Compositions of cxcr4 inhibitors and methods of making and using

Abstract

The present application provides compositions and methods of use for treating, preventing or ameliorating diseases, disorders or conditions associated with chemokine receptors (e.g., CXCR4).

Description

Technical Field

[0001] This invention relates to compounds that inhibit type 4 CXC receptor (CXCR4). The invention also provides pharmaceutically acceptable compositions comprising the compounds of this invention, and methods of treating various conditions using said compositions.

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62,726,010, filed August 31, 2018, and priority to U.S. Patent Application No. 16 / 215,963, filed December 11, 2018, each of which is incorporated herein by reference in its entirety. Background Technology

[0004] The type 4 CXC chemokine receptor (CXCR4), also known as fusionin or differentiation cluster 184 (CD184), is a seven-transmembrane G protein-coupled receptor (GPCR) belonging to the class I GPCR or rhodopsin-like GPCR family. Under normal physiological conditions, CXCR4 performs multiple roles and is primarily expressed in the hematopoietic and immune systems. CXCR4 was initially discovered as one of the co-receptors involved in the entry of human immunodeficiency virus (HIV) into cells. Subsequent studies have shown its expression in many tissues, including the brain, thymus, lymphoid tissue, spleen, stomach, and small intestine, as well as in specific cell types such as hematopoietic stem cells (HSCs), mature lymphocytes, and fibroblasts. CXCL12, formerly known as SDF-1α, is the only known CXCR4 ligand. During embryonic development and as a response to injury and inflammation, CXCR4 mediates stem cell migration. CXCR4 has been demonstrated to play multiple roles in human diseases such as proliferative disorders, Alzheimer's disease, HIV, rheumatoid arthritis, and pulmonary fibrosis. For example, the expression of CXCR4 and CXCL12 has been observed in several tumor types. CXCL12 is expressed by cancer-associated fibroblasts (CAFs) and is often present at high levels in the tumor microenvironment (TME). In clinical studies across a wide variety of tumor types, including breast, ovarian, kidney, lung, and melanoma, CXCR4 / CXCL12 expression has been associated with poor prognosis and an increased risk of metastasis to lymph nodes, lung, liver, and brain (sites of CXCL12 expression). CXCR4 is frequently expressed on melanoma cells, particularly on the CD133+ population considered representative of melanoma stem cells; in vitro experiments and mouse models have demonstrated the chemotactic effect of CXCL12 on these cells.

[0005] Furthermore, existing evidence suggests that the CXCL12 / CXCR4 axis causes a loss or absence of tumor response to angiogenesis inhibitors (also known as "angiogenesis evasion"). In animal cancer models, interference with CXCR4 function has been shown to alter the tumor microenvironment (TME) and sensitize tumors to immune attack through multiple mechanisms, such as elimination of tumor angiogenesis and an increased ratio of CD8+ T cells to Treg cells. These effects have resulted in a significant reduction in tumor burden and prolonged overall survival in xenograft, syngeneic, and transgenic cancer models. See Vanharanta et al. (2013) Nature Medicine 19:50-56; Gale and McColl (1999) BioEssays 21:17-28; Highfill et al. (2014) Science Translational Medicine 6:ra67; Facciabene et al. (2011) Nature 475:226-230.

[0006] These data highlight the significant unmet need for CXCR4 inhibitors in treating a variety of diseases and conditions mediated by aberrant or unwanted receptor expression, such as cell proliferation disorders. Summary of the Invention

[0007] It has now been found that the X4P-001 composition disclosed in this invention and pharmaceutically acceptable compositions thereof are effective as inhibitors of type 4 CXC receptor (CXCR4). In one aspect, the present invention provides an X4P-001 composition comprising a compound of formula I:

[0008]

[0009] Or a pharmaceutically acceptable salt thereof; and at least one compound selected from:

[0010]

[0011]

[0012] Or its pharmaceutically acceptable salt.

[0013] The X4P-001 composition of the present invention and pharmaceutically acceptable compositions thereof are suitable for treating a variety of diseases, conditions, or symptoms associated with CXCR4, such as hyperproliferative conditions, including various cancers. Such diseases, conditions, or symptoms include those described herein. Attached Figure Description

[0014] Figure 1A detailed summary of the manufacturing process for capsules (unit dosage form) containing X4P-001 solid pharmaceutical formulation is presented.

[0015] Figure 2 The original synthesis process (version 2 or process 2) for preparing X4P-001 for clinical trials is shown.

[0016] Figure 3 A comparison is shown between process 3 (an improved current synthesis method) and process 2 (the original process) for the preparation of X4P-001.

[0017] Figure 4 It presents a detailed comparison between the second and third versions of the process in terms of downstream continuous operation regarding API handling and separation.

[0018] Figure 5 HPLC and MS data for X4P-001 (PTL / ST / 0511, batch 3-1 (prepared using process 2), 25°C / 60% RH, t = 3 months) are presented. HPLC conditions 1 (described in detail below); 1 mg / mL in methanol, injection volume 100 μL.

[0019] Figure 6 HPLC and MS data for X4P-001 (PTL / ST / 0511, batch 3-1 (prepared using process 2), 25°C / 60% RH, t = 3 months) are presented. HPLC conditions 2 (described in detail below); 1 mg / mL in methanol, injection volume 100 μL.

[0020] Figure 7 HPLC and MS data for X4P-001 (PTL / ST / 0511, batch 3-1 (prepared using process 2), 25°C / 60% RH, t = 3 months) are presented. HPLC conditions 2 (described in detail below); sample concentration 10 mg / mL in methanol, 100 μL injection.

[0021] Figure 8 HPLC and MS data for X4P-001 (degraded sample, 80℃ / 80%RH, t=1 day) are presented. HPLC conditions 2 (described in detail below); sample concentration 10 mg / mL in methanol, 100 μL injection volume.

[0022] Figure 9 HPLC and MS data for X4P-001 (degraded sample, 80℃ / 80%RH, t=7 days) are presented. HPLC conditions 2 (described in detail below); sample concentration 10 mg / mL in methanol, 100 μL injection volume.

[0023] Figure 10HPLC and MS data for X4P-001 (PTL / ST / 0511, batch 3-1 (prepared using process 2), 25°C / 60% RH, t = 3 months) are presented. HPLC conditions 3 (described in detail below); sample concentration 10 mg / mL in methanol, 100 μL injection volume. Detailed Implementation

[0024] 1. General description of certain aspects of the present invention

[0025] In one aspect, the present invention provides compounds and compositions thereof suitable for treating, preventing, and / or reducing the risk of diseases, conditions, or symptoms in which CXCR4 is involved in the pathogenesis. In some embodiments, such compounds include those compounds of the chemical formula described herein or pharmaceutically acceptable salts thereof.

[0026] In another aspect, the present invention provides compositions comprising X4P-001 (i.e., compounds of formula I, the structure of which is shown below) or pharmaceutically acceptable salts thereof, including formulations and unit dosage forms, wherein such compositions exhibit improved purity characteristic profiles. In some embodiments, the disclosed X4P-001 compositions contain reduced levels of known impurities (e.g., those described herein) and / or reduced levels of unknown impurities compared to similar compositions prepared by conventional methods.

[0027] In another aspect, the present invention provides an X4P-001 composition comprising a compound of formula I:

[0028]

[0029] Or a pharmaceutically acceptable salt thereof; and at least one compound selected from:

[0030]

[0031] Or its pharmaceutically acceptable salt.

[0032] 2. definition

[0033] The compounds of this invention include those generally described above, and are further illustrated by the categories, subclasses and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are identified according to the CAS edition of the periodic table (Handbook of Chemistry and Physics, 75th edition). 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, edited by Smith MB and March J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0034] As used herein, the term "X4P-001 composition" or "disclosed X4P-001 composition" refers to a composition comprising a compound of formula I (i.e., X4P-001) or a pharmaceutically acceptable salt thereof, and at least one other compound selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7. For clarity, the term "pharmaceutical composition" of the disclosed X4P-001 composition refers to a composition comprising a compound of formula I (i.e., X4P-001) or a pharmaceutically acceptable salt thereof, and at least one other compound selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, and a pharmaceutically acceptable excipient, such as an adjuvant, filler, binder, carrier, or mediator.

[0035] For clarity, and not to be bound by theory, it is believed that compound I-1 exists at least partially in isomer form (e.g., tautomer); for example, it is believed that compound I-1 undergoes the following interconversion to become a compound with structure I-1a:

[0036]

[0037] Therefore, it should be understood that the single isomers of I-1 and I-1a, as well as tautomers and other isomer forms, are within the scope of this invention.

[0038] Other known or unknown impurities may be present in the disclosed X4P-001 composition. As used herein, the term "impurity" includes one or more degradation products that occur during the storage of X4P-001 and / or one or more byproducts formed in the chemical reactions used to manufacture X4P-001. In some embodiments, impurities arise from oxidation, photo-initiated decomposition, reactions with residual solvents (e.g., water or isopropyl acetate), side reactions that occur during the process used to prepare X4P-001, or reactions of X4P-001 with excipients present in the X4P-001 pharmaceutical composition.

[0039] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits CXCR4 with measurable affinity. In some embodiments, the inhibitor has an IC50 concentration 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 binding constant.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, to the extent of reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in the *Journal of Pharmaceutical Sciences*, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts formed by a basic group (e.g., an amino group) with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the field (e.g., ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbic acid salts, aspartate salts, benzenesulfonate, besylate, benzoates, hydrogen sulfates, borates, butyrates, camphorates, camphor sulfonates, citrates, cyclopentane propionate, distuberose, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptanoate, glycerophosphates, gluconate, hemisulfates, and heptanoates. Hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0041] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Where appropriate, other pharmaceutically acceptable salts include those containing halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, etc. 1-6 Non-toxic ammonium, quaternary ammonium, and amine cations are formed from alkyl sulfonate and aryl sulfonate ions.

[0042] Unless otherwise stated, the structures described herein also imply all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers) of said structures; for example, R and S configurations for each asymmetry center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformational isomers), are within the scope of this invention. Unless otherwise stated, all tautomers of the compounds of the present invention are within the scope of this invention.

[0043] As used herein, "therapeutic effective amount" or "effective amount" means the amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, symptom, or condition when administered as part of a dosing regimen to an individual suffering from or susceptible to the disease, symptom, or condition. As those skilled in the art will appreciate, the effective amount of a substance can vary depending on factors such as the desired biomarker, the substance to be delivered, the target cells, or tissues. For example, an effective amount of a compound in a formulation for treating a disease, symptom, or condition is an amount that alleviates, improves, reduces, inhibits, prevents, delays the onset of the disease, symptom, or condition, reduces the severity of the disease, symptom, or condition, and / or reduces the incidence of one or more symptoms or features of the disease, symptom, or condition. In some embodiments, a "therapeutic effective amount" is at least the minimum amount of a compound or a composition containing a compound sufficient to treat one or more symptoms of the disease or condition.

[0044] As used herein, the terms “treatment,” “treat,” and “treating” refer to the partial or complete relief, suppression, delay of onset, prevention, improvement, and / or reduction of one or more symptoms of a disease or condition, as described herein. In some embodiments, treatment may be administered after one or more symptoms have appeared. In some embodiments, the term “treating” includes preventing or pausing the progression of a disease or condition. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence. Thus, in some embodiments, the term “treating” includes preventing the recurrence or recurrence of a disease or condition.

[0045] As used herein, the term "CXCR4-mediated" refers to any disease, symptom, or condition in which CXCR4 or its mutants are known to function. Therefore, another embodiment of the invention relates to treating one or more diseases in which CXCR4 or its mutants are known to function, or to reducing their severity. "CXCR4-mediated" also includes diseases, symptoms, and conditions involving the CXCR4 / CXCL12 axis.

[0046] As used herein, the term "unit dosage form" refers to a physical, discontinuous unit of a therapeutic formulation suitable for the individual to be treated. However, it should be understood that the total daily dosage of the X4P-001 composition of the present invention will be determined by the attending physician within the bounds of reasonable medical judgment. The specific effective dose level for any particular individual or organism will depend on a variety of factors, including the condition being treated and its severity; the activity of the specific active agent used; the specific composition used; the individual's age, weight, general health condition, sex, and diet; the timing of administration and excretion rate of the specific active agent used; the duration of treatment; the drugs and / or other therapies used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field.

[0047] 3. Description of exemplary compounds

[0048] It has now been found that the compounds and compositions thereof of the present invention are suitable for treating, preventing, and / or reducing the risk of diseases, conditions or symptoms related to or in connection with CXCR4 or its pathogenesis.

[0049] In one aspect, the present invention provides a composition comprising X4P-001 or a pharmaceutically acceptable salt thereof with a purity of at least 98.5%. In some embodiments, the X4P-001 in the composition has a purity of at least 98.5% and contains less than 1.5% w / w impurities. In some embodiments, the composition comprises X4P-001 or a pharmaceutically acceptable salt thereof with a purity of at least 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%.

[0050] In one aspect, the present invention provides an X4P-001 composition comprising a compound of formula I:

[0051]

[0052] Or a pharmaceutically acceptable salt thereof; and at least one of the following compounds in detectable amounts:

[0053]

[0054] Or a pharmaceutically acceptable salt thereof; and wherein the X4P-001 composition does not contain detectable amounts of the following compounds:

[0055]

[0056] Or its pharmaceutically acceptable salt.

[0057] In some embodiments, the X4P-001 composition comprises each of I-1, I-2, I-3, I-5, I-6, and I-7; or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is less than about 0.5% w / w of the X4P-001 composition.

[0059] In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is less than about 0.3% w / w of the X4P-001 composition.

[0060] In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is less than about 0.4% w / w of the X4P-001 composition.

[0061] In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is less than about 0.4% w / w of the X4P-001 composition.

[0062] In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is less than about 0.4% w / w of the X4P-001 composition.

[0063] In some embodiments, the amount of I-7 or a pharmaceutically acceptable salt thereof is less than about 0.25% w / w of the X4P-001 composition.

[0064] In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is about 0.02 to about 0.5% w / w of the X4P-001 composition.

[0065] In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.3% w / w of the X4P-001 composition.

[0066] In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w / w of the X4P-001 composition.

[0067] In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w / w of the X4P-001 composition.

[0068] In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w / w of the X4P-001 composition.

[0069] In some embodiments, the amount of I-7 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.25% w / w of the X4P-001 composition.

[0070] In one aspect, the present invention provides a pharmaceutical composition comprising the disclosed X4P-001 composition and a pharmaceutically acceptable adjuvant, carrier, or mediator.

[0071] In some embodiments, pharmaceutically acceptable adjuvants include at least one diluent, disintegrant, lubricant, and glidant.

[0072] In another aspect, the present invention provides an X4P-001 composition or a pharmaceutical composition thereof, wherein:

[0073] (a) The amount of I-1 or a pharmaceutically acceptable salt thereof is less than about 0.5% w / w of the X4P-001 composition;

[0074] (b) The amount of I-2 or a pharmaceutically acceptable salt thereof is less than about 0.3% w / w of the X4P-001 composition;

[0075] (c) The amount of I-3 or a pharmaceutically acceptable salt thereof is less than about 0.4% w / w of the X4P-001 composition;

[0076] (d) The amount of I-5 or a pharmaceutically acceptable salt thereof is less than about 0.4% w / w of the X4P-001 composition;

[0077] (e) wherein the amount of I-6 or a pharmaceutically acceptable salt thereof is less than about 0.4% w / w of the X4P-001 composition; and

[0078] (f) The amount of I-7 or a pharmaceutically acceptable salt thereof is less than about 0.25% w / w of the X4P-001 composition.

[0079] In one aspect, the present invention provides an X4P-001 composition or a pharmaceutical composition thereof, wherein:

[0080] (a) The amount of I-1 or a pharmaceutically acceptable salt thereof is about 0.02 to about 0.5% w / w of the X4P-001 composition;

[0081] (b) The amount of I-2 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.3% w / w of the X4P-001 composition;

[0082] (c) The amount of I-3 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w / w of the X4P-001 composition;

[0083] (d) The amount of I-5 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w / w of the X4P-001 composition;

[0084] (e) The amount of I-6 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w / w of the X4P-001 composition; and

[0085] (f) The amount of I-7 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.25% w / w of the X4P-001 composition.

[0086] In one aspect, the present invention provides an X4P-001 composition, wherein:

[0087] (a) The amount of I-2 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.2% w / w of the X4P-001 composition;

[0088] (b) The amount of I-3 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.2% w / w of the X4P-001 composition;

[0089] (c) The amount of I-5 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.2% w / w of the X4P-001 composition;

[0090] (d) The amount of I-6 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w / w of the X4P-001 composition; and

[0091] (e) The amount of I-7 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.25% w / w of the X4P-001 composition.

[0092] In some embodiments, the X4P-001 composition optionally further comprises about 0.02 to about 0.5% w / w of I-1 or a pharmaceutically acceptable salt thereof.

[0093] In another aspect, the present invention provides a unit dosage form comprising a pharmaceutical composition, said pharmaceutical composition comprising:

[0094] (a) about 10-20% of the disclosed X4P-001 composition by weight of the composition;

[0095] (b) about 70-85% microcrystalline cellulose by weight of the composition;

[0096] (c) about 5-10% croscarmellose sodium by weight of the composition;

[0097] (d) Sodium stearoyl fumarate, about 0.5-2% by weight of the composition; and

[0098] (e) about 0.1-1.0% colloidal silica by weight of the composition.

[0099] In another aspect, the present invention provides a unit dosage form comprising a pharmaceutical composition, said pharmaceutical composition comprising:

[0100] (a) about 35-75% of the disclosed X4P-001 composition by weight of the composition;

[0101] (b) about 5-28% microcrystalline cellulose by weight of the composition;

[0102] (c) about 7-30% of dicalcium phosphate dihydrate by weight of the composition;

[0103] (d) about 2-10% croscarmellose sodium by weight of the composition;

[0104] (e) Sodium stearoyl fumarate, about 0.3-2.5% by weight of the composition;

[0105] (f) about 0.05-1.2% colloidal silica, based on the weight of the composition; and

[0106] (g) Sodium lauryl sulfate, about 0.2-1.2% by weight of the composition.

[0107] In one aspect, the present invention provides a method for treating, preventing, or reducing the risk of CXCR4-related diseases, conditions, or ailments in an individual of need, comprising administering an effective amount of the disclosed X4P-001 composition to said individual.

[0108] In some embodiments, the disease, condition, or symptom is a cancer selected from kidney cancer, kidney tumor, kidney cancer, ovarian cancer, or melanoma.

[0109] In one aspect, the present invention provides an X4P-001 composition comprising a compound of formula I:

[0110]

[0111] Or a pharmaceutically acceptable salt thereof; and at least one compound selected from:

[0112]

[0113]

[0114] Or its pharmaceutically acceptable salt.

[0115] In another aspect, the present invention provides an X4P-001 composition comprising a compound of formula I:

[0116]

[0117] Or a pharmaceutically acceptable salt thereof; and at least one compound selected from:

[0118]

[0119]

[0120] Or its pharmaceutically acceptable salt.

[0121] In some embodiments, the present invention provides an X4P-001 composition comprising a compound of formula I:

[0122]

[0123] Or a pharmaceutically acceptable salt thereof; and compounds with the following structures:

[0124]

[0125] Or a pharmaceutically acceptable salt thereof. In some embodiments, the total weight of I-6 and any additional impurities present does not exceed about 0.8% w / w in the X4P-001 composition.

[0126] In some embodiments, the X4P-001 composition contains at least a detectable amount of I-6 or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the X4P-001 composition comprises two, three, or four compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or pharmaceutically acceptable salts thereof. In some embodiments, the X4P-001 composition comprises at least detectable amounts of two, three, or four compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or pharmaceutically acceptable salts thereof.

[0128] In some embodiments, the X4P-001 composition comprises three compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or pharmaceutically acceptable salts thereof. In some embodiments, the X4P-001 composition comprises at least detectable amounts of three compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or pharmaceutically acceptable salts thereof.

[0129] In some embodiments, the X4P-001 composition comprises each of I-1, I-2, I-3, I-5, I-6, and I-7; or a pharmaceutically acceptable salt thereof. In some embodiments, the X4P-001 composition comprises at least a detectable amount of each of I-1, I-2, I-3, I-5, I-6, and I-7; or a pharmaceutically acceptable salt thereof.

[0130] In one aspect, the present invention provides an X4P-001 composition comprising a compound of formula I:

[0131]

[0132] Or a pharmaceutically acceptable salt thereof; and at least one of the following compounds in detectable amounts:

[0133]

[0134] Or its pharmaceutically acceptable salt.

[0135] In some embodiments, the X4P-001 composition does not include detectable amounts of the following compounds:

[0136]

[0137] Or its pharmaceutically acceptable salt.

[0138] In some embodiments, the X4P-001 composition does not include detectable amounts of the following compounds:

[0139]

[0140] Or its pharmaceutically acceptable salt.

[0141] In some embodiments, relative to the total weight of the X4P-001 composition of the compound of Formula I and one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6 or I-7 or their pharmaceutically acceptable salts, the total amount of I-6 or its pharmaceutically acceptable salts accounts for no more than about 0.2% w / w of the X4P-001 composition. In some embodiments, the X4P-001 composition contains at least a detectable amount of I-6 or its pharmaceutically acceptable salts.

[0142] In some embodiments, the X4P-001 composition contains no more than 0.15% w / w of I-6 relative to the total weight of the compound of Formula I and one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6 or I-7 or their pharmaceutically acceptable salts. In some embodiments, the X4P-001 composition contains at least a detectable amount of I-6 or its pharmaceutically acceptable salts.

[0143] In some embodiments, relative to the total weight of the X4P-001 composition of the compound of Formula I and one or more compounds selected from I-2, I-3, I-5, I-6 or I-7 or their pharmaceutically acceptable salts, the total amount of I-6 or its pharmaceutically acceptable salts accounts for no more than about 0.2% w / w of the X4P-001 composition. In some embodiments, the X4P-001 composition contains at least a detectable amount of I-6 or its pharmaceutically acceptable salts.

[0144] In some embodiments, the X4P-001 composition contains no more than 0.15% w / w of I-6 relative to the total weight of the compound of Formula I and one or more compounds selected from I-2, I-3, I-5, I-6 or I-7 or their pharmaceutically acceptable salts. In some embodiments, the X4P-001 composition contains at least a detectable amount of I-6 or its pharmaceutically acceptable salts.

[0145] In some embodiments, relative to the total weight of the X4P-001 composition containing the compound of Formula I and one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or pharmaceutically acceptable salts thereof, the total weight of the X4P-001 composition is less than about 3.0% w / w. In some embodiments, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or pharmaceutically acceptable salts thereof, are present in the X4P-001 composition in at least a detectable amount. In some embodiments, the X4P-001 composition contains, in detectable amounts, the compound of Formula I or a pharmaceutically acceptable salt thereof, but not the compound of Formula I-4 or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the total organic impurities (including one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6 or I-7 or pharmaceutically acceptable salts thereof) account for less than about 4.0% w / w of the X4P-001 composition.

[0147] In some embodiments, relative to the total weight of the X4P-001 composition of the compound of Formula I and one or more compounds selected from I-2, I-3, I-5, I-6, or I-7 or their pharmaceutically acceptable salts, the one or more compounds selected from I-2, I-3, I-5, I-6, or I-7 or their pharmaceutically acceptable salts constitute less than about 3.0% w / w of the X4P-001 composition. In some embodiments, one or more compounds selected from I-2, I-3, I-5, I-6, or I-7 or their pharmaceutically acceptable salts are present in the X4P-001 composition in at least a detectable amount. In some embodiments, the X4P-001 composition comprises, in detectable amounts, the compound of Formula I or its pharmaceutically acceptable salts, but does not comprise any of compounds I-1 or I-4 or their pharmaceutically acceptable salts.

[0148] In some embodiments, the total organic impurities (including one or more compounds selected from I-2, I-3, I-5, I-6 or I-7 or pharmaceutically acceptable salts thereof) account for less than about 4.0% w / w of the X4P-001 composition.

[0149] In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is less than about 0.5% w / w of the X4P-001 composition.

[0150] In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is less than about 0.3% w / w of the X4P-001 composition.

[0151] In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is less than about 0.4% w / w of the X4P-001 composition.

[0152] In some embodiments, the X4P-001 composition does not include a detectable amount of I-4 or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is less than about 0.07% w / w of the X4P-001 composition.

[0154] In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is less than about 0.4% w / w of the X4P-001 composition.

[0155] In some embodiments, the amount of I-7 or a pharmaceutically acceptable salt thereof is less than about 0.25% w / w of the X4P-001 composition.

[0156] In some embodiments, I-1, I-2, I-3, I-5, I-6 or I-7 or a pharmaceutically acceptable salt thereof are present in the X4P-001 composition in at least a detectable amount.

[0157] In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is about 0.02 to about 0.5% w / w of the X4P-001 composition.

[0158] In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.3% w / w of the X4P-001 composition.

[0159] In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w / w of the X4P-001 composition.

[0160] In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.07% w / w of the X4P-001 composition.

[0161] In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w / w of the X4P-001 composition.

[0162] In some embodiments, the amount of I-7 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.25% w / w of the X4P-001 composition.

[0163] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof with a purity of at least 99.3% (according to HPLC), and comprises less than 0.7% (as measured by HPLC) of a total of additional compounds selected from I-1, I-2, I-3, I-5, I-6, or I-7 or pharmaceutically acceptable salts thereof. In some embodiments, one or more additional compounds are present in at least a detectable amount.

[0164] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof with a purity of at least 99.3% (according to HPLC), and comprises less than 0.7% (as measured by HPLC) of a total of additional compounds selected from I-2, I-3, I-5, I-6, or I-7 or pharmaceutically acceptable salts thereof. In some embodiments, one or more additional compounds are present in at least a detectable amount. In some embodiments, each of I-2, I-3, I-5, I-6, and I-7 or a pharmaceutically acceptable salt thereof is present in at least a detectable amount (as measured by HPLC).

[0165] In one aspect, the present invention provides an X4P-001 composition comprising a compound of formula I:

[0166]

[0167] Or a pharmaceutically acceptable salt thereof, and one or more compounds selected from the following:

[0168]

[0169] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.5% w / w of the X4P-001 composition;

[0170]

[0171] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.3% w / w of the X4P-001 composition;

[0172]

[0173] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.4% w / w of the X4P-001 composition;

[0174]

[0175] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.5% w / w of the X4P-001 composition;

[0176]

[0177] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.4% w / w of the X4P-001 composition; or

[0178]

[0179] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.25% w / w of the X4P-001 composition; wherein each % w / w is measured relative to the total weight of the X4P-001 composition of the compound of formula I and one or more compounds selected from I-1, I-2, I-3, I-5, I-6 or I-7. In some embodiments, the X4P-001 composition comprises, in detectable amounts, the compound of formula I or a pharmaceutically acceptable salt thereof, but not the compound of formula I-4 or a pharmaceutically acceptable salt thereof.

[0180] In one aspect, the present invention provides an X4P-001 composition comprising a compound of formula I:

[0181]

[0182] Or a pharmaceutically acceptable salt thereof, and one or more compounds selected from the following:

[0183]

[0184] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.3% w / w of the X4P-001 composition;

[0185]

[0186] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.4% w / w of the X4P-001 composition;

[0187]

[0188] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.5% w / w of the X4P-001 composition;

[0189]

[0190] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.4% w / w of the X4P-001 composition; or

[0191]

[0192] Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.25% w / w of the X4P-001 composition; wherein each % w / w is measured relative to the total weight of the X4P-001 composition of the compound of formula I and one or more compounds selected from I-2, I-3, I-5, I-6 or I-7.

[0193] In some embodiments, the chiral purity of the X4P-001 composition is at least about 97% enantiomer excess (%ee).

[0194] In some embodiments, the X4P-001 composition contains 7000, 6000, 5000, 4500, 4000, 3500, 3000, 2500, 2000, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, or 1350 ppm or less of toluene.

[0195] In some embodiments, toluene is used as the crystallization solvent for separating X4P-001. In some embodiments, the specification regarding residual toluene in the free base of X4P-001 is that the X4P-001 composition contains no more than 4500 ppm. In other embodiments, the X4P-001 composition contains no more than 4000 ppm, 3500 ppm, 3000 ppm, 2500 ppm, 2000 ppm, 1750 ppm, 1700 ppm, 1650 ppm, 1600 ppm, 1550 ppm, 1500 ppm, 1450 ppm, 1400 ppm, or 1350 ppm of toluene. In some embodiments, the permissible daily exposure (PDE) method is used. The term permissible daily exposure (PDE) is defined as the pharmaceutically acceptable intake of residual solvent in the drug. See, for example, the "Guidance for Industry: Q3C Impurities: Residual Solvents" published by the U.S. Department of Health and Human Services and the Food and Drug Administration (FDA).

[0196] In some embodiments, when the X4P-001 composition is stored at 25°C / 60% relative humidity for three months, the purity % of the X4P-001 composition decreases by less than 1%, as measured by HPLC.

[0197] In some embodiments, the X4P-001 composition further comprises one or more of the following:

[0198]

[0199] Furthermore, compounds I-8, I-9, I-10 and / or I-11 are present in an amount of less than about 25 parts per million (ppm) of the X4P-001 composition.

[0200] In some embodiments, compounds I-8, I-9, I-10, and / or I-11 are present in amounts less than about 50, 40, 30, 20, 15, 10, 5, 4, 3, 2, or 1 ppm of the X4P-001 composition. In some embodiments, compounds I-8, I-9, I-10, and / or I-11 are each present independently in amounts between about 1 ppm and about 25 ppm, or between about 100 parts per billion (ppb) and 4 ppm. In some embodiments, the X4P-001 composition comprises, in detectable amounts, a compound of formula I or a pharmaceutically acceptable salt thereof, but not a compound of formula I-4 or a pharmaceutically acceptable salt thereof.

[0201] In one aspect, the present invention provides a pharmaceutical composition comprising the disclosed X4P-001 composition and a pharmaceutically acceptable adjuvant, carrier, or mediator.

[0202] In one aspect, the present invention provides a solid unit dosage form for oral formulation comprising the disclosed X4P-001 composition or pharmaceutical composition.

[0203] In some embodiments, the present invention provides a combination of the disclosed X4P-001 composition with another therapeutic agent.

[0204] In another aspect, the present invention provides a unit dosage form comprising a pharmaceutical composition, said pharmaceutical composition comprising:

[0205] (a) about 10-20% of the disclosed X4P-001 composition by weight of the composition;

[0206] (b) about 70-85% microcrystalline cellulose by weight of the composition;

[0207] (c) about 5-10% croscarmellose sodium by weight of the composition;

[0208] (d) Sodium stearoyl fumarate, about 0.5-2% by weight of the composition; and

[0209] (e) about 0.1-1.0% colloidal silica by weight of the composition.

[0210] In another aspect, the present invention provides a unit dosage form comprising a pharmaceutical composition, said pharmaceutical composition comprising:

[0211] (a) about 30-40% of the disclosed X4P-001 composition by weight of the composition;

[0212] (b) about 20-25% microcrystalline cellulose by weight of the composition;

[0213] (c) about 30-35% of dicalcium phosphate dihydrate by weight of the composition;

[0214] (d) about 5-10% croscarmellose sodium by weight of the composition;

[0215] (e) Sodium stearoyl fumarate, about 0.5-2% by weight of the composition;

[0216] (f) about 0.1-1.0% colloidal silica by weight of the composition; and

[0217] (g) Sodium lauryl sulfate, about 0.1-1.0% by weight of the composition.

[0218] In another aspect, the present invention provides a unit dosage form comprising a pharmaceutical composition, said pharmaceutical composition comprising:

[0219] (a) about 35-75% of the disclosed X4P-001 composition by weight of the composition;

[0220] (b) about 5-28% microcrystalline cellulose by weight of the composition;

[0221] (c) about 7-30% of dicalcium phosphate dihydrate by weight of the composition;

[0222] (d) about 2-10% croscarmellose sodium by weight of the composition;

[0223] (e) Sodium stearoyl fumarate, about 0.3-2.5% by weight of the composition;

[0224] (f) about 0.05-1.2% colloidal silica, based on the weight of the composition; and

[0225] (g) Sodium lauryl sulfate, about 0.2-1.2% by weight of the composition.

[0226] In some embodiments, the unit dosage form is in capsule form.

[0227] In some embodiments, the capsule contains about 25 mg, about 100 mg, or about 200 mg of X4P-001 or a pharmaceutically acceptable salt thereof.

[0228] In another aspect, the present invention provides a method for treating, preventing, or reducing the risk of CXCR4-related diseases, conditions, or symptoms in an individual in need, comprising administering the disclosed X4P-001 composition to said individual.

[0229] In some embodiments, the disease, condition, or symptom is cancer.

[0230] In some embodiments, the cancer is selected from kidney cancer, kidney tumor, kidney cancer (including clear cell carcinoma and papillary renal carcinoma), ovarian cancer, or melanoma.

[0231] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and another compound selected from I-1, I-2, I-3, I-4, I-5, I-6 or I-7; or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and two other compounds selected from I-1, I-2, I-3, I-4, I-5, I-6 or I-7; or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and three other compounds selected from I-1, I-2, I-3, I-4, I-5, I-6 or I-7; or pharmaceutically acceptable salts thereof.

[0234] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and four other compounds selected from I-1, I-2, I-3, I-4, I-5, I-6 or I-7; or pharmaceutically acceptable salts thereof.

[0235] In some embodiments, the X4P-001 composition contains, in terms of detectable amounts, a compound of formula I or a pharmaceutically acceptable salt thereof, but not a compound of formula I-4 or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, the one or more other compounds are present in at least a detectable amount.

[0237] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and each of I-1, I-2, I-3, I-4, I-5, I-6 and I-7; or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and another compound selected from I-2, I-3, I-5, I-6 or I-7; or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and two other compounds selected from I-2, I-3, I-5, I-6 or I-7; or pharmaceutically acceptable salts thereof.

[0240] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and three other compounds selected from I-2, I-3, I-5, I-6 or I-7; or pharmaceutically acceptable salts thereof.

[0241] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and four other compounds selected from I-2, I-3, I-5, I-6 or I-7; or pharmaceutically acceptable salts thereof.

[0242] In some embodiments, the X4P-001 composition comprises, in terms of detectable amounts, a compound of formula I or a pharmaceutically acceptable salt thereof, but not compounds of formulas I-1 and I-4 or pharmaceutically acceptable salts thereof.

[0243] In some embodiments, the one or more other compounds are present in at least a detectable amount.

[0244] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and each of I-2, I-3, I-5, I-6 and I-7; or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and I-1 or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and I-2 or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and I-3 or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and I-4 or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and I-5 or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and I-6 or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and I-7 or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof; and I-1, I-2, I-3, I-4, I-5, I-6 and I-7; or pharmaceutically acceptable salts thereof.

[0253] In some embodiments, the % w / w amount of a compound in the disclosed X4P-001 composition is measured by comparing the area percentage of the compound in HPLC chromatography with that of any other compound present in the X4P-001 composition. For example, if measured in this manner, the presence of 0.2% w / w of compound I-6 in an X4P-001 composition containing both I-6 and compound I means that the composition contains 0.2% (peak area %) of I-6 and 99.8% (peak area %) of compound I according to HPLC. In other embodiments, % w / w is measured using an alternative method known to those skilled in the art (e.g., those described herein).

[0254] In one aspect, the present invention provides a method for preparing the disclosed X4P-001 composition, wherein the composition is prepared substantially as described in the examples and figures herein.

[0255] In another aspect, the present invention provides compounds selected from those described in Table 1 below.

[0256] Table 1: Representative compounds of the present invention

[0257]

[0258] In some embodiments, the present invention provides the compounds depicted in Table 1 above, or pharmaceutically acceptable salts thereof.

[0259] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one compound or a pharmaceutically acceptable salt thereof depicted in Table 1 above. The composition may comprise 1, 2, 3, 4, 5, 6, or 7 of the compounds. In some embodiments, the composition does not contain a detectable amount of compound I-4. In some embodiments, the composition does not contain a detectable amount of compound I-1. In some embodiments, the composition does not contain detectable amounts of compounds I-1 and I-4.

[0260] Typically, the wt% of each impurity is determined by HPLC and is measured initially or after storage, and optionally continuously during the shelf life of the X4P-001 composition. In some embodiments, the impurity content is measured after storing the composition under stress conditions (elevated temperature, humidity, or both, to estimate the effects of long-term storage under environmental conditions).

[0261] In some embodiments, the Formula I compound or a pharmaceutically acceptable salt thereof is present in the X4P-001 composition in an amount of at least about 96, 97, 97.5, 98, 98.5, 98.7, 98.9, 99.0, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.75, 99.8, 99.85, 99.9, 99.95, 99.97, or 99.999% by weight, wherein the percentage is based on the free base of the compound and the total weight of the X4P-001 composition. In other embodiments, the X4P-001 composition contains no more than about 2.0 area% of total organic impurities per HPLC relative to the total area of ​​the HPLC chromatogram, or in other embodiments, no more than about 5.0, 4.0, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.25, 1, 0.75, 0.5, 0.25, 0.2, 0.1, 0.01, 0.005, or 0.001 area% of total organic impurities per HPLC.

[0262] In other embodiments, the X4P-001 composition contains, relative to the total area of ​​the HPLC chromatogram, no more than about 5.0, 4.0, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.25, 1, 0.75, 0.5, 0.25, 0.2, 0.1, 0.01, 0.005, or 0.001 area % (measured by HPLC) of compounds I-1, I-2, I-3, I-4, I-5, I-6, and I-7.

[0263] In other embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more other compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the X4P-001 composition contains from about 1% by weight to about 99% by weight of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the percentage is based on the free base of the compound and the total weight of the X4P-001 composition. In other embodiments, the X4P-001 composition contains no more than about 2.0 area% of total organic impurities per HPLC relative to the total area of ​​the HPLC chromatogram, or in other embodiments, contains no more than about 5.0, 4.0, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.25, 1.1, 1.05, 1, 0.95, 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.25, 0.2, 0.1, 0.01, 0.005, or 0.001 area% of total organic impurities per HPLC.

[0264] In some embodiments, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or their pharmaceutically acceptable salts, collectively or individually account for about 0.01-0.20% of the area of ​​the HPLC chromatogram relative to the compound of Formula I or its pharmaceutically acceptable salt. In some embodiments, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or their pharmaceutically acceptable salts, collectively or individually account for about 0.02-0.18, 0.03-0.16, 0.05-0.15, 0.075-0.13, 0.09-0.1, 0.1-0.2, or 0.15-0.2% of the area of ​​the HPLC chromatogram relative to the compound of Formula I or its pharmaceutically acceptable salt. In some embodiments, the above-mentioned area percentage of the HPLC chromatogram is measured relative to the total area of ​​the HPLC chromatogram, rather than relative to the peak area of ​​the compound of Formula I or its pharmaceutically acceptable salt.

[0265] In some embodiments, relative to the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7 or their pharmaceutically acceptable salts constitute less than about 5.0% by weight (% w / w) or about 0.01-5.0% w / w. In some embodiments, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7 or their pharmaceutically acceptable salts constitute less than about 3.0% w / w of the X4P-001 composition; or about 0.02-4.0, 0.03-3.5, 0.05-3.1, 0.05-2.9, 0.05-2.5, 0.05-2.0, or 0. 0.05-1.8, 0.05-1.6, 0.05-1.5, 0.05-1.4, 0.05-1.2, 0.05-1.1, 0.05-1.0, 0.05-0.9, 0.05-0.8, 0.05-0.7, 0.05-0.6, 0.05-0.5, 0.05-0.4, 0.05-0.3, 0.05-0.2, 0.05-0.1 or approximately 0.1-0.5% w / w.

[0266] In some embodiments, the total organic impurities (including one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6 or I-7 or their pharmaceutically acceptable salts) account for less than about 0.05% w / w, about 0.1, 0.5, 1.0, 2.0, 3.0 or about 4.0% w / w or less of the X4P-001 composition. In some embodiments, the total organic impurities account for about 0.02-4.0, 0.03-3.5, 0.05-3.1, 0.05-2.9, 0.05-2.5, 0.05-2.0, 0.05-1.8, 0.05-1.6, 0.05-1.5, 0.05-1.4, 0.05-1.2, 0.05-1.1, 0.05-1.0, 0.05-0.9, 0.05-0.8, 0.05-0.7, 0.05-0.6, 0.05-0.5, 0.05-0.4, 0.05-0.3, 0.05-0.2, 0.05-0.1 or about 0.1-0.5% w / w of the X4P-001 composition.

[0267] In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is less than about 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w / w of the X4P001 composition. In some embodiments, I-1 or a pharmaceutically acceptable salt thereof is undetectable.

[0268] In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is less than about 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w / w of the X4P-001 composition.

[0269] In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is less than about 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w / w of the X4P-001 composition.

[0270] In some embodiments, the amount of I-4 or a pharmaceutically acceptable salt thereof is less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w / w of the X4P-001 composition. In some embodiments, I-4 or a pharmaceutically acceptable salt thereof is undetectable.

[0271] In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w / w of the X4P-001 composition.

[0272] In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w / w of the X4P-001 composition.

[0273] In some embodiments, the amount of I-7 or a pharmaceutically acceptable salt thereof is less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w / w of the X4P-001 composition.

[0274] In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is about 0.001 to about 1.1%, about 0.01 to about 1.1%, about 0.01 to about 0.8%, about 0.01 to about 0.7%, about 0.01 to about 0.6%, about 0.01 to about 0.5%, about 0.01 to about 0.4%, about 0.01 to about 0.3%, about 0.01 to about 0.2%, about 0.01 to about 0.1%, about 0.01 to about 0.09%, about 0.01 to about 0.08%, about 0.01 to about 0.07%, about 0.01 to about 0.06%, about 0.01 to about 0.05%, about 0.01 to about 0.03%, or about 0.01 to about 0.02% w / w of the X4P-001 composition.

[0275] In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is about 0.001 to about 0.3%, about 0.01 to about 0.3%, 0.01 to about 0.2%, 0.01 to about 0.1%, 0.01 to about 0.09%, 0.01 to about 0.08%, 0.01 to about 0.07%, 0.01 to about 0.06%, 0.01 to about 0.05%, 0.01 to about 0.03%, or 0.01 to about 0.02% w / w of the X4P-001 composition.

[0276] In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is about 0.001 to about 0.4%, about 0.01 to about 0.4%, 0.01 to about 0.3%, 0.01 to about 0.2%, 0.01 to about 0.1%, 0.01 to about 0.09%, 0.01 to about 0.08%, 0.01 to about 0.07%, 0.01 to about 0.06%, 0.01 to about 0.05%, 0.01 to about 0.03%, or 0.01 to about 0.02% w / w of the X4P-001 composition.

[0277] In some embodiments, the amount of I-4 or a pharmaceutically acceptable salt thereof is about 0.001 to about 0.5%, about 0.01 to about 0.5%, about 0.01 to about 0.3%, 0.01 to about 0.2%, 0.01 to about 0.1%, 0.01 to about 0.09%, 0.01 to about 0.08%, 0.01 to about 0.07%, 0.01 to about 0.06%, 0.01 to about 0.05%, 0.01 to about 0.03%, or 0.01 to about 0.02% w / w of the X4P-001 composition.

[0278] In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is about 0.001 to about 0.5%, about 0.01 to about 0.5%, 0.01 to about 0.4%, 0.01 to about 0.3%, 0.01 to about 0.2%, 0.01 to about 0.1%, 0.01 to about 0.09%, 0.01 to about 0.08%, 0.01 to about 0.07%, 0.01 to about 0.06%, 0.01 to about 0.05%, 0.01 to about 0.03%, or 0.01 to about 0.02% w / w of the X4P-001 composition.

[0279] In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is about 0.001 to about 0.5%, about 0.01 to about 0.5%, about 0.01 to about 0.4%, about 0.01 to about 0.3%, 0.01 to about 0.2%, 0.01 to about 0.1%, 0.01 to about 0.09%, 0.01 to about 0.08%, 0.01 to about 0.07%, 0.01 to about 0.06%, 0.01 to about 0.05%, 0.01 to about 0.03%, or 0.01 to about 0.02% w / w of the X4P-001 composition.

[0280] In some embodiments, the amount of I-7 or a pharmaceutically acceptable salt thereof is about 0.001 to about 0.5%, about 0.01 to about 0.5%, about 0.01 to about 0.4%, about 0.01 to about 0.3%, 0.01 to about 0.2%, 0.01 to about 0.1%, 0.01 to about 0.09%, 0.01 to about 0.08%, 0.01 to about 0.07%, 0.01 to about 0.06%, 0.01 to about 0.05%, 0.01 to about 0.03%, or 0.01 to about 0.02% w / w of the X4P-001 composition.

[0281] In some embodiments, the amount of any additional or unknown impurities in the X4P-001 composition is about 0.01 to about 0.2% w / w of the composition.

[0282] In some embodiments, the amount of p-hydroxybenzoic acid present in the X4P-001 composition is from about 0.01 to about 0.5% w / w of the composition. In some embodiments, the composition is substantially free of p-hydroxybenzoic acid. In some embodiments, a detectable amount of p-hydroxybenzoic acid is absent from the composition. In some embodiments, the X4P-001 composition contains, in detectable amounts, a compound of formula I or a pharmaceutically acceptable salt thereof, but not compounds of formulas I-4 or pharmaceutically acceptable salts thereof.

[0283] In some embodiments, the chiral purity of the X4P-001 composition is at least about 97% enantiomer excess (%ee). In some embodiments, the chiral purity of the Formula I compound is at least 97%ee. In some embodiments, the chiral purity of the Formula I compound is at least 98%ee. In some embodiments, the chiral purity of the Formula I compound is at least 99%ee. In some embodiments, the chiral purity of the Formula I compound is at least 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9%ee.

[0284] In some embodiments, the present invention provides an isolated form of any of the compounds described above and herein. As used herein, the term "isolated" means providing a compound in a form separated from other components that may be present in the common environment in which the compound is found. In some embodiments, the isolated compound is in solid form. In some embodiments, the isolated compound has a purity of at least about 50%, as determined by a suitable HPLC method. In some embodiments, the isolated compound has a purity of at least about 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.95%, 99.99%, or 99.999%, as determined by a suitable HPLC method. The purity percentage may be measured as a weight percentage (w / w%) of the desired compound, as an area % relative to the total area of ​​the HPLC chromatogram, or by other methods known in the art.

[0285] Methods for the preparation and analysis of certain compounds applicable to this invention are disclosed in US 7,354,934, WO 00 / 56729, USSN 60 / 232,891 and USSN 60 / 234,510, and in the entirety of the references of An H., Wang T., Mohan V., Griffey RH, and Cook PD, Tetrahedron 1998, 54, 3999-4012.

[0286] The disclosed compounds can be purified by any method known in the art. Such methods include, for example, silica gel column chromatography; medium-pressure liquid chromatography (MPLC); high-pressure liquid chromatography (HPLC); preparative HPLC (prep-HPLC); rapid chromatography (FC); liquid chromatography (LC); supercritical fluid chromatography (SFC); thin-layer chromatography (TLC); preparative TLC (prep-TLC); liquid chromatography-mass spectrometry (LC-MS, LCMS, or LC / MS); recrystallization; precipitation; grinding; distillation; derivatization; acid-base extraction, etc.

[0287] For the purposes of a compound, the terms "purified," "purified form," or "isolated and purified form" refer to the physical state of the compound after it has been isolated from a synthetic process (e.g., from a reaction mixture) or from a natural source or a combination thereof. Thus, for the purposes of a compound, the terms "purified," "purified form," or "isolated and purified form" refer to the physical state of the compound (or its tautomers or stereoisomers, or pharmaceutically acceptable salts or solvates of the compound, the stereoisomers, or the tautomers) after it has been obtained from a purification process or a process described herein or well known to those skilled in the art (e.g., chromatography, recrystallization, etc.), the compound having sufficient purity for in vivo or pharmaceutical use and / or characterizable by standard analytical techniques described herein or well known to those skilled in the art.

[0288] As used herein, the term "detectable amount" means that a component present in a sample (e.g., a sample of the disclosed X4P-001 composition) is present in an amount that can be detected by at least an analytical method known in the art. For example, in some embodiments, "detectable amount" is an amount that can be detected by at least HPLC, LC-MS, mass spectrometry, NMR, or other analytical methods known to those skilled in the art or described herein.

[0289] A mixture of diastereomers can be separated into its individual diastereomers based on its physicochemical differences using methods well known to those skilled in the art (e.g., by chromatography and / or stepwise crystallization). Enantiomer mixtures can be converted into diastereomer mixtures by using appropriate optically active compounds (e.g., chiral adjuvants, such as chiral alcohols or Mosher's acid chloride), the diastereomers can be separated, and individual diastereomers can be converted (e.g., hydrolyzed) to their corresponding pure enantiomers. Enantiomers can also be separated using chiral HPLC columns.

[0290] 4. Uses, formulations and application

[0291] Pharmaceutically acceptable compositions

[0292] In one aspect, the present invention provides an X4P-001 composition comprising the disclosed compound, a pharmaceutically acceptable salt, or a pharmaceutically acceptable derivative; or the disclosed X4P-001 composition; and a pharmaceutically acceptable excipient, carrier, adjuvant, or mediator. The amount of the compound in the compositions of the present invention effectively produces measurable inhibition of CXCR4 or its mutants in biological samples or patients. In some embodiments, the amount of the compound in the compositions of the present invention effectively produces measurable inhibition of CXCR4 or its mutants in biological samples or patients. In some embodiments, the compositions of the present invention are formulated for administration to patients requiring such compositions. In some embodiments, the compositions of the present invention are formulated for oral administration to patients.

[0293] As used in this article, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0294] The term "pharmaceutically acceptable carrier, adjuvant, or catalyst" refers to a non-toxic carrier, adjuvant, or catalyst that does not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or catalysts that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0295] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of ester or other derivative of the compound of the present invention, which, when administered to a recipient, can directly or indirectly provide the compound of the present invention or its metabolites or residues with inhibitory activity.

[0296] As used herein, the term "metabolite or residue of which has inhibitory activity" means a metabolite or residue of which is also an inhibitor of CXCR4 or its mutants.

[0297] The compositions of this invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheathic, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of this invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, such as a solution in 1,3-butanediol. Acceptable mediators and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media.

[0298] For this purpose, any mild, non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Fatty acids (such as oleic acid and its glyceride derivatives) are suitable for the preparation of injectable formulations, as are pharmaceutically acceptable natural oils (such as olive oil or castor oil, especially their polyoxyethylated forms). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). For formulation purposes, other commonly used surfactants (such as Tweens and Spans) and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used.

[0299] The pharmaceutically acceptable compositions of the present invention can be taken orally in any orally acceptable dosage form, including (but not limited to) capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral administration, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are typically also added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. Sweeteners, flavoring agents, or coloring agents may also be added if necessary.

[0300] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of rectal suppositories. These suppositories can be prepared by mixing the pharmaceutical agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such substances include cocoa butter, beeswax, and polyethylene glycol.

[0301] The pharmaceutically acceptable compositions of the present invention can also be applied topically, especially when the therapeutic target includes areas or organs (including diseases of the eyes, skin, or lower intestine) that are easily accessible by topical application. Topical formulations suitable for each of these areas or organs are readily prepared.

[0302] Topical application to the lower intestine can be achieved as a rectal suppository formulation (see above) or as a suitable enema formulation. A local percutaneous patch may also be used.

[0303] For topical application, the pharmaceutically acceptable compositions provided may be formulated as suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include (but are not limited to) mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated as suitable lotions or creams 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 wax, cetearyl alcohol, 2-octyldodecanool, benzyl alcohol, and water.

[0304] For ophthalmic use, the pharmaceutically acceptable composition provided may be formulated as a micronized suspension in pH-adjusted isotonic sterile saline, with or without a preservative such as benzyl chlorobenzyl ammonium, or preferably as a solution in pH-adjusted isotonic sterile saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated in an ointment such as petrolatum.

[0305] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, bioavailability-enhancing absorption promoters, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0306] The pharmaceutically acceptable compositions of the present invention are most preferably formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered in the absence of food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered in the presence of food.

[0307] The amount of the compounds of the present invention that can be combined with a carrier to produce a single-dose composition will vary depending on the host being treated and the specific administration modality. Preferably, the provided compositions should be formulated to enable the administration of inhibitors to patients receiving these compositions at doses between 0.01 and 100 mg / kg body weight / day.

[0308] 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, weight, general health, sex, diet, timing of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compounds of the present invention in the composition will also depend on the specific compounds in the composition.

[0309] The compounds and compositions according to the methods of the present invention can be administered in any amount and via any route of administration for the effective treatment of cancer, autoimmune diseases, primary immunodeficiency, proliferative diseases, inflammatory diseases, neurodegenerative or neurological diseases, schizophrenia, bone-related diseases, liver diseases, or heart diseases, or to reduce their severity. The exact amount required will vary from person to person, depending on the individual's species, age and general condition, the severity of the infection, the specific agent, the mode of administration, etc. In some embodiments, the compounds of the present invention are formulated into easily administered and uniformly dosed unit dosage forms.

[0310] As used herein, the terms “patient” or “individual” refer to an animal, preferably a mammal, and most preferably a human.

[0311] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, orally, or via nasal spray, depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention can be administered orally or parenterally at dose levels of about 0.01 mg to about 50 mg per kilogram of individual body weight per day, or for example, about 1 mg to about 25 mg, once or more daily to achieve the desired therapeutic effect.

[0312] Oral liquid dosage forms include (but are not limited to) pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitol fatty acid esters and mixtures thereof. Besides inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0313] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable mediators and solvents that can be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. Additionally, sterile non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids, such as oleic acid, are used in the preparation of injectable formulations.

[0314] Injectable formulations can be sterilized, for example, by filtration via a bacterial trapping filter or by incorporation of a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0315] To prolong the effect of the compounds of this invention, it is generally necessary to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous substances with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of the parenteral administration of the compound can be achieved by dissolving or suspending the compound in an oil-based medium. Injectable storage formulations are prepared by forming microcapsule matrices of the compound in a biodegradable polymer (such as poly(lactide-polyglycolic acid)). The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable storage formulations are also prepared by trapping the compound in liposomes or microemulsions compatible with body tissues.

[0316] Compositions for rectal or vaginal application are preferably suppositories prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers (e.g., cocoa butter, polyethylene glycol); or suppository waxes that are solid at ambient temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compounds.

[0317] Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) dissolution inhibitors, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0318] Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose / milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation field). They may optionally contain emulsifiers and may also have a composition that allows for the delayed release of the active ingredient, either exclusively or preferentially, in a portion of the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose / milk sugar and high molecular weight polyethylene glycol.

[0319] The active compound can also be in the form of microencapsulation with one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells (such as enteric coatings, release-controlled coatings, and other coatings well known in pharmaceutical formulation techniques). In these solid dosage forms, the active compound can be mixed with at least one inert diluent (such as sucrose, lactose, or starch). In normal practice, such dosage forms may also contain additional substances besides inert diluents, such as tablet-making lubricants and other tablet-making aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain a buffer. It may optionally contain an emulsifier and may also have a composition that allows it to release the active ingredient, either in a delayed manner or preferentially, in a portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0320] Dosage forms for topical or transdermal application of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. Under aseptic conditions, the active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservatives or buffers, if necessary. Ophthalmic formulations, ear drops, and eye drops are also covered within the scope of this invention. Additionally, this invention covers the use of transdermal patches, which have the added advantage of providing controlled delivery of the compounds to the body. The dosage forms can be manufactured by dissolving or dispensing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0321] In some embodiments, the composition is formulated for oral administration in tablet or capsule form. In some embodiments, the composition comprising X4P-001 is formulated for oral administration in capsule form.

[0322] In some embodiments, the provided method includes administering one or more capsules to a patient, said capsules containing 10 mg to 1200 mg of the X4P-001 active ingredient and one or more pharmaceutically acceptable excipients. In some embodiments, the capsules contain hard gelatin.

[0323] In some embodiments, the present invention provides a pharmaceutical composition comprising an X4P-001 composition, one or more diluents, disintegrants, lubricants, flow aids, and humectants. In some embodiments, the present invention provides a pharmaceutical composition comprising 10 mg to 1200 mg of the X4P-001 composition, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, croscarmellose sodium, sodium stearoyl fumarate, colloidal silica, and sodium lauryl sulfate. In some embodiments, the present invention provides a unit dosage form comprising a pharmaceutical composition comprising 10-200 mg of the X4P-001 composition, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, croscarmellose sodium, sodium stearoyl fumarate, colloidal silica, and sodium lauryl sulfate. In some embodiments, the present invention provides a unit dosage form comprising a pharmaceutical composition comprising an X4P-001 composition present in amounts of about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg. In some embodiments, the provided composition (or unit dosage form) is administered to a patient once daily, twice daily, three times daily, or four times daily. In some embodiments, the provided composition (or unit dosage form) is administered to a patient once daily or twice daily.

[0324] In some embodiments, the present invention provides a pharmaceutical composition comprising:

[0325] (a) The disclosed X4P-001 composition, by weight of the composition, comprises about 30-40%;

[0326] (b) about 20-25% microcrystalline cellulose by weight of the composition;

[0327] (c) about 30-35% of dicalcium phosphate dihydrate by weight of the composition;

[0328] (d) about 5-10% croscarmellose sodium by weight of the composition;

[0329] (e) Sodium stearoyl fumarate, about 0.5-2% by weight of the composition;

[0330] (f) about 0.1-1.0% colloidal silica by weight of the composition; and

[0331] (g) Sodium lauryl sulfate, about 0.1-1.0% by weight of the composition.

[0332] In some embodiments, the present invention provides a pharmaceutical composition comprising:

[0333] (a) The disclosed X4P-001 composition, by weight of the composition, comprises about 8-25%;

[0334] (b) about 65-85% microcrystalline cellulose by weight of the composition;

[0335] (c) about 2-10% croscarmellose sodium by weight of the composition;

[0336] (d) Sodium stearoyl fumarate, about 0.1-3% by weight of the composition; and

[0337] (e) about 0.05-0.7% colloidal silica by weight of the composition.

[0338] In some embodiments, the present invention provides a pharmaceutical composition comprising:

[0339] (a) The disclosed X4P-001 composition, by weight of the composition, comprises about 25-45%;

[0340] (b) about 10-35% microcrystalline cellulose by weight of the composition;

[0341] (c) about 15-45% of dicalcium phosphate dihydrate by weight of the composition;

[0342] (d) about 2-10% croscarmellose sodium by weight of the composition;

[0343] (e) Sodium stearoyl fumarate, about 0.3-2.5% by weight of the composition;

[0344] (f) about 0.05-1.2% colloidal silica, based on the weight of the composition; and

[0345] (g) Sodium lauryl sulfate, about 0.2-1.2% by weight of the composition.

[0346] In some embodiments, the present invention provides a pharmaceutical composition comprising:

[0347] (a) The disclosed X4P-001 composition, by weight of the composition, comprises about 35-75%;

[0348] (b) about 5-28% microcrystalline cellulose by weight of the composition;

[0349] (c) about 7-30% of dicalcium phosphate dihydrate by weight of the composition;

[0350] (d) about 2-10% croscarmellose sodium by weight of the composition;

[0351] (e) Sodium stearoyl fumarate, about 0.3-2.5% by weight of the composition;

[0352] (f) about 0.05-1.2% colloidal silica, based on the weight of the composition; and

[0353] (g) Sodium lauryl sulfate, about 0.2-1.2% by weight of the composition.

[0354] In some embodiments, the X4P-001 composition is present in amounts of about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg.

[0355] In some embodiments, the composition comprises about 37 wt% of the disclosed X4P-001 composition.

[0356] In some embodiments, the present invention provides a unit dosage form comprising the disclosed X4P-001 composition or pharmaceutical composition.

[0357] In some embodiments, the present invention provides a unit dosage form comprising a pharmaceutical composition, the pharmaceutical composition comprising:

[0358] (a) about 10-30% of the disclosed X4P-001 composition by weight of the composition;

[0359] (b) by weight of the composition, approximately 60-80% microcrystalline cellulose;

[0360] (c) about 5-10% croscarmellose sodium by weight of the composition;

[0361] (d) Sodium stearoyl fumarate, about 0.5-2% by weight of the composition; and

[0362] (e) about 0.1-1.0% colloidal silica by weight of the composition.

[0363] In some embodiments, the present invention provides a unit dosage form comprising a pharmaceutical composition, the pharmaceutical composition comprising:

[0364] (a) about 14.7% of the disclosed X4P-001 composition by weight of the composition;

[0365] (b) approximately 78.1% microcrystalline cellulose by weight of the composition;

[0366] (c) About 6.0% croscarmellose sodium based on the weight of the composition;

[0367] (d) Sodium stearoyl fumarate, about 1.0% by weight of the composition; and

[0368] (e) about 0.2% colloidal silica by weight of the composition.

[0369] In some embodiments, the present invention provides a unit dosage form comprising a pharmaceutical composition, the pharmaceutical composition comprising:

[0370] (a) about 10-20% of the disclosed X4P-001 composition by weight of the composition;

[0371] (b) about 25-40% microcrystalline cellulose by weight of the composition;

[0372] (c) about 35-55% of dicalcium phosphate dihydrate by weight of the composition;

[0373] (d) about 4-15% croscarmellose sodium by weight of the composition;

[0374] (e) Sodium stearoyl fumarate, about 0.3-2% by weight of the composition;

[0375] (f) about 0.1-1.5% colloidal silica by weight of the composition; and

[0376] (g) Sodium lauryl sulfate, about 0.1-1.5% by weight of the composition.

[0377] In some embodiments, the present invention provides a unit dosage form comprising a pharmaceutical composition, the pharmaceutical composition comprising:

[0378] (a) Approximately 12.85% of the disclosed X4P-001 composition by weight of the composition;

[0379] (b) approximately 31.92% microcrystalline cellulose by weight of the composition;

[0380] (c) about 44.4% of dicalcium phosphate dihydrate by weight of the composition;

[0381] (d) Approximately 8.33% croscarmellose sodium based on the weight of the composition;

[0382] (e) Sodium stearoyl fumarate, about 1.38% by weight of the composition;

[0383] (f) about 0.42% colloidal silica by weight of the composition; and

[0384] (g) Sodium lauryl sulfate, about 0.7% by weight of the composition.

[0385] International Patent Application No. PCT / US2016 / 066634 describes other compositions and methods of use of X4P-001, which are incorporated herein by reference in their entirety.

[0386] Since it may be necessary to administer a combination of active compounds, for example, for the purpose of treating a specific disease or symptom, within the scope of this invention, two or more pharmaceutical compositions (at least one of which contains a compound according to the invention) can be conveniently combined into a kit form suitable for co-administration of the compositions. Therefore, the kits of this invention comprise two or more individual pharmaceutical compositions (at least one of which contains the X4P-001 composition of the invention), and components for holding said compositions, such as containers, dispensing vials, or dispensing foil packs. Examples of such kits are familiar blister packs used for encapsulating tablets, capsules, etc.

[0387] The kits of the present invention are particularly suitable for administering different dosage forms (e.g., oral and parenteral) to facilitate the administration of individual compositions at different dosing intervals, or for titrating individual compositions against each other. To aid compliance, the kits typically include instructions for use and may be equipped with memory aids.

[0388] Use of compounds and pharmaceutically acceptable compositions

[0389] It has been found that certain impurities are generated during the synthesis of X4P-001 (e.g., the compounds shown in Table 1 above, or their stereoisomers or pharmaceutically acceptable salts). The isolation and characterization of various impurities can be used for multiple purposes. Generally, pharmaceutical compositions require high levels of purity to meet regulatory standards for drug quality and purity. For example, impurities often form during the synthesis of X4P-001, including degradation products or byproducts from manufacturing, which may interfere with the therapeutic effect of X4P-001 and / or, if present in sufficiently high amounts, cause toxicity. Therefore, it is desirable to be able to determine the presence and amount of such impurities and monitor the chemical purity of X4P-001, including stereochemical purity. For this purpose, it is important to identify, isolate, and chemically characterize impurities that can be used as standards in chromatographic procedures to confirm the purity of X4P-001.

[0390] Therefore, in one aspect, the present invention provides a method for preparing a disclosed compound or a pharmaceutically acceptable salt thereof, comprising contacting one or more suitable starting materials under conditions, for example, shown in the following examples, to prepare the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is used as a reference standard and / or as a reference standard in a method for determining the presence of impurities in a sample (e.g., a sample of a compound of formula I or a pharmaceutically acceptable salt thereof).

[0391] The present invention also provides a method for determining impurities, comprising: injecting a reference solution containing a compound of formula I or a pharmaceutically acceptable salt thereof into an HPLC column under a set of conditions to obtain a first HPLC chromatogram, wherein the amount and / or chemical characteristics of the compound present in the reference solution are known; injecting a sample solution containing a compound of formula I or a pharmaceutically acceptable salt thereof into an HPLC column under the same set of conditions to obtain a second HPLC chromatogram; and determining the presence and / or amount of the compound in the sample solution. In some embodiments, the reference solution is injected multiple times. In some embodiments, the determination comprises comparing the retention times of the peaks in the first HPLC chromatogram and the peaks in the second HPLC chromatogram to determine the presence of the compound in the sample solution. In other embodiments, the determination comprises quantifying the peak area of ​​the sample solution and the peak area of ​​the reference solution on the HPLC chromatogram and thereby estimating the amount of the compound in the sample solution. In some embodiments, the HPLC column is a reversed-phase column and uses a mobile phase elution column containing water, methanol, trifluoroacetic acid, or mixtures thereof.

[0392] The present invention also provides a method for determining the presence or amount of impurities in a sample comprising or substantially consisting of a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising: injecting a sample solution containing the material and, with the addition of a reference compound of known chemical structure (e.g., compound I-1, I-2, I-3, I-4, I-5, I-6, or I-7) into an HPLC column in a single or continuous injection manner; obtaining an HPLC chromatogram; and determining the presence and / or amount of the compound in the material. In some embodiments, the HPLC column is a reversed-phase column and elution is performed using a mobile phase comprising water, methanol, trifluoroacetic acid, or mixtures thereof. The method may further comprise documenting in writing the chemical properties of the compound and the amount of the compound as an impurity.

[0393] In some embodiments, the method further comprises recording in writing the chemical properties of the compound and the amount of the compound as an impurity in the material. In some cases, the amount of the compound in the material is determined as follows: (i) identifying the peak on the chromatogram corresponding to a peak on a control chromatogram of a compound known to have a structure of formula I-1, I-2, I-3, I-4, I-5, I-6, or I-7; (ii) identifying the peak on the chromatogram corresponding to the relative retention time of a compound known to have a structure of formula I-1, I-2, I-3, I-4, I-5, I-6, or I-7; and / or (iii) identifying the peak on the chromatogram corresponding to a known amount of a sharp peak of a compound known to have a structure of formula I-1, I-2, I-3, I-4, I-5, I-6, or I-7. In some embodiments, the HPLC column is a reversed-phase column, and a mobile phase elution column comprising water, methanol, trifluoroacetic acid, or mixtures thereof is used.

[0394] In some embodiments, the present invention provides compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or pharmaceutically acceptable salts thereof, with sufficient purity to enable their use as references or standards in a variety of analytical methods (e.g., HPLC, GC, SFC, LCMS), as described more fully below. In some embodiments, the compounds or pharmaceutically acceptable salts thereof may be isolated with a purity of at least 0.5%, at least 1%, at least 5%, at least 10%, at least 15%, at least 25%, at least 50%, at least 75%, at least 95%, or at least 97%. In some embodiments, the compounds or pharmaceutically acceptable salts thereof are isolated and / or packaged in solid form.

[0395] In another aspect, the present invention provides a method for determining the presence and / or amount of I-1, I-2, I-3, I-4, I-5, I-6, or I-7 or their pharmaceutically acceptable salts. For example, compounds or their pharmaceutically acceptable salts may form as impurities during the synthesis of X4P-001. As used herein, the term "impurity" may refer to degradation products generated during the storage of X4P-001 and / or byproducts formed in the chemical reactions that manufacture X4P-001. In one embodiment, the method comprises: injecting a reference solution containing I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, into an HPLC column under a set of conditions to obtain a first HPLC chromatogram, wherein the amount and / or chemical characteristics of I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, present in the reference solution are known; injecting a sample solution containing X4P-001 into an HPLC column under the same set of conditions to obtain a second HPLC chromatogram; and comparing the first HPLC chromatogram with the second HPLC chromatogram to determine the presence and / or amount of impurities (I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof). A reference solution can be formed by dissolving a sample (e.g., a solid sample) of I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, in a first solvent, and a sample solution can be formed by dissolving the solid sample in a second solvent. In some embodiments, the reference solution may contain other compounds, wherein the amount and / or characteristics of the other compounds are also known. In one embodiment, the sample (e.g., the sample solution) may contain X4P-001. It should be understood that the invention may cover other samples suspected of containing compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or pharmaceutically acceptable salts thereof.

[0396] In one embodiment, the presence of I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or their pharmaceutically acceptable salts, in the sample solution can be determined by comparing the retention time of a peak in a first HPLC chromatogram with the retention time of a peak in a second HPLC chromatogram. For example, a standard solution containing I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or their pharmaceutically acceptable salts, can produce a chromatogram with peaks corresponding to I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or their pharmaceutically acceptable salts, and having specific retention times. The sample solution can then be injected into an HPLC column under the same conditions as the standard solution, and the resulting chromatogram can be studied to determine whether there are peaks with the same retention times as the peaks of I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or their pharmaceutically acceptable salts, in the HPLC chromatogram corresponding to the standard solution. The presence of such peaks indicates the presence of I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, in the sample solution. In another embodiment, the amount of I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, in the sample solution can be determined by comparing the peak area in the first HPLC chromatogram with the peak area in the second HPLC chromatogram and thereby calculating the amount of I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, in the sample solution.

[0397] In some embodiments, the present invention provides a method for determining impurities in a material substantially composed of X4P-001, wherein a sample solution containing said material and additionally having a known chemical structure of a reference compound or a pharmaceutically acceptable salt thereof, as described herein, is injected into an HPLC column, and HPLC chromatography is obtained to determine the presence and / or amount of said compound in said material.

[0398] The method of the present invention may further include recording in writing the chemical properties of the compound and the amount of the compound as an impurity in the material.

[0399] In other embodiments, the present invention provides a method for determining impurities in a material substantially composed of X4P-001, wherein a solution in which the material is dissolved is injected into an HPLC column and an HPLC chromatogram is obtained to determine the amount of a compound having a known structure of formula I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, in the material. The chemical characteristics of the compound and the amount of the compound as an impurity in the material can then be recorded. The amount of the compound in the material can be determined as follows: (i) identifying a peak on the chromatogram corresponding to a peak on a reference chromatogram; (ii) identifying a peak on the chromatogram corresponding to a relative retention time of a compound having a known structure of formula I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof; and / or (iii) identifying a peak on the chromatogram corresponding to a known amount of a sharp peak of a compound having a known structure of formula I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof.

[0400] Some embodiments of the present invention can be applied to determine the amount and / or presence of I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, in a sample containing X4P-001. The sample may be a sample of recently manufactured material, or a sample stored over a given period of time. In one embodiment, a sample of X4P-001 may be stored and periodically analyzed using the methods described herein to determine the presence and / or amount of I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, in a sample that may have been formed by, for example, degradation of X4P-001. In some cases, the sample may be placed under stress conditions, i.e., conditions that intentionally promote the degradation of X4P-001, such as high temperature and / or high humidity, wherein the sample is periodically analyzed using the methods described herein to determine the presence and / or amount of I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, in the sample.

[0401] The compounds and compositions described herein are generally suitable for inhibiting CXCR4 or its mutants. Some of the compounds and compositions described herein have been found to be suitable for treating, preventing, and / or reducing the risk of CXCR4-related diseases, conditions, or symptoms.

[0402] In one aspect, the present invention provides a method for inhibiting the activity of CXCR4 or its mutants in a patient, the method comprising administering the disclosed X4P-001 composition to the patient. In other embodiments, the present invention provides a method for treating a patient in need of a condition mediated by CXCR4 or its mutants, the method comprising administering the disclosed X4P-001 composition or a pharmaceutically acceptable composition thereof according to the present invention to the patient. Such conditions are described in detail herein.

[0403] Certain methods of treating diseases or conditions using X4P-001 are described in PCT application PCT / US2018 / 038776, filed June 21, 2018, the entire contents of which are incorporated herein by reference. The compounds and compositions disclosed in this invention are suitable for such methods of treating diseases or conditions.

[0404] In some embodiments, compositions containing X4P-001 or a pharmaceutically acceptable salt thereof are administered orally in doses from about 200 mg to about 1200 mg daily. In some embodiments, the dosage composition may be administered twice daily in divided doses, about 12 hours apart. In other embodiments, the dosage composition may be administered once daily. The terminal half-life of X4P-001 has been determined to be typically between about 12 and about 24 hours, or about 14.5 hours. Oral doses may be from about 100 mg to about 1200 mg once or twice daily. In some embodiments, the dose of X4P-0001 or a pharmaceutically acceptable salt thereof suitable for use in the present invention is from about 200 mg to about 800 mg daily. In other embodiments, the range of doses of X4P-001 or a pharmaceutically acceptable salt thereof suitable for use in the present invention may be from about 200 mg to about 600 mg, from about 400 mg to about 800 mg, from about 600 mg to about 1000 mg, or from about 800 mg to about 1200 mg daily.

[0405] In one aspect, the present invention provides a method of treating cancer (e.g., the cancer described herein) by administering an effective amount of the disclosed X4P-001 composition to a patient in need. In some embodiments, the method includes simultaneously or sequentially co-administering an effective amount of one or more other therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one other therapeutic agent. In some embodiments, the method includes co-administering two other therapeutic agents. In some embodiments, the disclosed compound or composition works synergistically with a combination of one or more other therapeutic agents to prevent or reduce immune evasion and / or angiogenesis evasion of the cancer. In some embodiments, the patient has previously received another anticancer agent, such as adjuvant therapy or immunotherapy. In some embodiments, the cancer is refractory.

[0406] In some embodiments, the disease, condition, or symptom associated with CXCR4 is selected from proliferative disorders, Alzheimer's disease, HIV, rheumatoid arthritis, or pulmonary fibrosis. In some embodiments, the disease, condition, or symptom is a hyperplastic disorder, such as cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, kidney cancer, lung cancer, or melanoma. In some embodiments, the cancer is selected from renal cell carcinoma (RCC), refractory RCC, or clear cell RCC (ccRCC).

[0407] In some embodiments, the present invention provides a method for treating a patient suffering from cancer manifested as a solid tumor. In some embodiments, the patient has kidney cancer, kidney tumor, kidney cancer (including clear cell carcinoma and papillary renal cell carcinoma), ovarian cancer, or melanoma.

[0408] The provided compounds are CXCR4 inhibitors and are therefore suitable for treating one or more conditions associated with CXCR4 activity. Accordingly, in some embodiments, the present invention provides a method for treating CXCR4-mediated conditions comprising the step of administering the disclosed X4P-001 composition or a pharmaceutically acceptable composition thereof to a patient in need.

[0409] In one aspect, the present invention provides a method for treating cancer in a patient in need, wherein the method comprises administering to the patient a combination of the disclosed X4P-001 composition and one or more other therapeutic agents (e.g., one or more immunostimulatory therapeutic compounds).

[0410] In some embodiments, one or more immunostimulatory compounds are selected from elotuzumab, mifamurtide, toll-like receptor agonists or activators, or RORγt activators.

[0411] In some embodiments, the method further comprises administering a third therapeutic agent, such as an immune checkpoint inhibitor, to the patient. In some embodiments, the method comprises administering three therapeutic agents to a patient in need, selected from the disclosed X4P-001 composition, immunostimulatory therapeutic compounds, and immune checkpoint inhibitors.

[0412] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0413] In another aspect, the present invention provides a method for treating cancer in a patient in need, wherein the method comprises administering to the patient a combination of the disclosed X4P-001 composition and one or more other therapeutic agents selected from indoleamine (2,3)-dioxygenase (IDO) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors, histone deacetylase (HDAC) inhibitors, CDK4 / CDK6 inhibitors, or phosphatidylinositol 3-kinase (PI3K) inhibitors.

[0414] In some embodiments, the IDO inhibitor is selected from epacadostat, indoximod, capmanitib, GDC-0919, PF-06840003, BMS:F001287, Phy906 / KD108, or an enzyme that breaks down kynurenine.

[0415] In some embodiments, the PARP inhibitor is selected from olaparib, such as rucaparib or niraparib.

[0416] In some embodiments, the HDAC inhibitor is selected from vorinostat, romidepsin, panobinostat, belinostat, entinostat, or chidamide.

[0417] In some embodiments, the CDK 4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, or trilaciclib.

[0418] In some embodiments, the method further comprises administering a third therapeutic agent, such as an immune checkpoint inhibitor, to the patient. In some embodiments, the method comprises administering a therapeutic agent selected from three of the following to a patient in need: the disclosed X4P-001 composition; a second therapeutic agent selected from indoleamine (2,3)-dioxygenase (IDO) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors, histone deacetylase (HDAC) inhibitors, CDK4 / CDK6 inhibitors, or phosphatidylinositol 3-kinase (PI3K) inhibitors; and a third therapeutic agent selected from immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0419] In some embodiments, the PI3K inhibitor is selected from idelalisib, alpelisib, taselisib, pictilisib, copanlisib, duvelisib, PQR309, or TGR1202.

[0420] In another aspect, the present invention provides a method for treating cancer in a patient in need, wherein the method comprises administering the disclosed X4P-001 composition in combination with one or more other therapeutic agents to the patient, said other therapeutic agents being selected from platinum-based therapeutic agents, taxanes, nucleoside inhibitors, or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapid cell proliferation.

[0421] In some embodiments, the platinum-based therapeutic agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, or satraplatin.

[0422] In some embodiments, taxane is selected from paclitaxel, docetaxel, albumin-bound paclitaxel, cabazitaxel, or SID530.

[0423] In some embodiments, the therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or otherwise interferes with the replication of rapidly proliferating cells is selected from trabectedin, mechlorethamine, vincristine, temozolomide, cytarabine, lomustine, azacitidine, omacetaxine mepesuccinate, Erwinia chrysanthemi asparaginase, eribulin mesylate, capacetrine, bendamustine, ixabepilone, nelarabine, cclofabine, trifluridine, or tipiracil.

[0424] In some embodiments, the method further comprises administering a third therapeutic agent, such as an immune checkpoint inhibitor, to the patient. In some embodiments, the method comprises administering a therapeutic agent selected from the following three therapeutic agents to a patient in need: the disclosed X4P-001 composition; a second therapeutic agent selected from platinum-based therapeutic agents, taxanes, nucleoside inhibitors, or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapid cell proliferation; and a third therapeutic agent selected from immune checkpoint inhibitors.

[0425] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0426] In some embodiments, any of the above methods further includes the steps of obtaining a biological sample from the patient and measuring the amount of disease-related biomarkers.

[0427] In some embodiments, the biological sample is a blood sample.

[0428] In some embodiments, disease-related biomarkers are selected from circulating CD8+ T cells or the CD8+ T cell:Treg cell ratio.

[0429] In some embodiments, the cancer is selected from: hepatocellular carcinoma, ovarian cancer, ovarian epithelial carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatobiliary carcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; undifferentiated thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic duct carcinoma or pancreatic cancer; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or neurotubular cell tumor.

[0430] In some embodiments, the cancer is selected from: hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, undifferentiated thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic duct carcinoma, pancreatic cancer, glioma, neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or neurotubular cell tumor.

[0431] In some embodiments, the present invention provides a method for treating cancer, said cancer being a solid tumor, such as sarcoma, carcinoma, or lymphoma, the method comprising the step of administering the disclosed X4P-001 composition to a patient in need. Solid tumors typically comprise abnormal tissue masses, said abnormal tissue masses typically excluding cysts or fluid-filled areas. In some embodiments, the cancer is selected from renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer. Cancer; hepatobiliary duct cancer; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; undifferentiated thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic duct carcinoma or pancreatic cancer; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenström macroglobulinemia; or neurotubular cell tumor.

[0432] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, undifferentiated thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic duct carcinoma, pancreatic cancer, glioma, brain cancer, neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or neurotubular cell tumor.

[0433] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial carcinoma, ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, undifferentiated thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic duct carcinoma, pancreatic cancer, glioma, neurofibroma-1-bound malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or neurotubular cell tumor.

[0434] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer or ovarian tumor. In some embodiments, the cancer is ovarian epithelial carcinoma. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is undifferentiated thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic duct carcinoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibroma-1 associated MPNST. In some embodiments, the cancer is Waldenström macroglobulinemia. In some embodiments, the cancer is neuroblastoma.

[0435] In some embodiments, the present invention provides a method of treating cancer selected from leukemia or blood cancers, comprising administering an effective amount of the disclosed X4P-001 composition to a patient in need, optionally in combination with another therapeutic agent (such as those described herein). In some embodiments, the cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or virus-induced leukemia.

[0436] In some embodiments, the patient has a resectable solid tumor, meaning the patient's tumor is considered easily removable surgically. In other embodiments, the patient has an unresectable solid tumor, meaning the patient's tumor has been considered difficult to remove completely or partially surgically.

[0437] In some embodiments, the cancer is an advanced cancer, such as advanced kidney cancer or advanced renal cell carcinoma.

[0438] In some embodiments, the present invention provides a method of treating refractory cancer in a patient in need, comprising administering to the patient in need an effective amount of the disclosed X4P-001 composition or a pharmaceutical composition thereof, optionally in combination with another therapeutic agent (such as those described herein).

[0439] In some embodiments, the patient has previously received a protein kinase inhibitor. In some embodiments, the patient has previously received a VEGF-R antagonist. In some embodiments, the patient has previously received an immune checkpoint inhibitor. In some embodiments, the patient has previously received an immune checkpoint inhibitor selected from the following: Nivolumab (… Bristol-Myers Squibb, pelizumab Merck, or ipilimumab Bristol-Myers Squibb.

[0440] In some embodiments, the disclosed X4P-001 composition is administered to a patient who is fasting.

[0441] Cellular proliferative disorders

[0442] The present invention is characterized by methods and compositions for diagnosing and prognosing proliferative disorders (e.g., cancer) and for treating these disorders by targeting CXCR4. Proliferative disorders described herein include, for example, cancer, obesity, and proliferation-dependent diseases. Such disorders can be diagnosed using methods known in the art.

[0443] cancer

[0444] In some embodiments, cancer includes (but is not limited to) leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström's macroglobulinemia, multiple myeloma, heavy chain disease. And solid tumors, such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphoendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor). Tumors, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, undifferentiated glioblastoma (GBM, also known as neuroblastoma), neuroblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0445] In some embodiments, the cancer is a glioma, astrocytoma, undifferentiated glioblastoma (GBM, also known as glioblastoma), neuroblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0446] In some embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., Grade I - pilocytic astrocytoma, Grade II - low-grade astrocytoma, Grade III - undifferentiated astrocytoma, or Grade IV - glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a subependymal tumor, a neuroblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primitive neuroectodermal (PNET) tumor, or a schwannoma. In some embodiments, the cancer is a type more commonly found in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a neuroblastoma, an optic nerve glioma, a pineal tumor, a primitive neuroectodermal tumor (PNET), or a rhabdomyosarcoma. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or a pediatric patient.

[0447] In another embodiment, cancers include (but are not limited to): mesothelioma, hepatobiliary (liver and bile duct) cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, gastrointestinal (stomach, colon, rectum, and duodenum) cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, and parathyroid cancer. Adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axonoma, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the aforementioned cancers.

[0448] Other features of the present invention are methods and compositions for diagnosing, prognosing, and treating virus-related cancers, including human immunodeficiency virus (HIV)-associated solid tumors, human papillomavirus (HPV)-16-positive incurable solid tumors, and adult T-cell leukemia caused by human T-cell leukemia type I (HTLV-I), said adult T-cell leukemia being a highly aggressive form of CD4+ T-cell leukemia in which HTLV-I clones are integrated into leukemia cells (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746); as well as virus-related tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, head and neck squamous cell carcinoma, and Merkel cell carcinoma. (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; also see https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886; https: / / clinicaltrials.gov / ct2 / show / NCT02426892)

[0449] In some embodiments, the present invention provides a method of treating a tumor in a patient in need, comprising administering the disclosed X4P-001 composition to the patient. In some embodiments, the tumor includes any of the cancers described herein. In some embodiments, the tumor includes melanoma carcinoma. In some embodiments, the tumor includes breast cancer. In some embodiments, the tumor includes lung cancer. In some embodiments, the tumor includes small cell lung cancer (SCLC). In some embodiments, the tumor includes non-small cell lung cancer (NSCLC).

[0450] In some embodiments, the tumor is treated by inhibiting its further growth. In some embodiments, the tumor is treated by reducing its size (e.g., volume or mass) relative to the size of the tumor before treatment by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99%. In some embodiments, the tumor is treated by reducing the number of tumors in the patient relative to the number of tumors before treatment by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99%.

[0451] Primary immunodeficiency

[0452] In some embodiments, the present invention provides a method for treating one or more conditions, diseases, and / or symptoms, wherein the conditions, diseases, or symptoms include (but are not limited to) primary immunodeficiency diseases or symptoms, the method comprising administering an effective amount of the disclosed X4P-001 composition to a patient in need. The primary immunodeficiency that can be treated by the method of this invention includes: warts, hypogammaglobulinemia, infections, myelodysplastic syndrome (WHIM) syndrome; severe congenital neutropenia (SCN), especially those caused by G6PC3 deficiency (McDermott et al. (2010) Blood 116:2793-2802); GATA2 deficiency (single MAC syndrome) (Maciejweski-Duval et al. (2015) Journal of Leukocyte Biology 5MA0815-288R (electronic publication before print); idiopathic CD4+ T lymphopenia (ICL); and Wiskott-Aldrich syndrome.

[0453] In other embodiments, the present invention relates to a method for inhibiting CXCR4 activity in a biological sample, comprising the step of contacting the biological sample with the disclosed X4P-001 composition.

[0454] According to another embodiment, the present invention relates to a method for inhibiting the activity of CXCR4 or its mutant in a biological sample, comprising the step of contacting the biological sample with the disclosed X4P-001 composition. In other embodiments, the present invention relates to a method for inhibiting the activity of CXCR4 or its mutant in a biological sample, comprising the step of contacting the biological sample with the disclosed X4P-001 composition.

[0455] As used herein, the term “biological sample” includes (but is not limited to) cell cultures or extracts thereof; biopsy material or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

[0456] Co-administration with other therapeutic agents

[0457] In one aspect, the present invention provides a method of treating cancer (e.g., the cancer described herein) by administering the disclosed X4P-001 composition to a patient in need. In some embodiments, the method includes simultaneously or sequentially co-administering an effective amount of one or more other therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one other therapeutic agent. In some embodiments, the method includes co-administering two other therapeutic agents. In some embodiments, the disclosed X4P-001 composition works synergistically with a combination of one or more other therapeutic agents to prevent or reduce immune evasion and / or angiogenesis evasion of the cancer. In some embodiments, the patient has previously received another anticancer agent, such as adjuvant therapy or immunotherapy. In some embodiments, the cancer is refractory.

[0458] Certain methods of treating a disease or condition by co-administering X4P-001 with one or more other agents are described in PCT application No. PCT / US2018 / 038776, filed June 21, 2018, the entire contents of which are incorporated herein by reference.

[0459] Depending on the specific symptom or disease to be treated, the compositions of the present invention may also contain other therapeutic agents that are normally administered for the treatment of said symptom. As used herein, other therapeutic agents that are normally administered for the treatment of a specific disease or symptom are referred to as “the disease or symptom suitable for treatment”.

[0460] In some embodiments, other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors suitable for use in this invention include: bevacizumab (… Genentech / Roche, an anti-VEGF monoclonal antibody; ramucirumab ( Eli Lilly, an anti-VEGFR-2 antibody; and ziv-aflibercept, also known as a VEGF scavenger. Regeneron / Sanofi; VEGFR inhibitors, such as regorafenib. Bayer; vandetanib AstraZeneca; axitinib Pfizer; and lenvatinib Eisai; Raf inhibitors, such as sorafenib ( Bayer and Onyx; dabrafenib Novartis; and vemurafenib Genentech / Roche); MEK inhibitors, such as cobimetanib ( Exelexis (Genentech / Roche); Trametinib ( Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib ( Novartis); Nilotinib Novartis); dasatinib Bristol-Myers Squibb); Bosutinib Pfizer); and ponatinib (Pfizer); Ariad Pharmaceuticals; Her2 and EGFR inhibitors, such as gefitinib ( AstraZeneca); Erlotinib Genentech / Roche / Astellas); Lapatinib Novartis); Afatinib Boehringer Ingelheim; osimertinib (targeting activated EGFR, AstraZeneca); and brigatinib (… Areyad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozantinib ( Exelexis; and multi-kinase inhibitors, such as sunitinib. Pfizer); Pazopanib Novartis); ALK inhibitors, such as crizotinib ( Pfizer); Ceritinib Novartis); and alectinib ( Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib. Famosli / Janssen (Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (… Novartis).

[0461] Other kinase inhibitors and VEGF-R antagonists under development and potentially applicable to this invention include tivozanib (Aveo Pharmacecuticals); vatalanib (Bayer / Novartis); lucitamb (Clovis Oncology); dovitinib (TKI258, Novartis); chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); and ratotinib. IY5511, Il-Yang Pharmaceuticals (S.Korea); ruxolitinib (… Incyte Corporation; PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo); and motesanib (Amgen / Takeda).

[0462] In some embodiments, other therapeutic agents are mTOR inhibitors that inhibit cell proliferation, angiogenesis, and glucose uptake. Approved mTOR inhibitors suitable for use in this invention include everolimus (…). Novartis); temsirolimus ( Pfizer); and sirolimus ( Pfizer).

[0463] In some embodiments, other therapeutic agents are poly-ADP-ribose polymerase (PARP) inhibitors. This invention is applicable to the present invention.

[0464] Approved PARP inhibitors include olaparib. AstraZeneca; such as rucaparib. Clovis Oncology; and niraparib ( Tesaro). Other PARP inhibitors under investigation that may be used in this invention include talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene Inc.).

[0465] In some embodiments, other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. Approved PI3K inhibitors suitable for use in this invention include idelalisib (…). Gilead Sciences. Other PI3K inhibitors that may be used in investigations in this invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvexib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0466] In some embodiments, other therapeutic agents are proteasome inhibitors. Approved proteasome inhibitors suitable for use in this invention include bortezomib. Takeda); carfilzomib( Amgen; and Essazomi Takeda).

[0467] In some embodiments, other therapeutic agents are histone deacetylase (HDAC) inhibitors. Approved HDAC inhibitors suitable for use in this invention include vorinostat (…). Merck); Romidesin Celgene; panobinostat Novartis); and belinostat ( Spectrum Pharmaceuticals). Other HDAC inhibitors that may be used in investigations in this invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (…). HBI-8000, Chipscreen Biosciences, China.

[0468] In some embodiments, other therapeutic agents are CDK inhibitors, such as CDK 4 / 6 inhibitors. Approved CDK 4 / 6 inhibitors suitable for use in this invention include palbociclib. Pfizer); and ribociclib ( Novartis). Other CDK 4 / 6 inhibitors that may be used in the investigations in this invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0469] In some embodiments, other therapeutic agents are indoleamine (2,3)-dioxygenase (IDO) inhibitors. IDO inhibitors that may be used in investigations in this invention include epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); and enzymes that break down kynurenine (kynurenase, Kyn Therapeutics).

[0470] In some embodiments, other therapeutic agents are growth factor antagonists, such as antagonists of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or their receptor (EGFR). Approved PDGF antagonists that can be used in this invention include olaratumab. Eli Lilly and Company). Approved EGFR antagonists that can be used in this invention include cetuximab (Cetuximab). Eli Lilly and Company); Necitumumab ( Eli Lilly and Company); panitumumab ( Amgen); and osimertinib (targeting activated EGFR, AstraZeneca).

[0471] In some embodiments, other therapeutic agents are aromatase inhibitors. Approved aromatase inhibitors that can be used in this invention include exemestane (…). Pfizer); Anatazol AstraZeneca) and letrozole ( Novartis).

[0472] In some embodiments, other therapeutic agents are hedgehog pathway antagonists. Approved hedgehog pathway inhibitors that can be used in this invention include sonidegib (…). Sun Pharmaceuticals; and vismodegib Genentech and Genentech are both used to treat basal cell carcinoma.

[0473] In some embodiments, other therapeutic agents are folic acid inhibitors. Approved folic acid inhibitors suitable for use in this invention include pemetrexed (…). Eli Lilly and Company).

[0474] In some embodiments, other therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. Investigative CCR4 inhibitors suitable for use in this invention include mogamulizumab (…). Kyowa Hakko Kirin (Japan)

[0475] In some embodiments, other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. IDH inhibitors that may be used in investigations for this invention include AG120 (SergeGene; NCT02677922); AG221 (SergeGene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); and IDH305 (Novartis, NCT02987010).

[0476] In some embodiments, other therapeutic agents are arginase inhibitors. Arginase inhibitors under investigation for use in this invention include AEB1102 (polyethylene glycolated recombinant arginase, Aeglea Biotherapeutics), which is being investigated in a Phase 1 clinical trial for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0477] In some embodiments, other therapeutic agents are glutaminase inhibitors. Among the glutaminase inhibitors under investigation that may be used in this invention is CB-839 (Gallicia Biosciences).

[0478] In some embodiments, other therapeutic agents are antibodies that bind to tumor antigens (i.e., proteins expressed on the cell surface of tumor cells). Approved antibodies that bind to tumor antigens and can be used in this invention include rituximab (…). Genentech / Biogen Idec); ofatumumab (anti-CD20, GlaxoSmithKline; obinutuzumab (anti-CD20, Genentech); Iberitumomab (anti-CD20 and yttrium-90, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Janssen Biotech; dinutuximab (anti-glycolipid GD2, United Therapeutics; trastuzumab (anti-HER2, Genentech); Ado-trastuzumab emtansine (anti-HER2, fused with emtansine), Genentech); and pertuzumab (anti-HER2, Genentech); and brentuximab vedotin (an anti-CD30 drug conjugate). SeattleGenetics.

[0479] In some embodiments, other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors suitable for use in this invention include irinotecan (Irinotecan). Merrimack Pharmaceuticals; Topotecan GlaxoSmithKline). Topoisomerase inhibitors under investigation that can be used in this invention include pixantrone (…). CTI Biopharmaceuticals (CTIBiopharma)

[0480] In some embodiments, other therapeutic agents are nucleoside inhibitors, or other therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapid cell proliferation. Such nucleoside inhibitors or other therapeutic agents include trabectedin (a guanidine alkylating agent). Janssen Oncology, a cancer drug, and mechlorethamine (an alkylating agent). Aktelion Pharmaceuticals; Vincristine ( Eli Lilly and Company; Teva Pharmaceuticals; Talon Therapeutics; temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazine-1-yl)-imidazol-4-carboxamide (MTIC)). Merck); cytarabine injection (ara-C, an antimetabolite cytidine analog, Pfizer); lomustine (alkylating agent, Bristol-Myers Squibb; NextSource Biotechnology; azacitidine (a pyrimidine nucleoside analog of cytidine, Celgene); Homoharringtonine (homoharringtonine ester) (protein synthesis inhibitor, Taihua Pharmaceutical); Erwinia chrysogenum asparaginase (an enzyme used to deplete asparagine). Lundbeck; EUSA Pharma); eribulin mesylate (a microtubule inhibitor, an antimitotic drug based on tubulin). Eisai; Cabazitaxel (microtubule inhibitor, an antimitotic drug based on tubulin). Sanofi-Aventis; capacetrine (a thymidylate synthase inhibitor); Genentech); Bendamustine (a bifunctional nitrogen mustard derivative, believed to form interstrand DNA crosslinks), Cephalon / Teva; ixabepilone (a semi-synthetic analogue of epothilone B, a microtubule inhibitor, a tubulin-based antimitotic drug) Bristol-Myers Squibb); nelarabine (a prodrug of deoxyguanosine analogues, a nucleoside metabolism inhibitor, Novartis); Clorafabine (a prodrug of ribonucleotide reductase inhibitors, a competitive inhibitor of deoxycytidine, Sanofi-Aventis; and trifluridine and tipiracil (nucleoside analogs and thymidine phosphorylase inhibitors based on thymidine). Taiho Oncology (a cancer-fighting pharmaceutical company)

[0481] In some embodiments, other therapeutic agents are platinum-based therapeutic agents, also known as platinum. Platinum causes DNA cross-linking, and therefore primarily inhibits DNA repair and / or DNA synthesis in rapidly regenerating cells (e.g., cancer cells). Approved platinum-based therapeutic agents that can be used in this invention include cisplatin (…). Bristol-Myers Squibb); Carboplatin Bristol-Myers Squibb; in addition, Taihua; Pfizer); oxaliplatin ( Sanofi-Aventis; and nedaplatin ( Shionogi, Inc. Other platinum-based therapeutic agents that have undergone clinical trials and can be used in this invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agenix).

[0482] In some embodiments, other therapeutic agents are taxane compounds that induce microtubule rupture, which is essential for cell division. Approved taxane compounds that can be used in this invention include paclitaxel (Pacific paclitaxel). Bristol-Myers Squibb, docetaxel ( Sanofi-Aventis; Sun Pharmaceuticals), albumin-bound paclitaxel ( Abraxis / Celgene and cabazitaxel Sanofi-Aventis. Other taxane compounds that have undergone clinical trials and can be used in this invention include SID530 (SK Chemicals) (NCT00931008).

[0483] In some embodiments, other therapeutic agents are inhibitors of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotic agents that can be used in this invention include venetoclax (…). AbbVie / Genentech); and blinatumomab Amgen. Other therapeutic agents that have undergone clinical testing and can be used in this invention to target apoptosis proteins include navitoclax (ABT-263, Abbott) and the BCL-2 inhibitor (NCT02079740).

[0484] As used in this article, the term "checkpoint inhibitor" refers to agents designed to prevent cancer cells from evading a patient's immune system. One of the main mechanisms of antitumor immune breakdown is known as "T-cell exhaustion," which is caused by prolonged exposure to antigens that have induced upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

[0485] PD-1 and co-inhibitory receptors, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuators (BTLA; CD272), T-cell immunoglobulin and mucin domain-3 (Tim-3), and lymphocyte activation gene-3 (Lag-3; CD223), are commonly referred to as checkpoint regulators. They act as molecular "gatekeepers," determining whether cell cycle progression and other intracellular signaling processes should proceed based on extracellular information.

[0486] In one respect, checkpoint inhibitors are biological therapeutic agents or small molecules. In another respect, checkpoint inhibitors are monoclonal antibodies, humanized antibodies, fully human antibodies, fusion proteins, or combinations thereof. In yet another respect, checkpoint inhibitors inhibit checkpoint proteins selected from the following: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In another aspect, checkpoint inhibitors interact with ligands selected from the following checkpoint proteins: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In one aspect, checkpoint inhibitors are immunostimulants, T-cell growth factors, interleukins, antibodies, vaccines, or combinations thereof. In another aspect, interleukins are IL-7 or IL-15. In a particular aspect, interleukin is glycosylated IL-7. In yet another aspect, vaccines are dendritic cell (DC) vaccines.

[0487] Checkpoint inhibitors include any agent that statistically significantly blocks or inhibits inhibitory pathways of the immune system. Such inhibitors may include small molecule inhibitors or may include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrated checkpoint molecules that can be targeted for blocking or inhibition include (but are not limited to) CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, and 2B4 (belonging to the CD2 molecule family and present in all NK, γδ, and memory CD8 molecules). + (αβ) T cell-expressed), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include (but are not limited to) B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies or their antigen-binding fragments, other binding proteins, biological therapeutics, or small molecules that bind to and block or inhibit the activity of one or more of the following: CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Illustrative immune checkpoint inhibitors include tramemumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), and nivolumab (…). The list includes, but is not limited to, BMS-936558 (anti-PDL1 antibody), CT-011 (anti-PDL1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody) and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0488] In some embodiments, the immune checkpoint inhibitor is selected from PD-1 antagonists, PD-L1 antagonists, and CTLA-4 antagonists. In some embodiments, a CXCR4 antagonist (e.g., X4P-001 or a pharmaceutically acceptable salt thereof) is administered in combination with nivolumab (an anti-PD-1 antibody). Bristol-Myers Squibb); Perizumab (anti-PD-1 antibody) Merck); Ipilimumab (anti-CTLA-4 antibody) Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody) AstraZeneca); or atezolizumab (anti-PD-L1 antibody). Genentech).

[0489] In some embodiments, other immune checkpoint inhibitors suitable for use in this invention include REGN2810 (Regeneron), an anti-PD-1 antibody that has been tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), squamous cell carcinoma of the skin (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1 and is in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avirumab (… Pfizer / Merck KGaA, also known as MSB0010718C, is a fully human IgG1 anti-PD-L1 antibody that is in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, kidney cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; and PDR001 (Novartis), an inhibitory antibody that binds to PD-1 that is in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Trimetazaprine (CP-675,206; AstraZeneca) is a fully human monoclonal antibody against CTLA-4, which is being investigated in clinical trials for a variety of indications, including: mesothelioma, colorectal cancer, renal cell carcinoma, breast cancer, lung cancer, non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell carcinoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic liver cancer, hepatocellular carcinoma, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic undifferentiated thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody (NCT02694822) currently being investigated in a Phase 1 clinical trial for advanced solid tumors.

[0490] Nivolumab ( BMS-93568 / MDX1106 (Bristol-Myers Squibb) is a fully human IgG4 monoclonal antibody that acts as an immunomodulator by binding to the planned cell death 1 (PD-1) receptor and selectively blocking its interaction with its ligands PD-L1 and PD-L2. The structure and other properties of nivorumab are described at http: / / www.drugbank.ca / drugs / DB09035 (accessed March 14, 2016), the contents of which are hereby incorporated herein by reference. Nivorumab is approved for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy; as a single agent for certain types of unresectable or metastatic melanoma; for the treatment of unresectable or metastatic melanoma, or in combination with ipilimumab for the treatment of unresectable or metastatic melanoma; and for the treatment of metastatic non-small cell lung cancer that has progressed during or after platinum-based chemotherapy. In addition, nivorumab has been tested or mentioned as a potential therapy for other oncology indications, including solid tumors; skin melanoma; glioblastoma; glioma; gliosarcoma; astrocytoma; brain cancer; leukemia; acute myeloid leukemia; chronic myeloid leukemia; chronic lymphocytic leukemia; advanced liver cancer or hepatocellular carcinoma; uveal melanoma; prostate cancer; pancreatic tumors and pancreatic cancer; bladder cancer; colorectal cancer; myelodysplastic syndrome; Hodgkin lymphoma; non-Hodgkin lymphoma; multiple myeloma; cervical cancer; endometrial cancer; uterine cancer; ovarian cancer and ovarian tumors; peritoneal cancer; squamous cell carcinoma of the head and neck; gastric cancer; esophageal cancer; Kaposi's sarcoma; breast tumors, breast cancer and breast cancer; osteosarcoma; soft tissue sarcoma; meningioma; and mesothelioma.

[0491] In a phase 3 trial, over 800 patients with advanced clear cell renal cell carcinoma who had received prior therapy with one or two anti-angiogenic regimens were randomized to receive either nivorumab at 3 mg / kg body weight (intravenously every two weeks) or everolimus tablets at 10 mg / kg body weight (orally daily). Patients treated with nivorumab showed longer median overall survival, a lower hazard ratio for death, and an objective response rate (25%) higher with nivorumab than with everolimus (5%) (P<0.001), with a lower incidence of treatment-related grade 3 or 4 adverse events (Motzer et al. (2015), New England Journal of Medicine, 373:1803-1813). Therefore, in some embodiments, the present invention provides a method for treating advanced clear cell renal cell carcinoma comprising administering an effective amount of an CXCR4 antagonist (e.g., X4P-001 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof) in combination with nivolumab or everolimus to a patient in need, optionally wherein the patient has received prior treatment with an anti-angiogenic therapy regimen.

[0492] Generally, the dosage of nivorumab or other immune checkpoint inhibitors applicable to this invention will depend on the patient's body size, weight, age and condition, the severity of the disease or symptoms, and the prescribing physician's judgment. For example, in current prescribing labels for unresectable or metastatic renal cell carcinoma, the recommended course of nivorumab administration is 3 mg / kg, administered intravenously over 60 minutes, every two weeks, until disease progression or unacceptable toxicity occurs. Clinicians may, at their discretion, increase the prescribed dose of nivorumab, for example, by increasing the dose and / or frequency, based on individual tolerability. Clinicians may, at their discretion, discontinue nivorumab administration or reduce the dose in the event of significant side effects, taking into account the warnings provided in the prescribing information. In some embodiments, in the method of this invention, nivorumab is administered according to the above-described labeling guidelines.

[0493] In some embodiments, the present invention provides a method of treating a patient by administering a combination of a CXCR4 antagonist (e.g., X4P-001 or a pharmaceutically acceptable salt thereof) and an immunostimulatory therapeutic agent. Approved immunostimulatory therapeutic agents that may be used in the present invention include elotuzumab (an anti-SLAMF7 antibody). Bristol-Myers Squibb). Immunostimulating compounds under investigation that can be used in this invention include mifamurtide (…). Takeda Oncology.

[0494] Another immunostimulatory agent that can be used in this invention is recombinant human interleukin-15 (rhIL-15). rhIL-15 has been tested in clinical trials as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). Another immunostimulatory agent that can be used in this invention is recombinant human interleukin-12 (rhIL-12). Another suitable IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a synthetic fusion complex consisting of endogenous IL-15 and a soluble IL-15-binding protein IL-15 receptor α chain (IL15:sIL-15RA), which has been tested in a phase 1 clinical trial for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). Recombinant human interleukin-12 (rhIL-12) has been tested in clinical trials for a variety of cancer indications, such as as a therapy for lymphoma (NM-IL-12, Neumedicines, Inc.) (NCT02544724 and NCT02542124).

[0495] Another example of immunostimulation is the use of oncolytic viruses. In some embodiments, the present invention provides a method of treating a patient by administering the disclosed X4P-001 composition in combination with an immunostimulatory therapy (e.g., an oncolytic virus). Approved immunostimulatory oncolytic viruses that can be used in the present invention include talimogenelaherparepvec (an attenuated live herpes simplex virus). Anjin).

[0496] As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production (e.g., the conversion of substrates androstenedione and testosterone into estrone and estradiol, respectively). The term includes (but is not limited to) steroids, particularly atamestane, exemestane, and formestane; and particularly nonsteroids, particularly aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is marketed under the trade name Aromasin. TMFor Sale. Formistan is sold under the trademark Lentaron. TM For sale. Faldrozol is sold under the brand name Afema. TM For sale. Anastrozole is sold under the brand name Arimidex. TM For sale. Letrozole is marketed under the brand name Femara. TM or Femar TM For sale. Ammonialumine is sold under the trademark Orimeten. TM Available for sale. The combinations of the present invention, comprising chemotherapeutic agents that act as aromatase inhibitors, are particularly suitable for treating hormone receptor-positive tumors, such as breast tumors.

[0497] As used herein, the term "anti-estrogenic" refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes (but is not limited to) tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Novadex. TM For Sale. Rhinoxetine hydrochloride is marketed under the brand name Evista. TM For Sale. Fluvestralc is available under the brand name Faslodex. TM Application. The combinations of the present invention, which contain chemotherapeutic agents as anti-estrogens, are particularly suitable for treating estrogen receptor-positive tumors, such as breast tumors.

[0498] As used herein, the term "antiandrogen" refers to any substance capable of inhibiting the biological effects of androgens, including (but not limited to) bicalutamide (Casodex). TM As used herein, the term "gonadotropin-releasing hormone agonist" includes (but is not limited to) abarelix, goserelin, and goserelin acetate. Goserelin may be marketed under the brand name Zoladex. TM Apply.

[0499] As used herein, the term "topoisomerase I inhibitor" includes (but is not limited to) topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecian and the macromolecular camptothecian conjugate PNU-166148. Irinotecan may be marketed, for example, in its marketing form (e.g., under the trademark Camptosar). TM Topotecan is administered under the trademark Hycamptin. TM sell.

[0500] As used herein, the term "topoisomerase II inhibitor" includes (but is not limited to) anthracyclines, such as doxorubicin (including liposome formulations, such as Caelyx). TM The drug contains daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones mitoxantrone and losoxantrone; and podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trademark Etopophos. TM For sale. Teniposide is sold under the trademark VM 26-Bristol. Cranberries are sold under the trademark Acriblastin. TM or Adriamycin TM For Sale. Farmorubicin trademark. TM For Sale. Idamycin is marketed under the trademark Zavedos. TM For sale. Mitoxantrone is sold under the trademark Novantron.

[0501] The term "microtubule activator" refers to microtubule stabilizing, microtubule destabilizing, and tubulin polymerization inhibitors, including (but not limited to) taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vincaine or vincaine sulfate, vincristine or vincaine sulfate, and vinorelbine; discodermolide; colchicine and epothilone and their derivatives. Pacific paclitaxel is marketed under the trademark Taxol. TM For Sale. Docetaxel is marketed under the trademark Taxotere. TM For Sale. Vinblastin sulfate under the trademark Vinblastin RP. TM For Sale. Changchun New Alkali Sulfate under the Trademark Farmistin TM sell.

[0502] As used herein, the term "alkylating agent" includes (but is not limited to) cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trademark Cyclostin. TM For Sale. Ifosfamide is marketed under the trademark Holoxan. TM sell.

[0503] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylases and have antiproliferative activity. This includes (but is not limited to) succinyl aniline isohydroxamic acid (SAHA).

[0504] The term "anti-metabolic antimetabolite" includes (but is not limited to) 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (such as 5-azacytidine and decitabine), methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trademark Xeloda. TM For Sale. Gemzathabine is sold under the trademark Gemzar. TM sell.

[0505] As used herein, the term "platinum compound" includes (but is not limited to) carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin may be sold, for example, in its form of trade (e.g., under the trademark Carboplatin). TM Oxaliplatin can be applied, for example, in its marketable form (e.g., under the trademark Eloxatin). TM ) application.

[0506] As used herein, the term "compounds that target / reduce the activity of protein or lipid kinases or protein or lipid phosphatases, or other anti-angiogenic compounds" includes (but is not limited to) protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce or inhibit platelet-derived growth factor receptor (PDGFR) activity, such as compounds that target, reduce or inhibit PDGFR activity, particularly compounds that inhibit PDGF receptors, such as N-phenyl-2-pyrimidinylamine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit fibroblast growth factor receptor (FGFR) activity; c) compounds that target, reduce or inhibit insulin-like growth factor receptor I (IGF-IR) activity, such as compounds that target, reduce or inhibit IGF-IR activity, particularly compounds that inhibit the kinase activity of IGF-I receptors, or antibodies that target the extracellular domain of IGF-I receptors or their growth factors; d) compounds that target, reduce or inhibit T Compounds that target, reduce, or inhibit the activity of the rk receptor tyrosine kinase family, or pterin B4 inhibitors; e) compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce, or inhibit the activity of Ret receptor tyrosine kinases; g) compounds that target, reduce, or inhibit the activity of Kit / SCFR receptor tyrosine kinases, such as imatinib; h) compounds that target, reduce, or inhibit the activity of C-kit receptor tyrosine kinases (part of the PDGFR family), such as those targeting, reducing, or inhibiting c-kit receptor tyrosine kinases. Compounds containing enzyme family activity, particularly those inhibiting the c-Kit receptor, such as imatinib; i) compounds that target, reduce, or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase), and mutants, such as N-phenyl-2-pyrimidinylamine derivatives, such as imatinib or nilotinib (AMN107), PD180970, AG957, NSC. 680410, PD173955 from Parke Davis, or dasatinib (BMS-354825); j) compounds that target, reduce or inhibit the activity of protein kinase C (PKC) and Raf family members, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC family members and / or cyclein-dependent kinase family (CDK) members, including astrocytocin derivatives such as midostaurin;Examples of other compounds include UCN-01, safingol, BAY43-9006, bryozoxin 1, perifosine, ilmofosine, RO 318220 and RO320432, GO 6976, lsis 3521, LY333531 / LY379196, isoquinoline compounds, FTI, PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, including imatinib mesylate (Gleevec); TM Or Tyrphostin, such as Tyrphostin A23 / RG-50810, AG 99, Tyrphostin AG 213, Tyrphostin AG 1748, Tyrphostin AG 490, Tyrphostin B44, Tyrphostin B44(+) enantiomers, Tyrphostin AG 555, AG 494, Tyrphostin AG556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantane benzoate; NSC 680410, Adafustin); l) Compounds that target, reduce, or inhibit the activity of epidermal growth factor family receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, such as compounds that target, reduce, or inhibit the activity of epidermal growth factor receptor family members, particularly those that inhibit EGF receptor tyrosine kinase family members (e.g., EGF receptor, ErbB2, ErbB3, and ErbB4) or bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180, compounds, proteins, or antibodies, trastuzumab (Herceptin) TM Cetuximab (Erbitux) TM(i) Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, reduce or inhibit c-Met receptor activity, such as compounds that target, reduce or inhibit c-Met activity, especially compounds that inhibit the kinase activity of c-Met receptors. Or antibodies that target the extracellular domain of c-Met or bind to HGF; n) compounds that target, reduce or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including (but not limited to) PRT-062070, SB-1578, baricitinib, pacritinib, molotinib, VX-509, AZD-1480, TG-101348, and toluene. Tofacitinib and ruxolitinib; o) compounds that target, reduce, or inhibit the kinase activity of PI3 kinase (PI3K), including (but not limited to) ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, and datoxib. ctolisib), XL-147, XL-765 and idelalisib; and q) compounds that target, reduce or inhibit signal transduction effects of the hedgehog protein (Hh) or smoothing receptor (SMO) pathway, including (but not limited to) cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0507] As used herein, the term "PI3K inhibitor" includes (but is not limited to) compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including (but not limited to) PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors suitable for use in this invention include (but are not limited to) ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0508] As used herein, the term "Bcl-2 inhibitor" includes (but is not limited to) compounds with inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including (but not limited to) ABT-199, ABT-731, ABT-737, apogossypol, pan-Bcl-2 inhibitors of Ascenta, curcumin (and its analogues), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogues; see WO2008118802), navitoclax (and its analogues; see US7390799), NH-1 (Shenyang Pharmaceutical University). Bcl-2 inhibitors include (University of Michigan), obatoclax (and its analogues, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (University of Michigan), and venetoclax. In some embodiments, Bcl-2 inhibitors are small molecule therapeutic agents. In some embodiments, Bcl-2 inhibitors are peptide mimics.

[0509] As used herein, the term "BTK inhibitor" includes (but is not limited to) compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including (but not limited to) AVL-292 and ibrutinib.

[0510] As used herein, the term “SYK inhibitor” includes (but is not limited to) compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including (but not limited to) PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0511] Other examples of BTK inhibitory compounds and the conditions that can be treated by combining such compounds with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0512] Other examples of SYK-inhibiting compounds and the conditions that can be treated by combining such compounds with the compounds of the present invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

[0513] Other examples of PI3K inhibitory compounds and the conditions that can be treated by combining such compounds with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

[0514] Other examples of JAK inhibitory compounds and conditions that can be treated in combination with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[0515] Other anti-angiogenic compounds include those with an alternative mechanism of activity (e.g., independent of protein or lipid kinase inhibition), such as thalidomide. TM ) and TNP-470.

[0516] Examples of proteasome inhibitors suitable for use in combination with the compounds of the present invention include (but are not limited to) bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), halosporin A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0517] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases are, for example, phosphatase 1 inhibitors, phosphatase 2A inhibitors, or CDC25 inhibitors, such as okadaic acid or its derivatives.

[0518] Compounds that induce cell differentiation include (but are not limited to) retinoic acid, α-tocopherol, γ-tocopherol or δ-tocopherol, or α-tocotrienol, γ-tocotrienol or δ-tocotrienol.

[0519] As used herein, the term cyclooxygenase inhibitor includes (but is not limited to) Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib. TM Etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroaniline)phenylacetic acid, lumiracoxib.

[0520] As used herein, the term "bisphosphonate" includes (but is not limited to) etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is marketed under the trademark Didronel. TM For Sale. Chlorphosphonic acid is marketed under the trademark Bonefos. TM For Sale. Tiludrotic acid is marketed under the trademark Skelid. TM For Sale. Pamidronate is available as a product of Aredia. TM For Sale. Alendronate is marketed under the brand name Fosamax. TM For Sale. Ibandronic acid is marketed under the trademark Bondranat. TM For Sale. Risedronic acid is marketed under the trademark Actonel.TM For Sale. Zoledronic acid is marketed under the trademark Zometa. TM For Sale. The term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus. ), everolimus (Certican) TM ), CCI-779 and ABT578.

[0521] As used herein, the term "heparinase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparin sulfate. This term includes (but is not limited to) PI-88. As used herein, the term "biological response modifier" refers to lymphokines or interferons.

[0522] As used herein, the term "inhibitor of Ras carcinogenic isoforms (e.g., H-Ras, K-Ras, or N-Ras)" refers to compounds that target, reduce, or inhibit the carcinogenic activity of Ras; for example, "farnesyltransferase inhibitors," such as L-744832, DK8G557, or R115777 (Zarnestra). TM As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces, or inhibits telomerase activity. Compounds that target, reduce, or inhibit telomerase activity are particularly compounds that inhibit telomerase receptors, such as telomestatin.

[0523] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include (but are not limited to) bengamide or its derivatives.

[0524] As used herein, the term "proteasome inhibitor" refers to compounds that target, reduce, or inhibit proteasome activity. Compounds that target, reduce, or inhibit proteasome activity include (but are not limited to) bortezomib (Velcade). TM ) and MLN341.

[0525] As used herein, the term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) includes (but is not limited to) collagen peptide mimicry and non-peptide mimicry inhibitors, tetracycline derivatives such as the oxime peptide mimicry inhibitor batimastat and its orally bioavailable analogues marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996.

[0526] As used herein, the term "compound for the treatment of hematologic malignancies" includes (but is not limited to) FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arasulfuran cytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds that target, reduce or inhibit undifferentiated lymphoma kinases.

[0527] Compounds that target, reduce, or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R), particularly compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, astrosporin derivatives, SU11248, and MLN518.

[0528] As used herein, the term "HSP90 inhibitor" includes (but is not limited to) compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin-proteosome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are particularly compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG) (a geldanamycin derivative); other geldanamycin-related compounds; radicicol; and HDAC inhibitors.

[0529] As used herein, the term "antiproliferative antibody" includes (but is not limited to) trastuzumab. TM Trastuzumab-DM1, Erbitux, Bevacizumab (Avastin) TM ), rituximab ( ), PRO64553 (anti-CD40) and 2C4 antibody. Antibody refers to complete monoclonal antibody, polyclonal antibody, multispecific antibody formed by at least two complete antibodies, and antibody fragment, as long as it exhibits the desired biological activity.

[0530] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly those for the treatment of AML. Specifically, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs suitable for the treatment of AML (e.g., doxorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, adamycin, carboplatinum, and PKC412).

[0531] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogues of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors (such as sodium butyrate and salinomycinoxime acid (SAHA)) inhibit the activity of enzymes called histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A, and compounds disclosed in US 6,552,065, including (but not limited to) N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, particularly lactate. As used herein, somatostatin receptor antagonists refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell destruction methods refer to methods such as ionizing radiation. The term "ionizing radiation" as used above and below refers to ionizing radiation in the form of electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the relevant field. See Hellman, Principles of Radiation Therapy, Cancer, Principles and Practice of Oncology, eds. Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

[0532] This also includes EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including (but not limited to) fludarabine and / or cytosine ara-C, 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0533] This also includes, in particular, compounds, proteins, or monoclonal antibodies against VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salts, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin TM Endostatin TM ; anthranilamide; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibodies, angiozyme (RPI 4610) and bevacizumab (Avastin) TM ).

[0534] As used in this article, photodynamic therapy refers to the treatment or prevention of cancer using certain chemicals called photosensitizing compounds. Examples of photodynamic therapy include, for example, Visudyne. TM Treatment with compounds such as porfimer sodium.

[0535] As used in this article, angiogenesis-inhibiting steroids refer to compounds that block or inhibit angiogenesis, such as anecocave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0536] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0537] Other chemotherapeutic compounds include (but are not limited to) alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or hybrid compounds or compounds with other or unknown mechanisms of action.

[0538] The structures of active compounds identified by code number, generic name, or trademark can be obtained from the actual version of the standard summary, The Merck Index, or from databases such as Patents International (e.g., IMS World Publications).

[0539] The compounds of this invention can also be used in combination with known treatment methods (e.g., hormone administration or radiation). In some embodiments, the provided compounds are used as radiosensitizers, particularly for treating tumors that are poorly sensitive to radiotherapy.

[0540] The compounds of this invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may be in a fixed combination form or may involve alternating or independent administration of the compounds of this invention and one or more other therapeutic compounds, or a fixed combination combined with one or more other therapeutic compounds. Furthermore, the compounds of this invention can be administered in particular in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof for cancer therapy. In the case of other treatment strategies, long-term therapy and adjuvant therapy are also possible, as described above. Other possible therapies include maintenance therapy after tumor regression, or even chemopreventive therapy (e.g., for patients at risk).

[0541] These other agents may be administered separately from the disclosed X4P-001 composition as part of a multiple-dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the disclosed X4P-001 composition to form a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or at intervals (typically within five hours of each other).

[0542] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to the invention. For example, the compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or mixed into a single unit dosage form. Therefore, the present invention provides a single unit dosage form comprising the compound of the invention, other therapeutic agents, and pharmaceutically acceptable carriers, adjuvants, or mediators.

[0543] The amounts of the disclosed X4P-001 composition and other therapeutic agents (present in those compositions containing another therapeutic agent as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific administration modality. The compositions of the present invention should preferably be formulated to allow administration at doses between 0.01 and 100 mg per kilogram of body weight per day.

[0544] In compositions that include other therapeutic agents, the other therapeutic agents and the compounds of the present invention can act synergistically. Therefore, the amount of the other therapeutic agents in such compositions will be lower than that required in a single therapy using only that particular therapeutic agent. In such compositions, the other therapeutic agents can be administered at doses between 0.01 and 1,000 μg per kilogram of body weight per day.

[0545] The amount of other therapeutic agents present in the compositions of the present invention will not exceed the amount normally applied in compositions containing that therapeutic agent as the sole active agent. Preferably, the range of the amount of other therapeutic agents in the X4P-001 compositions disclosed in the present invention will be about 50% to 100% of the amount normally present in compositions containing that agent as the sole active agent.

[0546] The compounds of the present invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, artificial blood vessels, stents, and catheters. Vascular stents have been used, for example, to overcome restenosis (the narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the devices with a pharmaceutically acceptable composition containing a kinase inhibitor. Implantable devices coated with the compounds of the present invention are another embodiment of the invention.

[0547] To provide a more comprehensive understanding of the invention described herein, the following examples are illustrated. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0548] Examples

[0549] As depicted in the examples below, in some exemplary embodiments, compounds are prepared according to the following general procedure. It should be understood that although the general method describes the synthesis of some of the compounds of the present invention, the following general method and other methods known to those skilled in the art can be applied to all compounds as described herein and to subclasses and types of each of these compounds.

[0550] Methods for the preparation of certain compounds applicable to this invention are disclosed in Crawford et al. (2008), *Organic Process Res.Dev.*, 12:823-830; US 7,354,934, WO 00 / 56729, USSN 60 / 232,891 and USSN 60 / 234,510; and An H.; Wang T.; Mohan V.; Griffey RH; Cook PD, *Tetrahedron*, 1998, 54, 3999-4012; the entire contents of each of these references are incorporated herein by reference. Those skilled in the art will be able to modify such disclosed methods using only conventional experiments to provide alternatives for the preparation, testing, and analysis of the compounds of this invention.

[0551] Example 1: Methylimine impurity

[0552] According to high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis, the peak located at a relative retention time (RRT) of 1.13 indicates [M+1]. +The value was 362 m / z (12 mass units higher than X4P-001). The peak disappeared after several hours if X4P-001 was dissolved in an acidic aqueous medium. The molecular weight and chemical behavior of the impurity indicate the presence of a methylimine structure on the primary amine. Without wishing to be bound by any particular theory, it is believed that compound I-1 is formed in the presence of formaldehyde or a formaldehyde source. The imine impurity I-1 and its possible formation pathway are shown in the following flowchart 1.

[0553] Process 1

[0554]

[0555] Example 2: N-formyl impurities

[0556] HPLC-MS analysis revealed an RRT peak at 1.28 with a [M+1]+ concentration of 378 m / z (28 mass units higher than X4P-001), indicating it to be an N-formyl derivative of X4P-001. This was confirmed by independent synthesis. X4P-001 reacted directly with ethyl formate to produce an N-formyl compound, I-2, which, according to MS and HPLC data, was identical to the batch impurities. The formation of the formate ester is shown in step 2 below.

[0557] Process 2

[0558]

[0559] Example 3: Aldehyde impurities

[0560] The RRT 1.14 peak is characteristic of I-6. Not wishing to be bound by any particular theory, it is believed that I-6 originates from the oxidation of the amine on the alkyl chain of X4P-001, as shown in the following flowchart 3:

[0561] Process 3

[0562]

[0563] Example 4: Acetamide impurities

[0564] HPLC-MS analysis revealed an RRT peak at 1.39 with a [M+1]+ concentration of 392 m / z (42 mass units higher than X4P-001), characteristic of X4P-001 acetamide. This is formed by the reaction of X4P-001 with isopropyl acetate crystallization solvent at high temperature, as shown in process 4. The structure was confirmed by the independent synthesis of the acetamide impurity. The reaction of X4P-001 with acetic anhydride yielded acetamide I-5, which, according to MS and HPLC data, was identical to the batch impurity. Isopropyl acetate is used in some methods for manufacturing the free base of X4P-001 using p-hydroxybenzoate of X4P-001.

[0565] Process 4

[0566]

[0567] Example 5: Benzimidazole impurities

[0568] According to LC-MS analysis, the RRT 1.67 peak showed [M+1]+ at 481 m / z (131 mass units higher than X4P-001), which is characteristic of M+ benzimidazole compound I-3. It forms as an impurity during the protection of 2-chloromethylbenzimidazole with a tert-butoxycarbonyl (Boc) group, as shown in step 5 below. The impurity undergoes alkylation during the N-alkylation reaction (step 2 in the synthesis of X4P-001) and is therefore present throughout the remainder of the manufacturing process.

[0569] Process 5

[0570]

[0571] The independent synthesis involved the reaction of secondary amine 2918 with boc-2-chloromethylbenzimidazole 2890 (I-9), followed by the removal of the protecting group to give I-3, which, according to MS and HPLC, was identical to the observed impurity.

[0572] Example 6: Acetalamine impurities

[0573] When the p-hydroxybenzoate of X4P-001 is produced by the reaction of imine impurities with p-hydroxybenzoic acid, acetal amine impurities are present. This impurity is relevant to the manufacture of X4P-001 in methods using the p-hydroxybenzoate of X4P-001 or its intermediates.

[0574] The structure and origin of acetal amine impurity I-4 are shown in the following process 6.

[0575] Process 6

[0576]

[0577] Example 7: Basis for setting acceptance criteria for organic impurities

[0578] Impurity results for X4P-001 and its p-hydroxybenzoic acid (PHB) salt batches are shown in Table 2 below. The X4P-001 batches used in the initial toxicology studies were primarily used to establish impurity specifications. PHB salt batches of X4P-001 used in longer-term toxicology studies are also shown in Table 2. The total impurities in these six batches ranged from <0.05% to 1.4%, with only one batch containing >0.05% of a single unlisted impurity at the 0.1% level. Considering the limited batch sizes produced and the impurity distribution of the X4P-001 batches used in toxicology and clinical studies, the total impurity release specification for the active pharmaceutical ingredient (API) was set at ≤3.0% w / w, with no single unlisted impurity exceeding 0.2% w / w (0.5% for stability) (Table 2). Except for imine impurities (which were set at 1.1% based on the level of such impurities used in toxicological studies), the content of individual listed impurities and p-hydroxybenzoic acid is ≤0.5% w / w. A single batch of the product (not shown in Table 2), namely X4P-001 batch 3-1 (Table 4), provides a high-purity drug substance with total impurities of 1.20% w / w and unlisted impurities greater than 0.07% w / w, except for imine impurities (0.62% w / w). Analysis of the clinical X4P-001 drug substance batch yielded a purity of 99.3% w / w and a chiral purity >99% ee.

[0579] Table 2

[0580]

[0581] Abbreviations used:

[0582] a Values ​​below the LOQ (limit of quantification)

[0583] b The only relevant specification for the clinical active pharmaceutical ingredient (API) of free base manufactured using X4P-001 p-hydroxybenzoate as a starting material is NA = Not Applicable.

[0584] ND = Not detected

[0585] NLT = not less than

[0586] NMT = not exceeding

[0587] NR = No report

[0588] Typically, the wt% of each impurity is determined by HPLC and is measured initially or after storage, and optionally continuously during the shelf life of the X4P-001 composition. In some embodiments, the impurity content is measured after storing the composition under stress conditions (elevated temperature, humidity, or both, to estimate the effects of long-term storage under environmental conditions). Thus, in some embodiments, the present invention provides an X4P-001 composition comprising: not more than 1.1% imine (I-1); not more than 0.3% formyl (I-2); not more than 0.4% benzimidazole (I-3); not more than 0.5% acetalamine (I-4); not more than 0.5% acetamide (I-5); not more than 0.4% aldehyde (I-6); not more than 0.3% de-BOC NT-316 (I-7); and not more than 0.2% of a single unlisted impurity. Additionally, when manufacturing a free base clinical active pharmaceutical ingredient via X4P-001 p-hydroxybenzoate, the composition contains no more than 1.0% PHB. In some embodiments, there is no more than 3.0% total impurities. In some embodiments, the enantiomer excess (%ee) of the R-enantiomer is not less than 97.0%.

[0589] Example 8: Identification of impurities that develop after storage

[0590] Stability test sample (PTL / ST / 0511) of X4P-001 stored at 25°C / 60% relative humidity (25 / 60) for three months by MET / CR / 1448 analysis showed the formation of two unknown impurities.

[0591] Unknown 1-RRT 1.14

[0592] Unknown 2-RRT 1.24

[0593] RRT 1.14 impurity is also a major degradation product of PTL / DA / 0175 under high temperature and high humidity (80℃ / 80%RH) conditions.

[0594] Overview

[0595] During the stability study, two impurities formed in X4P-001 at t=3 months at 25°C / 60%RH and in the forced degradation study at high temperature / high humidity were identified by LC-MS.

[0596]

[0597] experiment

[0598] Instrument parameters

[0599] The studies were conducted on a GMP Waters Alliance HPLC system connected to a ZQ 2000 single quadrupole MS. Data were collected and entered into Empower 2 software.

[0600] The analytical and impurity methods used for X4P-001 (MET / CR / 1448) are not suitable for mass spectrometry because they use TFA as a modifier in the eluent, and TFA significantly suppresses ionization. Initially, this was used to replace 0.15% v / v formic acid. The flow rate was also varied to allow direct connection to the MS inlet (maximum flow rate 0.3 mL / min) and the gradient was adjusted accordingly.

[0601] HPLC conditions 1

[0602] Column: Zorbax Bonus-RP, 150x4.6mm, 3.5μm

[0603] Injection volume: 100μL

[0604] Detection: UV@220nm (190-400nm)

[0605] MS ES+100-700Da, ES-100-700Da

[0606] Mobile phase A: 0.15% formic acid / water

[0607] Mobile phase B: 0.15% formic acid / MeCN

[0608] Time (minutes) ％A ％B 0.0 95 5 6 95 5 51 5 95 60 5 95 60.1 95 5 75 95 5

[0609] Flow rate: 0.3 mL / min

[0610] Column temperature: Ambient

[0611] Operation time: 75 minutes

[0612] MS tuning parameters 1

[0613] Ion source options ES+ ES- Capillary voltage (kV) 3.5 4 Tapered hole voltage (V) 25 25 Extractor (V) 3 0 RF lens 0.4 3 Source temperature ℃ 150 150 Desolventization temperature (°C) 150 150 Desolventizing gas flow rate (L / hr) 300 300 Conical orifice gas flow rate (L / hr) 50 50 Analyzer Options LM Res 15 15 HM Res 15 15 Ion energy 1.8 2 Multiplier 521 521

[0614] X4P-001 is not retained under these conditions because it requires ion pairing with TFA. The chromatogram and resulting mass spectra are shown in [image / description]. Figure 5 middle.

[0615] Experimental masses for both impurities were obtained. All mass spectra presented have been background corrected (regions acquired immediately before and after the peak of interest).

[0616] Unknown 1MET / CR / 1448RRT 1.14[M+H]=m / z 349.2

[0617] Unknown 2MET / CR / 1448RRT 1.24[M+H]=m / z 392.3

[0618] The inventors hypothesized the possibility of co-elution of the impurity of interest with other impurities. Therefore, the sample was processed using the chromatographic conditions specified in MET / CR / 1448. The concentration and injection volume were increased to counteract the ionization inhibition caused by TFA.

[0619] HPLC conditions 2

[0620] Column: Zorbax SB-C8, 150mm x 4.6mm, 3.5μm

[0621] Guard post: Zorbax SB-C8, 12.5mm x 4.6mm, 5μm

[0622] Injection volume: multiple

[0623] Detection: 270nm UV

[0624] Mobile phase: Mobile phase A: 0.2% TFA / water

[0625] Mobile phase B: 0.1% TFA / acetonitrile

[0626] Gradient elution

[0627] Time (minutes) ％A ％B Flow rate (mL / min) 0 92 8 0.8 5 90 10 0.8 15 89 11 0.8 25 80 20 0.8 28 80 20 0.8 37 55 45 0.8 44 20 80 0.8 47 20 80 0.8 48 92 8 1.2 53 92 8 1.2 54 92 8 0.8 55 92 8 0.8

[0628] Initial flow rate: 0.8 mL / min (referring to the gradient time schedule), 4:1 split to MS inlet.

[0629] Column temperature: 25℃

[0630] Operation time: 55 minutes

[0631] The MS parameters are as described in tuning parameter 1 above.

[0632] Several samples of X4P-001, in which the impurities of interest have been detected, were prepared in methanol at concentrations of 1 or 10 mg / mL:

[0633] PTL / ST / 0511, Batch 3-1, 25 / 60t = 3 months

[0634] PTL / DA / 0175 degradation sample: 80℃ / 80% relative humidity (80 / 80), t=1 and 7 days.

[0635] The obtained data is displayed on Figure 6-9 middle.

[0636] Mass spectrometry data obtained under HPLC condition 2 have been confirmed:

[0637] Unknown 1MET / CR / 1448RRT 1.14[M+H]=m / z 349.2

[0638] Unknown 2MET / CR / 1448RRT 1.24[M+H]=m / z 392.3

[0639] Finally, the chromatographic conditions were modified to allow the flow to enter the MS without splitting. The results obtained from HPLC condition 3 are shown in... Figure 10 middle.

[0640] HPLC conditions 3

[0641] Column: Zorbax SB-C8, 150mm × 4.6mm, 3.5μm

[0642] Guard post: Zorbax SB-C8, 12.5mm x 4.6mm, 5μm

[0643] Injection volume: multiple

[0644] Detection: 270nm UV

[0645] Mobile phase: Mobile phase A: 0.2% TFA / water

[0646] Mobile phase B: 0.1% TFA / acetonitrile

[0647] Gradient elution

[0648] Time (minutes) ％A ％B 0 92 8 13.3 90 10 39.9 89 11 66.50 80 20 74.48 80 20 98.42 55 45 117 20 80 125 20 80 125.10 92 8 140 92 8

[0649] Flow rate: 0.3 mL / min, directly into the MS inlet.

[0650] Column temperature: 25℃

[0651] Operating time: 140 minutes

[0652] The MS parameters are as described in tuning parameter 1 above.

[0653] Results Discussion

[0654] All obtained spectra confirmed the initial results, although the peak response and resolution of X4P-001 differed.

[0655] Unknown 1MET / CR / 1448RRT 1.14[M+H]=m / z 349.2

[0656] Unknown 2MET / CR / 1448RRT 1.24[M+H]=m / z 392.3

[0657] Unknown 1RRT 1.14 (aldehyde)

[0658] The molecular weight of 348 indicates nitrogen loss (nitrogen rule). This is consistent with the oxidation of amines on alkyl chains to produce aldehydes. The assumed structure is shown below.

[0659]

[0660] Empirical formula = C21H24N4O

[0661] Monoisotopic mass = 348.195

[0662] Unknown 2RRT 1.24 (acetamide)

[0663] The molecular weight of 391 is consistent with that of the I-5 acetamide impurity (formed by the reaction of X4P-001 with residual isopropyl acetate). The structure of I-5 is shown below.

[0664]

[0665] Empirical formula = C 23 H 29 N5O

[0666] Monoisotopic mass = 391.237

[0667] in conclusion

[0668] Two unknown impurities were identified from the obtained mass spectrometry data. Impurity RRT 1.14 is an aldehyde oxidation product and impurity RRT 1.24 is acetamide impurity I-5.

[0669] Example 9: Improvements to the X4P-001 manufacturing process to reduce and control impurity content

[0670] introduction

[0671] Final step in the prior preparation of GMP active pharmaceutical ingredients to support clinical studies (Version 2 process); Figure 2 The process (shown in the diagram) uses compounds NT-316 and AMD-2890 (I-9) as starting materials. Following an investigation into the structure and origin of the most significant impurities formed during this preparation, a new process (Version 3) has been developed, providing improved control over impurity distribution and API crystallization. Furthermore, this effort has significantly enhanced the reproducibility and robustness of the final steps in the process.

[0672] Description of the synthetic route and key intermediates

[0673] API X4P-001 is assembled from two key components (NT-316 and AMD-2890) in a combined manner through two steps. The penultimate intermediate, AMD-11070, is not separated but is immediately converted into API, which crystallizes after the processing.

[0674] Procedures 7 and 8 show the synthesis of the API molecule X4P-001.

[0675] Process 7: Early steps in the synthesis of X4P-001.

[0676]

[0677] Step 8: Post-synthesis steps in X4P-001 synthesis.

[0678]

[0679] The key fragment AMD-2890 was synthesized from RM-396 (I-8) in a single step. Although RM-396 is commercially available, its purity varies greatly depending on its source. HPLC analysis has shown that commercially sourced materials can exhibit high purity (>97 area %), however, true wt% purity has been found to be as low as 90%. RM-396 may have undergone self-alkylation, resulting in a diverse mixture of oligomeric impurities. Only after converting RM-396 to AMD-2890 can a stable compound with a well-defined impurity distribution be obtained.

[0680] Another key component is NT-316, a well-characterized, stable crystalline compound that contains most of the API structure. NT-316 is obtained through aggregation synthesis via the reaction of NT-319 with the chiral amine salt NT-272. NT-272 is a stable crystalline compound that can be obtained through custom synthesis.

[0681] NT-319 is a highly unstable intermediate that cannot be isolated without degradation. It is prepared from commercially available ABA in three steps (without isolating the intermediate in each step). The purity of ABA is difficult to control because it is not only an oily substance but also lacks UV chromophores, which severely limits its accurate analytical characterization methods.

[0682] Based on the above, the impurity distribution of the API is determined by the combination of the impurity distribution of the two fragments, NT-316 and AMD-2890 (I-9), and the exact conditions of the last two chemical steps (performed under GMP control).

[0683] In summary, the chemical purity and enantiomer purity of NT-316 and the chemical purity of AMD-2890 are directly related to the chemical purity and enantiomer purity of API (X4P-001).

[0684] Explanation of key process changes

[0685] Figure 3This demonstrates how the new process (Process 3) differs from the previous version (Process 2). In Process 2, it was confirmed that the API must first be isolated in its 4-hydroxybenzoate form. This salt was then converted to the corresponding free base via a separate step to obtain the API.

[0686] The chemical steps of the third-generation process remain unchanged. Compound NT-316 reacts with AMD-2890 (I-9), and the resulting product (Tri-Boc) is not separated but immediately deprotected to yield crude API. However, the method used to separate API has changed significantly in the third-generation process.

[0687] The most significant impurities produced by the second-generation process are imine A (RRT 1.08) and N-formyl B (RRT 1.28), as shown in process 9. These impurities have been shown to originate from the use of dichloromethane as a solvent during crude API extraction. Additionally, the formation of acetamide impurity C (RRT 1.37) may be related to the use of isopropyl acetate as a solvent in the final crystallization of the API free base.

[0688] Step 9: Impurities found in bulk raw materials

[0689]

[0690] Therefore, the dichloromethane and isopropyl acetate used in the second edition for processing and separating X4P-001 were replaced in the third edition with 1-butanol and a toluene / methanol mixture, respectively. We have found that these solvents do not react with API, and therefore we believe that this change has resulted in a significant reduction in the impurities A (imine), B (N-formyl), and C (acetamide) that we have observed.

[0691] Furthermore, the issue of API gelation and oil formation during final product crystallization in the second-version process was found to be due to the quality of the AMD-2890 starting material. This material, derived from commercially available 2-chloromethylbenzimidazole (RM-396), can have low wt% purity, even when the area % purity is good (>98%). The development of an improved AMD-2890 separation procedure is an integral part of the third-version process and has consistently resulted in the production of high-quality AMD-2890, exhibiting not only excellent % purity but also excellent analytical % w / w purity.

[0692] Further optimization of aeration and carbon treatment during API separation has enabled better control over the color of the separated API, and these operations have also been incorporated into the third version of the process.

[0693] Finally, a narrow definition of the crystallization of free base API in toluene was provided. The metastable region and optimal inoculation point were determined. We also developed the optimal cooling rate after seed bed formation, as well as appropriate washing and drying protocols.

[0694] Figure 4 A detailed comparison of the second and third versions of the process is provided regarding downstream continuous operations involving API handling and separation.

[0695] The robustness and reproducibility of the version 3 process were demonstrated by performing three identical laboratory experiments at a scale of 100g. As shown in Tables 3 and 4, this process demonstration was successful. We then scaled the process up to a scale of 10kg. Single batches of 9.75kg of GMP X4P-001 were prepared with virtually identical results. Details of these experiments are discussed below.

[0696] The third edition of the process description and improvements to process 1 and process 2.

[0697] The following sections provide brief descriptions of several operations in the final steps of the Version 3 process, including API synthesis and separation.

[0698] Synthetic NT-316

[0699] The early process steps for preparing the key starting material NT-316 from the custom-synthesized chiral amine NT-272 and ABA remained unchanged compared to earlier operations.

[0700] Synthetic AMD-2890

[0701] As mentioned above, the synthesis of AMD-2890 (I-9) has been improved, particularly its separation and crystallization, to accommodate the varying purities and colors of commercial 2-chloromethylbenzimidazole (RM-396). This material is typically dark brown to black. Therefore, carbon treatment was introduced to better control the color of AMD-2890.

[0702] Therefore, 2-chloromethylbenzimidazole (RM-396) was reacted with 1.3 equivalents of di-tert-butyl dicarbonate in 8.6 vols of DMF (N,N-dimethylformamide) in the presence of 0.1 equivalents of DIPEA (diisopropylethylamine) at 40°C. After the reaction was complete, decolorizing charcoal was added. After aging at 40°C for 1.5 hours, the mixture was filtered, and the solids were washed with 1 vol of DMF. Water (3.5 vol) was slowly added to the filtrate, producing a slightly turbid mixture inoculated with 1% AMD-2890. After aging, a slurry was produced, which was allowed to cool slowly to 20°C. After slowly adding more water (1 vol) and further cooling to 0°C, the slurry was filtered. The solids were first washed with a 2:1 mixture of DMF and water, then washed with water (2 × 3 vol), both at 0°C. The filter cake was dried under a nitrogen stream to give a pale yellow AMD-2890. The purity of this compound is typically >99 area% (according to HPLC) and >99 wt% (according to NMR).

[0703] Synthesis and Separation of X4P-001

[0704] As previously described, equimolar amounts of NT-316 and AMD-2890 were reacted in acetonitrile in the presence of diisopropylethylamine (DIPEA) and tetrabutylammonium iodide (TBAI) at 60–65 °C. Once complete, the reactants were cooled to ambient temperature and quenched with 0.3 vol ammonia, followed by the addition of 1 vol water. The resulting mixture was then added to a mixture of 2 vol concentrated hydrochloric acid and 3 vol water. The mixture was aged in this acidic solution at 35–40 °C for several hours to remove the protecting group from the protected intermediate, yielding API. Acetonitrile was subsequently removed by vacuum distillation.

[0705] At this point, 2 vol of 1-butanol was added, and the pH was adjusted to 12 with 20% NaOH solution. The resulting two-phase mixture was bubbled at 20°C with a mixture of 10% oxygen and nitrogen for 2 hours. Subsequently, the pH was adjusted to 3.0–3.5 with 18% HCl aqueous solution. The two phases were separated, and the aqueous layer was washed with 1-butanol (3 x 3 vol). The organic layers were combined and extracted with 3 vol of water. Then all aqueous phases were combined and 0.4% (wt) carbon was added. After 1–2 hours, the mixture was filtered, and the solids were washed with 3 vol of water.

[0706] Toluene (7 vol) and methanol (1 vol) were added to the combined filtrate, and the temperature was increased to 45–55 °C. The pH was then adjusted to 9.5–10.0 with 20% sodium hydroxide solution. The phases were separated, and the aqueous layer was extracted twice more with 3 vol of toluene.

[0707] All toluene layers were combined and partially concentrated by vacuum distillation at 45–50 °C. After several additions of fresh toluene and continued vacuum distillation at 45–50 °C to remove other volatile solvents, a solution of API in approximately 3 vol of toluene was obtained. This solution was heated to 60 °C and filtered through a line to remove impurities.

[0708] After cooling to 50°C, the solution was carefully inoculated with up to 0.5 wt% X4P-001. Once the seed bed was formed, the API was allowed to undergo stable crystallization over 2-3 hours, followed by slow cooling of the slurry to 0°C. The resulting slurry was gradually heated back to 30-35°C and then cooled back to 0°C to promote crystal growth. Finally, the slurry was filtered, and the final solid was washed with toluene and dried in a dry filter under vacuum at 60°C for 16 hours, with occasional careful stirring.

[0709] This process has been demonstrated on a 10kg scale, yielding X4P-001 with 99.0-99.5% area purity (>99.9% enantiomer purity) and 1337ppm residual toluene.

[0710] Comparison of Process 2 and Process 3

[0711] Table 3 provides a comparison of key process parameters and results for each batch produced using Process 2 and Process 3 recently. As mentioned above, the third-generation process was first demonstrated at a laboratory scale and then scaled up in the plant producing X4P-001. Table 4 provides a comparison of the impurity distribution of these batches.

[0712] Most importantly, Table 4 shows that switching from version 2 to version 3 has consistently reduced total impurities by 0.5–1.1 area% and significantly reduced total residual solvent in API, without adverse effects on other key process results.

[0713] Table 3: Comparison of key process parameters and results for each batch produced using the second and third versions of the process.

[0714]

[0715] ND = Not detected; iPAc = Isopropyl acetate; DCM = Dichloromethane; IPA = Isopropanol; Tol = Toluene.

[0716] Table 4: Comparison of HPLC impurity distribution of batches produced using the second and third versions of the process.

[0717] Batch number 3-1 3-2 3-3 3-4 3-5 3-6 Process Version 2 2 3 3 3 3 Analysis (wt%, oab) 99.3 97.9 99.9 96.7 97.8 98.4 purity(%) 98.8 98.3 99.46 99.40 99.28 99.51 Identified impurities (%) RRT 0.38(de-Boc NT-316)(I-7) ND ND 0.11 0.09 0.13 0.05 RRT 1.08 (imine) (I-1) 0.62 0.95 0.10 0.13 0.04 0.09 RRT 1.21 (aldehyde) (I-6) NT* NT* 0.09 0.14 0.20 0.14 RRT 1.28(formyl)(I-2) 0.03 ND 0.03 0.03 0.03 0.05 RRT 1.37 (acetamide) (I-5) 0.07 0.42 0.02 0.04 0.06 ND RRT 1.93 (benzimidazole) (I-3) 0.01 ND 0.06 0.05 0.04 0.04 Total impurities (%) 1.20 1.67 0.54 0.60 0.72 0.49

[0718] ND = Not detected.

[0719] NT = Untested.

[0720] *It is unknown whether any aldehyde impurities exist in these two batches.

[0721] Improvement of residual solvent level in process 3

[0722] During the early clinical development of X4P-001 (formerly AMD110170), ethyl acetate was used as a crystallization solvent to directly separate the active pharmaceutical ingredient (API) as a free base (Process 1). However, difficulties arose in removing ethyl acetate from the final API, and batch development was cumbersome and laborious, involving grinding and exposure to hot nitrogen to reduce the content below the International Conference on Harmonisation (ICH) limit of 5000 ppm NMT. ​​Early efforts in Process 1 during the development of AMD-110170 also used isopropyl acetate as a separation solvent in several batches of the API.

[0723] In later development, the p-hydroxybenzoate (PHB) of AMD-11070 was isolated as an intermediate and subsequently converted into a free base (Process 2). We have used this process to manufacture the active pharmaceutical ingredient for recent clinical trials. In Process 2, the free base is isolated after salt release using isopropyl acetate instead of ethyl acetate. The residual solvent in this API shows similarly high levels, as seen in APIs prepared via Process 1. Furthermore, we have found that isopropyl acetate is involved in the generation of acetamide impurities during production. Therefore, a change in the final API separation solvent is necessary.

[0724] Our recent process development has provided a direct free base separation procedure (PHB salt is no longer an intermediate in the process), which now uses toluene instead of isopropyl acetate as the final crystallization solvent (Process 3). We found that toluene does not react with X4P-001, and therefore provides a more suitable separation solvent. As noted above, excluding the use of isopropyl acetate also resulted in a reduction in impurity content. An overview of the residual solvent content and residual crystallization solvent content in each batch of X4P-001 is shown in Table 5.

[0725] Table 5: Residual separation solvent content in X4P-001 during development

[0726]

[0727] *API batches are analyzed because they were initially crystallized with isopropyl acetate and then reprocessed with toluene in the final crystallization stage.

[0728] **Batch 3-1.

[0729] Historically, the average residual solvent content of the main crystallizing solvent in X4P-001 batches has ranged from 1971 ppm to 9298 ppm. We have established specifications for residual toluene in the free base of X4P-001 using the PDE method.

[0730] Assuming a daily dose of 600 mg X4P-001 (exceeding the 50% safety tolerance of the exemplary clinical dose of 400 mg daily), the calculated toluene content in the X4P-001 API does not exceed 4500 ppm. Therefore, in some embodiments of the invention, the residual toluene specification in X4P-001 does not exceed 4500 ppm. Thus, in some embodiments, the invention provides X4P-001 compositions containing no more than 4500 ppm toluene or 1350 ppm toluene.

[0731] in conclusion

[0732] In summary, compared to version 2, the improvements in version 3 have resulted in more robust and reproducible final process steps. Most importantly, the purity of the separated API X4P-001 is significantly improved compared to previous process versions. Crucially, we have found that the choice of solvents used to process and separate X4P-001 is key to achieving the improved impurity distribution. Specifically, we have replaced the dichloromethane and isopropyl acetate used in version 2 for processing and separating X4P-001 with 1-butanol and a toluene / methanol mixture, respectively, in version 3. We have found that in batches produced using version 2, certain impurities are present in increased amounts in the final product due to the reaction of API, X4P-001, with dichloromethane and isopropyl acetate. Another key finding is that version 2 process resulted in the formation of gel-like and oily substances of API during the crystallization of the final product due to the varying (and often poor) quality of the AMD-2890 starting material. As mentioned above, we have introduced an improved AMD-2890 separation process that consistently produces high-quality AMD-2890 and avoids the formation of gels and oils from the API.

[0733] Example 10: Mutagenicity Assessment

[0734] We have performed a mutagenic risk assessment on the synthesis process that produces X4P-001, all process intermediates, and potential and actual impurities. The assessment included a review of all raw materials, including critical starting materials, as well as potential and actual process impurities and degradation products. All assessments were performed in accordance with ICH M7(R1) guidelines.

[0735] The following processes 10 and 11 describe process 2 and process 3 for the synthesis of X4P-001, respectively. Process 12 describes the synthesis of intermediates for NT-319 and AMD-2890 processes.

[0736] Table 6 below describes the identified potential mutagenic impurities in the X4P-001 manufacturing process.

[0737] Process 10: Synthesis process of X4P-001 2.

[0738]

[0739] Process 11: Synthesis process of X4P-001 3.

[0740]

[0741] Step 12: Synthesis of NT-319 and AMD-2890.

[0742]

[0743] Table 6: Identified potential mutagenic impurities in the X4P-001 synthesis process.

[0744]

[0745] The expected duration of treatment for patients in clinical trials is less than 10 years. In ICH M7(R1), according to Table 2, the acceptable intake of drugs with an exposure period of >1 to 10 years is 10 μg of mutagenic impurities per day.

[0746] Based on the X4P-001 at a daily dose of 400 mg, a potential mutagenic impurity limit of 25 ppm is acceptable (10 μg / day / 400 mg = 25 ppm (μg / g)).

[0747] Potential impurities I-10 and I-11 were never detected in X4P-001. Furthermore, according to published references, such as Teasdale et al. (Organic Process Res.Dev., 2013, 17, 221), the theoretical cleansing coefficient of synthesis process 3 indicates that the process effectively cleans potential impurities I-10 and I-11, with a theoretical cleansing coefficient of approximately 9 x 10⁻⁶. 8 (I-10) and approximately 9x10 10 (I-11).

[0748] Based on the calculated purification coefficient, the theoretical residual amounts of I-10 and I-11 in X4P-001 have been calculated to be approximately <0.0001ppm I-10 and approximately <0.000001ppm I-11, indicating that both potential mutagenic impurities are effectively purified by this process and no control is required for X4P-001.

[0749] The potential impurities RM-396 and AMD-2890(I-9) (limit of quantitation or LOQ: 2.5 ppm) were never detected in X4P-001, indicating that both potential mutagenic impurities were effectively purified by this process.

[0750] Example 11: 25mg, 100mg and 200mg solid formulations

[0751] During formulation development, excipients are selected based on short-term compatibility screening studies involving different excipients. For 25 mg and lower strength capsules, microcrystalline cellulose is selected as a diluent / filler. For higher strength formulations (100 mg), dicalcium phosphate dihydrate is added as a diluent / filler to improve flowability. The ratio of microcrystalline cellulose to dicalcium phosphate dihydrate is chosen to approximate the bulk density of the active pharmaceutical ingredient (API), thereby reducing the probability of segregation during mixing. Sodium stearoyl fumarate is selected as a lubricant. To facilitate capsule filling on automated capsule filling machines, colloidal silica is added to the formulation as a flow aid. Croscarmellose sodium is selected as a disintegrant to enable automated capsule filling. Sodium lauryl sulfate is added to the formulation to reduce API adhesion during encapsulation and as a wetting agent.

[0752] Table 7: Composition of Exemplary X4P-001 25mg Capsules

[0753] Components Reference Standard Function Quantity (mg / capsule) %w / w X4P-001 Composition internal Active ingredients 25.0 14.7 microcrystalline cellulose NF diluent 132.7 78.1 Sodium croscarmellose NF Disintegrant 10.2 6.0 Sodium stearoyl fumarate NF lubricant 1.7 1.0 colloidal silica USP Flow aid 0.4 0.2 sum 170.0 100.0 No. 1 hard gelatin capsules USP Packaging NA NA

[0754] Table 8: Composition of X4P-001 100mg Capsules

[0755]

[0756]

[0757] Table 9: Composition of X4P-001 200mg Capsules

[0758]

[0759] Continuous long-term stability studies of the drug have demonstrated the compatibility of the excipients, with the drug meeting stability requirements in three batches of 100 mg capsules under specified frozen storage conditions. X4P-001 100 mg capsules, batch number 15K227, packaged in amber glass vials of 30 capsules sealed in aluminum foil bags, showed stability results for up to 24 months under storage conditions of 5°C ± 3°C and 25°C / 60% RH. Under the recommended storage conditions of 5°C ± 3°C, no significant trend was observed in any stability test parameters (analytical, impurity, dissolution, moisture, and microbiological tests) over the 24-month period.

[0760] Stability results for 100 mg capsules stored at 5℃±3℃ and sealed in amber glass vials (sealed in aluminum foil bags) or Oxy-Guard HDPE bottles for up to 9 months showed an increase in imine impurities over time, but remained entirely within specifications. No trend deviating from initial values ​​was observed in any of the other stability test parameters.

[0761] Stability results for 100 mg capsules stored at 5℃±3℃ and 25℃ / 60%RH in Oxy-Guard HDPE vials for up to 3 months showed an increase in imine impurities over time, but remained entirely within specifications. No trend deviating from initial values ​​was observed in any of the other stability test parameters. These capsules were manufactured using X4P-001 active pharmaceutical ingredient, which was produced using a toluene reprocessing procedure.

[0762] Continued use of frozen cold chain storage is an expected requirement for X4P-001. The primary packaging container for X4P-001 used in the Phase 3 clinical trial was an Oxy-Guard 60cc HDPE bottle with a 33mm induction-sealed cap. A rayon roll was placed above the capsule in each bottle, and a desiccant packet (0.5g Sorb-It or equivalent) was positioned on top of each bottle, between the rayon roll and the cap (30 bottles total).

[0763] Figure 1 The document provides a detailed overview of the manufacturing process.

Claims

1. An X4P-001 composition comprising compound of formula I: I Or a pharmaceutically acceptable salt thereof; and in amounts of 0.001 to 0.5% w / w of the following compounds or pharmaceutically acceptable salts thereof in the X4P-001 composition: I-6; and The X4P-001 composition optionally includes at least one of the following compounds or a pharmaceutically acceptable salt thereof in a detectable amount: I-2、 I-3、 I-5or I-7; in, The X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof with a purity of at least 99.3% according to HPLC, and comprises less than 0.7% of a total additional compound selected from I-2, I-3, I-5, I-6 or I-7 or a pharmaceutically acceptable salt thereof as measured by HPLC.

2. The X4P-001 composition according to claim 1, wherein the composition comprises I-6 or a pharmaceutically acceptable salt thereof in an amount of 0.01 to 0.4% w / w of the X4P-001 composition.

3. The X4P-001 composition according to claim 1, wherein the composition comprises I-6 or a pharmaceutically acceptable salt thereof in an amount of 0.01 to 0.3% w / w of the X4P-001 composition.

4. The X4P-001 composition according to claim 1, wherein the composition comprises I-6 or a pharmaceutically acceptable salt thereof in an amount of 0.01 to 0.2% w / w of the X4P-001 composition.

5. The X4P-001 composition according to claim 1, wherein the composition comprises I-3 or a pharmaceutically acceptable salt thereof in an amount of 0.001 to 0.4% w / w of the X4P-001 composition.

6. The X4P-001 composition according to claim 1, wherein the composition comprises I-2 or a pharmaceutically acceptable salt thereof in an amount of 0.001% w / w to 0.3% w / w of the X4P-001 composition.

7. The X4P-001 composition according to claim 1, wherein the composition comprises I-5 or a pharmaceutically acceptable salt thereof in an amount of 0.001 to 0.5% w / w of the X4P-001 composition.

8. The X4P-001 composition according to claim 1, wherein the composition comprises I-7 or a pharmaceutically acceptable salt thereof in an amount of 0.001 to 0.5% w / w of the X4P-001 composition.

9. The X4P-001 composition according to claim 1, wherein the amount of I-3 or a pharmaceutically acceptable salt thereof is 0.01 to 0.4% w / w of the X4P-001 composition.

10. The X4P-001 composition according to claim 1 or 8, wherein the X4P-001 composition does not contain a detectable amount of I-2 or I-5 or a pharmaceutically acceptable salt thereof.

11. The X4P-001 composition according to claim 1, wherein the amount of I-2 or a pharmaceutically acceptable salt thereof is 0.01 to 0.3% w / w of the X4P-001 composition.

12. The X4P-001 composition according to claim 1, wherein the amount of I-5 or a pharmaceutically acceptable salt thereof is 0.01 to 0.4% w / w of the X4P-001 composition.

13. The X4P-001 composition according to claim 1, wherein the amount of I-7 or a pharmaceutically acceptable salt thereof is 0.01 to 0.25% w / w of the X4P-001 composition.

14. The X4P-001 composition according to claim 1, wherein the X4P-001 composition contains no more than 0.5 area% of total organic impurities per HPLC relative to the total area of ​​the HPLC chromatogram.

15. An X4P-001 composition comprising (1) A compound of formula I or a pharmaceutically acceptable salt thereof: I; as well as (2) At least one substance selected from the following (a) to (e): (a) A compound of formula I-2 or a pharmaceutically acceptable salt thereof, in an amount of 0.01 to 0.3% w / w of the X4P-001 composition. I-2； (b) A compound of formula I-3 or a pharmaceutically acceptable salt thereof, in an amount of 0.01 to 0.4% w / w of the X4P-001 composition. I-3; (c) A compound of formula I-5 or a pharmaceutically acceptable salt thereof, in an amount of 0.01 to 0.4% w / w of the X4P-001 composition. I-5; (d) A compound of formula I-6 or a pharmaceutically acceptable salt thereof, comprising 0.01 to 0.4% w / w of the X4P-001 composition. I-6; or (e) A compound of formula I-7 or a pharmaceutically acceptable salt thereof, in an amount of 0.01 to 0.25% w / w of the X4P-001 composition. I-7; Optionally, the X4P-001 composition does not contain a detectable amount of a compound of formula I-4 or a pharmaceutically acceptable salt thereof: I-4 。 16. The X4P-001 composition according to claim 15, wherein the X4P-001 composition comprises each of I-2, I-3, I-5, I-6 and I-7, or a pharmaceutically acceptable salt thereof.

17. The X4P-001 composition according to claim 15 or 16, wherein the amount of I-6 or a pharmaceutically acceptable salt thereof is 0.01 to 0.2% w / w of the X4P-001 composition.

18. The X4P-001 composition according to claim 15 or 16, wherein the amount of I-7 or a pharmaceutically acceptable salt thereof is 0.01 to 0.2% w / w of the X4P-001 composition.

19. The X4P-001 composition according to claim 15 or 16, wherein the amount of I-3 or a pharmaceutically acceptable salt thereof is 0.01 to 0.2% w / w of the X4P-001 composition.

20. The X4P-001 composition according to claim 15 or 16, wherein the amount of I-2 or a pharmaceutically acceptable salt thereof is 0.01 to 0.2% w / w of the X4P-001 composition.

21. The X4P-001 composition according to claim 15 or 16, wherein the amount of I-5 or a pharmaceutically acceptable salt thereof is 0.01 to 0.2% w / w of the X4P-001 composition.

22. The X4P-001 composition according to claim 1 or 8, wherein the composition further comprises 0.01 to 0.7% w / w of I-1 or a pharmaceutically acceptable salt thereof in the X4P-001 composition: I-1。 23. The X4P-001 composition according to claim 22, wherein the amount of I-1 or a pharmaceutically acceptable salt thereof is 0.02 to 0.5% w / w of the X4P-001 composition.

24. The X4P-001 composition according to claim 15, wherein the composition comprises at least two compounds selected from the group consisting of: I-2 or its pharmaceutically acceptable salts I-3 or its pharmaceutically acceptable salts I-5 or its pharmaceutically acceptable salt. I-6 or its pharmaceutically acceptable salt, and I-7 or its pharmaceutically acceptable salt.

25. The X4P-001 composition according to claim 15, wherein the composition comprises at least three compounds selected from the following: I-2 or its pharmaceutically acceptable salts I-3 or its pharmaceutically acceptable salts I-5 or its pharmaceutically acceptable salt. I-6 or its pharmaceutically acceptable salt, and I-7 or its pharmaceutically acceptable salt.

26. The X4P-001 composition according to claim 15, wherein the composition comprises at least four compounds selected from the group consisting of: I-2 or its pharmaceutically acceptable salts I-3 or its pharmaceutically acceptable salts I-5 or its pharmaceutically acceptable salt. I-6 or its pharmaceutically acceptable salt, and I-7 or its pharmaceutically acceptable salt.

27. The X4P-001 composition according to any one of claims 1, 8, 15 or 16, wherein the X4P-001 composition does not contain detectable amounts of the following compounds: I-4 Or its pharmaceutically acceptable salt.

28. The X4P-001 composition according to any one of claims 1, 8, 15 or 16, wherein the compound of formula I is present as a free base in the X4P-001 composition.

29. The X4P-001 composition according to any one of claims 1, 8, 15 or 16, wherein the composition contains no more than 3.0% total impurities.

30. The X4P-001 composition according to any one of claims 1, 8, 15 or 16, wherein the excess percentage of the R-enantiomer of the compound of formula I is not less than 97.0%.

31. A pharmaceutical composition comprising the X4P-001 composition according to any one of claims 1, 8, 15 or 16 and a pharmaceutically acceptable excipient.

32. The pharmaceutical composition of claim 31, wherein the pharmaceutically acceptable excipient comprises at least one diluent, disintegrant, lubricant, and flow aid.

33. A unit dosage form comprising a pharmaceutical composition, said pharmaceutical composition comprising: (a) 10-20% by weight of the X4P-001 composition according to any one of claims 1, 8, 15 or 16; (b) 70-85% microcrystalline cellulose by weight of the composition; (c) 5-10% croscarmellose sodium based on the weight of the composition; (d) 0.5-2% sodium stearoyl fumarate, based on the weight of the composition; and (e) 0.1-1.0% colloidal silica by weight of the composition.

34. A unit dosage form comprising a pharmaceutical composition, said pharmaceutical composition comprising: (a) 35-75% by weight of the X4P-001 composition according to any one of claims 1, 8, 15 or 16; (b) 5-28% microcrystalline cellulose by weight of the composition; (c) 7-30% of dicalcium phosphate dihydrate by weight of the composition; (d) 2-10% croscarmellose sodium based on the weight of the composition; (e) 0.3-2.5% sodium stearoyl fumarate by weight of the composition; (f) 0.05-1.2% colloidal silica, based on the weight of the composition; and (g) 0.2-1.2% sodium lauryl sulfate by weight of the composition.

35. Use of the X4P-001 composition according to any one of claims 1, 8, 15 or 16 in the preparation of a medicament for treating a subject in need of a CXCR4-related disease, condition or symptom, wherein the disease, condition or symptom is selected from the group consisting of: kidney cancer; liver cancer; melanoma; breast cancer; colorectal cancer; anal cancer; non-small cell lung cancer (NSCLC); small cell lung cancer (SCLC); ovarian cancer; Fallopian tube cancer; prostate cancer; testicular cancer; hepatobiliary duct cancer; soft tissue sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Undifferentiated thyroid cancer; adrenocortical carcinoma; pancreatic cancer; gastrointestinal cancer; gastrointestinal stromal tumor (GIST); lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; brain cancer; neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST); and Waldenström macroglobulinemia.

36. The use according to claim 35, wherein the disease, symptom, or condition is selected from the following cancers: renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), hepatoblastoma, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), gallbladder cancer, synovial sarcoma, Ewing's sarcoma, pancreatic ductal carcinoma, pancreatic cancer, gastric cancer, glioma, and neuroblastoma.

37. The use according to claim 35, wherein the disease, symptom or condition is selected from colon cancer or rectal cancer.

38. The use according to claim 35, wherein the disease, condition or symptom is ovarian epithelial cancer.

39. The use according to claim 35, wherein the disease, condition or symptom is selected from the following cancers: advanced renal cell carcinoma, clear cell renal cell carcinoma ccRCC, papillary renal cell carcinoma, metastatic melanoma, or Waldenström macroglobulinemia.

40. Use of the X4P-001 composition according to any one of claims 1, 8, 15 or 16 in the preparation of a medicament for treating a subject in need of a CXCR4-related disease, condition or symptom, wherein the disease, condition or symptom is a primary immunodeficiency, wherein the disease, condition or symptom is selected from warts, hypogammaglobulinemia, infection, myelodysplastic syndrome (WHIM), severe congenital neutropenia SCN, GATA2 deficiency, idiopathic CD4+ T lymphopenia ICL, or Wescott-Aldrich syndrome.

41. The use according to claim 40, wherein the disease, symptom or condition is a single MAC syndrome.

42. The use according to claim 40, wherein the disease, symptom or condition is WHIM syndrome.

43. The use according to claim 40, wherein the disease, symptom, or condition is SCN.

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