FIELD

The disclosure relates to chemokine CXCR4 receptor modulators and uses related thereto. In certain embodiments, the disclosure relates to pharmaceutical compositions comprising compounds disclosed herein or pharmaceutically acceptable salts or prodrugs thereof. In certain embodiments, the compositions disclosed herein are used for managing CXCR4 related conditions, typically prevention or treatment of viral infections such as HIV or for managing cancer.

BACKGROUND

As of the end of 2007, an estimated 33 million people worldwide were living with HIV/AIDS, and the Centers for Disease Control and Prevention (CDC) estimates that 1,200,000 U.S. residents are living with HIV infection (UNAIDS/WHO AIDS epidemic update, December2008; The Henry J Kaiser Family Foundation HIV/AIDS Policy Fact Sheet, July2007). Although new infections have decreased in recent years, an estimated 2.6 million new HIV infections occurred worldwide during 2007 and approximately 40,000 new HIV infections occur each year in the United States.

HIV entry within the target cells involves a series of molecular events. The three main steps of virus entry within the cell are: (i) attachment of the virus to the subject cells; (ii) interaction of the virus with the co-receptors; and (iii) fusion of the virus and subject cell membranes. Considering the complexity of the molecular events involved in viral infection, all three of these steps have been considered for drug design. The T-lymphocyte cell surface protein CD4 is the primary receptor involved in the interaction with the viral glycoprotein gp120, but a cellular co-receptor is also needed for the successful entry of the virus within the cell. At least two types of such co-receptors have been identified so far, both of which are chemokine receptors, CCR5 and CXCR4. These chemokine receptors are therefore gateways for HIV entry, determinants of viral tropism and sensitivity.

Compounds targeting viral entry have two advantages over those that target the HIV-1 reverse transcriptase or protease enzymes: entry inhibitors do not depend on efficient cellular uptake or intracellular activation processes to exert their biological effects, and they are highly unlikely to show any cross-resistance with protease inhibitors or reverse transcriptase inhibitors. Viral entry has been validated as a clinically effective pathway for targeted intervention by the first fusion inhibitor, enfuvirtide. Other classes of entry inhibitors under development target the initial binding of viral gp120 to CD4 and the interaction of gp120 with cell surface chemokine receptors that serve as co-receptors for HIV entry (CCR5 or CXCR4). (Westby et al.,Journal of Virology,2006, 80(10), 4909-4920).

Compounds targeting CXCR4 have been developed primarily for treatment of HIV because CXCR4 is a major co-receptor for T-tropic HIV infection. For example, U.S. Pat. No. 6,429,308 discloses an antisense oligonucleotide to CXCR4 to inhibit the expression of the CXCR4 protein for use as an anti-HIV agent. PCT application publication number WO 2001/56591 describes peptide fragments of viral macrophage inflammatory protein II, which are described as selectively preventing CXCR4 signal transduction and co-receptor function in mediating entry of HIV-I. Additional molecular antagonists of the chemokine CXCR4 receptor are disclosed in PCT application publication numbers WO 2009/121063 and WO 2006/020415 and U.S. Pat. No. 8,969,381.

Studies have shown that CXCR4 interactions also regulate the migration of metastatic cells. Hypoxia, a reduction in partial oxygen pressure, is a micro-environmental change that occurs in most solid tumors and is a major inducer of tumor angiogenesis and therapeutic resistance. Hypoxia increases CXCR4 levels (Staller et al., 2003, Nature425: 307-311). Microarray analysis on a sub-population of cells from a bone metastatic model with elevated metastatic activity showed that one of the genes increased in the metastatic phenotype was CXCR4. Furthermore, over-expression of CXCR4 in isolated cells significantly increased the metastatic activity (Kang et al., 2003, Cancer Cell3: 537-549). In samples collected from various breast cancer patients, Muller et al. (2001, Nature410: 50-56) found that CXCR4 expression levels are higher in primary tumors relative to normal mammary gland or epithelial cells. These results suggest that the expression of CXCR4 on cancer cell surfaces may direct the cancer cells to sites that express high levels of SDF-I. Consistent with this hypothesis, SDF-I is highly expressed in the most common destinations of breast cancer metastasis including lymph nodes, lung, liver, and bone marrow. Moreover, CXCR4 antibody treatment has been shown to inhibit metastasis to regional lymph nodes when compared to control isotypes that all metastasized to lymph nodes and lungs (Muller et al., 2001, Nature410: 50-56).

In addition to regulating migration of cancer cells, CXCR4-SDF-1 interactions may regulate vascularization necessary for metastasis. Blocking either CXCR4/SDF-1 interaction or the major G-protein of CXCR4/SDF-1 signaling pathway (Gαi) inhibits VEGF-dependent neovascularization. These results indicate that SDF-1/CXCR4 controls VEGF signaling systems that are regulators of endothelial cell morphogenesis and angiogenesis. Numerous studies have shown that VEGF and MMPs actively contribute to cancer progression and metastasis.

Thus, there is a need to identify CXCR4 antagonists for therapeutic applications in treating or preventing viral infections such as HIV and for treating or preventing cancer.

SUMMARY

The disclosure relates to chemokine CXCR4 receptor modulators and their uses in therapeutic and diagnostic applications.

In accordance with a first embodiment of the invention there is provided a compound of Formula (I)


or salts thereof wherein RA1is an optionally substituted heterocyclyl, wherein the substituents are selected from one or more, and the same or different RX1; RA2is a hydrogen or an alkyl; RBis selected from the group comprising alkyl, an optionally substituted aminoalkyl and an optionally substituted heterocyclyl; wherein the substituents are selected from one or more, and the same or different RX1; RCis a hydrogen, optionally substituted alkyl or an optionally substituted heterocyclyl; and RX1is selected from the group comprising alkyl, cyloalkyl, halogen, methoxy and triflouromethyl.

Further features of this embodiment provide for RA1to be selected from:


for RBto be selected from the group comprising: methyl,


for RCto be H,


CH═CHCH2RY2, OCH2CH2RY2, NHRY2, N(RY2)2,


for RY2to be selected from the group comprising H, OH, F, CH3, CH2CH3, CH2OCH3, CH2F, CF3, NH2,


wherein the substituent RY2may be individually and independently mono- or di-substituted onto RX2where appropriate; and for RX1to be selected from the group comprising methyl, ethyl, ethene, propyl, cyclopropyl, fluorine, chlorine, methoxy and trifluoromethyl.

In yet further features of this embodiment RA1is selected from the group comprising:



In an exemplary embodiment, the compound of Formula (I) is selected from the group comprising:



In accordance with a second embodiment of the invention there is provided a compound of Formula (II)


or salts thereof wherein RDis H or alkyl, REis methyl, isopropyl or an amino substituted carbocyclyl; RFis an optionally substituted heterocyclyl; wherein the substituents of RFare selected from one or more and the same or different RX2; and RX2is optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted amino, and wherein the substituents of RX2are selected from one or more and the same or different RY2; and RY2is selected from the group comprising methyl, ethyl, isopropyl, cyclopropyl, oxetane, amino, dimethylamino, methylpiperazine, pyridine, pyridinylmethyl, pyrimidine and trifluoromethylbenzene; with the proviso that when RDis H and REis CH3, then RFis not:



Further features of this embodiment provide for REto be selected from the group comprising:

*CH3,


for RFto be selected from the group comprising:


for R2to be selected from the group comprising:
CH2RY2, CH═CHCH2R2, OCH2CH2RY2, NHRY2, N(RY2)2,


for RY2to be selected from the group comprising H, OH, F, CH3, CH2CH3, CH2OCH3, CH2F, CF3, NH2,


wherein the substituent RY2may be individually and independently mono- or di-substituted onto RX2where appropriate; and
wherein RZis H or CH3and W is CH or N.

Yet further features of this embodiment provide for RFto be selected from the group comprising:



In an exemplary embodiment of this invention, the compounds of Formula (II) may be selected from the group comprising:



In accordance with a third embodiment of this invention there is provided a compound of Formula (III)


or salts thereof wherein RGis an optionally substituted alkene, which may be E or Z, an optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl or an optionally substituted quaternary carbon; X is C or N, and RHis a hydrogen or a heterocyclyl when X is C or absent when X is N.

Further features provide for RGto be selected from the group comprising:


wherein Y is H, alkyl or halogen; RIis selected from the group comprising H, NH2, halogen, CH2NHRJ, and in the case of the carbocycles, aryls and heterocycles RImay include one or more and the same or different substituent for each cycle; and RIis selected from the group comprising:
H


or for RGto be an alkyl linking the attached NMe to the tetrahydroquinoline;
and for RHto be H,


CH2RY2, CH═CHCH2RY2, OCH2CH2RY2, NHRY2, N(RY2)2,


for RY2to be selected from the group comprising H, OH, F, CH3, CH2CH3, CH2OCH3, CH2F, CF3, NH2,


wherein the substituent RY2may be individually and independently mono- or di-substituted onto RX2where appropriate when X is C or absent when X is N.

Yet further features of this embodiment provide for RGto be selected from the group comprising:


and a CH2CH2group linking the NCH3to the tetrahydroquinoline.

In an exemplary embodiment, the compound of Formula (III) is selected from the group comprising:



In accordance with a fourth embodiment of the invention there is provided a compound of Formula (IV)


or salts thereof wherein ring A is an heteroaromatic ring system, with or without a fused benzene ring system, RKis a C1 to C6 alkyl and Z is CH, NH, N or S.

Further features of this embodiment provide for A to be selected from the group comprising:



In an exemplary embodiment, the compound of Formula (IV) is selected from the group comprising:



In certain embodiments, the disclosure relates to isolated compositions comprising compounds disclosed herein in substantially pure form.

In certain embodiments, the disclosure relates to a pharmaceutical composition comprising a compound as described herein including salts and prodrugs thereof and a pharmaceutically acceptable excipient, diluent, or carrier.

In certain embodiments, the pharmaceutical composition comprises compounds in greater than 60%, 70%, 80%, 90%, 95%, 98% diastereomeric or enantiomeric excess.

In certain embodiments, the disclosure relates to uses of compounds disclosed herein in the production of a medicament for the treatment of CXCR4 related conditions, such as viral infections, abnormal cellular proliferation, retinal degeneration, inflammatory diseases, or as an immunostimulant or immunosuppressant.

In certain embodiments, the disclosure relates to pharmaceutical compositions comprising a compound as described herein and another active ingredient such as an antiviral agent or chemotherapeutic agent.

In certain embodiments, the disclosure relates to administering a CXCR4 antagonist disclosed herein in combination with a CCR5 antagonist such as maraviroc (selzentry) or vicriviroc.

In certain embodiments, the disclosure relates to methods of treating or preventing a viral infection comprising administering a pharmaceutical composition comprising a compound as described herein optionally in combination with another active ingredient to a subject in need thereof. In further embodiments, the subject is at risk of, exhibiting symptoms of, or diagnosed with a viral infection.

In certain embodiments, the disclosure relates to uses of a compound as described herein in the production of a medicament for the treatment of a viral infection. In typical embodiments, the viral infection is an HIV infection.

In certain embodiments, the disclosure relates to methods of treating or preventing cancer comprising administering a pharmaceutical composition comprising a compound as described herein optionally in combination with another active ingredient to a subject in need thereof. In further embodiments, the subject is at risk of, exhibiting symptoms of, or diagnosed with cancer.

