CXCR4 inhibitors for the treatment of neurological disorders

Abstract

The present invention provides CXCR4 inhibitors of formula (I) and pharmaceutically acceptable salts thereof, as well as methods of using them in the treatment of neurological and CNS diseases, disorders, and conditions. The provided compounds are inhibitors of CXCR4 and are therefore useful for treating one or more disorders associated with CXCR4 activity. Thus, in certain embodiments, the present invention provides a method for treating a CXCR4-mediated disorder, comprising 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. Certain embodiments of the present invention are directed to the use of CXCR4 inhibitors that, when administered to a subject, cross the blood-brain barrier (BBB) ​​and enter the brain and central nervous system (CNS). JPEG2026502774000083.jpg3135

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS The present invention claims the benefit of U.S. Provisional Application No. 63 / 419,598, filed October 26, 2022, which is incorporated herein by reference in its entirety.

[0002] Technical field of the invention The present invention relates to compounds and methods useful for inhibiting CXC receptor type 4 (CXCR4). The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention, and methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] Background of the Invention CXC 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 the class I GPCR or rhodopsin-like GPCR family. CXCR4 is expressed in many tissues, including the brain, thymus, lymphoid tissue, spleen, stomach, and small intestine, as well as in certain cell types, such as hematopoietic stem cells (HSCs), mature lymphocytes, and fibroblasts. CXCL12 is the only known ligand for CXCR4. CXCR4 is known to be associated with various neurodegenerative diseases, including, but not limited to, ALS, Alzheimer's disease, and Parkinson's disease. For example, 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 G93AMice 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 of 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 the degeneration of both upper and lower motor neurons. Symptoms include muscle weakness, muscle atrophy, behavioral disturbances, dysphagia, and dysarthria. The prevalence of ALS in the United States is 5 per 100,000 people. Globally, ALS cases are estimated to increase from 222,801 in 2015 to 376,674 by 2040. Causes of ALS include sporadic ALS (90–95%). Familial ALS (5–10%) also exists, caused by one of the following mutations: C9orf72 (40%), SOD1 (20%), FUS (1–5%), and TARBDP (TBP-43) (1–5%). The pathogenic mechanisms of ALS remain incompletely understood. Mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress, and neuroinflammation have been shown to contribute to the pathogenesis of ALS. There is no effective treatment available. Parkinson's disease affects 1-2 people per 1,000. There is no cure, and the only available medications are symptomatic. Misfolded alpha-synuclein protein forms toxic clumps (Lewy bodies) in neurons in the midbrain, causing neuronal and astrocyte death.

[0005] These data highlight an important unmet need for CXCR4 inhibitors to treat the numerous diseases and conditions mediated by aberrant or unwanted expression of the receptor. The present invention fulfills this need and realizes other related advantages. Summary of the Invention [Means for solving the problem]

[0006] Summary of the Invention It has now been found that the 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 comprise a compound of Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0007] In some embodiments, the CXCR4 inhibitor is: [ka] 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 disclosure provides a method of treating or reducing the severity and symptoms of a neurological disorder or disease of the central nervous system (CNS), 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 amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, Wilson's disease, dementia with Lewy bodies, frontotemporal dementia (FTD), cerebral palsy, Bell's palsy, progressive supranuclear palsy, HIV-associated dementia (HAND), epilepsy, tremor and seizure disorders, catalepsy, motor inhibition disorders, paralysis and muscle rigidity, spina bifida, anencephaly, encephalocele, encephalitis, myelopathy, migraine, cerebral ischemia. In some embodiments, the neurological disorder or disease of the CNS is selected from: ischemia, stroke, cerebellar ataxia, Friedreich's ataxia, prion diseases such as mad cow disease and Creutzfeldt-Jakob disease, atherosclerosis, motor neuron disease (MND), locked-in syndrome, restless legs syndrome, arachnoid cyst, sciatica, thalassemia, intracerebral hemorrhage, subarachnoid hemorrhage, muscular sclerosis, tardive dyskinesia, Charcot-Marie-Tooth disease (CMT), thrombosis, microembolization, sickle cell disease, and vaso-occlusive stroke (VOC). In some embodiments, the neurological disorder or disease of the CNS is dysregulation of 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, dementia with Lewy bodies, frontotemporal dementia (FTD), HIV-associated dementia (HAND), progressive supranuclear palsy, Friedreich's ataxia, prion diseases such as Creutzfeldt-Jakob disease, motor neuron 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 CNS neurological disorder or disease is a CNS infection, hi some embodiments, the CNS infection is selected from meningitis, shingles, or a viral infection such as HIV.

[0016] In some embodiments, the CNS infection is selected from an enterovirus, an arbovirus, and a herpesvirus 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, 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 addiction, neuronal damage caused by 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 affecting the CNS.

[0019] In some embodiments, the neurological disorder or disease of the CNS is selected from neurodegeneration, neuromuscular disorders, ischemia, neuroinflammatory diseases (also known as neuroinflammation), autoimmune disorders, anxiety disorders, and pain, and the neurological disorder or disease of the CNS results from a traumatic head or brain injury, spinal cord injury, or other medical condition involving loss, damage, and / or degeneration of nerve cells.

[0020] In some embodiments, neuroinflammation is caused by the infiltration of leukocytes and / or immune cells into the brain.In another embodiment, the infiltration of leukocytes and / or immune cells into the brain is caused by the increased level of CXCR4 in the brain.In some embodiments, the CNS neurological disorder or disease is selected from stroke, thrombosis and microembolism.

[0021] In some embodiments, the microembolization is microembolization in a COVID (e.g., COVID-19 or another strain of COVID) patient.

[0022] In some embodiments, the present invention provides methods 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 producing analgesia in a subject suffering from pain.

[0023] In certain 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-associated neuropathy, nerve injury, rheumatoid arthritis pain, osteoarthritis pain, burns, lower back pain, eye pain, visceral pain, cancer pain (e.g., bone cancer pain), toothache, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post-herpetic neuralgia, post-surgical 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, strain / sprain, burns, myocardial infarction, acute pancreatitis, post-operative pain (pain after any type of surgical procedure), post-traumatic pain, renal colic, pain associated with vaso-occlusive crisis (VOC), cancer pain, and lower back pain.

[0027] In some embodiments, the pain is neuropathic pain and is selected from the group consisting of peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, low 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 certain embodiments, the neuropathic pain is associated with a pain disorder selected from the group consisting of arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorders, hypoesthesia, hyperalgesia, neuralgia, neuritis, neuropathic pain, analgesia, anesthesia dolorosa, causalgia, sciatica disorders, degenerative joint disorders, fibromyalgia, visceral diseases, chronic pain disorders, migraine / headache pain, chronic fatigue syndrome, complex regional pain syndrome, neurological dystrophy, plantar fasciitis, and pain associated with cancer.

[0029] In some embodiments, the pain is inflammatory pain.

[0030] In certain embodiments, the inflammatory pain is associated with musculoskeletal disorders, muscle pain, fibromyalgia, spondylitis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, or pyomyositis.

[0031] In some embodiments, the pain is selected from cardiovascular pain, pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma, musculoskeletal ischemia, head pain, migraine, cluster headache, tension headache, mixed headache, headache associated with vascular disorders, orofacial pain, toothache, earache, burning mouth syndrome, and temporomandibular joint myofascial pain.

[0032] In one aspect, the present disclosure provides a method of treating or reducing 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 the infiltration of leukocytes into the subject's brain. 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, hi some embodiments, the neuroinflammation is associated with a malarial 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 herpesvirus infection.

[0037] In some embodiments, the neuroinflammation is associated with 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, 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 Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, or Haemophilus influenzae infection.

[0040] In one aspect, the present disclosure provides a method of treating a nervous 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 neural or CNS cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), ganglioneuroma, ganglioneuroma, ganglioneuroblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0042] In some embodiments, the neural 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 tumor, primitive neuroectodermal (PNET) tumor, or schwannoma.

[0043] In some embodiments, the neural or CNS cancer is a CNS lymphoma.

[0044] In some embodiments, the CNS lymphoma is a 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 Burkitt's or T-cell lymphoma.

[0046] In some embodiments, the CNS lymphoma is a secondary CNS lymphoma.

[0047] In some embodiments, the secondary CNS lymphoma is DLBCL. In some embodiments, the secondary CNS lymphoma is Burkitt's or T-cell lymphoma.

[0048] In another aspect, the present invention provides a method of treating Waldenstrom'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, a CXCR4 inhibitor, such as compound I-1 or a pharmaceutically acceptable salt thereof, is administered to a subject in a fed state. [Brief explanation of the drawings]

[0051] [Figure 1] Figure 1 shows brain, plasma, and cerebrospinal fluid (CSF) exposure levels of compound I-1 in male cynomolgus monkeys after 8 days of dosing at 10 mg / kg QD (daily) administered PO (oral, measured 4, 24, and 72 hours after the last dose; individually terminated animals; 50 mM citrate buffer, pH 4.0). Brain histopathology in all monkeys was normal 7-8 days after QD dosing at 10 mg / kg or 100 mg / kg (data not shown).

[0052] [Figure 2-1]Figure 2 shows the % apoptotic cells in cultures of OCI-LY19, a diffuse large B-cell lymphoma (DLBCL) cancer cell line, after exposure to various concentrations of compound I-1 and ibrutinib (BTK inhibitor), zanubrutinib (BTK inhibitor), or venetoclax (BCL-2 inhibitor). Of note, DLBCL accounts for approximately 90% of all CNS lymphomas. Assay time frame = 72 hours; ibrutinib (8 μM) + compound I-1 (2–5 μM) induces 60% apoptosis of DLBCL cells. [Figure 2-2] Same as above.

[0053] [Figure 3] Figure 3 shows the effect of compound I-1 on DLBCL cell migration. OCI-LY19 cells express high levels of CXCR4 and are known to migrate toward CXCL12, a CXCR4 ligand (data not shown). Compound I-1 effectively inhibited OCI-LY19 cell migration toward CXCL12. These data support its efficacy in central nervous system diffuse large B-cell lymphoma (CNS-DLBCL).

[0054] [Figure 4] Figure 4 shows the inhibition of CXCL12-CXCR4-mediated migration of various types of immune cells by compound I-1. Immune cells were isolated from whole blood from healthy donors (N=3, CXCL12 10 nM; assay time frame=3 hours).

[0055] [Figure 5] Figure 5 shows the inhibition of CXCL12-CXCR4-mediated migration of various types of immune cells by compound I-1. Immune cells were isolated from whole blood from healthy donors (N = 3, CXCL12 10 nM; assay time frame = 3 hours).

[0056] [Figure 6] FIG. 6 shows compound I-1-mediated inhibition of CXCL12 binding to various species of CXCR4 expressed in K562 cells.

[0057] [Figure 7] Figure 7 shows the inhibition of CXCL12-mediated ERK signaling in CXCR4-expressing K562 cells + / - compound I-1. K562 cells were transfected with WT CXCR4; Phosphoflow pERK (K562 stable clone).

[0058] [Figure 8] FIG. 8 shows the plasma exposure of compound I-1 after a single oral dose of 5 mpk (mg / kg) in female CB17-SCID mice.

[0059] [Figure 9] 9 shows the mean plasma concentration-time profiles of compound I-1 in male SD rats (N=3 / time point) after a single PO dose of 10 mg / kg of the free base of compound I-1, and 0.3, 1, 3, and 10 mg / kg of the HCl salt of compound I-1, respectively. Administration was under fasting conditions; SD rats; 0.3, 1, 3, 10 mpk po in HCl saline solution; or 10 mpk free base in saline w / Tween®. The calculated t was 6 hours.

[0060] [Figure 10] Figure 10 shows plasma exposure in fed or fasted beagle dogs after oral administration of compound I-1. Conditions: 1 mpk iv; 15 mpk po; free base; citrate buffer formulation. Fed: Animals were given food 1 hour prior to dosing and had free access to water. Fasted: Animals were deprived of food the morning of dosing; food was sampled and resumed 4 hours later; water was available ad libitum.

[0061] [Figure 11] Figures 11 and 12 show plasma exposure in cynomolgus monkeys after administration of compound I-1. D1 = Day 1 of administration. D7 = Day 7 of administration. The compound showed a dose-dependent increase in exposure and a relatively slow clearance. [Figure 12] Figures 11 and 12 show plasma exposure in cynomolgus monkeys after administration of compound I-1. D1 = Day 1 of administration. D7 = Day 7 of administration. The compound showed a dose-dependent increase in exposure and a relatively slow clearance.

[0062] [Figure 13] Figure 13 (top) shows the CXCR4-dependent release of monocytes sequestered by orally administered compound I-1 into the blood in cynomolgus monkeys. Monocytes were released into the blood (AMC) after oral administration of 3, 10, and 30 mpk of compound I-1 in citrate buffer (3 animals per dose group). Six days of QD administration showed a sustained and prolonged response (data not shown). The lower panel shows the CXCR4-dependent release of monocytes sequestered by orally administered compound I-1 into the blood in rats.

[0063] [Figure 14] Figure 14 (top) shows the CXCR4-dependent release of sequestered neutrophils into the blood by orally administered compound I-1 in cynomolgus monkeys. In male cynomolgus monkeys, compound I-1 is administered at doses of 3, 10 and 30 mpk po (N=3 for each dose). The bottom panel shows the CXCR4-dependent release of sequestered neutrophils into the blood after oral administration of compound I-1 in rats.

[0064] [Figure 15] Figure 15 (top) shows the CXCR4-dependent release of sequestered lymphocytes into blood after oral administration of compound I-1 in cynomolgus monkeys. Compound I-1 is administered at doses of 3, 10 and 30 mpk po in male cynomolgus monkeys (N=3 for each dose). The bottom panel shows the CXCR4-dependent release of sequestered lymphocytes into blood after oral administration of compound I-1 in rats.

[0065] [Figure 16]Figure 16 (top) shows the CXCR4-dependent release of sequestered WBCs into the blood after oral administration of compound I-1 in cynomolgus monkeys. Compound I-1 was administered at doses of 3, 10, and 30 mpk po in male cynomolgus monkeys (N=3 for each dose). The bottom panel shows the CXCR4-dependent release of sequestered WBCs into the blood after oral administration of compound I-1 in rats.

[0066] [Figure 17] Figure 17 shows apoptosis of DLBCL cells exposed to 3.2 nM venetoclax grown in the presence or absence of bone marrow stromal cells (BMSCs) and with or without exposure to compound I-1. Compound I-1 successfully overcame the BMSC-induced resistance of DLBCL cells to venetoclax, restoring apoptotic efficacy. These data support efficacy in central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) and diffuse large B-cell lymphoma (DLBCL) in peripheral tissues.

[0067] [Figure 18] Figure 18 (top) shows apoptosis of MEC-1 chronic lymphocytic leukemia (CLL) cells after exposure to ibrutinib with or without compound I-1. The middle panel shows apoptosis of MEC-1 CLL cells after exposure to zanubrutinib with or without compound I-1. The bottom panel shows apoptosis of MEC-1 CLL cells after exposure to venetoclax with or without compound I-1. The time frame for all assays was 72 hours.

[0068] [Figure 19]Figure 19 (top) shows apoptosis of Waldenstrom's Macroglobulinemia (MW) cells (MWCL-1; MYD88L265P-CXCR4WT) exposed to venetoclax with or without compound I-1. The lower panel shows apoptosis of MW cells exposed to 3.2 nM venetoclax grown in the presence or absence of bone marrow stromal cells (BMSCs) with or without compound I-1. Compound I-1 successfully overcame BMSC-induced resistance of WM cells to venetoclax, restoring apoptotic efficacy. Venetoclax is not cytotoxic to BMSCs at the concentrations tested. Compound I-1 alone does not induce apoptosis at 5 μM. Vene: venetoclax. BMSC: bone marrow stromal cell line HS27A. Assay time frame: 48 hours.

[0069] [Figure 20] Figure 20 (top) shows apoptosis of Waldenstrom's Macroglobulinemia (MW) cells (MWCL-1; MYD88L265P-CXCR4WT) exposed to zanubrutinib with or without compound I-1. The lower panel shows apoptosis of MW cells exposed to zanubrutinib grown in the presence or absence of bone marrow stromal cells (BMSCs) with or without compound I-1. Compound I-1 successfully overcame BMSC-induced resistance of WM cells to zanubrutinib, restoring apoptotic efficacy. Zanubrutinib is not cytotoxic to BMSCs at the concentrations tested. Compound I-1 alone does not induce apoptosis at 5 μM. Zanub: zanubrutinib. BMSC: bone marrow stromal cell line HS27A. Assay time frame: 72 hours.

[0070] [Figure 21] Figure 21 (top) shows inhibition of BMSC-induced IgM hypersecretion in WM cells (MWCL-1; MYD88L265P-CXCR4WT). The bottom panel shows inhibition of BMSC-induced IgM hypersecretion in WM cells with or without zanubrutinib.

[0071] [Figure 22] Figure 22 shows the inhibition of CXCL12-CXCR4-mediated migration in WM cells by compound I-1. WM: Waldenström's Macroglobulinemia (MWCL-1; MYD88L265P-CXCR4WT). Assay time frame: 4 hours.

[0072] [Figure 23] Figure 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 included tumor growth inhibition (TGI; determined by compound-induced changes in tumor volume) with and without treatment, human immunoglobulin M (IgM) secreted into mouse blood, mouse leukocytes in peripheral blood, pharmacokinetics (PK) of the compound in plasma, human tumor cell infiltration into the mouse spleen, and changes in body weight. The lower panel shows the efficacy of compound I-1 and venetoclax in combination with compound I-1 in inhibiting tumor growth in a mouse MCL model.

[0073] [Figure 24] Figure 24 (top) shows the efficacy of compound I-1 in combination with venetoclax in reducing hIgM in an MCL mouse model (see Figure 23 for protocol). The bottom panel shows inhibition of tumor cell infiltration in the spleen in a mouse MCL model by compound I-1 in combination with venetoclax.

[0074] [Figure 25]Figure 25 (top) shows an increase in plasma NK (natural killer) cells resulting from administration of Compound I-1 in combination with venetoclax versus the compound alone in a mouse lymphoma model. The bottom panel shows a decrease in plasma neutrophil counts resulting from administration of Compound I-1 in combination with venetoclax versus the compound alone in a mouse lymphoma model.

[0075] [Figure 26] Figure 26 (top) shows the increased tumor growth inhibition of compound I-1 alone and in combination with zanubrutinib in a mouse MCL model (see Figure 23 for protocol). The bottom panel shows the reduction of hIgM after zanubrutinib administration with or without compound I-1 in a mouse MCL model.

[0076] [Figure 27] Figure 27 (top) shows an increase in plasma NK cells by zanubrutinib in combination with compound I-1 in a mouse lymphoma model. The bottom panel shows a decrease in plasma neutrophil counts by zanubrutinib in combination with compound I-1 in a mouse lymphoma model.

[0077] [Figure 28] FIG. 28 shows % inhibition data demonstrating that compound I-1 is more effective as a single agent than temozolomide in inhibiting tumor cell growth of the T-98G CNS GBM (glioblastoma multiforme) cell line.

[0078] [Figure 29] Figure 29 shows % inhibition data demonstrating that compound I-1 enhances the efficacy of belzutifan by further reducing cell proliferation in U-87MG cells compared to belzutifan monotherapy. A more potent inhibition of cell proliferation with a higher Emax is observed in the combination therapy.

[0079] [Figure 30]Figure 30 shows that CXCR4 gene expression is elevated in GBM patients compared to normal brain. We performed bioinformatics analysis (GeneVestigator) on publicly available datasets (GSE15824 and GSE50161). Sample sources: GSE15824: Frozen tissue samples of human glioma and normal brain obtained from the operating room. GSE50161: Gene expression profiles were generated from surgical tumor and normal brain samples.

[0080] [Figure 31] Figure 31: (Top) CXCR4 mRNA expression by WHO glioma grade and in normal brain tissue, as determined using the GEO dataset GSE16011. See pubmed.ncbi.nlm.nih.gov / 33550492 / . (Bottom) CXCR4 mRNA expression in the Cancer Genome Atlas (TCGA) and French datasets. See spandidos-publications.com / 10.3892 / mmr.2018.9011.

[0081] [Figure 32] Figure 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 THE INVENTION

[0082] Detailed Description of Certain Embodiments 1. General Description of Certain Embodiments of the Invention: The provided compounds are inhibitors of CXCR4 and are therefore useful for treating one or more disorders associated with the activity of CXCR4. Accordingly, in certain embodiments, the present invention provides a method for treating a CXCR4-mediated disorder, comprising 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. Certain embodiments of the present invention are directed to the use of CXCR4 inhibitors that, when administered to a subject, cross the blood-brain barrier (BBB) ​​and enter the brain and central nervous system (CNS).

[0083] In some embodiments, the CXCR4 inhibitor is: [ka] 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 certain embodiments, the pharmaceutical composition is suitable for oral administration to a subject.

[0087] In one aspect, the present invention provides a method of treating or reducing the severity and symptoms of a neurological disorder or disease of the central nervous system (CNS), 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 amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, Wilson's disease, dementia with Lewy bodies, frontotemporal dementia (FTD), cerebral palsy, Bell's palsy, progressive supranuclear palsy, HIV-associated dementia (HAND), epilepsy, tremor and seizure disorders, catalepsy, motor inhibition disorders, paralysis and muscle rigidity, spina bifida, anencephaly, encephalocele, encephalitis, myelopathy, hemiplegia, and encephalopathy. In some embodiments, the neurological disorder or disease of the CNS is selected from pain, cerebral ischemia, ischemia, stroke, cerebellar ataxia, Friedreich's ataxia, prion diseases (such as mad cow disease and Creutzfeldt-Jakob disease), atherosclerosis, motor neuron disease (MND), locked-in syndrome, restless legs syndrome, arachnoid cyst, sciatica, thalassemia, intracerebral hemorrhage, subarachnoid hemorrhage, muscular sclerosis, tardive dyskinesia, Charcot-Marie-Tooth disease (CMT), thrombosis, microembolization, sickle cell disease, and vaso-occlusive stroke (VOC). In some embodiments, the neurological disorder or disease of the CNS is dysregulation of 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, dementia with Lewy bodies, frontotemporal dementia (FTD), HIV-associated dementia (HAND), progressive supranuclear palsy, Friedreich's ataxia, prion diseases (such as Creutzfeldt-Jakob disease), motor neuron diseases (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 CNS neurological disorder or disease is a CNS infection, hi some embodiments, the CNS infection is selected from meningitis, shingles, or a viral infection such as HIV.

[0094] In some embodiments, the CNS infection is selected from an enterovirus, an arbovirus, and a herpesvirus 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, 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 infection with group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae.

[0096] In some embodiments, the neurological disorder or disease of the CNS is selected from addiction, neuronal damage caused by 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 affecting the CNS.

[0097] In some embodiments, the neurological disorder or disease of the CNS is selected from neurodegeneration, neuromuscular disorders, ischemia, neuroinflammatory diseases (also known as neuroinflammation), autoimmune disorders, anxiety disorders, and pain, and the neurological disorder or disease of the CNS results from a traumatic head or brain injury, spinal cord injury, or other medical condition involving loss, damage, and / or degeneration of nerve cells.

[0098] In some embodiments, neuroinflammation is caused by the infiltration of leukocytes and / or immune cells into the brain.In another embodiment, the infiltration of leukocytes and / or immune cells into the brain is caused by the increased level of CXCR4 in the brain.In some embodiments, the CNS neurological disorder or disease is selected from stroke, thrombosis and microembolism.

[0099] In some embodiments, the microembolization is microembolization in a COVID (e.g., COVID-19 or another strain of COVID) patient.

[0100] In some embodiments, the present invention provides methods 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 producing analgesia in a subject suffering from pain.

[0101] In certain embodiments, the pain is acute pain, chronic pain, neuropathic pain, nociceptive pain, allodynia, inflammatory pain or inflammatory hyperalgesia.

[0102] In some embodiments, the pain is neuropathic pain.

[0103] In some embodiments, the pain is selected from neuralgia, diabetic neuropathy, human immunodeficiency virus-associated neuropathy, nerve injury, rheumatoid arthritis pain, osteoarthritis pain, burns, lower back pain, eye pain, visceral pain, cancer pain (e.g., bone cancer pain), toothache, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post-herpetic neuralgia, post-surgical pain, post-stroke pain, and menstrual pain.

[0104] In certain embodiments, the pain is nociceptive pain and is selected from the group consisting of central nervous system trauma, strain / sprain, burns, myocardial infarction, acute pancreatitis, post-operative pain (pain after any type of surgical procedure), post-traumatic pain, renal colic, pain associated with vaso-occlusive crisis (VOC), cancer pain, and lower back pain.

[0105] In some embodiments, the pain is neuropathic pain and is selected from the group consisting of peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, low 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.

[0106] 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.

[0107] In certain embodiments, the neuropathic pain is associated with a pain disorder selected from the group consisting of arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorders, hypoesthesis, hyperalgesia, neuralgia, neuritis, neuropathic pain, analgesia, anesthesia dolorosa, causlagia, sciatica disorders, degenerative joint disorders, fibromyalgia, visceral diseases, chronic pain disorders, migraine / headache pain, chronic fatigue syndrome, complex regional pain syndrome, neurological dystrophy, plantar fasciitis, and pain associated with cancer.

[0108] In certain embodiments, the neuropathic pain relates to a pain disorder selected from the group consisting of allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, neuralgia, neuritis, neuropathic pain, analgesia, anesthesia dolorosa, causalgia, and sciatica disorders.

[0109] In some embodiments, the pain is inflammatory pain.

[0110] In certain embodiments, the pain is associated with a musculoskeletal disorder, muscle pain, fibromyalgia, spondylitis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, or pyomyositis.

[0111] In some embodiments, the pain is selected from cardiovascular pain, pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma, musculoskeletal ischemia, head pain, migraine, cluster headache, tension headache, mixed headache, headache associated with vascular disorders, orofacial pain, toothache, earache, burning mouth syndrome, and temporomandibular joint myofascial pain.

[0112] In another aspect, the present invention provides a method of treating or reducing neuroinflammation, comprising administering to a subject in need thereof an effective amount of a CXCR4 inhibitor.

[0113] In some embodiments, the neuroinflammation is associated with CXCL12 upregulation. In some embodiments, the neuroinflammation is associated with the infiltration of leukocytes into the subject's brain. In some embodiments, the leukocytes are selected from monocytes, macrophages, neutrophils and lymphocytes.

[0114] In some embodiments, the neuroinflammation is associated with a viral or bacterial infection, hi some embodiments, the neuroinflammation is associated with a malarial infection.

[0115] In some embodiments, the neuroinflammation is associated with meningitis, shingles, or HIV infection.

[0116] In some embodiments, the neuroinflammation is associated with an enterovirus, arbovirus, or herpesvirus infection.

[0117] In some embodiments, the neuroinflammation is associated with 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, influenza virus, rabies, mumps, measles, or West Nile virus infection.

[0118] In some embodiments, the neuroinflammation is associated with a bacterial infection.

[0119] In some embodiments, the neuroinflammation is associated with infection with Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, or Haemophilus influenzae.

[0120] 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.

[0121] In some embodiments, the neural or CNS cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), ganglioneuroma, ganglioneuroma, ganglioneuroblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0122] In some embodiments, the neural 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 tumor, primitive neuroectodermal (PNET) tumor, or schwannoma.

[0123] In some embodiments, the neural or CNS cancer is a CNS lymphoma.

[0124] In some embodiments, the CNS lymphoma is a primary CNS lymphoma.

[0125] In some embodiments, the primary CNS lymphoma is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the primary CNS lymphoma is Burkitt's lymphoma or T-cell lymphoma.

[0126] In some embodiments, the CNS lymphoma is a secondary CNS lymphoma.

[0127] In some embodiments, the secondary CNS lymphoma is DLBCL. In some embodiments, the secondary CNS lymphoma is Burkitt's lymphoma or T-cell lymphoma.

[0128] In another aspect, the present invention provides a method of treating Waldenstrom'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.

[0129] 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.

[0130] In some embodiments, a CXCR4 inhibitor, such as compound I-1 or a pharmaceutically acceptable salt thereof, is administered to a subject in a fed state. 2. Compounds and Definitions:

[0131] The compounds of the present invention include those generally described herein and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of the present invention, chemical elements are identified according to the Handbook of Chemistry and Physics, 75th Edition, CAS Edition of the Periodic Table of the Elements. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Edition, eds. Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0132] The terms "aliphatic" or "aliphatic group," as used herein, mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), which has one point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and which has one 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 groups, alkenyl groups, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0133] 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, and 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 spiro-fused rings. As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring one or more heteroatoms to be present in one or both of the two rings. Such heteroatoms may be present at the ring junction 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, and the like. In some embodiments, bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridge, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or an atomic or valence bond, connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system attached to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups shown below, each attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, such as those shown for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [ka] Exemplary bridged bicyclics include: [ka]

[0134] The term "lower alkyl" refers to a straight or branched C 1~4 refers to an alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0135] The term "lower haloalkyl" refers to a straight or branched C alkyl group substituted with one or more halogen atoms. 1~4 Refers to an alkyl group.

[0136] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl) means one or more of:

[0137] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0138] As used herein, the term "divalent saturated or unsaturated, linear or branched C 1~8 (or C 1~6 ) Hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, which may be straight or branched, as defined herein.

[0139] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0140] The term "alkenylene" refers to a divalent 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 by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0141] The term "halogen" means F, Cl, Br or I.

[0142] The term "aryl," used alone or as part of a larger moiety, such as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and in which each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Similarly, the term "aryl," as used herein, also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0143] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, with 6, 10, or 14 pi-electrons shared in the cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. 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, but are not limited to, 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, alicyclic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, 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. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can 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, where the alkyl and heteroaryl portions independently are optionally substituted.

[0144] 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- to 10-membered bicyclic heterocyclic moiety, either saturated or partially unsaturated, having, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It may also be NR (as in N-substituted pyrrolidinyl).

[0145] 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 these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, 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 alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions, independently, are optionally substituted.

[0146] 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 with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0147] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been 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 can be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to a compound that is not substantially altered when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0148] The optional substituents on each substitutable carbon are halogen; -(CH2) 0~4 R ○ ;-(CH2) 0~4 OR ○ ;-O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 SR ○ ;-(CH2) 0~4 Ph(R ○ Optionally substituted by);-(CH2)0~4 O(CH2) 0~1 Ph(R ○ -CH=CHPh(R ○ Optionally substituted by);-(CH2) 0~4 O(CH2) 0~1 -pyridyl (R ○ -(CH) 0~4 N(R ○ )2;-(CH2) 0~4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH2) 0~4 N(R ○ )C(O)NR ○ 2;-N(R ○ )C(S)NR ○ 2;-(CH2) 0~4 N(R ○ )C(O)OR ○ ;-N(R ○ )N(R ○ )C(O)R ○ ;-N(R ○ )N(R ○ )C(O)NR ○ 2;-N(R ○ )N(R ○ )C(O)OR ○ ;-(CH2) 0~4 C(O)R ○ ;-C(S)R ○ ;-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 C(O)SR ○ ;-(CH2) 0~4 C(O)OSiR ○ 3;-(CH2) 0~4 OC(O)R ○ ;-OC(O)(CH2) 0~4 SR-, SC(S)SR ○ ;-(CH2) 0~4 SC(O)R ○ ;-(CH2) 0~4 C(O)NR ○ 2;-C(S)NR ○2;-C(S)SR ○ ;-SC(S)SR ○ , -(CH2) 0~4 OC(O)NR ○ 2;-C(O)N(OR ○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C(NOR ○ )R ○ ;-(CH2) 0~4 SSR ○ ;-(CH2) 0~4 S(O)2R ○ ;-(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2NR ○ 2;-S(O)(NR ○ )R ○ ;-S(O)2N=C(NR ○ 2)2;-(CH2) 0~4 S(O)R ○ ;-N(R ○ )S(O)NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;SiR ○ 3;-(C 1~4 Linear or branched alkylene)ON(R ○ )2; or -(C 1~4 Linear or branched alkylene)C(O)ON(R ○ )2 is a monovalent substituent independently selected from

[0149] R ○ are each independently hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, together with the intervening atom(s), regardless of the definition above, R ○ two independent occurrences of form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which ring is joined to R ○ may be substituted on a saturated carbon atom of R by a divalent substituent selected from =O and =S, or ○ are halogen and -(CH2) 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 Linear or branched alkylene)C(O)OR ● or -SSR ● and optionally substituted by monovalent substituents independently selected from:

[0150] R ● are respectively, C 1~4Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R ● Each is unsubstituted or, if preceded by halo, substituted only with one or more halogens, or the optional substituents on saturated carbons are ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O- or -S(C(R * 2)) 2~3 or the divalent substituent attached to a substitutable vicinal carbon of an "optionally substituted" group is -O(CR * 2) 2~3 O- and R * Each independent occurrence of represents hydrogen, C 1~6 It is selected from an aliphatic, or a 5- or 6-membered unsubstituted saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0151] R * C 1~6 If aliphatic, R * is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, and R ● are respectively, 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; R ● Each is unsubstituted or, if preceded by halo, substituted with only one or more halogens.

[0152] The optional substituents on a substitutable nitrogen are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R † )S(O)2R † and R † are each independently hydrogen, C 1~6 an 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 R † two independent occurrences of together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R † C 1~6 If aliphatic, R † is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, and R ● are respectively, C 1~4Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R ● Each is unsubstituted or, when preceded by halo, substituted with only one or more halogens.

[0153] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and is 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, Vol. 66, pp. 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups 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, and 2-hydroxy-ethanesulfonate. Examples of salts that may be used include phosphate, 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, and the like.

[0154] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N +(C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0155] Unless otherwise specified, structures depicted herein are also intended to include all isomers of the structure (e.g., enantiomers, diastereomeric isomers, and geometric (or conformational) isomers), e.g., R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E stereoisomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention. Unless otherwise specified, all tautomers of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise specified, structures depicted herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, including the replacement of a carbon with a C-rich carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention. In certain embodiments, the warhead moiety R of provided compounds is 1 contains one or more deuterium atoms.

[0156] 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 IC 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. 50 and / or have a binding constant.

[0157] The terms "measurable affinity" and "measurably inhibit," as used herein, mean that there is a measurable change in CXCR4 activity between a sample containing a compound of the present invention or a composition thereof and CXCR4 and an equivalent sample containing CXCR4 in the absence of said compound or composition thereof.

[0158] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof. In some embodiments, treatment occurs after one or more symptoms have developed. In other embodiments, treatment occurs after a subject has been diagnosed with a disease or disorder, regardless of whether the subject has already developed symptoms. 3. Description of Exemplary Embodiments:

[0159] The provided compounds are inhibitors of CXCR4 and are therefore useful for treating one or more disorders associated with the activity of CXCR4. Accordingly, in certain embodiments, the present invention provides a method for treating a CXCR4-mediated disorder, comprising administering to a patient in need thereof a CXCR4 inhibitor described herein.

[0160] As used herein, a "CXCR4-mediated" disorder, disease, and / or condition refers to any disease, disorder, or condition in which CXCR4 or its variants and / or overexpression are 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 its variants are known to play a role.

[0161] In some embodiments, the "CXCR4-mediated" disorder, disease and / or condition is a disease, disorder or condition that affects the central nervous system or is modulated by the central nervous system such as a neurodegenerative disease, a CNS infection, neuroinflammation, or pain or nerve damage or abnormality caused by a condition or disorder that affects the CNS.

[0162] In some embodiments, the CXCR4 inhibitor is a compound of formula XIV-c: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined in the same manner as for Formula I below.

[0163] In some embodiments, the CXCR4 inhibitor is: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0164] 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.

[0165] In some embodiments, the CXCR4 inhibitor is I-11 or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the CXCR4 inhibitor is I-1 administered in the form of the free base or a pharmaceutical composition thereof.

[0167] Unless otherwise indicated, the CXCR4 inhibitors of Formula I or pharmaceutically acceptable salts thereof, such as I-1, I-4, I-187, I-230, or I-11, are in the form of an all-cis racemate. For clarity, "all-cis racemate" means, in the case of compound I-1: [ka] It refers to a mixture of both.

[0168] 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 an enantiomerically pure cis isomer, meaning that the CXCR4 is substantially free of its cis enantiomer.

[0169] In some embodiments, compound I-1 is the substantially pure cis isomer of: [ka] or a pharmaceutically acceptable salt thereof, and I-1 is administered as its cis enantiomer, i.e. [ka] Substantially free of

[0170] In some embodiments, compound I-1 is the substantially pure cis isomer of: [ka] or a pharmaceutically acceptable salt thereof, and I-1 is administered as its cis enantiomer, i.e. [ka] Substantially free of

[0171] In certain embodiments, compound I-1, or a pharmaceutically acceptable salt thereof, is substantially free of its cis enantiomer and its trans isomer.

[0172] The term "substantially free" when referring to the cis enantiomer or other enantiomer includes embodiments in which the CXCR4 inhibitor has an enantiomeric excess (% ee) of at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9% ee or greater than 99.9% ee.

[0173] In some embodiments, compound I-1 or a pharmaceutically acceptable salt thereof is a racemate: [ka] It is administered as

[0174] In one aspect, the present invention provides a method for treating or alleviating the severity and symptoms of a central nervous system (CNS) neurological disorder or disease, 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).

[0175] In some embodiments, the neurological disorder or disease of the CNS is Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, Wilson's disease, dementia with Lewy bodies, frontotemporal dementia (FTD), cerebral palsy, Bell's palsy, progressive supranuclear palsy, amyotrophic lateral sclerosis (ALS), HIV-associated dementia (HAND), epilepsy, tremor and seizure disorders, catalepsy, motor inhibition disorders, paralysis and muscle rigidity, spina bifida, anencephaly, encephalocele, encephalitis, myelopathy, migraine, cerebral ischemia. In some embodiments, the neurological disorder or disease of the CNS is selected from: ischemia, stroke, cerebellar ataxia, Friedreich's ataxia, prion diseases (such as mad cow disease and Creutzfeldt-Jakob disease), atherosclerosis, motor neuron disease (MND), locked-in syndrome, restless legs syndrome, arachnoid cyst, sciatica, thalassemia, intracerebral hemorrhage, subarachnoid hemorrhage, muscular sclerosis, tardive dyskinesia, Charcot-Marie-Tooth disease (CMT), thrombosis, microembolization, sickle cell disease, and vaso-occlusive stroke (VOC). In some embodiments, the neurological disorder or disease of the CNS is dysregulation of affect (PBA).

[0176] CXCR4 is known to be involved in stroke. See, for example, 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); Cell Transplantation, Vol. 26, pp. 571-583, 2017; Huang, J., et al., Stroke. 2013;44:190-197, available at doi.org / 10.21203 / rs.3.rs-856199 / v1. CXCR4 promotes thrombus formation, microemboli formation, and thrombosis. Without wishing to be bound by theory, the pathogenic mechanism of action leading to this is thought to be via CXCR4-mediated NET (neutrophil extracellular trap) formation, which traps platelets, ultimately leading to intravascular thrombus formation. This is particularly problematic in patients with sickle cell disease (SCD), where such events lead to vaso-occlusive crises (VOCs) and pain. A similar phenomenon is observed in COVID-19 patients, where thrombus formation accounts for a significant number of deaths. The disclosed CXCR4 inhibitors, such as compound I-1, are expected to be advantageous in preventing or reducing thrombus formation, which can lead to stroke, VOCs, or death.

[0177] In some embodiments, the neurological disorder or disease of the CNS is a neurodegenerative disease.

[0178] CXCR4 is known to be associated with various neurodegenerative diseases, including but not limited to ALS, Alzheimer's disease and Parkinson's disease.Therefore, it is contemplated that the CXCR4 inhibitor described herein is useful for treating such diseases.For example, 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 G93AMice 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.See 1016 / S0165-5728(99)00049-1.

[0179] Furthermore, CXCR7 agonism promotes the neuroprotective phenotype of astrocytes (A2). As described in more detail below, compound I-1 and other related compounds are CXCR7 agonists (in addition to being CXCR4 antagonists). This CXCR7 agonism by the compounds of the present invention is expected to promote the neuroprotective phenotype of astrocytes, thereby providing beneficial effects in ALS and other neurological diseases in which astrocytes are important for maintaining healthy neurons.

[0180] For support of 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.

[0181] ALS is a rare, progressive, and fatal neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Symptoms include muscle weakness, muscle atrophy, behavioral disturbances, dysphagia, and dysarthria. The prevalence of ALS in the United States is 5 per 100,000 people. Globally, ALS cases are estimated to increase from 222,801 in 2015 to 376,674 by 2040. Causes of ALS include sporadic ALS (90–95%), the genetics of which are less well understood. Familial ALS (5–10%) also exists, caused by one of the following mutations: C9orf72 (40%), SOD1 (20%), FUS (1–5%), and TARBDP (TBP-43) (1–5%). The pathogenic mechanism of ALS remains incompletely 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 relationship between CXCR4 and ALS, CXCL12 levels are known to be increased in the cerebrospinal fluid (CSF) of patients with sporadic amyotrophic lateral sclerosis (ALS; mdpi.com / 1422-0067 / 21 / 22 / 8680). Furthermore, CXCR4 expression is increased on T cells in ALS patients compared to healthy controls; jneuroinflammation.biomedcentral.com / articles / 10.1186 / s12974-018-1135-3). Preclinical studies have shown that SOD1 G93A Long-term administration of AMD3100 (5 mg / kg, SC) to mice (a mouse model of ALS) significantly reduced SOD1 G93AThe mice showed a significant increase in lifespan, improved motor function and weight loss, improved microglial pathology, reduced proinflammatory cytokines in the spinal cord, reduced permeability of the blood-spinal cord barrier due to increased tight junction protein levels, and increased motor neuron numbers in lamina X of the spinal cord. See ncbi.nlm.nih.gov / pmc / articles / PMC4882847 / and US2016 / 0206592, which are incorporated herein by reference. Without wishing to be bound by theory, it is believed that the CXCR4 inhibitors described herein, such as the compound of Formula I and pharmaceutically acceptable salts thereof, will provide a more effective treatment for ALS. For example, the CXCR4 inhibitors described herein have the ability to penetrate the BBB and achieve therapeutically effective levels of CXCR4 inhibition in the brain and CNS.

[0182] Parkinson's disease affects 1–2 per 1,000 people. There is no cure, and the only available medications are symptomatic. Misfolded alpha-synuclein protein forms toxic clumps (Lewy bodies) in neurons of the midbrain (substantia nigra pars compacta), causing neuronal and astrocyte death. Non-motor symptoms include loss of smell, sleep, and mood disorders. Motor symptoms include stiffness, bradykinesia, resting tremor, and postural instability. Inflammation is a hallmark of Parkinson's disease. Microglia are a self-renewing pool of immune cells resident in the brain (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 the 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 levels have been observed in the serum of PD patients, and higher CXCR4 levels have been observed in PBMCs of PD patients (Bagheri et al., 2018, pubmed.ncbi.nlm.nih.gov / 30428473 / ). Furthermore, SNPs near CXCR4 are associated with an increased risk of developing 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 and CXCL12 expression and secretion in microglia were upregulated. In vitro, microglial chemotaxis to the substantia nigra was induced and could be inhibited by plerixafor.

[0183] In some embodiments, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, Wilson's disease, dementia with Lewy bodies, frontotemporal dementia (FTD), HIV-associated dementia (HAND), progressive supranuclear palsy, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, prion diseases such as Creutzfeldt-Jakob disease, motor neuron disease (MND), and Charcot-Marie-Tooth disease (CMT).

[0184] In some embodiments, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS).

[0185] In some embodiments, the neurodegenerative disease is Alzheimer's disease.

[0186] In some embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).

[0187] In some embodiments, the neurodegenerative disease is Parkinson's disease.

[0188] In some embodiments, the neurological disorder or disease of the CNS is selected from neuronal cell damage or death; neuronal damage resulting from cerebrovascular accidents such as stroke in the brain or spinal cord, atrial fibrillation, CNS infections, prion diseases, normal aging (e.g., anosmia), and head and / or brain injuries, as well as other medical diseases and conditions involving neuronal loss, damage, and / or degeneration. In some embodiments, the neurological disorder or disease of the CNS is selected from stroke, thrombosis, and microembolization.

[0189] In some embodiments, the microembolization is microembolization in a COVID (e.g., COVID-19 or another strain of COVID) patient.

[0190] In some embodiments, the CNS neurological disorder or disease is a CNS infection, hi some embodiments, the CNS infection is selected from meningitis, shingles, or a viral infection such as HIV.

[0191] In some embodiments, the CNS infection is selected from an enterovirus, an arbovirus, and a herpesvirus 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, influenza virus, rabies, mumps, measles, and West Nile virus infection.

[0192] Viruses can cause CNS infections through various 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 virus, and enteroviruses, cause the greatest number of cases in immunocompetent hosts. Other herpesviruses (e.g., cytomegalovirus, John Cunningham virus) are more common in immunocompromised hosts. Arboviruses, such as Japanese encephalitis virus and Zika virus, are important pathogens worldwide, but prevalence varies considerably by geographic region and often by season. Thus, in some embodiments, the CNS infection treated by the disclosed methods includes 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.

[0193] 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.

[0194] In some embodiments, the neurological disorder or disease of the CNS is selected from addiction, neuronal damage caused by 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 affecting the CNS.

[0195] In some embodiments, the neurological disorder or disease of the CNS is selected from neurodegeneration, neuromuscular disorders, ischemia, neuroinflammation, autoimmune disorders, anxiety disorders, and pain, and the neurological disorder or disease of the CNS results from a traumatic head or brain injury, spinal cord injury, or other medical condition involving loss, damage, and / or degeneration of nerve cells.

[0196] In some embodiments, the microembolization is microembolization in a COVID (e.g., COVID-19 or another strain of COVID) patient.

[0197] CXCR4 is known to be associated with certain autoimmune diseases.Therefore, the present invention provides a method for treating autoimmune diseases using the CXCR4 inhibitor described herein.For example, see Garcia-Cuesta Eva M., Santiago Cesar A., ​​Vallejo-Diaz Jesus, Juarranz Yasmina, Rodriguez-Frade Jose 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.

[0198] In some embodiments, the present invention provides methods 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 producing analgesia in a subject suffering from pain.

[0199] In certain embodiments, the pain is acute pain, chronic pain, neuropathic pain, nociceptive pain, allodynia, inflammatory pain or inflammatory hyperalgesia.

[0200] In some embodiments, the pain is neuropathic pain.

[0201] In some embodiments, the pain is selected from neuralgia, diabetic neuropathy, human immunodeficiency virus-associated neuropathy, nerve injury, rheumatoid arthritis pain, osteoarthritis pain, burns, lower back pain, eye pain, visceral pain, cancer pain (e.g., bone cancer pain), toothache, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post-herpetic neuralgia, post-surgical pain, post-stroke pain, and menstrual pain.

[0202] In certain embodiments, the pain is nociceptive pain and is selected from the group consisting of central nervous system trauma, strain / sprain, burns, myocardial infarction, acute pancreatitis, post-operative pain (pain after any type of surgical procedure), post-traumatic pain, renal colic, pain associated with vaso-occlusive crisis (VOC), cancer pain, and lower back pain.

[0203] In some embodiments, the pain is neuropathic pain and is selected from the group consisting of peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, low 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.

[0204] In certain embodiments, the neuropathic pain is associated with a pain disorder selected from the group consisting of arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorders, hypoesthesia, hyperalgesia, neuralgia, neuritis, neuropathic pain, analgesia, anesthesia dolorosa, causalgia, sciatica disorders, degenerative joint disorders, fibromyalgia, visceral diseases, chronic pain disorders, migraine / headache pain, chronic fatigue syndrome, complex regional pain syndrome, neurological dystrophy, plantar fasciitis, and pain associated with cancer.

[0205] In some embodiments, the pain is inflammatory pain.

[0206] In certain embodiments, the inflammatory pain is associated with musculoskeletal disorders, muscle pain, fibromyalgia, spondylitis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, or pyomyositis.

[0207] In some embodiments, the pain is selected from cardiovascular pain, pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma, musculoskeletal ischemia, head pain, migraine, cluster headache, tension headache, mixed headache, headache associated with vascular disorders, orofacial pain, toothache, earache, burning mouth syndrome, and temporomandibular joint myofascial pain.

[0208] In one aspect, the present disclosure provides a method for treating or alleviating 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).

[0209] In some embodiments, the neuroinflammation is associated with CXCL12 upregulation. In some embodiments, the neuroinflammation is associated with the infiltration of leukocytes into the subject's brain. In some embodiments, the leukocytes are selected from monocytes, macrophages, neutrophils and lymphocytes.

[0210] In some embodiments, the neuroinflammation is associated with a viral or bacterial infection, hi some embodiments, the neuroinflammation is associated with a malarial infection.

[0211] In some embodiments, the neuroinflammation is associated with meningitis, shingles, or HIV infection.

[0212] In some embodiments, the neuroinflammation is associated with an enterovirus, arbovirus, or herpesvirus infection.

[0213] In some embodiments, the neuroinflammation is associated with 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, influenza virus, rabies, mumps, measles, or West Nile virus infection.

[0214] In some embodiments, the neuroinflammation is associated with a bacterial infection.

[0215] In some embodiments, the neuroinflammation is associated with Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Neisseria meningitides, Streptococcus pneumoniae, or Haemophilus influenzae infection.

[0216] In one aspect, the present disclosure provides a method for treating nervous 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).

[0217] While not wishing to be bound by theory, a common pathogenic and therapeutic mechanism of action for GBM and other similar cancers is thought to be that CXCL12 promotes monocyte / macrophage infiltration into the brain, and after treatment with radiation, these cells promote angiogenesis, leading to GBM tumor regrowth. CXCR4 antagonism appears to inhibit monocyte / macrophage infiltration into the brain, thereby preventing or reducing angiogenesis.

[0218] Furthermore, binding of CXCL12 to the CXCR4 receptor in macrophages promotes an anti-tumor phenotype similar to tumor-associated macrophages (TAMs), which promote tumor growth. The CXCR4 inhibitors described herein are expected to block this tumor-promoting phenotype.

[0219] Furthermore, CXCL12 / CXCR4 promotes the growth and proliferation of GBM tumor cells (and other tumor cells), and therefore, antagonizing CXCR4 is effective in reducing tumor size. CXCR4 antagonism inhibits the infiltration of MDSCs (myeloid-derived immunosuppressive cells), which are known to promote tumor growth. Furthermore, CXCR4 is known to mediate tumor cell metastasis to tissues, including the brain. CXCR4 antagonism with the compounds described herein is believed to prevent tumor metastasis. For example, inhibiting 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. In the case of lymphomas, particularly primary lymphomas in the CNS, blocking CXCR4 is believed to induce apoptosis and reduce tumor cell growth and proliferation. In the case of secondary CNS lymphomas, CXCR4 antagonism is believed to prevent tumor cell migration and adhesion (or fixation) to metastatic tissues, including the brain. CXCR4 promotes adhesion to bone marrow stroma and chemoresistance of tumor cells. The 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.

[0220] In some embodiments, the neural or CNS cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), ganglioneuroma, ganglioneuroma, ganglioneuroblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0221] In some embodiments, the nerve or CNS cancer is acoustic neurinoma, 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 tumor, primitive neuroectodermal tumor (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type more commonly found in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human, hi some embodiments, the patient is a child or pediatric patient.

[0222] In some embodiments, the neural or CNS cancer is a CNS lymphoma.

[0223] In some embodiments, the CNS lymphoma is a primary CNS lymphoma.

[0224] In some embodiments, the primary CNS lymphoma is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the primary CNS lymphoma is Burkitt's or T-cell lymphoma. Of note, DLBCL often accounts for more than 90% of primary CNS lymphomas.

[0225] In some embodiments, the CNS lymphoma is a secondary CNS lymphoma.

[0226] In some embodiments, the secondary CNS lymphoma is DLBCL. In some embodiments, the secondary CNS lymphoma is Burkitt's or T-cell lymphoma.

[0227] In some embodiments, the neural or CNS cancer is a spinal axis tumor, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, neuroblastoma, or retinoblastoma.

[0228] In some embodiments, the neural or CNS cancer is neurofibromatosis type 1-associated malignant peripheral nerve sheath tumor (MPNST).

[0229] In some embodiments, the neural or CNS cancer is metastatic. In some embodiments, the cancer has spread from one location in the subject's body to the brain or nervous system.

[0230] In some embodiments, the method is effective for treating one or more neural or CNS tumors. In some embodiments, the tumor is treated by halting further growth of the tumor. In some embodiments, the tumor is treated by causing the tumor to shrink in size (e.g., volume or mass) by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99% compared to the size of the tumor before treatment. In some embodiments, the tumor is treated by causing the tumor mass in the patient to shrink by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99% compared to the tumor mass before treatment.

[0231] CXCR4 is known to be associated with a variety of neural, CNS and other cancers. For example, Alghamri, MS, et al., “Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy,” ACS Nano 2022 16 (6), 8729-8750; Giordano, FA, “Targeting the Post-Irradiation Tumor Microenvironment in Glioblastoma via Inhibition of CXCL12,” Cancers 2019, 11(3), 272; Gravina GL, 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.See Shen Jianzhong, “The Role of the CXCL12 / CXCR4 / CXCR7 Chemokine Axis in Cancer,” Frontiers in Pharmacology 2020, 11, 10.3389 / fphar.2020.574667.

[0232] In another aspect, the present invention provides a method of treating Waldenstrom'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. Waldenstrom's Macroglobulinemia (WM) is a unique B-cell lymphoproliferative disorder characterized by proliferation of lymphoplasmacytic cells in the bone marrow and other organs, accompanied by elevated serum levels of monoclonal immunoglobulin M (IgM) (gammopathy).

[0233] WM is sometimes called lymphoplasmacytic lymphoma (LPL) with an associated monoclonal IgM paraprotein. In WM, there is malignant transformation of B cells at a late stage of maturation, which continues to proliferate into clones of the same cells, primarily in the bone marrow, but also in 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). Approximately 95% of LPL cases are WM; the remaining 5% do not secrete IgM and therefore are not classified as WM.

[0234] 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.

[0235] In some embodiments, a CXCR4 inhibitor, such as compound I-1 or a pharmaceutically acceptable salt thereof, is administered to a subject in a fed state.

[0236] In some embodiments, the CXCR4 inhibitor for use in the methods of treatment described herein is a compound of Formula I: [ka] 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 carbocyclic aromatic ring, a saturated or partially unsaturated 4-8 membered 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; R 1 are each independently -R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR or -L 1 -R 6 and Each R is independently hydrogen or C 1~6 an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic carbocyclic aromatic ring, a saturated or partially unsaturated 4-8 membered 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; L 1 and L 2 are each independently a covalent bond or a divalent linear or branched C 1~8a hydrocarbon chain in which one, two or three methylene units of the chain are independently optionally replaced by -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-, -SON(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 an optionally substituted 3-8 membered saturated or partially unsaturated divalent monocyclic carbocyclic ring, an optionally substituted phenylene, an optionally substituted saturated or partially unsaturated 4-8 membered monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 2 are hydrogen, halogen, -CN, -N(R)2, -NO2, -N3, -SR, -L 2 -R 6 or optionally substituted C 1~8 is aliphatic, R 3 is hydrogen, optionally substituted C 1~6 Aliphatic or -L 3 -R 6 and L 3 is a divalent linear or branched C 1~6a hydrocarbon chain in which one, two or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -C(S)- or -Cy-; R 4 are each independently hydrogen, deuterium, halogen, -CN, -OR 6 Or C 1~4 alkyl or two R on the same carbon 4 The groups, optionally taken together, are ═NR 6 , =NOR 6 , forming =O or =S, R 5 are each independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR or -L 1 -R 6 or two R on the same saturated carbon atom 5 groups optionally taken together form =NR, =NOR, =O, =S or a 3- to 6-membered spirocyclic carbocyclic ring; R 6 are each independently hydrogen or C optionally substituted by 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1~6 is alkyl, m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4.

[0237] 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).

[0238] As generally defined above, ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic carbocyclic aromatic ring, a saturated or partially unsaturated 4-8 membered 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.

[0239] 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 carbocyclic aromatic ring. In some embodiments, ring A is a saturated or partially unsaturated 4-8 membered 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.

[0240] In some embodiments, ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0241] In some embodiments, ring A is: [ka] is selected from.

[0242] In some embodiments, ring A is: [ka] In some embodiments, ring A is selected from: [ka] In some embodiments, ring A is selected from: [ka] is.

[0243] In some embodiments, ring A is [ka] isn't it.

[0244] In some embodiments, ring A is not imidazo[1,2-a]pyridine.

[0245] In some embodiments, ring A is selected from those depicted in Table 1 below.

[0246] As generally defined above, R 1 are each independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR or -L 1 -R 6 is.

[0247] In some embodiments, R 1 is R. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -OR. In some embodiments, R 1 is -N(R). In some embodiments, R 1 is —NO. In some embodiments, R 1 is -N3. In some embodiments, R 1 is -SR. In some embodiments, R 1 Ha-L 1 -R 6 is.

[0248] In some embodiments, R 1is hydrogen. In some embodiments, R 1 is optionally substituted C 1~6 In some embodiments, R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic carbocyclic aromatic ring. In some embodiments, R 1 is an optionally substituted saturated or partially unsaturated 4-8 membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 1 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0249] In some embodiments, R 1 -R, halogen, -CN, -OR, -N(R)2, -SR, C 1~6 Aliphatic or -L 1 -R 6 Selected from L 1 is a divalent linear or branched C 1~6 a hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -C(S)-, or -Cy-; 1~6Aliphatic groups are optionally substituted with 1, 2, or 3 groups independently selected from halogen, —CN, —N(R), —NO, —N, ═NR, ═NOR, ═O, ═S, —OR, —SR, —SOR, —S(O)R, —R, —Cy-R, —C(O)R, —C(O)OR, —OC(O)R, —C(O)N(R), —(R)NC(O)R, —OC(O)N(R), —(R)NC(O)OR, —N(R)C(O)N(R), —SON(R), —(R)NSOR, —C(S)R, or —C(S)OR, wherein each R is independently selected from hydrogen, —CH-phenyl, phenyl, C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHF, -CHF, -CF, -CHCHF, or -CHCF, or each R is independently hydrogen or methyl, or R is hydrogen.

[0250] In some embodiments, R 1 is hydrogen, halogen, C 1~6 Alkyl (optionally substituted with 1, 2 or 3 halogens), -CN, -N(R)2, -OR, -SR, -S(O)R 6 , -SO2R 6 , -SO2NHR 6 , [ka] and each R is independently selected from hydrogen, —CH-phenyl, phenyl, C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHF, -CHF, -CF, -CHCHF, or -CHCF, or each R is independently hydrogen or methyl, or R is hydrogen.

[0251] In some embodiments, R 1 is hydrogen, halogen, C 1~6 Alkyl, -CN, -N(R)2, -OR, -SR, [ka] and each R is independently selected from hydrogen, —CH-phenyl, phenyl, C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHF, -CHF, -CF, -CHCHF, or -CHCF, or each R is independently hydrogen or methyl, or R is hydrogen.

[0252] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0253] As generally defined above, L 1 and L 2 are each independently a covalent bond or a divalent linear or branched C 1~8 A hydrocarbon chain wherein one, two, or three methylene units of the chain are independently optionally replaced by -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-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0254] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is a divalent linear or branched C 1~8 In some embodiments, L 1 is a divalent linear or branched C 1~8A hydrocarbon chain wherein one, two, or three methylene units of the chain are independently optionally replaced by -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-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0255] In some embodiments, L 1 is a divalent linear or branched C 1~6 a hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NSO2-, -C(S)-, or -Cy-, where each R is independently hydrogen, -CH2-phenyl, phenyl, C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHF, -CHF, -CF, -CHCHF, or -CHCF, or each R is independently hydrogen or methyl, or R is hydrogen.

[0256] In some embodiments, L 1 is selected from those illustrated in Table 1 below.

[0257] In some embodiments, L 2 is a covalent bond. In some embodiments, L 2 is a divalent linear or branched C 1~8 In some embodiments, L 2 is a divalent linear or branched C 1~8A hydrocarbon chain wherein one, two, or three methylene units of the chain are independently optionally replaced by -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-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0258] In some embodiments, L 2 is a divalent linear or branched C 1~6 a hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NSO2-, -C(S)-, or -Cy-, where each R is independently hydrogen, -CH2-phenyl, phenyl, C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHF, -CHF, -CF, -CHCHF, or -CHCF, or each R is independently hydrogen or methyl, or R is hydrogen.

[0259] In some embodiments, L 2 is selected from those illustrated in Table 1 below.

[0260] As generally defined above, each -Cy- is independently an optionally substituted 3-8 membered saturated or partially unsaturated divalent monocyclic carbocyclic ring, an optionally substituted phenylene, an optionally substituted saturated or partially unsaturated 4-8 membered 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 saturated or partially unsaturated bicyclic or bridged bicyclic 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.

[0261] In some embodiments, -Cy- is an optionally substituted divalent 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 saturated or partially unsaturated 4-8 membered 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 saturated or partially unsaturated bicyclic or bridged bicyclic 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.

[0262] In some embodiments, -Cy- is [ka] is.

[0263] In some embodiments, -Cy- is selected from those depicted in Table 1 below.

[0264] As generally defined above, R 2 is hydrogen, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, -L 2 -R 6 or optionally substituted C 1~8 It is aliphatic.

[0265] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -OR. In some embodiments, R 2 is -N(R). In some embodiments, R 2 is —NO. In some embodiments, R 2 is -N3. In some embodiments, R 2 is -SR. In some embodiments, R 2 Ha-L 2 -R 6 In some embodiments, R 2 is optionally substituted C 1~8 It is aliphatic.

[0266] In some embodiments, R 2 is hydrogen, halogen, -CN, -OR, -N(R)2, -SR, optionally substituted C 1~6 Aliphatic or -L 2 -R 6 and L 2 is a divalent linear or branched C 1~6 a hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -C(S)-, or -Cy-; 1~6Aliphatic groups are optionally substituted with 1, 2, or 3 groups independently selected from halogen, —CN, —N(R), —NO, —N, ═NR, ═NOR, ═O, ═S, —OR, —SR, —SOR, —S(O)R, —R, —Cy-R, —C(O)R, —C(O)OR, —OC(O)R, —C(O)N(R), —(R)NC(O)R, —OC(O)N(R), —(R)NC(O)OR, —N(R)C(O)N(R), —SON(R), —(R)NSOR, —C(S)R, or —C(S)OR, wherein each R is independently selected from hydrogen, —CH-phenyl, phenyl, C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHF, -CHF, -CF, -CHCHF, or -CHCF, or each R is independently hydrogen or methyl, or R is hydrogen.

[0267] In some embodiments, R 2 is hydrogen, halogen, -CN, -OR, -N(R)2, C 1~6 alkyl (optionally substituted with 1, 2 or 3 deuterium or halogen atoms), C 2~6 Alkynyl, -S(O)R 6 , -SO2R 6 , -SO2NHR 6 , -(CH2) 1~6 -N(R)R 6 , -(CH2) 1~6 -OR 6 or -(CH2) 0~6 -Cy-R 6 In some embodiments, R 2 is hydrogen, halogen, -OR, -N(R)2, -S(O)R 6 , -SO2R 6 , -SO2NHR 6 , -(CH2) 1~6 -N(R)R 6 , -(CH2) 1~6 -OR 6 , [ka] and each R is independently selected from hydrogen, —CH-phenyl, phenyl, C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHF, -CHF, -CF, -CHCHF, or -CHCF, or each R is independently hydrogen or methyl, or R is hydrogen.

[0268] In some embodiments, R 2 is C 2~4 alkynyl, -NH, F, Cl, Br, or I. In some embodiments, R 2 is hydrogen, Cl, —NH, or ethynyl. In some embodiments, R 2 is Cl.

[0269] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0270] As generally defined above, R 3 is hydrogen, optionally substituted C 1~6 Aliphatic or -L 3 -R 6 is.

[0271] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is optionally substituted C 1~6 In some embodiments, R 3 Ha-L 3 -R 6 is.

[0272] In some embodiments, R 3is optionally substituted by one, two, or three groups independently selected from hydrogen, deuterium, halogen, —CN, —N(R), —NO, —N, ═NR, ═NOR, ═O, ═S, —OR, —SR, —SOR, —S(O)R, —R, —Cy-R, —C(O)R, —C(O)OR, —OC(O)R, —C(O)N(R), —(R)NC(O)R, —OC(O)N(R), —(R)NC(O)OR, —N(R)C(O)N(R), —SON(R), —(R)NSOR, —C(S)R, or —C(S)OR; 1~6 In some embodiments, R 3 is hydrogen or C 1~6 alkyl (optionally substituted with 1, 2, or 3 deuterium or halogen atoms), —(CH) 1~6 -CN, -(CH2) 1~6 -N(R)(R 6 ), -(CH2) 1~6 -OR 6 or -(CH2) 0~6 -Cy-R 6 In some embodiments, R 3 is hydrogen, C 1~6 alkyl (optionally substituted with 1, 2, or 3 deuterium or halogen atoms), —(CH) 1~6 -CN, -(CH2) 1~6 -N(R)(R 6 ), -(CH2) 1~6 -OR 6 , [ka] and each R is independently selected from hydrogen, —CH-phenyl, phenyl, C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHF, -CHF, -CF, -CHCHF, or -CHCF, or each R is independently hydrogen or methyl, or R is hydrogen.

[0273] In some embodiments, R 3is hydrogen or C optionally substituted by 1, 2 or 3 deuterium or halogen atoms, phenyl, pyridyl, -CN, -N(R)2 or -OR; 1~6 alkyl, and each R is independently hydrogen, -CH-phenyl, phenyl, C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHF, -CHF, -CF, -CHCHF, or -CHCF, or each R is independently hydrogen or methyl, or R is hydrogen. 3 teeth, [ka] pyridyl, -N(R)2, -CN, or C optionally substituted by 1, 2, or 3 deuterium or halogen atoms 1~4 alkyl, and R is hydrogen or C 1~3 In some embodiments, R 3 is methyl, ethyl, -CD or -CHCF. In some embodiments, R 3 is methyl.

[0274] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0275] As generally defined above, L 3 is a divalent linear or branched C 1~6 A hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -C(S)-, or -Cy-.

[0276] In some embodiments, L 3 is a divalent linear or branched C 1~6 In some embodiments, L 3is a divalent linear or branched C 1~6 A hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -C(S)-, or -Cy-.

[0277] In some embodiments, L 3 is selected from those illustrated in Table 1 below.

[0278] As generally defined above, R 4 are each independently hydrogen, deuterium, halogen, -CN, -OR 6 Or C 1~4 alkyl or two R on the same carbon 4 The groups, optionally taken together, are ═NR 6 , =NOR 6 , forming =O or =S.

[0279] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is deuterium. In some embodiments, R 4 is a halogen. In some embodiments, R 4 is -CN. In some embodiments, R 4 HA-OR 6 In some embodiments, R 4 is C 1~4 In some embodiments, two R on the same carbon are alkyl. 4 The groups, optionally taken together, form =NR 6 , =NOR 6 , forming =O or =S.

[0280] In some embodiments, R 4 is hydrogen, deuterium, halogen, -CN, C 1~2 alkyl or two R on the same carbon 4 The groups together form =O or =S.

[0281] In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0282] As generally defined above, R 5 are each independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR or -L 1 -R 6 or two R on the same saturated carbon atom 5 The groups, optionally taken together, form =NR, =NOR, =O, =S or a 3- to 6-membered spirocyclic carbocyclic ring.

[0283] In some embodiments, R 5 is R. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is -CN. In some embodiments, R 5 is -OR. In some embodiments, R 5 is -N(R). In some embodiments, R 5 is —NO. In some embodiments, R 5 is -N3. In some embodiments, R 5 is -SR. In some embodiments, R 5 Ha-L 1 -R 6 In some embodiments, two R on the same saturated carbon atom are 5 The groups taken together form =NR, =NOR, =O, =S, or a 3- to 6-membered spirocyclic carbocyclic ring.

[0284] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is optionally substituted C 1~6 In some embodiments, R 5 is C optionally substituted by 1, 2, 3 or 4 deuterium or halogen atoms 1~6 In some embodiments, R 5is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 is optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic carbocyclic aromatic ring. In some embodiments, R 5 is an optionally substituted saturated or partially unsaturated 4-8 membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 5 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0285] In some embodiments, R 5 is hydrogen, C 1~6 Alkyl, halogen, -CN, -CF3, -CD3, cyclopropyl, ethynyl, -OCH3, -OCF3 or [ka] In some embodiments, R 5 is methyl.

[0286] In some embodiments, R 5 is selected from those illustrated in Table 1 below.

[0287] As generally defined above, R 6 are each independently hydrogen or C optionally substituted by 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1~6 It is alkyl.

[0288] In some embodiments, R 6 is hydrogen. In some embodiments, R6 is C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1~6 It is alkyl.

[0289] In some embodiments, R 6 is C optionally substituted by 1, 2 or 3 deuterium or halogen atoms 1~3 It is alkyl.

[0290] In some embodiments, R 6 is selected from those illustrated in Table 1 below.

[0291] As generally defined 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.

[0292] As generally defined 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.

[0293] As generally defined 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.

[0294] In some embodiments, the CXCR4 inhibitor is a compound of formula II-a or II-b: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , -Cy-, m, n and p, both alone and in combination, are as defined above and as described in embodiments herein.

[0295] In some embodiments, the CXCR4 inhibitor is a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , -Cy-, n and p, both alone and in combination, are as defined above and as described in embodiments herein.

[0296] In some embodiments, the CXCR4 inhibitor is a compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L3 , -Cy-, m and p, both alone and in combination, are as defined above and as described in embodiments herein.

[0297] In some embodiments, the CXCR4 inhibitor is a compound of Formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , -Cy-, m and p, both alone and in combination, are as defined above and as described in embodiments herein.

[0298] In some embodiments, the CXCR4 inhibitor is a compound of Formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , -Cy-, m, n and p, both alone and in combination, are as defined above and as described in embodiments herein.

[0299] In some embodiments, the CXCR4 inhibitor is a compound of Formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein R, R 1 , R 2 , R 3 , R4 , R 5 , R 6 , L 1 , L 2 , L 3 , -Cy-, m, n and p, both alone and in combination, are as defined above and in the embodiments herein.

[0300] In some embodiments, the CXCR4 inhibitor is a compound of Formula VIII-a or VIII-b: [ka] or a pharmaceutically acceptable salt thereof, wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , -Cy-, m, n and p, both alone and in combination, are as defined above and as described in embodiments herein.

[0301] In some embodiments, the CXCR4 inhibitor is a compound of formula IX: [ka] or a pharmaceutically acceptable salt thereof, wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , -Cy- and n, both alone and in combination, are as defined above and as described in embodiments herein.

[0302] In some embodiments, the CXCR4 inhibitor is a compound of formula Xa, Xb, Xc, Xd, or Xe: [ka] or a pharmaceutically acceptable salt thereof, wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , -Cy- and n, both alone and in combination, are as defined above and as described in embodiments herein.

[0303] In some embodiments, the CXCR4 inhibitor is a compound of formula XI: [ka] or a pharmaceutically acceptable salt thereof, wherein R, R 1 , R 2 , R 3 , R 5 , R 6 , L 1 , L 2 , L 3 , -Cy- and p, both alone and in combination, are as defined above and as described in embodiments herein.

[0304] In some embodiments, the CXCR4 inhibitor is a compound of Formula XII-a or XII-b: [ka] or a pharmaceutically acceptable salt thereof, wherein R, R 1 , R 2 , R 3 , R 5 , R 6 , L 1 , L 2 , L 3 , -Cy- and p, both alone and in combination, are as defined above and as described in embodiments herein.

[0305] In some embodiments, the CXCR4 inhibitor is a compound of Formula XIII-a or XIII-b: [ka] or a pharmaceutically acceptable salt thereof, wherein R, R 2 , R 3 , R 6 , L 2 , L 3 and -Cy-, both alone and in combination, are as defined above and as described in embodiments herein. In some embodiments of Formula XIII-a or XIII-b, -Cy- is an optionally substituted saturated or partially unsaturated 4-8 membered 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 two nitrogen atoms.

[0306] In some embodiments, the CXCR4 inhibitor is a compound of formula XIV-b or XIV-c: [ka] or a pharmaceutically acceptable salt thereof, 2 , R 3 , R 5 , R 6 , L 2 , L 3 and -Cy-, each alone and in combination, are as defined above and as described in embodiments herein. In some embodiments of Formulas XIV-a, XIV-b, and XIV-c, R 2 is selected from hydrogen or halogen. 2 is a halogen. In some embodiments, R 2 is Cl or Br. In some embodiments, R 2 is Cl. In some embodiments, R 2 is C 2~4 alkynyl, -NH, F, Cl, Br, or I. In some embodiments, R2 is hydrogen, Cl, —NH 2 or ethynyl.

[0307] Exemplary compounds of the invention are shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] Note: The stereochemistry of I-188 and I-189 was assigned arbitrarily. Each compound was isolated in a stereochemically enriched form. Compound I-149 corresponds to their racemic form. [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20]

[0308] In some embodiments, the present invention provides a compound shown in Table 1 above, or a pharmaceutically acceptable salt thereof. 4. General method for obtaining the compound:

[0309] The compounds of the invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods detailed in the Examples herein.

[0310] In the following schemes, where a particular protecting group ("PG"), leaving group ("LG"), or transformation condition is illustrated, one of skill in the art will understand that other protecting groups, leaving groups, and transformation conditions are also suitable and 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, 5th Edition, John Wiley & Sons, 2001; Comprehensive Organic Transformations, R.C. Larock, 2nd Edition, John Wiley & Sons, 1999; and Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, each of which is incorporated herein by reference in its entirety.

[0311] As used herein, the phrase "leaving group" (LG) includes, but is not limited to, halogen (e.g., fluoride, chloride, bromide, iodide), sulfonate (e.g., mesylate, tosylate, benzenesulfonate, brosylate, disylate, triflate), diazonium, and the like.

[0312] As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxyl protecting groups, and the like. 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, 3rd Edition, John Wiley & Sons, 1999, and "Protecting Groups" by Philip Kocienski, Georg Thieme Verlag, Stuttgart, New York, 1994, which are incorporated herein by reference in their entireties. 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 formates, benzoylformates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates, 4,4-(ethylenedithio)pentanoates, pivalates (trimethylacetyl), crotonates, 4-methoxycrotonates, benzoates, p-benzylbenzoates, 2,4,6-trimethylbenzoates, carbonates (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.

[0313] 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, 3rd Edition, John Wiley & Sons, 1999, and Philip Kocienski, "Protecting Groups," Georg Thieme Verlag Stuttgart, New York, 1994, which are incorporated herein by reference in their entireties. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimido, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0314] Those skilled in the art will recognize that various functional groups present in the compounds of the present 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," 5th Edition, eds. Smith, MB, and March, J., John Wiley & Sons, New York: 2001, which is incorporated herein by reference in its entirety. Such interconversions may require one or more of the techniques described above, and certain methods for synthesizing the compounds of the present invention are described below.

[0315] In one aspect, certain compounds of the present invention of Formula I or subformulas thereof are generally prepared according to Scheme 1, shown below: Scheme 1 [ka]

[0316] In Scheme 1 above, PG is a nitrogen protecting group and R 1 , R 2 , R 3 , R 4 , R 5 , ring A, m, n and p, both alone and in combination, are as defined above and as described in embodiments herein.

[0317] As generally shown in Scheme 1, for example, an aldehyde according to structure A can be condensed with a ketone such as acetone in the presence of a base to produce intermediate B by the following general procedures E or F. The general procedures are described in more detail in the examples below. 3Condensation of an amine, such as methylamine, with an aldehyde of structure C provides a compound of structure D. In some embodiments, such compounds are CXCR4 inhibitors according to the present invention. In other embodiments, a compound of structure D is reduced according to general procedure A to provide a compound of structure E. 2 Compounds of structure F, where R is a suitable leaving group (LG), can undergo cross-coupling (e.g., Pd-catalyzed coupling) to give compounds of structure G. 2 If R is hydrogen, halogenation or formation of a leaving group such as a triflate may be performed prior to the coupling reaction. 2 When is hydrogen, alkylation such as formylation with paraformaldehyde or DMF can be used to provide certain compounds of structure G. Scheme 2 [ka]

[0318] Alternatively, as shown in Scheme 2, piperidone compounds of structure H can be reduced according to general procedure A to give compounds of structure I, followed by the synthesis of compounds of formula LG-R 3 Upon reaction with an appropriate electrophile, where LG refers to a suitable leaving group such as a halide or mesylate, compounds of structure J can be obtained. 5. Uses, Formulation and Administration, and Co-Administered Additional Therapeutic Agents Pharmaceutically acceptable compositions

[0319] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the present invention is effective to measurably inhibit CXCR4 or a variant thereof in a biological sample or a patient. In certain embodiments, the amount of compound in the composition of the present invention is effective to measurably inhibit CXCR4 or a variant thereof in a biological sample or a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0320] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0321] 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 that is formulated together. Pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the composition of the present invention includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, etc.), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and wool fat.

[0322] The compositions of the present invention can 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, intrasynovial, 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 the present invention can be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0323] For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injections, as are natural pharmaceutically acceptable oils, particularly polyoxyethylated olive oil or castor oil. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers, or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0324] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets intended for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavorings or colorings can also be added.

[0325] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0326] The 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.

[0327] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical transdermal patches may also be used.

[0328] For topical application, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient 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 ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0329] For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0330] The 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 using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0331] Most preferably, the pharmaceutically acceptable composition of the present invention is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition of the present invention is administered without food. In other embodiments, the pharmaceutically acceptable composition of the present invention is administered with food.

[0332] The amount of the 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, etc. 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.

[0333] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also depend on the particular compound in the composition.

[0334] The activity of the compounds utilized in the present invention as inhibitors of CXCR4 or its mutants can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine the inhibition of CXCR4 or its mutants. An alternative in vitro assay quantifies the ability of an inhibitor to bind to CXCR4. Detailed conditions for assaying the compounds utilized in the present invention as inhibitors of CXCR4 or its mutants are provided in the Examples below.

[0335] The compounds and compositions according to the methods of the present invention can be administered in any amount and using any route of administration effective for treating or reducing the severity of the diseases or disorders described herein. The exact amount required will vary from subject to subject, depending on the subject's race, age, and general condition, the severity of the disease or disorder, the specific drug, its mode of administration, and the like. The compounds of the present invention are preferably formulated in unit dosage forms for ease of administration and uniformity of dosage. The term "unit dosage form" as used herein refers to a physically discrete unit of drug appropriate for the patient being treated. However, it will be understood that the total daily amount of the compounds and compositions of the present invention to be used will be determined by the attending physician within the scope of sound medical judgment. The specifically effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder and severity of the disorder being treated, the activity of the specific compound used, the specific composition used, the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration, and the excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field. The terms "subject" or "patient", as used herein, mean an animal, preferably a mammal, and most preferably a human.

[0336] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intravesically, intravaginally, intraperitoneally, topically (such as by powders, ointments, or drops), buccally, as an oral spray or nasal drops, etc., depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally, one or more times per day, at dosage levels of about 0.01 mg / kg to about 50 mg / kg of subject's body weight, and preferably about 1 mg / kg to about 25 mg / kg of subject's body weight per day, to obtain the desired therapeutic effect.

[0337] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0338] Injectable preparations, such as injectable aqueous or oleaginous sterile suspensions, can be formulated using suitable dispersing or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be injectable sterile solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating, fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable preparations.

[0339] Injectable preparations can be sterilized prior to use, 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 injectable sterile medium.

[0340] To prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compound forms can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms can be made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the nature of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0341] Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0342] 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, polyvinylpyrrolidone, 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 retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) humectants, 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 forms may also comprise buffering agents.

[0343] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as 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 compounding art. They may optionally contain opacifying agents and can also be composed so as to release the active ingredient(s) solely or preferentially in a certain part of the intestinal tract, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0344] The active compound can also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as 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 compounding art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, these dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and they may be composed to release the active ingredient(s) singly or preferentially in a certain part of the intestinal tract, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0345] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable 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.

[0346] According to one embodiment, the present invention relates to a method for inhibiting CXCR4 activity in a biological sample, comprising the step of contacting said biological sample with a compound of the present invention, or a composition comprising said compound.

[0347] According to another embodiment, the present invention relates to a method for inhibiting the activity of CXCR4 or a variant thereof in a biological sample, comprising contacting the biological sample with a compound of the present invention or a composition comprising said compound. In certain embodiments, the present invention relates to a method for irreversibly inhibiting the activity of CXCR4 or a variant thereof in a biological sample, comprising contacting the biological sample with a compound of the present invention or a composition comprising said compound.

[0348] The term "biological sample," as used herein, includes, but is not limited to, cell cultures or extracts thereof; biopsies obtained from mammals or extracts thereof; and blood, saliva, urine, stool, semen, tears, or other bodily fluids or extracts thereof.

[0349] Another embodiment of the invention relates to a method of inhibiting CXCR4 in a patient, comprising administering to said patient a compound of the invention or a composition comprising said compound.

[0350] According to another embodiment, the present invention provides a method for inhibiting the activity of CXCR4 or a variant thereof in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising said compound. According to certain embodiments, the present invention provides a method for irreversibly inhibiting the activity of CXCR4 or a variant thereof in a patient, the method comprising administering to the 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 variant thereof in a patient in need thereof, the method comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein. Co-administration of additional therapeutic agents

[0351] Depending on the particular condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of the invention or may be co-administered with the CXCR4 of the invention as a separate composition. 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."

[0352] In some embodiments, the present invention provides a method for 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 simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent(s) acts synergistically.

[0353] In some embodiments, the present invention provides a method of treating 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, a BCL-2 inhibitor, or a BH3 mimetic.

[0354] In some embodiments, the BTK inhibitor is selected from tirabrutinib, evobrutinib, fenebrutinib, posertinib, becabrutinib, spebrutinib, LCB03-0110, LFM-A13, PCI29732, PF06465469, (-)-tereic 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.

[0355] In some embodiments, the CXCR4 inhibitor is administered in combination with an effective amount of a BCL-2 inhibitor or a BH3 mimetic; or a pharmaceutically acceptable salt thereof.

[0356] The neural or CNS cancer can be any of those disclosed herein, such as GBM or DLBCL.

[0357] 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 (persitoclax), AT-101, TQB3909, obatoclax, GDC-0199, ABT-737, and navitoclax (ABT-263); or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, the CXCR4 inhibitor is co-administered with venetoclax or a pharmaceutically acceptable salt thereof.

[0359] 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), radiation, methotrexate, dexamethasone, lenalidomide, rituximab, bevacizumab, VEGFR tyrosine kinase inhibitors (TKIs) (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).

[0360] In some embodiments, the additional therapeutic agent is generally selected from agents that can be used for lymphoma and other CNS cancers, including temozolomide, CLR131, glucarpidase, VEGF inhibitors, and radiation therapy.

[0361] In some embodiments, the co-administered therapeutic agent is one useful for treating neurodegenerative diseases, such as lecanemab, aducanumab, donepezil, galantamine, rivastigmine, and memantine for Alzheimer's disease.

[0362] In some embodiments, the co-administered therapeutic agent is one for treating ALS, such as tofersen, riluzole, tiglutik (high concentration riluzole), Exservan™ (riluzole oral film), edaravone, and AMX0035 (Relyvrio®).

[0363] In some embodiments, the co-administered therapeutic agent is one for treating Parkinson's disease, such as electrical stimulation, levodopa, carbidopa, droxidopa, ropinirole, pramipexole, rotigotine, rasagiline, selegiline, safinamide, rivastigmine, apomorphine, amantadine, istradefylline, trihexyphenidyl, benztropine, pimavanserin, tolcapone, opicapone, and entacapone.

[0364] In some embodiments, the co-administered therapeutic agents are 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 inhibitors (INSTIs), attachment inhibitors, post-attachment inhibitors, pharmacokinetic enhancers and combination HIV medications, e.g., abacavir and lamivudine, or abacavir, lamivudine and zidovudine.

[0365] 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.

[0366] In some embodiments, the present invention comprises administering to the patient a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with T cells engineered to express a chimeric antigen receptor, or CAR, such T cells engineered to express a chimeric antigen receptor, referred to as CAR-T cells.

[0367] CARs are constructed that consist of a binding domain, which can be derived from a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, which is a natural ligand, and fused to an endodomain that is the functional end of a T cell receptor (TCR), such as the CD3-zeta signaling domain derived from the TCR, which can generate an activation signal in T lymphocytes. Upon binding to an antigen, such a CAR links to an endogenous signaling pathway in effector cells, generating an activation signal similar to that initiated by the TCR complex.

[0368] For example, in some embodiments, the CAR-T cells are one of those described in U.S. Pat. No. 8,906,682 (incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to include an extracellular domain having an antigen-binding domain (such as a domain that binds to CD19) fused to the intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3-zeta). When expressed in T cells, CARs can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. More than 200 clinical trials are currently underway using CAR-T cells in a wide range of indications [clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0369] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapy can be in the form of a fixed combination, or the compounds of the present invention and one or more other therapeutic compounds can be administered at different times or independently, or a fixed combination can be administered in combination with one or more other therapeutic compounds. The compounds of the present invention can also be administered for tumor treatment in combination with other or additional, inter alia, chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. Long-term treatment, as described above, is equally possible in the context of other treatment strategies, as well as adjuvant therapy. Another possible treatment is, for example, treatment to maintain the patient's condition after tumor regression or even after chemopreventive treatment in at-risk patients.

[0370] These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compound of the present invention in a single composition. When administered as part of a multiple dose regimen, the two active agents may be provided simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0371] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or may be administered together in a single dosage form. Thus, the present invention provides a single dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0372] The amount of either the compound of the present invention and additional therapeutic agent (in compositions containing such additional therapeutic agents) 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, the compositions of the present invention should be formulated so that a dosage of the compound of the present invention that is between 0.01 and 100 mg / kg body weight / day can be administered.

[0373] In compositions containing an additional therapeutic agent, such additional therapeutic agent and the compound of the present invention may act synergistically. Thus, the amount of additional therapeutic agent in such compositions will be less than the amount that would be required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of the additional therapeutic agent between 0.01 and 1,000 μg / kg body weight / day can be administered.

[0374] The amount of additional therapeutic agent present in the compositions of the present 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 disclosed compositions will be in the range of about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0375] The compounds of the present invention or their pharmaceutical compositions can also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents have been used, for example, to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients who use stents or other implantable devices are at risk of clot formation or platelet activation. An implantable device coated with the compounds of the present invention is another embodiment of the present invention. [Example]

[0376] General synthesis method The following examples are intended to illustrate the present invention and should not be construed as limiting thereof. Unless otherwise specified, one or more tautomers of the compounds of the examples described hereinafter may be prepared and / or isolated in situ. All tautomers of the compounds of the examples described hereinafter should be considered disclosed. Temperatures are given in degrees Celsius. Unless otherwise noted, all solvent evaporations are carried out under reduced pressure, preferably between about 15 mmHg and 100 mmHg (= 20-133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characterization, e.g., MS, IR, NMR. Abbreviations used are conventional in the art.

[0377] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art (Houben-Weyl, 4th Edition, 1952, Methods of Organic Synthesis, Thieme, Vol. 21). Additionally, the compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, as shown in the examples below.

[0378] As illustrated in the examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. While the general methods illustrate the synthesis of certain compounds of the present invention, it will be understood that the following general methods, and other methods known to those skilled in the art, can be applied to all compounds as described herein, as well as each subclass and species of these compounds. Synthetic and assay procedures for compounds such as I-1 are described in U.S. Pat. No. 10,759,796, the entire contents of which are incorporated by reference. Abbreviation equiv or eq: molar equivalent o / n: overnight rt: room temperature UV: Ultraviolet HPLC: High-pressure liquid chromatography Rt: retention time LCMS or LC-MS: Liquid Chromatography-Mass Spectrometry NMR: nuclear magnetic resonance CC: Column chromatography TLC: Thin Layer Chromatography sat: saturation aq: aqueous, aqueous solution Ac: Acetyl DCM: dichloromethane DCE: dichloroethane DEA: Diethylamine DMF: dimethylformamide DMSO: dimethyl sulfoxide 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 hexamethyldisilylazide 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-oxide hexafluorophosphate NCS: N-chlorosuccinimide Cy: Cyclohexyl Tol: Toluene 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

[0379] General Information: All solvent evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized by UV light (214 and 254 nm). Column and flash chromatographic purifications were performed using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. 1 All 1 H NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts are reported as δ values ​​in parts per million (ppm) using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integral (i.e., number of protons). LCMS spectra were obtained on an Agilent 1200 Series 6110 or 6120 mass spectrometer using electrospray ionization. Unless otherwise indicated, typical LCMS conditions were as follows: Waters X Bridge C18 column (50 mm × 4.6 mm × 3.5 μm), flow rate: 2.0 mL / min; column temperature: 40 °C.

[0380] General Procedure A (Wolff-Kishner Reduction): A mixture of 2,6-diarylpiperidin-4-one (0.1-1 M concentration), KOH (20 equivalents), and N2H4·HO (40 equivalents) in diethylene glycol was stirred at 80 °C for approximately 2 hours, then at approximately 150-200 °C until the reaction was complete. After cooling 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 vacuo. The residue was purified by column chromatography to afford the 2,6-diarylpiperidine.

[0381] General Procedure B (N-Alkylation of 2,6-Diarylpiperidines): To a solution of 2,6-diarylpiperidine (0.1–1 M concentration) in DMF or ACN under Ar was added the corresponding halide or mesylate (2 equiv.) and K2CO3 (2–3 equiv.). The mixture was stirred at 80 °C overnight. It was then diluted with HO and extracted with DCM. The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to give the desired N-alkylated products.

[0382] General Procedure C (reaction of alcohols with methanesulfonyl chloride): To a solution of alcohol (0.1–1 M concentration) and EtN (approximately 2.5 equiv.) in DCM at −70° C., MsCl (1.2–1.4 equiv.) was added dropwise, and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was then quenched with aqueous NaHCO and extracted with DCM. The combined organic layers were washed with water and brine, dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the corresponding mesylate.

[0383] General Procedure D (reaction of mesylates or halides with 2,6-diarylpiperidines): A mixture of 2,6-diarylpiperidine (0.1-1 M concentration), the corresponding mesylate or halide (approximately 2-3 equiv.), KI (0.2-0.3 equiv.), and DIPEA (2-3 equiv.) in DMF or ACN was stirred overnight at 60-80 °C and filtered. The filtrate was purified by preparative HPLC to give the alkylated 2,6-diarylpiperidine.

[0384] General Procedure E (Reaction of aryl aldehydes with acetone to give 4-(heteroaryl or aryl)but-3-en-2-ones): A mixture of the corresponding aryl aldehyde (0.1–1 M concentration), acetone (20 equiv.), and KCO (1.5–2 equiv.) in toluene / EtOH / HO (5:2:1) was stirred at 80 °C for approximately 13 h and cooled to room temperature. After dilution with EA, the reaction mixture was filtered through a basic silica gel column and washed with DCM / MeOH (100 / 1). The filtrate was concentrated in vacuo to give 4-(heteroaryl or aryl)but-3-en-2-ones, which were used in the next step without further purification.

[0385] General Procedure F (Reaction of aryl aldehydes with acetone to give 4-(heteroaryl or aryl)but-3-en-2-ones): To a mixture of aryl aldehydes in acetone (0.1-1 M concentration) at 0 °C was added a solution of NaOH in HO (approximately 8 M, 1.5 equiv.). The mixture was stirred at 0 °C for 1 h. It was then warmed to room temperature and stirred for an additional 2 h. The solution was adjusted to pH 8 with 35% aqueous HCl, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give 4-(heteroaryl or aryl)but-3-en-2-ones.

[0386] General Procedure G (Buchwald coupling of aryl bromides with alkylamines): A mixture of aryl bromide (0.1-1 M concentration), alkylamine (2 equivalents, 0.2-2 M), Pd(OAc) (0.1-0.15 equivalents), BINAP (0.2-0.3 equivalents), and CsCO (2-4 equivalents) in toluene was stirred overnight at 75-120 °C. Upon completion, the reaction mixture was concentrated in vacuo and purified by column chromatography to give the desired product.

[0387] General Procedure H (Suzuki coupling of aryl bromides with arylboronic acids): Aryl bromide (0.1–1 M concentration), arylboronic acid (1.1–1.5 equiv.), PdCl(dppf) (0.05–0.08 equiv.), and aqueous NaCO (1 M, 2.5 equiv.) in 1,4-dioxane were stirred at 80–100 °C for 10 min under microwave irradiation. After the reaction was complete, the mixture was diluted with water, and the aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated in vacuo, and the residue was purified using a silica gel column.

[0388] General Procedure I (reductive amination of secondary amines to tertiary amines): To a mixture of a secondary amine (0.1-1 M concentration), the corresponding aldehyde or ketone (1-2 equiv.), and NaBH(OAc)3 (3-6 equiv.) in DCM, a few drops of acetic acid were added, and the mixture was stirred at room temperature for 2-18 h. The mixture was neutralized with saturated aqueous NaHCO3 to pH = 8-9 and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the desired tertiary amine.

[0389] General Procedure J (Boc cleavage of N-Boc-protected amines): To a solution of N-Boc-protected amine in DCM (0.1-1 M concentration) was added TFA (1 / 15 volume of DCM) at room temperature. The reaction mixture was stirred for 2 h, then concentrated. Saturated aqueous NaHCO3 was added, and the mixture was extracted with DCM. The organic extract was dried over Na2SO4, filtered, and concentrated to give the free amine as the desired product.

[0390] General Procedure K: (Halogenation of imidazo[1,2-a]pyridines to obtain 3-halogenated imidazo[1,2-a]pyridines): A mixture of an imidazo[1,2-a]pyridine derivative (concentration: 0.1-1 M) and NBS or NCS (0.8-0.9 equiv.) in DCM (10 mL) was stirred at room temperature for 1 h. After the reaction was complete, the suspension was diluted with water and DCM, and the separated organic layer was concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product. Example 1 Synthesis of I-1 Synthesis scheme of I-1 [ka]

[0391] Synthesis of 1.2: General procedure E was followed to give 1.2 (1.9 g, 41%) as a yellow foam, which was used in the next step without further purification. LCMS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm* 4.6mm * 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under these conditions for 0.7 min). Purity: 69.13%; Rt = 1.38 min; MS calculated: 284.4; MS found: 285.4 [M+H] + .

[0392] Synthesis of 1.3: To a solution of 1.2 (1.4 g, 4.9 mmol) in MeOH (20 mL), L-proline (227 mg, 1.97 mmol), 3-methylpicolinaldehyde (656 mg, 5.4 mmol), and aqueous MeNH (1.5 g, 40 wt%, 19.72 mmol) were added sequentially. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by column chromatography to give the cis / trans mixture of 1.3 (mg, 50%) as a yellow foam, which was used in the next step without further purification. The cis / trans mixture of 1.3 (270 mg, 0.65 mmol) was purified by preparative TLC to give 1.3 (30 mg, 11%) as a white solid. LCMS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50 mm * 4.6mm * 3.5 μm); Column temperature: 40°C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under these conditions for 1.4 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under these conditions for 0.7 min.) 1.3: Purity: 92.86%. Rt = 1.49 min (trans), 1.52 min (cis); MS calculated: 418.3; MS found: 419.4 [M+H] +HPLC (Agilent HPLC1200, column: Waters X-Bridge C18 (150 mm) * 4.6mm * 3.5 μm); Column temperature: 40 °C; Flow rate: 1.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under these conditions for 5 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, and under these conditions for 5 min). Purity: 97.88%. Rt = 4.90 min. 1 H 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 = 8.8Hz, 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).

[0393] Synthesis of I-1: According to general procedure A, a mixture of the 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 at 80 °C for 2 h and then at 150 °C for 5 h. After cooling 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 vacuo. The residue was purified by column chromatography to give 276 mg of crude I-1, which was purified by preparative HPLC to give 80 mg of I-1 as a white solid. LCMS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50 mm) * 4.6mm * 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under these conditions for 0.7 min). Purity: 96.44%. Rt = 1.66 min; MS calculated: 404.3; MS observed: 405.4 [M+H] + HPLC (Agilent HPLC1200; column: L-column 2 ODS (150 mm) * 4.6mm * 5.0 μm); Column temperature: 40 °C; Flow rate: 1.0 mL / min; Mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 10 min to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then under these conditions for 5 min, and finally under 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 0.1 min, and under these conditions 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 Synthesis scheme of I-4 [ka]

[0394] 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 (50 mm) * 4.6mm * 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under these conditions for 0.7 min). Purity: 92.35%; Rt = 1.81 min; MS calculated: 504.7, MS found: 505.7 [M+1] + .

[0395] 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 (50 mm) *4.6mm * 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under these conditions for 0.7 min). Purity: 93.71%; Rt = 1.99 min; MS calculated: 490.7, MS found: 491.7 [M+1] + .

[0396] 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 (50 mm) * 4.6mm * 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under these conditions for 0.7 min). Purity: 99.8%; Rt = 1.48 min; MS calculated: 390.7; MS found: 391.7 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2 ODS (150 mm) * 4.6mm *5.0 μm); Column temperature: 40 °C; Flow rate: 1.0 mL / min; Mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 10 min to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then 5 min under these conditions, and finally 0.1 min to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA], and 5 min under these conditions. Purity: 98.8%; Rt = 4.362 min; MS calculated: 390.7; MS found: 391.7 [M+H] + . 1 H 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 Synthesis scheme of I-11 [ka]

[0397] Synthesis of I-11: A mixture of I-1 (120 mg, 0.3 mmol) and acetic acid (0.5 mL) in 37% aqueous formaldehyde (10 mL) was stirred at 50° C. for 24 h. Then, 37% aqueous formaldehyde (5 mL) was added, and the mixture was stirred at 50° C. for an additional 48 h. After the reaction was complete, the suspension was adjusted to pH 8 with saturated aqueous sodium carbonate and extracted with DCM (20 mL). The organic layer was concentrated in vacuo, and the residue was purified by preparative HPLC to give I-11 (90 mg, 70% yield) as a white solid. LCMS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50 mm) * 4.6mm * 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under these conditions for 0.7 min). Purity: 99.25%; Rt = 1.54 min; MS calculated: 434.3; MS found: 435.3 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2 ODS (150 mm) * 4.6mm * 5.0 μm); Column temperature: 40 °C; Flow rate: 1.0 mL / min; Mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 10 min to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then changed to these conditions for 5 min, and finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 0.1 min, and then changed to these conditions 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). Example 4 Synthesis of I-187 Synthesis scheme of I-187 [ka]

[0398] Synthesis of X4-438-1. A mixture of 4.1 (2.5 g, 8.8 mmol), 3-methylpicolinaldehyde (1.1 g, 8.8 mmol), and K2CO3 (1.8 g, 13.2 mmol) in toluene (100 mL), EtOH (40 mL), and H2O (20 mL) was stirred at 80 °C overnight. After the reaction was complete, the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified on a flash silica gel pad (3 cm) eluted with 1:1 EtOAc:petroleum ether to 100:1 DCM / MeOH to give 2.3 g of 4.2 as a yellow foam (68% yield), which was used directly in the next step. LCMS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm) * 4.6mm *3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under these conditions for 0.7 min). Purity: 77.36%; Rt = 1.59 min; MS calculated: 387.2; MS found: 388.3 [M+H] + .

[0399] Synthesis of I-204. To a solution of 4.2 (2.3 g, 5.9 mmol) in MeOH (120 mL), concentrated aqueous NH3 (5 mL, 20%, 59 mmol) was added at room temperature, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated in vacuo and purified by flash silica gel pad (3 cm) eluted with DCM / MeOH = 60 / 1 to 30 / 1 to give 1 g of I-204 as a yellow foam (yield: 42%), which was used directly in the next step. LCMS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm) * 4.6mm * 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under these conditions for 0.7 min). Purity: 78.15%; Rt = 1.41 min; MS calculated: 404.2; MS found: 405.4 [M+H] + .

[0400] Synthesis of I-187 [ka]

[0401] 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 heated to 160 °C to remove N2H4·H2O in vacuo, and stirred at 160 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with H2O (90 ml) / DCM (120 ml). The aqueous layer was extracted with DCM (120 ml × 3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by CC (eluted with DCM / MeOH) to give 220 mg of cis-I-187 (220 mg) (racemic), 400 mg of a mixture of cis / trans-I-187 (400 mg, trans:cis = 4:5) (racemic), and 270 mg of trans-I-187 (270 mg) (racemic). Yield = 91%. LCMS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50 mm) * 4.6mm * 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under these conditions for 0.7 min. (Cis: Purity: 71.18%; Rt = 1.51 min; Trans: Purity: 64.10%; Rt = 1.48 min; Mixture: Purity: 84.07%; MS calculated: 390.3; MS found: 391.4 [M+H] + . Example 5 Distribution of Compound I-1 in the brain, plasma, and CSF of cynomolgus monkeys, rats, and beagle dogs

[0402] Compound I-1 was administered to three male cynomolgus monkeys by oral gavage every day for 8 days (vehicle is 50mM citrate buffer, pH 4.0; formulation concentration 10mg / mL; dose volume 1mL / kg; dose level 10mg / kg / day).Animals were allowed free access to water and fasted on the morning of administration, and food was sampled and resumed 2 hours later.

[0403] Blood, CSF, and brain samples were obtained from individually terminated animals at 4, 24, and 72 hours after the last dose. Blood samples collected in pre-chilled EDTA-K2 tubes were processed to plasma within 15 minutes by centrifugation at 2000 g for 10 minutes at approximately 4°C.

[0404] For plasma, a 20 μL aliquot of sample was thoroughly mixed with 40 μL of formic acid solution (5% in water) followed by 200 μL of glipizide internal standard (50 ng / mL in CHCN). The mixture was vortexed for 10 minutes and centrifuged at 5800 rpm for 10 minutes.

[0405] For CSF, a 10 μL aliquot of sample was diluted with 40 μL of blank plasma (dilution factor 5). 20 μL of sample was thoroughly mixed with 40 μL of formic acid solution (5% in HO) followed by 200 μL of glipizide internal standard (50 ng / mL in CHCN). The mixture was vortexed for 10 minutes, centrifuged at 5800 rpm for 10 minutes, and 70 μL of the supernatant was thoroughly mixed with 40 μL of HO.

[0406] For the brain, 1-5 mm cross-sections of brain tissue were homogenized with 3 volumes (v / w) of PBS (dilution factor 4). 10 μL of the sample was thoroughly mixed with 30 μL of NH4OH solution (10% in HO) followed by 200 μL of glipizide internal standard (50 ng / mL in CH3CN). The mixture was vortexed for 10 minutes, centrifuged at 5800 rpm for 10 minutes, and 70 μL of the supernatant was thoroughly mixed with 40 μL of HO.

[0407] Compound I-1 in the supernatant was quantified 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+ Q1 405.20 Da, Q3 374.20 Da; mobile phase A 0.025% FA, 1 mM NHOAc in HO; mobile phase B 5 mM NHOAc in MeOH; linear gradient from 2 to 95% mobile phase B over 42 s, followed by 95% mobile phase B for 30 s; retention time 1.11 min.

[0408] The concentrations of compound I-1 in plasma, CSF, and brain were determined absolutely by reference to a calibration curve (5% MeOH) of 1.00-3000 ng / mL of compound I-1 in cynomolgus monkey plasma, 1.00-3000 ng / mL of compound I-1 in cynomolgus monkey CSF, or 3.00-3000 ng / g of compound I-1 in cynomolgus monkey brain homogenate, respectively.

[0409] Figure 1 shows brain, plasma, and cerebrospinal fluid (CSF) exposure levels of compound I-1 in male cynomolgus monkeys 8 days after oral administration at 10 mg / kg QD (measured 4, 24, and 72 hours after the last dose; individually terminated animals; 50 mM citrate buffer, pH 4.0). Brain histopathology in all monkeys was normal 7–8 days after QD administration at 10 mg / kg or 100 mg / kg (data not shown). No leukocyte infiltration or lesions in the brain were observed, even at high exposures. [Table 2]

[0410] Compound I-1 distributes favorably to the brain of cynomolgus monkeys (brain:plasma ratio of 5:1 or higher). A high brain exposure of approximately 400 ng / g was achieved, which persisted with slow clearance for 72 hours after administration. No visible lesions were observed during histopathological analysis. The profile of this compound supports its use in diseases where sustained brain exposure of the drug is required for efficacy.

[0411] Compound I-1 exhibited linear PK after repeated dosing (7 days, QD administration) as shown below: fasted administration; iv: 1 mpk; po: 3, 10, 30 mpk; citrate buffer formulation; male cynomolgus monkeys. [Table 3] *PK data excluding outlier monkeys (#1602353) @ 3 mpk: C max = 66.1 ng / mL; 24時間時の C trough = 16.4 ng / mL; AUC last = 530*ng / mL; F = 19.2% + T max There are only two time points available after T 1 / 2 is C max Later time points were not calculated due to limited time available.

[0412] As shown below and in Figure 9, we investigated the mean plasma concentration-time profile of compound I-1 in male SD rats (N=3 / time point) after a single PO dose of 10 mg / kg of the free base of compound I-1, and 0.3, 1, 3, and 10 mg / kg of the HCl salt of compound I-1, respectively. Administration in fasted SD rats: 0.3, 1, 3, 10 mpk po in HCl saline solution; or 10 mpk free base in saline w / tween®. The calculated t1 / 2 was 6 hours. BLQ or BQL = below the limit of quantification. [Table 4]

[0413] As shown below, compound I-1 inhibited T max is about 1.3 hours, T 1 / 2 It takes about 15 hours, and C max , C trough and AUC showed linear PK. [Table 5] *PK data excluding outlier monkey (#1602353) @ 3 mpk: Cmax = 44.2 ng / mL; Ctrough at 24 hours = 8.9 ng / mL; AUClast = 371.5 ng / mL; F = 18.6%

[0414] We observed sustained brain exposure in rats treated with a single oral dose of compound I-1. As shown in the table below, the compound distributes favorably in the brain (brain:plasma ratio 12:1), and the clearance rate is exposure-dependent. [Table 6] [Table 7] [Table 8]

[0415] Histopathology of the rat brains did not reveal any visible lesions or abnormal findings. Exposure increased in the brain after multiple days of dosing. Rats given 10 mpk PO daily for 3 days had increased brain exposure from 66.2 ng / g to 136 ng / g.

[0416] Beagle dogs were administered compound I-1 (PO) every day for 14 days. Histopathological examination of the brains of all male and female dogs from the 45mpk group revealed no visible lesions. Compound concentrations are shown in the table below. [Table 9] a One female euthanized on day 8 had a "brain concentration" of 4130 ng / mL; other females in this group were not evaluated. Example 6 Combination effects of compound I-1 with BTK and BCL-2 inhibitors

[0417] Apoptosis assay: OCI-LY19 cells were cultured at 2 × 10 in RPMI-1640 medium (Fisher Scientific, #32404-014) containing 10% fetal bovine serum (FBS) (Sigma-Aldrich, #F7524) supplemented with 100 U / mL penicillin-streptomycin (Gibco™, Thermo Fisher Scientific, #11548876). 5 Cells were seeded into 96-well plates at a density of 1000 cells / ml and incubated with various concentrations of compound I-1 alone or in combination with the BTK inhibitors ibrutinib (MedChemExpress, #HY-10997 / CS), zanubrutinib (MedChemExpress, #HY-101474A), or the B-cell lymphoma 2 (BCL2) inhibitor venetoclax (MedChemExpress, #HY-15531) at 37°C and 5% CO for 72 hours. After 72 hours, cells were washed with PBS, resuspended in Annexin V binding buffer (BioLegend, #422201), 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.

[0418] Cultures of OCI-LY19, a DLBCL cancer cell line, were exposed to various concentrations of compound I-1 and ibrutinib (a BTK inhibitor), zanubrutinib (a BTK inhibitor), or venetoclax (a BCL-2 inhibitor). The results are shown in Figure 2. A dose-dependent increase in the percentage of apoptotic cells was observed. Compound I-1 at a concentration of 1 μM showed a potent and near-maximal effect when combined with ibrutinib. This combination showed a surprisingly large improvement over ibrutinib alone (lower data series). The combination of compound I-1 with zanubrutinib or venetoclax demonstrated increased cell death compared to zanubrutinib or venetoclax alone. Example 7 Effect of compound I-1 on migration of DLBCL cells and various immune cells

[0419] Cell migration assay: OCI-LY19 cell migration to CXCL12 was determined using a Transwell migration assay. OCI-LY19 cells were stained with 500 nM calcein AM (Invitrogen, #C1430) and pre-incubated with compound I-1 for 15 min before being transferred to the upper well of a 5.0 μM pore size Transwell® (Corning, #3421) (5×10 5 The lower chamber contained CXCL12 (30 nM) in medium supplemented with 1% FBS. After 4 hours of incubation, cells that had migrated to the lower chamber 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.

[0420] Peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) were isolated from heparinized blood samples using Ficoll-Paque Plus (Amersham Biosciences, Uppsala, Sweden) density gradient centrifugation according to the manufacturer's instructions. Freshly isolated PBMCs and PMNs were cultured at 2.0 × 10 in chemotaxis buffer (RPMI 1640 medium containing 20 mM HEPES, L-glutamine, and 0.5% BSA). 6 Cells were pretreated with the indicated concentrations of compound I-1 for 30 min at 37°C, 5% CO2, and resuspended at 1.0 x 10 cells / mL. Cells were pretreated with the indicated concentrations of compound I-1 for 30 min at 37°C, 5% CO2. 1.0 x 10 cells in 100 μL were injected into the upper chamber of a Transwell 24-well plate (Corning Life Sciences, Corning, NY, USA) separated by a 6.5 mm insert with 3 μm pores from the lower chamber containing 600 μL of buffer with 10 nM CXCL12. 5 Chemotaxis assays were performed immediately after drug treatment by placing cells in the lower chamber. After 2.5 hours of incubation at 37°C in a 5% CO2 incubator, cells that migrated to the lower chamber were collected by centrifugation and resuspended in assay buffer. Cells were blocked for 10 minutes at room temperature using human TruStain FcX (BioLegend, Inc.), followed by lymphocyte subtyping. 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) was added to each sample. Both migrated cells and counting beads were counted by flow cytometry (CytoFLEX). Data was analyzed using FCS Express software to calculate the total number of migrated cells according to the count and total number of beads present in the sample.

[0421] OCI-LY19 cells express high levels of CXCR4 (data not shown). These cells are known to migrate toward CXCL12, a CXCR4 ligand. As shown in Figure 3, compound I-1 effectively inhibited the migration of OCI-LY19 cells. This suggests that compound I-1 and similar compounds are effective in preventing the migration of DLBCL cells into CXCL12-producing niches.

[0422] Figure 4 shows the inhibition of CXCL12-CXCR4-mediated migration of various types of immune cells by compound I-1. Immune cells were isolated from whole blood from healthy donors (N=3, CXCL12 10 nM; assay time frame=3 hours).

[0423] Figure 5 shows the inhibition of CXCL12-CXCR4-mediated migration of various types of immune cells by compound I-1. Immune cells were isolated from whole blood from healthy donors (N = 3, CXCL12 10 nM; assay time frame = 3 hours). Example 8 Dietary effects of compound I-1 in beagle dogs

[0424] As shown in Figure 10 and the table below, the inventors investigated the plasma exposure and food effect of compound I-1 in beagle dogs. As can be seen, under fasting conditions, the compound showed 48% oral bioavailability, while under fed conditions, the compound showed 88% oral bioavailability. Fed: Animals were given food 1 hour before administration and had free access to water. Fasted: Animals were not given food on the morning of administration, and food was sampled and resumed 4 hours later, and water was available ad libitum. [Table 10] Example 9 Compound I-1 inhibits glioblastoma cell proliferation in vitro

[0425] CXCR4 is the primary chemokine receptor on the surface of 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) for GBM patients is only 15 months. GBM includes astrocytic tumors (astrocytoma, anaplastic astrocytoma, and glioblastoma), oligodendroglioma, ependymoma, and mixed glioma. The incidence of GBM is 3.19-4.17 cases per 100,000 people per year. Genetic and molecular etiologies include ATRX (α-thalassemia / X-linked mental retardation syndrome) mutations; TERT (telomerase reverse transcriptase) promoter mutations; TP53 (tumor protein P53) mutations; B-RAF V600E mutations; EGFR mutations and amplifications; and PDGFA / PDGFRa overexpression. Conventional treatments include surgery, radiation therapy, and chemotherapy (temozolomide). However, one of the greatest challenges to developing effective new therapies is the inability of the above to cross the blood-brain barrier.

[0426] CXCR4 is overexpressed in both GBM and GSCs and influences GBM malignancy, grade, invasiveness, and poor prognosis. GBM patients with high CXCR4 expression have reduced survival rates. GSCs express both CXCL12 and CXCR4, which induces an autocrine loop, leading to activation of the PI3K-MAPK-ERK1 / 2 signaling pathway for cell survival. CXCL12 / CXCR4 signaling contributes to tumor resistance / invasiveness in GBM. There is some support for a common mechanism of action for CXCR4 antagonists to treat GBM. For example, the combination of AMD3100 with the MDM2 / 4 inhibitor RS3594 further reduces GBM cell growth and invasiveness. Daniele, S. et al. 2021; see 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 / .

[0427] We investigated the IC value of compound I-1 against two glioblastoma cell lines expressing CXCR4 and BTK. 50 The 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 growth inhibition was measured after 96 hours of treatment with CellTiter Glo. ATP was used as a readout for cell viability (an indicator of metabolically active cells). Staurosporine was used as a positive control: U87 (IC 50=0.15uM), T-98(IC 50 =0.002uM), U251(IC 50 =0.003uM). Compound I-1 had an IC of 1.67uM 50 Compound I-1 inhibited U251 cells with an IC of 6.47 μM. 50 inhibited U87 cells. Example 10 Beneficial role of CXCR7 agonism on astrocytes in maintaining healthy neurons

[0428] CXCR7, or atypical chemokine receptor 3, is a non-classical seven-transmembrane receptor expressed in the hematopoietic system, heart, vascular endothelial cells, bone, kidney, and brain. CXCR7 has approximately 10-fold higher binding affinity for CXCL12 than CXCR4, and further binds interferon-induced T cell alpha chemoattractant (I-TAC, CXCL11) as a secondary 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). Several studies have shown that CXCR7 mediates both classical G protein-mediated signaling and typical chemokine-induced Ca signaling. 2+It has been shown that CXCR7 does not trigger the release of CXCL-12. CXCR7 functions as a scavenger receptor for its cognate ligand and, in this 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 associates with CXCR4, leading to alterations in CXCR4 signaling and cellular function (Levoye, A., et al., "CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling." Blood. 2009; 113, 6085-6093). Furthermore, several studies have demonstrated that CXCR7 can independently induce cell signaling via β-arrestins 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. USA 2010; 107, 628-632; Chen, Q., et al. "CXCR7 mediates neural progenitor cell migration to CXCL12 independent of CXCR4." Stem Cells 2015; 33, 2574-2585). These findings suggest that the biological function of CXCR7, its signaling, and further effects may depend on the cell type examined.

[0429] Astrocytes, the major type of glial cell, are involved in various hematopoietic processes in the CNS. One of the most important astrocyte functions is to deliver energy to neurons via the astrocyte-neuron lactate shuttle. Astrocytes also mediate Ca release, which influences neuronal activity and releases gliotransmitters. 2+ Furthermore, astrocytes also connect to blood vessels in the brain and transport nutrients to neurons and other cells (Belanger, 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 the central nervous system: A mixed blessing.” Cell Prolif. 2020 Mar;53(3):e12781). Interestingly, in astrocytes, CXCR7 can couple with Gi / o proteins, which subsequently regulate intracellular Ca2+ levels. 2+It has been shown that CXCR7-dependent Gi / o signaling increases SDF-1 release and induces cell signaling (i.e., Erk and Akt signaling). Furthermore, CXCR7-dependent Gi / o signaling has been reported to regulate astrocyte proliferation and migration (Odemis, V., et al. "CXCR7 is an active component of SDF-1 signaling in astrocytes and Schwann cells". J Cell Sci. 2010 Apr 1;123(Pt 7):1081-8). Furthermore, A1 astrocytes have been shown to contribute to the development of chronic postoperative pain syndrome (CPSP), while A2 astrocytes have advantages in alleviating CPSP. Recently, it has been demonstrated that microglia induce astrocyte conversion to the A1 phenotype in the spinal cord by reducing the activation of the CXCR7 / PI3K / Akt signaling pathway during CPSP. Therefore, for example, reverting A1-reactive astrocytes to A2 astrocytes by activating the CXCR7 receptor may be a novel 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 plays an important role in regulating astrocyte proliferation, migration, and activation, which may contribute to maintaining nervous system health. Agonism of the CXCR7 receptor on astrocytes by compounds of the present invention, including compound I-1, promotes a neuroprotective phenotype of astrocytes, which is expected to alleviate or prevent neurodegenerative diseases such as, but not limited to, ALS.

[0430] Assay Procedure:

[0431] GPCR arrestins

[0432] Prior to testing, 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. For agonist and inverse agonist determinations, 5 μL of an intermediate dilution (5x) of the sample stock was added to the cells and incubated at 37°C or room temperature for 90–180 minutes. For allosteric determinations, 5 μL of an intermediate dilution (5x) of the sample stock was added to the cells and incubated at 37°C or room temperature for 30 minutes. Subsequently, 5 μL of the EC20 agonist in assay buffer was added to the cells and further incubated at 37°C or room temperature for an additional 90 or 180 minutes. For antagonist determinations, cells were preincubated with the antagonist for 30 minutes and then challenged with the agonist at the EC80 concentration for an additional 90 or 180 minutes at 37°C or room temperature. The vehicle concentration was 1%. At the end of the incubation, 12.5 or 15 μL (50% v / v) of PathHunter detection reagent cocktail was added to the cells and further incubated for 1 hour at room temperature. Chemiluminescent signals were measured using a PerkinElmer Envision™ instrument. Compound activity was analyzed using the CBIS data analysis suite (ChemInnovation, CA).

[0433] For the agonist mode assay, the percent activity was calculated using the following formula: % activity = 100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean maximum control ligand - mean RLU of vehicle control).

[0434] For the inverse agonist mode assay, the percent activity was calculated using the following formula: % Inverse Agonist Activity = 100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of vehicle control)).

[0435] For positive allosteric mode assays, the modulation rate was calculated using the following formula: % Modulation = 100% x ((mean RLU of test sample - mean RLU of EC20 control) / (mean RLU of maximum control ligand - mean RLU of EC20 control)).

[0436] For antagonist and negative allosteric mode assays, the percentage of 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)).

[0437] The table below shows the efficacy of compound I-1 in recruiting β-arrestin to CXCR7 (EC50 0.032 nM for compound I-1 and EC50 0.012 nM for CXCL12), suggesting that compound I-1 may have an agonistic effect on the CXCR7 receptor. [Table 11]

[0438] While the inventors have described several embodiments of the present invention, it is clear that the inventors' basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present invention. It will therefore be understood that the scope of the present invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. The complete disclosures of all patents, scientific references and other references cited herein are incorporated herein by reference for the teachings and disclosures in which they are cited.

Claims

1. A method for treating or reducing the severity and symptoms of a neurological disorder or disease of the central nervous system (CNS), comprising administering to a subject in need thereof an effective amount of compound I-1: 【Chemistry 48】 or a pharmaceutically acceptable salt thereof, wherein the CNS neurological disorder or disease is amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, Wilson's disease, dementia with Lewy bodies, frontotemporal dementia (FTD), cerebral palsy, Bell's palsy, progressive supranuclear palsy, HIV-associated dementia (HAND), epilepsy, tremor and seizure disorders, catalepsy, motor inhibition disorders, paralysis and muscle rigidity, spina bifida, anencephaly, encephalocele ... encephalitis, myelopathy, migraine, cerebral ischemia, ischemia, stroke, cerebellar ataxia, Friedreich's ataxia, Creutzfeldt-Jakob disease, atherosclerosis, motor neuron disease (MND), locked-in syndrome, restless legs syndrome, arachnoid cyst, sciatica, thalassemia, intracerebral hemorrhage, subarachnoid hemorrhage, muscular sclerosis, tardive dyskinesia, Charcot-Marie-Tooth disease (CMT), thrombosis, microembolization, sickle cell disease, and vaso-occlusive crisis (VOC).

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

3. 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, dementia with Lewy bodies, frontotemporal dementia (FTD), HIV-associated dementia (HAND), progressive supranuclear palsy, Friedreich's ataxia, Creutzfeldt-Jakob disease, motor neuron disease (MND), and Charcot-Marie-Tooth disease (CMT).

4. 3. 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. 3. The method of claim 2, wherein the neurodegenerative disease is ALS.

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

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

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

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

10. 9. The method of claim 8, wherein the CNS infection is selected from an enterovirus, an arbovirus, and a herpesvirus infection.

11. 9. The method of claim 8, wherein the CNS infection is selected from 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, influenza virus, rabies, mumps, measles, and West Nile virus infection.

12. 9. The method of claim 8, wherein the CNS infection is a bacterial infection.

13. 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. 2. The method of claim 1, wherein the neurological disorder or disease of the CNS is selected from addiction, neuronal damage caused by 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 affecting the CNS.

15. 10. The method of claim 1, wherein the CNS neurological disorder or disease is selected from neurodegeneration, neuromuscular disorders, ischemia, neuroinflammation, autoimmune disorders, anxiety disorders, and pain, and wherein the CNS neurological disorder or disease results from a traumatic head or brain injury, spinal cord injury, or other medical condition involving neuronal loss, damage, and / or degeneration.

16. 10. The method of claim 1, wherein the CNS neurological disorder or disease is selected from stroke, thrombosis, and microembolization.

17. 10. The method of claim 1, wherein the microembolization is microembolization in a COVID patient.

18. A method for treating or alleviating pain, comprising administering to a subject in need thereof an effective amount of compound I-1: 【Chemistry 49】 or a pharmaceutically acceptable salt thereof.

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

21. 19. The method of claim 18, wherein the pain is selected from neuralgia, diabetic neuropathy, human immunodeficiency virus-associated neuropathy, nerve injury, rheumatoid arthritis pain, osteoarthritis pain, burns, lower back pain, eye pain, visceral pain, cancer pain, toothache, 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. 19. The method of claim 18, wherein the pain is nociceptive pain and is selected from the group consisting of central nervous system trauma, strain / sprain, burns, myocardial infarction, acute pancreatitis, post-operative pain, post-traumatic pain, renal colic, pain associated with vaso-occlusive crisis (VOC), cancer pain, and lower back pain.

23. 21. The method of claim 20, wherein the neuropathic pain is selected from the group consisting of peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, low 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.

24. 21. The method of claim 20, wherein the neuropathic pain is associated with a pain disorder selected from the group consisting of arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorders, hypoesthesia, hyperalgesia, neuralgia, neuritis, neuropathic pain, analgesia, anesthesia dolorosa, causalgia, sciatica disorders, degenerative joint disorders, fibromyalgia, visceral diseases, chronic pain disorders, migraine / headache pain, chronic fatigue syndrome, complex regional pain syndrome, neurological dystrophy, plantar fasciitis, and pain associated with cancer.

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

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

27. 19. The method of claim 18, wherein the pain is selected from cardiovascular pain, pain caused by angina pectoris, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma, musculoskeletal ischemia, cephalic pain, migraine, cluster headache, tension-type headache, mixed headache, headache associated with vascular disorders, orofacial pain, toothache, earache, burning mouth syndrome, and temporomandibular joint myofascial pain.

28. A method for treating or reducing neuroinflammation, comprising administering to a subject in need thereof an effective amount of compound I-1: [Transformation 50] or a pharmaceutically acceptable salt thereof.

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

30. 29. The method of claim 28, wherein the neuroinflammation is associated with leukocyte invasion into the brain of the subject.

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

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

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

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

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

36. 33. The method of claim 32, wherein the neuroinflammation is associated with 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, influenza virus, rabies, mumps, measles, or West Nile virus infection.

37. 33. The method of claim 32, wherein the neuroinflammation is associated with a bacterial infection.

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

39. 1. A method for treating nerve or central nervous system (CNS) cancer, comprising administering to a subject in need thereof an effective amount of compound I-1: 【Chemistry 51】 or a pharmaceutically acceptable salt thereof.

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

41. 40. The method of claim 39, wherein the nerve 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 tumor, primitive neuroectodermal (PNET) tumor, or schwannoma.

42. 40. The method of claim 39, wherein the nerve or CNS cancer is GBM.

43. 40. The method of claim 39, wherein the neural or CNS cancer is a CNS lymphoma.

44. 44. The method of claim 43, wherein the CNS lymphoma is a primary CNS lymphoma.

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

46. 45. The method of claim 44, wherein the primary CNS lymphoma is Burkitt's or T-cell lymphoma.

47. 44. The method of claim 43, wherein the CNS lymphoma is a secondary CNS lymphoma.

48. 48. The method of claim 47, wherein the secondary CNS lymphoma is DLBCL.

49. 48. The method of claim 47, wherein the secondary CNS lymphoma is Burkitt's or T-cell lymphoma.

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

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

52. 52. The method of claim 51, wherein compound I-1 is administered to the subject in a fed state.

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