MX2007001802A - Chemokine combinations to mobilize progenitor/stem cells - Google Patents

Abstract

Methods to elevate progenitor and stem cell counts in animal subjects using compounds which bind to the chemokine receptor CXCR4 in combination with the CXCR2 chemokine GROβ, including its modified forms, are disclosed.

Description

COMBINATIONS OF OUIMOCINES TO MOBILIZE CELLS PROGENITURAS / MADRE Technical Field The invention is in the therapeutic field and medicinal chemistry. More particularly, the invention concerns methods for mobilizing progenitor / stem cells using combination therapy. BACKGROUND ART Blood cells play a crucial part in maintaining the health and viability of animals, including humans. White blood cells include neutrophils, macrophages, eosinophils and basophils / mast cells, as well as B and T cells of the immune system. White blood cells are continuously replaced by the hematopoietic system, by the action of colony stimulating factors (CSF), and several cytokines in stem cells and progenitor cells in hematopoietic tissues. The nucleotide sequences encoding a number of these growth factors have been cloned and sequenced. Perhaps the most widely known of these is the granulocyte colony stimulation factor (G-CSF), which has been approved for use in counteracting the negative effects of chemotherapy by stimulating the production of white blood cells and progenitor cells (mobilization of peripheral blood stem cells). A discussion of the hematopoietic effects of this factor can be found, for example, in US Patent 5,582,823, incorporated herein by reference. Several other factors have been reported to increase white blood cells and progenitor cells in both human and animal subjects. These agents include granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-1 (IL-1), interleukin-3 (IL-3), interleukin-8 (IL-8), PIXY-321 ( GM-CSF / IL-3 fusion), macrophage inflating protein, stem cell factor (SCF), thrombopoietin, flt-3, myelopoietin, anti-VLA4 antibody, and growth-related oncogene (GRO), as single agents or in combination (Dale, D., et al., Am. J. of Hematol. (1998) 57: 7-15; Rosenfeld, C, et al., Bone Maw Transplantation (1997) 17: 179-183; Pruijt, J., et al., Cur. Op. In Hematol. (1999) 6: 152-158; Broxmeyer, H., et al., Exp. Hematol. (1995) 23: 335-340; Broxmeyer, et al. Blood Cells, Molecules and Diseases (1998) 24: 14-30; Glaspy, J., et al., Cancer Chemother, Pharmacol. (1996) 38 (suppl): S53-S57; Vadhan-Raj, S., et al. Ann, Intern. Med. (1997) 126: 673-681; King, A., et al., Blood (2001) 97: 1534-1. 542; Glaspy, J., et al., Blood (1997) 90: 2939-2951). Furthermore, King, et al. (King, A., and collaborators, Blood (2001) 97: 1534-1542) have shown that a truncated N-terminal 4-amino acid form of the human GROß chemokine (also known as SB-251353 or Garnocestim) can mobilize progenitor cells after administration of SB-251353 in combination with G-CSF where neutrophils and platelets were mobilized during studies. Chimocines such as SB-251353, GROa, GROß, and GRO? they are discussed further in WO 94/29341; WO 97/15594; WO 97/15595; WO 99/26645; WO 02/02132; US Patent 6,080,398; US Patent 6,399,053; and US Pat. No. 6,447,766, all incorporated herein by reference. SB-251353 is a heparin-binding protein, basic, with a molecular mass of approximately 7,500 Da, and is a specific agonist of the CXCR2 receptor (King, A., et al., J. Immunol. (2000) 164: 3774- 3782, Hepburn, T., et al., Journal of Pharmacology and Experimental Therapeutics (2001) 298: 886-893). Other chemokines, in addition to GROß, acting through the CXCR2 receptor include GROa, GRO ?, GCP-2 (granulocyte-chemoattractant protein 2), IL-8, NAP-2 (neutrophil activating peptide 2), ENA-78 ( neutrophil activator protein 78 derived from epithelial cell), and MGSA. The chemokine receptor of CXCR4 and its factor-1 derived from natural ligand stromal cells (SDF-1) appear to be important in the process of development and maturation of blood cells, where mature blood cells are derived from hematopoietic precursor cells (progenitors) ) and stem cells present in specific hematopoietic tissues including bone marrow (for reviews see Maekawa, T., et al., Internal Med. (2000) 39: 90-100; Nagasawa, T., and collaborators, Znt. J. "Hematol. (2000) 72: 408-411.) This is demonstrated by reports that CXCR4 or SDF-1 knock out mice that exhibit hematopoietic defects (Ma, Q., et al., Proc. Nati. Acad. Sci. USA (1998) 95: 9448-9453; Tachibana, K., et al., Nature (1998) 393: 591-594; Zou, YR., Et al., Nature (1998) 393: 595-599). CD34 + progenitor cells express CXCR4 and require SDF-1 produced by bone marrow stromal cells for chemo-attraction and grafting (Peled, A., et al., Science (1999) 283: 845-848) and that in vi tro, SDF-1 is chemotactic for both CD34 + cells (Aiuti, A., et al., J. Exp. Med. (1997) 185: 111-120; Viardot, A., et al., Ann.Hetmatol. (1998) 77: 194-197) and for progenitor / stem cells (Jo, DY., And collaborators, J. "Clin. Invest. (2000) 105: 101-111). SDF-1 is also an important chemo-attractant, signaling through the CXCR4 receptor, for several other more involved progenitor and mature blood cells including T-lymphocytes and monocytes (Bleul, C, et al., J. "Exp. Med. 1996) 184: 1101-1109), pro- and pre-B lymphocytes (Fedyk, ER, et al., J. Leukoc, Biol. (1999) 66: 667-673; Ma, Q., et al., Immuni ty ( 1999) 10: 463-471) and megakaryocytes (Hodohara, K., et al., Blood (2000) 95: 769-775; Riviere, C, et al., Blood (1999) 95: 1511-1523; Majka, M. , and collaborators, Blood (2000) 96: 4142-4151; Gear, A., et al., Blood (2001) 97: 937-945; Abi-Younes, S., et al., Circ. Res. (2000) 86 : 131-138) Thus, in summary, it seems that SDF-1 is able to control the positioning and differentiation of cells carrying CXCR4 receptors, whether these cells are stem cells (ie, cells which are CD34 +) or progenitor cells (which result in the formation of specific types of colonies in response to particular stimuli, which may be CD34 + or CD34"), or cells that are somewhat more differentiated. Recently, considerable attention has been focused on the number of CD34 + cells mobilized in The set of peripheral blood progenitor cells for autologous stem cell transplantation Stem cell transplantation can be characterized as either allogeneic, where cells are transplanted from a healthy donor, usually a sibling, or as autologous, where cells are transplanted. they collect from the patient and re-infuse after chemotherapy. During a typical procedure to collect stem cells, patient or donor receives a daily dose of G-CSF, for four or five consecutive days to stimulate the production of stem cells with apheresis occurring in next days until a target level of cells is reached.G-CSF use is also continued in apheresis days It is common where significant number of patients requires multiple apheresis sessions to reach the target cell level.

The population of CD34 + is the component that is believed to be primarily responsible for the improved recovery time after chemotherapy, and the cells most likely responsible for long-term graft and restoration of hematopoiesis (Croop, JM, et al., Bone Marrow Trans -plantation (2000) 26: 1271-1279). The mechanism by which CD34 + cells are re-engrafted may be due to the chemotactic effects of SDF-1 on cells expressing CXCR4 (Voermans, C, Blood (2001) 97: 799-804; Ponomaryov, T., et al. , J. Clin. Invest. (2000) 106: 1331-1339). More recently, adult hematopoietic stem cells proved capable of restoring damaged cardiac tissue in mice (Jackson, M., et al., J. Clin. Invest. (2001) 107: 1395-1402; Kocher, A., et al., Nature Med. (2001) 7: 430-436). Thus, the role of the CXCR4 receptor in managing cell positioning and differentiation has assumed considerable significance. The compound AMD3100, which is 1, 1 [1,4-phenylene-bis (methylene)] -bis-1, 4,8,11-tetraazacyclotetra-decane, is known as a CXCR4 antagonist that mobilizes the same progenitor cells ( see, for example, Hubel, K., and collaborators, Supportive Cancer Therapy (2004) 1: 165-172, citing De Clercq, E., et al., Nat. Rev. Drug Discov. (2003) 2: 581-587 ). In addition, PCT publication WO 00/45814 discloses that several cyclic polyamine compounds, including AMD3100, raise white blood cell counts. PCT publication WO 03/011277 further shows that such compounds, including AMD3100, mobilize progenitor / stem cells; a combination of AMD3100 with several other factors, including GM-CSF, IL-1, IL-8, macrophage inflammatory protein PIXY-312, skin cell factor, thrombopoietin, growth-related oncogene or chemotherapy, or additional active ingredients, generally , such as antibiotics, vitamins, herbal extracts, anti-inflammatory, glucose, anti-pyretic, analgesic, are also mentioned. It has now been found that the combination of a CXCR4 antagonist with GROß, including the modified forms of GROß, is particularly effective in mobilizing progenitor cells. The citation of the above documents is not intended as an admission that any of the foregoing are relevant state of the art. All statements regarding the date or representation with respect to the content of these documents are based on information available to applicants and do not constitute any admission as to the accuracy of the dates or content of these documents. In addition, all documents referenced through this application are incorporated in their entirety by reference herein. Disclosure of the Invention The invention is directed to methods for treating animal subjects, in particular, veterinary and human subjects, to improve the number of progenitor cells and / or stem cells. The progenitor and / or stem cells may have been harvested and used in cell transplantation. The methods of the invention employ inhibitors of the CXCR4 receptor such as certain polyamines described below in combination with at least one form of GROß, ie GROß itself or a modified form thereof. The methods are useful in the context of stem cell transplantation, tissue repair, and in situations where direct in vivo stimulation of hematopoiesis is desirable. As used herein, the terms "one," "one," and "the" or "the" encompass singular and plural references, unless the context clearly dictates otherwise. Thus, for example, references to a CXCR4 antagonist encompass one or more CXCR4 antagonists. In one aspect, therefore, the invention is directed to a method for raising the progenitor cells and / or stem cells, in a subject, which method comprises administering to said subject an amount of a compound that inhibits the CXCR4 receptor, such as that of formula (1) shown below, in combination with a collection member represented by GROß and its modified forms. In one embodiment, bone marrow cells are mobilized for myocardial repair. Other embodiments include mobilization of cells ex vivo or in vi tro for subsequent transplantation to autologous or allogenic subjects. Thus, the methods of the invention also include treatment of ex vivo cell populations with combinations of an inhibitor of CXCR4 and GROß or their modified forms and introducing the treated populations towards a compatible subject to improve the population of stem cells and / or cells. progenitors in the peripheral blood. An improved production of white blood cells in the bone marrow may also result. In additional aspects, the invention is directed to a combination product comprising a CXCR4 antagonist and a GROß protein, wherein the combination is capable of raising the population of progenitor cells and / or mother in peripheral blood or bone marrow. The combination product may be a mixture, a solution, or a pharmaceutical composition. In another aspect, the invention is directed to pharmaceutical compositions containing a CXCR4 inhibitor and a GROß chemokine for use in effecting an elevation of progenitor cells and / or stem cells in animal subjects or in ex vivo cultures. Moreover, the present invention provides for the use of a combination product comprising a CXCR4 antagonist and a GROß protein, or pharmaceutical compositions thereof, for raising the population of progenitor cells and / or stem in peripheral blood or bone marrow. The present invention also provides for the use of a combination product comprising an antagonist of CXCR4 and a GROß protein, or pharmaceutical compositions thereof, for the manufacture of a medicament for raising the population of progenitor cells and / or mother in peripheral blood or bone marrow. In addition, the present invention is directed to compounds or drugs comprising a CXCR4 antagonist and a GROß protein, to elevate progenitor cell population and / or stem in peripheral blood or bone marrow. Surprisingly, the combination of a CXCR4 antagonist, such as a compound of the formula (1) together with the GROß chemokine, including a modified form thereof, is capable of effecting a marked mobilization of progenitor and stem cells in a short time - in less than one hour, unlike hours or days as would be required by any agent alone. CXCR4 antagonists for use in the methods of the present invention are exemplified by compounds of formula (1) of the formula: Z-linker-Z '(1) wherein Z is an optionally substituted cyclic polyamine containing 9-32 members of ring of which 2-8 are nitrogen atomssaid nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms in addition to nitrogen and / or may be fused with an additional ring system; or Z is of the formula wherein A comprises a monocyclic or bicyclic fused ring system containing at least one of N and B is H or an organic fraction of 1-20 atoms; Z 'may be represented in a form as defined by Z above, or alternatively may be of the formula -N (R) - (CR2) nX where each R is independently H or straight, branched or cyclic alkyl, n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is mercaptan; or where Z 'can be nitrogen containing heterocycle, or it can be NR2 where each R is as defined above; "linker" represents a bond, alkylene (Cx_6) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms. The CXCR4 antagonists are preferably compounds having the formula (1), as described above. The invention also is directed to a method for raising progenitor cells and / or stem cells, in a subject, comprising administering to said subject an amount of at least one Incompound which inhibits the CXCR4 receptor, such as that of the formula (1A) - (1F), (2A) - (2B), (3), (3A) - (3C), (4), (4A) - (4C), (5), (6), (6A) ) - (6D), (7) and (8) as shown below, in combination with at least one harvesting member represented by GROß and its modified forms. Modes for Carrying Out the Invention The invention relates to the specific combination of a CXCR4 antagonist with a GROß protein to mobilize or enhance the proliferation of progenitor and / or stem cells. The combination is able to achieve this stimulation in a much shorter time than any of the components alone and in a much shorter time than previously disclosed combinations. The mobilization of stem cells and / or progenitor cells is useful in a number of contexts, as will be described below. The combination can be administered directly to a subject or can be used to treat cells in ex vivo cultures, which treated cells can then be administered to a subject, generally the subject from which the cells are derived (autologous transplant) or a related subject from close way (allogeneic transplant). Each of the essential elements of the combination can be provided as a single member of the class or can be supplied as a mixture or other combination of the members of the class. Each component of the combination (in fact, each member of the sub-combination representing a single class) can be administered independently, at the same time, by the same route, or at the same time by different routes, or at different times by the same or different routes as any other component in the combination. Thus, for example, if two different CXCR4 antagonists are used, both can be, but do not need to be, administered at the same time; both can be, but do not need to be, administered intravenously. Similarly, if two or more GROß proteins are used, they can also be subject to the variable types of administration just described. The same applies to administration of a member of the class of CXCR4 antagonists and a member of the GROß class of proteins. The combination of GROß proteins and CXCR4 antagonists can also be administered according to such variable protocols, independently or in the same composition. The class of "GROß proteins" or "GROß chemokines" includes GROß itself as well as modified forms of GROß. As further described herein, these modified forms can be truncated, multimerized, contain amino acid substitutions, deletions or insertions, or can comprise combinations of these. The CXCR4 antagonists are preferably compounds of the formula (1). Other preferred CXCR4 antagonists for use in the methods of the invention are compounds of the formula (A) - (IF), (2A) - (2B), (3), (3A) - (3C), (4), (4A) - (4C), (5), (6), (6A) - (6D), ( 7) and (8) as shown below. The compounds of the formula (1) inhibit HIV replication by inhibition of CXCR4, the co-receptor required for fusion and entry of T-tropic HIV strains, and also inhibit ligation and signaling induced by the natural ligand, chemokine SDF -1. Although not wishing to be bound by any theory, the compounds of the formula (1) which inhibit the ligation of SDF-1 to CXCR4 effect an increase in stem and / or progenitor cells by virtue of such inhibition. Improving stem cells and / or progenitors in blood is useful in treatments to alleviate the effects of protocols that adversely affect the bone marrow, such as those that result in leukopenia. These are known side effects of chemotherapy and radiotherapy. The compounds of formula (1) also improve the success of bone marrow transplantation, improve wound healing and burn treatment, and aid in the restoration of damaged organ tissue. They also fight the bacterial infections that prevail in leukemia. As described in WO 03/011277, the compounds of formula (1) are used to mobilize and harvest CD34 + cells by apheresis with or without combinations with other mobilization factors. The harvested cells are used in treatments requiring stem cell transplants. As used herein, the term "progenitor cells" refers to cells that, in response to certain stimuli, can form differentiated hematopoietic or myeloid cells. The presence of progenitor cells can be evaluated by the ability of cells in a sample to form colony forming units of various types, including, for example, CFU-GM (colony-forming units, granulocyte-macrophage); CFU-GEMM (colony forming units, multipotentials); BFU-E (explosion-forming units, erythroids); HPP-CFC (highly proliferative potential colony forming cells); or other types of differentiated colonies that can be obtained in culture using known protocols. As used herein, "stem" cells are less differentiated forms of progenitor cells. Typically, such cells are frequently positive for CD34. Some stem cells do not contain this marker, however. These CD34 + cells can be assayed using fluorescence activated cell selection (FACS) and thus their presence can be evaluated in a sample using this technique. In general, CD34 + cells are present only at low levels in the blood, but are present in large numbers in bone marrow. Although other cell types such as endothelial cells and mast cells may exhibit this marker, CD34 is considered as an index of the presence of stem cells. In some compounds of the formula (1), Z and Z 'are - cyclic polyamine infractions having 9-24 carbons including 3-5 nitrogen atoms, as described in US Patents 5,021,409; 6,001,826; and 5,583,131, incorporated herein by reference. Particularly preferred are 1,5,9,13-tetraazacyclohexadecane; 1,5,8,11,14-pentaazacylcohexadecane, 1,4,8,11-tetraazacyclotetradecane; 1,5,9-triazacyclododecane; 1, 4, 7, 10-tetraazacyclododecane; and the like, including such cyclic polyamines that are fused to additional aromatic or heteroaromatic rings and / or containing a heteroatom other than nitrogen incorporated in the ring. These and embodiments where the cyclic polyamine contains a further fused cyclic system or one or more additional heteroatoms are described in US Pat. No. 5,698,546 incorporated herein by reference. Also preferred are 3.7, 11, 17-tetraazabicyclo (13.3.1) heptadeca-1 (17), 13,15-triene; 4,7,10, 17-tetraazabicyclo (13.3.1) heptadeca-1 (17), 13, 15-triene; 1,4,7,10-tetraazacyclotetradecane; 1,4, 7-triazacyclote-tradecan; and 4.7, 10-triazabicyclo (13.3.1) heptadeca-1 (17), 13-15-triene. When Z 'is different from a cyclic polyamine as defined in Z, its preferred embodiments are expressed in US Patents 5,817,807; 6,756,391; 6,506,770; and 6,667,310, also incorporated herein by reference. Ways where or Z is of the formula wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic fraction of 1-20 atoms is disclosed in US Patents 6,734,191; 6,750,348, and patent applications US 09 / 957,682, requested on September 17, 2001 and now granted; 09 / 957,654 requested on September 17, 2001 and now granted, all incorporated herein by reference. Preferred forms of the linking moiety include those where the linker is a bond, or where the linker is an alkylene or includes an aromatic moiety flanked by alkylene, preferably methylene moieties. Preferred linker groups include the grouped methylene forms of 1,3-phenylene, 2,5-pyridine, 3,5-pyridine, 2,5-thiophene, 4,4 '- (2,2'-bipyrimidine); 2, 9- (1, 10-phenanthroline) and the like. A particularly preferred linker is 1,4-phenylene-bis- (methylene). In one aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by compounds having the formula (1A): V - CR2 - Ar1 - CR2NR - (CR2) X - Ar2 (1A) where V is a heterocycle substituted of 9-24 members containing 2-4 nitrogen atoms optionally substituted with amine separated from each other by 2 or more optionally substituted carbon atoms, and which heterocycle optionally may comprise a fused aromatic or heteroaromatic ring, and wherein (a) said heterocycle contains at least one of O u S, said O u S separated from any adjacent heteroatom by at least 2 carbon atoms, and wherein said S is optionally oxidized or (b) at least one carbon atom in said ring is substituted by a substituent that removes electrons, or (c) both (a) and (b); and wherein each R is independently H or a straight, branched or cyclic chain alkyl containing 1-6 carbons; x is 0-4; Ar1 is an unsubstituted or substituted aromatic or heteroaromatic moiety; and Ar2 is an unsubstituted or substituted aromatic or heterocyclic group. In formula (1A) above, V may contain 2-4 nitrogens, preferably 3-4 nitrogens if there are no additional heteroatoms. Preferred ring sizes for V are 9-18 members, more preferably 12-16 members. V may also include a fused aromatic or heteroaromatic ring, preferably 1,2- or 1,3- or 1,4-phenylene or 2,6- or 2,5- or 2,4- or 2,3-pyridinylene. The fused ring can also be, for example, 2,5- or 2,6-pyridinylene or 2,4- or 2,3-pyrrolylene. In formula I above, substituents that remove electrons present in at least one C in ring V can be halogen, nitro, cyano, carboxylic acid, a carboxylic ester formed from an alcohol of 1-6 carbons, an amide formed from an amine of 0-12 carbons, a sulfonic or sulfinic acid, ester or amide, CF3, and the like. A preferred electron withdrawing substituent is = 0, as well as halo. Examples of halogen include fluorine, chlorine, bromine, iodine, with fluorine and chlorine. In formula (1A) above, Ar2 can be a heterocyclic group or optionally substituted aromatic group. Examples of aromatic groups include but are not limited to benzene, naphthalene, dihydronaphthalene and tetrahydronaphthalene. Examples of heterocyclic groups include 5-6 membered saturated, partially saturated or aromatic heterocyclic rings containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycles can be pyridine, quinoline, isoquinoline, imidazole, benzimidazole, azabenzimidazole, benzotriazole, furan, benzofuran, thiazole, benzothiazole, oxazole, benzooxazole, pyrrole, indole, indoline, indazole, pyrrolidine, pyrrolidone, pyrroline, piperidine, piperazine, tetrahydroquinoline, tetrahydroisoquinoline, pyrazole, thiophene, isoxazole, isothiazole, triazole, tetrazole, oxadiazole, thiadiazole, morpholino, thiamorpholino, pyrazolidine, imidazolidine, imidazoline, tetrahydropyran, dihydropyran, benzopyran, dioxane, dithiane, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, dihydrothiophene, and the like. Oxides of the heterocycles containing nitrogen and sulfur are also included in the present invention. Optional substituents on Ar2 include alkyl (C_6), alkenyl (Ct_6), alkynyl (Xg), halo, nitro, cyano, carboxylic acid, carboxylic ester formed from an alcohol with 1-6 carbons, an amide formed from of a 0-12 carbon amine, a sulphonic or sulfinic acid, ester or amide, OR, SR, NR2, OCR, OOCR, NRCOR, all where R is hydrogen or straight or branched chain alkyl, an aromatic or heterocyclic group optionally replaced, CF3, and the like. Preferred substituents include alkyl, OR, NR2, and halo. Preferred embodiments of Ar2 include phenyl, pyridinyl, pyrimidinyl and imidazolyl. In formula (1A) above, Ar1 can be a 5-6 member aromatic system which is bivalent benzene, pyridine, thiophene, pyrimidine, and the like. Ar1 can optionally be substituted by alkyl, alkenyl, halo, nitro, cyano, CF3, COOR, CONR2, OCR, OOCR, NRCOR, OR, NR2, SR (where R is H or C ^ alkyl, sulfonic or sulfinic acids, esters or Amides and the like Preferred embodiments of Ar 1 are phenylene, especially 1,3- and 1,4-phenylene and pyridinylene, preferably 2,6-pyridinylene, and 3,5-pyridinylene Preferable substituents are alkyl, OR , NR2 and halo In addition, in the compounds of the formula (1A), each R group can be hydrogen or alkyl of 1-2 carbons, preferably hydrogen The group R can be coupled to a nitrogen, is hydrogen or Cx alkyl. 6, preferably straight chain C ^ alkyl, more preferably H or methyl In one example, 1, 2, 3, 4, or 5 of the R groups are methyl or ethyl and the remaining R groups are hydrogen. of embodiment, the CXCR4 antagonist has the formula V-CH2-Ar1-CH2NR-CH2-Ar2 where V is a heterocycle as defined in the formula (1A), and onde: (a) said heterocycle is replaced with halo or = 0; or (b) said heterocycle contains O or S; or (c) both of (a) and (b), and where Ar1 is 1,3- or 1,4-unsubstituted phenylene, R is H, methyl or ethyl and Ar2 is unsubstituted phenyl or pyridinyl. Preferred embodiments of x are 0-2 and 1-2. The heterocycle V can contain 3 nitrogens and at least one carbon atom in the heterocycle which is replaced by at least one fluoro substituent. The fraction R can independently be hydrogen or methyl. The number of groups (CR2) X can be 0-4, 0-2, or 1-2. The Ar1 fraction can be 1,3- or 1,4-phenylene. The Ar2 moiety can be phenyl or pyridyl. The heterocycle V can be a 12-16 member heterocycle, or it can contain O or S as a ring member. The heterocycle V may also contain an oxidized sulfur as a ring member. In one example, at least one carbon in the heterocycle V is replaced by = 0. Compounds of the formula (1A), and methods for synthesizing such compounds are described in WO 01/44229, incorporated herein by reference. Examples of compounds of the formula (1A), their pharmaceutically acceptable salts or metal complexes thereof, include, but are not limited to: N- [4- (11-fluoro-1,4,7-triazacyclotetradecanyl) -1 , 4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [4- (11,11-difluoro-1,4-, 7-triazacyclotetradecanyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [4- (1,4,7-triazacyclotetradecan-2-onyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [12- (5-oxa-l, 9-diazacyclotetradecanyl) -1,4-phenylene-bis (methylene)] -2- (aminomethyl) pyridine; N- [4- (11-oxa-1,4,7-triazacyclotetradecanyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [4- (1-thia-l, 4,7-triazacyclotetradecanyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [4- (11-sulfoxo-l, 4,7-triazacyclotetradecanyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [4- (11-sulfone-1,4-, 7-triazacyclotetradecanyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; or N- [4- (3-carboxy-l, 4,7-triazacyclotetradecanyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine. In another aspect, the CXCR4 compound for use in the methods of the present invention is exemplified by compounds having the formula (IB): V-CR1R2-Ar-CR3R4-N (R5) - (CR6R7) x-R8 (IB) where V is an optionally substituted system of 1,4,8, 11-tetraazacyclotetradecanil, 4,7,10, 17-tetraazabicyclo [13.3.1] heptadeca-1 (17), 13, 15-trienyl, 1,4, 7-triazacyclotetrade-canyl, 4,7 , 10-triazabicyclo [13.3.1] heptadeca-1 (17), 13, 15-trienyl, 1,7-diazacyclotetradecanyl, or 4, 10-diazabicyclo [13.31.1] heptadeca-l (17), 13, 15- trienyl; R1 to R7 may be the same or different and are independently selected from hydrogen or straight, branched or cyclic alkyls; R8 is pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiophene-yl, thiophenyl, aminobenzyl, piperidinyl, purine, piperazinyl, phenylpiperazinyl, or mercaptan; Ar is a phenylene ring optionally substituted in one or multiple positions with alkyl, aryl, amino, alkoxy, hydroxy, halogen, carboxyl and / or carboxamido; and x is 1 or 2.

In formula (IB) above, fraction V can optionally be replaced by hydroxyl, alkoxy, thiol, thioalkyl, halogen, nitro, carboxy, amido, sulfonic acid, and / or phosphate. Compounds of the formula (IB), their pharmaceutically acceptable salts or metal complexes, and methods for synthesizing such compounds are described in WO 00/02870, which is incorporated herein by reference. Examples of compounds having the formula (IB) include but are not limited to: N- [1, 4, 8, 11-tetraazacyclotetra-decanyl-l, 4-phenylene-bis (methylene)] -2- (aminomethyl) pyridine; N- [1,4,8,11-tetraazacyclotetra-decanyl-1,4-phenylene-bis (methylene)] - N -methyl-2- (aminomethyl) pyridine; N- [1,4,8,11-tetraazacyclotetra-decanyl-l, 4-phenylene-bis (methylene)] -4- (aminomethyl) pyridine; N- [1,4,8,11-tetraazacyclotetra-decanyl-l, 4-phenylene-bis (methylene)] -3- (aminomethyl) pyridine; N- [1,4,8,11-tetraazacyclotetra-decanyl-l, 4-phenylene-bis (methylene)] - (2-aminomethyl-5-methyl) pyrazine; N- [1, 4, 8, 11-tetraazacyclotetra-decanyl-1,4-phenylene-bis (methylene)] -2- (aminoethyl) pyridine; N- [1,4,8,11-tetraazacyclotetra-decanyl-l, 4-phenylene-bis (methylene)] -2- (aminomethyl) thiophene; N- [1,4,8, 11-tetraazacyclotetra-decanyl-l, 4-phenylene-bis (methylene)] -2- (aminomethyl) mercaptan; N- [1,4,8,11-tetraazacyclotetra-decanyl-l, 4-phenylenebis (methylene)] -2-aminobenzylamine; N- [1,4,8,11-tetraazacyclotetra-decanyl-l, 4-phenylenebis (methylene)] -4-aminobenzylamine; N- [1, 4, 8, 11-tetraazacyclotetra-decanyl-l, 4-phenylene-bis (methylene)] -4- (aminoethyl) imidazole; N- [1,4,8,11-tetraazacyclotetra-decanyl-l, 4-phenylenebis (methylene)] -benzylamine; N- [4- (1,4,7-triazacyclotetra-decanyl) -1,4-phenylene-bis (methylene)] -2- (aminomethyl) pyridine; N- [7- (4,7,10,17-tetraazabicyclo [13.3.1] heptadeca-1 (17), 13, 15-trienyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [7- (4,7,1-triazabicyclo [13.3.1] heptadeca-1 (17), 13, 15-trienyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [1- (1,4,7-triazacyclotetra-decanyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [4- [4, 7, 10, 17-tetraazabicyclo [13.3.1] eptadeca-1 (17), 13, 15-trienyl] -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [4- [4,7,10-triazabicyclo [13.3.1] heptadeca-1 (17), 13, 15-trienyl] -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine; N- [1, 4, 8, 11-tetraazacyclotetradecanyl-l, 4-phenylene-bis (methylene)] -purine; 1- [1, 4, 8, 11-tetraazacyclotetradecanyl-l, 4-f-eneylenebis (methylene)] -4-f-enylpiperazine; N- [4 - (1, 7-diazacyclotetradecanyl) -1,4-f-ene -bis (methylene)] -2- (aminomethyl) pyridine; and N- [7- (4,10-diazabicyclo [13.3.1] heptadeca-l (17), 13,15-trienyl) -1,4-phenylenebis (methylene)] -2- (aminomethyl) pyridine. In yet another aspect, CXCR4 for use in the methods of the present invention can be exemplified by compounds having the formula (1C): V2-CR9C10-Ar2 (1C) where V2 is an optionally substituted system of 1.4.8, -tetraazacyclotetra-decanyl or 4,7,10, 17-tetraazabicyclo [13.3.1] heptadeca-1 (17), 13, 15-trienyl; R9 and R10 may be the same or different and are independently selected from hydrogen or straight, branched or cyclic Cx, 6 alkyl; Ar2 is an aromatic or heterocyclic ring each optionally substituted in single or multiple positions with donor groups or which withdraw electrons and / or aromatic and heterocyclic groups and their alkyl derivatives, and the acid addition salts and metal complexes. In formula (1C) above, Ar2 can optionally be substituted with alkyl, aryl, amino, alkoxy, hydroxy, halogen, carboxyl and / or carboxamido. In particular examples, Ar2 is optionally substituted with alkoxy, alkyl, or halogen. Compounds having the formula (1C), and methods for synthesizing them, are described in WO 00/02870, incorporated herein by reference. Examples of compounds having the formula (1C) include but are not limited to: 1- [2,6-dimethoxypyrid-4-yl (methylene)] -1,, 8, 11-tetraaza-cyclotetradecane; 1- [2-chloropyrid-4-yl (methylene)] -1,4,8,11-tetraazacyclo-tetradecane; 1- [2,6-dimethylpyrid-4-yl (methylene)] -1,4,8,11-tetraaza-cyclotetradecane; 1- [2-methylpyrid-4-yl (methylene)] -1,4,8,11-tetraazacyclo-tetradecane; 1- [2,6-dichloropyrid-4-yl (methylene)] -1,4,8,8-tetraaza-cyclotetradecane; 1- [2-chloropyrid-5-yl (methylene)] -1,4,8,11-tetraazacyclo-tetradecane; and 7- [4-methylphenyl (methylene)] -4, 7, 10, 17-tetraazabicyclo [13.3.1] heptadeca-1 (17), 13, 15-triene. In yet another aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by a compound having the formula (ID): V - R - A - R '- W (ID) where V and W are independently cyclic polyamine fractions having from 9 to 32 ring members and from 3 to 8 amine nitrogens in the ring separated by 2 or more carbon atoms from each other, and having one or more aromatic or heteroaromatic rings fused to each other the same, A is an aromatic or heteroaromatic fraction when V and W have one or more aromatic or heteroaromatic moieties fused thereto, with or without an additional heteroatom other than nitrogen incorporated in the ring, or A is an aromatic or heteroaromatic moiety when V and W contain a heteroatom other than nitrogen incorporated in the ring without having one or more aromatic or heteroaromatic moieties fused thereto, and R and R 'are, each, an alkylene chain or chain having substituted or unsubstituted heteroatom separating the cyclic polyamines and the fraction A. In the above formula (ID), R and R 'may each be methylene. In one example, A is 1,3- or 1, -phenylene. In another example, each of V and W is an unsubstituted or substituted tricyclic or bicyclic ring system containing only carbon and nitrogen atoms in the rings. One of the cyclic ring systems may be a 10 to 20 member polyamine ring system having from 3 to 6 nitrogen atoms of amine, and the ring system or systems are a fused benzyl or pyridinyl ring system. Compounds having the formula (ID), and methods for synthesizing such compounds, are described in US Pat. No. 5,698,546, incorporated herein by reference. These compounds include but are not limited to: 7,7 '- [1,4-f-ene-bis (methylene)] bis-3,7,11,1-tetraazabicyclo [13.3.1] heptadeca-1 (17) , 13, 15-triene; 7, 7 '- [1,4-phenyl ene-bis (methylene)] bis [15-chloro-3,7,11,17-tetraazabicyclo [13.3.1] heptadeca-1 (17), 13, 15-triene ]; 7, 7 '- [1,4-phenylene-bis (methylene)] bis [15-methoxy-3,3,7,17-tetraazabicyclo [13.3.1] heptadeca-1 (17), 13,15-triene]; 7,7'- [1, -f eni leno-bis (methylene)] bis-3,7,11,17-tetraazabicyclo [13.3.1] -heptadeca-13,16-trien-15-one; 1,1 '- [1,4-fyl-bis (methylene)] bis-4, 7, 10,17-tetraazabicyclo [13.3.1] -heptadeca-1 (17), 13, 15-triene; 8, 8 '- [1,4-f-methylene-bis (methylene)] bis-4, 8, 12, 19-tetraazabicyclo [15.3.1] nonadeca-1 (19), 15, 17-triene; 6, 6 '- [1, -f enyl-bis (methylene)] bis-3, 6, 9,15-tetraazabicyclo [11.3. l] pentadeca-l (15), 11, 13 -trieno; 6, 6 '- [1,3-phenylene-bis (methylene)] bis-3,6,9,15-tetraazabicyclo [11.3.1] pentadeca-1 (15), 11, 13-triene; and 17, 17 '- [1,4-f-methylene-bis (methylene)] bis-3, 6, 14, 17, 23, 24-hexaazatricyclo [17.3.1.18'12] tetracosa-1 (23), 8, 10, 12 (24), 19, 21-hexane. In yet another aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by compounds having the formula (1E): ZRA-R'-Y (1E) wherein Z and Y are identical cyclic polyamine fractions having from 10 to 15 ring members and from 3 to 6 amine nitrogens in the ring separated by 2 or more carbon atoms from each other, said amine nitrogens being the only ring heteroatoms, A is an aromatic or heteroaromatic fraction other than quinoline , R and R 'are each methylene bonded to nitrogen atoms in Z and Y, the amine nitrogen atoms being otherwise unsubstituted. In formula (1E) above, each fraction of Z and Y may have 14 ring members and 4 amine nitrogens in the ring. Compounds having the formula (1E), and methods for synthesizing such compounds, are described in US Patent 5,583,131, incorporated herein by reference. These compounds include but are not limited to: 1, 1 '- [1,3-phenylenebis (methylene)] -bis-1,4,8,11-tetra-azacyclotetradecane; 1,1'- [1,4-phenylenebis (methylene)] -bis-1,4,8,11-tetra-azacyclotetradecane (AMD 3100); 1,1'- [1,4-phenylene-bis- (methylene)] -bis-1,4,8,11-tetraazacyclotetradecane; bis-zinc or bis-copper complex of 1,1 '- [1,4-phenylenebis- (methylene)] -bis-1, 4,8,11-tetraazacyclotetradecane; 1, 1 '- [3, 3'-biphenylene-bis- (methylene)] -bis-1,4,8,8-tetraazacyclotetradecane; 11, 11 '- [1,4-phenylene-bis- (methylene)] -bis-1,, 7,11-tetraazacyclotetradecane; 1, 11 '- [1,4-phenylene-bis- (methylene)] -1,4,8,11-tetraazacyclotetradecane-1,, 7, 11-tetraazacyclotetradecane; 1,1'- [2,6-pyridine-bis- (methylene)] -bis-1,4,8,11-tetraazacyclotetradecane; 1,1- [3,5-pyridine-bis- (methylene)] -bis-1,4,8,11-tetraazacyclotetradecane; 1, 1 '- [2,5-thiophene-bis- (methylene)] -bis-1,4,8,11-tetraazacyclotetradecane; 1,1'- [4,4'- (2, 2'-bipyridine) -bis- (methylene)] -bis-1,4,8,11-tetraazacyclotetradecane; 1,1'- [2,9- (1,10-phenanthroline) -bis- (methylene)] -bis-1,4,8,11-tetraazacyclotetradecane; 1,1'- [1,3-phenylene-bis- (methylene)] -bis-1,4,7,10-tetraazacyclotetradecane; 1,1'- [1, phenyl ene-bis- (methylene)] -bis-1,4,7,10-tetraazacyclotetradecane; 1 '- [5-nitro-1,3-phenylenebis (methylene)] bis-1, 4,8, 11-tetraazacyclotetradecane; 1,1'- [2,4,5,6-tetrachloro-l, 3-phenylenebis (methylene)] bis-1,4,8,11-tetraazacyclotetradecane; 1,1'- [2,3,5,6-tetra-fluoro-1,4-phenylenebis (methylene)] bis-1,4,8,8-tetraazacyclotetradecane; 1,1'- [1,4-naphthylene-bis- (methylene)] bis-1,4,8,8-tetraazacyclotetradecane; 1,1'- [1,3-phenylenebis- (methylene)] bis-1,5,9-triazacyclododecane; 1,1'- [1,4-phenylene-bis- (methylene)] -1,5,9-triazacyclododene; 1,1'- [2,5-dimethyl-1,4-phenylenebis- (methylene)] -bis-1,4,8,11-tetraazacyclotetradecane; 1,1'- [2,5-dichloro-l, 4-phenylenebis- (methylene)] -bis-1,4,8,11-tetraazacyclotetradecane; 1,1'- [2-bromo-l, 4-phenylenebis- (methylene)] -bis-1,4,8,14-tetraazacyclotetradecane; and 1,1 '- [6-phenyl-2,4-pyridinebis- (methylene)] -bis-1,4,8,18-tetraazacyclotetradecane. In yet another aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by compounds having the formula (1F): Z- (A) nY (1F) where Z and Y are independently cyclic polyamine fractions having from 9 to 32 ring members and from 3 to 8 nitrogen atoms of amine in the ring, A is an atom or linking group, and n is O or an integer from 1 to 6. In the formula (1F) above, each fraction of Z and Y can have from 10 to 24 ring members, or 12 to 18 ring members. Each fraction of Z and Y can also have from 4 to 6 nitrogen atoms of amine in the ring. In one example, n is 0. In another example, A is methylene. Compounds having the formula (1F), and methods for synthesizing such compounds, are described in US Patent 5,021,409, incorporated herein by reference. These compounds include but are not limited to: 2,2'-bicyclolamine; 3,3'- (bis-1, 5,9, 13-tetraazacyclohexadecane); 3,3'- (bis-1, 5, 8, 11, 14-pentaazacyclohexadecane); methylene (or polymethylene) di-l-N-1,4,8,8-tetraaza cyclootetradecane; 3,3'-bis-1, 5, 9, 13-tetraazacyclohexadecane; 3,3'-bis-1, 5,8,11,14-pentaazacyclohexadecane; 5,5'-bis-1, 4,8, 11-tetraazacyclotetradecane; 2,5'-bis-1, 4,8,11-tetraazacyclotetradecane; 2,6'-bis-1, 4,8, 11-tetraazacyclotetradecane; 11, 11 '- (1, 2-ethanediyl) bis-1,4,8,8-tetraazacyclotetra-decane; 11, 11 '- (1,2-propanediyl) bis-1, 4,8, 11-tetraazacyclote-tradecan; 11, 11 '- (1,2-butanediyl) bis-1,4,8,8-tetraazacyclotetra-decane; 11, 11 '- (1, 2-pentanediyl) bis-1,4,8,8-tetraazacyclote-brancan; and 11,11 '- (1, 2-hexanediyl) bis-1,4,8,8-tetraazacyclotetra decane. In another aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by compounds having the formula (2A): W is a nitrogen atom and Y is empty, or W is a carbon atom and Y = H; R1 to R7 may be the same or different and are independently hydrogen or straight, branched or cyclic C1_6 alkyl; R8 is an optionally substituted heterocyclic group or an optionally substituted aromatic group; Ar is an aromatic or heteroaromatic ring optionally substituted in a single or multiple positions not binding to donor or electron withdrawing groups; n and n 'are, independently, 0-2; X is a group of the formula: wherein, ring A is a 5 or 6 membered saturated or unsaturated ring, optionally substituted, and P is an optionally substituted nitrogen atom and wherein any heteroatom in addition to P in ring A is N; wherein ring B is an optionally substituted 5 to 7 membered ring; where ring A or ring B is linked to a group W from any position through group V; where V is a chemical bond or V is a group (CH2) n "(where n" = l-2), or V is a group C = 0, and where Z is selected from the group consisting of: an atom of hydrogen, an optionally substituted C 1-6 alkyl group, an optionally substituted aromatic or heterocyclic group, an optionally substituted amino group, an optionally substituted C 1-6 alkylamino or C 3-7 cycloalkylamino group, and a substituted carbonyl group, or the acid addition salts pharmaceutically acceptable thereof, wherein said compound may be in any stereoisomeric form or present as a mixture of its stereoisomeric forms, wherein ring B is selected from the group consisting of: benzene and a 5- to 7-membered cycloalkyl ring; and its optionally substituted forms In the above formula (2A), ring A may be pyridine, pyrimidine, pyrazine, pyridazine, triazine, piperidine, piperazine; imidazole; pyrazole; or triazole, and optionally substituted forms thereof. Ring B can be cyclopentyl; cyclohexyl; cycloheptyl; cyclopentenyl; cyclohexenyl; or cycloheptenyl, and optionally substituted forms thereof. In one embodiment, ring A and ring B together are optionally substituted dihydroquinoline or tetrahydroquinoline. In formula (2A) above, ring A and ring B are independently optionally substituted with a substituent selected from the group consisting of: halogen; nitro; cyano; carboxylic acid; an optionally substituted alkyl, alkenyl or cycloalkyl group; an optionally substituted hydroxyl group; an optionally substituted thiol group; an optionally substituted amino or acyl group; an optionally substituted carboxylate, carboxamide or sulfonamide group; and an optionally substituted aromatic or heterocyclic group. In one embodiment, the optional substituent on ring A or ring B is independently an aralkyl or optionally substituted wherein said heterocycloalkyl is a 5- or 6-membered heterocycloalkyl containing 1-4 heteroatoms. For example, the optionally substituted aralkyl or heterocycloalkyl may be phenyl-C1_i alkyl; phenylmethyl (benzyl); phenethyl; priidinylmethyl; or pyridinylethi-lo. In formula (2A) above, Z may be an optionally substituted C _ 6 alkyl group, wherein said C 1 alkyl group is substituted with one or more substituents selected from the group consisting of: halogen; nitro; cyano; carboxylic acid; an optionally substituted alkyl, alkenyl or cycloalkyl group; an optionally substituted hydroxyl group; an optionally substituted thiol group; an optionally substituted amino or acyl group; an optionally substituted carboxylate, carboxamide or sulfonamide group; and an optionally substituted aromatic or heterocyclic group. In the above formula (2A), Z is an optionally substituted aromatic or heterocyclic group or an alkyl group optionally substituted by an optionally substituted aromatic or heterocyclic group. In one embodiment, Z is a C1_s alkyl group substituted with an optionally substituted aromatic or heterocyclic group. The optionally substituted aromatic group may be substituted with a substituent selected from the group consisting of: benzene; naphthalene; dihydronafatnole; and tetrahydronaphthalene; and wherein said optionally substituted heterocyclic group is a heterocyclic ring of 5 to 6, partially saturated, or aromatic containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur membered saturated. The heterocyclic group selected from the group consisting of: pyridine, quinoline, isoquinoline, imidazole, benzimidazole, azabencimidazola, benzotriazole, furan, benzofuran, thiazole, benzothiazole, oxazole, benzoxazole, pyrrole, indole, indoline, indazola, pyrrolidine, pyrrolidone, pyrroline, piperidine, piperazine, tetrahydroquinoline, tetrahydroquinoline, pyrazole, thiophene, isoxazole, isothiazole, triazole, tetrazole, oxadiazole, thiadiazole, morpholino, thiamorpholino, pyrazolidine, imidazolidine, imidazoline, tetrahydropyran, dihydropyran, benzopyran, dioxane, dithiane, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, and dihydrothiophene. The heterocyclic group may also contain nitrogen or sulfur heteroatoms; and wherein said nitrogen or sulfur heteroatoms are optionally in the form of oxides. In another embodiment, the CXCR4 antagonist for use in the methods of the present invention can be a compound having the formula (2B): where W is a nitrogen atom and Y is empty; R1 to R7 may be the same or different and are independently hydrogen or straight, branched or cyclic C1_6 alkyl; R8 is an optionally substituted heterocyclic group or an optionally substituted aromatic group; Ar is an aromatic or heteroaromatic ring optionally substituted in a single or multiple positions not binding to donor groups or withdrawing electrons; n and n 'are, independently, 0-2; X is a group of the formula: wherein, ring A is a 5 or 6 membered saturated or unsaturated ring, optionally substituted, and P is an optionally substituted nitrogen atom and wherein any hetero atom in rings A or B is N; wherein ring B is an optionally substituted 5 to 7 membered ring; where ring A or ring B is linked to a group W from any position through group V; where V is a chemical bond or V is a group (CH2) n " (where n "= l-2), or V is a group C = 0, and where Z is selected from the group consisting of: a hydrogen atom, an optionally substituted C grupo g alkyl group, an aromatic group or optionally substituted heterocyclic, an optionally substituted amino group, an optionally substituted C1_6 alkylamino or C3_7 cycloalkylamino group, and a substituted cnyl group, or the pharmaceutically acceptable acid addition salts thereof, wherein said compound may be in any stereoisomeric form or present as In the formula (2B) above, the ring A can be pyridine, pyrimidine, pyrazine, pyridazine, triazine, piperidine, piperazine, imidazole, pyrazole, or triazole, and the optionally substituted forms thereof. Ring B can be benzene or a 5- to 7-membered cycloalkyl ring, and optionally substituted forms thereof For example, ring B can be cyclopentyl; ilo; cicioheptyl; cyclopentenyl; cyclohexenyl; or cycloheptenyl, and optionally substituted forms thereof. In formula (2B) above, ring A and ring B together may be an optionally substituted dihydroquinoline or tetrahydroquinoline. For example, ring A and ring B are independently optionally substituted with a substituent selected from the group consisting of: halogen; nitro; cyano; cxylic acid; an optionally substituted alkyl, alkenyl or cycloalkyl group; an optionally substituted thiol group; an optionally substituted amino or acyl group; an optionally substituted cxylate, cxamide or sulfonamide group; and an optionally substituted aromatic or heterocyclic group. In one example, the optional substituent on ring A or ring B is independently an optionally substituted aralkyl or heterocycloalkyl, wherein said heterocycloalkyl is a 5- or 6-membered ring containing 1-4 heteroatoms. The optionally substituted aralkyl or heterocycloalkyl is selected from the group consisting of: phenyl-C 1-4 alkyl; phenylmethyl (benzyl); phenethyl; pyridinylmethyl; and pyridinylethyl. In formula (2B) above, Z may be an optionally substituted C ^ 6 alkyl group, wherein said X.sub.1 alkyl group is substituted with one or more substituents selected from the group consisting of: halogen; nitro; cyano; cxylic acid; an optionally substituted alkyl, alkenyl or cycloalkyl group; an optionally substituted thiol group; an optionally substituted amino or acyl group; an optionally substituted cxylate, cxamide or sulfonamide group; and an optionally substituted aromatic or heterocyclic group. In one example, Z is an alkyl group substituted with an optionally substituted aromatic or heterocyclic group. In another example, Z is an optionally substituted aromatic or heterocyclic group or an alkyl group optionally substituted with an optionally substituted aromatic or heterocyclic group. For example, the optionally substituted aromatic group is substituted with a substituent selected from the group consisting of: benzene; naphthalene; dihydronaphthalene; and tetrahydronaphthalene; and wherein said optionally substituted heterocyclic group is a saturated, partially saturated, or aromatic 5 to 6 membered heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocyclic group can be pyridine, quinoline, isoquinoline, imidazole, benzimidazole, azabenzimidazole, benzotriazole, furan, benzofuran, thiazole, benzothiazole, oxazole, benzoxazole, pyrrole, indole, indolino, indazole, pyrrolidine, pyrrolidone, pyrroline, piperidine, piperazine, tetrahydroquinoline, tetrahydroisoquinoline, pyrazole, thiophene, isoxazole, isothiazole , triazole, tetrazole, oxadiazole, thiadiazole, morpholino, thiamorpholino, pyrazolidine, imidazolidine, imidazoline, tetrahydropyran, dihydropyran, benzopyran, dioxane, dithiane, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, and dihydrothiophene. In other examples, the heterocyclic group contains nitrogen or sulfur heteroatoms; and wherein said nitrogen or sulfur heteroatoms are optionally in the form of oxides. In one embodiment, the CXCR4 antagonist is a compound selected from the group consisting of: N- (2-pyridinylmethyl) -N'- (6,7,8,9-tetrahydro-5H-cyclohepta [£ >] pyridin-9-yl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N'- (5,6,7,8-t-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (6,7-dihydro-5H-cyclopenta [b] pyridin-7-yl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (1,2,3,4-tetrahydro-1-naphthalenyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N'- (1-naphthalenyl) -1,4-benzenedimem-tanamine; N- (2-pyridinylmethyl) -N'- (8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- [(2-pyridinylmethyl) amino] ethyl] -N' - (1-methyl-1,2,4-tetrahydro-8-quinolinyl) -1, 4-benzenedi-methanamine; N- (2-pyridinylmethyl) -N '- [2- [(L-imidazol-2-ylmethyl) amino] ethyl] -N' - (1-methyl-l, 2,3,4-tetrahydro-8-quinolinyl) ) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N'- (1,2,3,4-t-ehydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- [(1 J-imidazol-2-ylmethyl) amino] ethyl] -N' - (1,2,3,4-t-tetrahydro-1-naphthalenyl) - 1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (2-phenyl-5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethamine; N, N'-bis (2-pyridinylmethyl) -N '- (2-f-enyl-5,6,7,8-t-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N'- (5,6,7,8-t-ehydro-5-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (lido-imidazol-2-ylmethyl) -N' - (5,6,7,8-tetrahydro-5-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (1-yl-imidazol-2-ylmethyl) -N' - (5,6,7,8-t-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [(2-amino-3-f-enyl) propyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (lff-imidazol-4-ylmethyl) -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (2 -quinolinylmethyl) -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; NT (2-pyridinylmethyl) -N '- (2- (2-naphl) aminoethyl) -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [(S) - (2-acetylamino-3-phenyl) propyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1, 4-benzenedi-methanamine; N- (2-pyridinylmethyl) -N '- [(S) - (2-acetylamino-3-phenyDpropyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1, 4- benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [3- ((2-naphthalenylmethyl) amino) propyl] -N1- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethane N, N- (2-pyridinylmethyl) -N '- [2- (S) -pyrolidinylmethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; - (2-pyridinylmethyl) -N '- [2- (R) -pyrolidinylmethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2- pyridinylmethyD-N'- [3-pyrazolylmethyl] -N'- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- pyrrolylmethyl] -N '- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N'- [2-thiophenoylmethyl] -N'- (5 , 6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2-thiazolylmethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1, -benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2-furanylmethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- [(phenylmethyl) amino] ethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridylmethyl) -N '- (2-aminoethyl) -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N 1 -3-pyrrolidinyl-N '- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N'-4-piperidinyl-N '- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- [(phenyl) amino] ethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (7-mey-1,2,3,4-tetrahydro-2-naphthalenyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (6-mey-1,2,3,4-tetrahydro-2-naphthalenyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (1-methyl-1,2,4,4-tetrahydro-2-naphthalenyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (7-mey-3,4-dihydronaphthalenyl) -1- (aminomethyl) -4-benzamide; N- (2-pyridinylmethyl) -N '- (6-mey-3,4-dihydronaph-alenyl) -1- (aminomethyl) -4-benzamide; N- (2-pyridinylmethyl) -N '- (1JI-imidazol-2-ylmethyl) -N'- (7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (1H-imidazol-2-ylmethyl) -N' - (8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N'- (8-fluoro-1,2,3,4-tetrahydro-2-naphthalenyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (1H-imidazol-2-ylmethyl) -N' - (8-fluoro-1, 2,3,4-tetrahydro-2-naphthalenyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (5,6,7,8-tetrahydro-7-quinol-nyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (li? -imidazol-2-ylmethyl) -N' - (5,6,7,8-tetrahydro-7-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridylmethyl) -N '- [2- [(2-naphthalenylmethyl) amino] ethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- (isobutylammo) ethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- [(2-pyridinylmethyl) amino] ethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- [(2-furanylmethyl) amino] ethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N'- (2-guanidinoethyl) -N'- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- [bis- [(2-methoxy) phenylmethyl] amino] ethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1 , 4-benzenedimethanamine; N- (2-pyridinylmethyl) -N1 - [2- [(1H-imidazol-4-ylmethyl) amino] ethyl] -N '- (5,6,7,8-tetrahydro-8-quinolinyl) -1, 4 -benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- [(1H-imidazol-2-ylmethyl) amino] ethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1, 4-benzenedimemetanamine; N- (2-pyridinylmethyl) -N '- [2- (phenylureido) ethyl] -' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [[N "- (n-butyl) carboxamido] methyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethane -min; N- (2-pyridinylmethyl) -N '- (carboxamidomethyl) -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [(N "-phenyl) carboxamidomethyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N 1 - (carboxymethyl) -N '- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (phenylmethyl) -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (lff-benzimidazol-2-ylmethyl) -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N1- (5,6-dimethyl-lH-benzimidazol-2-ylmethyl) -N '- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine (hydrobromide salt); N- (2-pyridinylmethyl) -N '- (5-nitro-lJ? -benzimidazol-2-ylmethyl) -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [(1 H) -5-azabenzimidazol-2-yl-methyl] -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1, 4- benzenedimethanamine; N- (2-pyridinylmethyl) -N- (4-phenyl-lff-imidazol-2-ylmethyl) -N '- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- [2- (2-pyridinyl) ethyl] -N "- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- ( 2-pyridinylmethyl) -N '- (2-benzoxazolyl) -N' - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N '- (trans-2-aminocyclohexyl) -N '- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N' - (2-phenylethyl) - N '- (5, 6,7, 8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N'- (3-phenylpropyl) -N'- (5,6, 7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N'- (trans-2-aminocyclopentyl) -N '- (5,6,7,8-tetrahydro- 8-quinolinyl) -1,4-benzenedimethanamine; N- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -N- (5,6,7,8-tetrahydro-8-quinolinyl) -glycinamide; N- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -N- (5,6,7,8-tetrahydro-8-quinolinyl) - (L) -alaninamide; N- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -N- (5,6,7,8-tetrahydro-8-quinolinyl) - (L) -aspartamide; N- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -N- (5,6,7,8-tetrahydro-8-quinolinyl) -pyrazinamide; N- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -N- (5,6,7,8-tetrahydro-8-quinolinyl) - (L) -prolinamide; N- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -N- (5,6,7,8-tetrahydro-8-quinolinyl) - (L) -lysinamide; N- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -N- (5,6,7,8-tetrahydro-8-quinolinyl) -benzamide; N- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -N- (5,6,7,8-tetrahydro-8-quinolinyl) -picolinamide; N '-benzyl-N- [[4- [[(2-pyridinylmethyl) amino] ethyl] phenyl] methyl] -N- (5,6,7,8-tetrahydro-8-quinolinyl) -urea; N '-phenyl-N- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -N- (5,6,7,8-tetrahydro-8-quinolinyl) -urea; N- (6,7,8,9-tetrahydro-5J? -cyclohepta [_acteriapyridin-9-yl) -4- [[(2-pyridinylmethyl) mino] methyl] benzamide; N- (5, 6, 7, 8-tetrahydro-8-quinolinyl) -4 - [[(2-pyridinylmethyl) amino] methyl] benzamide; N, N '-bis (2-pyridinylmethyl) -N' - (5, 6, 1, 8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N, N'-bis (2-pyridinylmethyl) -N '- (6,7,8,9-tetrahydro-5-cyclohepta [bacterialpyridin-9-yl] -1,4-benzenedimethanamine; N, N'-bis (2-pyridinylmethyl) -N '- (6,7-dihydro-5JÍ-cyclopenta [bacteriumpyridin-7-yl] -1,4-benzenedimethamine; N, N '-bis (2-pyridinylmethyl) -N' - (1, 2, 3, 4-tetrahydro-l-naphthalenyl) -1,4-benzenedimethanamine; N, N '-bis (2-pyridinylmethyl) -N' - [(5,6,7,8-tetrahydro-8-quinolinyl) methyl] -1,4-benzenedimethamine; N, N '-bis (2 ^ pyridinylmethyl) -N' [(6,7-dihydro-51? -cyclopenta [_bacteriapyridin-7-yl] methyl] -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N- (2-methoxyethyl) -N '- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (2-pyridinylmethyl) -N- [2- (4-methoxyphenyl) ethyl] -N '- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N, N'-bis (2-pyridinylmethyl) -1,4- (5,6,7,8-tetrahydro-8-quinolinyl) benzenedimethanamine; N- [(2,3-dimethoxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N, N'-bis (2-pyridinylmethyl) -N- [1- (N "-phenyl-N" -methyl-ureido) -4-piperidinyl] -1,3-benzenedimethanamine; N, N'-bis (2-pyridinylmethyl) -N- [N "-p-toluenesulfonyl-phenylalanyl) -4-piperidinyl] -1, 3-benzenedimethanamine; N, N'-bis (2-pyridinylmethyl) -N- [1- [3- (2-chlorophenyl) -5-methyl-isoxazole-4-oil] -4-piperidinyl] -1,3-benzenedimethanamine; N- [(2-hydroxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta [bacteriumpyridin-9-yl] -1,4-benzenedimethanamine; N- [(4-cyanophenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta [bac t eriapyridin-9-yl] -1,4- benzenedimethanamine; N- [(4-cyanophenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [(4-acetamidophenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [(4-phenoxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5i-cyclohepta [Jbacteriapyridin-9-yl] -1,4-benzenedimethanamine; N- [(1-methyl-2-carboxamido) ethyl] -N, N'-bis (2-pyridinyl-methyl) -1, 3-benzenedimethanamine; N- [(4-benzyloxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta [bacterium-pyridin-9-yl] -1,4-benzenedimethanamine; N- [(thiophene-2-yl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5Ji-cyclohepta [bacterium-pyridin-9-yl] -1,4-benzenedimethanamine; N- [1- (benzyl) -3-pyrrolidinyl ] -N, N'-bis (2-pyridinyl-methyl) -1,3-benzenedimethanamine; N- [[l-methyl-3- (pyrazol-3-yl)] propyl] -N, N'-bis ( 2-pyridinylmethyl) -1,3-benzenedimethanamine; N- [1- (phenyl) ethyl] -N, N'-bis (2-pyridinylmethyl) -1,3-benzenedimethanamine; N- [(3,4-methylenedioxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5i? -cyclohepta [b] pyridin-9-yl) - 1,4-benzenedimethanamine; N- [1-benzyl-3-carboxymethyl-4-piperidinyl] -N, N'-bis (2-pyridinylmethyl) -1,3-benzenedimethanamine; N- [(3,4-methylenedioxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (3-pyridinylmethyl) -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5 £ T-cyclohepta [b] pyridin-9-yl) -1,4-benzenedimethanamine; N- [[1-methyl-2- (2-tolyl) carboxamido] ethyl] -N, N'-bis (2-pyridinylmethyl) -1, 3-benzenedimethanamine; N- [(1, 5-dimethyl-2-phenyl-3-pyrazolinone-4-yl) methyl] -N1 - (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [(4 -propoxy phenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl) -1,4 -benzenedimethanamine; N- (1- phenyl-3,5-dimethyl-ilpyrazolin-4-ylmethyl) - '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimet anamina; N- [lH-imidazol-4-ylmethyl] -N, N '-bis (2-pyridinylmethyl) -1, 3-benzenedimethanamine; N- [(3-methoxy -4,5-methylenedioxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5-cyclohepta [b] pyridine-9- il) -1,4-benzenedimethanamine; N- [(3-cyanophenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5 __-cyclohepta [b] pyridin-9-yl) -1, 4- benzenedimethanamine; N- [(3-cyanophenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (5-ethylthiophene-2-ylmethyl) -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5 __-cyclohepta [b] pyridin-9-yl) -1, 4 -benzenedimethanamine; N- (5-ethylthiophene-2-ylmethyl) -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [(2,6-difluorophenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl) -1, 4-benzenedimethanamine; N- [(2,6-difluorophenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [(2-difluoromethoxyphenyl) methyl] -N1- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5? -cyclohepta [b] pyridin-9-yl) -1, 4- benzenedimethanamine; N- (2-difluoromethoxyphenylmethyl) -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (1,4-benzodioxan-6-ylmethyl) -N'- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5Ji-cyclohepta [b] pyridin-9-yl) -1 , 4-benzenedimethanamine; N, N '-bis (2-pyridinylmethyl) -N- [1- (N "-phenyl-N" -methyl-ureido) -4-piperidinyl] -1,4-benzenedimethanamine; N, N'-bis (2-pyridinylmethyl) -N- [N "-p-toluenesulfonyl-phenylalanyl) -4-piperidinyl] -1, -benzenedimethanamine; N- [1- (3-pyridinecarboxamido) -4-piperidinyl] -N, N'-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [1- (cyclopropylcarboxamido) -4-piperidinyl] -N, N'-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [1- (1-phenylcyclopropylcarboxamido) -4-piperidinyl] -N, N'-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- (1,4-benzodioxan-6-ylmethyl) -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [1- [3- (2-chlorophenyl) -5-methyl- isoxazole-4-carboxamido] -4-piperidinyl] -N, N '-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [1- (2-thiomethylpyridine-3-carboxamido) -4-piperidinyl] - N, N'-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [(2,4-difluorophenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8) -tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (1-methylpyrrol-2-ylmethyl) -N '- (2-pyridinylmethyl) -N- (5, 6,7, 8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [(2-Hydroxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [(3-methoxy-, 5-methylenedioxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzene-dimethanamine; N- (3-pyridinylmethyl) -N'- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [2- (N "-morpholinomethyl) -1-cyclopentyl] -N, N '-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [(1-methyl-3-piperidinyl) propyl] - N, N'-bis (2-pyridinyl-methyl) -1,4-benzenedimethanamine; N- (1-methylbenzimidazol-2-ylmethyl) -N '- (2-pyridinylmethyl) -N- (5,6,7, 8-tetrahydro-8-quinolinyl) -1,4-benzenedimetaneamine; N- [1- (benzyl) -3-pyrrolidinyl] -N, N'-bis (2-pyridinyl-methyl) -1,4-benzenedimethanamine; N- [[(1-phenyl-3- (N "-morpholino)] ropil] -N, N '-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [1- (iso -propyl); -4-piperidinyl] -N, N '-bis (2-pyridinyl-methyl) -1,4-benzenedimethanamine; N- [1- (ethoxycarbonyl) -4-piperidinyl] -N' - (2-pyridinyl-methyl) -N- (5, 6, 7, 8-tetrahydro-8-quinolinyl) -1,4-benzenedimetaneamine; N- [(1-methyl-3-pyrazolyl) propyl] -N '- (2-pyridinylmethyl) • N- (5, 6, 7, 8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [1-methyl-2- (N ", N" -diethylcarboxamido) ethyl] -N, N ' -bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [(l-met il-2-phenylsulfonyl) ethyl] -N '- (2-pyridinyl-methyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- [(2-Chloro-4,5-methylenedioxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N ~ (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzene- dimethanamine; N- [1-methyl-2-N "- (4-chlorophenyl) carboxamido] ethyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1 , 4-benzenedimethanamine; N- (l-acetoxyindol-3-ylmethyl) -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl) ) -1,4-benzenedimethanamine; N- [(3-benzyloxy-4-methoxyphenyl) methyl] -N '- (2-pyridinyl-methyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta) [b] pyridin-9-yl-l, 4-benzenedimethanamine; N- (3-quinolylmethyl) -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) - 1,4-benzenedimethanamine; N- [(8-hydroxy) -2-quinolylmethyl] -N '- (2-pyridinylmethyl) -N- (6,7,9,9-tetrahydro-5H-cyclohepta [b] pyridine) 9-yl) -1,4-benzene-dimethanamine; N- (2-quinolylmethyl) -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5J? -cyclohepta [b] pyridin-9-yl) -1,4-benzenedimetaneamine; N - [(4-acetamidophenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5I. -cyclohepta [b] pyridin-9-yl) -1,4-benzenedi-methanamine; N- [L-imidazole-2-methylmethi] l] -N, N'-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- (3-quinolylmethyl) -N '- (2-pyridinylmethyl) -N- (6,7,8,9-t ehydro-5H-cyclohept a [b] pyridin-9-yl) -1,4- benzenedimethanamine; N- (2-thiazolylmethyl) -N '- (2-pyridinylmethyl) -N- (6,7,8,9-t ehydro-5H-cyclohept a [b] pyridin-9-yl) -1,4-benzenedimethanamine; N- (4-pyridinylmethyl) -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl) -1,4-benzenedimet anami - na N- [(5-benzyloxy) benzo [b] pyrrol-3-ylmethyl] -N, N'-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- (1-methylpyrazol-2-ylmethyl) -N '- (2-pyridylmethyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl) -1,4 -bencenodimet anami na; N- [(4-methyl) -li. "- imidazol-5-ylmethyl] -N, N '-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [[(4-dimethylamino) -1- naph talenyl] methyl] -N, N'-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [1,5-dimethyl-2-phenyl-3-pyrazolinone-4-ylmethyl] -N, N '-bis (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [1- [(1-acetyl-2- (R) -prolinyl] -4-piperidinyl] -N- [2- (2-pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1, 3-benzenedimethanamine; N- [1- [2 -acetamidobenzoyl-4-piperidinyl] -4-piperidinyl] -N- [2- (2-pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1, 3-benzenedimethanamine; N- [(2-cyano-2-phenyl) ethyl] -N' - (2-pyridinylmethyl) -N- (6, 7, 8, 9 -tetrahydro-5H-cyclohepta [b] pyridin-9-yl) -1,4-benzenediomide; N- [(N "-acetyltriptophanyl) -4-piperidinyl] -N- [2- (2- pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1, 3-benzenedimethanamine; N- [(N "-benzoylvalinyl) -4-piperidinyl] -N- [2- (2-pyridinyl) ethyl] -N' - (2-pyridinylmethyl) -1, 3 -benzenedimet anami na N- [(4-dimethylaminophenyl) methyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5Ji-cyclohepta [b] pyridin-9-yl) -1,4 - benzenedimethanamine; N- (4-pyridinylmethyl) -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (1-methylbenzimadazol-2-ylmethyl) - '- (2-pyridinyl-methyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl) -1, 4-benzenedimethanamine; N- [1-butyl-4-piperidinyl] -N- [2- (2-pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1, 3-benzenedimethamine; N- [l-benzoyl-4-piperidinyl] -N- [2- (2-pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1, 3-benzenedimethanamine; N- [1- (benzyl) -3-pyrrolidinyl] -N- [2- (2-pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1, 3-benzenedimethanamine; N- [(1-methyl) benz or [b] pyrrol-3-ylmethyl] -N- [2- (2-pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1, 3-benzenedimethanamine; N- [lJI-imidazol-4-ylmethyl] -N- [2- (2-pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1, 3-benzenedimethanamine; N- [1- (benzyl) -4-piperidinyl] -N- [2- (2-pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [1-methylbenzimidazol-2-ylmethyl] -N- [2- (2-pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [(2-phenyl) benzo [b] pyrrol-3-ylmethyl] -N- [2- (2-pyridinyl) ethyl] -N '- (2-pyridinylmethyl) -1,4-benzenedimethanamine; N- [(6-methylpyridin-2-yl) methyl] -N '- (2-pyridylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine; N- (3-methyl-lH-pyrazol-5-ylmethyl) -N '- (2-pyridylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,3-benzenedimethanamine; N- [(2-methoxyphenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,3-benzenedimethanamine; N- [(2-ethoxyphenyl) ethyl] -N '- (2-pyridinylmethyl) -N- (6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl) -1, 3- benzenedimethanamine; N- (benzyloxyethyl) -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1, 3-benzenedimethanamine; N- [(2-ethoxy-1-naphthalenyl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,3-benzenedimethanamine; N- [(6-methylpyridin-2-yl) methyl] -N '- (2-pyridinylmethyl) -N- (5,6,7,8-tetrahydro-8-quinolinyl) -1,3-benzenedimethanamine; 1- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] guanidine; N- (2-pyridinylmethyl) -N- (8-methyl-8-azabicyclo [3.2.1] octan-3-yl) -1,4-benzenedimethamine; 1- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] homopiperazine; 1- [[3- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] homopiperazine; trans and cis-1- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -3,5-piperidinediamine; N, N'- [1,4-phenylenebis (methylene)] bis-4- (2-pyrimidyl) piperazine; 1- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -1- (2-pyridinyl) methylamine; 2- (2-pyridinyl) -5 - [[(2-pyridinylmethyl) amino] methyl] -1,2,3,4-tetrahydroisoquinoline; 1- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -3,4-diaminopyrrolidine; 1- [[4- [[(2-pyridinylmethyl) amino] methyl] phenyl] methyl] -3,4-diacetylaminopyrrolidine; 8- [[4- [[(2-pyridinylmethyl) mino] methyl] phenyl] methyl] -2,5,8-triaza-3-oxabicyclo [4.3.0] nonane; and 8- [[4- [[(2-pyridinylmethyl) amino] methyl] plienyl] methyl] -2,5,8-triazabicyclo [4.3.0] nonane. Compounds having the formulas (2A) and (2B) and methods for synthesizing such compounds are expressed in WO 00/56729, incorporated herein by reference. In another aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by compounds having the formula (3): or the salts, pro-drugs and stereochemical forms thereof, wherein: ring A optionally comprises a heteroatom selected from N, O and S; dotted lines represent optional unsaturation; R1 is halo, nitro, cyano, optionally substituted hydroxy, optionally substituted thiol, optionally substituted amino, carboxylate, carboxamide, sulfonate, sulfonamide, C2_4 alkanoyl, alkylsulfonyl, or aroyl; R2 and R3 are independently H, an optionally halogenated C4, alkyl, an optionally substituted aryl or heterocyclic group, or R2 and R3 together with ring E can form a substituted or unsubstituted 5-7 membered ring; k is 0-4; m is 0-2; L1 is a covalent bond of alkyl _6 optionally containing N or 0; X is C or N unsubstituted or substituted; u O u S; Ar is phenylene; each n is independently 0-2; each R is independently H or alkyl; Y And it is a fused or non-fused aromatic or heteroaromatic ring, or a 5-6 membered heterocyclic group. In the above formula (3), Y may be, substituted or unsubstituted, a benzene, naphthalene, dihydronaphthalene, tetrahi-dronaphthalene, pyridine, quinoline, isoquinoline, imidazole, benzimidazole, azabenzimidazole, benzotriazole, furan, benzofu-rano, thiazole, benzothiazole, oxazole, benzoxazole, pyrrole, indole, indolino, indazole, pyrrolidine, pyrrolidone, pyrroline, piperidine, piperazine, tetrahydroquinoline, tetrahydroisoquinoline, pyrazole, thiophene, isoxazole, isothiazole, triazole, tetrazole, oxidiazole, thiadiazole, morpholino, thiamorpholino, pyrazolidine, imidazolidine, imidazoline, tetrahydropyran, dihydropyran, benzopyran, dioxane, dithiane, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, or dihydrothiophene. In formula (3) above, L1 can be linked to position 2 of ring E. The dotted line in ring E can also represent a double bond between the nitrogen shown and position 2. In an example, R2 and R3 are connected such that they form a benzo-substituent on ring E. In formula (3) above, ring A can be saturated. In some examples, m is l and k is O or l. In another embodiment, the CXCR4 antagonist for use in the methods of the present invention has the formula (3A): or the salts, pro-drugs and stereochemical forms thereof, wherein: R, m, n, Ar, and each Y is defined as in formula (3); L2 is a covalent bond or C1-6 alkyl optionally containing N or O; and each Z is independently CR2, NR, 0 or S, with the provision that only two Z may be different from CR2. In formula (3A) above, L2 may be methylene or ethylene. In one example, m is 1 and all embodiments of Z are CR2, particularly CH2. In formula (3A) above, each Y can be pyrimidyl, pyridyl, phenyl, benzimidazole or benzoxazole. In yet another embodiment, the CXCR4 antagonist for use in the methods of the present invention has the formula (3B): or the salts, pro-drugs and stereochemical forms thereof, wherein: W1 is a monocyclic (5-6 membered) or fused bicyclic (8-12 membered) ring system not substituted or substituted containing at least one heteroatom selected from from N, O and S; W2 is H, or is selected from the group consisting of: an optionally substituted Cj.g alkyl group; a C0_6 alkyl group substituted with an optionally substituted aromatic or heterocyclic group; a C0_6 alkylamino group or optionally substituted C3.7 cycloalkylamino group; and an optionally substituted carbonyl or sulfonyl group; Ar, R and n are as defined in formula (3), and is a saturated or unsaturated 5-membered ring containing 1-2 heteroatoms selected from N, O and S. In yet another embodiment, the antagonist of CXCR4 for use in the methods of the present invention has the formula (3C): or the salts, pro-drugs or stereochemical forms thereof, wherein: W1 is phenyl, pyridyl, pyridyimyl, imidazolyl, thiophenyl, and a ring system optionally fused having a heteroatom selected from N, O and S; W2 is H; Ar, R and n are defined as in formula (3); Y represents a system of fused rings of 10 members, optionally containing 1 or 2 heteroatoms selected from N, 0 and S. Compounds having the formula (3), and (3A) - (3C) and methods for synthesizing such compounds are expressed in WO 02/22600, which is incorporated herein by reference. In another aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by compounds having the formula (4): or the salts, pro-drugs and stereochemical forms thereof, wherein: X is a ring system monocyclic (5-6 members) or fused bicyclic (9-12 members) unsubstituted or substituted containing at least one heteroatom selected from N, O and S; Z is H, or is a 5-6 membered monocyclic or fused bicyclic ring system of 9-12 members optionally substituted containing N, 0 or S; Ar is an optionally substituted aromatic or heteroaromatic ring; each of L1, L2 and L3 is independently a link, CO, S02, or CH2, where at least one of L2 and L3 must comprise CO or S02; and wherein L1 can also be alkylene (C2_5) where one or two C can optionally be replaced by N and which alkylene can optionally be substituted by a bridging alkylene (C3_4); L2 and L3 can also be, independently S02NH, CONH, S02NHCH2 or CONHCH2; n is 0, 1 or 2; each R1 and R2 is independently H or alkyl (XX straight or branched chain or cyclic which can be optionally substituted, and where R2 can be alkylene coupled to Y, and Y comprises at least one aromatic or heteroaromatic ring or other In the above formula (4), X can be dihydroquinoline, tetrahydroquinoline, pyranopyridine, dihydropyranopyridine, thiapyranopyridine, dihydrothiarapranopyridine, dihydronaphthyridine, tetrahydronaphthyridine, imidazolyl, oxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, or In the formula (4) above, L1 can be alkylene (C2_5) where a C can optionally be replaced by N and which can be optionally substituted by a bridging alkylene (C3_4) For example, L1 can be alkylene, CO or S02, and X is an imidazole, oxazole, thiazole, benzimidazole, benzothiazole, or optionally substituted benzoxazole Alternatively, L1 can be a n bond, and X is dihydroquinoline, tetrahydroquinoline, pyranopyridine, dihydropyranopyridine, thiapyranopyridine, dihydrotiapyranopyridine, dihydronaphthyridine, or substituted or unsubstituted tetrahydronaphthyridine. In formula (4) above, Z can be hydrogen. In formula (4) above, Y can be an optionally substituted imidazole, benzimidazole, pyridine, pyrimidine, or phenyl, wherein the ring nitrogen may optionally be oxidized. For example, Y can be substituted with halogen, nitrile, alkyl, -OR, -SR, -NR2, -NRCOR, -OOCR, -COR, -CONR2, -COOR, -N02, -NOH, -CF3, where R is H or alkyl. In the above formula (4), each X or Z can optionally be replaced by halo, nitro, cyano, carboxy, alkyl ^^, C2_10 alkenyl, C3_10 cycloalkyl, hydroxy, thiol, amino, acyl, carboxylate, carbamate, carboxamide, sulfonamide, a carbonyl or sulfonyl linking to a hydrogen, or substituted with an alkyl -1-10 C2_10 alkenyl, C3_7 cycloalkyl or a 5-6 membered monocyclic aromatic group; or X or Z can optionally be substituted by a 5-6 membered monocyclic aromatic group, naphthyl or a 5-6 membered heterocyclic ring. In one embodiment, the compound for use in the methods of the present invention has the formula (4A): or the formula (4B) where 1 is 0-3, and R 'is OH, MeO, SH, SMe, CN, C02Me, F, Cl, Br, N02, CH3CO, NH2, NHCH3, N (CH3) 2, CH3CONH, CH3S02NH, CONH2, S02NH2 , CF3, or Me; each Z1, Z2 and Z3 is independently CH, CR 'or N, where only two of said Z1, Z2 and Z3 can be N; and L2 and L3 are as defined in formula (4). In the formulas (4A) or (4B) above, all of Z1, Z2 and Z3 can be CH or CR '. In one example, Z3 is N and L3 is CO. Moreover, one of L2 and L3 can be S02 and the other is a link or CH2. Alternatively, one of L2 and L3 is CO and the other is a link or CH2 In another embodiment, the compound for use in the methods of the present invention has the formula (4C): where 1 is 0-3, and R 'is OH, MeO, SH, SMe, CN, C02Me, F, Cl, Br, N02, CH3C0, NH2, NHCH3, N (CH3) 2, CH3C0NH, CH3S02NH, C0NH2, S02NH2 , CF3, or Me; k is 0-2; each Z1, Z2 and Z3 is independently CH, CR 'or N, where only two of said Z1, Z2 and Z3 can be N; and X, L2 and L3 are as defined in formula (4). In formula (4C) above, all of Z1, Z2 and Z3 can be CH or CR '. In one example, Z3 is N and L3 is CO. Moreover, one of L2 and L3 can be S02 and the other is a link or CH2. Alternatively, one of L2 and L3 is CO and the other is a bond or CH2. Compounds having the formula (4), and (4A) - (4C) and methods for synthesizing such compounds are expressed in WO 02/22599, which is incorporated herein by reference. In another aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by compounds having the formula (5): or the salts, pro-drugs and stereoisomeric forms thereof; Ring A optionally comprises a heteroatom selected from N, O and S; dotted lines represent optional unsaturation; R1, R2 and R3 are independently H, halo, substituted or unsubstituted alkyl, hydroxyl, amino, thiol, or acyl; or R2 and R3 can together form a benzo ring; k is 0-4; 1 is 0, 1, or 2; X is C or N substituted or unsubstituted; is O u S; Ar is the residue of an aromatic or heteroaromatic fraction; each n is independently 0-2; each R is independently H or alkyl; j is 0-3; and each Y is independently selected from the group consisting of halo, OR; SH; SW; S02; optionally substituted phenyl; - (CR2 mOR; - (CR_) mCOR; - (CR2) mCOOR; - (CR2 mN = CH-NR2; - (CR2 mCONHNHR; - (CR_ mCN; - (CR2 mNR5 - (CR2 mNR (CR2) raNRR4; - (CR2 mNR (CR2) raNR (CR2) mNR52; - (CR_ mCO (CR2) mNR52; - (CR2 raCO (CR2) raNR (CR2) mNRR4; - (CR2 raCO (CR2) raNR (CR2) raNR (CR2) RNR52; - (CR2 mNRCO (CR2) mNRR4; - (CR_) mNRCO (CR2) raNR (CR2) mNR52; - (CR_) mNRCO (CR2) raNR (CR2) mNR (CR2) raNR (CR2) mNR52; - (CR2) mNROH; - (CR2) mCONROH; - (CR2) mCR = NOH; -NHNHR; -CH = N- Z; and -guanidino or amidino, each of which can be linked to Y through a fraction (CR2) m; where R is H or alkyl (Cx_g), each m is independently 0-4, and each R4 and each R5 is independently H, alkyl (Cx_6), alkenyl (C2_6), alkynyl (C2_6), or acyl, each optionally substituted by one or more non-aromatic, non-heterocyclic substituents, where two R5 can be connected to form a cyclic amine optionally containing one or more additional heteroatoms selected from N, O or S; a indicates the linker between ring A and N; b indicates the linker between ring E and N; and where Z is an aromatic or heteroaromatic fraction containing 5-12 ring members. In formula (5) above, Ar may be a 5-6 membered monocyclic ring or a ring system fused to 9-12 members. For example, Ar may be benzene, naphthalene, dihydronaphthalene, tetrahydronaphthalene, pyridine, pyrimidine, quinoline, isoquinoline, imidazole, benzimidazole, azabencimida-Zola, benzotriazole, furan, benzofuran, thiazole, benzothiazole, oxazole, benzoxazole, pyrrole, indole, imidazole, tetrahydroquinoline, tetrahydroisoquinoline, pyrazole, thiophene, isoxazole, isotiazola, triazole, tetrazole, oxadiazole, thiadiazole, imidazoline, and benzopyran. In particular examples, Ar is benzene, benzimidazole, benzothiazole, imidazole, oxazole, benzotriazole, thiazole, pyridine, or pyrimidine. In one embodiment, at least one Y can be - (CR2) raNR52. In formula (5) above, ring A can be saturated and 1 is 1. In one example, k is 0-1. In other examples, the ring system including A is tetrahydroquinoline or a substituted form thereof. In formula (5) above, one of (CR2) an and (CR2) bn can be CH2 and the other is a link. For example, (CR2) an can be a bond and (CR2) bn is CH2. Compounds having the formula (5) and methods for synthesizing such compounds are expressed in WO 02/34745, which is incorporated herein by reference. In another aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by compounds having the formula (6): or the salts, pro-drugs and stereoisomeric forms thereof; where X and Y are independently N or CR1; Z is S, O, NR1 or CR12; each R1-Rs is independently H, halo, 0 (C = 0) R, NR (C = 0) R, OR, SR, NR2, COOR, CONR2, where R is H or alkyl, alkenyl, alkynyl or aryl optionally substituted; or each R1-R6 is alkyl Cx_w) alkyl, (C2.10) alkenyl, (C2- ?.) aryl (C5_12), arylalkyl, arylalkenyl, arylalkynyl, each optionally substituted and optionally containing one 0, S, or N; or an optionally substituted acyl, arylacyl, alkyl-, alkenyl-, alkynyl- or arylsulfonyl wherein each alkyl, alkenyl, alkynyl or aryl moiety may contain O S, or N; nor is 0-4; n2 is 0-1, where * means that C = C can be replaced by CR5 = CR5; n3 is 0-4; where nl + n2 + n3 is greater than or equal to 2; b is 0-2; where the following combinations of R groups can be coupled to generate a ring, which ring can be saturated or unsaturated: R2 + R2, R2 + R3, R3 + one R4, R4 + R4, one R5 + another R5, one R5 + an R6, and Rs + Rs; where the ring may not be aromatic when the participants in the ring formation are two R5; and where when n2 is 1, ni or ni3 can be 0. In one embodiment, the compounds for use in the methods of the present invention have the formula (6A): (6A) or the salts, pro-drugs and stereoisomeric forms thereof, wherein R1-R6 and nl-n3 are as defined in the formula (6) In another embodiment, the compounds for use in the methods of the present invention have the formula (6B) or the formula (6C): . (€ C) or the salts, pro-drugs and stereoisomeric forms thereof, wherein n is 0-1; d is 0-3; the dotted line is an optional p-link; Y R1-R6 are defined as in formula (6). In yet another embodiment, the compounds for use in the methods of the present invention have the formula (6D): C < 3D) or salts, pro-drugs and stereoisomeric forms thereof, wherein R1-R6 are defined as in formula (6), and n4 is 2-6. In formulas (6) or (6A) - (6D) above, each R1 may be H, halo, alkyl, alkoxy, or CF3. In one embodiment, each R2 is H or alkyl. In another embodiment, each R3 is H, alkyl, alkenyl, arylalkyl, or aryl. In the formulas (6) or (6A) - (6D) above, each R 4 can be H, alkyl or aryl. Alternatively, two R4 can form an optionally substituted aromatic or heteroaromatic ring. For example, two R 4 can form a phenyl or pyridyl ring, which can be substituted with halo, alkyl, halogenated alkyl, hydroxy, or alkoxy. In formulas (6) or (6A) - (6D) above, each R5 can be H, alkyl, or alkenyl, wherein said alkyl or alkenyl can be optionally substituted. In one embodiment, the alkyl or alkenyl substituents on a single carbon, or on non-adjacent or adjacent carbons, form a saturated or unsaturated ring. In one example, the substituents form a non-aromatic ring. In another embodiment, an R5 is an oxime, an alkylated oxime, an alkylated hydroxylamine, a hydroxylamine or a halo. In formulas (6) or (6A) - (6D) above, each R6 may independently be H, or an arylalkyl or arylsul-fonyl, where the aryl fraction may comprise a heteroatom; or two Rs may comprise a guanidyl, carbonyl, or carbamino group. In one embodiment, two R6 together, or one R5 and one R6 together can form a saturated, unsaturated or aromatic ring, where each ring can optionally contain N, S or 0. Compounds having the formula (6) and methods for synthesizing such compounds are expressed in WO 03/055876, which is incorporated herein by reference. In another aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by compounds having the formula (7): or the salts, pro-drugs or stereoisomeric forms thereof, wherein X is (CR32) 0 - (CR3 = CR3) p- (CR32) q-NR52; (CR32) r-R4; or an optionally substituted benzyl, or a monocyclic or bicyclic ring optionally containing N, O or S; and is an optionally substituted 5-12 membered heterocyclic ring containing a nitrogen atom, said heterocyclic ring may be monocyclic or fused, and is aromatic or partially aromatic; A and R1 are independently halo, CF3, cyano, nitro, OR, SR, NR2, COOR, CONR2, NS02R, OS02R, or OS02NR, where each R is H, alkyl, alkenyl, alkynyl or aryl; or A and R1 are independently an alkoxy (C? _10), alkyl (X.-L-), alkenyl (C2_10), alkynyl (C2_10), aryl (5-12 members), arylalkyl, arylalkenyl, or arylalkynyl optionally substituted, each of which may optionally contain O, S, or N; R2 and R3 are independently H or an optionally substituted alkyl; R 4 is an optionally substituted heterocyclic or heteroaryl ring; or R4 comprises a fraction of urea, hydroxyurea, sulfamide, acetamide, guanidine, cyanamide, hydroxylamine, cyanamine, imidazolidin-2-one, or a nicotinamide, each of which may be substituted with a heterocyclic ring; R5 is H or alkyl; 1 and n are independently 0-4; p is 0-1; or and q are independently 1-4; and r is 1-6. In formula (7) above, at least one of R1 and R2 may not be H, and may be connected to form an additional ring such as an aryl or heteroaryl. In one example, two As may not form an additional ring. In another example, X is (CR32) r-R4, r is at least two, and R4 is 2-pyridinyl, quinolini-lo, imidazolyl or furan. In formula (7) above, X can be (CR32) 0- (CR3 = CR3) p- (CR32) q-NR52, where each of R3 and R5 are independently H and p can be zero. In particular embodiments, o and q together are 2-6. Alternatively, X may be (CR32) r-R4, where R4 is a heterocyclic or heteroaryl ring, each of which contains a nitrogen atom. For example, R 4 may be azetidine, pyrrolidinyl, pyridinyl, thiophenyl, imidazolyl, or benzimidazolyl. Alternatively, X may be a monocyclic or bicyclic ring optionally containing N, 0 or S, such as cyclohexyl, piperidino, 8-aza-bicyclo [3.2.1] octane or 3-aza-bicyclo [3.2.1] octane. In yet another embodiment, X is an optionally substituted benzyl, particularly a disubstituted benzyl. In formula (7) above, Y may be a 5-6 membered heterocyclic ring containing a nitrogen atom adjacent to the atom that binds to the rest of the molecule. The 5-6 membered heterocyclic ring can be fused to another ring. For example, Y can be pyridine, pyrimidine, pyrazine, indole, benzimidazole, benzothiazole, imidazole, isoquinoline, tetrahydro-quinoline, pyridazine, thiazole, or benzoimidazole. In particular examples, Y is tetrahydroquinoline, particularly a 5, 6, 7, 8-tetrahydroquinoline fraction, linked at position 8 to the rest of the molecule. In the above formula (7), each optionally substituted moiety can be substituted with a heteroatom, halo, CF3, cyano, nitro, hydroxy, alkoxy, carbonyl, carboxy, amino, amido, imino, cyano, sulfonyl; C2_6 alkyl or alkenyl each of which may contain N, O or S; or substituted with an aryl, heteroaryl, carbocyclic or heterocyclic ring, each of which can also be substituted with the same substituents. Compounds having the formula (7) and methods for synthesizing such compounds are expressed in WO 04/091518, which is incorporated herein by reference. In another aspect, the CXCR4 antagonist for use in the methods of the present invention can be exemplified by compounds having the formula (8) 0 salts, pro-drugs and stereoisomeric forms thereof, wherein each of the rings A and B is independently an optionally substituted 5-6 membered monocyclic heteroaryl; ring C is a 5-7 membered saturated or partially saturated ring optionally substituted, and may contain a heteroatom in addition to nitrogen, wherein said heteroatom is N, O or S; Y is H, an alkyl X.g containing one or more heteroatoms, or a cyclic fraction, each of which is optionally substituted; R1 and R2 are independently H, halo or an optionally substituted alkyl; L is (CR32) 1 or NR (CR32) i where an alkyl bond can be replaced with an alkenyl or alkynyl bond; 1 is 1-6; and each R3 is H or alkyl. In formula (8) above, at least one of R1 and R2 may not be H when C is piperidinyl or 1, 2, 3, 6-tetrahydropyridinyl and rings A and B are pyridinyl. In other embodiments, R1 and R2 are not both naphtenyl when ring C is piperidinyl and ring A and B are pyridinyl. In still other embodiments, ring C is not 4-oxo-piperidine-3,5-dicarboxylic acid if L-Y is CH 3; Ring C is not 4-hydroxy-2,5,5,6-tetrahydro-pyridine-3-carboxylic acid ester if L-Y is benzyl. In formula (8) above, R1 and R2 may be at positions adjacent to the bonds to ring C. In one example, R1 and R2 are independently unsubstituted alkyl, such as methyl. In the above formula (8), each of the rings A and B can be pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3-triazine, 1, 2,4-triazine, 1, 3, 5-triazine, 1, 2, 4, 5-etrazine, pyrrole, imidazole, pyrazole, 1, 2, 3-triazole, 1, 2,4-triazole, tetrazole, thiazole, oxazole, isothiazole, isoxazole, 1,2,3-thiadiazole, 1, 3, 4-thiadiazole, 1, 2, 3-oxadiazole, 1,3,4-oxadiazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, 1,2,3-benzotriazine, 1, 2, 4- benzotriazine, indole, benzimidazole, lH-indazole, benzoxazole, benzothiazole, benz [d] i -soxazole, benz [d] isothiazole, or purine. In particular examples, each of the rings A and B is pyridine, pyrimidine, imidazole, or benzimidazole, and each of the rings A and B may be identical. Each of the rings A and B may also contain a single constituent, which may be identical, in the position adjacent to the bond linking the rings to the ring C. In the formula (8) above, the ring C may be a Saturated ring, or it may contain a double bond. For example, the C ring can be pyrrolidine, piperidine, hexahydro-1H-azepine, piperazine, morpholine, thiomorpholine, azepane, azocan, 2,3,4,7-tetrahydro-1 J? -azepine, 2,3,6,7 -tetrahydro-líT-azepine, 3-pyrroline, 1, 2, 3, 6-tetrahydropyridine, isoindoline, 1,2,3,4-tetrahydroisoquinoline, 2,3,4, 5-tetrahydro-l-l-benzo [d] azepine , 2,3,4, 5-tetrahydro-lff-benzo [c] azepine, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexe-no, cycloheptene, cyclooctene, tetrahydropyran, tetrahydrothiopiran, oxepane, tiepane, oxocane , or thiocano. In particular examples, ring C is pyrrolidine, piperidine, piperazine or hexahydro-1J-azapine. Ring C can be substituted with an optionally substituted alkyl, halo, cyano, oxime, OR or C = N-0R, where R is an optionally substituted alkyl. In formula (8) above, Y can be selected from the group consisting of: - (CR2) raNR2, - (CR2) mNR2 (CR3), - (CR2) mNR (CR2) mNR2, - (CR_) raNR ( CR2) mNR (CR2) raNR2, - (CR.) MOR, - (CR.) MCO (CR2) raOR, - (CR2) mCO (CR2) raNR2, - (CR.) MCO (CR2) raNR (CR2) mNR2 , - (CR.) RaNCO (CR2) mNR2, - (CR, raNR (CR2) mC02R, - (CR2) mNR (CR2) mCOR, - (CR.) MNR (CR2) mS02R, - (CR.) RaNRCO ( CR2) raNR (CR2) mNR2, - (CR.RNRCO (CR2) mNR (CR2) RaNR (CR2) RaNR (CR2) mNR2, - (CR2 RaNR (CR2) mOR, - (CR2 mCR = NOH, - (CR2 raCONR (CR2) mOR, - (CR2 raN [(CR2) mC02R] 2, - (CR2, mONRCONR2, - (CR.m "Z, - (CR2 raNR- (CO) raZ, - (CR2; mNR- (CR2) mZ, and - (CR2; m-CR = N = Z; where each R is H or an optionally substituted alkyl, each m is independently 0-4, and Z is an aromatic or optionally substituted heteroaromatics containing 5-12 ring members In particular embodiments, Y is (CH ^ NR;, and 1 is 1-10) Alternatively, Y may be an aromatic, heteroaromatic, or heterocyclic fraction of 5-12 members , each of which may be a monocyclic or fused ring, for example, and may be phenyl, imidazole, pyridine, thiophene, pyrrolidine, pyrazole, piperidine, azetidine, benzimidazole, benzo [d] isoxazole, or thiazole. Y may optionally be substituted with halo; cyano; nitro; alkoxy; halogenated alkyl; substituted carbonyl; a cyclic fraction such as aryl or 5-12 membered heteroaryl containing N, O or S; or an optionally containing alkyl, alkenyl, or heteroalkyl moiety; one or more N, O, S, each of which is optionally substituted and optionally in the form of oxides. In particular examples, And it is substituted with pyridine, phenyl, piperidine or 2H-tetrazole. In the above formula (8), each optionally substituted group can be substituted with inorganic moieties such as a heteroatom, halo, nitro, hydroxy, carboxy, amino, amido, cyano, or sulfonyl; or they may be substituted with alkyl (C ^, (C2_10 alkenyl, C2_10 alkynyl, aryl (5-12 members), arylalkyl, arylalkenyl, and arylalkynyl, each of which may optionally contain a heteroatom such as O, S, or N, and each of which may further be substituted with the same substituents For example, each optionally substituted alkyl may be substituted with a heteroatom such as N, 0, or S, or with a carbocyclic, heterocyclic, aryl or heteroaryl substituent.

Compounds having the formula (8) and methods for synthesizing such compounds are expressed in WO 04/093817, and in the patent application US 10 / 977,221, filed on October 28, 2004, each of which is incorporated herein by reference. Other inhibitors of CXCR4 that can be used to carry out the methods of the invention include but are not limited to CTCF-0214; CTCF-9908; CP-1221 (linear peptides, cyclic peptides, natural amino acids, non-natural amino acids, and peptidomimetic compounds); T140 and the like; 4F-benzoyl-TN24003; KRH-1120; KRH-1636; KRH-2731; polifemusin analog, ALX40-4C; or those described in WO 01/85196; WO 99/50461; WO 01/94420; WO 03/090512, each of which is incorporated by reference herein. Other agents that can be used either as agents alone or in combination with the above CXCR4 inhibitors, include the following: cyclophosphamide; gemcitabine; cyclosporin; Rituxane; Thalidomide; Clofarabine; Velcada; Antegrene; Ontak; Revlimid (Thalidomide analogue); Prochymal; Genasense / Oblimer-sen; Gleevec; Glivec (imatinib); Tamibarotene; Nelarabine; gallium nitrate; PT-100; Bexxar; Zevalin; Pixantrone; Onco-TCS; agents that are topoisomerase inhibitors; Recombinant G-CSF (filgrastim; lenograstim; ETRX101; and TLK199 / Telintra); Recombinant GM-CSF (sargramostim, molgramostim); Recombinant SCF (ancestim); covalent conjugate of recombinant G-CSF (peffil-grastim) and the like. Particularly preferred embodiments of the compound of the formula (1) include 2,2'-bicyclolamine; 6,6'-biciclam; the embodiments expressed in US Patents 5,021,409 and 6,001,826, and in particular 1, 1 '- [1,4-phenylenebis (methylene)] -bis-1, 4,8,11-tetraazacyclotetradecane, expressed in US Patent 5,583,131 , and designated in this AMD3100. Also preferred are N '- (IH-benzimidazol-1-yl-methyl) -N' - (5,6,7,8-tetrahydroquinoline-8-yl) -butane-1,4-diamine as described in WO 03 / 055876. Other methods for synthesizing the compounds useful in the method of the invention are expressed in the above US patents and applications as well as in US patent 6,489,472 and provisional application 60 / 553,589 filed on March 15, 2004. The compounds of the invention are they can be prepared in the form of pro-drugs, ie, protected forms that release the compounds of the invention after administration to the subject. Typically, the protecting groups are hydrolyzed in body fluids such as in the bloodstream thereby releasing the active compound or oxidizing or reducing in vivo to release the active compound. A discussion of pro-drugs is found in Smith and Williams Introduction to the Principles of Drug Desiqn, Smith, H. J.; Wright, 2nd. edition, London (1988). The compounds of the formula (1), such as amines, can be administered prepared in the forms of their acid addition salts or metal complexes thereof. Suitable acid addition salts include salts of inorganic acids which are biocompatible, including HCl, HBr, sulfuric, phosphoric and the like, as well as organic acids such acetic, propionic, butyric and the like, as well as acids containing more than one carboxyl group, such as oxalic, glutaric, adipic and the like. Typically, at physiological pH, the compounds of the invention will be in the form of acid addition salts. Particularly preferred are hydrochlorides. In addition, when prepared as purified forms, the compounds can also crystallize like hydrates. Those forms of the compounds of formula (1) which contain chiral centers may be optically pure or may contain a mixture of stereoisomers, including racemic mixtures or mixtures of varying optical purity. As mentioned above, the compounds of the formula (1) are used in combination with GROß, including modified forms thereof. "Modified forms of GROß" include their truncated forms, such as those described in US Patents 6,447,766; 6,399,053; 6,080,398; PCT publication 99/26645; PCT publication WO 97/15595; PCT publication WO 02/02132; PCT publication WO 97/15594; and PCT publication WO 94/29341. Also included in "modified forms of GROß" are multimeric forms thereof. Thus "modified forms" include those with truncation of between 2 to about 8 amino acids at the amino terminals of the mature protein, truncated from about 2 to about 10 amino acids at the carboxy terminals of the mature protein, multimeric forms of the modified and / or truncated proteins, e.g., dimers, trimers, tetramers and other aggregated forms. Particularly preferred are truncated forms of GROß and in particular SB251353 consisting of amino acids 5-73 and their forms where amino acid 69 is deamidated. The CXCR4 inhibitors including their mixtures are administered in combination with the GROß chemokine and / or its modified forms. Additional active ingredients that are useful therapeutically or nutritionally may also be employed, such as antibiotics, vitamins, herbal extracts, anti-inflammatory, glucose, antipyretics, analgesics, cyclophosphamide, recombinant G-CSF (Neupogen, Granocyte / Neutrogin, and Stemgen) , and covalent conjugates of recombinant G-CSF (Neulas-ta), granulocyte-macrophage colony stimulating factor (GM-CSF) (such as Leukine, and Luecomax), ETRX-101, TLK 199 / TILENTRA, CTCE-0214, (SFD-1 truncated alpha SDF-1 peptide analog), inhibitors of VLA-4, Interleukin-1 (IL-1), Interleukin-3 (IL-3), Interleukin-8 (IL-8), PIXY- 321 (GM-CSF / IL-3 fusion protein), macrophage inflammatory protein, stem cell factor, thrombopoietin, other members of the GRO family or chemotherapy and the like. These can all be used together with stem cell expansion systems or kits that are medical devices, such as Replicell, Allogen, and ACE TransStrem Device System and TransCord Device. Formulations for administration to animal subjects use commonly understood formulation techniques well known in the art. Formulations which are suitable for particular modes of administration and for compounds of the type represented by those of formula (1) can be found in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, Pennsylvania, United States; similarly, methods for administering polypeptides such as those represented by GROß and modified forms thereof are found in this source. Preferably, the compounds are administered by injection, most preferably by intravenous injection, but also by subcutaneous or intraperitoneal injection, and the like. Additional parenteral administration routes include intramuscular and intra-articular injection. For intravenous or parenteral administration, the compounds are formulated in suitable liquid form with excipients as required. The compositions may contain liposomes or other suitable vehicles. For injection intravenously, the solution is made isotonic using standard preparations such as Hank's solution. In addition to injection, other administration routes can also be used. The compounds can be formulated into tablets, capsules, syrups, powders, or other forms suitable for oral administration. By using suitable excipients, these compounds can be administered through the mucosa using suppositories or intranasal sprays. Transdermal administration can also be effected by using suitable penetrants and controlling the rate of release. The formulation of the chosen administration route will be tailored to the individual subject, the nature of the condition to be treated in the subject, and generally, the judgment of the practitioner who attends it. Suitable dose ranges for the CXCR4 inhibitor vary according to these considerations, but in general, the compounds when administered alone are administered in the range of about 0.1 μg / kg-5 mg / kg body weight; of preference the range is around 1-300 μg / kg of body weight; more preferably around 10-100 μg / kg of body weight. For a typical human subject of 70 kg, well, the dose range is around 0.7 μg-350 mg; preferably around 700 μg-21 mg; most preferable around 700 μg-7mg. As the methods of the invention involve a combination of at least one compound of the formula (1) with a related GROß-chemokine, lower doses, typically 2x minor, more typically 4x minor, are advantageously employed. The combination of at least one CXCR4 inhibitor and the GROß composition can be administered together in a single formulation, simultaneously in formulations separated by the same or different routes, or in staggered times, again by the same or different routes. The optimization of protocols for administration to a particular subject is well within the state of the art. The inhibitor of CXCR4 and the chemokines of composition of GROß can be administered as a dose of a single bolus, a dose over time, as in intravenous or transdermal administration, or in multiple doses. In addition to direct administration to the subject, combinations of the invention can be used in ex vivo treatment protocols to prepare cell cultures which are then used to restore the subject's blood cells. Ex vivo treatment can be conducted on autologous cells harvested from peripheral blood or bone marrow or allografts from matching donors. The concentration of the compound or compounds that inhibit the combination of CXCR4 with the composition of GROß and optionally other agents, is a matter of routine optimization. The subjects who respond favorably to the method of the invention generally include medical and veterinary subjects, including human patients. Other subjects for which the methods of the invention are useful are cats, dogs, large animals, birds such as chickens, and the like. In general, any subject that can benefit from an elevation of progenitor cells and / or stem cells, or whose progenitor cells and / or stem cells are desirable for stem cell transplantation are appropriate for the method of the invention. Typical conditions that can be improved or otherwise benefited by the method of the invention include hematopoietic disorders, such as aplastic anemia, leukemia, drug-induced anemia, and hematopoietic deficit from chemotherapy or radiation therapy, including neutropenia, and thrombocytopenia The method of the invention is also useful for improving the success of transplantation during and after immunosuppressive treatments as well as for more efficient wound healing and treatment of bacterial inflammation. The method of the present invention is also useful for treating subjects who are immunocompromised or whose immunological system is otherwise impaired. Typical conditions which are improved or otherwise benefited by the method of the present invention, include those subjects that are infected with a retro-virus and more specifically that are infected with human immunodeficiency virus (HIV). The method of the invention thus attacks a broad spectrum of conditions for which the elevation of progenitor cells and / or stem cells for subsequent stem cell transplantation could be beneficial. The combinations of the invention are also administered to regenerate the myocardium by mobilizing bone marrow stem cells.

Having now generally described the invention, it will be more readily understood by reference to the following example, which is provided by way of illustration, and is not intended to be limiting of the present invention, unless specified. Example 1 Preparation of 1,1'-Ti, 4-phenylenebis (methylene) 1 bis-1,4,8,1- tetraazacyclotetradecane 1,1'- [1,4-phenylenebis (methylene)] -bis-tris- (trifluoro- acetyl) -1,, 8, 11-azatetradecane (3.30 g, 3.05 mmol) was dissolved in MeOH (6.0 mL). K2CO3 (1.27 g, 9.1 mmol) was added in one portion. The suspension was heated to reflux for 3 h. Toluene (30 mL) was then added to the cooled mixture. MeOH was removed by forming an azeotrope with toluene. After all of the MeOH was removed, the hot toluene solution suspended with inorganic salt was filtered and concentrated to give AMD3100 free base (1.32 g, 86%) as a white solid. All the features of this product are in good agreement with an authentic sample prepared according to reported methods.

Example 2 Preparation of N '- (lH-benzimidazol-2-ylmethyl) -N' - (5, 6, 7, tetrahydrocruinoline-8-yl) -butane-1,4-diamine To a solution of (1- tert -butoxycarbonyl-li-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) -amine (0.169 g, 0.145 mmol) in CH3CN (5 mL) was added N. N-diisopropylethylamine (0.25 mL, 1.44 mmol) followed by 4-bromobutyronitrile (0.10 mL, 1.01 mmol). The resulting mixture was heated at 80 ° C for 5 d, then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2C12 (20 mL) and brine. (10 mL). The phases separated and the aqueous phase was extracted with CH2C12 (3 x 10 mL). The combined organic extracts were dried (? a2S04) and concentrated. Purification of the crude material by column chromatography on silica gel (30: 1: 1 CH2C12-CH30H-? H4OH) afforded 108 mg (54%) of a yellow foam. The intermediate from the previous one (108 mg, 0.24 mmol) was dissolved in methanol saturated with? H3 (4 mL), treated with nickel Raney (100 mg), and placed under H2 at 50 psi in a Parr shaker, for 24 h. The mixture was filtered through Celite and the cake was washed with methanol. The extractant compound was concentrated under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 20: 1: 1 CH2C12-CH30H-NH40H) afforded 33 mg (39%) of the free base of the title compound as white foam. The conversion of the white foam (33 mg) to the hydrobromide salt, followed by re-precipitation of the intermediate solid from methanol / ether, gave the desired compound (40 mg) as a white solid. XH NMR (D20) d 1.52 (br s, 4H), 1.74-1.88 (m, 1H), 1.95-2.08 (m, 1H), 2.15-2.21 (m, 1H), 2.34-2.39 (m, 1H), 2.50-2.61 (m, 1H), 2.79-2.86 (m, 3H), 2.99-3.02 (m, 2H), 4.38 (d, 1H, J "= 16.8 Hz), 4.47-4.56 (m, 2H), 7.58 -7.63 (m, 2H), 7.76-7.88 (m, 3H), 8.34 (d, 1H, J "= 7.8 Hz), 8.62 (d, 1H, J = 5.7 Hz); X3C NMR (D20) d 20.42 (2 carbons), 25.03, 25.42, 27.64, 39.50, 48.20, 51.71, 60.64, 114.26, 125.93, 126.93, 131.05, 139.32, 140.62, 148. 09, 150.31, 151.82; ES-MS m / z 350 (M + H). Analytical calculation for C21H27N5 «2.9 HBr« 2.2 H20: C, 40.44; H, 5.54; N, 11.23; Br, 37.15. Found: C, 40.38; H, 5.42; N, 10.85; Br, 37.42.

Use 3 Preparation of N '- (lH-benzimidazol-2-ylmethyl) -N' - (S) -5,6,7, tetrahydro-quinolin-8-yl-butane-1-diamine (hydrochloride salt) Preparation of 4-phthalamido-butaraldehyde: A solution of 4-amino-1-butanol (5.0 g, 56 mmol) and phthalic anhydride (8.3 g, 56 mmol) in 20% MeOH / CHCl 3 (140 mL) was stirred at reflux for 66 h. The mixture was cooled to room temperature and washed sequentially with water (3 x 75 mL) in? AOH 1? (3 x 50 mL). The separated organic layer was dried (MgSO 4), concentrated, and purified by flash separation chromatography (5 cm id., 120 g of silica gel, extracted with 2% MeOH / CH 2 Cl 2) to give the desired alcohol as a white solid (4.21 g, 34%). To a stirred TPAP slurry (340 mg, 0.96 mmol), MO MO (3.4 g, 29 mmol) and 3 Á molecular sieves (10 g) in CH 2 Cl 12 (100 mL) was added dropwise a solution of the above alcohol (4.2 g, 19 mmol) in CH2C12 (50 mL) over 30 min. The black slurry was stirred under? 2 for 30 min after the addition, concentrated in vacuo, and purified by flash separation chromatography (5 cm id., 80 g of silica gel, extracted with EtOAc) to obtain the pure title compound as a gray solid (3.30 g, 80%). aH NMR (CDC13) d 1.97-2.07 (m, 2H), 2.54 (t, 2H, J "= 7.2 Hz), 3.74 (t, 2H, J" = 6.8 Hz), 7.71-7.75 (m, 2H), 7.82-7.88 (m, 2H), 9.77 (s, 1H). Using General Procedure B: 4-phthalamido-butyraldehyde above (3.21 g, 14.8 mmol) was reacted with S- (5, 6, 7, 8-tetrahydro-quinolin-8-yl) -amine (2.40 g, 16.3 mmol ) and NaBH (0Ac) 3 (9.54 g, 45.0 mmol) in dichloromethane (150 mL). Flash separation chromatography (5 cm id., 200 g of silica gel, extracted with 5% MeOH / CH 2 Cl 2) provided the pure secondary amine as a white foamy solid (2.48 g, 48%). To a solution of the above amine (2.5 g, 7.1 mmol) in acetonitrile (70 mL) was added diisopropylethylamine (1.9 mL, 10.7 mmol), l-boc-2-chloromethylbenzimidazole (2.3 g, 8.6 mmol), and potassium iodide. (115 mg, 0.70 mmol). The mixture was stirred under an N2 atmosphere at 60 ° C for 15 h, cooled to room temperature and concentrated in vacuo. The residue was partitioned between chloroform (150 mL) and water (100 mL). The separated organic layer was dried (MgSO4), concentrated, and purified by flash chromatography (5 cm id., 120 g of silica gel, extracted with CH2C12 to remove unreacted chloride and then 2% MeOH / CH2Cl2 to remove the desired product) to give the desired amine as a pale yellow foamy solid (3.50 g, 85%). A solution of the above amine (3.33 g, 5.7 mmol) in ethanol (30 mL) was treated with hydrazine monohydrate (1.80 g, 36 mmol), stirred for three hours. The mixture was then concentrated in vacuo and purified by flash separation chromatography (5 cm id., 80 g of silica gel, extracted with 5% MeOH / CH 2 Cl 2) to give the unprotected amine as a pale yellow foamy solid. (1.70 g, 86%). The above amine (1.70 g, 4.86 mmol) was dissolved in glacial acetic acid (5 mL) and treated with saturated acetic acid with HCl (5 mL). The solution was allowed to stir at room temperature for 5 min, then it was slowly dripped into diethyl ether (400 mL) with vigorous stirring. The resulting slurry was filtered with suction through a glass-fritted funnel and the filter cake was washed with diethyl ether (3 x 100 mL) and dried in a vacuum oven at 40 ° C for 16 h to give the compound desired as a white solid (2.34 g, 94%). 1 H NMR (D20) d 1.46-1.63 (m, 4H), 1.70-1.87 (m, 1H), 1.97-2.07 (m, 1H), 2.10-2.21 (m, 1H), 2.28-2.38 (m, 1H) , 2.55-2.65 (m, 1H), 2.81-2.90 (m, 3H), 2.91-3.00 (m, 2H), 4.30 (d, 1H, J = 16.3 Hz), 4.41 (d, 1H, J "= 16.3 Hz), 4.42-4.48 (m, 1H), 7.48-7.51 (m, 2H), 7.70-7.75 (m, 3H), 8.20 (d, 1H, J- = 8.2 Hz), 8.53 (d, 1H, J "= 4.5 Hz); 13C NMR (D20) d 20.36, 20.43, 21.67, 24.99, 25.24, 27.60, 39.51, 48.29, 51.78, 60.54, 114.46 (2 carbons), 125.63, 126.10 (2 carbons), 132.53, 139.58, 140.16, 147.34, 151.41, 151.81. ES-MS m / z 350 (M + H).

Analytical calculation for C21H27N5 «2.5 HCl • 2.0 H20 • 0.6 CH3C00H: C, 52.01; H, 7.06; N, 13.66; Cl, 17.29. Found: C, 52.15; H, 7.09; N, 13.40; Cl, 17.56. The enantiomeric purity of the compound was determined to be 96.7% by chiral HPLC using the following conditions: Instrument: Hewlett Packard 1100 HPLC (VWDl); Column: Chiralpak OD, 0.46 cm x 25 cm; Mobile Phases: A: 90:10 hexanes / isopropanol with 0.1% DEA, B: isopropanol; Isocreatic: 90% A, 10% B; Total Run Time: 20 min; Flow Rate: 0.5 mL / min; Temperature: 10 ° C; Detector: UV @ 270 nm; Injection volume: 20 μL. Retention time of the enantiomer £ 7 = 16.3 min. Retention time of the enantiomer ¿2 = 21.9 min. Example 4 Exemplary procedures are as previously described (Pelus, L.M., et al., Blood (2001) 97: 1534-1542; Blood (2004) 103: 110-119). AMD3100 is 1, 1 '- [1,4-phenylenebis (methylene)] -bis-1, 4,8,11-tetraazacyclotetradecane. Peripheral Blood Mobilization Using a combination of AMD3100 and GROß Compared with AMD3100 Solo or GROß Solo Mobilization experiments were carried out in BALB / c mice (group of 3 mice). For mobilization with AMD3100 or GROß alone, the PBSC mobilization was quantified at the mobilization peak determined for each agent in previous experiments. Thus, the PBSC mobilization was quantified in 15 minutes following a subcutaneous injection of 2.5 mg / kg of GROß and at 1 hour following a subcutaneous injection of 5 mg / kg of AMD3100. In the combination experiment, PBSC mobilization was quantified at 5, 15, 30, 60 and 150 minutes after a single subcutaneous injection of 2.5 mg / kg of GROß in saline and 5 mg / kg of AMD3100. The compounds were injected separately and simultaneously in different subcutaneous sites. The injections were programmed such that control and mobilized mice were evaluated at the same time in each experiment. The mice were killed by asphyxia with C02 and the blood was obtained by cardiac puncture using syringes coated with EDTA (ethylene-diaminetetraacetic acid). PBMC's were obtained by peripheral blood separation (0.4 mL) in Lympholyte-M (Cedarlane Labs, Hornby, Ontario, Canada). Complete blood counts (CBC's) were carried out in a Hemavet Mascot (CDC Technologies, Oxford, Connecticut, United States). Manual differentials were carried out in blood smears stained with Wright-Giemsa (Hema-Tex 1000, Bayer, Elkhart, Indiana, United States) and cytospin preparations of spleen cells and bone marrow (Shandon, Pittsburgh, Pennsylvania, United States). CFU-GM Assay PMBC's were tested for CFU-GM in McCoy 5A medium with 15% heat-inactivated fetal bovine serum (Hyclone Sterile Systems, Logan, Utah, United States) and 0.3% agar (Difco Laboratories, Detroit, Michigan , U.S). PBMC's were cultured at 2xl05 / mL. CFU-GM were stimulated with 10 ng / mL of recombinant murine GM-CSF (rmGM-CSF), 10 ng / mL rmlL-la, and 50 ng / mL of stem cell factor (SCF). Triplicate cultures from individual animals were incubated at 37 ° C, 5% C02, 5% 02 in air for 7 days. Total CFU-GM / mL of blood was determined by multiplying CFU frequencies by PBMC / mL of blood corrected for white blood cell (WBC) recovery after separation with Lympholyte-M. Table 1 CFU-GM Mobilized on Control 2383. 50 929.5 576.15 148.7 3494.09 599.3 8573.40 648.4 6346.82 641.1 2536.97 226.7 2282.11 333.6 Table 2 SUMMARY OF PERIPHERAL BLOOD DIFFERENTIAL As shown in Tables 1 and 2, the combination of AMD3100 plus GROß acts in an additive synergistic fashion for mobilization of progenitor cells, neutrophils and total white blood cells when compared to any agent alone; the answer is much faster. It is understood that the above detailed description and accompanying examples are merely illustrative, and should not be taken as limitations on the scope of the invention. Various changes and modifications to the disclosed embodiments that are apparent to those skilled in the art can be made without departing from the spirit and scope thereof. The US patents and publications referred to herein are incorporated herein by reference.

Claims (26)

1. CLAIMS 1. A method for raising the population of progenitor cells and / or stem in peripheral blood or bone marrow, which method comprises treating said peripheral blood or bone marrow with a CXCR4 antagonist in combination with a protein GROß; in effective amounts to raise said population of progenitor cells and / or mother in said peripheral blood or bone marrow.
2. 2. The method of claim 1, wherein said GROß protein is a modified form of GROß protein.
3. 3. The method of claim 2, wherein said modified form is SB-251353.
4. The method of claim 1, wherein said CXCR4 antagonist is of the formula Z-linker-Z '(1) or a pharmaceutically acceptable salt or prodrug form thereof wherein Z is a cyclic polyamine containing 9-32 ring members of which 2-8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle optionally may contain additional heteroatoms in addition to nitrogen and / or may be fused to a system of additional rings; or Z is of the formula where A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic fraction of 1-20 atoms, Z 'may be represented in a form as defined for Z above, or alternatively may be from the formula -N (R) - (CR2) nX wherein each R is independently H or straight, branched or cyclic alkyl (C? _e), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or it is mercaptan; or where Z 'can be nitrogen containing heterocycle, or it can be NR2 where each R is as defined above; "linker" represents a bond, alkylene (Cx.g) or may comprise aryl, fused aryl, and / or oxygen atoms contained in an alkylene chain, and / or may contain keto groups and / or nitrogen or sulfur atoms; or a pro-drug or salt thereof.
5. The method of claim 4, wherein at least one of Z and Z 'is a cyclic polyamine.
6. 6. The method of claim 5, wherein Z and Z 'are identical.
7. The method of claim 6, wherein the compound of the formula (1) is 1,1'- [1,4-phenylene-bis- (methylene) -bis-1,4,8,11-tetraazacyclotetradecane or a pro-drug or salt thereof.
8. The method of claim 4, wherein the compound is N- [1,4,8,1-tetraazacyclotetradecanyl-1,4-phenylenebis (methylene)] -2- (amino-methyl) pyridine; N- [1,4,8,11-tetraazacyclotetradecanyl-l, 4-phenylenebis (methylene)] - N -methyl-2 - (aminomethyl) pyridine; ? - [1,4,8, 11-tetraazacyclotetradecanyl-l, 4-phenylenebis (methylene)] -4- (amino-methyl) pyridine; ? - [1,4,8, 11-tetraazacyclotetradecanyl-l, 4-phenylenebis (methylene)] -3- (amino-methyl) pyridine; ? - [1,4,8, 11-tetraazacyclotetradecanyl-l, 4-phenylenebis (methylene)] - (2-amino-methyl-5-methyl) pyrazine; and? - [1, 4, 8, 11-tetraazacyclotetradecanyl-l, 4-phenylenebis (methylene)] -2- (amino-ethyl) pyridine; or a pro-drug or salt thereof.
9. 9. The method of claim 4, wherein Z is of the formula wherein A comprises a monocyclic or bicyclic fused ring system containing at least one? and B is H or an organic fraction of 1-20 atoms.
10. The method of claim 9, wherein the compound of the formula (1) is N '- (lH-benzimidazol-2-ylmethyl) -N' - (5,6,7,8-tetrahydroquinoline-8-yl) -butane-1, 4-diamine, or a pro-drug or salt thereof.
11. The method of claim 4, wherein the formula (1) is in the form of its acid addition salt.
12. 12. The method of claim 1, wherein the peripheral blood cells or bone marrow are contained in a living subtlety.
13. The method of claim 12, wherein the subject exhibits a hematopoietic deficit of chemotherapy or radiation therapy.
14. The method of claim 12, wherein the subject has a condition selected from the group consisting of aplastic anemia, leukemia, drug-induced anemia, neutropenia and thrombocytopenia.
15. The method of claim 12, wherein the subject is a transplant recipient or is a healthy stem cell donor.
16. The method of claim 12, wherein said progenitor and / or stem cells improve wound healing, or ameliorate bacterial inflammation, or restore cardiac tissue or other damaged organ.
17. 17. The method of claim 16, wherein said progenitor and / or stem cells restore damaged heart tissue.
18. 18. The method of claim 12, wherein the CXCR4 antagonist or GROß protein is administered to said subject by an intravenous or subcutaneous route.
19. The method of claim 12, wherein said CXCR4 antagonist and GROß protein are administered simultaneously.
20. The method of claim 12, wherein said CXCR4 antagonist and said GROß protein are administered in tandem.
21. The method of claim 1, wherein said peripheral blood or bone marrow is maintained in ex vivo culture.
22. 22. A combination product comprising a CXCR4 antagonist and a GROß protein.
23. 23. The combination product of the claim 22, where said combination is capable of raising the population of progenitor cells and / or mother in peripheral blood or bone marrow.
24. 24. A pharmaceutical composition comprising the combination product of claim 22, and a pharmaceutically acceptable excipient.
25. 25. A pharmaceutical composition comprising an effective amount of a CXCR4 antagonist in combination with a GROß protein.
26. 26. The pharmaceutical composition of claim 25, for raising the population of progenitor cells and / or stem in peripheral blood or bone marrow.