis, osteophyte, Klippel-Trenaunay-Weber syndrome, Marfan syndrome, McCune-Albright syndrome, osteitis, osteoarthritis, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, Leri-Weill dyschondrosteosis, osteochondrosis, osteodystrophy, osteogenesis imperfecta, osteolysis, Gorham-Stout syndrome, osteomalacia, osteomyelitis, 28 / 75 13870760osteonecrosis, osteopenia, osteopetrosis, osteoporosis, osteosclerosis, otospondylomegaepiphyseal dysplasia, pachydermoperiostosis, Paget disease of bone, Polydactyly, Meckel syndrome, rickets, Rothmund-Thomson syndrome, Sotos syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, syndactyly, Apert syndrome, syndactyly type II, and Werner syndrome.

[0075] As used herein, “derivative” refers to a compound that is derived from a similar compound by a chemical reaction.

[0076] As used herein, “analog” refers to a compound having a structure similar to that of another compound, but differing from it in respect to a certain component (e.g., one or more atoms, functional groups, or substructures). For example, an analog may be a compound that can be imagined arising from another compound, if one atom or group of atoms is replaced with another atom or group of atoms. DETAILED DESCRIPTION

[0077] Among other aspects, the present disclosure provides dendrimer conjugates, compositions comprising dendrimer conjugates, and methods of using dendrimer conjugates and compositions thereof. Compounds

[0078] In one aspect, provided herein are dendrimer conjugates of Formula (0):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; q is an integer from 0-50, inclusive; p is an integer from 0-20, inclusive; m is an integer from 16-4095, inclusive;f is an integer from 1-20, inclusive; 29 / 75 13870760g is an integer from 0-20, inclusive; each instance of RZis independently, hydrogen, -CH3, -OH, or -OCH3; R1is a colony stimulating factor-1 receptor (CSF1R) inhibitor; and n is an integer from 1-20, inclusive.

[0079] In one aspect, provided herein are dendrimer conjugates of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; q is an integer from 0-50, inclusive; p is an integer from 0-20, inclusive; m is an integer from 16-4095, inclusive;f is an integer from 1-3, inclusive; g is an integer from 0-10, inclusive; R1is a colony stimulating factor-1 receptor (CSF1R) inhibitor; and n is an integer from 1-20, inclusive.

[0080] In one aspect, provided herein are dendrimer conjugates of Formula (I-A):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; q is 1; m is an integer from 16-4095, inclusive;f is an integer from 1-3, inclusive; 30 / 75 13870760g is an integer from 0-10, inclusive; R1is a colony stimulating factor-1 receptor (CSF1R) inhibitor; and p is 0 and n is 8, or p is 1 and n is 7.

[0081] In one aspect, provided herein are dendrimer conjugates of Formula (I-B):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; q is 1; m is an integer from 16-4095, inclusive;f is an integer from 1-3, inclusive; g is an integer from 0-10, inclusive; R1is a colony stimulating factor-1 receptor (CSF1R) inhibitor; and n is 8.

[0082] In one aspect, provided herein are dendrimer conjugates of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; q is an integer from 0-50, inclusive; p is an integer from 3-7, inclusive; m is an integer from 16-4095, inclusive;f is an integer from 1-20, inclusive; g is an integer from 0-20, inclusive; 31 / 75 13870760R1is a colony stimulating factor-1 receptor (CSF1R) inhibitor; and n is an integer from 1-5, inclusive.

[0083] In one aspect, provided herein are dendrimer conjugates of Formula (II-A):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; q is an integer from 0-50, inclusive; p is 3; m is an integer from 16-4095, inclusive;f is an integer from 1-3, inclusive; g is an integer from 0-10, inclusive; R1is a colony stimulating factor-1 receptor (CSF1R) inhibitor; and n is 5.

[0084] As provided herein, R1is a colony stimulating factor-1 receptor (CSF1R) inhibitor. In some embodiments, R1is pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580, or a derivative or analog thereof. In some embodiments, R1is pexidartinib, dasatinib, or PLX5622, or a derivative or analog thereof. In some embodiments, R1is pexidartinib, dasatinib, or PLX5622. In some embodiments, R1is pexidartinib. In some embodiments, R1is imatinib. In some embodiments, R1is dasatinib. In some embodiments, R1is PLX5622. In some embodiments, R1is ARRY-382. In some embodiments, R1is sotuletinib. In some embodiments, R1is edicotinib. In some embodiments, R1is Ki20227. In some embodiments, R1is GW 2580.

[0085] In certain embodiments, R1is a derivative of: pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580. In certain embodiments, R1is a derivative of: pexidartinib, dasatinib, or PLX5622. In certain embodiments, R1is a derivative of pexidartinib. In certain embodiments, R1is a derivative of imatinib. In certain embodiments, R1is a derivative of dasatinib. In certain embodiments, R1is a derivative of PLX5622.In certain embodiments, R1is a derivative of ARRY-382. In 32 / 75 13870760certain embodiments, R1is a derivative of sotuletinib. In certain embodiments, R1is a derivative of edicotinib. In certain embodiments, R1is a derivative of Ki20227. In certain embodiments, R1is a derivative of GW 2580.

[0086] In some embodiments, the derivative of: pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580, comprises Z2between Z and pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580; where Z2is a linker. Thus, in some embodiments, the compound of Formula (I) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, Z2is a linker comprising a disulfide bond (i.e., -S-S-). In certain embodiments, Z2is -S-S-CH2-CH2- or -CH2-CH2-S-S-.

[0088] In some embodiments, Z2is a linker comprising a carbonyl. In some embodiments, Z2is a linker comprising an amine. In some embodiments, Z2is -NH-CH2-C(=O)- or -C(=O)- CH2-NH-.

[0089] In some embodiments, Z2is a linker comprising two rings. In some embodiments, Z2is of the formula:, wherein Ring A and Ring B are each independently a carbocyclylene, heterocyclylene, arylene, or heteroarylene. In some embodiments, Ring A is a carbocyclylene or heterocyclylene, and Ring B is an arylene or heteroarylene. In some embodiments, Ring A is a heterocyclylene, and Ring B is a heteroarylene. In some embodiments, Ring A is piperidinylene or piperazinylene, and Ring B is pyrazolylene. In some embodiments, Z2is. 33 / 75 13870760. In some embodiments,. some embodiments, R1is 34 / 75 13870760. , ..35 / 75 13870760

[0092] In some embodiments (e.g., of Formula (0) or Formula (II)), Z is,

[0093] In some embodiments (e.g., of Formula (0) or Formula (II)), Z is,[, . In some embodiments, Z is. , . 36 / 75 13870760

[0096] In some embodiments, Z is. In some embodiments, Z isand f is 1-10, inclusive. In some embodiments, Z is. some embodiments,embodiments, Z is. In certain embodiments, Z is, and f is 1. In some embodiments, Z is, and f is 3. In some embodiments, Z is, inclusive, and g is 1-3, inclusive. In some embodiments, Z is, f is 3, and g is 3.

[0097] In some embodiments (e.g., Formula (0) and Formula (II)), f is an integer from 1-20, inclusive. In some embodiments (e.g., Formula (0) and Formula (II)), f is an integer from 1- 10, inclusive. In some embodiments, f is 10. In certain embodiments, f is 9. In some embodiments, f is 8. In some embodiments, f is 7. In some embodiments, f is 6. In some embodiments, f is 5. In some embodiments, f is 4. In some embodiments, f is 3. In some embodiments, f is 2. In some embodiments, f is 1.

[0098] As provided herein, in some embodiments (e.g., of Formula (I)), f is an integer from 1-3, inclusive. In some embodiments, f is 1. In certain embodiments, f is 2. In some embodiments, f is 3.

[0099] In some embodiments (e.g., Formula (0) and Formula (II)), g is an integer from 0-20, inclusive. As provided herein, in some embodiments (e.g., of Formula (I)), g is an integer from 0-10, inclusive. In certain embodiments, g is 1-3. In some embodiments, g is 1. In some embodiments, g is 2. In certain embodiments, g is 3.

[0100] In certain embodiments, f is 1-3, inclusive, and g is 1-3, inclusive. In some embodiments, f is 3, and g is 3. 37 / 75 13870760

[0101] In some embodiments, Z comprises RZ. In some embodiments, each instance of RZis independently, hydrogen, -CH3, -OH, or -OCH3. In some embodiments,Zis hydrogen. In some embodiments, each instance of RZis hydrogen. In certain embodiments, one instance of RZis -OH. In certain embodiments, one instance of RZis -CH3. In certain embodiments, one instance of RZis -OCH3.

[0102] As provided herein, D is a dendrimer. In some embodiments, the dendrimer, D, is a polyamidoamine (PAMAM), polypropylamine (POPAM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), or an aromatic polyether dendrimer. In some embodiments, the dendrimer, D, is a polypropylamine (POPAM) dendrimer. In some embodiments, the dendrimer, D, is a polyethylenimine dendrimer. In some embodiments, the dendrimer, D, is a polylysine dendrimer. In some embodiments, the dendrimer, D, is a polyester dendrimer. In some embodiments, the dendrimer, D, is an iptycene dendrimer. In some embodiments, the dendrimer, D, is an aliphatic poly(ether) dendrimer. In some embodiments, the dendrimer, D, is an aromatic polyether dendrimer

[0103] In some embodiments, the dendrimer, D, is a polyamidoamine (PAMAM) dendrimer. In some embodiments, a PAMAM dendrimer comprises different cores with amidoamine building blocks. In some embodiments, a PAMAM dendrimer comprises carboxylic, amine, and / or hydroxyl terminal groups of any generation including, but not limited to, generation 1, generation 2, generation 3, generation 4, generation 5, generation 6, generation 7, generation 8, generation 9, or generation 10 PAMAM dendrimers. In some embodiments, a PAMAM dendrimer comprises an ethylenediamine with amidoamine building blocks. In some embodiments, the dendrimer, D, is a generation 4, generation 5, generation 6, generation 7, or generation 8 PAMAM dendrimer. In some embodiments, the dendrimer, D, is a generation 4 or generation 6 PAMAM dendrimer. In some embodiments, the dendrimer, D, is a generation 3 PAMAM dendrimer. In certain embodiments, the dendrimer, D, is a generation 4 PAMAM dendrimer. In some embodiments, the dendrimer, D, is a generation 5 PAMAM dendrimer. In some embodiments, the dendrimer, D, is a generation 6 PAMAM dendrimer. In some embodiments, the dendrimer, D, is a generation 7 PAMAM dendrimer. In some embodiments, the dendrimer, D, is a generation 8 PAMAM dendrimer.

[0104] In some embodiments, the number of terminal sites on a dendrimer can depend on the particular dendrimeric scaffold and its generation. For example, in some embodiments, a dendrimer is based on a generation 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PAMAM dendrimeric scaffold, which have 4, 8, 16, 32, 64, 128, 256, 512, 1024, 2048, and 4096 terminal sites, respectively. However, it should be appreciated that different dendrimeric scaffolds having a 38 / 75 13870760different number of terminal sites at each generation can be used in accordance with the disclosure. In some embodiments, all terminal sites of a dendrimer comprise hydroxyl groups. In some embodiments, each terminal site of a dendrimer comprises either a hydroxyl group or an amine group. In some embodiments, each terminal site of a dendrimer conjugate comprises a hydroxyl group, an amine group, or an agent conjugated to the dendrimer through an ether or amide bond. In some embodiments, each terminal site of a dendrimer conjugate comprises either a hydroxyl group or an agent conjugated to the dendrimer through an ether bond.

[0105] In some embodiments, at least 50% of terminal sites on a dendrimer conjugate comprise hydroxyl groups (e.g., at least 50% of terminal sites do not comprise either an amine group or an agent). For example, in some embodiments, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of terminal sites on a dendrimer conjugate comprise hydroxyl groups. In some embodiments, about 50-99%, about 60-99%, about 70-99%, about 80-99%, about 90-99%, about 95-99%, about 98-99%, about 70-95%, about 70-90%, about 80-95%, or about 80-90% of terminal sites on a dendrimer conjugate comprise hydroxyl groups.

[0106] In some embodiments, one or more terminal sites on a dendrimer conjugate comprise an agent. In some embodiments, at least 2, at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, or more, terminal sites on a dendrimer conjugate comprise R1. In some embodiments, at least 1% of terminal sites on a dendrimer conjugate comprise R1. For example, in some embodiments, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% of terminal sites on a dendrimer conjugate comprise R1. In some embodiments, about 1-50%, about 1-40%, about 1-25%, about 1-10%, about 5-50%, about 5-40%, about 5-25%, about 5-10%, about 10-50%, about 10-40%, or about 10-25% of terminal sites on a dendrimer conjugate comprise R1. In some embodiments, about 1%, about 2%, about 3%, about 4%, or about 5% of terminal sites on a dendrimer comprise R1. In some embodiments, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75% of terminal sites on a dendrimer comprise R1.

[0107] In some embodiments, a desired R1loading can depend on certain factors, including the choice of agent, dendrimer structure and size, and cell or tissue to be treated. In some embodiments, a dendrimer conjugate is about 0.01% to about 45% by mass (m / m) of R1. In some embodiments, a dendrimer conjugate is about 10% to about 20% by mass of R1. In 39 / 75 13870760some embodiments, a dendrimer conjugate is about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10%, about 1% to about 10%, about 1% to about 5%, about 3% to about 20%, about 3% to about 10% by mass of R1.

[0108] As described herein, in some embodiments, a dendrimer conjugate can be characterized in terms of mass percentage (e.g., % by mass (m / m)) of agent. In some embodiments, mass percentage refers to a molecular weight (Da) percentage of R1in a dendrimer conjugate. In some embodiments, mass percentage can be determined by the general formula of: (agent MW) / (conjugate MW) × 100. For example, in some embodiments, (agent MW) can be determined by calculating or approximating the molecular weight of an agent as a single molecule or compound (conjugated or unconjugated), and multiplying this value by the number of terminal sites at which the agent is present in a dendrimer conjugate. In some embodiments, (agent MW) can be determined by calculating or approximating the sum of the atomic mass of all atoms which form the agent in a dendrimer conjugate. The value for (agent MW) can be taken as a fraction of total molecular weight of the dendrimer conjugate (conjugate MW), and multiplied by 100 to provide a mass percentage. In some embodiments, mass percentage can be determined by experimental or empirical means. For example, in some embodiments, mass percentage can be determined using proton nuclear magnetic resonance (1H NMR) or other analytical methods known in the art.

[0109] In some embodiments, a dendrimer has a diameter of between about 1 nm and about 50 nm. For example, in some embodiments, the diameter is between about 1 nm and about 20 nm, between about 1 nm and about 10 nm, or between about 1 nm and about 5 nm. In some embodiments, the diameter is between about 1 nm and about 2 nm. In some embodiments, a dendrimer has a molecular weight of between about 500 Daltons (Da) and about 100,000 Da (e.g., between about 500 Da and about 50,000 Da, or between about 1,000 Da and about 20,000 Da).

[0110] In some embodiments, an agent (e.g., R1) is conjugated to a dendrimer through a linker, which is attached to the dendrimer and to the agent in a non-releasable manner (e.g., by ether and / or amide bonds). In some embodiments, a linker has a composition that is minimally releasable (e.g., minimally cleavable) under physiological conditions.

[0111] In some embodiments, a dendrimer is conjugated to an agent through covalent bonds that are stable under in vivo conditions. In some embodiments, the covalent bonds are minimally cleavable when administered to a subject and / or excreted intact from the body. For example, in some embodiments, less than 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or less than 0.1% of the total dendrimer conjugates have agent cleaved within 24 40 / 75 13870760hours, or 48 hours, or 72 hours after in vivo administration to a subject. In some embodiments, the covalent bonds comprise ether bonds. In some embodiments, the covalent bonds between dendrimer and agent are not hydrolytically or enzymatically cleavable bonds, such as ester bonds.

[0112] In some embodiments, the dendrimer is a generation 4 PAMAM. In some embodiments, the dendrimer is of the formula:, wherein p terminal hydroxy groups are replaced with:, and n terminal hydroxy groups are replaced with:.

[0113] In some embodiments, the dendrimer is a generation 6 PAMAM. In some embodiments, the dendrimer is of the formula: 41 / 75 13870760, wherein p terminal hydroxy groups are replaced with:, and n terminal hydroxy groups are replaced with:.

[0114] As provided herein, q is an integer from 0-50, inclusive. In some embodiments, q is an integer from 0-25, inclusive. In some embodiments, q is an integer from 0-10, inclusive. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0115] As provided herein, m is an integer from 16-4095, inclusive. In some embodiments, m is an integer from 50-250, inclusive. In certain embodiments, m is an integer from 50-70, inclusive. In certain embodiments, m is an integer from 54-63, inclusive. In some embodiments, m is 60. In some embodiments, m is an integer from 53-58, inclusive. In certain embodiments, m is an integer from 52-56, inclusive. In certain embodiments, m is an integer from 54-57, inclusive. In some embodiments, m is 54. In certain embodiments, m is an integer from 200-300, inclusive. In certain embodiments, m is an integer from 240-255, inclusive. In some embodiments, m is 251. In some embodiments, m is an integer from 240- 245, inclusive. In certain embodiments, m is 241. 42 / 75 13870760

[0116] As provided herein, p is an integer from 0-20, inclusive. In some embodiments, p is an integer from 1-10, inclusive. In certain embodiments, p is an integer from 1-5, inclusive. In some embodiments, p is an integer from 3-7, inclusive. In some embodiments, p is 7. In certain embodiments, p is 6. In some embodiments, p is 5. In certain embodiments, p is 4. In certain embodiments, p is 3. In some embodiments, p is 2. In certain embodiments, p is 1. In some embodiments, p is 0.

[0117] As provided herein, n is an integer from 1-20, inclusive. In some embodiments, n is an integer from 2-15, inclusive. In certain embodiments, n is an integer from 5-15, inclusive. In some embodiments, n is an integer from 1-5, inclusive. In some embodiments, n is 1. In some embodiments, n is 2. In certain embodiments, n is 3. In some embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10. In certain embodiments, n is 11. In certain embodiments, n is 12. In certain embodiments, n is 13. In certain embodiments, n is 14. In certain embodiments, n is 15.

[0118] In some embodiments, the sum of p and n is from 5-15, inclusive. In certain embodiments, the sum of p and n is from 5-10, inclusive. In certain embodiments, the sum of p and n is from 5-10, inclusive. In certain embodiments, the sum of p and n is 5. In certain embodiments, the sum of p and n is 6. In certain embodiments, the sum of p and n is 7. In certain embodiments, the sum of p and n is 8. In certain embodiments, the sum of p and n is 9. In certain embodiments, the sum of p and n is 10. In certain embodiments, the sum of p and n is 11. In certain embodiments, the sum of p and n is 12. In certain embodiments, the sum of p and n is 13. In certain embodiments, the sum of p and n is 14. In certain embodiments, the sum of p and n is 15. In certain embodiments, the sum of p and n is 8 or 15.

[0119] In some embodiments, p is 0 and n is 8, or p is 1 and n is 7. In some embodiments, p is 0 and n is 8. In some embodiments, p is 1 and n is 7. In some embodiments, p is 2 and n is 6. In some embodiments, p is 3 and n is 5. In some embodiments, p is 4 and n is 4. In some embodiments, p is 5 and n is 3. In certain embodiments, p is 6 and n is 2. In some embodiments, p is 7 and n is 1.

[0120] In some embodiments, the sum of m, p, and n is 64. In some embodiments, the sum of m, p, and n is 128. In some embodiments, the sum of m, p, and n is 256.

[0121] In some embodiments, D is a generation 2, 3, 4, 5, 6, 7, 8, 9, or 10 PAMAM dendrimer, which has 16, 32, 64, 128, 256, 512, 1024, 2048, or 4096 terminal sites, respectively. Accordingly, in some embodiments, D is a generation 2, 3, 4, 5, 6, 7, 8, 9, or 10 PAMAM dendrimer, and the sum of m, p, and n is 16, 32, 64, 128, 256, 512, 1024, 2048, or 43 / 75 138707604096, respectively. In some embodiments, D is a generation 4 PAMAM dendrimer, and the sum of m, p, and n is 64. In some embodiments, D is a generation 5 PAMAM dendrimer, and the sum of m, p, and n is 128. In some embodiments, D is a generation 6 PAMAM dendrimer, and the sum of m, p, and n is 256.

[0122] In some embodiments, –Z–R1is:.

[0123] In some embodiments, the dendrimer conjugate of Formula (I) is of the formula:; 44 / 75 1387076045 / 75 13870760; or a pharmaceutically acceptable salt thereof.

[0124] Also provided herein are dendrimer conjugates of the formula:pharmaceutically acceptable salt thereof. Methods

[0125] Provided herein are methods of modulating biological processes, as well as methods of treating and preventing diseases. The methods of modulating biological processes may lead to treating and preventing diseases.

[0126] Thus, in one aspect, provided herein are methods of modulating CSF1R in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a dendrimer conjugate provided herein, or pharmaceutically acceptable salt thereof, or composition provided herein. In some embodiments, the modulation is inhibition. In certain embodiments, the method treats a disease or disorder. In some embodiments, the modulation is in vitro or ex vivo. 46 / 75 13870760

[0127] In another aspect, provided herein are methods of modulating CSF1R in a subject, the method comprising administering to the subject an effective amount of a dendrimer conjugate provided herein, or pharmaceutically acceptable salt thereof, or composition provided herein. In some embodiments, the modulation is inhibition. In certain embodiments, the method treats a disease or disorder. In some embodiments, the modulation is in vitro or ex vivo.

[0128] In another aspect, provided herein are methods of treating a disease or disorder in a subject, the method comprising administering to the subject an effective amount of a dendrimer conjugate provided herein, or pharmaceutically acceptable salt thereof, or composition provided herein.

[0129] In some embodiments, the disease or disorder is a neurological disorder, an inflammatory disease, an autoimmune disorder, a cancer, a central nervous system disease, a painful condition, a bone disease, or a tumor.

[0130] In some embodiments, the disease or disorder is a neurological disorder. In certain embodiments, the neurological disorder is a neurodegenerative disorder. In certain embodiments, the neurodegenerative disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In certain embodiments, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS). In certain embodiments, the neurodegenerative disorder is multiple sclerosis (MS). In certain embodiments, the multiple sclerosis is relapsing remitting MS, primary progressive multiple sclerosis, or secondary progressive MS. In certain embodiments, the neurodegenerative disorder is Alzheimer’s disease. In certain embodiments, the neurodegenerative disorder is Parkinson’s disease. In certain embodiments, the neurodegenerative disorder is Huntington’s disease. In certain embodiments, the neurological disorder is epilepsy.

[0131] In certain embodiments, the disease or disorder is an inflammatory disease.

[0132] In some embodiments, the disease or disorder is an autoimmune disorder.

[0133] In some embodiments, the inflammatory disease or autoimmune disease is selected from the group consisting of arthritis, inflammatory bowel disease, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune thrombocytopenic purpura, Bechet’s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn’s disease, Degos disease, 47 / 75 13870760dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, Graves’ disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgA nephropathy, insulin-dependent diabetes, Meniere’s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter’s syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren’s syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener’s granulomatosis. In some embodiments, the arthritis is rheumatoid arthritis or psoriatic arthritis.

[0134] In certain embodiments, the disease or disorder is a cancer. In certain embodiments, the cancer is brain cancer, breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, gastric cancer, esophagus cancer, lung cancer, liver cancer, renal cell cancer, skin cancer, colon cancer, a sarcoma, a lymphoma, a leukemia, or a malignant tumor. In some embodiments, the skin cancer is melanoma. In certain embodiments, the melanoma is acral melanoma or mucosal melanoma. In certain embodiments, the brain cancer is glioblastoma. In some embodiments, the lymphoma is Hodgkin lymphoma or non-Hodgkin lymphoma. In certain embodiments, the leukemia is chronic myeloid leukemia chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL).

[0135] In some embodiments, the disease or disorder is a central nervous system disease. In certain embodiments, the central nervous system disease is Charcot-Marie-Tooth disease type 1.

[0136] In certain embodiments, the disease or disorder is a painful condition. In some embodiments, the painful condition is neuropathic pain.

[0137] In some embodiments, the disease or disorder is a bone disease. In some embodiments, the bone disease is osteoporosis or osteolysis.

[0138] In certain embodiments, the disease or disorder is a tumor. In some embodiments, the tumor is a solid tumor, diffuse-type tenosynovial giant cell tumor, or neurofibroma.

[0139] In some embodiments, the dendrimer conjugate, or composition thereof, is administered to the subject systemically. In certain embodiments, the dendrimer conjugate, or composition thereof, is administered to the subject intraperitoneally, intravenously, intrathecally, intratumorally, or orally. 48 / 75 13870760Compositions, Kits, and Administration

[0140] Also provided herein are compositions. In one aspect, provided herein are compositions comprising a dendrimer conjugate disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. The pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers / excipients. In certain embodiments, a dendrimer conjugate described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount.

[0141] In some embodiments, a composition comprises a dendrimer conjugate disclosed herein and one or more pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include solvents, diluents, pH modifying agents, preservatives, antioxidants, suspending agents, wetting agents, viscosity modifiers, tonicity agents, stabilizing agents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, buffering agents, lubricating agents, oils, butters, and waxes, and combinations thereof. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition. Suitable pharmaceutically acceptable excipients are, in some embodiments, selected from materials which are generally recognized as safe and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.

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

[0143] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage. Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the 49 / 75 13870760identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0144] Dendrimer conjugates provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0145] The exact amount of a dendrimer conjugate required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular dendrimer conjugate, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a dendrimer conjugate described herein.

[0146] The dendrimer conjugates and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In some embodiments, the dendrimer conjugate, or pharmaceutically acceptable salt thereof, or composition is administered to the 50 / 75 13870760subject systemically. In some embodiments, the dendrimer conjugate, or pharmaceutically acceptable salt thereof, or composition is administered to the subject intraperitoneally, intravenously, intrathecally, intratumorally, or orally.

[0147] A dendrimer conjugate or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The dendrimer conjugates or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[0148] In some aspects, the disclosure provides a kit comprising a dendrimer conjugate or composition described herein. In some embodiments, the kit comprises a single dose or a plurality of doses of a composition comprising a dendrimer conjugate of the disclosure, and instructions for administering the composition. In some embodiments, the instructions direct that an effective amount of the composition be administered to an individual with a particular condition / disease as indicated and in accordance with the disclosure. The composition can be formulated as described above with reference to a particular treatment method and can be packaged in any convenient manner.

[0149] In some embodiments, a kit comprises one or more containers, such as a vial, test tube, flask, bottle, syringe, or other container means into which a component may be placed, where at least one container comprises a composition of the disclosure. In some embodiments, the kit comprises a single container comprising a composition of the disclosure. In some embodiments, the kit comprises two or more (e.g., 2, 3, 4, 5, or more) containers comprising the composition. In some embodiments, the components of a kit are packaged in solution or lyophilized form. In some embodiments, the kit comprises at least one container comprising the composition in lyophilized form, and at least one container comprising a liquid component for reconstituting the composition in solution form. In some embodiments, the kit comprises at least one container comprising one or more stabilizers, bulking agents (e.g., mannitol), or other additives known in the art.

[0150] The present invention will be further understood by reference to the following non- limiting examples. 51 / 75 13870760EXAMPLES

[0151] In order that the present disclosure may be more fully understood, the following examples are set forth. The examples described in this Application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Example 1 First Generation Compounds

[0152] The first generation of colony stimulating factor-1 receptor tyrosine kinase inhibitors (CSF1 RTKi) were synthesized with different linkers for conjugation to generation 4 polyaminoamide (PAMAM) hydroxyl dendrimers (HDs) containing 7 to 8 alkyne terminal groups or generation 6 PAMAM HDs containing 12 to 15 alkyne terminal groups (FIGs.4A- 4B). Each CSF1 RTKi was conjugated to the HD using copper catalyzed click chemistry between the alkyne on the HD and the azide on the CSF1 RTKi linker. The parent CSF1 RTKi structures were derived from dasatinib or compounds in the literature. The CSF1 RTKi with linker and the resulting conjugated hydroxyl dendrimer therapeutic (HDT) were evaluated for stability at physiological conditions and in plasma. The binding affinity and cellular activity of each compound for CSF1R was also evaluated. A. Ester linked CSF1 RTKi HDTs

[0153] GW2580, a CSF1 RTKi, was conjugated to the HDs with an ester bond and a three- polyethylene glycol group (3PEG) spacer (AVT-4513). The resulting hydroxyl dendrimer therapeutic (HDT) (D4-4513) had low stability and rapidly hydrolyzed back to the parent compound, GW2580. The binding (Kd) of GW2580 to CSF1 RTK was 2.4 nM. In contrast, the ether linked version of GW2580 (AVT-4516 and D4-4516) with the same PEG spacer was stable but had a lower binding affinity for CSF1 RTK (AVT-4516: 340 nM; D4-4516: 8800 nM).

[0154] Dasatinib, which has CSF1 RTKi activity, was also linked to the HDs with an ester bond and 3PEG spacer (AVT-4531). The resulting HDT (D4-4531) was soluble and did not appear to release the parent drug, dasatinib, during production. D4-4531 had high affinity for CSF1 RTK (0.26 nM). However, as shown in Table 1 below, D4-4531 released dasatinib in plasma. 52 / 75 13870760Table 1: Release of Dasatinib from D4-4531 in Plasma at 37°C*: %AUC of Dasatinib as measured using C18 column on HPLC B. Impact of Ester at HD Surface

[0155] As shown in FIGs.4A-4B, some HDTs had an ester linkage at the terminal hydroxyl group on the surface of the HD. For example, D4-4550 (ester at HD) was observed to degrade over time in plasma (Table 2). Table 2: Release of Drug-Linker arm from D4-4550 in Plasma at 37°C*: %AUC of Drug-Linker arm cleaved at ester on HD as measured using C18 column on HPLC C. Binding Affinity & Cell Based Assay Screening

[0156] Binding affinity screening was performed at Eurofins. In brief, kinases were produced in either BL21 strain of E. coli or HEK-293 human embryonic kidney cells. Small molecule ligands associated with the target kinases were immobilized on streptavidin-coated magnetic beads. Binding affinity assay was carried out by combining the purified kinase, ligand coated beads, and test compounds in binding buffer. The coated beads were isolated, washed, and suspended in elution buffer. Captured kinases eluted from the coated beads were measured by qPCR. A Kd (binding affinity) curve was constructed by using an 11-point 3- fold compound dilution series of the test compound.

[0157] EOC20 cells were seeded into wells (2000 cells / well) in 30 µL of media (DMEM, 10% fetal bovine serum, 20% LADMAC cells expressing CSF-1) at 37 °C and 5% CO2for 24 h. Each compound (10 µL) was added to each well at varying concentrations and incubated at 37 °C and 5% CO2 for three days. CellTiter-Glo™ for cell viability (40 µL) was 53 / 75 13870760then added to each well. After 10 min at room temperature, the luminescence was measured with a plate reader.

[0158] D4-4550, D4-45101, and D4-4531 were not active in the assay, and D4-4547 was not tested. D4-45113 had a CSF1 RTK binding affinity (Kd) of 0.04 nM and an EC50 of 7 nM in the EOC cell assay compared to free dasatinib with an EC50 of 27 nM. D. D4-45113

[0159] Based upon the activity of D4-45113, it was further studied for stability and release of the thiol-dasatinib analog. To analyze samples, a C18 symmetry 300, 5 µm 4.6×250mm column from Waters was used. The chromatograms were recorded at 210, 254 and 330 nm. A 45-minute-long method with the gradient flow was used where mobile phase comprising buffer A: 0.1% TFA in Water and buffer B: 0.1% TFA in Acetonitrile. The gradient starts from 90:10 (A:B) gradually increasing to 40:60 (A:B) at 18 min. remains at 40:60 until 35 min, and finally returns to 90:10 (A:B) at 45 minutes with a flow rate of 1 mL / min. The thiol- dasatinib analog absorption maximum is at 330nm, and the D4 precursor is detectable at 210 nm. D4-45113 is detectable at 210 and 330 nm and the D4 absorption at 330 nm decreases if thiol-dasatinib is cleaved from the D4.

[0160] Under intracellular conditions (10 mM glutathione, 37°C), D4-45113 released the thiol-dasatinib analog with near complete release over 24 h (FIG.1).

[0161] D4-45113 was incubated in mouse, rat or human plasma at 37°C and analyzed immediately (0 h), and at 24 and 48 h as shown in FIGs.2A-2C. There was no detectable release of the thiol-dasatinib analog in plasma and no apparent degradation over 48 h. E. In Vivo Proof of Concept

[0162] Experimental autoimmune encephalomyelitis (EAE) is a mouse model of MS that involves induction of an autoimmune response including inflammation, demyelination, axonal loss and gliosis recapitulating aspects of human Multiple Sclerosis (MS). Female C57BL / 6 animals (n=15 / group) at an age of ~10 weeks received MOG35-55 / CFA (Complete freund’s adjuvant) and PTX (pertussis toxin) via subcutaneous or intraperitoneal injection according to hookslab protocol for experimental autoimmune encephalitis (EAE) induction. A group of 15 animals (no EAE induction, vehicle) served as control.

[0163] On treatment day 14 after EAE induction, animals received either 20 or 100 mg / kg D4-45113 (increased to 200 mg / kg over final 4 doses) or vehicle intraperitoneally (ip) daily until a period of 28 days after EAE induction. Clinical Score was monitored daily after EAE induction. 54 / 75 13870760

[0164] As shown in FIG.3, D4-45113 resulted in a significant reduction of symptoms after EAE induction. There was no effect of the 20 mg / kg D4-45113 dose on clinical scores compared to vehicle. F. Non-GLP Toxicology

[0165] A single dose non-GLP rat toxicology study was conducted with D4-45113 compared to dasatinib. A single oral dose of dasatinib at 30 mg / kg in rats was observed to have limited toxicity, no observed adverse effect level (FDA Summary Basis of Approval for Sprycel™(dasatinib)). The mass of D4-45113 equivalent to the dasatinib dose (215 mg / kg; ~14% w / w dasatinib) was administered ip due to unknown oral bioavailability of D4-45113. A lower dose (70 mg / kg) of D4-45113 was also administered ip. Each group comprised 5 male and 5 female rats and an additional 5 male and 5 female rats in the recovery group. Animals were dosed on Day 1 and sacrificed on Day 4, with recovery group animals sacrificed on Day 16.

[0166] Dasatinib-related hematology changes following administration of dasatinib in males and females at 30 mg / kg comprised reversible, minimally to mildly lower reticulocyte counts. Following the recovery period, females at 30 mg / kg showed minimally higher lymphocyte counts, resulting in minimally higher white blood cell counts. Dasatinib-related coagulation changes comprised reversible, minimally higher fibrinogen concentrations in males and females. Dasatinib-related clinical chemistry findings included reversible, minimally higher aspartate aminotransferase (AST) activities in females, and reversible, minimally lower alkaline phosphatase (ALP) activities in males. Reversible, minimally lower albumin concentrations were observed in males and females, reflected in minimally lower total protein concentrations in females. In males, reversible and mildly lower triglyceride concentrations were seen. Following the recovery period, in females at 30 mg / kg / day, minimally higher globulin concentrations with lower albumin-to-globulins (A / G) ratios and minimally higher cholesterol concentrations were observed.

[0167] D4-45113-related hematology findings comprised minimally to mildly lower reticulocyte counts in males at ≥ 70 mg / kg and females at 215 mg / kg with reversible, minimally lower red blood cell mass in females at ≥ 70 mg / kg. Males at ≥ 70 mg / kg and females at 215 mg / kg had minimally lower lymphocyte counts, resulting in minimally lower white blood cell counts in males. Following the recovery period, reticulocyte counts completely reversed in males at 215 mg / kg and remained slightly lower in males at 70 mg / kg, while females at 215 mg / kg showed higher reticulocyte counts. D4-45113-related coagulation changes comprised reversible, minimally higher fibrinogen concentrations in males and 55 / 75 13870760females at ≥ 70 mg / kg. D4-45113-related clinical chemistry findings included reversible, minimally higher AST activities in males and females at ≥ 70 mg / kg with minimally higher, reversible alanine aminotransferase (ALT) activities in males and females at 215 mg / kg; females at 215 mg / kg / day additionally had reversible, minimally higher ALP activities. Reversible, minimally lower albumin concentrations were observed in males and females at ≥ 70 mg / kg resulting in reversible, minimally lower total protein concentrations in females at 70 mg / kg. Reversible, minimally higher globulin concentrations with associated lower A / G ratios were seen in females at ≥ 70 mg / kg and in males at 215 mg / kg. Males and females at ≥ 70 mg / kg had reversible, minimally higher cholesterol concentrations, and males at ≥ 70 mg / kg had reversible, minimally to mildly lower triglyceride concentrations. Phosphorus concentrations were minimally lower in males and females ≥ 70 mg / kg and were reversible.

[0168] In summary, administration of dasatinib at 30 mg / kg once by oral gavage on Day 1 and administration of D4-45113 at 70 mg / kg by ip injection once on Day 1 were well tolerated in rats. However, delayed and recurring clinical findings in males treated with 215 mg / kg D4-45113 were considered to have led to mortality in 1 male. The 30 mg / kg dasatinib treatment was associated with reduced body weights, thymus macroscopic findings, and clinical pathology findings, all of which were transient. D4-45113-associated body weight loss, reduced food consumption, intestinal discolorations, and clinical pathology findings were also seen at 70 mg / kg and all found to be transient. Second Generation Compounds

[0169] Given the in vitro and in vivo activity of the dasatinib derived compounds, an additional set of compounds were designed to be stable without the release of dasatinib or dasatinib analogs. All structures were based on bonds (amide / ether / alkyl) that are known to be metabolically stable as shown in FIGs.5A-5D.

[0170] Another CSF1 RTKi, pexidartinib, was also used as a basis of creating stable compounds that would not undergo metabolism as shown in FIGs.6A-6F.

[0171] The compounds in FIGs.5A-5D and FIGs.6A-6F were evaluated for biological activity in vitro (Table 3). In addition to the binding affinity (Kd) assay, kinase activity assay was performed at Reaction Biology. Substrates of target kinases were freshly prepared in reaction buffer with the addition of cofactors. Test compounds were serially diluted and added along with the target kinase.33P-ATP was then added, resulting in transfer of the 33P- labelled phosphate to the kinase substrate by active kinases. Kinase activity was then measured by the radioactivity detected via spotting of the reaction mixture on filter membranes. 56 / 75 13870760

[0172] Compounds were evaluated in a cell-based assay using Promega’s CellTiter-Glo 2.0 viability assay in EOC20 cells (a CSF1-dependent murine microglial cell line) grown in LADMAC-conditioned media. CellTiter-Glo was a proxy measurement of the number of viable cells through ATP concentration. Increasing inhibition of CSF1R pathway resulted in a corresponding reduction in proliferation, and hence a lower quantity of viable cells after 3 days of incubation with CSF1Ri. On Day 1, EOC20 cells were seeded at 1,381 cells per well. On Day 2, the compound of interest was added in a tenfold dilution series in triplicate. On Day 5, CellTiter-Glo assay was performed and its luminescence read. IC50 curves were generated based on luminescence levels of EOC20 cells treated with the various concentrations of CSF1Ri. Table 3: In vitro binding affinity (Kd), kinase activity (IC50) and cell-based assay (IC50) results for compounds in FIGs.5A-5D and FIGs.6A-6F57 / 75 13870760

[0173] Based on the results of in vitro assays, selected HDTs were further evaluated in the standard preclinical EAE model of MS (Table 4). Table 4: Efficacy of HDTs in an EAE Mouse Model1. % Efficacy was calculated as difference in mean clinical score relative to vehicle, and statistical significance was compared to vehicle by mixed effects model or 2-way ANOVA * p < 0.05, ** p < 0.01, *** p < 0.005, **** p < 0.001 2. QD: daily, Q2D: every other day, IP: intraperitoneal administration, SC: subcutaneous administration 3. From three independent experiments 4. From two independent experiments

[0174] During the preparation of the HDTs for the EAE mouse model studies, the HDTs were observed to change their physical properties in aqueous solution. To further assess the observed changes in the aqueous solutions of the HDTs, each HDT was tested for solubility in water at 100 and 200 mg / mL. The HDTs with a PEG space of 7 were viscous and gelled 58 / 75 13870760over time. If the PEG was linked to the CSF1 RTKi with an amide or alkyl (or alkyl-amide) bond, the solubility was improved. Third Generation Compounds

[0175] To optimize the physical properties of the HDTs in solution, dasatinib analog and pexidartinib analog HDTs were produced with shorter PEG spacers and amide or alkyl bond to the CSF1 RTKi as shown in FIGs.7A-7C. As the PEG spacer (alkyl bond to CSF1 RTKi) was increased from one (H67DS1L7) to two or three (H70DS2L8, H68DS3L7) the solubility decreased and the HDT formed a gel in aqueous solution at 200 mg / mL. However, a three PEG spacer with an amide bond to the CSF1 RTKi (H74DS3M8) was soluble and did not form a gel at 200 mg / mL. These results suggested that the improved physical properties in solution were obtained using single PEG alkyl or three (or less) PEG amide linkers for the CSF1 RTKis.

[0176] The in vitro activity of the third generation HDTs was evaluated as shown in Table 5. The modifications made to improve the aqueous solubility did not affect the in vitro activity of the HDTs. Table 5: In vitro binding affinity (Kd), kinase activity (IC50) and cell-based assay (IC50) results for compounds in FIGs.7A-7C

[0177] To confirm that the in vivo efficacy was also retained with the third generation HDTs, an EAE mouse model study was conducted (Table 6). These results indicated that H74DS3M8 had efficacy comparable to that observed with the second generation HDTs (Table 4) administered at the same dose (60 mg / kg, QD, IP). The other third generation HDTs were less efficacious in this mouse model. Table 6: Efficacy of HDTs in an EAE Mouse Model59 / 75 138707601. % Efficacy was calculated as difference in mean clinical score relative to vehicle, and statistical significance was compared to vehicle by 2-way ANOVA, **p < 0.01 2. QD: daily, Q2D: every other day, IP: intraperitoneal administration, SC: subcutaneous administration

[0178] Thus, a series of modifications to the HDT chemical structures in successive generations of CSF1R HDTs resulted in improved physical properties while conserving both in vitro and in vivo activity. Example 2

[0179] Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Accumulating evidence suggests that MS pathogenesis is related to peripheral macrophage and CNS resident microglia activation that leads to production of inflammatory molecules, causing axonal damage and cell death. Polarization of these cells toward an M1 phenotype is associated with relapse-independent disease progression (RIDP), whereas M2- polarized cells are involved in remyelination processes. Therefore, re-programming macrophages and microglia toward an M2 phenotype could be a viable therapeutic option.

[0180] Colony stimulating factor 1 receptor (CSF1R), a type III receptor tyrosine kinase (RTK), is critical for survival and proliferation of CNS microglia, peripheral tissue macrophages and blood myeloid cells. Increased expression of CSF1 in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE) and in the brain and CSF of MS patients correlate with microglial activation and disease progression. Targeting CSF1R with selective tyrosine kinase inhibitors such as dasatinib and masitinib lowers EAE severity and delay disease onset.

[0181] ASH41020 is a new class of tyrosine kinase inhibitors referred to as “dendranibs”, which are metabolically stable and eliminated intact through the kidneys. ASH41020 selectively inhibits CSF1R tyrosine kinase only in activated microglia and macrophages. As presented herein 1) effects of ASH41020 on macrophage phenotypes were studied in vitro using differentiated human primary monocytes, and 2) effects of ASH41020 on macrophage phenotype and clinical symptoms were studied in a mouse EAE model of MS. Symptomatic animals (EAE mean score of ~1.5) were treated daily for 14 days at 20, 60 or 200 mg / kg ASH41020 (IP) and compared to fingolimod (3 mg / kg, oral (PO) daily) as a positive control. 60 / 75 13870760Clinical scores were monitored daily, and spinal cords were analyzed for M1 / M2 macrophage markers using fluorescence-activated single cell (FACS) In Vitro Effect of ASH41020 on Macrophage Phenotype

[0182] ASH41020 decreased M1 and increased M2 macrophages in the M1 polarizing environment in a dose dependent manner, while dasatinib and masitinib did not (FIG.8A). In the M2 polarizing environment, ASH41020 treatment did not affect M1 macrophage proportion but showed a similar trend with dasatinib in increasing M2 macrophage proportion. Dasatinib and masitinib both increased the proportion of M1 macrophages in the M2 polarizing environment (FIG.8B). Efficacy of ASH41020 in EAE Mouse Model of MS

[0183] Mice treated with 60 mg / kg ASH41020 recovered more body weight than other treatment groups and ended with weights similar to fingolimod treated animals (FIG.9).

[0184] ASH41020 administration significantly decreased EAE disease severity in a dose dependent manner compared to vehicle. To benchmark ASH41020 against similar compounds, dasatinib and masitinib were administered daily after disease onset at 30 and 50 mg / kg, respectively. However, they did not show significant efficacy (FIG.10A). Cumulative scores followed a similar trend with significant effects after ASH41020 administration (FIG. 10B). EAE animals scored from 0 (asymptomatic) – 8 (premorbid or dead). Peak scores showed that control animals peaked at 5.8, indicative of a tail paralysis and paralysis of a pair of limbs, while animals treated with ASH41020 at 20, 60 and 200 mg / kg had mean peak scores of 5, 4.7 and 5, respectively. These scores were indicative of only a tail paralysis and paralysis of one limb (FIG.10C). The magnitude of this effect was similar to that of fingolimod with a mean peak score of 4.6, indicating improved well-being.

[0185] ASH41020 daily administration increased the percentage of M1 and M2 macrophages, showing a trend toward dose dependency for M2 macrophages (FIGs.11A- 11B). Conclusions for Example 2

[0186] Tyrosine kinase inhibitor, dasatinib, showed efficacy in the mouse EAE model of MS when treatment started before disease onset and masitinib demonstrated efficacy in a Phase 3 study of progressive MS. However, whether they can modulate macrophage phenotype has not been investigated. Dendranib ASH41020 is a potent tyrosine kinase inhibitor and a macrophage switching nanomedicine technology. In this study, ASH41020 significantly directed macrophage polarization toward the anti-inflammatory M2 phenotype, which in turn ameliorated symptoms in the mouse EAE model of MS after disease onset. These preclinical 61 / 75 13870760studies suggest that ASH41020 could be a potent anti-inflammatory and immunomodulatory agent that warrants further development as a promising treatment for MS patients. Example 3

[0187] The therapeutic utility of H74DS3M8 is shown in Table 8 and FIGs.12A to 15 and demonstrate the superior activity of H74DS3M8 over dasatinib.

[0188] H74DS3M8 inhibited CSF1R and c-Src activity more than dasatinib9. ABL1 and c- Kit inhibition were within the same magnitude as dasatinib, whereas H74DS3M8 inhibited PDGFRb and EGFR less than dasatinib. Masitinib has been shown to be a weaker inhibitor of CSF1R with an IC50of 1.48 nM.

[0189] H74DS3M8 demonstrates nanomolar potency in inhibiting microglial proliferation (FIGs.12A to 12C).

[0190] H74DS3M8 directed macrophage polarization toward the anti-inflammatory M2 phenotype (FIGs 13A and 13B). FIG.13A shows that H74DS3M8 showed a trend towards increasing M2 macrophages in the M1 polarized environment. Dasatinib (Das) did not have an effect on M2 cells in the M1 environment. FIG.13B shows H74DS3M8 (H74) showed a strong trend towards decreasing M1 macrophages while significantly increasing M2 macrophages in the M2 polarized environment.

[0191] In a study evaluating efficacy of H74DS3M8 compositions in a mouse model of multiple sclerosis (Experimental Autoimmune Encephalomyelitis (EAE)), H74DS3M8 (20 mg / kg twice / week p.o.) improved disease severity compared to control animals (FIGs.14A and 14B; positive control, fingolimod (FTY720, daily p.o.), is further shown for comparison).

[0192] FIG.15 supports that fewer microglia are observed with treatment not because of cell death but due to decreased proliferation. EQUIVALENTS AND SCOPE

[0193] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, 62 / 75 13870760more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0194] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0195] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. 63 / 75 13870760

[0196] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims. 64 / 75 13870760

Claims

CLAIMS What is claimed is:

1. A dendrimer conjugate of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; q is an integer from 0-50, inclusive; p is an integer from 0-20, inclusive; m is an integer from 16-4095, inclusive;f is an integer from 1-3, inclusive; g is an integer from 0-10, inclusive; R1is a colony stimulating factor-1 receptor (CSF1R) inhibitor; and n is an integer from 1-20, inclusive.

2. The dendrimer conjugate of claim 1, wherein R1is pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580, or a derivative or analog thereof.

3. The dendrimer conjugate of claim 1 or 2, wherein R1is a derivative of: pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580.

4. The dendrimer conjugate of claim 3, wherein the derivative of: pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580, comprises Z2between Z and pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580; wherein Z2is a linker. 65 / 75 138707605. The dendrimer conjugate of claim 4, wherein Z2is.

6. The dendrimer conjugate of any one of claims 1-5, wherein R1is:.

7. The dendrimer conjugate of any one of claims 1-6, wherein Z is.

8. The dendrimer conjugate of any one of claims 1-6, wherein Z is,.

9. The dendrimer conjugate of any one of claims 1-6, wherein Z is, and f is 1.

10. The dendrimer conjugate of any one of claims 1-6, wherein Z is, and f is 3. 66 / 75 1387076011. The dendrimer conjugate of any one of claims 1-6, wherein Z is, - , , g - , .

13. The dendrimer conjugate of any one of claims 1-6, wherein Z is, f is 3, and g is 3.

14. The dendrimer conjugate of any one of claims 1-13, wherein the dendrimer, D, is a polyamidoamine (PAMAM), polypropylamine (POPAM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), or an aromatic polyether dendrimer.

15. The dendrimer conjugate of any one of claims 1-14, wherein the dendrimer, D, is a polyamidoamine (PAMAM) dendrimer.

16. The dendrimer conjugate of any one of claims 1-15, wherein the dendrimer, D, is a generation 4, generation 5, generation 6, generation 7, or generation 8 PAMAM dendrimer.

17. The dendrimer conjugate of any one of claims 1-16, wherein the dendrimer, D, is a generation 4 PAMAM dendrimer.

18. The dendrimer conjugate of any one of claims 1-16, wherein the dendrimer, D, is a generation 6 PAMAM dendrimer.

19. The dendrimer conjugate of any one of claims 1-18, wherein q is 0, 1, or 2.

20. The dendrimer conjugate of any one of claims 1-19, wherein q is 1. 67 / 75 1387076021. The dendrimer conjugate of any one of claims 1-20, wherein m is an integer from 50- 250, inclusive.

22. The dendrimer conjugate of any one of claims 1-21, wherein m is an integer from 53- 58, inclusive.

23. The dendrimer conjugate of any one of claims 1-22, wherein m is an integer from 54- 57, inclusive.

24. The dendrimer conjugate of any one of claims 1-21, wherein m is an integer from 240-245, inclusive.

25. The dendrimer conjugate of any one of claims 1-21 and 24, wherein m is 241.

26. The dendrimer conjugate of any one of claims 1-25, wherein p is an integer from 1- 10, inclusive.

27. The dendrimer conjugate of any one of claims 1-26, wherein p is an integer from 1-5, inclusive.

28. The dendrimer conjugate of any one of claims 1-27, wherein n is an integer from 2- 15, inclusive.

29. The dendrimer conjugate of any one of claims 1-28, wherein n is an integer from 5- 15, inclusive.

30. The dendrimer conjugate of any one of claims 1-29, wherein the sum of p and n is from 5-15, inclusive.

31. The dendrimer conjugate of claim 30, wherein the sum of p and n is from 5-10, inclusive.

32. The dendrimer conjugate of claim 30 or 31, wherein the sum of p and n is 8. 68 / 75 1387076033. The dendrimer conjugate of claim 30, wherein the sum of p and n is from 10-15, inclusive.

34. The dendrimer conjugate of any one of claims 1-33, wherein –Z–R1is:.

35. The dendrimer conjugate of claim 1, wherein the dendrimer conjugate is of the formula:; 69 / 75 1387076070 / 75 13870760; or a pharmaceutically acceptable salt thereof.

36. A dendrimer conjugate of the formula:, or pharmaceutically acceptable salt thereof.

37. A composition comprising the dendrimer conjugate of any one of claims 1-36, or a pharmaceutically acceptable salt thereof.

38. The composition of claim 37, wherein the composition comprises a pharmaceutically acceptable excipient.

39. A method of modulating CSF1R in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a 71 / 75 13870760dendrimer conjugate of any one of claims 1-36, or pharmaceutically acceptable salt thereof, or composition of claim 37 or 38.

40. A method of modulating CSF1R in a subject, the method comprising administering to the subject an effective amount of a dendrimer conjugate of any one of claims 1-36, or pharmaceutically acceptable salt thereof, or composition of claim 37 or 38.

41. The method of claim 39 or 40, wherein the modulation is inhibition.

42. The method of any one of claims 39-41, wherein the method treats a disease or disorder.

43. A method of treating a disease or disorder in a subject, the method comprising administering to the subject an effective amount of a dendrimer conjugate of any one of claims 1-36, or pharmaceutically acceptable salt thereof, or composition of claim 37 or 38.

44. The method of claim 42 or 43, wherein the disease or disorder is a neurological disorder, an inflammatory disease, an autoimmune disorder, a cancer, a central nervous system disease, a painful condition, a bone disease, or a tumor.

45. The method of claim 44, wherein the central nervous system disease is Charcot- Marie-Tooth disease type 1.

46. The method of claim 44, wherein the painful condition is neuropathic pain.

47. The method of claim 44, wherein the bone disease is osteoporosis or osteolysis.

48. The method of claim 44, wherein the neurological disorder is a neurodegenerative disorder.

49. The method of claim 48, wherein the neurodegenerative disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. 72 / 75 1387076050. The method of claim 49, wherein the multiple sclerosis is relapsing remitting MS, primary progressive multiple sclerosis, or secondary progressive MS.

51. The method of claim 44, wherein the cancer is brain cancer, breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, gastric cancer, esophagus cancer, lung cancer, liver cancer, renal cell cancer, skin cancer, colon cancer, a sarcoma, a lymphoma, a leukemia, or a malignant tumor.

52. The method of claim 51, wherein the skin cancer is melanoma.

53. The method of claim 52, wherein the melanoma is acral melanoma or mucosal melanoma.

54. The method of claim 51, wherein the brain cancer is glioblastoma.

55. The method of claim 51, wherein the lymphoma is Hodgkin lymphoma or non- Hodgkin lymphoma.

56. The method of claim 51, wherein the leukemia is chronic myeloid leukemia chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL).

57. The method of claim 44, wherein the tumor is a solid tumor, diffuse-type tenosynovial giant cell tumor, or neurofibroma.

58. The method of claim 44, wherein the inflammatory disease or autoimmune disease is selected from the group consisting of arthritis, inflammatory bowel disease, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune thrombocytopenic purpura, Bechet’s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn’s disease, Degos disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, Graves’ disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, idiopathic pulmonary fibrosis, 73 / 75 13870760idiopathic thrombocytopenia purpura, IgA nephropathy, insulin-dependent diabetes, Meniere’s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter’s syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren’s syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener’s granulomatosis.

59. The method of claim 58, wherein the arthritis is rheumatoid arthritis or psoriatic arthritis.

60. The method of claim 44, wherein the neurological disorder is epilepsy.

61. The method of any one of claims 40-60, wherein the dendrimer conjugate, or pharmaceutically acceptable salt thereof, or composition is administered to the subject systemically.

62. The method of any one of claims 40-60, wherein the dendrimer conjugate, or pharmaceutically acceptable salt thereof, or composition is administered to the subject intraperitoneally, intravenously, intrathecally, intratumorally, or orally.

63. A kit comprising: a dendrimer conjugate of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, or a composition of claim 37 or 38; and instructions for using the dendrimer conjugate, or pharmaceutically acceptable salt thereof, or the composition. 74 / 75 13870760

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