WO2024092069A1

WO2024092069A1 - Cxcr4 inhibitors for treatment of neurological diseases

Info

Publication number: WO2024092069A1
Application number: PCT/US2023/077817
Authority: WO
Inventors: Art Taveras; Chi Nguyen; Angelina Roberta SEKIRNIK
Original assignee: X4 Pharmaceuticals Inc
Current assignee: X4 Pharmaceuticals Inc
Priority date: 2022-10-26
Filing date: 2023-10-26
Publication date: 2024-05-02
Anticipated expiration: 2025-04-26
Also published as: EP4608508A1; CN120418245A

Abstract

The present invention provides CXCR4 inhibitors of Formula (I): and pharmaceutically acceptable salts thereof, and methods for their use in treating neurological and CNS diseases, disorders, and conditions.

Description

CXCR4 INHIBITORS FOR TREATMENT OF NEUROLOGICAL DISEASES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present invention claims the benefit of U.S. Provisional Application No.63/419,598, filed on October 26, 2022, the entirety of which is hereby incorporated by reference. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to compounds and methods useful for inhibition of C- X-C receptor type 4 (CXCR4). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION [0003] C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or cluster of differentiation 184 (CD184), is a seven transmembrane G-protein coupled receptor (GPCR) belonging to Class I GPCR or rhodopsin-like GPCR family. CXCR4 is expressed in many tissues, including brain, thymus, lymphatic tissues, spleen, stomach, and small intestine, and also specific cell types such as hematopoietic stem cells (HSC), mature lymphocytes, and fibroblasts. CXCL12 is the only known ligand for CXCR4. CXCR4 is known to be implicated in various neurodegenerative diseases including, but not limited to, ALS, Alzheimer’s disease, and Parkinson’s disease. See, e.g., Rabinovich-Nikitin et al., “Chronic administration of AMD3100 increases survival and alleviates pathology in SOD1G93A mice model of ALS,” Journal of Neuroinflammation (2016) 13:123; Inna Rabinovich-Nikitin, Beka Solomon, “Lactate Transport and Signaling Mediated by AMD3100 Ameliorates Astrocyte Pathology and Remyelination Without Additional Extension of SOD1^G93A Mice Life-Span,” bioRxiv 2022.01.28.478264; Li, Ting & Tongtong, Liu & Chen, Xuhui & Li, Li & Feng, Miaomiao & Zhang, Yue & Wan, Li & Zhang, Chuanhan & Yao, Wenlong. (2020). “Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain,” Journal of Neuroinflammation 17.10.1186/s12974-020-01891-5; Gavriel, Y., et al. (2020). “Subcutaneous Administration of AMD3100 into Mice Models of Alzheimer’s Disease Ameliorated Cognitive Impairment, Reduced Neuroinflammation, and Improved Pathophysiological Markers,” Journal of Alzheimer's Disease, 78(2), 653-671; Li, Y., Niu, M., Zhao, A. et al. CXCL12 is involved in α-synuclein-triggered neuroinflammation of Parkinson’s disease. J Neuroinflammation 16, 263 (2019); Zheng, J., et al., “Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia,” Journal of Neuroimmunology, Volume 98, Issue 2, P185-200, August 3, 1999, doi.org/10.1016/S0165-5728(99)00049-1. For support for the role of CXCR4 in neuroinflammation, neurodegeneration, and neuropathic pain, see Geeta Ramesh, Andrew G. MacLean, Mario T. Philipp, “Cytokines and Chemokines at the Crossroads of Neuroinflammation, Neurodegeneration, and Neuropathic Pain,” Mediators of Inflammation, vol.2013, Article ID 480739, 20 pages, 2013. doi.org/10.1155/2013/480739. [0004] ALS is a rare, progressive and fatal neurodegenerative disease, characterized by degeneration of both upper and lower motor neurons. Symptoms include muscle weakness, muscle atrophy, behavioral impairment, dysphagia, dysarthria. The prevalence of ALS in the United States is 5 in 100,000. ALS cases across the globe are projected to increase from 222,801 in 2015 to 376,674 in 2040. The causes of ALS include Sporadia ALS (90-95%). There is also Familial ALS (5-10%) caused by one of the following mutations: C9orf72 (40%), SOD1 (20%), FUS (1–5%), TARBDP (TBP-43) (1–5%). The ALS pathogenetic mechanisms are still not fully understood. Mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation have been shown to contribute to the pathogenesis of ALS. No effective treatments are available. Parkinson’s disease affects 1-2 per 1,000 people. No cure exists, and the only medications available are symptomatic treatments. Misfolded alpha- synuclein protein forms toxic clumps (Lewy bodies) in neurons in the midbrain, causing death of neurons and astrocytes. [0005] These data underscore the significant, unmet need for CXCR4 inhibitors to treat the many diseases and conditions mediated by aberrant or undesired expression of the receptor. The present invention meets this need and provides other, related, advantages. SUMMARY OF THE INVENTION [0006] It has now been found that CXCR4 inhibitors described herein, and pharmaceutically acceptable salts thereof, are effective in treating neurological and central nervous system (CNS) diseases, disorders, and conditions, such as those described herein. In one aspect, such CXCR4 inhibitors are compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. [0007] In some embodiments, the CXCR4 inhibitor is selected from the following:

I-230 I-11 or a pharmaceutically acceptable salt thereof. [0008] In some embodiments, the CXCR4 inhibitor is I-1 or a pharmaceutically acceptable salt thereof. [0009] In one aspect, the present invention provides a method of treating a neurological disorder or disease of the central nervous system (CNS), or a method of alleviating the severity and symptoms thereof, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor. [0010] In some embodiments, the neurological disorder or disease of the CNS is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular dystrophy, Wilson’s disease, Lewy body dementia, Frontotemporal Dementia (FTD), cerebral palsy, Bell’s palsy, progressive supranuclear palsy, HIV-associated dementia (HAND), epilepsy, tremors and seizure disorders, catalepsy, immobilization disorders, paralysis and muscle rigidity, spina bifida, encephaly, encephalocele, encephalitis, myelopathy, migraines, cerebral ischemia, ischemia, stroke, cerebellar ataxia, Friedrich’s ataxia, prion diseases such as mad cow disease and Creutzfelt- Jakob disease, atherosclerosis, motor neurone disease (MND), Locked In Syndrome, Restless Leg Syndrome, arachnoid cysts, sciatica, thalassemia, cerebral hemorrhage, subarachnoid hemorrhage, muscular sclerosis, tardive dyskinesia, Charcot-Marie-Tooth Disease (CMT), thrombus formation, microembolus formation, Sickle cell disease, and Vaso Occlusive Crises (VOCs). In some embodiments, the neurological disorder or disease of the CNS is pseudobulbar affect (PBA). [0011] In some embodiments, the neurological disorder or disease of the CNS is a neurodegenerative disease. [0012] In some embodiments, the neurodegenerative disease is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular dystrophy, Wilson’s disease, Lewy body dementia, Frontotemporal Dementia (FTD), HIV-associated dementia (HAND), progressive supranuclear palsy, Friedrich’s ataxia, prion diseases such as Creutzfelt-Jakob disease, motor neurone disease (MND), and Charcot-Marie- Tooth Disease (CMT). [0013] In some embodiments, the neurodegenerative disease is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. [0014] In some embodiments, the neurodegenerative disease is ALS. [0015] In some embodiments, the neurological disorder or disease of the CNS is a CNS infection. In some embodiments, the CNS infection is selected from a viral infection such as meningitis, shingles, or HIV. [0016] In some embodiments, the CNS infection is selected from an enterovirus, arbovirus, and herpes virus infection. In some embodiments, the CNS infection is selected from a herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), Japanese encephalitis virus, Zika virus, tick-borne encephalitis virus (TBEV), Murray Valley encephalitis virus, St. Louis encephalitis virus, La Crosse encephalitis virus (LCEV), John Cunningham virus (PML), HHV-6, an influenza virus, rabies, mumps, measles, and West Nile virus infection. [0017] In some embodiments, the CNS infection is a bacterial infection. In some embodiments, the CNS infection is selected from a Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae infection. [0018] In some embodiments, the neurological disorder or disease of the CNS is selected from neurological damage caused by addiction, alcoholism or alcohol abuse, autism, anxiety, depression, satiety disorders (including obesity, anorexia, and bulimia), affective disorders, Tourette’s syndrome, schizophrenia, obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder, post-traumatic stress disorder (PTSD), gastroesophageal reflux disease (GERD), memory loss, dementia, sleep apnea, narcolepsy, urinary incontinence, and metabolic disorders that affect the CNS. [0019] In some embodiments, the neurological disorder or disease of the CNS is selected from neurodegeneration, a neuromuscular disorder, ischemia, a neuroinflammatory disease (also known as neuroinflammation), an autoimmune disorder, an anxiety disorder, and pain, wherein the neurological disorder or disease of the CNS arises from a traumatic head or brain injury, spinal cord injury, or another medical condition with neurological cell loss, damage and/or degeneration. [0020] In some embodiments, the the neuroinflammation is due to infiltration of leukocytes and/or immune cells into the brain. In another embodiment, leukocyte and/or immune cell infiltration into the brain is caused by elevated levels of CXCR4 in the brain. In some embodiments, the neurological disorder or disease of the CNS is selected from stroke, thrombus formation, and microembolus formation. [0021] In some embodiments, the microemboli formation is microemboli in a COVID (e.g., COVID-19 or another strain of COVID) patient. [0022] In some embodiments, the present invention provides a method of treating and/or alleviating pain, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor. In various embodiments, the present invention contemplates, in part, a method of providing analgesia to a subject having pain. [0023] In particular embodiments, the pain is acute pain, chronic pain, neuropathic pain, nociceptive pain, allodynia, inflammatory pain, or inflammatory hyperalgesia. [0024] In some embodiments, the pain is neuropathic pain. [0025] In some embodiments, the pain is selected from neuralgia, diabetic neuropathy, human immunodeficiency virus-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, a burn, back pain, eye pain, visceral pain, cancer pain (e.g., bone cancer pain), dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post herpetic neuralgia, post-operative pain, post stroke pain, and menstrual pain. [0026] In certain embodiments, the pain is nociceptive pain and is selected from the group consisting of central nervous system trauma, strains/sprains, burns, myocardial infarction, acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, pain associated with Vaso Occlusive Crises (VOCs), cancer pain, and back pain. [0027] In some embodiments, the pain is neuropathic pain and is selected from the group consisting of: peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson’s disease, epilepsy, and vitamin deficiency. [0028] In particular embodiments, the neuropathic pain is related to a pain disorder selected from the group consisting of: arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorder, hypoesthesis, hypealgesia, neuralgia, neuritis, neurogenic pain, analgesia, anesthesia dolorosa, causlagia, sciatic nerve pain disorder, degenerative joint disorder, fibromyalgia, visceral disease, chronic pain disorders, migraine/headache pain, chronic fatigue syndrome, complex regional pain syndrome, neurodystrophy, plantar fasciitis, and pain associated with cancer. [0029] In some embodiments, the pain is inflammatory pain. [0030] In certain embodiments, the pain is associated with a musculoskeletal disorder, myalgia, fibromyalgia, spondylitis, a sero-negative (non-rheumatoid) arthropathy, non- articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, or pyomyositis. [0031] In some embodiments, the pain is selected from heart and vascular pain, pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud’s phenomenon, scleroderma, skeletal muscle ischemia, head pain, migraine, cluster headache, tension-type headache, mixed headache, headache associated with vascular disorders, orofacial pain, dental pain, otic pain, burning mouth syndrome, and temporomandibular myofascial pain. [0032] In another aspect, the present invention provides a method of treating or ameliorating neuroinflammation, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor. [0033] In some embodiments, the neuroinflammation is associated with CXCL12 upregulation. In some embodiments, the neuroinflammation is associated with penetration of leukocytes into the brain of the subject. In some embodiments, the leukocytes are selected from monocytes, macrophages, neutrophils, and lymphocytes. [0034] In some embodiments, the neuroinflammation is associated with a viral or bacterial infection. In some embodiments, the neuroinflammation is associated with a malaria infection. [0035] In some embodiments, the neuroinflammation is associated with meningitis, shingles, or HIV infection. [0036] In some embodiments, the neuroinflammation is associated with an enterovirus, arbovirus, or herpes virus infection. [0037] In some embodiments, the neuroinflammation is associated with a herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), Japanese encephalitis virus, Zika virus, tick-borne encephalitis virus (TBEV), Murray Valley encephalitis virus, St. Louis encephalitis virus, La Crosse encephalitis virus (LCEV), John Cunningham virus (PML), HHV-6, an influenza virus, rabies, mumps, measles, or West Nile virus infection. [0038] In some embodiments, the neuroinflammation is associated with a bacterial infection. [0039] In some embodiments, the neuroinflammation is associated with a Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, or Haemophilus influenzae infection. [0040] In one aspect, the present invention provides a method of treating a neurological or central nervous system (CNS) cancer, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor described herein. [0041] In some embodiments, the neurological or CNS cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), ganglioma, ganglioneuroma, ganglioneuroblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma. [0042] In some embodiments, the neurological or CNS cancer is acoustic neuroma, astrocytoma (e.g. Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, optic pathway glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. [0043] In some embodiments, the neurological or CNS cancer is CNS lymphoma. [0044] In some embodiments, the CNS lymphoma is Primary CNS Lymphoma. [0045] In some embodiments, the Primary CNS Lymphoma is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the Primary CNS Lymphoma is a Burkitt or T- cell lymphoma. [0046] In some embodiments, the CNS lymphoma is Secondary CNS Lymphoma. [0047] In some embodiments, the Secondary CNS Lymphoma is DLBCL. In some embodiments, the Secondary CNS Lymphoma is a Burkitt or T-cell lymphoma. [0048] In another aspect, the present invention provides a method of treating Waldenström’s Macroglobulinemia (WM), comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor, such as I-1 or a pharmaceutically acceptable salt thereof. [0049] In some embodiments, the subject is a human and the CXCR4 inhibitor, such as Compound I-1 or a pharmaceutically acceptable salt thereof, is administered orally. [0050] In some embodiments, the CXCR4 inhibitor, such as Compound I-1 or a pharmaceutically acceptable salt thereof, is administered to the subject in a fed state. BRIEF DESCRIPTION OF THE DRAWINGS [0051] FIG. 1 shows brain, plasma, and cerebrospinal fluid (CSF) exposure levels for compound I-1 in male cynomolgus monkeys after 8 days of administration at 10 mg/kg QD (every day), administered PO (orally; measured @ 4, 24 & 72 hr post last dose; individually terminated animals; 50mM citrate buffer, pH 4.0). Brain histopathology of all monkeys was normal after 7-8 days after QD dosing at 10 mg/kg or 100 mg/kg (data not shown). [0052] FIG. 2 shows % apoptotic cells in cultures of OCI-LY19, a Diffuse Large B-Cell Lymphoma (DLBCL) cancer cell line, after exposure to varying concentrations of Compound I-1 and ibrutinib (BTK inhibitor), zanubrutinib (BTK inhibitor), or venetoclax (BCL-2 inhibitor). Of note, DLBCL accounts for about 90% of all CNS lymphomas. Time frame of assay = 72 hr; ibrutinib (8 uM) + Compound I-1 (2-5 uM) causes 60% apoptosis of DLBCL cells. [0053] FIG. 3 shows the effect of Compound I-1 on migration of DLBCL Cells. OCI- LY19 cells express high levels of CXCR4 and are known to migrate towards CXCL12, the ligand of CXCR4 (data not shown). Compound I-1 effectively inhibited migration of OCI- LY19 cells towards CXCL12. These data support efficacy in central nervous system Diffuse Large B-Cell Lymphoma (CNS-DLBCL). [0054] FIG. 4 shows Compound I-1 inhibition of CXCL12-CXCR4 mediated migration of various types of immune cells. Immune cells were isolated from whole blood from healthy donors, N=3, CXCL1210 nM; time frame of assay = 3 hr. [0055] FIG. 5 shows Compound I-1 inhibition of CXCL12-CXCR4 mediated migration of various types of immune cells. Immune cells were isolated from whole blood from healthy donors, N=3, CXCL1210 nM; time frame of assay = 3 hr. [0056] FIG. 6 shows Compound I-1 mediated inhibition of CXCL12 binding to CXCR4 of various species expressed in K562 cells. [0057] FIG. 7 shows inhibition of CXCL12-mediated ERK signaling in CXCR4- expressing K562 cells +/- Compound I-1. K562 cells transfected with WT CXCR4; Phosphoflow pERK (K562 stable clones). [0058] FIG.8 shows plasma exposure of Compound I-1 in female CB17-SCID mice after a single oral dose @ 5 mpk (mg/kg). [0059] FIG. 9 shows mean plasma concentration-time profiles of Compound I-1 after single PO dose of Compound I-1 free base at 10 mg/kg, Compound I-1 HCl salt at 0.3, 1, 3 and 10 mg/kg, respectively, in male SD rats (N=3/timepoint). Fasted dosing; SD Rats; p.o. 0.3, 1, 3, 10 mpk in HCl saline solution; or 10 mpk free base in saline w/ tween. The calculated t1/2 was 6 h. [0060] FIG.10 shows plasma exposure in beagle dogs in fed or fasted state following oral dosing of Compound I-1. Conditions: 1 mpk i.v.; 15 mpk p.o.; free base; citrate buffer formulation. FED: Animals received food 1 hour before dosing, free access to water. FASTED: Animals did NOT receive food on the morning of dosing and food resumed post 4 hr sampling, free access to water. [0061] FIG. 11 and FIG. 12 show plasma exposure in cynomolgus monkeys following dosing of Compound I-1. D1 = day 1 of dosing. D7 = day 7 of dosing. The compound exhibited a dose-dependent increase in exposure and relatively slow clearance. [0062] FIG. 13 (top) shows CXCR4-dependent release into blood of sequestered monocytes by orally-administered Compound I-1 in cynomolgus monkeys. Monocytes released into blood (AMC) following oral dosing with Compound I-1 @ 3, 10 & 30 mpk in citrate buffer (3 animals per dose group). QD dosing for 6 days shows continued and durable response (data not shown). In the bottom panel is shown CXCR4-dependent release into blood of sequestered monocytes by orally-administered Compound I-1 in rats. [0063] FIG. 14 (top) shows CXCR4-dependent release into blood of sequestered neutrophils by orally-administered Compound I-1 in cynomolgus monkeys. Compound I-1 @

3, 10 & 30 mpk p.o. doses in male cyno monkeys (N=3 for each dose). In the bottom panel is shown CXCR4-dependent release of sequestered neutrophils into blood following oral dosing of compound I-1 in rats. [0064] FIG. 15 (top) shows CXCR4-dependent release of sequestered lymphocytes into blood following oral dosing of Compound I-1 in cyno monkeys. Compound I-1 @ 3, 10 & 30 mpk p.o. doses in male Cyno monkeys (N=3 for each dose). In the bottom panel is shown CXCR4-dependent release of sequestered lymphocytes into blood following oral dosing of Compound I-1 in rats. [0065] FIG. 16 (top) shows CXCR4-dependent release of sequestered WBCs into blood following oral dosing of Compound I-1 in cyno monkeys. Compound I-1 @ 3, 10 & 30 mpk p.o. doses in male Cyno monkeys (N=3 for each dose). In the bottom panel is shown shows CXCR4-dependent release of sequestered WBCs into blood following oral dosing of Compound I-1 in rats. [0066] FIG.17 shows apoptosis of DLBCL cells exposed to venetoclax at 3.2 nM grown in the presence or absence of bone marrow stromal cells (BMSC) and either exposed or not exposed to Compound I-1. Compound I-1 successfully overcame BMSC-induced resistance of the DLBCL cells to venetoclax to restore apoptotic efficacy. These data support efficacy in Central Nervous System Diffuse Large B-Cell Lymphoma (CNS-DLBCL) as well as Diffuse Large B-Cell Lymphoma (DLBCL) in peripheral tissues. [0067] FIG. 18 (top) shows apoptosis of MEC-1 chronic lymphocytic leukemia (CLL) cells following exposure to ibrutinib with or without Compound I-1. The middle panels shows apoptosis of MEC-1 CLL cells following exposure to zanubrutinib with or without Compound I-1. The bottom panel shows apoptosis of MEC-1 CLL cells following exposure to venetoclax with or without Compound I-1. Time frame of all assays was 72 h. [0068] FIG. 19 (top) shows apoptosis of Waldenström’s Macroglobulinemia (MW) cells (MWCL-1; MYD88^L265P-CXCR4^WT) exposed to venetoclax with or without Compound I-1. The bottom panel shows apoptosis of MW cells exposed to venetoclax at 3.2 nM grown in the presence or absence of bone marrow stromal cells (BMSC) with or without Compound I-1. Compound I-1 successfully overcame BMSC-induced resistance of the WM cells to venetoclax to restore apoptotic efficacy. Venetoclax is not cytotoxic to BMSCs at concentrations tested. Compound I-1 alone does not induce apoptosis at 5 µM. Vene: venetoclax. BMSC: Bone Marrow Stroma Cell line HS27A. Time frame of assay: 48 h. [0069] FIG. 20 (top) shows apoptosis of Waldenström’s Macroglobulinemia (MW) cells (MWCL-1; MYD88^L265P-CXCR4^WT) exposed to zanubrutinib with or without Compound I-1. The bottom panel shows apoptosis of MW cells exposed to zanubrutinib grown in the presence or absence of bone marrow stromal cells (BMSC) with or without Compound I-1. Compound I-1 successfully overcame BMSC-induced resistance of the WM cells to zanubrutinib to restore apoptotic efficacy. Zanubrutinib is not cytotoxic to BMSCs at concentrations tested. Compound I-1 alone does not induce apoptosis at 5 µM. Zanub: zanubrutinib. BMSC: Bone Marrow Stroma Cell line HS27A. Time frame of assay: 72 h. [0070] FIG.21 (top) shows inhibition of BMSC-induced IgM hypersecretion in WM cells (MWCL-1; MYD88^L265P-CXCR4^WT). The bottom panel shows inhibition of BMSC-induced IgM hypersecretion in WM cells with or without zanubrutinib. [0071] FIG.22 shows inhibition of CXCL12-CXCR4 mediated migration in WM cells by Compound I-1. WM: Waldenström’s Macroglobulinemia (MWCL-1; MYD88^L265P- CXCR4^WT). Time frame of assay: 4 h. [0072] FIG.23 (top) shows the experimental design for a mouse model of human mantle cell lymphoma (Mino Cells, CDX). Mino cells are known to express CXCR4 and secrete human IgM. The CXCR4 antagonist tested was Compound I-1. Zanubrutinib and venetoclax were tested. Analyses performed were Tumor Growth Inhibition (TGI; as determined by compound-induced changes in tumor volume), human immunoglobulin M (IgM) secreted in mouse blood, mouse leukocytes in peripheral blood, pharmacokinetics (PK) of compound in plasma, human tumor cell infiltration into mouse spleen, and changes in body weight with and without treatment. The bottom panel shows efficacy of Compound I-1 as well as venetoclax in combination with Compound I-1 in inhibiting tumor growth in the mouse MCL model. [0073] FIG.24 (top) shows the efficacy of Compound I-1 in combination with venetoclax in decreasing hIgM in the MCL mouse model (see FIG.23 for procedure). The bottom panel shows inhibition of tumor cell infiltration in spleen in the mouse MCL model by Compound I- 1 in combination with venetoclax. [0074] FIG. 25 (top) shows increases in plasma NK (natural killer) cells in a mouse lymphoma model resulting from administration of Compound I-1 in combination with venetoclax vs. either compound alone. The bottom panel shows decreases in plasma neutrophil count in a mouse lymphoma model resulting from administration of Compound I-1 in combination with venetoclax vs. either compound alone. [0075] FIG.26 (top) shows the enhanced tumor growth inhibition of Compound I-1 alone and in combination with zanubrutinib in a mouse MCL model (see FIG.23 for procedure). The bottom panel shows decreases in hIgM in a mouse MCL model after administration with zanubrutininb with or without Compound I-1. [0076] FIG.27 (top) shows increases in plasma NK cells in a mouse lymphoma model by zanubrutinib in combination with Compound I-1. The bottom panel shows decreases in plasma neutrophil count in a mouse lymphoma model by zanubrutinib in combination with Compound I-1. [0077] FIG. 28 shows % inhibition data demonstrating that Compound I-1 is more effective as a single agent than temozolomide in inhibiting tumor cell proliferation of T-98G CNS GBM (gliobastoma multiforme) cell line. [0078] FIG. 29 shows % inhibition data demonstrating that Compound I-1 enhances efficacy of belzutifan by further decreasing cell proliferation of U-87MG cells compared to belzutifan monotherapy. More potent inhibition of cell proliferation with a greater Emax is seen for the combination therapy. [0079] FIG.30 shows CXCR4 gene expression is increased in GBM patients compared to normal brains. We performed bioinformatics analysis (GeneVestigator) on publicly available datasets (GSE15824 and GSE50161). Sample source: GSE15824: Frozen tissue samples of human gliomas and normal brain obtained from the operating room. GSE50161: Gene expression profiles were generated from surgical tumor and normal brain samples. [0080] FIG.31: (top) CXCR4 mRNA expression according to WHO glioma grade and in normal brain tissue determined with GEO dataset GSE16011. See pubmed.ncbi.nlm.nih.gov/33550492/. (Bottom) CXCR4 mRNA expression in the Cancer Genome Atlas (TCGA) and French dataset. See spandidos- publications.com/10.3892/mmr.2018.9011. [0081] FIG. 32: (top) Survival of GBM patients with low and high CXCR4 expression. See hgserver1.amc.nl/cgi-bin/r2/main.cgi. (Bottom) Survival of GBM patients with low and high CXCR4 expression in a French dataset. See spandidos- publications.com/10.3892/mmr.2018.9011. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention: [0082] Provided compounds are inhibitors of CXCR4 and are therefore useful for treating one or more disorders associated with activity of CXCR4. Thus, in certain embodiments, the present invention provides a method for treating a CXCR4-mediated disorder comprising the step of administering to a patient in need thereof a CXCR4 inhibitor described herein, such as a compound of Formula I, or a pharmaceutically acceptable salt thereof. Particular embodiments of the present invention are directed to the use of CXCR4 inhibitors that cross the blood-brain barrier (BBB) and enter the brain and central nervous system (CNS) upon administration to a subject. [0083] In some embodiments, the CXCR4 inhibitor is selected from the following:

I-230 I-11 or a pharmaceutically acceptable salt thereof. [0084] In some embodiments, the CXCR4 inhibitor is I-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR4 inhibitor is I-4 or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR4 inhibitor is I-187 or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR4 inhibitor is I-230 or a pharmaceutically acceptable salt thereof. [0085] In some embodiments, the CXCR4 inhibitor is I-11 or a pharmaceutically acceptable salt thereof. [0086] In some embodiments, the CXCR4 inhibitor is I-1 administered in the form of a free base, or a pharmaceutical composition thereof. In a particular embodiment, the pharmaceutical composition is suitable for oral administration to the subject. [0087] In one aspect, the present invention provides a method of treating a neurological disorder or disease of the central nervous system (CNS), or a method of alleviating the severity and symptoms thereof, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor. [0088] In some embodiments, the neurological disorder or disease of the CNS is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular dystrophy, Wilson’s disease, Lewy body dementia, Frontotemporal Dementia (FTD), cerebral palsy, Bell’s palsy, progressive supranuclear palsy, HIV-associated dementia (HAND), epilepsy, tremors and seizure disorders, catalepsy, immobilization disorders, paralysis and muscle rigidity, spina bifida, encephaly, encephalocele, encephalitis, myelopathy, migraines, cerebral ischemia, ischemia, stroke, cerebellar ataxia, Friedrich’s ataxia, prion diseases such as mad cow disease and Creutzfelt- Jakob disease, atherosclerosis, motor neurone disease (MND), Locked In Syndrome, Restless Leg Syndrome, arachnoid cysts, sciatica, thalassemia, cerebral hemorrhage, subarachnoid hemorrhage, muscular sclerosis, tardive dyskinesia, Charcot-Marie-Tooth Disease (CMT), thrombus formation, microembolus formation, Sickle cell disease, and Vaso Occlusive Crises (VOCs). In some embodiments, the neurological disorder or disease of the CNS is pseudobulbar affect (PBA). [0089] In some embodiments, the neurological disorder or disease of the CNS is a neurodegenerative disease. [0090] In some embodiments, the neurodegenerative disease is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular dystrophy, Wilson’s disease, Lewy body dementia, Frontotemporal Dementia (FTD), HIV-associated dementia (HAND), progressive supranuclear palsy, Friedrich’s ataxia, prion diseases such as Creutzfelt-Jakob disease, motor neurone disease (MND), and Charcot-Marie- Tooth Disease (CMT). [0091] In some embodiments, the neurodegenerative disease is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. [0092] In some embodiments, the neurodegenerative disease is ALS. [0093] In some embodiments, the neurological disorder or disease of the CNS is a CNS infection. In some embodiments, the CNS infection is selected from a viral infection such as meningitis, shingles, or HIV. [0094] In some embodiments, the CNS infection is selected from an enterovirus, arbovirus, and herpes virus infection. In some embodiments, the CNS infection is selected from a herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), Japanese encephalitis virus, Zika virus, tick-borne encephalitis virus (TBEV), Murray Valley encephalitis virus, St. Louis encephalitis virus, La Crosse encephalitis virus (LCEV), John Cunningham virus (PML), HHV-6, an influenza virus, rabies, mumps, measles, and West Nile virus infection. [0095] In some embodiments, the CNS infection is a bacterial infection. In some embodiments, the CNS infection is selected from a Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae infection. [0096] In some embodiments, the neurological disorder or disease of the CNS is selected from neurological damage caused by addiction, alcoholism or alcohol abuse, autism, anxiety, depression, satiety disorders (including obesity, anorexia, and bulimia), affective disorders, Tourette’s syndrome, schizophrenia, obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder, post-traumatic stress disorder (PTSD), gastroesophageal reflux disease (GERD), memory loss, dementia, sleep apnea, narcolepsy, urinary incontinence, and metabolic disorders that affect the CNS. [0097] In some embodiments, the neurological disorder or disease of the CNS is selected from neurodegeneration, a neuromuscular disorder, ischemia, a neuroinflammatory disease (also known as neuroinflammation), an autoimmune disorder, an anxiety disorder, and pain, wherein the neurological disorder or disease of the CNS arises from a traumatic head or brain injury, spinal cord injury, or another medical condition with neurological cell loss, damage and/or degeneration. [0098] In some embodiments, the the neuroinflammation is due to infiltration of leukocytes and/or immune cells into the brain. In another embodiment, leukocyte and/or immune cell infiltration into the brain is caused by elevated levels of CXCR4 in the brain. In some embodiments, the neurological disorder or disease of the CNS is selected from stroke, thrombus formation, and microembolus formation [0099] In some embodiments, the microemboli formation is microemboli in a COVID (e.g., COVID-19 or another strain of COVID) patient. [00100] In some embodiments, the present invention provides a method of treating and/or alleviating pain, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor. In various embodiments, the present invention contemplates, in part, a method of providing analgesia to a subject having pain. [00101] In particular embodiments, the pain is acute pain, chronic pain, neuropathic pain, nociceptive pain, allodynia, inflammatory pain, or inflammatory hyperalgesia. [00102] In some embodiments, the pain is neuropathic pain. [00103] In some embodiments, the pain is selected from neuralgia, diabetic neuropathy, human immunodeficiency virus-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, a burn, back pain, eye pain, visceral pain, cancer pain (e.g., bone cancer pain), dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post herpetic neuralgia, post-operative pain, post stroke pain, and menstrual pain. [00104] In certain embodiments, the pain is nociceptive pain and is selected from the group consisting of central nervous system trauma, strains/sprains, burns, myocardial infarction, acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, pain associated with Vaso Occlusive Crises (VOCs), cancer pain, and back pain. [00105] In some embodiments, the pain is neuropathic pain and is selected from the group consisting of: peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson’s disease, epilepsy, and vitamin deficiency. [00106] In some embodiments, the pain is neuropathic pain and is selected from the group consisting of: peripheral neuropathy, diabetic neuropathy, cancer neuropathy, and central post- stroke pain. [00107] In particular embodiments, the neuropathic pain is related to a pain disorder selected from the group consisting of: arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorder, hypoesthesis, hypealgesia, neuralgia, neuritis, neurogenic pain, analgesia, anesthesia dolorosa, causlagia, sciatic nerve pain disorder, degenerative joint disorder, fibromyalgia, visceral disease, chronic pain disorders, migraine/headache pain, chronic fatigue syndrome, complex regional pain syndrome, neurodystrophy, plantar fasciitis, and pain associated with cancer. [00108] In particular embodiments, the neuropathic pain is related to a pain disorder selected from the group consisting of: allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, neuralgia, neuritis, neurogenic pain, analgesia, anesthesia dolorosa, causlagia, and sciatic nerve pain disorder. [00109] In some embodiments, the pain is inflammatory pain. [00110] In certain embodiments, the pain is associated with a musculoskeletal disorder, myalgia, fibromyalgia, spondylitis, a sero-negative (non-rheumatoid) arthropathy, non- articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, or pyomyositis. [00111] In some embodiments, the pain is selected from heart and vascular pain, pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud’s phenomenon, scleroderma, skeletal muscle ischemia, head pain, migraine, cluster headache, tension-type headache, mixed headache, headache associated with vascular disorders, orofacial pain, dental pain, otic pain, burning mouth syndrome, and temporomandibular myofascial pain. [00112] In another aspect, the present invention provides a method of treating or ameliorating neuroinflammation, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor. [00113] In some embodiments, the neuroinflammation is associated with CXCL12 upregulation. In some embodiments, the neuroinflammation is associated with penetration of leukocytes into the brain of the subject. In some embodiments, the leukocytes are selected from monocytes, macrophages, neutrophils, and lymphocytes. [00114] In some embodiments, the neuroinflammation is associated with a viral or bacterial infection. In some embodiments, the neuroinflammation is associated with a malaria infection. [00115] In some embodiments, the neuroinflammation is associated with meningitis, shingles, or HIV infection. [00116] In some embodiments, the neuroinflammation is associated with an enterovirus, arbovirus, or herpes virus infection. [00117] In some embodiments, the neuroinflammation is associated with a herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), Japanese encephalitis virus, Zika virus, tick-borne encephalitis virus (TBEV), Murray Valley encephalitis virus, St. Louis encephalitis virus, La Crosse encephalitis virus (LCEV), John Cunningham virus (PML), HHV-6, an influenza virus, rabies, mumps, measles, or West Nile virus infection. [00118] In some embodiments, the neuroinflammation is associated with a bacterial infection. [00119] In some embodiments, the neuroinflammation is associated with a Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, or Haemophilus influenzae infection. [00120] In one aspect, the present invention provides a method of treating a neurological or central nervous system (CNS) cancer, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor described herein. [00121] In some embodiments, the neurological or CNS cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), ganglioma, ganglioneuroma, ganglioneuroblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma. [00122] In some embodiments, the neurological or CNS cancer is acoustic neuroma, astrocytoma (e.g. Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, optic pathway glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. [00123] In some embodiments, the neurological or CNS cancer is CNS lymphoma. [00124] In some embodiments, the CNS lymphoma is Primary CNS Lymphoma. [00125] In some embodiments, the Primary CNS Lymphoma is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the Primary CNS Lymphoma is a Burkitt or T- cell lymphoma. [00126] In some embodiments, the CNS lymphoma is Secondary CNS Lymphoma. [00127] In some embodiments, the Secondary CNS Lymphoma is DLBCL. In some embodiments, the Secondary CNS Lymphoma is a Burkitt or T-cell lymphoma. [00128] In another aspect, the present invention provides a method of treating Waldenström’s Macroglobulinemia (WM), comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor, such as I-1 or a pharmaceutically acceptable salt thereof. [00129] In some embodiments, the subject is a human and the CXCR4 inhibitor, such as Compound I-1 or a pharmaceutically acceptable salt thereof, is administered orally. [00130] In some embodiments, the CXCR4 inhibitor, such as Compound I-1 or a pharmaceutically acceptable salt thereof, is administered to the subject in a fed state. 2. Compounds and Definitions: [00131] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March’s Advanced Organic Chemistry, 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [00132] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C₃-C₆ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [00133] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

Exemplary bridged bicyclics include:

[00134] The term “lower alkyl” refers to a C_1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [00135] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [00136] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)). [00137] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [00138] As used herein, the term “bivalent C_1-8 (or C_1-6) saturated or unsaturated, straight or branched, hydrocarbon chain,” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [00139] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH₂)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [00140] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [00141] The term “halogen” means F, Cl, Br, or I. [00142] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. [00143] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin– 3(4H)–one. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [00144] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as in N– substituted pyrrolidinyl). [00145] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. [00146] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [00147] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [00148] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH₂)_0–4R°; –(CH₂)_0–4OR°; -O(CH₂)_0–4R^o, –O–(CH₂)_0– 4C(O)OR°; –(CH₂)_0–4CH(OR°)₂; –(CH₂)_0–4SR°; –(CH₂)_0–4Ph, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1-pyridyl which may be substituted with R°; –NO₂; – CN; –N₃; -(CH₂)_0–4N(R°)₂; –(CH₂)_0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH₂)_0– 4N(R°)C(O)NR°₂; -N(R°)C(S)NR°₂; –(CH₂)_0–4N(R°)C(O)OR°; – N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°₂; -N(R°)N(R°)C(O)OR°; –(CH₂)_0–4C(O)R°; – C(S)R°; –(CH₂)_0–4C(O)OR°; –(CH₂)_0–4C(O)SR°; -(CH₂)_0–4C(O)OSiR°3; –(CH₂)_0–4OC(O)R°; – OC(O)(CH₂)_0–4SR–, SC(S)SR°; –(CH₂)_0–4SC(O)R°; –(CH₂)_0–4C(O)NR°₂; –C(S)NR°₂; – C(S)SR°; –SC(S)SR°, -(CH₂)_0–4OC(O)NR°₂; -C(O)N(OR°)R°; –C(O)C(O)R°; – C(O)CH₂C(O)R°; –C(NOR°)R°; -(CH₂)_0–4SSR°; –(CH₂)_0–4S(O)₂R°; –(CH₂)_0–4S(O)₂OR°; – (CH₂)_0–4OS(O)₂R°; –S(O)₂NR°₂; –S(O)(NR°)R°; –S(O)₂N=C(NR°₂)₂; -(CH₂)_0– ₄S(O)R°; -N(R°)S(O)₂NR°₂; –N(R°)S(O)₂R°; –N(OR°)R°; –C(NH)NR°₂; – P(O)₂R°; -P(O)R°₂; -OP(O)R°₂; –OP(O)(OR°)₂; SiR°3; –(C1–4 straight or branched alkylene)O–N(R°)₂; or –(C_1–4 straight or branched alkylene)C(O)O–N(R°)₂. [00149] Each R° is independently hydrogen, C_1–6 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, -CH₂- (5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =O and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, –(CH₂)_0–2R^●, –(haloR^●), –(CH₂)_0–2OH, –(CH₂)_0–2OR^●, – (CH₂)_0–2CH(OR^●)₂; -O(haloR^●), –CN, –N3, –(CH₂)_0–2C(O)R^●, –(CH₂)_0–2C(O)OH, –(CH₂)_0– ₂C(O)OR^●, –(CH₂)_0–2SR^●, –(CH₂)_0–2SH, –(CH₂)_0–2NH₂, –(CH₂)_0–2NHR^●, –(CH₂)_0–2NR^● ₂, – NO₂, –SiR^●3, –OSiR^●3, -C(O)SR^●, –(C1–4 straight or branched alkylene)C(O)OR^●, or –SSR^●. [00150] Each R^● is independently selected from C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^● is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR^* ₂, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)₂R^*, =NR^*, =NOR^*, –O(C(R^* ₂))_2–3O–, or –S(C(R^* ₂))_2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is –O(CR^* ₂)_2–3O–, wherein each independent occurrence of R^* is selected from hydrogen, C_1–6 aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00151] When R^* is C_1–6 aliphatic, R^* is optionally substituted with halogen, –R^●, -(haloR^●), -OH, –OR^●, –O(haloR^●), –CN, –C(O)OH, –C(O)OR^●, –NH2, –NHR^●, –NR^●2, or –NO₂, wherein each R^● is independently selected from C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0– 1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [00152] An optional substituent on a substitutable nitrogen is independently –R^†, –NR^† ₂, – C(O)R^†, –C(O)OR^†, –C(O)C(O)R^†, –C(O)CH₂C(O)R^†, -S(O)₂R^†, -S(O)₂NR^† ₂, –C(S)NR^† ₂, – C(NH)NR^†2, or –N(R^†)S(O)₂R^†; wherein each R^† is independently hydrogen, C_1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when is C_1–6 aliphatic, R^† is optionally substituted with halogen, –R ^{^}, -(haloR ^{^}), -OH, –OR ^{^}, – O(haloR ^{^}), –CN, –C(O)OH, –C(O)OR ^{^}, –NH₂, –NHR ^{^}, –NR ^{^} ₂, or –NO₂, wherein each R ^{^} is independently selected from C1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^{^} is unsubstituted or where preceded by halo is substituted only with one or more halogens. [00153] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3– phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [00154] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [00155] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, a warhead moiety, R¹, of a provided compound comprises one or more deuterium atoms. [00156] As used herein, the term “inhibitor” is defined as a compound that binds to and /or inhibits CXCR4 with measurable affinity. In certain embodiments, an inhibitor has an IC₅₀ and/or binding constant of less than about 100 µM, less than about 50 µM, less than about 1 µM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. [00157] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in CXCR4 activity between a sample comprising a compound of the present invention, or composition thereof, and CXCR4, and an equivalent sample comprising CXCR4, in the absence of said compound, or composition thereof. [00158] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered after the subject has been diagnosed with the disease or disorder, whether or not the subject has already developed a symptom. 3. Description of Exemplary Embodiments: [00159] Provided compounds are inhibitors of CXCR4 and are therefore useful for treating one or more disorders associated with activity of CXCR4. Thus, in certain embodiments, the present invention provides a method for treating a CXCR4-mediated disorder comprising the step of administering to a patient in need thereof a CXCR4 inhibitor described herein. [00160] As used herein, a “CXCR4-mediated” disorder, disease, and/or condition refers to any disease, disorder, or condition in which CXCR4, or a mutant thereof, and/or overexpression thereof, is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which CXCR4, or a mutant thereof, are known to play a role. [00161] In some embodiments, the “CXCR4-mediated” disorder, disease and/or condition is a disease, disorder or condition affecting the central nervous system, or a disorder, disease or condition that is modulated by the central nervous system, such as a neurodegenerative disease, CNS infection, neuroinflammation, or pain or neurological damage or abnormality caused by a condition or disorder that affects the CNS. [00162] In some embodiments, the CXCR4 inhibitor is a compound of Formula XIV-c:

XIV-c or a pharmaceutically acceptable salt thereof, wherein each variable is as defined in the same manner as for Formula I below. [00163] In some embodiments, the CXCR4 inhibitor is selected from the following:

I-1 I-4 I-187

or a pharmaceutically acceptable salt thereof. [00164] In some embodiments, the CXCR4 inhibitor is I-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR4 inhibitor is I-4 or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR4 inhibitor is I-187 or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR4 inhibitor is I-230 or a pharmaceutically acceptable salt thereof. [00165] In some embodiments, the CXCR4 inhibitor is I-11 or a pharmaceutically acceptable salt thereof. [00166] In some embodiments, the CXCR4 inhibitor is I-1 administered in the form of a free base, or a pharmaceutical composition thereof. [00167] Unless indicated otherwise, the CXCR4 inhibitor of Formula I or pharmaceutically acceptable salt thereof, such as I-1, I-4, I-187, I-230, or I-11, is in the form of an all-cis racemate. For clarity, “all-cis racemate” refers to a mixture of both

in the case of compound I-1. [00168] In some embodiments, the CXCR4 inhibitor is administered as a racemate of cis and trans isomers. In some embodiments, the CXCR4 inhibitor is administered as the enantiomerically pure cis isomer, meaning that the CXCR4 is substantially free of its cis enantiomer. [00169] In some embodiments, compound I-1 is administered as the following substantially pure cis isomer:

or a pharmaceutically acceptable salt thereof, wherein I-1 is substantially free of its cis enantiomer, i.e.,

. [00170] In some embodiments, compound I-1 is administered as the following substantially pure cis isomer:

. [00171] In particular embodiments, compound I-1 or a pharmaceutically acceptable salt thereof is substantially free of its cis enantiomer and its trans isomers. [00172] The term “substantially free” in reference to a cis enantiomer or other enantiomers includes embodiments wherein the CXCR4 inhibitor has an enantiomeric excess percentage (% ee) of at least 80, 85, 90, 9192, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9, or greater than 99.9% ee. [00173] In some embodiments, compound I-1 or a pharmaceutically acceptable salt thereof is administered as a racemate:

. [00174] In one aspect, the present invention provides a method of treating a neurological disorder or disease of the central nervous system (CNS), or a method of alleviating the severity and symptoms thereof, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor. In some embodiments, the CXCR4 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt thereof, such as compound I-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR4 inhibitor penetrates the blood-brain barrier (BBB). [00175] In some embodiments, the neurological disorder or disease of the CNS is selected from Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular dystrophy, Wilson’s disease, Lewy body dementia, Frontotemporal Dementia (FTD), cerebral palsy, Bell’s palsy, progressive supranuclear palsy, amyotrophic lateral sclerosis (ALS), HIV- associated dementia (HAND), epilepsy, tremors and seizure disorders, catalepsy, immobilization disorders, paralysis and muscle rigidity, spina bifida, encephaly, encephalocele, encephalitis, myelopathy, migraines, cerebral ischemia, ischemia, stroke, cerebellar ataxia, Friedrich’s ataxia, prion diseases such as mad cow disease and Creutzfelt- Jakob disease, atherosclerosis, motor neurone disease (MND), Locked In Syndrome, Restless Leg Syndrome, arachnoid cysts, sciatica, thalassemia, cerebral hemorrhage, subarachnoid hemorrhage, muscular sclerosis, tardive dyskinesia, Charcot-Marie-Tooth Disease (CMT), thrombus formation, microembolus formation, Sickle cell disease, and Vaso Occlusive Crises (VOCs). In some embodiments, the neurological disorder or disease of the CNS is pseudobulbar affect (PBA). [00176] CXCR4 is known to be implicated in stroke. See, e.g., Wenhao Qu, Ying Cheng, Wei Peng et al. Reducing the Amount of M1 Microglia by Inhibiting CXCR4 and iNOS Exerts Neuroprotection in a Rat Model of Subarachnoid Hemorrhage, 07 September 2021, PREPRINT (Version 1) available at doi.org/10.21203/rs.3.rs-856199/v1; Cell Transplantation, Vol. 26, pp. 571–583, 2017; Huang, J., et al., Stroke. 2013;44:190–197. CXCR4 promotes thrombi formation, formation of microemboli and thrombosis. Without wishing to be bound by theory, it is believed that the pathogenic mechanism of action leading to this is believed to be through CXCR4-mediated NET (Neutrophil Extracellular Traps) formation, which trap platelets, in turn leading to thrombi formation in blood vessels. This is especially an issue in Sickle Cell Disease (SCD) patients where such events lead to vaso-occlusive crises (VOC) and pain. A similar phenomenon is seen in COVID patients where thrombi formation accounts for a significant number of deaths. Disclosed CXCR4 inhibitors such as Compound I-1 are expected to be beneficial in preventing or diminishing thrombi formation leading to stroke, VOCs or death. [00177] In some embodiments, the neurological disorder or disease of the CNS is a neurodegenerative disease. [00178] CXCR4 is known to be implicated in various neurodegenerative diseases including, but not limited to, ALS, Alzheimer’s disease, and Parkinson’s disease. Accordingly, it is contemplated that the CXCR4 inhibitors described herein are useful in the treatment of such diseases. See, e.g., Rabinovich-Nikitin et al., “Chronic administration of AMD3100 increases survival and alleviates pathology in SOD1G93A mice model of ALS,” Journal of Neuroinflammation (2016) 13:123; Inna Rabinovich-Nikitin, Beka Solomon, “Lactate Transport and Signaling Mediated by AMD3100 Ameliorates Astrocyte Pathology and Remyelination Without Additional Extension of SOD1^G93A Mice Life-Span,” bioRxiv 2022.01.28.478264; Li, Ting & Tongtong, Liu & Chen, Xuhui & Li, Li & Feng, Miaomiao & Zhang, Yue & Wan, Li & Zhang, Chuanhan & Yao, Wenlong. (2020). “Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain,” Journal of Neuroinflammation 17.10.1186/s12974-020-01891-5; Gavriel, Y., et al. (2020). “Subcutaneous Administration of AMD3100 into Mice Models of Alzheimer’s Disease Ameliorated Cognitive Impairment, Reduced Neuroinflammation, and Improved Pathophysiological Markers,” Journal of Alzheimer's Disease, 78(2), 653-671; Li, Y., Niu, M., Zhao, A. et al. CXCL12 is involved in α-synuclein-triggered neuroinflammation of Parkinson’s disease. J Neuroinflammation 16, 263 (2019); Zheng, J., et al., “Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia,” Journal of Neuroimmunology, Volume 98, Issue 2, P185-200, August 3, 1999, doi.org/10.1016/S0165-5728(99)00049-1. [00179] In addition, CXCR7 agonism promotes a neuroprotective phenotype of astrocytes (A2). As described in further detail below, Compound I-1 and other related compounds are also CXCR7 agonists (in addition to being CXCR4 antagonists). This CXCR7 agonism by the compounds of this invention is expected to promote a neuroprotective phenotype of astrocytes leading to beneficial effects in ALS and other neurologic diseases where astrocytes are critical for maintaining healthy neurons. [00180] For support for the role of CXCR4 in neuroinflammation, neurodegeneration, and neuropathic pain, see Geeta Ramesh, Andrew G. MacLean, Mario T. Philipp, “Cytokines and Chemokines at the Crossroads of Neuroinflammation, Neurodegeneration, and Neuropathic Pain,” Mediators of Inflammation, vol. 2013, Article ID 480739, 20 pages, 2013. doi.org/10.1155/2013/480739. [00181] ALS is a rare, progressive and fatal neurodegenerative disease, characterized by degeneration of both upper and lower motor neurons. Symptoms include muscle weakness, muscle atrophy, behavioral impairment, dysphagia, dysarthria. The prevalence of ALS in the United States is 5 in 100,000. ALS cases across the globe are projected to increase from 222,801 in 2015 to 376,674 in 2040. The causes of ALS include Sporadia ALS (90-95%): The genetics of sporadic ALS is less well understood. There is also Familial ALS (5-10%) caused by one of the following mutations: C9orf72 (40%), SOD1 (20%), FUS (1–5%), TARBDP (TBP- 43) (1–5%). The ALS pathogenetic mechanisms are still not fully understood. Mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation have been shown to contribute to the pathogenesis of ALS. No effective treatments are available. Regarding the connection between CXCR4 and ALS, it is known that CXCL12 levels are increased in cerebrospinal fluid (CSF) in sporadic amyotrophic lateral sclerosis (ALS) Patients; mdpi.com/1422-0067/21/22/8680). Furthermore, CXCR4 expression is increased in T cells in ALS patients compared to healthy controls; jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1135-3). In preclinical studies, chronic administration of AMD3100 ( 5mg/kg, SC) to SOD1^G93A mice (mice model of ALS) led to: significant extension SOD1^G93A mice lifespan; improved motor function and weight loss; improved microglial pathology; decreased proinflammatory cytokines in spinal cords; decreased blood-spinal cord barrier permeability by increasing tight junction proteins levels; and increased the motor neurons count in the lamina X area of the spinal cord. See ncbi.nlm.nih.gov/pmc/articles/PMC4882847/) and US 2016/0206592, which is hereby incorporated by reference. Without wishing to be bound by theory, it is believed that CXCR4 inhibitors described herein, such as compounds of Formula I, and pharmaceutically acceptable salts thereof, are more effective treatments for ALS. For example, CXCR4 inhibitors described herein can have the ability to penetrate the BBB and provide therapeutically effective levels of CXCR4 inhibition in the brain and CNS. [00182] Parkinson’s disease affects 1-2 per 1,000 people. No cure exists, and the only medications available are symptomatic treatments. Misfolded alpha-synuclein protein forms toxic clumps (Lewy bodies) in neurons in the midbrain (substantia nigra pars compacta), causing death of neurons and astrocytes. Non-motor symptoms include loss of smell, sleep and mood disorders. Motor symptoms include rigidity, bradykinesia, resting tremors and postural instability. Inflammation is a hallmark of Parkinson’s Disease. Microglia are a self- renewing pool of brain-resident immune cells (Hashimoto et al., 2013; pubmed.ncbi.nlm.nih.gov/23601688/). In the PD brain, microglia undergo morphological and functional changes, with complex roles in disease burden. IL-1β, IL-2, IL-4, IL-6, TNFα and IFNγ are increased in the CSF. (Lecours et al., 2018 pubmed.ncbi.nlm.nih.gov/30214398/). In healthy brain, almost all basic cell types (neurons, glia, microglia) express CXCR4 (Lavi et al., 1997; pubmed.ncbi.nlm.nih.gov/9327737/). CXCR4 and CXCL12 are upregulated in the substantia nigra of PD brains. See Shimoji et al., 2009, pubmed.ncbi.nlm.nih.gov/19551455/; Li et al., 2019, pubmed.ncbi.nlm.nih.gov/31831012/; and Bonham et al., 2018, nature.com/articles/s41398-017-0049-7. Higher CXCL12 has been observed in serum of PD patients, higher CXCR4 in PBMCs of PD patients (Bagheri et al., 2018, pubmed.ncbi.nlm.nih.gov/30428473/). Furthermore, SNPs near CXCR4 are associated with increased risk to develop PD (Bonham et al., 2018). In a mouse model of PD (alpha-syn A53T overexpression) Li et al., 2019, pubmed.ncbi.nlm.nih.gov/31831012/. CXCR4 expression and CXCL12 expression and secretion in microglia was upregulated. In vitro chemotaxis of microglia to the substantia nigra was induced; could be inhibited by Plerixafor. [00183] In some embodiments, the neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular dystrophy, Wilson’s disease, Lewy body dementia, Frontotemporal Dementia (FTD), HIV-associated dementia (HAND), progressive supranuclear palsy, amyotrophic lateral sclerosis (ALS), Friedrich’s ataxia, prion diseases such as Creutzfelt-Jakob disease, motor neurone disease (MND), and Charcot-Marie- Tooth Disease (CMT). [00184] In some embodiments, the neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS). [00185] In some embodiments, the neurodegenerative disease is Alzheimer’s disease. [00186] In some embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). [00187] In some embodiments, the neurodegenerative disease is Parkinson’s disease. [00188] In some embodiments, the neurological disorder or disease of the CNS is selected from neuronal cell damage or death; nerve damage from cerebrovascular disorders such as stroke in the brain or spinal cord, atrial fibrillation, a CNS infection, a prion disease, ordinary aging (e.g., anosmia), and head and/or brain injury and other medical diseases and conditions involving neurological cell loss, damage and/or degeneration. In some embodiments, the neurological disorder or disease of the CNS is selected from stroke, thrombus formation, and microembolus formation. [00189] In some embodiments, the microemboli formation is microemboli in a COVID (e.g., COVID-19 or another strain of COVID) patient. [00190] In some embodiments, the CNS infection is selected from a viral infection such as meningitis, shingles, or HIV. [00191] In some embodiments, the CNS infection is selected from an enterovirus, arbovirus, and herpes virus infection. In some embodiments, the CNS infection is selected from a herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), Japanese encephalitis virus, Zika virus, tick-borne encephalitis virus (TBEV), Murray Valley encephalitis virus, St. Louis encephalitis virus, La Crosse encephalitis virus (LCEV), John Cunningham virus (PML), HHV-6, an influenza virus, rabies, mumps, measles, and West Nile virus infection. [00192] Viruses can be responsible for CNS infection through a variety of mechanisms including direct infection and replication within the CNS resulting in encephalitis, infection limited to the meninges, or immune-related processes such as acute disseminated encephalomyelitis. Common pathogens including herpes simplex virus, varicella zoster, and enterovirus are responsible for the greatest number of cases in immunocompetent hosts. Other herpes viruses (e.g., cytomegalovirus, John Cunningham virus) are more common in immunocompromised hosts. Arboviruses such as Japanese encephalitis virus and Zika virus are important pathogens globally, but the prevalence varies significantly by geographic region and often season. Accordingly, in some embodiments, the CNS infection to be treated in a disclosed method comprises one of: encephalitis, infection limited to the meninges, and acute disseminated encephalomyelitis. In some embodiments, the subject is immunocompetent. In some embodiments, the subject is immunocompromised. [00193] In some embodiments, the CNS infection is a bacterial infection. In some embodiments, the CNS infection is selected from a Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae infection. [00194] In some embodiments, the neurological disorder or disease of the CNS is selected from neurological damage caused by addiction, alcoholism or alcohol abuse, autism, anxiety, depression, satiety disorders (including obesity, anorexia, and bulimia), affective disorders, Tourette’s syndrome, schizophrenia, obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder, post-traumatic stress disorder (PTSD), gastroesophageal reflux disease (GERD), memory loss, dementia, sleep apnea, narcolepsy, urinary incontinence, and metabolic disorders that affect the CNS. [00195] In some embodiments, the neurological disorder or disease of the CNS is selected from neurodegeneration, a neuromuscular disorder, ischemia, neuroinflammation, an autoimmune disorder, an anxiety disorder, and pain, wherein the neurological disorder or disease of the CNS arises from a traumatic head or brain injury, spinal cord injury, or another medical condition with neurological cell loss, damage and/or degeneration. [00196] In some embodiments, the microemboli formation is microemboli in a COVID (e.g., COVID-19 or another strain of COVID) patient. [00197] CXCR4 is known to be implicated in certain autoimmune diseases. Accordingly, the present invention provides methods of treating autoimmune diseases using a CXCR4 inhibitor described herein. See, e.g., García-Cuesta Eva M., Santiago César A., Vallejo-Díaz Jesús, Juarranz Yasmina, Rodríguez-Frade José Miguel, Mellado Mario, “The Role of the CXCL12/CXCR4/ACKR3 Axis in Autoimmune Diseases,” Frontiers in Endocrinology 2019, Volume 10, 10.3389/fendo.2019.00585. [00198] In some embodiments, the present invention provides a method of treating and/or alleviating pain, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor. In various embodiments, the present invention contemplates, in part, a method of providing analgesia to a subject having pain. [00199] In particular embodiments, the pain is acute pain, chronic pain, neuropathic pain, nociceptive pain, allodynia, inflammatory pain, or inflammatory hyperalgesia. [00200] In some embodiments, the pain is neuropathic pain. [00201] In some embodiments, the pain is selected from neuralgia, diabetic neuropathy, human immunodeficiency virus-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, a burn, back pain, eye pain, visceral pain, cancer pain (e.g., bone cancer pain), dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post herpetic neuralgia, post-operative pain, post stroke pain, and menstrual pain. [00202] In certain embodiments, the pain is nociceptive pain and is selected from the group consisting of central nervous system trauma, strains/sprains, burns, myocardial infarction, acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, pain associated with Vaso Occlusive Crises (VOCs), cancer pain, and back pain. [00203] In some embodiments, the pain is neuropathic pain and is selected from the group consisting of: peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson’s disease, epilepsy, and vitamin deficiency. [00204] In particular embodiments, the neuropathic pain is related to a pain disorder selected from the group consisting of: arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorder, hypoesthesis, hypealgesia, neuralgia, neuritis, neurogenic pain, analgesia, anesthesia dolorosa, causlagia, sciatic nerve pain disorder, degenerative joint disorder, fibromyalgia, visceral disease, chronic pain disorders, migraine/headache pain, chronic fatigue syndrome, complex regional pain syndrome, neurodystrophy, plantar fasciitis, and pain associated with cancer. [00205] In some embodiments, the pain is inflammatory pain. [00206] In certain embodiments, the pain is associated with a musculoskeletal disorder, myalgia, fibromyalgia, spondylitis, a sero-negative (non-rheumatoid) arthropathy, non- articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, or pyomyositis. [00207] In some embodiments, the pain is selected from heart and vascular pain, pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud’s phenomenon, scleroderma, skeletal muscle ischemia, head pain, migraine, cluster headache, tension-type headache, mixed headache, headache associated with vascular disorders, orofacial pain, dental pain, otic pain, burning mouth syndrome, and temporomandibular myofascial pain. [00208] In another aspect, the present invention provides a method of treating or ameliorating neuroinflammation, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor. In some embodiments, the CXCR4 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt thereof, such as compound I-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR4 inhibitor penetrates the blood-brain barrier (BBB). [00209] In some embodiments, the neuroinflammation is associated with CXCL12 upregulation. In some embodiments, the neuroinflammation is associated with penetration of leukocytes into the brain of the subject. In some embodiments, the leukocytes are selected from monocytes, macrophages, neutrophils, and lymphocytes. [00210] In some embodiments, the neuroinflammation is associated with a viral or bacterial infection. In some embodiments, the neuroinflammation is associated with a malaria infection. [00211] In some embodiments, the neuroinflammation is associated with meningitis, shingles, or HIV infection. [00212] In some embodiments, the neuroinflammation is associated with an enterovirus, arbovirus, or herpes virus infection. [00213] In some embodiments, the neuroinflammation is associated with a herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), Japanese encephalitis virus, Zika virus, tick-borne encephalitis virus (TBEV), Murray Valley encephalitis virus, St. Louis encephalitis virus, La Crosse encephalitis virus (LCEV), John Cunningham virus (PML), HHV-6, an influenza virus, rabies, mumps, measles, or West Nile virus infection. [00214] In some embodiments, the neuroinflammation is associated with a bacterial infection. [00215] In some embodiments, the neuroinflammation is associated with a Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, or Haemophilus influenzae infection. [00216] In one aspect, the present invention provides a method of treating a neurological or central nervous system (CNS) cancer, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor described herein. In some embodiments, the CXCR4 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt thereof, such as compound I-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR4 inhibitor penetrates the blood-brain barrier (BBB). [00217] Without wishing to be bound by theory, it is believed that the general pathogenic and therapeutic mechanism of action for GBM and other similar cancers is that CXCL12 drives monocyte/macrophage infiltration into brain and after treatment with irradiation, these cells drive vasculogenesis, causing regrowth of the GBM tumor. CXCR4 antagonism would inhibit monocyte/macrophage infiltration into brain, thereby preventing or reducing vasculogenesis. [00218] Further, CXCL12 binding to CXCR4 receptors on macrophages promotes an anti- tumor phenotype similar to a tumor associated macrophage (TAM) which promotes tumor growth. CXCR4 inhibitors described herein are expected to block this pro-tumoral phenotype. [00219] Additionally, CXCL12/CXCR4 drives growth and proliferation of GBM tumor cells (as well as other tumor cells) and hence antagonizing CXCR4 will be efficacious in reducing tumor size. CXCR4 antagonism inhibits infiltration of MDSCs (myeloid-derived suppressor cells) which are known to promote tumor growth. In addition, CXCR4 is known to mediate metastasis of tumor cells to tissues including brain. CXCR4 antagonism with the presently described compounds would inhibit tumor metastasis. For example, inhibition of CXCR4 is believed to reduce or prevent immunosuppressive neutrophil infiltration into tumors thereby allowing immune cells such as NK cells and pro-inflammatory CD8+ T-cells to kill tumor cells. For lymphomas, if primary in the CNS, it is believed that blocking CXCR4 would induce apoptosis and decrease tumor cell growth and proliferation. If a secondary CNS lymphoma, CXCR4 antagonism would prevent migration, as well as adhesion (or anchoring), of tumor cells to metastatic tissues including brain. CXCR4 promotes adhesion to bone marrow stroma and chemoresistance of tumor cells. CXCR4 inhibitors described herein are expected to block this bone marrow-induced chemoresistance and adhesion to bone marrow stroma, thereby inducing apoptosis of tumor cells. [00220] In some embodiments, the neurological or CNS cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), ganglioma, ganglioneuroma, ganglioneuroblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma. [00221] In some embodiments, the neurological or CNS cancer is acoustic neuroma, astrocytoma (e.g. Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, optic pathway glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient. [00222] In some embodiments, the neurological or CNS cancer is CNS lymphoma. [00223] In some embodiments, the CNS lymphoma is Primary CNS Lymphoma. [00224] In some embodiments, the Primary CNS Lymphoma is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the Primary CNS Lymphoma is a Burkitt or T- cell lymphoma. Of note, DLBCL is frequently attributed to be a factor in greater than 90% of primary CNS lymphoma. [00225] In some embodiments, the CNS lymphoma is Secondary CNS Lymphoma. [00226] In some embodiments, the Secondary CNS Lymphoma is DLBCL. In some embodiments, the Secondary CNS Lymphoma is a Burkitt or T-cell lymphoma. [00227] In some embodiments, the neurological or CNS cancer is spinal axis tumor, brain stem glioma, pituitary adenoma, adrenocortical cancer, neuroblastoma, or retinoblastoma. [00228] In some embodiments, the neurological or CNS cancer is neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST). [00229] In some embodiments, the neurological or CNS cancer is metastatic. In some embodiments, the cancer has metastasized to the brain or nervous system from elsewhere in the body of the subject. [00230] In some embodiments, method is effective to treat one or more neurological or CNS tumors. In some embodiments, the tumor is treated by arresting further growth of the tumor. In some embodiments, the tumor is treated by reducing the size (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the size of the tumor prior to treatment. In some embodiments, tumors are treated by reducing the quantity of the tumors in the patient by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the quantity of tumors prior to treatment. [00231] CXCR4 is known to be implicated in a variety of neurological cancers, CNS cancers, and other cancers. See, for example, Alghamri, M.S., et al., “Systemic Delivery of an Adjuvant CXCR4–CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy,” ACS Nano 202216 (6), 8729-8750; Giordano, F.A., “Targeting the Post-Irradiation Tumor Microenvironment in Glioblastoma via Inhibition of CXCL12,” Cancers 2019, 11(3), 272; Gravina G.L., et al., “The novel CXCR4 antagonist, PRX177561, reduces tumor cell proliferation and accelerates cancer stem cell differentiation in glioblastoma preclinical models,” Tumor Biology 2017;39(6); Rios, A., “The Promise of Plerixafor in Glioblastoma Treatment,” cancercommons.org/latest-insights/the-promise-of- plerixafor-in-glioblastoma-treatment/; Urszula M. Domanska, et al., “A review on CXCR4/CXCL12 axis in oncology: No place to hide,” European Journal of Cancer, Volume 49, Issue 1, 2013, Pages 219-230; Shi Yi, Riese David J., Shen Jianzhong, “The Role of the CXCL12/CXCR4/CXCR7 Chemokine Axis in Cancer,” Frontiers in Pharmacology 2020, 11, 10.3389/fphar.2020.574667. [00232] In another aspect, the present invention provides a method of treating Waldenström’s Macroglobulinemia (WM), comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor, such as I-1 or a pharmaceutically acceptable salt thereof. Waldenström’s macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized by the proliferation of lymphoplasmacytic cells in the bone marrow in other organs, along with elevated serum levels of monoclonal immunoglobulin M (IgM) gammopathy. [00233] WM is sometimes referred to as a lymphoplasmacytic lymphoma (LPL) with an associated monoclonal IgM paraprotein. In WM, there is a malignant change to the B-cell in the late stages of maturing, and it continues to proliferate into a clone of identical cells, primarily in the bone marrow but also in the lymph nodes and other tissues and organs of the lymphatic system. WM is classified as a type of non-Hodgkin’s lymphoma called lymphoplasmacytic lymphoma (LPL). About 95% of LPL cases are WM; the remaining 5% do not secrete IgM and consequently are not classified as WM. [00234] In some embodiments, the subject is a human and the CXCR4 inhibitor, such as Compound I-1 or a pharmaceutically acceptable salt thereof, is administered orally. [00235] In some embodiments, the CXCR4 inhibitor, such as Compound I-1 or a pharmaceutically acceptable salt thereof, is administered to the subject in a fed state. [00236] In some embodiments, the CXCR4 inhibitor for use in a method of treatment described herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R¹ is independently -R, halogen, -CN, -OR, -N(R)₂, -NO₂, -N3, -SR, or -L¹-R⁶; each R is independently hydrogen or an optionally substituted group selected from C_1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each L¹ and L² is independently a covalent bond or a C1-8 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)- , -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO₂-, -SO₂N(R)-, -(R)NSO₂-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-; each -Cy- is independently a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R² is hydrogen, halogen, -CN, -OR, -N(R)₂, -NO₂, -N3, -SR, -L²-R⁶, or optionally substituted C_1-8 aliphatic; R³ is hydrogen, optionally substituted C1-6 aliphatic, or -L³-R⁶; L³ is a C_1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)- , -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -C(S)-, or -Cy-; each R⁴ is independently hydrogen, deuterium, halogen, -CN, -OR⁶, or C1-4 alkyl, or two R⁴ groups on the same carbon are optionally taken together to form =NR⁶, =NOR⁶, =O, or =S; each R⁵ is independently R, halogen, -CN, -OR, -N(R)₂, -NO₂, -N3, -SR, or -L¹-R⁶, or two R⁵ groups on the same saturated carbon atom are optionally taken together to form =NR, =NOR, =O, =S, or a spirocyclic 3-6 membered carbocyclic ring; each R⁶ is independently hydrogen or C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [00237] In some embodiments, the CXCR4 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt thereof, provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the CXCR4 inhibitor penetrates the blood-brain barrier (BBB). [00238] As defined generally above, Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00239] In some embodiments, Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00240] In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00241] In some embodiments, Ring A is selected from:

[ , i

[00243] In some embodiments, Ring A is not

. [00244] In some embodiments, Ring A is not imidazo[1,2-a]pyridine. [00245] In some embodiments, Ring A is selected from those depicted in Table 1, below. [00246] As defined generally above, each R¹ is independently R, halogen, -CN, -OR, - N(R)₂, -NO₂, -N3, -SR, or -L¹-R⁶. [00247] In some embodiments, R¹ is R. In some embodiments, R¹ is halogen. In some embodiments, R¹ is -CN. In some embodiments, R¹ is -OR. In some embodiments, R¹ is - N(R)₂. In some embodiments, R¹ is -NO₂. In some embodiments, R¹ is -N3. In some embodiments, R¹ is -SR. In some embodiments, R¹ is -L¹-R⁶. [00248] In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is an optionally substituted C_1-6 aliphatic group. In some embodiments, R¹ is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R¹ is an optionally substituted phenyl. In some embodiments, R¹ is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R¹ is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R¹ is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R¹ is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00249] In some embodiments, R¹ is selected from R, halogen, -CN, -OR, -N(R)₂, -SR, C1- 6 aliphatic, or -L¹-R⁶, wherein L¹ is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -C(S)-, or -Cy-; wherein the C1-6 aliphatic group is optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -N(R)₂, -NO₂, -N₃, =NR, =NOR, =O, =S, -OR, -SR, -SO₂R, -S(O)R, -R, -Cy-R, -C(O)R, -C(O)OR, - OC(O)R, -C(O)N(R)₂, -(R)NC(O)R, -OC(O)N(R)₂, -(R)NC(O)OR, -N(R)C(O)N(R)₂, - SO₂N(R)₂, -(R)NSO₂R, -C(S)R, or -C(S)OR; and each R is independently hydrogen, -CH₂- phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂F, -CHF2, - CF₃, -CH₂CHF₂, or -CH₂CF₃; or each R is independently hydrogen or methyl; or R is hydrogen. [00250] In some embodiments, R¹ is selected from hydrogen, halogen, C1-6 alkyl (optionally substituted with 1, 2, or 3 halogens), -CN, -N(R)₂, -OR, -SR, -S(O)R⁶, -SO₂R⁶, -SO₂NHR⁶, ,

each R is independently hydrogen, -CH₂-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂F, -CHF₂, -CF₃, -CH₂CHF₂, or -CH₂CF₃; or each R is independently hydrogen or methyl; or R is hydrogen. [00251] In some embodiments, R¹ is selected from hydrogen, halogen, C_1-6 alkyl, -CN, -

independently hydrogen, -CH₂-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂F, -CHF₂, -CF₃, -CH₂CHF₂, or -CH₂CF₃; or each R is independently hydrogen or methyl; or R is hydrogen. [00252] In some embodiments, R¹ is selected from those depicted in Table 1, below. [00253] As defined generally above, each L¹ and L² is independently a covalent bond or a C_1-8 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO₂-, - SO₂N(R)-, -(R)NSO₂-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-. [00254] In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is a C_1-8 bivalent straight or branched hydrocarbon chain. In some embodiments, L¹ is a C1-8 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO₂-, - SO₂N(R)-, -(R)NSO₂-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-. [00255] In some embodiments, L¹ is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, or -Cy-, and each R is independently hydrogen, -CH₂-phenyl, phenyl, C_1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂F, -CHF2, -CF3, -CH₂CHF2, or -CH₂CF3; or each R is independently hydrogen or methyl; or R is hydrogen. [00256] In some embodiments, L¹ is selected from those depicted in Table 1, below. [00257] In some embodiments, L² is a covalent bond. In some embodiments, L² is a C_1-8 bivalent straight or branched hydrocarbon chain. In some embodiments, L² is a C1-8 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-. [00258] In some embodiments, L² is a C_1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO₂-, -SO₂N(R)-, -(R)NSO₂-, -C(S)-, or -Cy-, and each R is independently hydrogen, -CH₂-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂F, -CHF₂, -CF₃, -CH₂CHF₂, or -CH₂CF₃; or each R is independently hydrogen or methyl; or R is hydrogen. [00259] In some embodiments, L² is selected from those depicted in Table 1, below. [00260] As defined generally above, each -Cy- is independently a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00261] In some embodiments, -Cy- is a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, -Cy- is an optionally substituted phenylene. In some embodiments, -Cy- is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [

[00263] In some embodiments, -Cy- is selected from those depicted in Table 1, below. [00264] As defined generally above, R² is hydrogen, halogen, -CN, -OR, -N(R)₂, -NO₂, -N₃, -SR, -L²-R⁶, or optionally substituted C1-8 aliphatic. [00265] In some embodiments, R² is hydrogen. In some embodiments, R² is halogen. In some embodiments, R² is -CN. In some embodiments, R² is -OR. In some embodiments, R² is -N(R)₂. In some embodiments, R² is -NO₂. In some embodiments, R² is -N3. In some embodiments, R² is -SR. In some embodiments, R² is -L²-R⁶. In some embodiments, R² is optionally substituted C1-8 aliphatic. [00266] In some embodiments, R² is hydrogen, halogen, -CN, -OR, -N(R)₂, -SR, optionally substituted C1-6 aliphatic, or -L²-R⁶, wherein L² is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -C(S)-, or -Cy-; wherein the C1- ₆ aliphatic group is optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -N(R)₂, -NO₂, -N3, =NR, =NOR, =O, =S, -OR, -SR, -SO2R, -S(O)R, -R, -Cy-R, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)₂, -(R)NC(O)R, -OC(O)N(R)₂, -(R)NC(O)OR, - N(R)C(O)N(R)₂, -SO2N(R)₂, -(R)NSO2R, -C(S)R, or -C(S)OR; wherein each R is independently hydrogen, -CH₂-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂F, -CHF2, -CF3, -CH₂CHF2, or -CH₂CF3; or each R is independently hydrogen or methyl; or R is hydrogen. [00267] In some embodiments, R² is selected from hydrogen, halogen, -CN, -OR, -N(R)₂, C1-6 alkyl (optionally substituted with 1, 2, or 3 deuterium or halogen atoms), C2-6 alkynyl, - S(O)R⁶, -SO₂R⁶, -SO₂NHR⁶, -(CH₂)_1-6-N(R)R⁶, -(CH₂)_1-6-OR⁶, or -(CH₂)_0-6-Cy-R⁶. In some embodiments, R² is selected from hydrogen, halogen, -OR, -N(R)₂, -S(O)R⁶, -SO2R⁶, - S

is independently hydrogen, -CH₂-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂F, -CHF₂, -CF₃, -CH₂CHF₂, or -CH₂CF₃; or each R is independently hydrogen or methyl; or R is hydrogen. [00268] In some embodiments, R² is C_2-4 alkynyl, -NH₂, F, Cl, Br, or I. In some embodiments, R² is hydrogen, Cl, -NH2, or ethynyl. In some embodiments, R² is Cl. [00269] In some embodiments, R² is selected from those depicted in Table 1, below. [00270] As defined generally above, R³ is hydrogen, optionally substituted C1-6 aliphatic, or -L³-R⁶. [00271] In some embodiments, R³ is hydrogen. In some embodiments, R³ is optionally substituted C1-6 aliphatic. In some embodiments, R³ is -L³-R⁶. [00272] In some embodiments, R³ is selected from hydrogen or C_1-6 alkyl optionally substituted with 1, 2, or 3 groups independently selected from deuterium, halogen, -CN, -N(R)₂, -NO₂, -N₃, =NR, =NOR, =O, =S, -OR, -SR, -SO₂R, -S(O)R, -R, -Cy-R, -C(O)R, -C(O)OR, - OC(O)R, -C(O)N(R)₂, -(R)NC(O)R, -OC(O)N(R)₂, -(R)NC(O)OR, -N(R)C(O)N(R)₂, - SO₂N(R)₂, -(R)NSO₂R, -C(S)R, or -C(S)OR. In some embodiments, R³ is selected from hydrogen or C1-6 alkyl (optionally substituted with 1, 2, or 3 deuterium or halogen atoms), - (CH₂)_1-6-CN, -(CH₂)_1-6-N(R)(R⁶), -(CH₂)_1-6-OR⁶, or -(CH₂)_0-6-Cy-R⁶. In some embodiments, R³ is selected from hydrogen, C1-6 alkyl (optionally substituted with 1, 2, or 3 deuterium or

-CH₂-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂F, - CHF₂, -CF₃, -CH₂CHF₂, or -CH₂CF₃; or each R is independently hydrogen or methyl; or R is hydrogen. [00273] In some embodiments, R³ is hydrogen or C_1-6 alkyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms, phenyl, pyridyl, -CN, -N(R)₂, or -OR, wherein each R is independently hydrogen, -CH₂-phenyl, phenyl, C_1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂F, -CHF2, -CF3, -CH₂CHF2, or -CH₂CF3; or each R is independently hydrogen or methyl; or R is hydrogen. In some embodiments, R³ is C_1-4 alkyl optionally substituted w

, pyridyl, -N(R)₂, -CN, or 1, 2, or 3 deuterium or halogen atoms, wherein R is hydrogen or C_1-3 alkyl. In some embodiments, R³ is methyl, ethyl, -CD₃, or -CH₂CF3. In some embodiments, R³ is methyl. [00274] In some embodiments, R³ is selected from those depicted in Table 1, below. [00275] As defined generally above, L³ is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, - C(S)-, or -Cy-. [00276] In some embodiments, L³ is a C1-6 bivalent straight or branched hydrocarbon chain. In some embodiments, L³ is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)- , -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO₂-, -C(S)-, or -Cy-. [00277] In some embodiments, L³ is selected from those depicted in Table 1, below. [00278] As defined generally above, each R⁴ is independently hydrogen, deuterium, halogen, -CN, -OR⁶, or C_1-4 alkyl, or two R⁴ groups on the same carbon are optionally taken together to form =NR⁶, =NOR⁶, =O, or =S. [00279] In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is deuterium. In some embodiments, R⁴ is halogen. In some embodiments, R⁴ is -CN. In some embodiments, R⁴ is -OR⁶. In some embodiments, R⁴ is C_1-4 alkyl. In some embodiments, two R⁴ groups on the same carbon are optionally taken together to form =NR⁶, =NOR⁶, =O, or =S. [00280] In some embodiments, R⁴ is hydrogen, deuterium, halogen, -CN, C_1-2 alkyl, or two R⁴ groups on the same carbon are taken together to form =O or =S. [00281] In some embodiments, R⁴ is selected from those depicted in Table 1, below. [00282] As defined generally above, each R⁵ is independently R, halogen, -CN, -OR, - N(R)₂, -NO₂, -N3, -SR, or -L¹-R⁶, or two R⁵ groups on the same saturated carbon atom are optionally taken together to form =NR, =NOR, =O, =S, or a spirocyclic 3-6 membered carbocyclic ring. [00283] In some embodiments, R⁵ is R. In some embodiments, R⁵ is halogen. In some embodiments, R⁵ is -CN. In some embodiments, R⁵ is -OR. In some embodiments, R⁵ is - N(R)₂. In some embodiments, R⁵ is -NO₂. In some embodiments, R⁵ is -N₃. In some embodiments, R⁵ is -SR. In some embodiments, R⁵ is -L¹-R⁶. In some embodiments, two R⁵ groups on the same saturated carbon atom are taken together to form =NR, =NOR, =O, =S, or a spirocyclic 3-6 membered carbocyclic ring. [00284] In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is an optionally substituted C1-6 aliphatic group. In some embodiments, R⁵ is a C1-6 alkyl group optionally substituted with 1, 2, 3, or 4 deuterium or halogen atoms. In some embodiments, R⁵ is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R⁵ is an optionally substituted phenyl. In some embodiments, R⁵ is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R⁵ is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R⁵ is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R⁵ is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00285] In some embodiments, R⁵ is hydrogen, C1-6 alkyl, halogen, -CN, -CF3, -CD3, cyclopropyl, ethynyl, -

In some embodiments, R⁵ is methyl. [00286] In some embodiments, R⁵ is selected from those depicted in Table 1, below. [00287] As defined generally above, each R⁶ is independently hydrogen or C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. [00288] In some embodiments, R⁶ is hydrogen. In some embodiments, R⁶ is C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. [00289] In some embodiments, R⁶ is C1-3 alkyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. [00290] In some embodiments, R⁶ is selected from those depicted in Table 1, below. [00291] As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3. [00292] As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3. [00293] As defined generally above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3. [00294] In some embodiments, the CXCR4 inhibitor is a compound of Formula II-a or II- b:

II-a II-b or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R, R¹, R², R³, R⁴, R⁵, R⁶, L¹, L², L³, -Cy-, m, n, and p is as defined above and described in embodiments herein, both singly and in combination. [00295] In some embodiments, the CXCR4 inhibitor is a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R, R¹, R², R³, R⁴, R⁵, R⁶, L¹, L², L³, -Cy-, n, and p is as defined above and described in embodiments herein, both singly and in combination. [00296] In some embodiments, the CXCR4 inhibitor is a compound of Formula IV:

IV or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R, R¹, R², R³, R⁴, R⁵, R⁶, L¹, L², L³, -Cy-, m, and p is as defined above and described in embodiments herein, both singly and in combination. [00297] In some embodiments, the CXCR4 inhibitor is a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R, R¹, R², R³, R⁴, R⁵, R⁶, L¹, L², L³, -Cy-, m, and p is as defined above and described in embodiments herein, both singly and in combination. [00298] In some embodiments, the CXCR4 inhibitor is a compound of Formula VI:

or a pharmaceutically acceptable salt thereof, wherein each of R, R¹, R², R³, R⁴, R⁵, R⁶, L¹, L², L³, -Cy-, m, n, and p is as defined above and described in embodiments herein, both singly and in combination. [00299] In some embodiments, the CXCR4 inhibitor is a compound of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein each of R, R¹, R², R³, R⁴, R⁵, R⁶, L¹, L², L³, -Cy-, m, n, and p is as defined above and described in embodiments herein, both singly and in combination. [00300] In some embodiments, the CXCR4 inhibitor is a compound of Formula VIII-a or VIII-b:

VIII-a VIII-b or a pharmaceutically acceptable salt thereof, wherein each of R, R¹, R², R³, R⁴, R⁵, R⁶, L¹, L², L³, -Cy-, m, n, and p is as defined above and described in embodiments herein, both singly and in combination. [00301] In some embodiments, the CXCR4 inhibitor is a compound of Formula IX:

or a pharmaceutically acceptable salt thereof, wherein each of R, R¹, R², R³, R⁴, R⁵, R⁶, L¹, L², L³, -Cy-, and n is as defined above and described in embodiments herein, both singly and in combination. [00302] In some embodiments, the CXCR4 inhibitor is a compound of Formula X-a, X-b, X-c, X-d, or X-e:

X-e or a pharmaceutically acceptable salt thereof, wherein each of R, R¹, R², R³, R⁴, R⁵, R⁶, L¹, L², L³, -Cy-, and n is as defined above and described in embodiments herein, both singly and in combination. [00303] In some embodiments, the CXCR4 inhibitor is a compound of Formula XI:

or a pharmaceutically acceptable salt thereof, wherein each of R, R¹, R², R³, R⁵, R⁶, L¹, L², L³, -Cy-, and p is as defined above and described in embodiments herein, both singly and in combination. [00304] In some embodiments, the CXCR4 inhibitor is a compound of Formula XII-a or XII-b:

XII-a XII-b or a pharmaceutically acceptable salt thereof, wherein each of R, R¹, R², R³, R⁵, R⁶, L¹, L², L³, -Cy-, and p is as defined above and described in embodiments herein, both singly and in combination. [00305] In some embodiments, the CXCR4 inhibitor is a compound of Formula XIII-a or XIII-b:

XIII-a XIII-b or a pharmaceutically acceptable salt thereof, wherein each of R, R², R³, R⁶, L², L³, and -Cy- is as defined above and described in embodiments herein, both singly and in combination. In some embodiments of Formulae XIII-a or XIII-b, -Cy- is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is a 5- or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 2 nitrogen atoms. [00306] In some embodiments, the CXCR4 inhibitor is a compound of Formula XIV-a,

XIV-c or a pharmaceutically acceptable salt thereof, wherein each of R, R², R³, R⁵, R⁶, L², L³, and - Cy- is as defined above and described in embodiments herein, both singly and in combination. In some embodiments of Formulae XIV-a, XIV-b, and XIV-c, R² is selected from hydrogen or halogen. In some embodiments, R² is halogen. In some embodiments, R² is Cl or Br. In some embodiments, R² is Cl. In some embodiments, R² is C_2-4 alkynyl, -NH₂, F, Cl, Br, or I. In some embodiments, R² is hydrogen, Cl, -NH2, or ethynyl. [00307] Exemplary compounds of the invention are set forth in Table 1, below. Table 1. Exemplary Compounds

I-1 I-2 I-3

I-13 I-14 I-15

I-49 I-50 I-51

I-85 I-86 I-87

I-97 I-98 I-99

I-121 I-122 I-123

I-160 I-161 I-162

I-175 I-176 I-177

I-187 I-188 I-189 Note: Stereochemistry arbitrarily assigned for I-188 and I-189; each compound was isolated in stereochemically enriched form; compound I-149 corresponds to their racemate.

[00308] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. 4. General Methods of Providing the Present Compounds: [00309] The compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein. [00310] In the Schemes below, where a particular protecting group (“PG”), leaving group (“LG”), or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5^th Edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2^nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, the entirety of each of which is hereby incorporated herein by reference. [00311] As used herein, the phrase “leaving group” (LG) includes, but is not limited to, halogens (e.g. fluoride, chloride, bromide, iodide), sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like. [00312] As used herein, the phrase “oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, and Philip Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which is incorporated herein by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy- 39425906USP2 (148744)

crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9- fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl. [00313] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, and Philip Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which is incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like. [00314] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See, for example, “March’s Advanced Organic Chemistry”, 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entirety of which is incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below. [00315] In one aspect, certain compounds of the present invention of Formula I, or subformulae thereof, are generally prepared according to Scheme 1 set forth below: 394259034USP1 (191386)

Scheme 1

[00316] In Scheme 1 above, PG is a nitrogen protecting group, and each of R¹, R², R³, R⁴, R⁵, Ring A, m, n, and p is as defined above and described in embodiments herein, both singly and in combination. [00317] As shown generally in Scheme 1, an aldehyde according to structure A may be condensed with a ketone such as acetone in the presence of a base to yield intermediate B, for example by following General Procedures E or F. The General Procedures are described in more detail in the Exemplification, below. Condensation with an amine such as NH2R³, e.g. methylamine, and an aldehyde of structure C, provides compounds of structure D. In some embodiments, such compounds are CXCR4 inhibitors according to the present invention. In other embodiments, compounds of structure D are reduced according to General Procedure A to provide compounds of structure E. In compounds of structure F where R² is an appropriate leaving group (LG), cross-coupling (such as Pd-catalyzed coupling) may be performed to provide compounds of structure G. If R² is hydrogen in structure F, halogenation or formation of a leaving group such as triflate precedes the coupling reaction. Alternatively, if R² is hydrogen in structure F, alkylation 394259034USP1 (191386)

such as a formylation with paraformaldehyde or DMF may be used to provide certain compounds of structure G. Scheme 2

[00318] Alternatively, as shown in Scheme 2, piperidone compounds of structure H may be reduced according to General Procedure A to afford compounds of structure I and subsequently reacted with an appropriate electrophile of formula LG-R³, wherein LG refers to an appropriate leaving group such as halide or mesylate, affording compounds of structure J. 5. Uses, Formulation and Administration, and Co-Administered Additional Therapeutic Agents Pharmaceutically acceptable compositions [00319] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit CXCR4, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit CXCR4, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. 394259034USP1 (191386)

[00320] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human. [00321] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. [00322] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [00323] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar 394259034USP1 (191386)

dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. [00324] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. [00325] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. [00326] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [00327] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. [00328] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream 394259034USP1 (191386)

containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [00329] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. [00330] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00331] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food. [00332] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. [00333] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition. 394259034USP1 (191386)

[00334] The activity of a compound utilized in this invention as an inhibitor of CXCR4, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of CXCR4, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to CXCR4. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of CXCR4, or a mutant thereof, are set forth in the Examples below. [00335] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease or disorder described herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or disorder, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human. [00336] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. 394259034USP1 (191386)

[00337] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00338] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00339] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00340] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular 394259034USP1 (191386)

polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [00341] Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [00342] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00343] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin 394259034USP1 (191386)

capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00344] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00345] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. [00346] According to one embodiment, the invention relates to a method of inhibiting CXCR4 activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. [00347] According to another embodiment, the invention relates to a method of inhibiting CXCR4, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. 394259034USP1 (191386)

In certain embodiments, the invention relates to a method of irreversibly inhibiting CXCR4, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. [00348] The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. [00349] Another embodiment of the present invention relates to a method of inhibiting CXCR4 in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. [00350] According to another embodiment, the invention relates to a method of inhibiting CXCR4, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. According to certain embodiments, the invention relates to a method of irreversibly inhibiting CXCR4, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by CXCR4, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein. Co-Administration of Additional Therapeutic Agents [00351] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, may also be present in the compositions of this invention or may be co-administered as a separate composition together with a CXCR4 of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” [00352] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one 394259034USP1 (191386)

additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically. [00353] In some embodiments, the present invention provides a method of treating a neurological or central nervous system (CNS) cancer, comprising administering to a subject in need thereof an effective amount of a disclosed CXCR4 inhibitor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BTK inhibitor, BCL-2 inhibitor, or BH3 mimetic. [00354] In some embodiments, the BTK inhibitor is selected from tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK-1026); or a pharmaceutically acceptable salt thereof. [00355] In some embodiments, the CXCR4 inhibitor is administered in combination with an effective amount of a BCL-2 inhibitor or BH3-mimetic; or a pharmaceutically acceptable salt thereof. [00356] The neurological or CNS cancer can be any disclosed herein, such as GBM or DLBCL. [00357] In some embodiments, the BCL-2 inhibitor or BH3 mimetic is selected from venetoclax, BGB-11417, LOXO-338, LP-108, S55746, APG-2575, APG-1252 (pelcitoclax), AT- 101, TQB3909, obatoclax, GDC-0199, ABT-737, and navitoclax (ABT-263); or a pharmaceutically acceptable salt thereof. [00358] In some embodiments, the CXCR4 inhibitor is co-administered with venetoclax or a pharmaceutically acceptable salt thereof. [00359] In some embodiments, the additional therapeutic agent is selected from chemotherapy (e.g., Vincristine, Etoposide, Temozolomide, Procarbazine, Cytarabine, Carmustine, Cyclophosphamide, cisplatin, Doxorubicin, Vinblastine, Bleomycin, Dacarbazine, Fludarabine, Bendamustine, and Prednisolone), Irradiation, Methotrexate, Dexamethasone, lenalidomide , rituximab, Bevacizumab, VEGFR tyrosine kinase inhibitors (TKI), including cediranib, nintedanib, sorafenib, pazopanib, sunitinib, and vandetanib, checkpoint-inhibitors such as nivolumab and pembrolizumab, and small molecule inhibitors (e.g., ibrutinib, acalabrutinib, copanlisib, duvelisib, and idelalisib). 394259034USP1 (191386)

[00360] In some embodiments, the additional therapeutic agent is selected from agents that can be used for lymphomas and other CNS cancers in general, including temozolomide, CLR 131, glucarpidase, VEGF inhibitors, and radiation therapy. [00361] In some embodiments, the co-administered therapeutic agent is one useful for treating a neurodegenerative disease, such as lecanemab for Alzheimer’s disease, aducanumab, donepezil, galantamine, rivastigmine, and memantine. [00362] In some embodiments, the co-administered therapeutic agent is for treating ALS, such as tofersen, riluzole, Tiglutik (thickened riluzole), Exservan™ (riluzole oral film), edaravone, and AMX0035 (Relyvrio^®). [00363] In some embodiments, the co-administered therapeutic agent is for treating Parkinson’s disease, e.g., electrostimulation, levodopa, carbidopa, droxidopa, ropinirole, pramipexole, rotigotine, rasagiline, selegiline, safinamide, rivastigmine, apomorphine, amantadine, istradefylline, trihexyphenidyl, benztropine, pimavanserin, tolcapone, opicapone and entacapone. [00364] In some embodiments, the co-administered therapeutic agent is for treating HIV or HAND, such as Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (PIs), Fusion Inhibitors, CCR5 antagonists, Integrase Strand Transfer Inhibitor (INSTIs), Attachment Inhibitors, Post-Attachment Inhibitors, Pharmacokinetic Enhancers, and combination HIV medications, e.g., abacavir with lamivudine or abacavir, lamivudine, and zidovudine. [00365] In some embodiments, the co-administered therapeutic agent is selected from AZT, abacavir, emtricitabine, dextromethorphan and quinidine sulfate, lamivudine, tenofovir disoproxil fumarate, doravirine, efavirenz, etravirine, nevirapine, rilpivirine, atazanavir, darunavir, fosamprenavir, ritonavir, enfuvirtide, maraviroc, cabotegravir, dolutegravir, raltegravir, fostemsavir, ibalizumab-uiyk, and cobicistat. [00366] In some embodiments, the present invention comprises administering to said patient a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with a T- cell engineered to express a chimeric antigen receptor, or CAR. The T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells. [00367] CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell 394259034USP1 (191386)

receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes. Upon antigen binding, such CARs link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex. [00368] For example, in some embodiments the CAR-T cell is one of those described in U.S. Patent 8,906,682 (hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in the T cell, the CAR is able to redirect antigen recognition based on the antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently in progress employing CAR-T in a wide range of indications. [clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1]. [00369] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. [00370] Those additional agents may be administered separately from an inventive compound- containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. 394259034USP1 (191386)

[00371] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. [00372] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered. [00373] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 ^g/kg body weight/day of the additional therapeutic agent can be administered. [00374] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. [00375] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. Implantable devices coated with a compound of this invention are another embodiment of the present invention. 394259034USP1 (191386)

EXEMPLIFICATION General Synthetic Methods [00376] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereafter should be considered to be disclosed. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. [00377] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed.1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. [00378] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. The synthesis of compounds such as I-1 and assay procedures are described in US 10,759,796, which is incorporated by reference in its entirety. Abbreviations equiv or eq: molar equivalents o/n: overnight rt: room temperature UV: ultra violet HPLC: high pressure liquid chromatography Rt: retention time 394259034USP1 (191386)

LCMS or LC-MS: liquid chromatography-mass spectrometry NMR: nuclear magnetic resonance CC: column chromatography TLC: thin layer chromatography sat: saturated aq: aqueous Ac: acetyl DCM: dichloromethane DCE: dichloroethane DEA: diethylamine DMF: dimethylformamide DMSO: dimethylsulfoxide ACN or MeCN: acetonitrile DIPEA: diisopropylethylamine EA or EtOAc: ethyl acetate BINAP: (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene TEA: triethylamine THF: tetrahydrofuran TBS: tert-butyldimethylsilyl KHMDS: potassium hexamethyl disilylazide Tf: trifluoromethanesulfonate Ms: methanesulfonyl NBS: N-bromosuccinimide PE: petroleum ether TFA: trifluoroacetic acid MMPP: magnesium monoperoxyphthalate HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid Hexafluorophosphate NCS: N-chlorosuccinimide Cy: cyclohexyl Tol: toluene 394259034USP1 (191386)

DMP: Dess-Martin periodinane IBX: 2-iodoxybenzoic acid PMB: p-methoxybenzyl SEM: [2-(Trimethylsilyl)ethoxy]methyl XPhos or X-Phos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [00379] General information: All evaporations were carried out in vacuo with a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC) was performed on silica gel plates, spots were visualized by UV light (214 and 254 nm). Purification by column and flash chromatography was carried out using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. All ¹H NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer.¹H chemical shifts are reported in δ values in parts per million (ppm) with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), integration (i.e. number of protons). LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization and except as otherwise indicated, the general LCMS conditions were as follows: Waters X Bridge C18 column (50 mm*4.6 mm*3.5 µm), Flow Rate: 2.0 mL/min, the column temperature: 40 °C. [00380] General procedure A (Wolff-Kishner Reduction): A mixture of 2,6-diaryl piperidin- 4-one (concentration 0.1-1 M), KOH (20 eq.) and N2H4•H2O (40 eq.) in diethylene glycol was stirred for about 2 hours at 80 ºC and then at approx.150-200 ºC until the reaction completed. After cooled down to room temperature, the reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography to give 2,6-diaryl piperidine. [00381] General procedure B (N-Alkylation of 2,6-diaryl piperidine): To a solution of 2,6- diaryl piperidine (concentration 0.1-1 M ) in DMF or ACN was added corresponding halide or mesylate (2 eq.) and K₂CO₃ (2 eq.) under Ar atmosphere. The mixture was stirred at 80 ºC overnight, then it was diluted with H2O and extracted with DCM. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give desired N- alkylated target. 394259034USP1 (191386)

[00382] General procedure C (Reaction of alcohols with methanesulfonyl chloride): To a solution of alcohol (concentration 0.1-1 M) and Et3N (approx.2.5 eq.) in DCM was added MsCl (1.2-1.4 eq.) drop wise at -70 ºC, and the reaction mixture was stirred at room temperature for 30 mins, then the resulting mixture was quenched with NaHCO₃ aq. and extracted with DCM. The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the corresponding mesylate. [00383] General procedure D (Reaction of mesylates or halides with 2,6-diaryl piperidine): A mixture of 2,6-diaryl piperidine (concentration 0.1-1 M), corresponding mesylate or halide (approx.2-3 eq.), KI (0.2-0.3 eq.), DIPEA (2-3 eq.) in DMF or ACN was stirred overnight at 60- 80 ºC and filtered. The filtrate was purified by prep-HPLC to get the alkylated 2,6-diaryl piperidine. [00384] General procedure E (Reaction of aryl aldehyde with acetone to give 4-(heteroaryl or aryl)but-3-en-2-one): A mixture of corresponding aryl aldehyde (concentration 0.1-1 M), acetone (20 eq.) and K₂CO₃ (1.5-2 eq.) in toluene/EtOH/H₂O (5:2:1) was stirred at 80 ºC for approx.13 hours and cooled down to room temperature. After diluted with EA, The reaction mixture was filtered through basic silica gel column and washed with DCM/MeOH (100/1). The filtrate was concentrated in vacuum to give 4-(heteroaryl or aryl)but-3-en-2-one which was used in the next step without further purification. [00385] General procedure F (Reaction of aryl aldehyde with acetone to give 4-(heteroaryl or aryl)but-3-en-2-one): To a mixture of aryl aldehyde (concentration 0.1-1 M) in acetone were added a solution of NaOH (approx.8 M, 1.5 eq.) in H₂O at 0 ºC. The mixture was stirred at 0 ºC for 1 hour. Then it was warmed to room temperature and stirred another 2 hours. The solution was adjusted pH to 8 with 35% HCl aq., dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 4-(heteroaryl or aryl)but-3- en-2-one. [00386] General procedure G (Buchwald coupling of aryl bromide with alkyl amine): A mixture of aryl bromide (concentration 0.1-1 M), alkyl amine (2 eq, 0.2-2 M), Pd(OAc)₂ (0.1-0.15 eq), BINAP (0.2-0.3 eq), and Cs2CO3 (2-4 eq) in toluene was stirred at 75-120 °C overnight. After completed, the reaction mixture was concentrated in vacuum and purified by column chromatography to afford the desired product. [00387] General procedure H (Suzuki coupling of aryl bromide with aryl boronic acid): aryl 394259034USP1 (191386)

bromide (concentration 0.1-1 M), aryl boronic acid (1.1-1.5 eq), PdCl₂(dppf) (0.05-0.08 eq), and Na2CO3 aq. (1 M, 2.5 eq) in 1,4-dioxane was stirred at 80-100 °C for 10 mins under microwave irradiation. After the reaction was completed, the mixture was diluted with water and the aqueous layer was extracted with DCM 3 times. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum and the residue was purified by silica gel column. [00388] General procedure I (reductive amination of secondary amine to tertiary amine): To a mixture of secondary amine (concentration 0.1-1 M), corresponding aldehyde or ketone (1-2 eq) and NaBH(OAc)3 (3-6 eq) in DCM was added several drops of acetic acid, and then the mixture was stirred at room temperature for 2-18 h. The mixture was neutralized with saturated NaHCO₃ aqueous solution to pH = 8-9 and extracted with DCM. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give the desired tertiary amine. [00389] General procedure J (Boc cleavage of N-Boc protected amines): To a solution of N- Boc protected amine (concentration 0.1-1 M) in DCM was added TFA (1/15 volume of DCM) at room temperature. The reaction mixture was stirred for 2 h, then concentrated and saturated NaHCO3 aqueous solution was added and the mixture was extracted with DCM. The organic extracts were dried over Na₂SO₄, filtered and concentrated to give the free amine as the desired product. [00390] General procedure K (halogenation of imidazo[1,2-a]pyridine to give 3-halogenated imidazo[1,2-a]pyridine): A mixture of imidazo[1,2-a]pyridine derivatives (concentration 0.1-1 M) and NBS or NCS (0.8-0.9 eq) in DCM (10 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the suspension was diluted with water and DCM, the separated organic layer was concentrated by vacuum and the residue was purified by prep-HPLC to give the desired product. 394259034USP1 (191386)

Example 1: Synthesis of I-1 Synthetic Scheme for I-1

[00391] Synthesis of 1.2: Following general procedure E, 1.2 (1.9 g, 41%) was obtained as yellow foam, which was used in the next step without further purification. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm*4.6 mm*3.5 μm); Column Temperature: 40 ºC; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH₃CN] to 0% [water + 10 mM NH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.); Purity: 69.13%; Rt = 1.38 min; MS Calcd.: 284.4; MS Found: 285.4[M+H]⁺. [00392] Synthesis of 1.3: To a solution of 1.2 (1.4 g, 4.9 mmol) in MeOH (20 mL) was added L-proline (227 mg, 1.97 mmol), 3-methylpicolinaldehyde (656 mg, 5.4 mmol) and aq. MeNH2 (1.5 g, 40% wt, 19.72 mmol) sequentially. The reaction mixture was stirred overnight at room temperature and concentrated in vacuum. The residue was purified by column chromatography to give cis/trans mixture of 1.3 (mg, 50%) as a yellow foam, which was used in the next step without further purification. Cis/trans mixture of 1.3 (270 mg, 0.65 mmol) was purified by prep-TLC to give 1.3 (30 mg, 11%) as a white solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X- 394259034USP1 (191386)

Bridge C18 (50mm*4.6 mm*3.5 μm); Column Temperature: 40 ºC; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1 min and under this condition for 0.7 min). 1.3: Purity: 92.86%. Rt = 1.49 min (trans), 1.52 min (cis); MS Calcd.: 418.3; MS Found: 419.4 [M + H]⁺. HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6 mm*3.5 μm); Column Temperature: 40 ºC; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1 min and under this condition for 5 min.); Purity: 97.88%. Rt = 4.90 min. ¹H NMR (400 MHz, CDCl₃) δ: 8.58-8.56 (m, 1H), 7.62 (s, 1H), 7.48 (dd, J = 1.2 Hz, J = 7.6 Hz, 1H), 7.36 (d, J = 8.8 Hz 1H), 7.19 (dd, J = 7.2 Hz, J = 8.8 Hz, 1H), 7.13 (dd, J = 4.8 Hz, J = 7.6 Hz, 1H), 6.34 (d, J = 6.4 Hz, 1H), 4.03 (dd, J = 3.2 Hz, J = 12.0 Hz, 1H ), 3.93 (dd, J = 7.2 Hz, J = 8.8 Hz, 1H), 3.49 (s, 1H), 3.33-3.18 (m, 6H), 2.78-2.68 (m, 5H), 2.50 (s, 3H), 2.42 (s, 3H), 1.94 (s, 3H). [00393] Synthesis of I-1: Following general procedure A, a mixture of cis/trans mixture of 1.3 (770 mg, 1.84 mmol), KOH (2.1 g, 36.8 mmol) and N₂H₄•H₂O (4.6 g, 80% wt, 73.6 mmol) in diethylene glycol was stirred for 2 hours at 80 ºC and then 5 hours at 150 ºC. After cooled down to room temperature, the reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography to give 276 mg of crude I-1, which was purified by prep-HPLC to give 80 mg of I-1 as a white solid. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm*4.6 mm*3.5 μm); Column Temperature: 40 ºC; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.); Purity: 96.44%. Rt = 1.66 min; MS Calcd.: 404.3; MS Found: 405.4 [M + H]⁺. HPLC (Agilent HPLC 1200; Column: L-column2 ODS (150mm*4.6 mm*5.0 μm); Column Temperature: 40 ºC; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 0.05% TFA] and 5% [CH₃CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH₃CN + 0.05% TFA] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 0.05% 394259034USP1 (191386)

TFA] and 5% [CH₃CN + 0.05% TFA] in 0.1 min and under this condition for 5 min.); Purity: 94.20%. Rt = 4.44 min. ¹H NMR (400 MHz, CD3OD) δ: 8.46 (s, 1H), 7.96 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.34-7.25 (m, 2H), 7.22-7.19 (m, 1H), 6.51 (d, J = 6.8 Hz, 1H), 3.65 (d, J = 10.0 Hz, 1H), 3.46 (d, J = 8.4 Hz, 1H), 3.17 (s, 4H), 2.81 (s, 4H), 2.51 (s, 3H), 2.47 (s, 3H), 2.05-1.94 (m, 4H), 1.89 (s, 3H), 1.79-1.68 (m, 2H). Example 2: Synthesis of I-4 Synthetic Scheme for I-4

[00394] Synthesis of 2.2: Following general procedure G, 2.2 (0.92 g, 24% yield) was obtained as a yellow solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm*4.6 mm*3.5 μm); Column Temperature: 40 ºC; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1 min and under this condition for 0.7 min.); Purity: 92.35%; Rt = 1.81 min; MS Calcd.: 504.7, MS Found: 505.7 [M+1] ⁺. [00395] Synthesis of 2.3: Following general procedure A, 2.3 (140 mg, 16% yield) was obtained as a light-yellow solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm*4.6 mm*3.5 μm); Column Temperature: 40 ºC; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% 394259034USP1 (191386)

[water + 10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1 min and under this condition for 0.7 min.); Purity: 93.71%; Rt = 1.99 min; MS Calcd.: 490.7, MS Found: 491.7 [M+1]⁺. [00396] Synthesis of I-4: Following general procedure J, I-4 (110 mg, 99% yield) was obtained as a light-yellow solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm*4.6 mm*3.5 μm); Column Temperature: 40 ºC; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 99.8%; Rt = 1.48 min; MS Calcd.: 390.7; MS Found: 391.7 [M+H]⁺. HPLC (Agilent HPLC 1200, Column: L-column2 ODS (150mm*4.6 mm*5.0 μm); Column Temperature: 40 ºC; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 0.05% TFA] and 5% [CH₃CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.1 min and under this condition for 5 min.); Purity: 98.8%; Rt = 4.362 min; MS Calcd.: 390.7; MS Found: 391.7 [M+H]⁺.¹H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 3.6 Hz, 1H), 7.63 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.12-7.16 (m, 1H), 7.04-7.07 (m, 1H), 6.27 (d, J = 7.2 Hz, 1H), 3.57 (dd, J = 11.2 Hz , J = 2.4 Hz, 1H), 3.47 (dd, J = 10.0 Hz, J = 3.6 Hz, 1H), 3.11- 3.15 (m, 8H), 2.47 (s, 3H), 2.22 (s, 3H), 1.97-2.06 (m, 4H), 1.61-1.75 (m, 2H). Example 3: Synthesis of I-11

[00397] Synthesis of I-11: A mixture of I-1 (120 mg, 0.3 mmol) and acetic acid (0.5 mL) in 37% formaldehyde aq. (10 mL) was stirred at 50 ºC for 24 hours, then 37% formaldehyde aq.(5 mL) was added, and the mixture was stirred at 50 ºC for another 48 hours. After the reaction was 394259034USP1 (191386)

completed, the suspension was adjust to pH 8 with sat. sodium carbonate aq. and extracted with DCM (20 mL). The organic layer was concentrated by vacuum and the residue was purified by prep-HPLC to give I-11 (90 mg, 70% yield) as white solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 ºC; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1 min and under this condition for 0.7 min.); Purity: 99.25%; Rt = 1.54 min; MS Calcd.: 434.3; MS Found: 435.3 [M+H]⁺. HPLC (Agilent HPLC 1200,Column: L-column2 ODS (150 mm*4.6 mm*5.0 μm); Column Temperature: 40 ºC; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 0.05% TFA] and 5% [CH₃CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH₃CN + 0.05% TFA] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.1 min and under this condition for 5 min.); Purity: 95.82%; Rt = 4.28 min. ¹H NMR (400 MHz, CD₃OD) 1.81-1.60 (m, 2H), 1.85 (s, 3H), 1.97-2.01 (m, 2H), 2.10-2.22 (m, 2H), 2.45 (s, 6H), 2.48-2.62 (m, 4H), 2.95-3.11 (m, 4H), 3.45-3.50 (m, 1H), 3.62- 3.70 (m, 2H), 5.32 (d, J = 13.6Hz, 1H), 5.71 (br, 1H), 6.70-6.72 (m, 1H), 7.19 (dd, J1 = 4.4Hz, J2 = 4.8Hz, 1H), 7.28-7.35 (m, 1H), 7.60 (d, J = 7.6Hz, 1H), 8.39-8.46 (m, 1H). 394259034USP1 (191386)

Example 4: Synthesis of I-187 Synthetic Scheme for I-187

[00398] Synthesis of X4-438-1. A mixture of 4.1 (2.5 g, 8.8 mmol), 3-methylpicolinaldehyde (1.1 g, 8.8 mmol), K2CO3 (1.8 g, 13.2 mmol) in toluene (100 ml)/EtOH (40 ml)/H2O (20 ml) was stirred at 80 °C overnight. After reaction completed, the mixture was cooled down to room temperature and concentrated in vacuum. The residue was purified by flash silica gel pad (3 cm), eluted with EtOAc:petroleum ether = 1:1 to DCM/MeOH = 100/1 to give 2.3 g of 4.2 as yellow foam (yield: 68%), which was used for the next step directly. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1 min and under this condition for 0.7 min). Purity: 77.36%; Rt = 1.59 min; MS Calcd.: 387.2; MS Found: 388.3 [M+H]⁺. [00399] Synthesis of I-204. To a solution of 4.2 (2.3 g, 5.9 mmol) in MeOH (120 ml) was added conc. NH₃ aq. (5 ml, 20%, 59 mmol) at room temperature and the mixture was stirred at room temperature overnight. After reaction completed, the mixture was concentrated in vacuum and the residue was purified by flash silica gel pad (3 cm), eluting with DCM/MeOH = 60/1 to 30/1 to give 1 g of I-204 as yellow foam (yield: 42%), which was used for the next step directly. 394259034USP1 (191386)

LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH₄HCO₃] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 78.15%; Rt = 1.41 min; MS Calcd.: 404.2; MS Found: 405.4 [M+H]⁺. [00400] Synthesis of I-187

[00401] A mixture of I-204 (1 g, 2.5 mmol), KOH (2.8 g, 50 mmol) and N₂H₄•H₂O (5 g, 100 mmol) in diethylene glycol (30 ml) was stirred at 80 °C for 2 h; then removed N2H4•H2O in vacuum when heating to 160 °C and stirred at 160 °C for 2 h. After the reaction was completed, the mixture was cooled down to room temperature and quenched with H₂O (90 ml)/DCM (120 ml). The aqueous layer was extracted with DCM (120 ml x 3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by CC (eluted with DCM/MeOH) to give 220 mg of (racemic) cis-I-187 (220 mg), 400 mg of (racemic) mix of cis/trans-I-187 (400 mg, trans:cis = 4:5) and 270 mg of (racemic) trans- I-187 (270 mg). Yield = 91%. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water + 10 mM NH₄HCO₃] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Cis: Purity: 71.18%; Rt = 1.51 min; Trans: Purity: 64.10%; Rt = 1.48 min; Mix: Purity: 84.07%; MS Calcd.: 390.3; MS Found: 391.4 [M+H]⁺. Example 5: Distribution of Compound I-1 in Brain, Plasma, and CSF of Cynomolgus Monkeys, Rats, and Beagles 394259034USP1 (191386)

[00402] Compound I-1 was administered daily to three male cynomolgus monkeys via oral gavage for eight days (vehicle 50mM citrate buffer, pH 4.0; formulation concentration 10 mg/mL; dose volume 1 mL/kg; dose level 10 mg/kg/day). Animals had free access to water, were fasted on the morning of dosing and food resumed 2 hr post sampling. [00403] Blood, CSF, and brain samples were obtained from individually terminated animals at 4, 24, and 72 hrs post last dose. Blood samples collected in pre-cooled EDTA-K2 tubes was processed into plasma by centrifugation for 10 minutes at 2000g and approximately 4 °C within 15 min. [00404] For plasma, an aliquot of 20 µL sample was mixed well with 40 µL formic acid solution (5% in water), followed by 200 µL Glipizide internal standard (50 ng/mL in CH₃CN). The mixture was vortexed for 10 min and centrifuged at 5800 rpm for 10 min. [00405] For CSF, an aliquot of 10 µL sample was diluted with 40 µL of blank plasma (dilution factor 5).20 µL sample was mixed well with 40 µL formic acid solution (5% in H2O), followed by 200 µL Glipizide internal standard (50 ng/mL in CH₃CN). The mixture was vortexed for 10 min and centrifuged at 5800 rpm for 10 min, and 70 µL of supernatant was mixed well with 40 µL H2O. [00406] For brain, a 1-5 mm cross section of brain tissue was homogenized with 3 volumes (v/w) of PBS (dilution factor 4).10 µL sample was mixed well with 30 µL NH₄OH solution (10% in H2O), followed by 200 µL Glipizide internal standard (50 ng/mL in CH₃CN). The mixture was vortexed for 10 min and centrifuged at 5800 rpm for 10 min, and 70 µL of supernatant was mixed well with 40 µL H₂O. [00407] Compound I-1 was quantified in the supernatant by LC-MS/MS (Triple Quad 6500+): Waters X-Bridge BEH C18 column (2.1×50 mm, 2.5 µm); flow rate 0.80 mL/min; column temperature 50 °C; injection volume 0.5 µL; MRM detection ESI+ Q1405.20 Da, Q3374.20 Da; Mobile Phase A 0.025% FA, 1 mM NH4OAc, in H2O; Mobile Phase B 5 mM NH4OAc in MeOH; elution with linear gradient 2-95% Mobile Phase B over 42 seconds, followed by 95% Mobile Phase B for 30 sec; retention time 1.11 min. [00408] Concentration of Compound I-1 in plasma, CSF, and brain was determined absolutely with reference to calibration curves (5% MeOH) of 1.00-3000 ng/mL Compound I-1 in cynomolgus monkey plasma, or 1.00-3000 ng/mL Compound I-1 in cynomolgus monkey CSF, or 3.00-3000 ng/g Compound I-1 in cynomolgus monkey brain homogenate, respectively. 394259034USP1 (191386)

[00409] FIG. 1 shows brain, plasma, and cerebrospinal fluid (CSF) exposure levels for compound I-1 in male cynomolgus monkeys after 8 days of administration at 10 mg/kg QD, administered orally (Measured @ 4, 24 & 72 hr post last dose; individually terminated animals; 50mM citrate buffer, pH 4.0). Brain histopathology of all monkeys was normal after 7-8 days after QD dosing at 10 mg/kg or 100 mg/kg (data not shown). No leukocyte infiltration or lesions in brain were seen even at high exposures.

[00410] Compound I-1 favorably partitions into cynomolgus monkey brains (brain:plasma ration 5:1 or greater). The significant brain exposures of ~400 ng/g are attained and persist with slow clearance at 72 h post-dose. No visible lesions were found upon histopathology analysis. The profile of this compound supports its use in diseases where durable brain exposure of the drug is required for efficacy. [00411] As shown below, Compound I-1 showed linear PK after multiple doses (7 days QD dosing). Fasted dosing; i.v.: 1 mpk; p.o.3, 10, 30 mpk; citrate buffer formulation; cynomolgus monkey males.

394259034USP1 (191386)

* PK Data excluding outlier monkey (#1602353) @ 3 mpk: Cmax = 66.1 ng/mL; Ctrough @ 24 hr = 16.4 ng/mL; AUClast = 530 hr*ng/mL; F = 19.2% + Only two time points available post T_max and hence T_1/2 was not calculated due to limited time points post Cmax [00412] As shown below and in FIG.9, we tested mean plasma concentration-time profiles of Compound I-1 after a single PO dose of Compound I-1 free base at 10 mg/kg, Compound I-1 HCl salt at 0.3, 1, 3, and 10 mg/kg, respectively, in male SD rats (N=3/timepoint). Fasted dosing; SD Rats; p.o.0.3, 1, 3, 10 mpk in HCl saline solution; or 10 mpk free base in saline w/ tween. The calculated t1/2 was 6 h. BLQ or BQL = Below Limit of Quantitation.

[00413] As shown below, Compound I-1 showed linear PK after a single oral dose in Cmax, Ctrough & AUC with a Tmax ~ 1.3 hr, T1/2 ~ 15 hr.

394259034USP1 (191386)

* PK Data excluding outlier monkey (#1602353) @ 3 mpk: Cmax = 44.2 ng/mL; Ctrough @ 24 hr = 8.9 ng/mL; AUClast = 371.5 hr*ng/mL; F = 18.6% [00414] We observed durable brain exposure in rats treated with a single oral dose of compound I-1. As shown in the tables below, the compound favorably partitions into brain (brain:plasma ratio of 12:1) with clearance rates dependent on exposure.

394259034USP1 (191386)

[00415] Histopathology of the rat brains did not show any visible lesions or abnormal findings. Exposure increased in the brain following multiple days of dosing. Dosing rats at 10 mpk PO every day for three days increased brain exposure from 66.2 ng/g to 136 ng/g. [00416] Beagle dogs were dosed with Compound I-1 every day for 14 days (PO). No visible lesions were found from histopathology examination of brains from all male and female dogs from 45 mpk group. Compound concentrations are shown in the table below.

^a “Brain concentration” of one female euthanized on Day 8 was 4130 ng/mL; the other female in this group was not evaluated. Example 6: Combination Effect of Compound I-1 With BTK and BCL-2 Inhibitors [00417] Apoptisis assay: OCI-LY19 cells were seeded in 96-well plates at density of 2 x10⁵ cells/ml in RPMI-1640 medium (Fisher Scientific, # 32404-014) containing 10% fetal bovine 394259034USP1 (191386)

serum (FBS) (Sigma-Aldrich, # F7524), supplemented with 100 U/mL of Penicillin-Streptomycin (Gibco™, Thermo Fisher Scientific, # 11548876). Cells were incubated with various concentration of compound I-1 alone or in combination with BTK inhibitors ibrutinib (MedChemExpress, # HY- 10997/CS), zanubrutinib (MedChemExpress, # HY-101474A), or B-cell lymphoma 2 (BCL2) inhibitor venetoclax (MedChemExpress, # HY-15531) for 72 hours at 37 °C and 5% CO2. After 72 hours, cells were washed with PBS, resuspended in Annexin V binding buffer (BioLegend, # 422201), and stained with Alexa Fluor^® 647 Annexin V (BioLegend, # 640943), propidium iodide (BD Pharmingen, # 51-66211E), and CD45 antibody (BioLegend, # 368502) for 15 minutes at room temperature and analyzed by flow cytometry. Annexin V positive cells were considered apoptotic. [00418] Cultures of OCI-LY19, a DLBCL cancer cell line, were exposed to varying concentrations of Compound I-1 and ibrutinib (BTK inhibitor), zanubrutinib (BTK inhibitor), or venetoclax (BCL-2 inhibitor). The results are shown in FIG. 2. Dose-dependent increases in percentage of apoptotic cells were observed. Compound I-1 at a concentration of 1 µM showed a strong and nearly-maximal effect in combination with ibrutinib. The combination showed a surprisingly large improvement vs. ibrutinib alone (bottom data series). Combinations of Compound I-1 with zanubrutinib or venetoclax showed increased cell death vs. zanubrutinib or venetoclax alone. Example 7: Effect of Compound I-1 on Migration of DLBCL Cells and Various Immune Cells [00419] Cell migration assay: OCI-LY19 cells migration toward CXCL12 was determined using the Transwell migration assay. OCILY19 cells were stained with 500^nM Calcein AM (Invitrogen, # C1430) and preincubated with compound I-1 for 15 minutes before transfer (5 × 10⁵ cells) to an upper well of a 5.0 µM pore size Transwell^® (Corning, # 3421). The lower chamber contained CXCL12 (30 nM) in medium supplemented with 1% FBS. After 4 hours of incubation, cells that migrated to the lower chambers were collected and resuspended in Dulbecco’s phosphate-buffered saline (DPBS) containing Precision Count Beads™ (BioLegend, # 424902). Migrated cells and counting beads were counted by flow cytometry. [00420] Peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) were isolated from heparin-treated blood samples using Ficoll-Paque Plus (Amersham, 394259034USP1 (191386)

Biosciences, Uppsala, Sweden) density gradient centrifugation according to manufacturer’s instructions. Freshly isolated PBMCs and PMNs were resuspended in chemotaxis buffer (RPMI 1640 media containing 20 mM HEPES, L-glutamine, and 0.5% BSA) at 2.0 x 10⁶ cells/mL. Cells were pretreated with the indicated concentrations of compound I-1 for 30 minutes at 37°C with 5% CO2. Chemotaxis was assayed immediately after treatment with drug by placing 1.0 x 10⁵ cells in 100 µL in the upper chamber of a Transwell 24-well plate separated by a 6.5 mm insert with 3 µm pores (Corning Life Sciences, Corning, NY, USA) from the lower chamber containing 600 µL of buffer with 10 nM of CXCL12. After incubation for 2.5 hours at 37°C in a 5% CO2 incubator, the cells that migrated into the lower chamber were collected by centrifugation and resuspended in the assay buffer. Cells were blocked using Human TruStain FcX (BioLegend, Inc) for 10 minutes at RT, and subsequently lymphocyte subtyping was performed. Lymphocyte subtyping was performed using fluorescent mAbs specific for T-cell antigens (CD3, CD8, and CD4), B-cell antigen (CD19) and natural killer (NK)-cell antigen (CD56). A fixed number of flow cytometry counting beads (Precision Count Beads; BioLegend) were added to each sample. Both migrated cells and counting beads were counted by flow cytometry (CytoFLEX). Data were analyzed using FCS Express software, and the total number of migrated cells was calculated, according to the counted and total number of beads present in the sample. [00421] OCI-LY19 cells express high levels of CXCR4 (data not shown). These cells are known to migrate towards CXCL12, the ligand of CXCR4. As shown in FIG.3, Compound I-1 effectively inhibited migration of OCI-LY19 cells. This suggests that Compound I-1 and similar compounds are effective in blocking migration of DLBCL cells to CXCL12-producing niches. [00422] FIG. 4 shows Compound I-1 inhibition of CXCL12-CXCR4 mediated migration of various types of immune cells. Immune cells were isolated from whole blood from healthy donors, N=3, CXCL1210 nM; time frame of assay = 3 hr. [00423] FIG. 5 shows Compound I-1 inhibition of CXCL12-CXCR4 mediated migration of various types of immune cells. Immune cells were isolated from whole blood from healthy donors, N=3, CXCL1210 nM; time frame of assay = 3 hr. Example 8: Food Effect of Compound I-1 in Beagles [00424] As shown in FIG. 10 and the table below, we investigated the plasma exposure and food effect of Compound I-1 in beagle dogs. As can be seen, under fasted conditions, the 394259034USP1 (191386)

compound showed 48% oral bioavailability, whereas under fed conditions, the compound showed 88% oral bioavailability. FED: Animals received food 1 hour before dosing, free access to water. FASTED: Animals did NOT receive food on the morning of dosing and food resumed post 4 hr sampling, free access to water.

Example 9: Compound I-1 Inhibits Glioblastoma Cell Proliferation In Vitro [00425] CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. Glioblastoma multiforme (GBM) is one of the most aggressive malignancies, accounting for 14.5% of all central nervous system tumors and 48.6% of malignant central nervous system tumors. The median overall survival (OS) of GBM patients is only 15 months. GBM include astrocytic tumors (astrocytoma, anaplastic astrocytoma and glioblastoma), oligodendrogliomas, ependymomas, and mixed gliomas. Incidence of GBM is 3.19 -4.17 cases per 100,000 person- years. Genetic and molecular pathogenesis includes ATRX (a-thalassemia/mental-retardation- syndrome-X-linked) mutation; TERT (Telomerase Reverse Transcriptase) promoter mutation; TP53 (Tumor protein P53) mutation; B-RAF V600E mutation; EGFR mutation and amplification; 394259034USP1 (191386)

and Overexpression of PDGFA/PDGFRa. The conventional therapies include surgery, radiotherapy, and chemotherapy (temozolomide). However, the single biggest challenge to developing effective new therapies is their inability to cross the blood-brain barrier. [00426] CXCR4 is overexpressed in both GBM and GSCs, influencing GBM malignancy, grade, and invasiveness and poor prognosis. GBM Patients with high CXCR4 expression have reduced survival probabilities. GSCs express both CXCL12 and CXCR4 which induces an autocrine loop, resulting in activation of the PI3K–MAPK–ERK1/2 signaling pathway for cell survival. CXCL12/CXCR4 signalling contributes to tumor resistance/invasiveness in GBM. There is some support for the general mechanism of action of CXCR4 antagonists for treating GBM. For example, the combination of AMD3100 and MDM2/4 inhibitor RS3594 further reduced GBM cell growth and invasiveness; see Daniele, S. et al. 2021; pubmed.ncbi.nlm.nih.gov/33581134/. See also Kioi M. et al. 2010; ncbi.nlm.nih.gov/pmc/articles/PMC2827954/; Gravina G. et al. 2017; pubmed.ncbi.nlm.nih.gov/28639900/. See also Hira, V. et al.; ncbi.nlm.nih.gov/pmc/articles/PMC7168055/ and Thomas, R. et al. 2019; pubmed.ncbi.nlm.nih.gov/31537527/. [00427] We determined the IC₅₀ for Compound I-1 for two glioblastoma cell lines that express CXCR4 and BTK. GBM cell lines U87, T-98 and U251 express both CXCR4 (jbc.org/article/S0021-9258(19)32918-7/fulltext) and BTK (ncbi.nlm.nih.gov/pmc/articles/PMC5613332/). Cell proliferation inhbition measured after 96h treatment by CellTiter Glo; ATP as a read out of cell viability (indicator of metabolically active cells). Staurosporine used as positive control: U87 (IC50 = 0.15 uM), T-98 (IC50 = 0.002 uM), U251 (IC50 = 0.003 uM). Compound I-1 inhibited U251 cells with an IC50 of 1.67 µM. Compound I-1 inhibited U87 cells with an IC₅₀ of 6.47 µM. Example 10: The Beneficial Role of CXCR7 Agonism on Astrocytes in Maintaining Healthy Neurons [00428] CXCR7 or atypical chemokine receptor 3 is a non-classical seven transmembrane- spanning receptor which is expressed in the haematopoetic system, heart, vascular endothelial cells, bone, kidney and brain. CXCR7 has a roughly 10 times higher binding affinity for CXCL- 12 as compared with CXCR4 and additionally binds interferon-inducible T-cell α chemoattractant 394259034USP1 (191386)

(I-TAC, CXCL11) as a second ligand (Balabanian, K., et al., “The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes.” J. Biol. Chem. 2005;280, 35760–35766). A number of studies indicate that CXCR7 does not trigger classical G- protein mediated signaling and the typical chemokine-induced Ca²⁺ release. It functions as a scavenger receptor for its cognate ligand and in that way can regulate the extracellular availability of CXCL-12 (Naumann, U., et al. “CXCR7 functions as a scavenger for CXCL12 and CXCL11.” PLoS ONE.2010; 5:e9175). However, other evidence suggests that CXCR7 physically associated with CXCR4, leading to a change of CXCR4 signaling and cellular functions (Levoye, A., et al., “CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling.” Blood. 2009; 113, 6085–6093). In addition, a few studies demonstrate that CXCR7 can independently induce cell signaling via β-arrestin in certain cell lines (Rajagopal, S., et al. Beta- arrestin- but not G protein-mediated signaling by the ‘decoy’ receptor CXCR7.” Proc. Natl. Acad. Sci. U.S.A. 2010; 107, 628–632; Chen, Q., et al. “CXCR7 mediates neural progenitor cells migration to CXCL12 independent of CXCR4.” Stem Cells.2015; 33, 2574–2585). These findings suggest that the biological function of CXCR7, its signal transduction, and further effects may depend on the cell types investigated. [00429] Astrocytes, a major type of glial cell, are involved in various homeostatic processes in the CNS. One of the most important astrocyte’s functions is to deliver energy to neurons by the astrocyte-neuron lactate shuttle. Astrocytes also modulate Ca²⁺ variations that influence neuronal activity releasing gliotransmitters. Moreover, astrocytes are also connected to blood vessels in the brain and transport nutrients to neurons and other cells (Bélanger, M., et al. “The role of astroglia in neuroprotection.” Dialogues Clin Neurosci. 2009;11(3):281-95; Chen, Y., et al. “The role of astrocytes in oxidative stress of central nervous system: A mixed blessing”. Cell Prolif. 2020 Mar;53(3):e12781) Interestingly, in astrocytes, it was shown that CXCR7 was able to couple with Gi/o proteins subsequent increased intracellular Ca²⁺ release and induced cell signaling (i.e. Erk and Akt signaling). Moreover, CXCR7-dependent Gi/o signaling was reported to regulate astrocytic proliferation and migration (Odemis, V., et al."CXCR7 is an active component of SDF- 1 signalling in astrocytes and Schwann cells". J Cell Sci. 2010 Apr 1;123(Pt 7):1081-8). In addition, A1 astrocytes was shown to contribute to the development of chronic post-surgical pain (CPSP), while A2 astrocytes are beneficial for relieving CPSP. Recently, it was demonstrated that microglia induced the transformation of astrocytes to the A1 phenotype in the spinal cord by 394259034USP1 (191386)

reducing the activation of the CXCR7/PI3K/Akt signaling pathway during CPSP. Therefore, reverting A1 reactive astrocytes to A2 astrocytes, for example by activation of CXCR7 receptor, may represent a new strategy for preventing CPSP (Li, T., et al. "Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post- surgical pain" J Neuroinflammation.2020 Jul 14;17(1):211.). These findings suggest that CXCR7 may play a crucial role in regulating astrocyte proliferation, migration, and activation which in turn contribute to the maintaining the health of the nervous system. Agonism of the CXCR7 receptor on astrocytes by compounds of this invention including Compound I-1 is expected to promote a neuroprotective phenotype of astrocytes thereby reducing or preventing neurodegenerative diseases such as but not limited to ALS. [00430] Assay procedure: [00431] GPCR Arrestin [00432] PathHunter cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing. For agonist and inverse agonist determination, 5 µL of intermediate dilution of sample stocks (5X) was added to cells and incubated at 37°C or room temperature for 90 to 180 minutes. For allosteric determination, 5 μL of intermediate dilution of sample stocks (5X) was added to cells and incubated at 37°C or room temperature for 30 minutes. After that, 5 μL of EC20 agonist in assay buffer was added to the cells and further incubated at 37°C or room temperature for another 90 or 180 minutes. For antagonist determination, cells were pre-incubated with antagonist for 30 min followed by agonist challenge at the EC80 concentration at 37°C or room temperature for another 90 or 180 minutes. Vehicle concentration was 1%. At the end of incubation, 12.5 or 15 μL (50% v/v) of PathHunter detection reagent cocktail was added to cells and further incubated for one hour at room temperature. The Chemiluminescent signal were measure using a PerkinElmer Envision TM instrument. Compound activity was analyzed using CBIS data analysis suite (ChemInnovation, CA). [00433] For agonist mode assays, percentage activity was calculated using the following formula: % Activity =100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean MAX control ligand - mean RLU of vehicle control). [00434] For inverse agonist mode assays, percentage activity was calculated using the following formula: 394259034USP1 (191386)

% Inverse Agonist Activity =100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of vehicle control)). [00435] For positive allosteric mode assays, percentage modulation was calculated using the following formula: % Modulation =100% x ((mean RLU of test sample - mean RLU of EC20 control) / (mean RLU of MAX control ligand - mean RLU of EC20 control)). [00436] For antagonist and negative allosteric mode assays, percentage inhibition was calculated using the following formula: % Inhibition =100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of EC80 control - mean RLU of vehicle control)). [00437] The table below shows the potency of ß-arrestin recruitment to CXCR7 by compound I-1 (EC50 0.032 nM for Compound I-1 and EC50 0.012 nM for CXCL12) suggesting that compound I-1 may has agonism effect on CXCR7 receptor.

[00438] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. The full disclosures of all patent, scientific and other references cited in this specification are herein incorporated by reference for the teachings and disclosures for which they are cited. 394259034USP1 (191386)

Claims

CLAIMS We claim: 1. A method of treating a neurological disorder or disease of the central nervous system (CNS), or a method of alleviating the severity and symptoms thereof, comprising administering to a subject in need thereof an effective amount of Compound I-1:

or a pharmaceutically acceptable salt thereof; wherein the neurological disorder or disease of the CNS is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular dystrophy, Wilson’s disease, Lewy body dementia, Frontotemporal Dementia (FTD), cerebral palsy, Bell’s palsy, progressive supranuclear palsy, HIV-associated dementia (HAND), epilepsy, tremors and seizure disorders, catalepsy, immobilization disorders, paralysis and muscle rigidity, spina bifida, encephaly, encephalocele, encephalitis, myelopathy, migraines, cerebral ischemia, ischemia, stroke, cerebellar ataxia, Friedrich’s ataxia, Creutzfelt-Jakob disease, atherosclerosis, motor neurone disease (MND), Locked In Syndrome, Restless Leg Syndrome, arachnoid cysts, sciatica, thalassemia, cerebral hemorrhage, subarachnoid hemorrhage, muscular sclerosis, tardive dyskinesia, Charcot-Marie- Tooth Disease (CMT), thrombus formation, microembolus formation, Sickle cell disease, and Vaso Occlusive Crises (VOCs).

2. The method of claim 1, wherein the neurological disorder or disease of the CNS is a neurodegenerative disease.

3. The method of claim 2, wherein the neurodegenerative disease is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular dystrophy, Wilson’s disease, Lewy body dementia, Frontotemporal Dementia 394259034USP1 (191386)

(FTD), HIV-associated dementia (HAND), progressive supranuclear palsy, Friedrich’s ataxia, Creutzfelt-Jakob disease, motor neurone disease (MND), and Charcot-Marie-Tooth Disease (CMT).

4. The method of claim 2, wherein the neurodegenerative disease is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

5. The method of claim 2, wherein the neurodegenerative disease is ALS.

6. The method of claim 2, wherein the neurodegenerative disease is Alzheimer’s disease.

7. The method of claim 2, wherein the neurodegenerative disease is Parkinson’s disease.

8. The method of claim 1, wherein the neurological disorder or disease of the CNS is a CNS infection.

9. The method of claim 8, wherein the CNS infection is meningitis, shingles, or HIV.

10. The method of claim 8, wherein the CNS infection is selected from an enterovirus, arbovirus, and herpes virus infection.

11. The method of claim 8, wherein the CNS infection is selected from a herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), Japanese encephalitis virus, Zika virus, tick-borne encephalitis virus (TBEV), Murray Valley encephalitis virus, St. Louis encephalitis virus, La Crosse encephalitis virus (LCEV), John Cunningham virus (PML), HHV-6, an influenza virus, rabies, mumps, measles, and West Nile virus infection.

12. The method of claim 8, wherein the CNS infection is a bacterial infection. 394259034USP1 (191386)

13. The method of claim 12, wherein the CNS infection is selected from a Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae infection.

14. The method of claim 1, wherein the neurological disorder or disease of the CNS is selected from neurological damage caused by addiction, alcoholism or alcohol abuse, autism, anxiety, depression, satiety disorders (including obesity, anorexia, and bulimia), affective disorders, Tourette’s syndrome, schizophrenia, obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder, post-traumatic stress disorder (PTSD), gastroesophageal reflux disease (GERD), memory loss, dementia, sleep apnea, narcolepsy, urinary incontinence, and metabolic disorders that affect the CNS.

15. The method of claim 1, wherein the neurological disorder or disease of the CNS is selected from neurodegeneration, a neuromuscular disorder, ischemia, neuroinflammation, an autoimmune disorder, an anxiety disorder, and pain, wherein the neurological disorder or disease of the CNS arises from a traumatic head or brain injury, spinal cord injury, or another medical condition with neurological cell loss, damage and/or degeneration.

16. The method of claim 1, wherein the neurological disorder or disease of the CNS is selected from stroke, thrombus formation, and microembolus formation.

17. The method of claim 1, wherein the microemboli formation is microemboli in a COVID patient.

18. A method of treating or alleviating pain, comprising administering to a subject in need thereof an effective amount of Compound I-1: 394259034USP1 (191386)

I-1 or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the pain is acute pain, chronic pain, neuropathic pain, nociceptive pain, allodynia, inflammatory pain, or inflammatory hyperalgesia.

20. The method of claim 19, wherein the pain is neuropathic pain.

21. The method of claim 18, wherein the pain is selected from neuralgia, diabetic neuropathy, human immunodeficiency virus-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, a burn, back pain, eye pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post herpetic neuralgia, post-operative pain, post stroke pain, and menstrual pain.

22. The method of claim 18, wherein the pain is nociceptive pain and is selected from the group consisting of central nervous system trauma, strains/sprains, burns, myocardial infarction, acute pancreatitis, post-operative pain, posttraumatic pain, renal colic, pain associated with Vaso Occlusive Crises (VOCs), cancer pain, and back pain.

23. The method of claim 20, wherein the neuropathic pain is selected from the group consisting of peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson’s disease, epilepsy, and vitamin deficiency. 394259034USP1 (191386)

24. The method of claim 20, wherein the neuropathic pain is related to a pain disorder selected from the group consisting of arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorder, hypoesthesis, hypealgesia, neuralgia, neuritis, neurogenic pain, analgesia, anesthesia dolorosa, causlagia, sciatic nerve pain disorder, degenerative joint disorder, fibromyalgia, visceral disease, chronic pain disorders, migraine/headache pain, chronic fatigue syndrome, complex regional pain syndrome, neurodystrophy, plantar fasciitis, and pain associated with cancer.

25. The method of claim 18, wherein the pain is inflammatory pain.

26. The method of claim 25, wherein the inflammatory pain is associated with a musculoskeletal disorder, myalgia, fibromyalgia, spondylitis, a sero-negative (non-rheumatoid) arthropathy, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, or pyomyositis.

27. The method of claim 18, wherein the pain is selected from heart and vascular pain, pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud’s phenomenon, scleroderma, skeletal muscle ischemia, head pain, migraine, cluster headache, tension-type headache, mixed headache, headache associated with vascular disorders, orofacial pain, dental pain, otic pain, burning mouth syndrome, and temporomandibular myofascial pain.

28. A method of treating or ameliorating neuroinflammation, comprising administering to a subject in need thereof an effective amount of Compound I-1:

or a pharmaceutically acceptable salt thereof. 394259034USP1 (191386)

29. The method of claim 28, wherein the neuroinflammation is associated with CXCL12 upregulation.

30. The method of claim 28, wherein the neuroinflammation is associated with penetration of leukocytes into the brain of the subject.

31. The method of claim 30, wherein the leukocytes are selected from monocytes, macrophages, neutrophils, and lymphocytes.

32. The method of claim 28, wherein the neuroinflammation is associated with a viral or bacterial infection.

33. The method of claim 28, wherein the neuroinflammation is associated with a malaria infection.

34. The method of claim 28, wherein the neuroinflammation is associated with meningitis, shingles, or HIV infection.

35. The method of claim 32, wherein the neuroinflammation is associated with an enterovirus, arbovirus, or herpes virus infection.

36. The method of claim 32, wherein the neuroinflammation is associated with a herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), Japanese encephalitis virus, Zika virus, tick-borne encephalitis virus (TBEV), Murray Valley encephalitis virus, St. Louis encephalitis virus, La Crosse encephalitis virus (LCEV), John Cunningham virus (PML), HHV-6, an influenza virus, rabies, mumps, measles, or West Nile virus infection.

37. The method of claim 32, wherein the neuroinflammation is associated with a bacterial infection. 394259034USP1 (191386)

38. The method of claim 32, wherein the neuroinflammation is associated with a Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, or Haemophilus influenzae infection.

39. A method of treating a neurological or central nervous system (CNS) cancer, comprising administering to a subject in need thereof an effective amount of Compound I-1:

I-1 or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein the neurological or CNS cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), ganglioma, ganglioneuroma, ganglioneuroblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

41. The method of claim 39, wherein the neurological or CNS cancer is acoustic neuroma, astrocytoma (selected from Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, and Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, optic pathway glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.

42. The method of claim 39, wherein the neurological or CNS cancer is GBM. 394259034USP1 (191386)

43. The method of claim 39, wherein the neurological or CNS cancer is CNS lymphoma.

44. The method of claim 43, wherein the CNS lymphoma is Primary CNS Lymphoma.

45. The method of claim 44, wherein the Primary CNS Lymphoma is diffuse large B-cell lymphoma (DLBCL).

46. The method of claim 44, wherein the Primary CNS Lymphoma is a Burkitt or T-cell lymphoma.

47. The method of claim 43, wherein the CNS lymphoma is Secondary CNS Lymphoma.

48. The method of claim 47, wherein the Secondary CNS Lymphoma is DLBCL.

49. The method of claim 47, wherein the Secondary CNS Lymphoma is a Burkitt or T-cell lymphoma.

50. The method of claim 1, wherein the neurological disorder or disease of the CNS is pseudobulbar affect (PBA).

51. The method of any one of claims 1-50, wherein the subject is a human and Compound I-1 is administered orally.

52. The method of claim 51, wherein Compound I-1 is administered to the subject in a fed state. 394259034USP1 (191386)