Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and medical uses thereof

Abstract

The present disclosure relates to compounds and methods for inhibiting Leucine-Rich Repeat Kinase 2 (LRRK2), the methods comprising administering to the subject a compound of Formula (I). In some embodiments, the disclosure provides compounds and methods for treating cancer.

Description

[0001] TITLE OF THE INVENTION

[0002] INHIBITORS OF LEUCINE-RICH REPEAT KINASE 2 (LRRK2) AND MEDICAL USES THEREOF

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to, and benefit of, U.S. Provisional Application No. 63 / 575,982, filed April 8, 2024, which is hereby incorporated by reference in its entirety.

[0005] BACKGROUND OF THE INVENTION

[0006] Leucine-rich repeat kinase 2 (LRRK2), encoded by LRRK2 gene, is a multidomain protein. LRRK2, in addition to its kinase domain, possesses a second enzymatic guanosine triphosphatase (GTPase) domain and other domains and motifs that are involved in proteinprotein interactions. The scaffolding function of LRRK2 also plays an important functional role in both the canonical / p-catenin and non-canonical / PCP Wnt signaling pathways. LRRK2 appears to act as a scaffolding protein in these pathways where overexpression of LRRK2 represses canonical Wnt signaling while activating the non-canonical / PCP pathway. Pathological mutations in the kinase domain and GTPase domain of LRRK2 can increase the kinase activity of LRRK2 and eventually lead to pathogenic hallmarks associated with cancer, Alzheimer’s disease (AD), and Parkinson’s Disease (PD), such as ciliogenesis inhibition, defective mitophagy and autophagy, and mitochondrial dysfunction. LRRK2 is a promising target for Parkinson’s disease, as 1-3% of sporadic and 4-8% of familial PD cases exhibit increased LRRK2 kinase activity. Activity, independent of LRRK2 mutations, has also been reported in idiopathic PD patients. Conversely, LRRK2 knockout or pharmacological inhibition of LRRK2 kinase activity is neuroprotective in cellular and animal models. The overall prevalence of the LRRK2 G2019S mutation was 11.4% among all patients with PD. Mutation carriers were younger at PD diagnosis and more likely to be women (53.1%) and of Ashkenazi Jewish descent (76.8%) in comparison with individuals who were not mutation carriers.

[0007] Thus, there is a need in the art for improved compositions and methods for the inhibiting LRRK2 and treating diseases associated with its overactivity. This invention satisfies this unmet need. SUMMARY OF THE INVENTION

[0008] In some embodiments, the present invention provides a compound of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0009] Formula (I), wherein: Z1is selected from the group consisting of S(O)2, S(O), S(O)(NH), and N-L- Ubiig; X1is selected from the group consisting of N, C, and CH, wherein: when X1is N, X2is CR5and the bond between X1and X2is a single bond; when X1is C, X2is CR5and the bond between X1and X2is a double bond; and when X1is CH, X2is CR5R?and the bond between X1and X2is a single bond; each of X3, X4, and X?is independently selected from the group consisting of O, S, NR6, and CR7R7; each of A1, A2, and A3is independently selected from the group consisting of an aromatic ring and a heteroaromatic ring; each of RA1, RA2, and RA3represents mono to the maximum allowable substitution; each occurrence of RA1, R^2, and RA3is independently selected from the group consisting of H, D, F, Me, CF3, OCH3, OCD3, and OCF3; each of R1, R1, R2, R2, R3, R3, R5, R5, R6, R7, R7, are independently selected from the group consisting of H, D, F, Me, CF3, OMe, and OCF3; Rsis selected from the group consisting of CH3, CD3, and CF3; L is a divalent linking group; and Ubiig is an E3 ubiquitin ligase ligand.

[0010] In some embodiments, A1, A2, and A3are each independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A1, A2, and A3is optionally further substituted. In some embodiments, -XLALX3- is represented by wherein: each of Z2, Z3, Z4, and Z5is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D, F, Me, CF3, OCH3, OCD3, and OCF3. In some embodiments, each of Z2, Z3, Z4, and Z5is CRZ. In some embodiments, Z2, Z4, and Z5are CH; and Z3is CRZ, wherein Rzis selected from the group consisting of D, F, Me, CF3, OCH3, OCD3, and OCF3. In some embodiments, -X3-A2-X4- is represented by wherein: each of Z6, Z7, Z8, and Z9is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D, F, Me, CF3, OCH3, OCD3, and OCF3. In some embodiments, Z6and Z9are each N; and Z7and Z8are CRZ. In some embodiments, Z7is CH; and Z8is CRZ, wherein Rzis selected from the group consisting of D, F, Me, CF3, OCH3, OCD3, and OCF3.

[0011] In some embodiments, -X4-A3-X5- is represented by wherein: each of Z10, Z11, Z12, and Z13is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D, F, Me, CF3, OCH3, OCD3, and OCF3. In some embodiments, each of Z10, Z11, Z12, and Z13is CRZ. In some embodiments, each instance of Rzis H.

[0012] In some embodiments, at least one of X3, X4, and X5is NH. In some embodiments, each ofX3, X4, and X5is NH.

[0013] In some embodiments, Rsis CH3.

[0014] In some embodiments, Z1is N-L-Ubiigand L is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0015] In some embodiments, Z1is N-L-Ubiig and Ubiig is selected from the group consisting of pomalidomide, Von Hippel-Lindau (VHL), thalidomide, lenalidomide, iberdomide, avadomide, apremilast, Mouse double minute 2 homolog (MDM2), bestatin, and an MV1 derivative.

[0016] In some embodiments, the compound of Formula (I) is a compound of Formula (II):

[0017]

[0018] Formula (II), wherein: R8is selected from the group consisting of D, F, Me, CF3, OMe, and OCF3; each of Z6, Z7, Z8, and Z9is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D, F, Me, CF3, OCH3, OCD3, and OCF3. In some embodiments, Z6and Z9are N; and Z7and Z8are CRZ. In some embodiments, Z7is CH; and Z8is CRZ, wherein Rzis selected from the group consisting of D, F, Me, CF3, OCH3, OCD3, and OCF3.

[0019] In some embodiments, at least one of X3and X4is NH. In some embodiments, each of X3and X4are NH.

[0020] In some embodiments, Z1is N-L-Ubiigand L is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0021] In some embodiments, Z1is N-L-Ubiig and Ubiig is selected from the group consisting of pomalidomide, Von Hippel-Lindau (VHL), thalidomide, lenalidomide, iberdomide, avadomide, apremilast, Mouse double minute 2 homolog (MDM2), bestatin, and an MV1 derivative.

[0022] In some embodiments, the compound of Formula (I) is selected from the group consisting

[0023] pharmaceutically acceptable salt or solvate thereof.

[0024] In some embodiments, the compound of Formula (I) is selected from the group consisting of:

[0025] thereof, wherein R and R’ are each independently selected from the group consisting of H, D, Ci-Cio alkylene, C3-C10 cycloalkylene, C1-C10 heteroalkylene, C3-C10 heterocycloalkylene, C2- C10 alkenylene, C2-C10 alkynylene, arylene, heteroarylene, amide, ester, ether, carbonyl, and combinations thereof. In some embodiments, the present invention provides a method of decreasing leucine-rich repeat kinase 2 (LRRK2) activity in a subject comprising administering to the subject the compound of the present invention.

[0026] In some embodiments, the present invention provides a method of treating a disease or disorder associated with increased LRRK2 activity in a subject comprising administering to the subject the compound of the present invention. In some embodiments, the disease or disorder associated with LRRK2 activity is selected from the group consisting of cancer, Parkinson’s disease, Alzheimer’s disease, leprosy, fibrosis, and inflammatory diseases and disorders.

[0027] In some embodiments, the inflammatory disease or disorder is selected from the group consisting of peritonitis, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, graft vs. host disease, osteoporosis, multiple myeloma-related bone disorder, leukemias and related disorders, myelodysplastic syndrome, acute myelogenous leukemia, chlonal hematopoesis, anemia of chronic diseases, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, infectious hepatitis, juvenile diabetes, lichen planus, acute dermatomyositis, eczema, primary cirrhosis, uveitis, Behcet's disease, atopic skin disease, pure red cell aplasia, aplastic anemia, amyotrophic lateral sclerosis, nephrotic syndrome, burns, bronchitis, tendinitis, bursitis, periarteritis nodosa, thyroiditis, Hodgkin's disease, rheumatic fever, sarcoidosis, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, allergic rhinitis, endotoxin shock syndrome, atherosclerosis, psoriatic arthritis, vasculitis, Polymyalgia, Rheumatica, Wegener's granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection, and ataxia telangiectasia. In some embodiments, the fibrosis is one or more selected from the group consisting of renal fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, Crohn’s disease, liver fibrosis, heart fibrosis, scleroderma, or progressive massive fibrosis.

[0028] In some embodiments, the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, uterine cancer, acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma, carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellulare, glandular carcinoma, granulose cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, carcinoma medullare, medullary carcinoma, carcinoma melanodes, melanotonic carcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocullare, mucoepidermoid carcinoma, mucous carcinoma, carcinoma myxomatodes, masopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteroid carcinoma, ovarian carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, scheinderian carcinoma, scirrhous carcinoma, carcinoma scrota, signet-ring cell carcinoma, carcinoma simplex, small cell carcinoma, solandoid carcinoma, pancreatic, breast, melanoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, carcinoma vilosum liposarcomas, leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors, primitive neuroectodermal tumors (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST), osteosarcoma (also known as osteogenic sarcoma) skeletal and extra-skeletal, chondrosarcoma, mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acutelymphoblastic leukemia, Burkitt lymphoma, myeloma, immunocytoma, acute promyelocyte leukemia, chronic myeloid / acute lymphoblastic leukemia, acute leukemia, B-cell acute lymphoblastic leukemia, anaplastic large cell leukemia, myelodysplasia syndrome / acute myeloid leukemia, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia (AML), common (pre-B) acute lymphocytic leukemia, malignant melanoma, T-cell lymphoma, leukemia, B-cell lymphoma, epithelial malignancies, lymphoid malignancies, gynecologic carcinoma, pancreatic biliary adenocarcinoma, and pancreatic ductal adenocarcinomas. In some embodiments, the compound of the present invention is administered in combination with one or more therapies selected from the group consisting of radiation therapy, surgery, chemotherapy, and immune checkpoint inhibitors.

[0029] In some embodiments, the therapy comprises one or more selected from the group consisting of alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinum agents, topoisomerase I inhibitors, topoisomerase II inhibitors, vinca alkaloids, taxanes, nucleoside analogs, angiogenesis inhibitors, anti neoplastic agents, and chemotherapeutic agents.

[0030] In some embodiments, the present invention provides a method of inhibiting angiogenesis in a subject comprising administering to the subject the compound of the present invention.

[0031] In some embodiments, the present invention provides a method of sensitizing a tumor in a subject to treatment comprising administering to the subject the compound of the present invention.

[0032] In some embodiments, the present invention provides a method of treating a pain disorder in a subject comprising administering to the subject the compound of the present invention. In some embodiments, the pain disorder is one or more selected from the group consisting of inflammatory pain, post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and post-herpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain. In some embodiments, the pain disorder comprises neuropathic or nociceptive pain. In some embodiments, the subject with a pain disorder comprising neuropathic pain has one or more selected from the group consisting of spinal cord injury, multiple sclerosis, stroke, diabetes, herpes zoster infection, HIV infection, nutritional deficiencies, exposure to toxins, remote manifestations of malignancies, immune-related disorders, and physical trauma to the nerve trunk.

[0033] In some embodiments, the present invention provides a method of reducing autophagy in a cell comprising contacting the cell with a compound of the present invention. In some embodiments, the present invention provides a method of inhibiting replication of a cell comprising contacting the cell with a compound of the present invention. In some embodiments, the present invention provides a method of reducing cancer cell viability comprising contacting the cell with a compound of the present invention.

[0034] In some embodiments, the cell has a mutation in an fms-like receptor tyrosine kinase 3 (FLT-3) gene. In some embodiments, the mutation in an FLT-3 gene is an internal tandem duplication (ITD) mutation.

[0035] BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The following detailed description of embodiments of the invention will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0037] Figure 1 depicts representative survival curves of patients with ovarian cystadenocarcinoma having high (n = 72) or low (n = 303) leucine-rich repeat kinase 2 (LRRK2) expression, demonstrating LRRK2 overexpression predicts poor survival (p = 0.046). Figure 2 depicts representative survival curves of patients with ovarian adenocarcinoma having high (n = 99) or low (n = 8) LRRK2 expression, demonstrating LRRK2 overexpression predicts poor survival (p = 0.099).

[0038] Figure 3 depicts representative survival curves of patients with colon cancer having high (n = 128) or low (n = 469) LRRK2 expression, demonstrating LRRK2 overexpression predicts poor survival (p = 0.0064).

[0039] Figure 4 depicts representative survival curves of patients with colon cancer having high (n = 55) or low (n = 269) LRRK2 expression, demonstrating LRRK2 overexpression predicts poor survival (p = 0.025). The average 5-year survival for patients with high LRRK2 expression is 24%, while patients with low expression exhibit a 40% survival rate.

[0040] Figure 5 depicts representative survival curves of patients with liver cancer having high (n = 238) or low (n = 127) LRRK2 expression, demonstrating LRRK2 overexpression predicts poor survival (p = 0.27). The average 5-year survival for patients with high LRRK2 expression is 45%, while patients with low expression exhibit a 54% survival rate.

[0041] Figure 6 depicts representative survival curves of patients with urothelial cancer having high (n = 283) or low (n = 123) LRRK2 expression, demonstrating LRRK2 overexpression predicts poor survival (p = 0.0052). The average 5-year survival for patients with high LRRK2 expression is 34%, while patients with low expression exhibit a 60% survival rate.

[0042] Figure 7 depicts representative survival curves of patients with melanoma having high (n = 53) or low (n = 49) LRRK2 expression, demonstrating LRRK2 overexpression predicts poor survival (p = 0.22). The average 5-year survival for patients with high LRRK2 expression is 18%, while patients with low expression exhibit a 57% survival rate.

[0043] Figure 8 depicts representative LRRK2 inhibition data with UR-032 and UR-0442. The ICso values for UR-032 and UR-044 were found to be 8.595 nM and 6.919 nM, respectively, with maximum curve slopes of -1.626 and -1.332, respectively.

[0044] Figure 9 depicts representative images of Western blots demonstrating that UR-032 inhibits production of autophagy proteins X-box binding protein 1 first isoform (XBP-1S) and microtubule-associated proteins 1 A / lb light chain 3B (LC3) in MOLM-13 (left) and MV-4-11 (right) monocytic leukemia cells carrying an FLT3 mutation.

[0045] Figure 10 depicts representative cell stage distribution of MOLM-13 cells demonstrating that UR-032 inhibits cells from exiting the G1 growth phase. Figure 11 depicts representative results demonstrating that UR-032 reduces the viability of MOLM-13 (top left) and MV-4-11 (top right) monocytic leukemia cells, which carry an FLT3 mutation, but does not impact viability of THP-1 (bottom) leukemia cells, which have wildtype FLT3.

[0046] Figure 12 depicts representative results demonstrating that prophylactic exposure of MOLM-13 leukemia cells to UR-032 inhibits tumor growth in an NSG tumor xenograph model. MOLM-13 cells were pretreated once with DMSO (control) or 20 pM UR-032 in DMSO overnight and implanted.

[0047] DETAILED DESCRIPTION

[0048] In one aspect, the disclosure is based in part on the unexpected finding of novel compounds which inhibit leucine-rich repeat kinase 2 (LRRK2). In some embodiments, these compounds are useful for treating diseases and / or disorders associated with LRRK2 overexpression. For example, in some embodiments, the compounds of the disclosure may treat cancer. In some embodiments, the compounds may treat neurodegenerative diseases.

[0049] Definitions

[0050] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0051] As used herein, each of the following terms has the meaning associated with it in this section.

[0052] The articles “a” and “an” are used herein to refer to one or to more than one ( / .e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0053] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0054] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0055] A disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.

[0056] The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human.

[0057] As used herein, the term “pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0058] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs or symptoms of pathology disease or disorder, for the purpose of diminishing or eliminating those signs or symptoms.

[0059] As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, i.e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder contemplated herein, a sign or symptom of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a disease or disorder contemplated herein, the signs or symptoms of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

[0060] As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a sufficient amount of an agent to provide the desired biological or physiologic result. That result may be reduction and / or alleviation of a sign, a symptom, or a cause of a disease or disorder, or any other desired alteration of a biological system. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0061] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0062] As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, paratoluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like. Furthermore, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), and ammonium salts.

[0063] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0064] As used herein, the term “potency” refers to the dose needed to produce half the maximal response (ED50).

[0065] As used herein, the term “efficacy” refers to the maximal effect (Emax) achieved within an assay.

[0066] As used herein, “activity” includes physiological activity, binding affinity, and / or the enzymatic activity of a molecule.

[0067] As used herein, “LRRK2” refers to leucine-rich repeat kinase 2. As used herein, “associated” refers to coincidence with the development or manifestation of a disease, condition, or phenotype. Association may be due to, but is not limited to, genes responsible for housekeeping functions, those that are part of a pathway that is involved in a specific disease, condition, or phenotype and those that indirectly contribute to the manifestation of a disease, condition or phenotype.

[0068] As used herein, the term “cancer” refers to any of various types of malignant neoplasms, most of which invade surrounding tissues, may metastasize to several sites and are likely to recur after attempted removal and to cause death of the patient unless adequately treated. As used herein, neoplasia comprises cancer. Representative cancers include, for example, squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias, including non-acute and acute leukemias, such as acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, T-lineage acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, neutrophilic leukemia and stem cell leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas, among others, which may be treated by one or more compounds of the present invention.

[0069] As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. Ci-6 means one to six carbon atoms) and including straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl.

[0070] As used herein, the term “substituted alkyl” means alkyl as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, -OH, alkoxy, -NH2, amino, azido, -N(CH3)2, -C(=O)OH, trifluoromethyl, -C=N, -C(=O)O(Ci-C4)alkyl, -C(=0)NH2, -SO2NH2, -C(=NH)NH2, and -NO2. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2-carboxy cyclopentyl and 3 -chloropropyl.

[0071] As used herein, the term “heteroalkyl” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quatemized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(=O)-CH3, and -CH2-CH2-S(=O)2-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-O-CH3 or -CH2-CH2-S-S-CH3.

[0072] As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.

[0073] As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0074] As used herein, the term “cycloalkyl” refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl group is saturated or partially unsaturated. In another embodiment, the cycloalkyl group is fused with an aromatic ring. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moi eties:

[0075] Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycyclic cycloalkyls include adamantine and norbornane. The term cycloalkyl includes “unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon double bond or one carbon triple bond.

[0076] As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, S and N. In some embodiments, each heterocycloalkyl group has from 4 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms. In another embodiment, the heterocycloalkyl group is fused with an aromatic ring. In some embodiments, the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quatemized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. A heterocycle may be aromatic or nonaromatic in nature. In some embodiments, the heterocycle is a heteroaryl.

[0077] An example of a 3-membered heterocycloalkyl group includes, and is not limited to, aziridine. Examples of 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam. Examples of 5-membered heterocycloalkyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine and piperazine. Other non-limiting examples of heterocycloalkyl groups are:

[0078]

[0079] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2, 3 -dihydrofuran, 2, 5 -dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran,

[0080] 2.3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine,

[0081] 1.3-dioxepane, 4,7-dihydro-l,3-dioxepin, and hexamethyleneoxide.

[0082] As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n + 2) delocalized it (pi) electrons, where n is an integer.

[0083] As used herein, the term “aryl,” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples of aryl groups include phenyl, anthracyl, and naphthyl.

[0084] As used herein, the term “aryl-(Ci-C3)alkyl” means a functional group wherein a one- to three-carbon alkylene chain is attached to an aryl group, e.g., -CfbCfk-phenyl. In some embodiments, aryl-(Ci-C3)alkyl is aryl-CH2- or aryl-CH(CH3)-. The term “substituted aryl-(Ci-C3)alkyl” means an aryl-(Ci-C3)alkyl functional group in which the aryl group is substituted. Similarly, the term “heteroaryl-(Ci-C3)alkyl” means a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g, -CHzCHz-pyridyl. The term “substituted heteroaryl-(Ci-C3)alkyl” means a heteroaryl-(Ci-C3)alkyl functional group in which the heteroaryl group is substituted.

[0085] As used herein, the term “heteroaryl” or “heteroaromatic” refers to a heterocycle having aromatic character. A polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include the following moi eties:

[0086] Examples of heteroaryl groups also include pyridyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

[0087] Examples of polycyclic heterocycles and heteroaryls include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (particularly 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (particularly 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

[0088] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. The term “substituted” further refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In some embodiments, the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two.

[0089] As used herein, the term “optionally substituted” means that the referenced group may be substituted or unsubstituted. In some embodiments, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

[0090] In some embodiments, the substituents are independently selected from the group consisting of oxo, halogen, -CN, -NHz, -OH, -NH(CH3), -N(CH3)2, alkyl (including straight chain, branched and / or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, fluoro alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy, -S-alkyl, S(=O)2alkyl, -C(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -C(=O)N[H or alkyl]?, - OC(=O)N[substituted or unsubstituted alkyl]2, -NHC(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -NHC(=O)alkyl, -Nfsubstituted or unsubstituted alkyl]C(=O)[substituted or unsubstituted alkyl], -NHC(=O)[substituted or unsubstituted alkyl], -C(OH)[substituted or unsubstituted alkyl]2, and -C(NH2)[substituted or unsubstituted alkyl]2. In another embodiment, by way of example, an optional substituent is selected from oxo, fluorine, chlorine, bromine, iodine, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2CF3, -0CH3, -OCH2CH3, -OCH(CH3)2, -OCF3, - OCH2CF3, -S(=O)2-CH3, -C(=O)NH2, -C(=O)-NHCH3, -NHC(=O)NHCH3, -C(=O)CH3, -ON(O)2, and -C(=O)OH. In yet one embodiment, the substituents are independently selected from the group consisting of C1-6 alkyl, -OH, C1-6 alkoxy, halo, amino, acetamido, oxo and nitro. In yet another embodiment, the substituents are independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halo, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic.

[0091] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0092] Compounds

[0093] The compounds of the present disclosure may be synthesized using techniques well- known in the art of organic synthesis. The starting materials and intermediates required for the synthesis may be obtained from commercial sources or synthesized according to methods known to those skilled in the art.

[0094] In one aspect, the disclosure provides compounds of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0095] Formula (I), wherein:

[0096] Z1is selected from the group consisting of S(O)2, S(O), S(O)(NH), and N-L-Ubiig;

[0097] X1is selected from the group consisting of N, C, and CH, wherein: when X1is N, X2is CR5and the bond between X1and X2is a single bond; when X1is C, X2is CR5and the bond between X1and X2is a double bond; and when X1is CH, X2is CR3R5and the bond between X1and X2is a single bond; each of X3, X4, and X5is independently selected from the group consisting of O, S, NR6, and CR7R7; each of A1, A2, and A3is independently selected from the group consisting of an aromatic ring and a heteroaromatic ring; each of RA1, R^2, and RA3represents mono to the maximum allowable substitution, or no substitution; each occurrence of RA1, RA2, and RA3is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3; each of R1, R1, R2, R2, R3, R3, R5, R5, R7, and R7is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3, Cl, Br, ;

[0098] R6is selected from the group consisting of H, D, C1-C10 alkylene, C3-C10 cycloalkylene, C1-C10 heteroalkylene, C3-Cio heterocycloalkylene, C2-C10 alkenylene, C2- C10 alkynylene, arylene, heteroarylene, amide, ester, ether, carbonyl, and combinations thereof;

[0099] Rsis selected from the group consisting of CH3, CD3, and CF3, Cl, 0CH3, OCF3;

[0100] L is a divalent linking group; and

[0101] Ubiig is an E3 ubiquitin ligase ligand.

[0102] In some embodiments, Z1is selected from the group consisting of S(O)2, S(O), S(O)(NH), and N-L-Ubiig. In some embodiments, Z1is S(O)2. In some embodiments, Z1is S(O). In some embodiments, Z1is S(O)(NH). In some embodiments, Z1is N-L-Ubiig.

[0103] In some embodiments, X1is selected from the group consisting of N, C, and CH, wherein: when X1is N, X2is CR5and the bond between X1and X2is a single bond; when X1is C, X2is CR5and the bond between X1and X2is a double bond; and when X1is CH, X2is CR5R3and the bond between X1and X2is a single bond. In some embodiments, X1is N, X2is CR5, and the bond between X1and X2is a single bond. In some embodiments, X1is N, X2is CR5, and the bond between X1and X2is a double bond. In some embodiments, X1is C, X2is CR5R”, and the bond between X1and X2is a single bond.

[0104] In some embodiments, each of X3, X4, and X5is independently selected from the group consisting of O, S, NR6, and CR7R7. In some embodiments, X3is NR6and X4and X5are each independently selected from the group consisting of O, S, NR6, and CR7R7. In some embodiments, X3is NH and X4and X3are each independently selected from the group consisting of O, S, NR6, and CR7R7. In some embodiments, X4is NR6and X3and X5are each independently selected from the group consisting of O, S, NR6, and CR7R7. In some embodiments, X4is NH and X3and X3are each independently selected from the group consisting of O, S, NR6, and CR7R7. In some embodiments, X5is NR6and X3and X4are each independently selected from the group consisting of O, S, NR6, and CR7R7. In some embodiments, X5is NR6and X3and X4are each independently selected from the group consisting of O, S, NR6, and CR7R7. In some embodiments, X3, X4, and X5are all NR6. In some embodiments, X3, X4, and X5are all NH.

[0105] In some embodiments, each of A1, A2, and A3is independently selected from the group consisting of an aromatic ring and a heteroaromatic ring. In some embodiments, A1is an aromatic ring and A2and A3are each independently selected from the group consisting of an aromatic ring and a heteroaromatic ring. In some embodiments, A2is a heteroaromatic ring and A1and A3are each independently selected from the group consisting of an aromatic ring and a heteroaromatic ring. In some embodiments, A3is an aromatic ring and A1and A2are each independently selected from the group consisting of an aromatic ring and a heteroaromatic ring. In some embodiments, A1and A3are aromatic rings and A2is a heteroaromatic ring.

[0106] In some embodiments, each of RA1, RA2, and RA3each represent mono to the maximum allowable substitution, or no substitution. In some embodiments, RA1, RA2, and RA3each represent no substitution. In some embodiments, RA1, R^, and RA3each represent mono substitution. In some embodiments, RA1, RA2, and RA3each represent the maximum allowable substitution. In some embodiments, RA1represents mono and RA2and RA3each represent mono to the maximum allowable substitution or no substitution. In some embodiments, RA2represents mono substitution and RA1and R43each represent mono to the maximum allowable substitution or no substitution. In some embodiments, RA3represents no substitution and RA1and RA2each represent mono to the maximum allowable substitution or no substitution. In some embodiments, RA1and RA2each represent mono substitution and RA3represents no substitution.

[0107] In some embodiments, each occurrence ofRA1, RA2, and RA3is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, RA1represents mono substitution and is selected from the group consisting of D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, RA1is selected from the group consisting of OCH3, OCD3, and OCF3. In some embodiments, RA2represents mono substitution and is selected from the group consisting of D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, RA2is F. In some embodiments, RA3represents no substitution.

[0108] In some embodiments, A1, A2, and A3are each independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A1, A2, and A3is optionally further substituted. In some embodiments, A1is phenyl and A2and A3are each independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A2and A3is optionally further substituted. In some embodiments, A1is substituted phenyl and A2and A3are each independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A2and A3is optionally further substituted. In some embodiments, RA2is pyrimidinyl and A1and A3are each independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A1and A3is optionally further substituted. In some embodiments, RA2is substituted pyrimidinyl and A1and A3are each independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A1and A3is optionally further substituted. In some embodiments, A3is phenyl and A1and A2are each independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A1and A2is optionally further substituted. In some embodiments, RA3is substituted phenyl and A1and A2are each independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A1and A2is optionally further substituted. In some embodiments, A1is substituted phenyl, A2is pyrimidinyl, and RA3is phenyl.

[0109] In some embodiments, -X^A^X3- is represented wherein: each of Z2, Z3, Z4, and Z5is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D,

[0110] F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

[0111] In some embodiments, each of Z2, Z3, Z4, and Z5is selected from the group consisting of N and CRZ. In some embodiments, each of Z2, Z3, Z4, and Z5is CRZ. In some embodiments, each of Z2, Z3, Z4, and Z5is CH. In some embodiments, both of Z2and Z?are CH and one of Z3and Z4is CH, and the other is selected from the group consisting of OCH3, OCD3, and OCF3.

[0112] Z6' z^7Z8 z X

[0113] In some embodiments, -X3-A2-X4- is represented byzx3z9x4, wherein: each of Z6, Z7, Z8, and Z9is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

[0114] In some embodiments, each of Z6, Z7, Z8, and Z9is selected from the group consisting of N and CRZ. In some embodiments, Z6and Z9are both N and Z7and Z8are both CRZ. In some embodiments, Z6and Z9are both N, Z7is CH, and Z8is CRZ. In some embodiments, Z6and Z9are both N, Z7is CH, and Z8is CF.

[0115] In some embodiments, -X4-A3-X5- is represented wherein: each of Z10, Z11, Z12, and Z13is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D,

[0116] F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

[0117] In some embodiments, each of Z10, Z11, Z12, and Z13is selected from the group consisting ofN and CRZ. In some embodiments, each ofZ10, Z11, Z12, and Z13is CRZ. In some embodiments, each ofZ10, Z11, Z12, and Z13is CH.

[0118] In some embodiments, each instance of R1, R1, R2, R2, R3, R3, R5, R5, R7, and R7is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, R1, R1, R2, R2, R3, and R3are all H. In some embodiments, R1, R1, R2, R2, R3, and R3’are all D.

[0119] In some embodiments, X1is C, X2is CR5and R5is selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, R5is H. In some embodiments, X1is CH, X2is CR5R and R5and R5are each independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, R5and R5’ are both H.

[0120] In some embodiments, one or more of X3, X4, and X5is CR7R7and each instance of R7and R7is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, R7and R7are both H.

[0121] In some embodiments, one or more of X3, X4, and X5is NR6and each instance of R6is independently selected from the group consisting of H, D, C1-C10 alkylene, C3-C10 cycloalkylene, Ci-Cio heteroalkylene, C3-C10 heterocycloalkylene, C2-C10 alkenylene, C2-C10 alkynylene, arylene, heteroarylene, amide, ester, ether, carbonyl, and combinations thereof. In some embodiments, R6is H.

[0122] In some embodiments, Rsis selected from the group consisting of CH3, CD3, and CF3. In some embodiments, Rsis CH3. In some embodiments, Rsis CD3. In some embodiments, Rsis CF3.

[0123] In some embodiments, Z1is N-L-Ublig and L is a divalent linking group. In some embodiments, L is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0124] In some embodiments, Z1is N-L-Ublig and Ubiig is selected from the group consisting of piperidine-2, 6-dione, (R)-3-phenylpiperidine-2, 6-dione, (S)-3-phenylpiperidine-2, 6-dione, pomalidomide, a Von Hippel-Lindau ligand, thalidomide, lenalidomide, iberdomide, avadomide, apremilast, bestatin, methyl bestatin, and an MV1 derivative.

[0125] In some embodiments, the compound of Formula (I) is a compound of Formula (II):

[0126] Formula (II), wherein:

[0127] R8is selected from the group consisting of D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3; each of Z6, Z7, Z8, and Z9is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, Z1is selected from the group consisting of S(O)2, S(O), S(O)(NH), and N-L-Ubiig. In some embodiments, Z1is S(O)2. In some embodiments, Z1is S(O). In some embodiments, Z1is S(O)(NH). In some embodiments, Z1is N-L-Ubiig.

[0128] In some embodiments, X1is selected from the group consisting of N, C, and CH, wherein: when X1is N, X2is CR5and the bond between X1and X2is a single bond; when X1is C, X2is CR5and the bond between X1and X2is a double bond; and when X1is CH, X2is CR5R5and the bond between X1and X2is a single bond.

[0129] In some embodiments, each of R1, R1, R2, R2, R3, and R3is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, R1, R1, R2, R2, R3, and R3’are all H.

[0130] In some embodiments, R8is selected from the group consisting of D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, R8is selected from the group consisting of OCH3, OCD3, and OCF3.

[0131] In some embodiments, each of X3and X4is independently selected from the group consisting of O, S, NR6, and CR7R7. In some embodiments, X3is NR6and X4is selected from the group consisting of O, S, NR6, and CR7R7. In some embodiments, X4is NR6and X3is selected from the group consisting of O, S, NR6, and CR7R7. In some embodiments, both X3and X4are NR6.

[0132] In some embodiments, at least one of X3and X4is NR6and each instance of R6is selected from the group consisting of H, D, C1-C10 alkylene, C3-C10 cycloalkylene, C1-C10 heteroalkylene, C3-C10 heterocycloalkylene, C2-C10 alkenylene, C2-C10 alkynylene, arylene, heteroarylene, amide, ester, ether, carbonyl, and combinations thereof. In some embodiments, X3is NR6and R6is H. In some embodiments, X4is NR6and R6is H. In some embodiments, X3and X4are both NR6and each instance of R6is selected from the group consisting of H, D, C1-C10 alkylene, C3-C10 cycloalkylene, C1-C10 heteroalkylene, C3-C10 heterocycloalkylene, C2-C10 alkenylene, C2-C10 alkynylene, arylene, heteroarylene, amide, ester, ether, carbonyl, and combinations thereof. In some embodiments, each instance of R6is H.

[0133] In some embodiments, at least one of X3and X4is CR7R7and each instance of R7and R7’ are each independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, X3and X4are both CR7R7and each instance of R7and R7’ are each independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

[0134] In some embodiments, each of Z6, Z7, Z8, and Z9is selected from the group consisting of N and CRZ. In some embodiments, Z6and Z9are both N and Z7and Z8are both CRZ. In some embodiments, Z6and Z9are both N, Z7is CH, and Z8is CF.

[0135] In some embodiments, Rsis selected from the group consisting of CH3, CD3, and CF3. In some embodiments, Rsis CH3. In some embodiments, Rsis CD3. In some embodiments, Rsis CF3.

[0136] In some embodiments, Z1is N-L-Ubiig and L is a divalent linking group. In some embodiments, L is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0137] In some embodiments, Z1is N-L-Ubiig and Ubiig is selected from the group consisting of piperidine-2, 6-dione, (R)-3-phenylpiperidine-2, 6-dione, (S)-3-phenylpiperidine-2, 6-dione, pomalidomide, a Von Hippel-Lindau ligand, thalidomide, lenalidomide, iberdomide, avadomide, apremilast, bestatin, methyl bestatin, and an MVl derivative.

[0138] In some embodiments, the compound of Formula (I) is selected from the group consisting of:

[0139] thereof, wherein R and R’ are each independently selected from the group consisting of H, D, Ci- Cio alkylene, C3-C10 cycloalkylene, C1-C10 heteroalkylene, C3-C10 heterocycloalkylene, C2-C10 alkenylene, C2-C10 alkynylene, arylene, heteroarylene, amide, ester, ether, carbonyl, and combinations thereof. The compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration. In some embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In some embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In another embodiment, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0140] The compounds described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound of the invention, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In another embodiment, the compounds described herein exist in unsolvated form.

[0141] In some embodiments, the compounds of the invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0142] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. In some embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In another embodiment, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0143] In some embodiments, sites on, for example, the aromatic ring portion of compounds of the invention are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In some embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.

[0144] Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,nC,13C,14C,36C1,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In some embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet another embodiment, substitution with positron emitting isotopes, such asnC,18F,1?O and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent otherwise employed.

[0145] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0146] The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference in their entirety). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein.

[0147] In some embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In another embodiment, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0148] In some embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t- butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.

[0149] In some embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidativelyremovable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with fluoride labile silyl carbamates.

[0150] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react.

[0151] Once released from the resin, the functional group is available to react.

[0152] Typically blocking / protecting groups may be selected from: Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

[0153] Methods

[0154] In some embodiments, the disclosure provides methods of inhibiting LRRK1 activity in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a composition comprising a compound of the disclosure. In some embodiments, the compound of the disclosure binds to LRRK1 thereby inhibiting its activity.

[0155] In some embodiments, the disclosure provides methods comprising administering to a subject a compound of the disclosure. In some embodiments, the subject has a disease or disorder associated with LRRK1 activity. In some embodiments, the disclosure provides method of treating or preventing a disease or disorder associated with LRRK1 activity. As used herein, the term “disease or disorder associated with LRRK1 activity” refers to any disease, disorder, or condition which is caused or characterized by abnormal LRRK1 enzymatic activity or LRRK1 overexpression. Exemplary diseases or disorders associated with LRRK1 activity include, but are not limited to cancer, Parkinson’s disease, Alzheimer’s disease, leprosy, fibrosis, and inflammatory diseases and disorders.

[0156] In some embodiments, the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, uterine cancer, acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma, carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellulare, glandular carcinoma, granulose cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, carcinoma medullare, medullary carcinoma, carcinoma melanodes, melanotonic carcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocullare, mucoepidermoid carcinoma, mucous carcinoma, carcinoma myxomatodes, masopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteroid carcinoma, ovarian carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, scheinderian carcinoma, scirrhous carcinoma, carcinoma scrota, signet-ring cell carcinoma, carcinoma simplex, small cell carcinoma, solandoid carcinoma, pancreatic, breast, melanoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, carcinoma vilosum liposarcomas, leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors, primitive neuroectodermal tumors (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST), osteosarcoma (also known as osteogenic sarcoma) skeletal and extra-skeletal, chondrosarcoma, mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acutelymphoblastic leukemia, Burkitt lymphoma, myeloma, immunocytoma, acute promyelocyte leukemia, chronic myeloid / acute lymphoblastic leukemia, acute leukemia, B-cell acute lymphoblastic leukemia, anaplastic large cell leukemia, myelodysplasia syndrome / acute myeloid leukemia, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia (AML), common (pre-B) acute lymphocytic leukemia, malignant melanoma, T-cell lymphoma, leukemia, B-cell lymphoma, epithelial malignancies, lymphoid malignancies, gynecologic carcinoma, pancreatic biliary adenocarcinoma, and pancreatic ductal adenocarcinomas.

[0157] In some embodiments, the fibrosis is one or more selected from the group consisting of renal fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, Crohn’s disease, liver fibrosis, heart fibrosis, scleroderma, or progressive massive fibrosis.

[0158] In some embodiments, the inflammatory disease or disorder is selected from the group consisting of peritonitis, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, graft vs. host disease, osteoporosis, multiple myeloma-related bone disorder, leukemias and related disorders, myelodysplastic syndrome, acute myelogenous leukemia, chlonal hematopoesis, anemia of chronic diseases, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, infectious hepatitis, juvenile diabetes, lichen planus, acute dermatomyositis, eczema, primary cirrhosis, uveitis, Behcet's disease, atopic skin disease, pure red cell aplasia, aplastic anemia, amyotrophic lateral sclerosis, nephrotic syndrome, burns, bronchitis, tendinitis, bursitis, periarteritis nodosa, thyroiditis, Hodgkin's disease, rheumatic fever, sarcoidosis, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, allergic rhinitis, endotoxin shock syndrome, atherosclerosis, psoriatic arthritis, vasculitis, Polymyalgia, Rheumatica, Wegener's granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection, and ataxia telangiectasia.

[0159] In some embodiments, the disclosure provides methods of treating cancer in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the disclosure.

[0160] In some embodiments, the method further comprises administering to the subject at least one additional therapy. In some embodiments, the therapy is selected from the group consisting of a selected from the group consisting of radiation therapy, surgery, chemotherapy, checkpoint inhibitors, and combinations thereof.

[0161] In some embodiments, the therapy comprises one or more selected from the group consisting of alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinum agents, topoisomerase I inhibitors, topoisomerase II inhibitors, vinca alkaloids, taxanes, nucleoside analogs, angiogenesis inhibitors, antineoplastic agents, and chemotherapeutic agents.

[0162] Examples of alkylating agents include, but are not limited to, chlorambucil, cyclophosphamide, lomustine, melphalan, procarbazine, thiotepa, thiotepa, dacarbazine, procarbazine, carmustine, and busulfan.

[0163] Examples of antimetabolites include, but are not limited to, 6-mercaptopurine, 5- fluorouracil, cytarabine, methotrexate, hydroxyurea, fluoridine, 6-thioguanine, fludarabine, pentostatin, and chlorodeoxyadenosine.

[0164] Examples of anthracyclines include, but are not limited to, daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone.

[0165] Examples of antitumor antibiotics include, but are not limited to, bleomycin. Examples of monoclonal antibodies include, but are not limited to, alemtuzumab, bevacizumab, cetuximab, gemtuzumab, ibritumomab, panitumumab, rituximab, tositumomab, and trastuzumab.

[0166] Examples of platinum agents include, but are not limited to, cisplatin, oxaliplatin, and carboplatin.

[0167] Examples of topoisomerase I and topoisomerase II inhibitors include, but are not limited to, camptothecin, irinotecan, topotecan, amacrine, etoposide, etoposide phosphate, and teniposide.

[0168] Examples of vinca alkaloids include, but are not limited to, vincristine, vinblastine, vinorelbine, and vindesine.

[0169] Examples of taxanes include, but are not limited to, paclitaxel and docetaxel.

[0170] Examples of angiogenesis inhibitors include, but are not limited to, beracizumab, 2- methoxyestradiol, AG3340, angiostatin, antithrombin-III, anti-VEGF antibodies, batimastat, BMS-275291, CAI, canstatin, combretastatin, combretastatin-A4 phosphate, CC5013, captopril, celecoxib, dalteparin, EMD121974, endostatin, erlotininb, gefitinib, genistein, halofuginone, ID1, IDS3, IM862, imatinib mesylate, inducible protein-10, interferon-a, interleukin- 12, lavendustin A, LY317615, AE-941, marimasat, mapsin, medroxyprogesterone acetate, METH-1, METH-2, neovastat, osteopontin cleavage product, PED, pigment epithelium growth factor, platelet growth factor 4, prolactin fragment, proliferin-related protein, PTK787 / ZK222584, recombinant human platelet factor 4, restin, squalamine, SU5416, SU6668, suramin, taxol, tecogalan, thalidomide, tetrathiomolybdate, thrombospondin, TNP-470, troponin 1, vasostatin, VEDG1, VEGF-TPvAP, and ZD6474.

[0171] Chemotherapeutic agents that can be combined with the compounds disclosed herein include, but are not limited to, DNA damaging agents and these include topoisomerase inhibitors (e.g., etoposide, camptothecin, topotecan, irinotecan, teniposide, mitoxantrone), anti -microtubule agents (e.g. , vincristine, vinblastine), antimetabolite agents (e.g. , cytarabine, methotrexate, hydroxyurea, 5-fluorouracil, flouridine, 6-thioguanine, 6-mercaptompurine, fludarabine, pentostatin, chlorodeoxyadenosine), DNA alkylating agents (e.g. , cisplatin, mecholorethamine, cyclophosphamide, ifosphamide, melphalan, chlorambucil, busulfan, thiotepa, carmustine, lomustine, carboplatin, dacarbazine, procarbazine) and DNA strand break inducing agents( e.g. , bleomycin, doxorubicin, daunorubicin, idarubicin, mitomycin C). Examples of chemotherapeutic agents include, but are not limited to, avicine, aclarubicin, acodazole, acronine, adozelesin, adriamycin, aldesleukin, alitretinoin, auopurinol sodium, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrazole, annonaceous acetogenins, anthramycin, asimicin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bexarotene, bicalutamide, bisantrene, bisnafide, bizelesin, bleomycin, brequinar, bropirimine, bullatacin, busulfan, cabergoline, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin, cedefmgol, chlorambucil, celecoxib, cirolemycin, cisplatin, cladribine, crisnatol, cyclophosphamide, cytarabine, dacarbazine, DACA, dactinomycin, daunorubicin, daunomycin, decitabine, denileukin, dexormaplatin, dezaguanine, diaziquone, docetaxel, doxorubicin, droloxifene, dromostalone, duazomycin, edatrexate, eflomithine, elsamitrucin, estramustine, etanidazole, etoposide, etoprine, fadrozole, fazarabine, fenretinide, floxuridine, fludarabine, fluorouracil, flurocitabine, 5-FdUMP, fosquidone, fosteuecine, FK-317, FK-973, FR-66979, FR-900482, gemcitabine, gemtuzumab, gold Au198, goserelin, guanacone, hydroxyurea, idarubicin, ilmofosine, interferon- a and analogs, iproplatin, irinotecan, lanreotide, letrozole, leuprolide, liarozole, lometrexol, lomustine, losoxantrone, masoprocol, maytansine, mechlorethamine, megestrol, melengestrol, melphalan, menogaril, metoprine, maturedepa, mitindomide, mitocarcin, mitogillin, mitomalacin, mitomycin, mitomycin C, mitosper, mitotane, mitoxantrone, mycophenolic acid, nocodazole, nogalamycin, oprelvekin, ormaplatin, oxisuran, ozogamacin, paclitaxel, pamidronate, pegaspargase, peliomycin, pentamustine, peplomycin, perfosfamide, pipobroman, piposulfan, piroxantrone, plicamycin, plomestane, porfimer, porfiromycin, prednimustine, procarbazine, puromycin, pyrazofurin, riboprine, rituximab, rogletimide, rolliniastatin, safingol, samarium, semustine, simtrazene, sparfosate, sparsomycin, spirogermanium, spiromustine, spiroplatin, squamocin, squamotacin, streptonigrin, streptozocin, SrC12, sulphofenur, talisomycin, taxane, toxoid, tecoglan, tegafur, teloxantrone, temoporfin, teniposide, teroxirone, testolactone, thiamiprine, thiotepa, thymitaq, tiazofurin, tirapazamine, tomudex, Top-53, topotecan, toremixifme, trastuzumab, trestolone, triciribine, triciribine, trimetrexate, trimetrexate glucuronate, triptorelin, tubulozole, uracil mustard, uredepa, valrubicin, vapreotide, vinblastine, vincristine, vindesine, vinepidine, vinglycinate, vinleurosine, vinorelbine, vinrosidine, vinzolidine, vorozole, zeniplatin, zinostatin, zorubicin, 2-cholrodeoxyrubicine, 2'-deoxyformycin, 9-aminocamptothecin, raltitrexed, N-propargyl-5,8-didezafolic acid, 2-cholo-2'arabinofluoro-2' deoxyadenosine, 2-cholo- 2'-deoxyadenosine, anisomycin, trichostatin, hPRL-G129R, CEP-751, linomide, sulfur mustard, nitrogen mustard, N- methyl-N-nitrosourea, fotemustine, streptozotocin, mitozolomide, temozolomide, AZQ, CI-973, DWA21 14R, JM216, JM335, bisplatinum, cytrabincine, 6-mercaptopurine, hypoxanthine, CPT-11, epirubicin, darubicin, pyrazoloacridine, all-trans-retinol, 14- hydroxy -retro-retinol, all-trans retinoic acid, N-(4-hydroxyphenyl) retinamide, 13-cis-retinoic acid, 3 -methyl TTNEB, 9-cis-retenoic acid, 2-Cda, 20-epil,25-dihydroxyvitamin-D3, 5-ethynyl uracil, abiraterone, acylfulvene, adecylpenol, ALL-TK antagonists, ambumastine, amidox, amifostine, amino levulinic acid, anagrelide, andrographolide, antagonists D, antarelix, anti-dorsalizing morphogenetic protein- 1, antiandrogen, antiestrogen, antineoplastone, antisense oligonucleotides, aphidicolin, apoptosis gene modulators, apoptosis regulators, apurinic acid, ara-cdp-dl-PTBA, arginine aminase, asulacrine, atamestine, atrimustine, axinamastine 1, axinamastine 2, axinamastine 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, BCR / ABL antagonist, benzochlorins, benzoyl saurosporine, beta lactam derivatives, beta-alethine, pentomone, perillyl alcohol, phenozenomyein, phenyl acetate, phosphatase inhibitors, picibanil, pilocarbine and salts and analogs thereof, pirarubucin, piritrexim, piritrexim isothiocyanate, placetin A, placetin B, plasminogen activator inhibitor, platinum complex, phenyl ethyl isothiocyanate and analogs thereof, platinum triamine complex, podophylotoxin, porfimer sodium, propyl bis acridones, prostaglandin J2, protease inhibitors, protein A based immune modulators, PKC inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyridoxylated hemoglobin polyoxyethylene conjugate, raf antagonists, raltitrexed, ramosetron, ras famesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitors, ratellitptine demethylated, RBX2258, Rhenium Re186etidronate, rhizoxine, ribozymes, RII retinide, rosagliatazone and analogs and derivatives thereof, rohitukine, romurtide, roquinimex, rubiginone Bl , ruboxyl, saintopin, SarCNU, sarcophytol A, sargrmostim, sdi 1 mimetics, senescence derived inhibitor 1 , sense oligonucleotides, signal transduction inhibitors, signal transduction modulators, single chain antigen binding protein, sitogluside, sizofiran, sobuzoxane, sodium borocaptate, sodium phenyl acetate, solverol, somatomedin binding protein, sonermin, spicamycin D, splenopentine, spongistatin 1, squalamine, stem cell inhibitors, stem cell division inhibitors, stipiamide, stromelysin, sulfinosine, superactive vasoactive intestinal peptide antagonists, suradista, siramin, swainsonine, synthetic glycosaminoglycans, tallimustine, tamoxifen methiodide, tauromustine, tazarotene, tacogalan sodium, tellurapyrilium, telomerase inhibitors, tetrachlorodecaoxide, tetrazomine, thaliblastine, thalidomide, thiocoraline, thrombopoetin and mimetics thereof, thymalfasin, thymopoetin receptor agonist, thymotrinan, thyroid stimulating harmone, tin ethyl etiopurpin, titanocene and salts thereof, tomsulosine, topsentin, toremifene, totipotent stem cell factors, translation inhibitors, tretinoin, triacetyluridine, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus derived growth inhibitory factor, urokinase receptor antagonists, variolin B, vector system, erythrocyte gene therapy, velaresol, veramine, verdins, verteporfin, vinorelbine, vinxaltine, vitaxin, zanoterone, zilascorb zinostatin,125I fibrinogen,18F fludeoxyglucose,18F fluorodopa,125I insulin,123I iobenguane,131I iodipamine sodium,131I iodoantipyrine,131I iodocholesterol,125I iodopyracet,123I iofetamine HC1,131I iomethin,125I iothalamate sodium,131I iothalamate,131I iotyrosine,125I liothyronine,197Hg merosproprol,131I methyl iodobenzoguanine,75Se selenomethionine, "mTc technetium furifosmin, "mTc technetium gluceptate, "mTc technetium biscisate, "mTc technetium disofenin, "mTc technetium lidofenin, "mTc technetium mebrofenin, "mTc technetium medronate and sodium salts thereof, "mTc technetium sestambi, "mTc technetium siboroxime, "mTc technetium succimer, "mTc technetium sulfur colloid, "mTc technetium teboroxime, "mTc technetium tetrofosmin, "raTc technetium tiatide,125I thyroxine,13’I thyroxine,131I tolpovidone,125I triolein, and131I triolein.

[0172] In some embodiments, the therapy comprises one or more immune checkpoint inhibitors. Immune checkpoint inhibitors include any agent that blocks or inhibits, in a statistically significant manner, the inhibitory pathways of the immune system. Immune checkpoint inhibitors include antibodies or antigen binding fragments thereof, other binding proteins, biologic therapeutics, and small molecules, that bind to and block or inhibit the activity of a target. Examples of immune checkpoint targets for blocking or inhibition include, but are not limited to, CTLA-4, PD-L1, PD-L2, PD-1, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4, CD160 (also referred to as BY55), CGEN-15049, CHK1 kinase, CHK2 kinase, A2aR, and various B-7 family ligands. Examples of B-7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Examples of immune checkpoint inhibitors include, but are not limited to, tremelimumab, anti-OX40, anti-B7-Hl, MEDI4736, MK-3475, nivolumab, CT-011, BY55, AMP224, BMS-936559, MPLDL3280A, MSB0010718C, ipilimumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0173] In some embodiments, the immune checkpoint inhibitor blocks the interaction between programmed cell death protein (PD-1) and its ligand PD-L1. Examples of such antibodies include, but are not limited to, those listed in Mullard, A. (2013, Nature Reviews: Drug Discovery, 12:489-492.)

[0174] In some embodiments, the immune checkpoint inhibitor targets CTLA-4. In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody. Examples of anti- CTLA-4 antibodies suitable for use in the present invention include any known in the art, and are described in PCT Publication Nos. WO 1998 / 042752, WO 2000 / 037504, WO 2001 / 014424, and WO 2004 / 035607, U.S. Publication No. US 2005 / 0201994, European Patent No. EP 1212422, US. Pat. Nos. 5,811,097, 5,855,887, 5,977,318, 6,051,227, 6,207,720, 6,682,736, 6,984,720, 7,109,003, and 7,132,281, Hurwitz et al. (1998, Proceedings of the National Academy of Sciences USA, 95(17):10067-10071), Camacho et al. (2004, Journal of Clinical Oncology, 22(145):Abstract No. 2505), and Mokyr et al. (1998, Cancer Research, 58:5301-5304).

[0175] In some embodiments, the immune checkpoint inhibitor that targets CTLA-4 disrupts binding of CTLA-4 to its ligand or disrupt B7 binding to CD28 and / or CTLA-4. IN some embodiments, the immune checkpoint inhibitor that targets CTLA-4 inhibits binding of CD80 or CD86 to CD28 or CTLA-4. In some embodiments, the inhibitor is selected from the group consisting of small molecules, antibodies, antisense nucleic acid molecules, adnectins, and RNAi inhibitors.

[0176] In some embodiments, the immune checkpoint inhibitor targets TIM-3. In some embodiments, the immune checkpoint inhibitor blocks TIM-3 from binding to its ligand.

[0177] In some embodiments, the present invention provides methods of inhibiting angiogenesis. In some embodiments, the method inhibits angiogenesis in a cancer. In some embodiments, the method comprises administering to a subject a compound of the present invention. In some embodiments, the method comprises administering to a subject a compound of the present invention, wherein the subject has cancer. In some embodiments, the present invention provides methods of sensitizing a cancer or tumor. In some embodiments, the cancer or tumor is sensitized to one or more chemotherapeutic agents. In some embodiments, the method comprises administering to a subject a compound of the present invention. In some embodiments, the method comprises administering to a subject a compound of the present invention, wherein the subject has a cancer or tumor. In some embodiments, the cancer or tumor is resistant to one or more chemotherapeutic agents.

[0178] In some embodiments, the present invention provides methods of treating a pain disorder. In some embodiments, the method comprises administering to a subject a compound of then present invention. In some embodiments, the method comprises administering to a subject a compound of the present invention, wherein the subject has a pain disorder. In some embodiments, the pain disorder is one or more selected from the group consisting of inflammatory pain, post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic neuralgia, post-herpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain.

[0179] In some embodiments, the pain disorder comprises neuropathic or nociceptive pain. In some embodiments, the pain disorder comprising neuropathic or nociceptive pain is associated with a disease, disorder, infection, or injury. In some embodiments, the pain disorder comprising neuropathic or nociceptive pain is one or more selected from the group consisting of spinal cord injury, multiple sclerosis, stroke, diabetes, herpes zoster infection, human immunodeficiency virus (HIV) infection, nutritional deficiencies, exposure to toxins, remote manifestations of malignancies, immune-related disorders, and physical trauma to the nerve trunk.

[0180] In some embodiments, the present invention provides methods of reducing or inhibiting autophagy in a cell. In some embodiments, the present invention provides methods of reducing or inhibiting replication of a cell. In some embodiments, the present invention provides methods of reducing the viability of a cell. In some embodiments, the cell is a cancer cell.

[0181] In some embodiments, the cell has at least one mutation in at least one tyrosine kinase. In some embodiments, the cell has at least one mutation in an fins-like tyrosine kinase 3 (FLT-3) gene. In some embodiments, the at least one mutation in an FLT-3 gene is an internal tandem duplication (ITD) mutation.

[0182] In some embodiments, the method is an in vitro method comprising contacting a cell with a compound of the present invention. In some embodiments, the method is an in vivo method. In some embodiments, the method comprises inhibiting autophagy in a cell of a subject in need thereof. In some embodiments, the method comprises administering to the subject a compound of the present invention.

[0183] Admini strati on / Dosage / Formulations

[0184] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either before or after the onset of a disease or infection. Further, several divided dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0185] Administration of the compositions of the present invention to a patient or subject, such as a mammal, (e.g., human), may be carried out using known procedures, at dosages and for periods of time effective to treat the disease or infection in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the subject; the age, sex, and weight of the subject; and the ability of the therapeutic compound to treat a disease in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily. In another example, the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 mg / kg to about 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to assess the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0186] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without generating excessive side effects in the subject.

[0187] In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well, known in the medical arts.

[0188] A medical professional, e g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start with a dosage of the compound of the invention in the pharmaceutical composition at a level that is lower than the level required to achieve the desired therapeutic effect, and then increase the dosage over time until the desired effect is achieved.

[0189] In particular embodiments, it is advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. “Dosage unit form” as used herein refers to a physically discrete unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical vehicle. The dosage unit forms of the invention can be selected based upon (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound for the treatment of a disease or infection in a patient.

[0190] In some embodiments, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In some embodiments, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

[0191] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), vegetable oils, and suitable mixtures thereof. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In some embodiments, it is useful to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be achieved by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In some embodiments, the pharmaceutically acceptable carrier is DMSO, alone or in combination with other carriers.

[0192] The therapeutically effective amount or dose of a compound of the present invention depends on the age, sex and weight of the subject, the current medical condition of the subject and the severity of the disease in the subject being treated. The skilled artisan is able to determine appropriate doses depending on these and other factors.

[0193] The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

[0194] Doses of the compound of the invention for administration may be in the range of from about 1 pg to about 10,000 mg, from about 20 pg to about 9,500 mg, from about 40 pg to about 9,000 mg, from about 75 pg to about 8,500 mg, from about 150 pg to about 7,500 mg, from about 200 pg to about 7,000 mg, from about 3050 pg to about 6,000 mg, from about 500 pg to about 5,000 mg, from about 750 pg to about 4,000 mg, from about 1 mg to about 3,000 mg, from about 10 mg to about 2,500 mg, from about 20 mg to about 2,000 mg, from about 25 mg to about 1,500 mg, from about 30 mg to about 1,000 mg, from about 40 mg to about 900 mg, from about 50 mg to about 800 mg, from about 60 mg to about 750 mg, from about 70 mg to about 600 mg, from about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0195] In some embodiments, the dose of a compound of the invention is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dosage of a second compound as described elsewhere herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0196] The compounds for use in the method of the invention may be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0197] In some embodiments, the compositions of the invention are administered to the subject from about one to about five times per day or more. In various embodiments, the compositions of the invention are administered to the subject, 1-7 times per day, 1-7 times every two days, 1-7 times every 3 days, 1-7 times every week, 1-7 times every two weeks, and 1-7 times per month. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from individual to individual depending on many factors including, but not limited to, age, the disease or disorder to be treated, the severity of the disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosing regime and the precise dosage and composition to be administered to any subject is determined by the medical professional taking all other factors about the subject into account.

[0198] In the case wherein the subject’s status does improve, upon the doctor’s discretion the administration of the inhibitor of the invention is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0199] Once improvement of the subject’s condition has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced to a level at which the improved disease is retained. In some embodiments, a subject may require intermittent treatment on a long-term basis, or upon any recurrence of the disease or disorder.

[0200] Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LDso (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0201] In some embodiments, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat or prevent a disease or infection in a patient.

[0202] Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

[0203] Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intratumoral, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0204] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for parenteral administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

[0205] Oral Administration

[0206] For oral administration, suitable forms include tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gel caps. The compositions formulated for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0207] For oral administration, the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fdlers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OP ADR Y™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).

[0208] Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a “granulation.” For example, solvent-using “wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.

[0209] Melt granulation involves the use of materials that are solid or semi-solid at room temperature (i.e., having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e., drug) by forming a solid dispersion or solid solution.

[0210] U.S. Patent No. 5,169,645 discloses directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) melt.

[0211] The present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providing for the immediate release of a medication for treatment of G-protein receptor-related diseases or disorders. Using a wax / pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.

[0212] Parenteral Administration

[0213] For parenteral administration, the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions, or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used.

[0214] Controlled Release Formulations

[0215] In some embodiments, the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

[0216] The term sustained release refers to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a day, a week, or a month or more and should be a release which is longer that the same amount of agent administered in bolus form. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

[0217] For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use the method of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

[0218] In some embodiments of the invention, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

[0219] The term pulsatile release refers to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration. The term immediate release refers to a drug formulation that provides for release of the drug immediately after drug administration.

[0220] As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

[0221] As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

[0222] Those skilled in the art recognize, or are able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

[0223] Additional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757. EMBODIMENTS

[0224] Embodiment 1 is a compound of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0225] Formula (I), wherein:

[0226] Z1is selected from the group consisting of S(O)2, S(O), S(O)(NH), and N-L-Ubiig;

[0227] X1is selected from the group consisting of N, C, and CH, wherein: when X1is N, X2is CR5and the bond between X1and X2is a single bond; when X1is C, X2is CR5and the bond between X1and X2is a double bond; and when X1is CH, X2is CR5R?and the bond between X1and X2is a single bond; each of X3, X4, and X5is independently selected from the group consisting of O, S, NR6, and CR7R7; each of A1, A2, and A3is independently selected from the group consisting of an aromatic ring and a heteroaromatic ring; each of RA1, R^2, and RA3represents mono to the maximum allowable substitution, each occurrence of RA1, RA2, and RA3is independently selected from the group consisting of H, D, F, Me, CF3, OCH3, OCD3, and OCF3; each of R1, R1, R2, R2, R3, R3, R5, R5, R6, R7, R7, are independently selected from the group consisting of H, D, F, Me, CF3, OMe, and OCF3;

[0228] Rsis selected from the group consisting of CH3, CD3, and CF3;

[0229] L is a divalent linking group; and

[0230] Ubiig is an E3 ubiquitin ligase ligand.

[0231] Embodiment 2 is the compound of embodiment 1, wherein A1, A2, and A3are each independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A1, A2, and A3is optionally further substituted. Embodiment 3 is the compound of embodiment 1 or 2, wherein -X^A^X3- is represented by wherein: each of Z2, Z3, Z4, and Z5is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D,

[0232] F, Me, CF3, OCH3, OCD3, and OCF3.

[0233] Embodiment 4 is the compound of embodiment 3, wherein each of Z2, Z3, Z4, and Z3is

[0234] CRZ.

[0235] Embodiment 5 is the compound of embodiment 3 or 4, wherein Z2, Z4, and Z5are CH; and Z3is CRZ, wherein Rzis selected from the group consisting of D, F, Me, CF3, OCH3, OCD3, and OCF3.

[0236] Embodiment 6 is the compound of any one of embodiments 1-5, wherein -X3-A2-X4- is represented by wherein: each of Z6, Z7, Z8, and Z9is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D,

[0237] F, Me, CF3, OCH3, OCD3, and OCF3.

[0238] Embodiment 7 is the compound of embodiment 6, wherein Z6and Z9are each N; and Z7and Z8are CRZ.

[0239] Embodiment 8 is the compound of embodiment 6 or 7, wherein Z7is CH; and Z8is CRZ, wherein Rzis selected from the group consisting of D, F, Me, CF3, OCH3, OCD3, and OCF3

[0240] Embodiment 9 is the compound of any one of embodiments 1-8, wherein -X4-A3-X5- is represented by wherein: each of Z10, Z11, Z12, and Z13is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D, F, Me, CF3, OCH3, OCD3, and OCF3.

[0241] Embodiment 10 is the compound of embodiment 9, wherein each of Z10, Z11, Z12, and Z13is CRZ.

[0242] Embodiment 11 is the compound of embodiment 9 or 10, wherein each instance of Rzis H.

[0243] Embodiment 12 is the compound of any one of embodiments 1-11, wherein at least one ofX3, X4, and X5is NH.

[0244] Embodiment 13 is the compound of any one of embodiments 1-12, wherein each of X3, X4, and X5is NH.

[0245] Embodiment 14 is the compound of any one of embodiments 1-13, wherein Rsis CH3.

[0246] Embodiment 15 is the compound of any one of embodiments 1-14, wherein Z1is N-L- Ubiig and L is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0247] Embodiment 16 is the compound of any one of embodiments 1-15, wherein Z1is N-L- Ubiig and Ubiig is selected from the group consisting of pomalidomide, Von Hippel-Lindau (VHL), thalidomide, lenalidomide, iberdomide, avadomide, apremilast, Mouse double minute 2 homolog (MDM2), bestatin, and an MV1 derivative.

[0248] Embodiment 17 is the compound of embodiment 1, wherein the compound of Formula (I) is a compound of Formula (II):

[0249]

[0250] Formula (II), wherein:

[0251] R8is selected from the group consisting of D, F, Me, CF3, OMe, and OCF3; each of Z6, Z7, Z8, and Z9is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D,

[0252] F, Me, CF3, OCH3, OCD3, and OCF3.

[0253] Embodiment 18 is the compound of embodiment!?, wherein Z6and Z9are N; and Z7and Z8are CRZ.

[0254] Embodiment 19 is the compound of embodiment 17 or 18, wherein Z7is CH; and Z8is CRZ, wherein Rzis selected from the group consisting of D, F, Me, CF3, OCH3, OCD3, and OCF3.

[0255] Embodiment 20 is the compound of any one of embodiments 17-19, wherein at least one of X3and X4is NH.

[0256] Embodiment 21 is the compound of any one of embodiments 71-20, wherein each of X3and X4are NH.

[0257] Embodiment 22 is the compound of any one of embodimentsl7-21, wherein Z1is N-L- Ubiig and L is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0258] Embodiment 23 is the compound of any one of embodiments 17-22, wherein Z1is N-L- Ubiig and Ubiig is selected from the group consisting of pomalidomide, Von Hippel-Lindau (VHL), thalidomide, lenalidomide, iberdomide, avadomide, apremilast, Mouse double minute 2 homolog (MDM2), bestatin, and an MV1 derivative.

[0259] Embodiment 22 is the compound of embodiment 1 or 17, wherein the compound of Formula (I) is selected from the group consisting of:

[0260] pharmaceutically acceptable salt or solvate thereof.

[0261] Embodiment 25 is the compound of embodiment 1 , wherein the compound of Formula (T) is selected from the group consisting of: thereof, wherein R and R’ are each independently selected from the group consisting of H, D, Ci- Cio alkylene, C3-C10 cycloalkylene, C1-C10 heteroalkylene, C3-C10 heterocycloalkylene, C2-C10 alkenylene, C2-C10 alkynylene, arylene, heteroarylene, amide, ester, ether, carbonyl, and combinations thereof.

[0262] Embodiment 26 is a method of decreasing leucine-rich repeat kinase 2 (LRRK2) activity in a subject comprising administering to the subject the compound of any one of embodiments 1- 25.

[0263] Embodiment 27 is a method of treating a disease or disorder associated with increased LRRK2 activity in a subject comprising administering to the subject the compound of any one of embodiments 1-25.

[0264] Embodiment 28 is the method of embodiment 27, wherein the disease or disorder associated with LRRK2 activity is selected from the group consisting of cancer, Parkinson’s disease, Alzheimer’s disease, leprosy, fibrosis, and inflammatory diseases and disorders.

[0265] Embodiment 29 is the method of embodiment 28, wherein the inflammatory disease or disorder is selected from the group consisting of peritonitis, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, graft vs. host disease, osteoporosis, multiple myeloma-related bone disorder, leukemias and related disorders, myelodysplastic syndrome, acute myelogenous leukemia, chlonal hematopoesis, anemia of chronic diseases, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, infectious hepatitis, juvenile diabetes, lichen planus, acute dermatomyositis, eczema, primary cirrhosis, uveitis, Behcet's disease, atopic skin disease, pure red cell aplasia, aplastic anemia, amyotrophic lateral sclerosis, nephrotic syndrome, burns, bronchitis, tendinitis, bursitis, periarteritis nodosa, thyroiditis, Hodgkin's disease, rheumatic fever, sarcoidosis, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, allergic rhinitis, endotoxin shock syndrome, atherosclerosis, psoriatic arthritis, vasculitis, Polymyalgia, Rheumatica, Wegener's granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection, and ataxia telangiectasia.

[0266] Embodiment 30 is the method of embodiment 28, wherein the fibrosis is one or more selected from the group consisting of renal fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, Crohn’s disease, liver fibrosis, heart fibrosis, scleroderma, or progressive massive fibrosis.

[0267] Embodiment 31 is the method of embodiment 28, wherein the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, uterine cancer, acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma, carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellulare, glandular carcinoma, granulose cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, carcinoma medullare, medullary carcinoma, carcinoma melanodes, melanotonic carcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocullare, mucoepidermoid carcinoma, mucous carcinoma, carcinoma myxomatodes, masopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteroid carcinoma, ovarian carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, scheinderian carcinoma, scirrhous carcinoma, carcinoma scrota, signet-ring cell carcinoma, carcinoma simplex, small cell carcinoma, solandoid carcinoma, pancreatic, breast, melanoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, carcinoma vilosum liposarcomas, leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors, primitive neuroectodermal tumors (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST), osteosarcoma (also known as osteogenic sarcoma) skeletal and extra-skeletal, chondrosarcoma, mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acutelymphoblastic leukemia, Burkitt lymphoma, myeloma, immunocytoma, acute promyelocyte leukemia, chronic myeloid / acute lymphoblastic leukemia, acute leukemia, B-cell acute lymphoblastic leukemia, anaplastic large cell leukemia, myelodysplasia syndrome / acute myeloid leukemia, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia (AML), common (pre-B) acute lymphocytic leukemia, malignant melanoma, T-cell lymphoma, leukemia, B-cell lymphoma, epithelial malignancies, lymphoid malignancies, gynecologic carcinoma, pancreatic biliary adenocarcinoma, and pancreatic ductal adenocarcinomas.

[0268] Embodiment 32 is the method of embodiment 31, wherein the compound of any one of embodiments 1-25 is administered in combination with one or more therapies selected from the group consisting of radiation therapy, surgery, chemotherapy, and immune checkpoint inhibitors.

[0269] Embodiment 33 is the method of embodiment 32, wherein the therapy comprises one or more selected from the group consisting of alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinum agents, topoisomerase I inhibitors, topoisomerase II inhibitors, vinca alkaloids, taxanes, nucleoside analogs, angiogenesis inhibitors, antineoplastic agents, and chemotherapeutic agents.

[0270] Embodiment 34 is a method of inhibiting angiogenesis in a subject comprising administering to the subject the compound of any one of embodiments 1-25.

[0271] Embodiment 35 is a method of sensitizing a tumor in a subject to treatment comprising administering to the subject the compound of any one of embodiments 1-25.

[0272] Embodiment 36 is a method of treating a pain disorder in a subject comprising administering to the subject the compound of any one of embodiments 1-25.

[0273] Embodiment 37 is the method of embodiment 36, wherein the pain disorder is one or more selected from the group consisting of inflammatory pain, post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and post-herpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain.

[0274] Embodiment 38 is the method of embodiment 36, wherein the pain disorder comprises neuropathic or nociceptive pain.

[0275] Embodiment 39 is the method of embodiment 38, wherein the subject with a pain disorder comprising neuropathic pain has one or more selected from the group consisting of spinal cord injury, multiple sclerosis, stroke, diabetes, herpes zoster infection, HIV infection, nutritional deficiencies, exposure to toxins, remote manifestations of malignancies, immune- related disorders, and physical trauma to the nerve trunk.

[0276] Embodiment 40 is a method of reducing autophagy in a cell comprising contacting the cell with the compound of any one of embodiments 1-25.

[0277] Embodiment 41 is a method of inhibiting replication of a cell comprising contacting the cell with the compound of any one of embodiments 1-25.

[0278] Embodiment 42 is a method of reducing cell viability comprising contacting the cell with the compound of any one of embodiments 1-25.

[0279] Embodiment 43 is the method of any one of embodiments 40-42, wherein the cell has a mutation in an fms-like receptor tyrosine kinase 3 (FLT-3) gene.

[0280] Embodiment 44 is the method of embodiment 44, wherein the mutation in an FLT-3 gene is a internal tandem duplication (ITD) mutation. EXPERIMENTAL EXAMPLES

[0281] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0282] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples, therefore, specifically point out certain embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

[0283] Example 1 : A novel small molecule inhibitor of LRRK2

[0284] Carriers of the leucine-rich repeat kinase 2 (LRRK2) G2019S mutation exhibit statistically significant increased risks for nonskin cancers (OR, 1.62; 95% CI, 1.04-2.52), hormone-related cancers (OR, 1.87; 95% CI, 1.07-3.26) and breast cancer (OR, 2.34; 95% CI, 1.05-5.22) in comparison with noncarriers. LRRK2 correlates with the recruitment of tumor-associated macrophages (Yan, J., et al., 2022, Genomics, 114(1):316-327). LRRK2 influences the cross-talking within the tumor microenvironment in a cancer type-dependent manner. LRRK2 deficiency facilitated M2 transition of macrophages and promoted the neoplastic virtues of cancer cells at the early stage of tumor progression. LRRK2 also has been linked to vesicle trafficking, presynaptic homeostasis, mammalian target of rapamycin (mTOR) signaling, signaling through the receptor tyrosine kinase MET in papillary renal and thyroid carcinomas, cytoskeletal dynamics, the mitogen-activated protein kinase (MAPK) pathway, the tumor necrosis factor-a (TNF-a) pathway, the Wnt pathway, and autophagy.

[0285] In a comparison of the survival outcomes, patients with high LRRK2 expression exhibited poor survival in all forms of cancer examined (Figure 1 through Figure 7). The starkest examples of this are in colon and liver cancer, where the 10-year survival for subjects with LRRK2 overexpression is virtually 0 (Figure 3 and Figure 5). This outcome is particularly shocking for liver cancer, where there is no statistically significant difference in 5-year survival between patients with high or low LRRK2 expression (Figure 5). Development of novel LRRK2 inhibitors:

[0286] Two LLRK2 inhibitors (UR-032 and UR-034) were prepared, and their inhibitory activity was examined in vitro. UR-032 demonstrated an ECso of 8.595 nM, while the ECso of UR-044 was 6.919 nM (Figure 8).

[0287] Inhibition of Autophagy

[0288] The impact of UR-032 on cell autophagy was investigated in human monocytic leukemia cells (MOLM-13 - acute monocytic leukemia, MV-4-11, biphenotypic B-myelomonocytic leukemia) with mutations in their fms-like receptor tyrosine kinase 3 (FLT-3) gene. Cells were treated with DMSO (negative control) or with various concentrations of UR-032 in DMSO (2.5 pM, 5 pM, and 10 pM). Protein expression of two autophagy-related proteins, spliced isoform of X-box binding protein 1 (XBP-1S) and microtubule-associated protein 1 light chain 3 (LC-3), was then examined by Western blot, and it was observed that UR-032 significantly reduced expression of XBP-1S and LC-3 in both MOLM-13 and MV-4-11 cells (Figure 9). From this, it can be seen that, through reduction in protein levels, UR-032 inhibits autophagy.

[0289] Therapeutic Selectivity

[0290] In order to examine the selectivity of UR-032, cell viability was examined in MOLM-13 and MV-4-11 cancer cells, which have mutations in FLT-3, and THP-1 acute monocytic leukemia cells that have wildtype FLT-3. While all doses of UR-032 (5 pM, 10 pm, and 20 pM) exhibited substantial and significant toxicity against cells with mutant FLT-3, the THP-1 cells experienced no reduction in cell viability (Figure 11).

[0291] Inhibition of Cell Division

[0292] UR-032 was further investigated for its impact on cell division. MOLM-13 cells were treated with DMSO (negative control) or UR-032 suspended in DMSO. More than a third of control DMSO-treated cells exited the G1 growth phase, while UR-032 treatment reduced the number of cells exiting G1 to less than 10%, demonstrating anti-proliferative activity in FLT-3 mutant cancerous cells (Figure 10). Inhibition of Tumor Growth

[0293] As UR-032 was successfully demonstrated to reduce FLT-3 mutant cancer cells and inhibit their proliferation, its impact on tumor growth was examined through a tumor xenograft model. MOLM-13 cells were pre-treated overnight a single time with DMSO or UR-032 in DMSO (20 pM) and implanted into NSG mice. Tumor volume of UR-032-pre-treated cells remained significantly less than that of control cells throughout the experiment. After six days, the control tumor volume was over 100 mm3, while treatment with UR-032 reduced tumor volume to less than 20 mm3, and after 10 days, the control tumor volume was over 500 mm3while UR-032 tumor volume had just reached 200 mm3. From this, it can be seen that even a single pre-emptive treatment with UR-032 significantly inhibits tumor development and growth. Experiments demonstrating that multiple administration of UR-032 further inhibits tumor growth are ongoing.

[0294] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:Formula (I), wherein:Z1is selected from the group consisting of S(O)2, S(O), S(O)(NH), and N-L-Ubiig;X1is selected from the group consisting of N, C, and CH, wherein: when X1is N, X2is CR5and the bond between X1and X2is a single bond; when X1is C, X2is CR5and the bond between X1and X2is a double bond; and when X1is CH, X2is CR3R5and the bond between X1and X2is a single bond; each of X3, X4, and X5is independently selected from the group consisting of O, S, NR6, and CR7R7; each of A1, A2, and A3is independently selected from the group consisting of an aromatic ring and a heteroaromatic ring; each of RA1, R^2, and RA3represents mono to the maximum allowable substitution, each occurrence of RA1, RA2, and RA3is independently selected from the group consisting of H, D, F, Me, CF3, OCH3, OCD3, and OCF3; each of R1, R1, R2, R2, R3, R3, R5, R5, R6, R7, R7, are independently selected from the group consisting of H, D, F, Me, CF3, OMe, and OCF3;Rsis selected from the group consisting of CH3, CD3, and CF3;L is a divalent linking group; andUbiig is an E3 ubiquitin ligase ligand.

2. The compound of claim 1, wherein A1, A2, and A3are each independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A1, A2, and A3is optionally further substituted.

3. The compound of claim 1, wherein -X'-A^X3- is represented bywherein: each of Z2, Z3, Z4, and Z5is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D, F, Me, CFs, OCH3, OCD3, and OCF3.

4. The compound of claim 3, wherein each of Z2, Z3, Z4, and Z5is CRZ.

5. The compound of claim 4, wherein Z2, Z4, and Z5are CH; and Z3is CRZ, wherein Rzis selected from the group consisting of D, F, Me, CF3, OCH3, OCD3, and OCF3.

6. The compound of claim 1, wherein -X3-A2-X4- is represented bywherein: each of Z6, Z7, Z8, and Z9is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D,F, Me, CF3, OCH3, OCD3, and OCF3.

7. The compound of claim 6, wherein Z6and Z9are each N; and Z7and Z8are CRZ.

8. The compound of claim 7, wherein Z7is CH; and Z8is CRZ, wherein Rzis selected from the group consisting of D, F, Me, CF3, OCH3, OCD3, and OCF3.

9. The compound of claim 1, wherein -X4-A3-X?- is represented bywherein: each of Z10, Z11, Z12, and Z13is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D, F, Me, CF3, OCH3, OCD3, and OCF3.

10. The compound of claim 9, wherein each of Z10, Z11, Z12, and Z13is CRZ.

11. The compound of claim 10, wherein each instance of Rzis H.

12. The compound of claim 1, wherein at least one of X3, X4, and X5is NH.

13. The compound of claim 12, wherein each of X3, X4, and X5is NH.

14. The compound of claim 1, wherein Rsis CH3.

15. The compound of claim 1, wherein Z1is N-L-Ubiig and L is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

16. The compound of claim 1, wherein Z1is N-L-Ubiig and Ubiig is selected from the group consisting of pomalidomide, Von Hippel-Lindau (VHL), thalidomide, lenalidomide, iberdomide, avadomide, apremilast, Mouse double minute 2 homolog (MDM2), bestatin, and an MV1 derivative.

17. The compound of claim 1, wherein the compound of Formula (I) is a compound ofFormula (II):Formula (II), wherein:R8is selected from the group consisting of D, F, Me, CF3, OMe, and OCF3; each of Z6, Z7, Z8, and Z9is selected from the group consisting of N and CRZ; and each instance of Rzis independently selected from the group consisting of H, D,F, Me, CF3, OCH3, OCD3, and OCF3.

18. The compound of claim 17, wherein Z6and Z9are N; and Z7and Z8are CRZ.

19. The compound of claim 18, wherein Z7is CH; and Z8is CRZ, wherein Rzis selected from the group consisting of D, F, Me, CF3, OCH3, OCD3, and OCF3.

20. The compound of claim 17, wherein at least one of X3and X4is NH.

21. The compound of claim 20, wherein each of X3and X4are NH.

22. The compound of claim 17, wherein Z1is N-L-Ubiigand L is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

23. The compound of claim 17, wherein Z1is N-L-Ubiig and Ubiig is selected from the group consisting of pomalidomide, Von Hippel-Lindau (VHL), thalidomide, lenalidomide, iberdomide, avadomide, apremilast, Mouse double minute 2 homolog (MDM2), bestatin, and an MV1 derivative.

24. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of:pharmaceutically acceptable salt or solvate thereof.

25. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of:thereof, wherein R and R’ are each independently selected from the group consisting of H, D, Ci- Cio alkylene, C3-C10 cycloalkylene, C1-C10 heteroalkylene, C3-C10 heterocycloalkylene, C2-C10 alkenylene, C2-C10 alkynylene, arylene, heteroarylene, amide, ester, ether, carbonyl, and combinations thereof.

26. A method of decreasing leucine-rich repeat kinase 2 (LRRK2) activity in a subject comprising administering to the subject the compound of claim 1.

27. A method of treating a disease or disorder associated with increased LRRK2 activity in a subject comprising administering to the subject the compound of claim 1.

28. The method of claim 27, wherein the disease or disorder associated with LRRK2 activity is selected from the group consisting of cancer, Parkinson’s disease, Alzheimer’s disease, leprosy, fibrosis, and inflammatory diseases and disorders.

29. The method of claim 28, wherein the inflammatory disease or disorder is selected from the group consisting of peritonitis, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmuneneutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, graft vs. host disease, osteoporosis, multiple myeloma-related bone disorder, leukemias and related disorders, myelodysplastic syndrome, acute myelogenous leukemia, chlonal hematopoesis, anemia of chronic diseases, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, infectious hepatitis juvenile diabetes, lichen planus, acute dermatomyositis, eczema, primary cirrhosis, uveitis, Behcet's disease, atopic skin disease, pure red cell aplasia, aplastic anemia, amyotrophic lateral sclerosis, nephrotic syndrome, burns, bronchitis, tendinitis, bursitis, periarteritis nodosa, thyroiditis, Hodgkin's disease, rheumatic fever, sarcoidosis, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, allergic rhinitis, endotoxin shock syndrome, atherosclerosis, psoriatic arthritis, vasculitis, Polymyalgia, Rheumatica, Wegener's granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection, and ataxia telangiectasia.

30. The method of claim 28, wherein the fibrosis is one or more selected from the group consisting of renal fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, Crohn’s disease, liver fibrosis, heart fibrosis, scleroderma, or progressive massive fibrosis.

31. The method of claim 28, wherein the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, uterine cancer, acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma,carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellulare, glandular carcinoma, granulose cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, carcinoma medullare, medullary carcinoma, carcinoma melanodes, melanotonic carcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocullare, mucoepidermoid carcinoma, mucous carcinoma, carcinoma myxomatodes, masopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteroid carcinoma, ovarian carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, scheinderian carcinoma, scirrhous carcinoma, carcinoma scrota, signet-ring cell carcinoma, carcinoma simplex, small cell carcinoma, solandoid carcinoma, pancreatic, breast, melanoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, carcinoma vilosum liposarcomas, leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors, primitive neuroectodermal tumors (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST), osteosarcoma (also known as osteogenic sarcoma) skeletal and extra-skeletal, chondrosarcoma, mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acutelymphoblastic leukemia, Burkitt lymphoma, myeloma, immunocytoma, acute promyelocyte leukemia, chronic myeloid / acute lymphoblastic leukemia, acute leukemia, B-cell acute lymphoblastic leukemia, anaplastic large cell leukemia, myelodysplasia syndrome / acute myeloid leukemia, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia (AML), common (pre-B) acute lymphocytic leukemia, malignant melanoma, T-cell lymphoma, leukemia,B-cell lymphoma, epithelial malignancies, lymphoid malignancies, gynecologic carcinoma, pancreatic biliary adenocarcinoma, and pancreatic ductal adenocarcinomas.

32. The method of claim 31, wherein the compound is administered in combination with one or more therapies selected from the group consisting of radiation therapy, surgery, chemotherapy, and immune checkpoint inhibitors.

33. The method of claim 32, wherein the therapy comprises one or more selected from the group consisting of alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinum agents, topoisomerase I inhibitors, topoisomerase II inhibitors, vinca alkaloids, taxanes, nucleoside analogs, angiogenesis inhibitors, anti neoplastic agents, and chemotherapeutic agents.

34. A method of inhibiting angiogenesis in a subject comprising administering to the subject the compound of claim 1.

35. A method of sensitizing a tumor in a subject to treatment comprising administering to the subject the compound of claim 1.

36. A method of treating a pain disorder in a subject comprising administering to the subject the compound of claim 1.

37. The method of claim 36, wherein the pain disorder is one or more selected from the group consisting of inflammatory pain, post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and post-herpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain.

38. The method of claim 36, wherein the pain disorder comprises neuropathic or nociceptive pain.

39. The method of claim 38, wherein the subject with a pain disorder comprising neuropathic pain has one or more selected from the group consisting of spinal cord injury, multiple sclerosis, stroke, diabetes, herpes zoster infection, HIV infection, nutritional deficiencies, exposure to toxins, remote manifestations of malignancies, immune-related disorders, and physical trauma to the nerve trunk.

40. A method of reducing autophagy in a cell comprising contacting the cell with the compound of claim 1.

41. The method of claim 40, wherein the cell has a mutation in an fms-like receptor tyrosine kinase 3 (FLT-3) gene.

42. The method of claim 41, wherein the mutation in an FLT-3 gene is an internal tandem duplication (ITD) mutation.

43. A method of inhibiting replication of a cell comprising contacting the cell with the compound of claim 1.

44. The method of claim 43, wherein the cell has a mutation in an fms-like receptor tyrosine kinase 3 (FLT-3) gene.

45. The method of claim 44, wherein the mutation in an FLT-3 gene is an internal tandem duplication (ITD) mutation.

46. A method of reducing cancer cell viability comprising contacting the cell with the compound of claim 1.

47. The method of claims 46, wherein the cell has a mutation in an fms-like receptor tyrosine kinase 3 (FLT-3) gene.

48. The method of claim 47, wherein the mutation in an FLT-3 gene is an internal tandem duplication (ITD) mutation.

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