WO2019165315A1

WO2019165315A1 - Method for treating cancer using chemokine antagonists alone or in combination

Info

Publication number: WO2019165315A1
Application number: PCT/US2019/019305
Authority: WO
Inventors: John A. Zebala; Dean Y. Maeda; Aaron D. Schuler
Original assignee: Syntrix Biosystems Inc.
Priority date: 2018-02-23
Filing date: 2019-02-22
Publication date: 2019-08-29

Abstract

What is described is a method for treating cancer in a patient in need of such treatment through the use of an antagonist to CXCR1 and/or CXCR2 receptors by administering a therapeutically effective amount of an antagonist of CXCR1 and/or CXCR2, or pharmaceutical compositions thereof, either alone as monotherapy, or in combination with at least one other anticancer therapy.

Description

METHOD FOR TREATING CANCER USING CHEMOKINE ANTAGONISTS ALONE OR IN COMBINATION

GOVERNMENT RIGHTS

[0001] This invention was made with government support under Grant Number HL072614 awarded by the National Institutes of Health. The government has certain rights in the invention.

TECHNICAL FIELD

[0002] The disclosure herein relates to a method for treating cancer in a patient in need of such treatment through the use of an antagonist to CXCR1 and/or CXCR2 receptors. More specifically, the method comprises administering to said patient a therapeutically effective amount of a compound of formula I, described herein, or pharmaceutical compositions thereof, either alone as monotherapy, or in combination with at least one other anticancer therapy.

BACKGROUND

[0003] Terminally differentiated myeloid cells are essential to normal function of both the innate and adaptive immune systems. These cells protect organisms from pathogens, eliminate dying cells and mediate tissue remodeling. However, cancer pathologically alters myeloid cells into potent immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs) that enable cancer progression and spread. The tumor-mediated alteration of myeloid cells is not confined to the tumor, but is a systemic phenomenon (Gabrilovich, 2012, Nat Rev Immunol, 12:253-68). Soluble factors released by the tumor act at distant sites that include bone marrow and spleen, where they alter macrophages and granulocytes to become immunosuppressive and accumulate within the tumor. Peripheral blood from advanced cancer patients have much higher MDSC levels compared to healthy donors (P<0.00l), who have near undetectable levels (Alfaro, 2016, Clin Cancer Res , 22:3924-36). The MDSC lifespan is short (24-96 hours), and tumors require continuous MDSC resupply to maintain homeostasis of tumor MDSC populations (Condamine, 2014, J Clin Invest, 124:2626-39). Thus, an effective strategy to abrogate MDSC activity in the tumor microenvironment may be to prevent MDSC arrival to tumors, which has been shown to deplete tumors of MDSCs. [0004] Chemokines are chemotactic proteins that have the potential to attract macrophages, T-cells, eosinophils, basophils, neutrophils and endothelial cells to sites of inflammation and tumor growth. Chemokines are typically low molecular mass (7-9 kD) proteins that can be divided into four subfamilies: CC (or b-chemokines), CXC, C (or y- chemokines) and CX3C (or d-chemokines). The CXC-chemokines (i.e.. the ligands for CXCR1 and/or CXCR2) include, but are not limited to, interleukin-8 (IL-8, CXCL8), GROa (CXCL1), GROP (CXCL2), GROy (CXCL3), ENA-78 (CXCL5), GCP-2 (CXCL6), and NAP-2 (CXCL7). IP-10. Tumor secreted chemokines CXCL1, CXCL2 and CXCL5 recruit MDSCs to tumors (or a pre-metastatic niche) in numerous mouse tumor models (Condamine, 2015, Annu Rev Med, 66: 97-110). These chemokines all bind chemokine receptor CXCR2. Tumor secreted CXCL8 (IL-8) also recruits MDSCs (Mestas, 2004, J Immunol, 172:2731-38; Ben-Baruch, 2012, Cancer Microenviron, 5: 151-64), which signals via both CXCR1 and CXCR2 receptors (Rot, 2004, Annu Rev Immunol, 22: 891-928). Thus, there is a clear therapeutic advantage to find a means to target both CXCR1 and CXCR2 to block MDSC recruitment during cancer growth and metastasis.

SUMMARY

[0005] The disclosure herein relates to a method for treating cancer in a patient in need of such treatment through the use of an antagonist to CXCR1 and/or CXCR2 receptors. The method comprises administering to said patient a therapeutically effective amount of at least one compound of formula I (further described herein), or pharmaceutical compositions thereof, either alone as monotherapy, or in combination another anticancer therapy.

[0006] In one embodiment, the method of treating cancer in a patient in need of such treatment, comprising administering to the patient a pharmaceutical formulation comprising a therapeutically effective amount of a CXCR1 and/or CXCR2 antagonist of formula I,

I wherein R¹ and R² are independently selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein R³ is selected from— B(R⁴R⁵),— R⁶— B(R⁴R⁵), R⁶,— C(O)— R⁶,— O— R⁶, — S(0)_y— R⁶ (wherein y=0, 1, or 2),— P(O)— (R⁴R⁵) and— N(R⁷R⁸); wherein R⁴ and R⁵ are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R⁴ and R⁵ together form a cyclic ester, or an acid anhydride (either mixed or symmetrical);

wherein R⁶ is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl,

heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

wherein R⁷ and R⁸ are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl and heterocyclylalkyl; R⁷ and R⁸ are both oxygen to form a nitro group; or R⁷ and R⁸ together with the nitrogen to which they are attached, form a heterocyclyl;

wherein R⁹ is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; or— B(R⁴R⁵),— BF3 M⁺,— R⁶— B(R⁴R⁵),— R⁶— BF₃ M⁺, R⁶,— C(O)— R⁶,— O— R⁶,— S(0)_y— R⁶ (wherein y=0, 1, or 2),— P(O)— (R⁴R⁵) and— N(R⁷R⁸); or an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; wherein X¹ is carbon or nitrogen; X² is— S(0)_y— (wherein y=0, 1, or 2),— N(R⁹)— , or oxygen; and

n is an integer between 0 and 8;or a pharmaceutically acceptable salt or solvate thereof.

[0007] In certain embodiments, the method comprises administering to a patient in need of treatment for cancer a therapeutically effective amount of at least one compound of formula I selected from compounds in FIG. 1 either as monotherapy, or in combination with another anticancer therapy.

[0008] In preferred embodiments, the method comprises administering to a patient in need of treatment for cancer a therapeutically effective amount of compound SX-682 either as monotherapy, or in combination with another anticancer therapy.

[0009] The disclosure herein includes methods of inhibiting CXCR1 and/or CXCR2-mediated immunosuppression by administering to the subject a CXCR1 and/or CXCR2 receptor antagonist of formula I. [0010] Another aspect of the disclosure herein is a method of inhibiting tumor- mediated recruitment of myeloid derived suppressor cells (MDSCs) by administering to the cancer patient a CXCR1 and/or CXCR2 receptor antagonist of formula I. .

[0011] The disclosure herein includes methods of inhibiting CXCR1 and/or CXCR2-mediated tumor cell proliferation by administering to the cancer patient a CXCR1 and/or CXCR2 receptor antagonist of formula I.

[0012] Examples of the cancers that may be treated using the compounds and compositions described herein include, but are not limited to: cancers of the prostate, colorectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, blood (including lymphoma, leukemia, and myelodysplastic syndromes) esophagus, breast, muscle, connective tissue, lung (including small-cell lung carcinoma and non-small-cell carcinoma), adrenal gland, thyroid, kidney, lymphoid tissue, bone marrow or bone, glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, and testicular seminoma. In some embodiments of the disclosure herein, the cancer is melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, a brain tumor, lymphoma, sarcoma, ovarian cancer, head and neck cancer, cervical cancer, or myelodysplastic syndromes. Cancers that are candidates for treatment with the compounds and compositions of the disclosure herein are discussed further hereafter

[0013] The disclosure herein further contemplates the method of treating cancer through the use of at least one antagonist of CXCR1 and/or CXCR2 receptors, including those that antagonize by acting on the CXC receptor or its ligand, in combination with one or more additional agents. The one or more additional agents may have some CXCR1 and/or CXCR2 modulating activity and/or they may function through distinct mechanisms of action. In some embodiments, such agents comprise radiation ( e.g ., localized radiation therapy or total body radiation therapy) and/or other treatment modalities of a non-pharmacological nature, such as cell therapy or vaccination. When combination therapy is utilized, the antagonist of CXCR1 and/or CXCR2 and the one additional agent(s) may be in the form of a single composition or multiple compositions, and the treatment modalities may be administered concurrently, sequentially, or through some other regimen. By way of example, the disclosure herein contemplates a treatment regimen wherein administration of an antagonist to CXCR1 and/or CXCR2 receptors is maintained on a daily basis, with additional anticancer treatments (e.g., anti-PDl antibody, carboplatin, T-cell therapy, cancer vaccination, radiation) given intermittently during the treatment period. The combination therapy may have an additive or synergistic effect. Other benefits of combination therapy are described hereafter.

[0014] In particular embodiments, the disclosure herein contemplates the use of at least one antagonist of CXCR1 and/or CXCR2 receptors in combination with immune checkpoint inhibitors. The blockade of immune checkpoints, which results in the amplification of antigen-specific T cell responses, has been shown to be a promising approach in human cancer therapeutics. Examples of immune checkpoints (enzymes, ligands and receptors), some of which are selectively upregulated in various types of tumor cells, that are candidates for blockade include indolamine 2,3-dioxygenase (IDO), tryptophan 2,3- dioxygenase (TDO), programmed cell death protein 1 (PD1); PD1 ligand (PDL1); B and T lymphocyte attenuator (BTLA); cytotoxic T-lymphocyte associated antigen 4 (CTLA4); T- cell membrane protein 3 (TIM3); lymphocyte activation gene 3 (LAG3); adenosine A2a receptor (A2aR); and killer inhibitory receptors. Immune checkpoint inhibitors, and combination therapy therewith, are discussed in detail elsewhere herein.

[0015] In particular embodiments, the disclosure herein contemplates the use of an antagonist of CXCR1 and/or CXCR2 receptors in combination with cancer vaccines. Cancer vaccines are used to treat established cancers not due to viral infections, and include the use of antigen vaccines, tumor cell vaccines, dendritic vaccines, deoxyribonucleic acid vaccines, and viral vector vaccines.

[0016] In particular embodiments, the disclosure herein contemplates the use of an antagonist of CXCR1 and/or CXCR2 receptors in combination with T-cell therapy. T-cell therapy involves the isolation, expansion, and re-introduction of a cancer patient’s tumor reactive T-cells. T-cell therapy also includes the use of genetically modified T-cells expressing chimeric antigen receptors (CARs).

[0017] In other embodiments, the disclosure herein provides methods for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of at least one antagonist of CXCR1 and/or CXCR2 receptors and at least one chemotherapeutic agent, such agents including, but not limited to alkylating agents (e.g, nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nucleoside analogs (e.g., gemcitabine); nitroso ureas such as carmustine, lomustine, and streptozocin; topoisomerase 1 inhibitors (e.g, irinotecan); platinum complexes such as cisplatin and carboplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); DNA strand-breakage agents (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); DNA minor groove binding agents (e.g., plicamydin); antimetabolites (e.g., folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, pentostatin; asparginase; and ribonucleotide reductase inhibitors such as hydroxyurea); tubulin interactive agents (e.g., vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives, and paclitaxel); hormonal agents (e.g., estrogens;

conjugated estrogens; ethinyl estradiol; diethylstilbesterol; chlortrianisen; idenestrol;

progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate, fluoxymesterone, and

methyltestosterone); adrenal corticosteroids (e.g., prednisone, dexamethasone,

methylprednisolone, and prednisolone); leutinizing hormone releasing agents or

gonadotropin-releasing hormone antagonists (e.g., leuprolide acetate and goserelin acetate); and antihormonal antigens (e.g., tamoxifen, antiandrogen agents such as flutamide; and antiadrenal agents such as mitotane and aminoglutethimide). The disclosure herein also contemplates the use of at least one antagonist of CXCR1 and/or CXCR2 in combination with other agents known in the art (e.g., arsenic trioxide) and other chemotherapeutic agents.

[0018] In some embodiments drawn to methods of treating cancer, the

administration of a therapeutically effective amount of at least one antagonist of CXCR1 and/or CXCR2 receptors in combination with at least one other anticancer therapy (e.g. chemotherapeutic agent, immune checkpoint inhibitor, T-cell therapy, cancer vaccination, radiation) results in a cancer survival rate greater than the cancer survival rate observed by administering either therapy alone. In further embodiments drawn to methods of treating cancer, the administration of a therapeutically effective amount of at least one antagonist of CXCR1 and/or CXCR2 in combination with at least one other anticancer therapy results in a reduction of tumor size or a slowing of tumor growth greater than reduction of the tumor size or tumor growth observed by administration of one agent alone.

[0019] In further embodiments, the disclosure herein contemplates methods for treating or preventing cancer in a subject, comprising administering to the subject a therapeutically effective amount of at least one antagonist of CXCR1 and/or CXCR2 receptors and at least one signal transduction inhibitor (STI). In a particular embodiment, the at least one STI is selected from the group consisting of bcr/abl kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, her-2/neu receptor inhibitors, and famesyl transferase inhibitors (FTIs). Other candidate STI agents are set forth elsewhere herein.

[0020] The disclosure herein also contemplates methods of augmenting the rejection of tumor cells in a subject comprising administering at least one antagonist of CXCR1 and/or CXCR2 receptors in conjunction with at least one chemotherapeutic agent,

immunotherapeutic, and/or radiation therapy, wherein the resulting rejection of tumor cells is greater than that obtained by administering either the CXCR1 and/or CXCR2 antagonist, the chemotherapeutic agent, immunotherapy, or the radiation therapy alone.

[0021] In further embodiments, the disclosure herein provides methods for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of at least one antagonist of CXCR1 and/or CXCR2 receptors and at least one immunomodulator other than a CXCR1 and/or CXCR2 antagonist. In particular

embodiments, the at least one immunomodulator is selected from the group consisting of CD40L, B7, B7RP1, ant-CD40, anti-CD38, anti-ICOS, 4-IBB ligand, dendritic cell cancer vaccine, IL2, IL12, ELC/CCL19, SLC/CCL21, MCP-l, IL-4, IL-18, TNF, IL-15, MDC, IFN- a/-b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-lO. Other candidate immunomodulator agents are set forth elsewhere herein.

BRIEF DESCRIPTION OF THE FIGURES

[0022] FIG. 1A shows structures of selected antagonists of CXCR1 and/or CXCR2 of formula I that include SX-517, SX-520, SX-557, SX-574, SX-577, SX-603, SX-622, SX- 660, SX-662, SX-671, SX-677, SX-678, and SX-682.

[0023] FIG. 1B shows structural formulas of CXCR1 and/or CXCR2 receptor antagonists.

[0024] FIG. 1C shows structural formulas of immunotherapeutic compounds consisting of inhibitors of indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO).

[0025] FIG. 2 shows the results of inhibition of myeloid derived suppressor cells (MDSCs) migration by SX-682 in a dose-dependent fashion. The graph shows SX-682 concentration, micromolar (pmolar), vs. the number of migrating MDSCs as measured by flow cytometry. As a control, an aqueous solution with carrier solvent DMSO was used (0 pmolar). [0026] FIG. 3A shows the results of direct inhibition of tumor cell proliferation of leukemia cell lines by SX-682 in a dose-dependent fashion. The leukemia cell lines included CCRF-CEM, MOLT-4, HL-60, RPMI-8226, K-562 and SR. These were independently culture in grown medium at five concentrations of SX-682 between 10 ⁸ M to 10 ⁴ molar. Percentage growth inhibition was measured by dye adsorption.

[0027] FIG. 3B shows the results of direct inhibition of tumor cell proliferation of non-small cell lung cancer cell lines by SX-682 in a dose-dependent fashion as measured in FIG. 3A. The non-small cell lung cancer cell lines included A549, H226, H460, H23, H522, H322M, HOP-62, and HOP-92.

[0028] FIG. 3C shows the results of direct inhibition of tumor cell proliferation of colon cancer cell lines by SX-682 in a dose-dependent fashion as measured in FIG. 3A. The colon cancer cell lines included COLO 205, HCT-15, HCC-2998, KM12, HCT-116, and SW- 620.

[0029] FIG. 3D shows the results of direct inhibition of tumor cell proliferation of CNS cancer cell lines by SX-682 in a dose-dependent fashion as measured in FIG. 3A. The CNS cancer cell lines included SF-268, SNB-19, SF-295, SNB-75, and SF-539.

[0030] FIG. 3E shows the results of direct inhibition of tumor cell proliferation (melanoma cell lines by SX-682 in a dose-dependent fashion. The melanoma cell lines included LOX IMVI, MDA-MB-435, SK-MEL-5, MALME-3M, SK-MEL-2, UACC-257,

Ml 4, SK-MEL-28, and UACC-62.

[0031] FIG. 3F shows the results of direct inhibition of tumor cell proliferation of ovarian cancer cell lines by SX-682 in a dose-dependent fashion. The ovarian cancer cell lines included IBROV1, OVCAR-8, OVCAR-3, NCI/ADR-RES, OVCAR-5, and SK-OV-3.

[0032] FIG. 3G shows the results of direct inhibition of tumor cell proliferation of renal cancer cell lines by SX-682 in a dose-dependent fashion. The renal cancer cell lines included 786-0, CAK-l, TK-10, RXF 393, UO-31, ACHN, and SN12C.

[0033] FIG. 3H shows the results of direct inhibition of tumor cell proliferation of prostate cancer cell lines by SX-682 in a dose-dependent fashion. The prostate cancer cell lines included PC-3 and DU-145.

[0034] FIG. 31 shows the results of direct inhibition of tumor cell proliferation of breast cancer cell lines by SX-682 in a dose-dependent fashion. The breast cancer cell lines included MCF7, BT-549, MDA-MB-231, T-47D, HS 578T, and MDA-MB-468.

[0035] FIG. 4 shows that SX-682 alone or in combination with carboplatin (CP) was an effective therapy for breast cancer in a validated mouse model. The volume (mm³) of tumors in Tl 1 genetically engineered mice was measured during 1-2 week treatment by daily oral administration of SX-682 (10 mg/day/mouse) with or without administration by weekly IP injection of CP (50 mg/kg). The mean, SE, and statistical significance of PO.OOOl (***) for cohorts of seven mice are shown.

[0036] FIG. 5 shows that SX-682 alone or synergistically in combination with CP was an effective treatment for breast cancer in a validated animal model. The volume (mm³) of tumors in C3Tag genetically engineered mice was measured during 4-6 week treatment dosing as in FIG. 4. The mean, SE, and statistical significance of PO.OOOl for cohorts of 10- 12 mice are shown.

[0037] FIG. 6 shows that SX-682 synergized CP to improve survival in a treatment for breast cancer. The treatments were administered in the C3Tag genetically engineered mouse model of breast cancer as described in FIG. 5. The treatment extended for up to 60 days. The results show that the combination therapy (SX-682 + CP) significantly improved survival over CP or SX-682 alone (P=0.008).

[0038] FIG. 7 shows that SX-682 alone or in combination with CP was an effective treatment for melanoma in a validated animal model. The volume (mm³) of tumors in TRIA genetically engineered mice was measured during 15-20 week treatment dosing SX-682 and CP as in FIG. 4. The mean, SE, and statistical significance of PO.OOOl for cohorts of 10-12 mice are shown.

[0039] FIG. 8 shows that SX-682 synergized with CP to cause remission of melanomas in the validated mouse model as described in FIG. 7. 21 -days of combination treatment caused a significant percentage change in tumor volume in TRIA genetically engineered mice compared to CP treatment alone.

[0040] FIG. 9 shows that SX-682 alone or in combination with anti-PD-l antibody was effective in treating melanomas in a mouse model. The tumor area (mm²) in B16-F10 syngeneic mice was measured during 26 days of treatment with SX-682 orally administered twice daily (50 mg/kg) with and without 100 pg anti-PD-l administered twice weekly by IP injection. SX-682 monotherapy significantly slowed tumor growth vs. control (P=0.0002,

**) and synergized with anti-PDl therapy vs. monotherapy with either SX-786 or anti-PD-l (P<0.0005, ***). Data and error bars are the mean ± SE of 4 or 5 mice per cohort.

[0041] FIG. 10 shows that SX-682 alone or in combination with anti-PD-l antibody inhibited lung cancer in a validated animal model using the dosing amounts as in FIG. 9. Tumor area (mm²) was measured in LLC syngeneic mice . SX-682 monotherapy significantly slowed tumor growth vs. control (P=0.0002, **) and synergized with anti-PDl therapy vs. monotherapy with either SX-682 or anti-PD-l (P<0.002, ***). Data and error bars are the mean ± SE in cohorts of 5 mice.

[0042] FIG. 11 shows that SX-682 synergized with anti-PD-l antibody to increase survival in the LLC syngeneic mice as described in FIG. 10. Drug administration and survival determinations continued up to 66 days after tumor injection. The combination of SX-682 and anti-PD-l therapy significantly enhanced survival compared to vehicle or anti- PD-l therapy alone (P=0.002).

[0043] FIG. 12 shows that SX-682 alone and in combination with immune checkpoint blockade (anti-PDl and anti-CTLA4) inhibited prostate cancer in a validated animal model. Pten^{pc /}p53^{pc /}Smad4^{pc /} mice were administered 50 mg/kg SX-682 by oral gavage b.i.d. and 200 pg each of anti-PDl and anti-CTLA4 antibodies (ICB), 3x/week. Prostate weight (g) was measured after 4-6 weeks. SX-682 plus ICB was significantly better than control (P=0.00l6, **), and ICB or SX682 alone (P=0.02l, *) (unpaired t-test). Mean + SE are shown.

DETAILED DESCRIPTION

[0044] Immune dysregulation is intimately associated with tumor evasion of the host immune system, resulting in tumor growth and progression. Traditional treatment approaches comprising chemotherapy and radiotherapy are generally difficult for the patient to tolerate and become less effective as tumors evolve to survive such treatments. By utilizing the patient's own immune system to identify and eliminate tumor cells,

immunotherapy has the benefit of reduced toxicity. As mobilization of immunosuppressive MDSCs through CXCR1 and/or CXCR2 receptor activation comprises one mechanism manipulated by tumors to promote growth and metastasis, agents (e.g., small molecule compounds) that antagonize these receptors present a promising avenue for prophylaxis and/or treatment.

Definitions

[0045] When any substituent or variable occurs more than one time in any moiety, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. [0046] Unless indicated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. For example, the definition of“alkyl” also applies to the“alkyl” portion of the defined term“alkoxy”.

[0047] The phrase“an effective amount” or a“therapeutically effective amount” refers to the administration of an agent to a subject, either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount capable of having any detectable, positive effect on any symptom, aspect, or characteristic of a disease, disorder or condition when administered to the subject. The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject's condition, and the like. By way of example, measurement of the serum level of an antagonist of CXCR1 and/or CXCR2 receptors (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been used.

[0048] “At least one” means one or more (e.g., 1-3, 1-2, or 1).

[0049] “Composition” includes a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from

combination of the specified ingredients in the specified amounts.

[0050] “In combination with” as used to describe the administration of at least one antagonist of CXCR1 and/or CXCR2 receptors with other medicaments in the methods of treatment of the disclosure herein, means that the compounds of formula I and the other medicaments are administered sequentially or concurrently in separate dosage forms, or are administered concurrently in the same dosage form.

[0051] ‘‘Mammal” means a human or other mammal, or means a human being.

[0052] “Patient” includes both human and other mammals, preferably human.

[0053] “Prodrug” denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of or a salt and/or solvate thereof. Prodrugs of the compounds of formula I or formula II or pharmaceutically acceptable salts or solvates thereof are within the scope of the disclosure herein. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the disclosure herein. Additionally, a prodrug can be converted to a compound of formula I by chemical or biochemical methods in an ex vivo environment, for example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0054] “Alkyl” is a saturated or unsaturated, straight or branched, hydrocarbon chain. In various embodiments, the alkyl group has 1-18 carbon atoms, i.e., is a Ci-Cie group, or is a C1-C12 group, a C1-C6 group, or a C1-C4 group. A lower alkyl group has 1-6 carbons. Independently, in various embodiments, the alkyl group has zero branches (i.e., is a straight chain), one branch, two branches, or more than two branches. Independently, in one embodiment, the alkyl group is saturated. In another embodiment, the alkyl group is unsaturated. In various embodiments, the unsaturated alkyl may have one double bond, two double bonds, more than two double bonds, and/or one triple bond, two triple bonds, or more than two triple bonds. Alkyl chains may be optionally substituted with 1 substituent (i.e.. the alkyl group is mono-substituted), or 1-2 substituents, or 1-3 substituents, or 1-4 substituents, etc. The substituents may be selected from the group consisting of hydroxy, amino, alkylamino, boronyl, carboxy, nitro, cyano, and the like. When the alkyl group incorporates one or more heteroatoms, the alkyl group is referred to herein as a heteroalkyl group. When the substituents on an alkyl group are hydrocarbons, then the resulting group is simply referred to as a substituted alkyl. In various aspects, the alkyl group including substituents has less than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, or 7 carbons.

[0055] “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which chain may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and n-hexyl.

[0056] “Alkoxy” means an alkyl-O-group wherein alkyl is as defined above. Non limiting examples of alkoxy groups include: methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen.

[0057] “Alkoxyalkyl” means an alkoxy-alkyl-group in which the alkoxy and alkyl are as previously described. Preferred alkoxyalkyl comprise a lower alkyl group. The bond to the parent moiety is through the alkyl.

[0058] “Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are as previously described. Preferred alkylaryl compounds comprise a lower alkyl group. The bond to the parent moiety is through the aryl.

[0059] “Aminoalkyl” means an NTh-alkyl-group, wherein alkyl is as defined above, bound to the parent moiety through the alkyl group.

[0060] “Aryl” (sometimes abbreviated“Ar”) is an aromatic carbocyclic

hydrocarbon ring system. The ring system may be monocyclic or fused polycyclic (e.g., bicyclic, tricyclic, etc.)· In one embodiment, the aryl group is monocyclic, and is preferably a C6 ring system, i.e. a phenyl ring is a preferred aryl ring, where preferred bicyclic aryl rings are C8-C12, or C9-C10. A naphthyl ring, which has 10 carbon atoms, is a preferred polycyclic aryl ring. Unless otherwise indicated herein, the term“aryl” as used herein is meant to include aryl rings optionally substituted by one or more substituents selected from acyl (- C(O)-R), alkoxy (-0-R), alkyl, aryl, alkylamino (-N(H)-R and -N(R)R), alkylthio (-S-R), amino (-NH2), azido (-N3), boronyl (-B(R)R or -B(OH)₂ or -B(OR)₂), carboxy (-C(O)-OH), alkoxy carbonyl (-C(O)-OR), aminocarbonyl (-C(0)-NH₂), aminosulfonyl (-S(0)₂-NH₂), alkylaminocarbonyl (-C(0)-N(H)R and -C(0)-N(R)R), cyano, halo (fluoro, bromo, chloro, iodo), haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl (-OH), acyloxy (-O-C(O)- R), ketone (-C(O)-R), substituted halomethylketone (-C(O)-CHmXn, where m+n=3, X=F, Cl, Br), mercapto (-SH and -S-R) and nitro (-N0₂) where each R group is an alkyl group having less than about 12 carbons, preferably where the R group is a lower alkyl group. Non limiting examples of suitable aryl groups include: phenyl, naphthyl, indenyl,

tetrahydronaphthyl, indanyl, anthracenyl, and fluorenyl.

[0061] “Arylalkyl” refers to an alkyl group as defined substituted by one or more aryl groups as defined below. Phenyl and naphthyl are preferred aryl groups in an arylalkyl group. A preferred alkyl group is methyl, so that a preferred arylalkyl group is benzyl or benzyl having one or more substituents on the phenyl ring. Unless otherwise indicated, the term“arylalkyl” as used herein is meant to include arylalkyl groups wherein the aryl ring therein is optionally substituted by one or more substituents selected from acyl (-C(O)-R), alkoxy (-0-R), alkyl, aryl, alkylamino (-N(H)-R and -N(R)R), alkylthio (-S-R), amino (- NH₂), azido (-N3), boronyl (-B(R)R or -B(OH)₂ or -B(OR)₂), carboxy (-C(O)-OH),

alkoxy carbonyl (-C(O)-OR), aminocarbonyl (-C(0)-NH₂), aminosulfonyl (-S(0)₂-NH₂), alkylaminocarbonyl (-C(0)-N(H)R and -C(0)-N(R)R), cyano, halo (fluoro, bromo, chloro, iodo), haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl (-OH), acyloxy (-O-C(O)- R), ketone (-C(O)-R), substituted halomethylketone (-C(O)-CHmXn, where m + n = 3, X = F, Cl, Br), mercapto (-SH and -S-R) and nitro (-NC ) where each R is an alkyl group having less than about 12 carbons, preferably where the R group is a lower alkyl group.

[0062] “Aryloxy” means an aryl-O-group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

[0063] “Carboxyalkyl” means an HOOC-alkyl-group, wherein alkyl is as defined above, bound to the parent moiety through the alkyl group. [0064] ‘‘Chemokine” means a protein molecule involved in chemotaxis.

[0065] A“chemokine-mediated disease” means a disease of which at least one element or cause is related to the regulation of a CXC chemokine.

[0066] “Cycloalkyl” means a non-aromatic mono-or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. A multicyclic cycloalkyl substituent may include fused, spiro, or bridged ring structures. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include l-decabn, norbomyl, adamantly and the like. Cycloalkyl substituents may be substituted or unsubstituted. In one embodiment, the cycloalkyl is unsubstituted. In another embodiment, the cycloalkyl is substituted with, e.g., 1 substituent (i.e.. the cycloalkyl group is mono- substituted), or 1-2 substituents, or 1-3 substituents, or 1-4 substituents, etc. In one embodiment, the substituents that may be present on the cycloalkyl aliphatic ring are selected from acyl (-C(O)-R), alkoxy (-0-R), alkyl, aryl, alkylamino (-N(H)-R and -N(R)R), alkylthio (-S-R), amino (-NH2), azido (-N3), boronyl (-B(R)R or -B(OH)₂ or -B(OR)₂), carboxy (- C(O)-OH), alkoxy carbonyl (-C(O)-OR), aminocarbonyl (-C(0)-NH₂), aminosulfonyl (- S(0)₂-NH₂), alkylaminocarbonyl (-C(0)-N(H)R and -C(0)-N(R)R), cyano, halo (fluoro, bromo, chloro, iodo), haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl (-OH), acyloxy (-O-C(O)-R), ketone (-C(O)-R), substituted halomethylketone (-C(O)-CHmXn, where m+n=3, X = F, Cl, Br), mercapto (-SH and -S-R) and nitro (-NCh) In one aspect the R group in the above substituents is an alkyl group having less than about 12 carbons, while in another aspect the R group is a lower alkyl group.

[0067] “Cycloalkylalkyl” means a cycloalkyl group bound to the parent moiety through an alkyl group. Non-limiting examples include: cyclopropylmethyl and

cyclohexylmethyl.

[0068] “Cycloalkylaryl” means a cycloalkyl group bound to the parent moiety through an aryl group. Non-limiting examples include: cyclopropylphenyl and

cyclohexylphenyl.

[0069] “Effective amount” or“therapeutically effective amount” is meant to describe an amount of compound or a composition of the disclosure herein effective in decreasing the action of a CXC chemokine at a CXC chemokine receptor and thus producing the desired therapeutic effect in a suitable patient. [0070] “Fluoroalkoxy” means an alkoxy group as defined above wherein one or more hydrogen atoms on the alkoxy is or are replaced by a fluoro group.

[0071] “Fluoroalkyl” means an alkyl group as defined above wherein one or more hydrogen atoms on the alkyl are replaced by a fluoro group.

[0072] “Halo” means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.

[0073] “Halogen” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.

[0074] “Heteroalkyl” is a saturated or unsaturated, straight or branched, chain containing carbon and at least one heteroatom. The heteroalkyl group may, in various embodiments, have on heteroatom, or 1-2 heteroatoms, or 1-3 heteroatoms, or 1-4 heteroatoms. In one aspect the heteroalkyl chain contains from 1 to 18 (i.e., 1-18) member atoms (carbon and heteroatoms), and in various embodiments contain 1-12, or 1-6, or 1-4 member atoms. Independently, in various embodiments, the heteroalkyl group has zero branches (i.e., is a straight chain), one branch, two branches, or more than two branches. Independently, in one embodiment, the heteroalkyl group is saturated. In another embodiment, the heteroalkyl group is unsaturated. In various embodiments, the unsaturated heteroalkyl may have one double bond, two double bonds, more than two double bonds, and/or one triple bond, two triple bonds, or more than two triple bonds. Heteroalkyl chains may be substituted or unsubstituted. In one embodiment, the heteroalkyl chain is

unsubstituted. In another embodiment, the heteroalkyl chain is substituted. A substituted heteroalkyl chain may have 1 substituent (i.e., by monosubstituted), or may have 1-2 substituents, or 1-3 substituents, or 1-4 substituents, etc. Exemplary heteroalkyl substituents include esters (-C(O)-O-R) and carbonyls (-C(O)-).

[0075] “Heterocyclic” (or“heterocycloalkyl” or“heterocyclyl”) refers to a non aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms (e.g., 3 to 7 ring atoms), or 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Examples of heterocyclic or heterocycloalkyl compounds include rings having 5 to 6 ring atoms. The prefix aza, oxa or thia before the heterocyclic or heterocycloalkyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen or sulfur atom of the heterocyclic or heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Any nitrogen atoms may be optionally quatemized. Non-limiting examples of monocyclic heterocyclic or heterocycloalkyl rings include: piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3- dioxolanyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophen-yl, and tetrahydrothiopyranyl The heterocyclyl may be unsubstituted or substituted. In one embodiment, the heterocyclyl is unsubstituted. In another embodiment, the heterocyclyl is substituted. The substituted heterocyclyl ring may contain 1 substituent, or 1-2 substituents, or 1-3 substituents, or 1-4 substituents, etc. In one embodiment, the substituents that may be present on the heterocyclyl ring are selected from acyl (-C(O)-R), alkoxy (-0-R), alkyl, aryl, alkylamino (-N(H)-R and - N(R)R), alkylthio (-S-R), amino (-NTk), azido (-N3), boronyl (-B(R)R or -B(OH)2 or - B(OR)₂), carboxy (-C(O)-OH), alkoxy carbonyl (-C(O)-OR), aminocarbonyl (-C(0)-NH2), aminosulfonyl (-S(0)2-NH2), alkylaminocarbonyl (-C(0)-N(H)R and -C(0)-N(R)R), cyano, halo (fluoro, bromo, chloro, iodo), haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl (-OH), acyloxy (-O-C(O)-R), ketone (-C(O)-R), substituted halomethylketone (-C(O)- CHmXn, where m+n=3, X=F, Cl, Br), mercapto (-SH and -S-R) and nitro (-NO2) In one aspect, the R group which is, or is part of the substituent attached to the heterocyclic ring is an alkyl group having less than about 12 carbons, while in another aspect the R group is a lower alkyl group.

[0076] “Heterocycloalkylalkyl” means a heterocycloalkyl-alkyl group, wherein said heterocycloalkyl and said alkyl are as defined above, bound to a parent moiety through the alkyl group.

[0077] “Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, or 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Heteroaryls can contain 5 to 6 ring atoms. The prefix aza, oxa or thio before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Any nitrogen atoms may be optionally quatemized. Non-limiting examples of heteroaryls include: pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, and benzothiazolyl. The heteroaryl may be unsubstituted or substituted. In one embodiment, the heteroaryl is unsubstituted. In another embodiment, the heteroaryl is substituted. The substituted heteroaryl ring may contain 1 substituent, or 1-2 substituents, or 1-3 substituents, or 1-4 substituents, etc. In one embodiment, the substituents that may be present on the heteroaryl ring are selected from acyl (-C(O)-R), alkoxy (-0-R), alkyl, aryl, alkylamino (-N(H)-R and - N(R)R), alkylthio (-S-R), amino (-Nth), azido (-N3), boronyl (-B(R)R or -B(OH)₂ or - B(OR)₂), carboxy (-C(O)-OH), alkoxy carbonyl (-C(O)-OR), aminocarbonyl (-C(0)-NH₂), aminosulfonyl (-S(0)₂-NH₂), alkylaminocarbonyl (-C(0)-N(H)R and -C(0)-N(R)R), cyano, halo (fluoro, bromo, chloro, iodo), haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl (-OH), acyloxy (-O-C(O)-R), ketone (-C(O)-R), substituted halomethylketone (-C(O)- CHmXn, where m + n = 3, X = F, Cl, Br), mercapto (-SH and -S-R) and nitro (-N0₂) In one aspect, the R group which is, or is part of the substituent attached to the heteroaryl ring is an alkyl group having less than about 12 carbons, while in another aspect the R group is a lower alkyl group.

[0078] “Heteroaralkyl” or“heteroarylalkyl” means a heteroaryl-alkyl-group, in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyl compounds can contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

[0079] “Hydroxyalkyl” means an HO-alkyl-group, in which alkyl is previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxy ethyl.

[0080] “Hydrate” is a solvate wherein the solvent molecule is H₂0.

[0081] “Solvate” means a physical association of a compound of the disclosure herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

[0082] The term“substituted” means substitution with specified groups other than hydrogen, or with one or more groups, moieties or radicals which can be the same or different, with each, for example, being independently selected.

[0083] The compounds of formula I form salts that are also within the scope of the disclosure herein. Reference to compounds of formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term“salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term“salt(s)” as used herein. The salts can be pharmaceutically acceptable (i.e.. non-toxic, physiologically acceptable) salts, although other salts are also useful. Salts of the compounds of formula I may be formed, for example, by reacting it with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0084] Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-napthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates (also known as tosylates), undecanoates, and the like.

Additionally, acids which are generally considered suitable for the formation of

pharmaceutically useful salts from basic pharmaceutical compounds.

[0085] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with V, V-bis(dehydroabietyl)ethylenediamine), /V-methyl-D-glucamines, /V-methyl-D-glucamides. t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0086] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the disclosure herein and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the disclosure herein.

[0087] Compounds of formula I can exist in unsolvated and solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for the purposes of the disclosure herein.

[0088] Compounds of formula I and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the disclosure herein.

[0089] Also within the scope of the disclosure herein are polymorphs of the compounds of the disclosure herein (i.e., polymorphs of the compounds of formula I are within the scope of the disclosure herein).

[0090] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of the disclosure herein. Individual stereoisomers of the compounds of the disclosure herein may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the compounds herein can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”,“solvate”,“prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the disclosed compounds.

[0091] The compounds of formula I may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as, for example, tritium (³H), iodine-l25 (¹²⁵I) or carbon-l4 (¹⁴C), or non-radioactive isotopes, such as deuterium (²H) or carbon-l3 (¹³C).

Such isotopic variations can provide additional utilities to those described elsewhere within this application. For instance, isotopic variants of the compounds of the disclosure herein may find additional utility, including but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents. Additionally, isotopic variants of the compounds of the disclosure herein can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment. All isotopic variations of the compounds of the disclosure herein, whether radioactive or not, are intended to be encompassed within the scope of the disclosure herein.

[0092] The term“small molecules” refers to chemical compounds having a molecular weight that is less than about 10 kDa, less than about 2 kDa, or less than about 1 kDa. Small molecules include, but are not limited to, inorganic molecules, organic molecules, organic molecules containing an inorganic component, molecules comprising a radioactive atom, and synthetic molecules. Therapeutically, a small molecule may be more permeable to cells, less susceptible to degradation, and less likely to elicit an immune response than large molecules.

[0093] The terms“inhibitors” and“antagonists”, or“activators” and“agonists” refer to inhibitory or activating molecules, respectively, for example, for the activation of, e.g., a ligand, receptor, cofactor, gene, cell, tissue, or organ. Inhibitors are molecules that decrease, block, prevent, delay activation, inactivate, desensitize, or down-regulate, e.g., a gene, protein, ligand, receptor, or cell. Activators are molecules that increase, activate, facilitate, enhance activation, sensitize, or up-regulate, e.g., a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates a constitutive activity. An“agonist” is a molecule that interacts with a target to cause or promote an increase in the activation of the target. An“antagonist” is a molecule that opposes the action(s) of an agonist. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce constitutive activity of a target, e.g., a target receptor, even where there is no identified agonist.

[0094] The terms“modulate”,“modulation” and the like refer to the ability of a molecule (e.g., an activator or an inhibitor) to increase or decrease the function or activity of a biological target, either directly or indirectly. A modulator may act alone, or it may use a cofactor, e.g., a protein, metal ion, or small molecule. Examples of modulators include small molecule compounds and other bioorganic molecules. Numerous libraries of small molecule compounds (e.g., combinatorial libraries) are commercially available and can serve as a starting point for identifying a modulator. The skilled artisan is able to develop one or more assays (e.g., biochemical or cell-based assays) in which such compound libraries can be screened in order to identify one or more compounds having the desired properties;

thereafter, the skilled medicinal chemist is able to optimize such one or more compounds by, for example, synthesizing and evaluating analogs and derivatives thereof. Synthetic and/or molecular modeling studies can also be utilized in the identification of an Activator.

[0095] The“activity” of a molecule may describe or refer to the binding of the molecule to a ligand or to a receptor; to catalytic activity; to the ability to stimulate gene expression or cell signaling, differentiation, or maturation; to antigenic activity; to the modulation of activities of other molecules; and the like. The term“proliferative activity” encompasses an activity that promotes, that is necessary for, or that is specifically associated with, for example, normal cell division, as well as cancer, tumors, dysplasia, cell

transformation, metastasis, and angiogenesis.

[0096] “Anticancer therapy” means any therapeutic intervention used to treat cancer in a patient in need of such treatment. Anticancer therapy can include the use of

chemotherapeutic agents, immunotherapy, radiation therapy, or surgery.

[0097] Classes of compounds that can be used as the chemotherapeutic agent (antineoplastic agent) include: alkylating agents (e.g., nitrogen mustards such as

chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nucleoside analogs (e.g., gemcitabine); nitroso ureas such as carmustine, lomustine, and streptozocin; topoisomerase 1 inhibitors (e.g., irinotecan); platinum complexes such as cisplatin and carboplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); DNA strand-breakage agents (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); DNA minor groove binding agents (e.g., plicamydin);

antimetabolites (e.g., folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxy uridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, pentostatin; asparginase; and ribonucleotide reductase inhibitors such as hydroxyurea);

tubulin interactive agents (e.g., vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives, and paclitaxel); hormonal agents (e.g., estrogens; conjugated estrogens; ethinyl estradiol; diethylstilbesterol; chlortrianisen; idenestrol; progestins such as

hydroxy progesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate, fluoxymesterone, and methyltestosterone); adrenal corticosteroids (e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone); leutinizing hormone releasing agents or gonadotropin-releasing hormone antagonists (e.g., leuprolide acetate and goserelin acetate); and antihormonal antigens (e.g., tamoxifen, antiandrogen agents such as flutamide; and antiadrenal agents such as mitotane and aminoglutethimide).

[0098] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art.

[0100] As used herein, a microtubule affecting agent is a compound that interferes with cellular mitosis, /. e.. having an anti-mitotic effect, by affecting microtubule formation and/or action. Such agents can be, for instance, microtubule stabilizing agents or agents that disrupt microtubule formation.

[0101] “Immunotherapy” means anticancer treatments that use the patient’s immune system to attack cancer cells. Immunotherapy can include: immune checkpoint inhibitors, cancer vaccines, and T-cell therapy. Examples of these immunotherapies are given below.

[0102] Immune checkpoint inhibitors include inhibitors (both small molecule and biological) of programmed cell death protein 1 (PD-l), PD-L1, cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4), indoleamine 2,3 -di oxygenase (IDO), tryptophan 2,3- dioxygenase (TDO), T-cell Ig and mucin domain 3 (TIM3), lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT), B- and T-lymphocyte attenuator (BTLA), V-domain Ig suppressor of T-cell activation (VISTA), inducible T-cell COStimulator (ICOS), killer Ig-like receptors (KIRs), and CD39. Examples of biologic immune checkpoint inhibitors include ipilimumab, abatacept, nivolumab, pembrolizumab, tremelimumab, pidilizumab, atezolizumab, durvalumab, and avelumab. Examples of small molecule immune checkpoint inhibitors of IDO and/or TDO include indoximod, GDC-0919, F001287, GDC-0919 (NLG919), F001287, epacadostat (INCB024360), IDO-IN-l, IDO-IN-2, and navoximod (IDO-IN-7).

[0103] Cancer vaccines are used to treat established cancers not due to viral infections, and include the use of antigen vaccines, tumor cell vaccines, dendritic vaccines, deoxyribonucleic acid vaccines, and viral vector vaccines.

[0104] T-cell therapy involves the isolation, expansion, and re-introduction of a cancer patient’s tumor reactive T-cells. T-cell therapy also includes the use of genetically modified T-cells expressing chimeric antigen receptors (CARs) on their surface, wherein CARs are proteins that allow the T cells to recognize an antigen on targeted tumor cells. As used herein, such an antigen on targeted tumors cells is also referred to as a“tumor antigen”.

[0105] An“antagonist of CXCR1 and/or CXCR2 receptors” is a molecule that opposes the action(s) of an agonist at CXCR1 and/or CXCR2 receptors. The antagonist may oppose the action of an agonist at CXCR1 and/or CXCR2 by acting at the receptor (e.g., an allosteric small-molecule) or acting at the chemokine ligand (e.g., the HuMax-IL8 monclonal antibody that binds CXCL8). The agonist may be selected from (but not limited to) chemokine ligands CXCL1, CXCL2, CXCL3, CXCL5, and CXCL8. The activity of an agonist may include cellular processes resulting from CXCR1 and/or CXCR2 receptor activation such as intracellular calcium release, cyclic AMP generation, cellular chemotaxis, and b-arrestin recruitment. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce constitutive activity of a target, e.g., a target receptor, even where there is no identified agonist.

[0106] In one embodiment, the method of treating cancer in a patient in need of such treatment, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount a CXCR1 and/or CXCR2 receptor antagonist of formula I,

wherein R⁶ is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl,

heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

wherein R⁷ and R⁸ are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl and heterocyclylalkyl; R⁷ and R⁸ are both oxygen to form a nitro group; or R⁷ and R⁸ together with the nitrogen to which they are attached, form a heterocyclyl; and

wherein R⁹ is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; or— B(R⁴R⁵),— BF3 M⁺,— R⁶— B(R⁴R⁵),— R⁶— BF3 M⁺ R⁶,— C(O)— R⁶,— O— R⁶,— S(0)_y— R⁶ (wherein y=0, 1, or 2),— P(O)— (R⁴R⁵) and— N(R⁷R⁸); or an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; wherein X¹ is carbon or nitrogen; X² is— S(0)_y— (wherein y=0, 1, or 2),— N(R⁹)— , or oxygen; and

n is an integer between 0 and 8;

or a pharmaceutically suitable solvate or salt thereof.

[0107] In one embodiment, the method of treating cancer in a subject in need of such treatment, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from the group consisting of formulas SX-517, SX-520, SX- 557, SX-574, SX-577, SX-603, SX-622, SX-660, SX-662, SX-671, SX-677, SX-678, and SX-682, shown in FIG. 1.

[0108] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula II:

Functional groups are as defined in W02006024823A9 as follows. R¹ is a group selected from C3-7carbocyclyl, Ci-6alkyl, C2-6alkenyl and C2-6alkynyl; wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from fluoro, nitrite, -OR⁴, - NR⁵R⁶, -CONR⁵R⁶, -COOR⁷, -NR⁸COR⁹, -SR¹⁰, -SO2R¹⁰, -S0₂NR⁵R⁶, -NR⁸S0₂R⁹, phenyl or heteroaryl; wherein phenyl and heteroaryl are optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, -OR⁴, - NR⁵R⁶, -CONR⁵R⁶, - COOR⁷, -NR⁸COR⁹, -SR¹⁰, -SO2R¹⁰, -S0₂NR⁵R⁶, -NR⁸S0₂R⁹, Ci-ealkyl and trifluoromethyl; X is -CH2-, a bond, oxygen, sulphur, sulphoxide, or sulphone; R² is C3-7carbocyclyl, optionally substituted by 1, 2 or 3 substituents independently selected from: fluoro, -OR⁴, - NR⁵R⁶ -CONR⁵R⁶, -COOR⁷, -NR⁸COR⁹, -SR¹⁰, -SO2R¹⁰, -S0₂NR⁵R⁶, -NR⁸S0₂R⁹; or R² is a 3-8 membered ring optionally containing 1, 2 or 3 atoms selected from O, S, -NR⁸ and whereby the ring is optionally substituted by 1, 2 or 3 substituents independently selected from Cmalkyl, fluoro, -OR⁴, -NR⁵R⁶ -CONR⁵R⁶, -COOR⁷, -NR⁸COR⁹, -SR¹⁰, -SO2R¹⁰, - S02NR⁵R⁶, -NR⁸S02R⁹; or R² is phenyl or heteroaryl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, -OR⁴, -NR⁵R⁶, - CONR⁵R⁶, -NR⁸COR⁹, - S02NR⁵R⁶, -NR⁸S02R⁹, Ci-6alkyl and trifluoromethyl; or R² is a group selected from Ci-6alkyl, C2-6alkenyl or C2-6alkynyl wherein the group is substituted by 1, 2 or 3 substituents independently selected from hydroxy, amino, Ci-6alkoxy, Ci- 6alkylamino, diCi-6alkylamino, N-(Ci-6alkyl)-N-(phenyl)amino, iV-Cuealkylcarbamoyl, iy,N- di(Ci.6alkyl)carbamoyl, N-(Ci.6alkyl)-N-(phenyi)carbamoyl, carboxy, phenoxycarbonyl, - NR⁸COR⁹, -SO2R¹⁰, -S0₂NR⁵R⁶ ,-NR⁸S0₂R⁹ and -CONR⁵R⁶; R³ is trifluoromethyl or a group-NR⁵R⁶, or R is phenyl, napthyl, monocyclic or bicyclic heteroaryl wherein a heteroring may be partially or fully saturated and one or more ring carbon atoms may form a carbonyl group, and wherein each phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, phenyl, heteroaryl, -OR⁴, - NR⁵R⁶, -CONR⁵R⁶, -COR⁷, -COR²⁰, -COOR⁷, -NR⁸COR⁹, -SR¹⁰, -SO2R¹⁰, -S0₂NR⁵R⁶, - NR⁸S02R⁹, trifluoromethyl or Ci-oalkyl optionally further substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, -OR²⁰ , -COOR²⁰, -COR²⁰, -NR¹⁸R¹⁹, - CONR¹⁸R¹⁹, -NR¹⁸COR¹⁹, -SO2R²⁰, -S0₂NR¹⁸R¹⁹, NR¹⁸S0₂R¹⁹, phenyl or monocyclic or bicyclic heteroaryl, wherein a hetero-ring may be partially or fully saturated; and wherein each phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 substituents

independently selected from halo, cyano, nitro, -OR²⁰, -NR⁵R⁶, -CONR⁵R⁶, -COR⁷, -COOR⁷, -NR⁸COR⁹, -SR¹⁰, -SO2R¹⁰, -S02NR⁵R⁶, -NR⁸S02R⁹, heteroaryl, Ci-oalkyl optionally further substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, -OR , - COOR²⁰, -COR²⁰, -NR¹⁸R¹⁹, -CONR¹⁸R¹⁹, -NR¹⁸COR¹⁹, -SO2R²⁰, -S0₂NR¹⁸R¹⁹,

NR¹⁸S02R¹⁹, or R³ is a group selected from C3-7carbocyclyl, Ci-salkyl, C2-6alkenyl and C2- 6alkynyl whereby the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, -OR⁴, -NR⁵R⁶, -CONR⁵R⁶, -COR⁷, -COOR⁷, -NR⁸COR⁹, -SR¹⁰, -SO2R¹⁰, -S02NR⁵R⁶, -NR⁸S02R⁹, phenyl or monocyclic or bicyclic heteroaryl, wherein a heteroring may be partially or fully saturated; and wherein each phenyl or monocyclic or bicyclic heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, -OR⁴, -NR⁵R⁶, -CONR⁵R⁶, -COR⁷' -COOR⁷, -NR⁸COR⁹, -SR¹⁰, - SO2R¹⁰, -S02NR⁵R⁶, -NR⁸S02R⁹, Ci-oalkyl, or trifluoromethyl; R⁴ is hydrogen or a group selected from Ci-oalkyl and phenyl, wherein the group is optionally substituted by 1 or 2 substituents independently selected from halo, phenyl, -OR¹¹ and - NR¹²R¹³; R⁵ and R⁶ are independently hydrogen or a group selected from Ci-6alkyl and phenyl and monocyclic or bicyclic heteroaryl, wherein a heteroring may be partially or fully saturated; wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, phenyl, -OR¹⁴,-NR¹⁵R¹⁶, -COOR¹⁴, -CONR¹⁵R¹⁶, -NR¹⁵COR¹⁶, -SO2R¹⁰, - S0₂NR¹⁵R¹⁶ and NR¹⁵S0₂R¹⁶; or R⁵ and R⁶together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen , -SO(n)- (where n = O, 1 or 2) and nitrogen atoms, in which the ring is optionally substituted by 1, 2 or 3 substituents independently selected from phenyl, heteroaryl, -OR¹⁴, -COR²⁰, -COOR¹⁴, -NR¹⁵R¹⁶, -CONR¹⁵R¹⁶, -NR¹⁵COR¹⁶, -S0₂R¹⁰, - S0₂NR¹⁵R¹⁶, NR¹⁵S0₂R¹⁶ or Q-ealkyl (optionally further substituted by 1 or 2 or 3 substituents independently selected from halo, -NR¹⁵R¹⁶and -OR¹⁷ or cyano, nitro, -OR²⁰ , - COOR²⁰, -COR²⁰, -NR¹⁸R¹⁹, -CONR¹⁸R¹⁹, -NR¹⁸COR¹⁹, -S0₂R²⁰, -S0₂NR¹⁸R¹⁹, and NR¹⁸S0₂R¹⁹ groups), R¹⁰ is hydrogen or a group selected from Ci-6alkyl or phenyl, wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, phenyl, -OR¹⁷ and - NR¹⁵R¹⁶; and each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴ R¹⁵, R¹⁶, R¹⁷is independently hydrogen, Ci-6alkyl or phenyl, R¹⁸, R¹⁹, and R²⁰ are hydrogen or a group selected from Ci-6alkyl or heteroaryl (wherein a heteroring may be partially or fully saturated) or phenyl, wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, nitro, -CN, -OR⁴, - NR⁸R⁹, -CONR⁸R⁹, -COR⁷' -COOR⁷, - NR⁸COR⁹, -SR¹⁰, -S0₂R¹⁰, -S0₂NR⁸R⁹, -NR⁸S0₂R⁹, Ci-ealkyl or heteroaryl. A

representative antagonist from this genus is N-[2-[[(2,3-difluorophenyl)methyl]thio]-6- { [(1 R,2S)-2,3-dihy droxy-l -methylpropyljoxy } -4-pyrimidinyl] - 1 -azetidinesulfonamide (AZD5069)

[0109] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula III:

[0110] Functional groups are as defined in EP1123276B1 as follows. R₂ is an aryl group, R is a straight or branched Ci-Ci6-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3- pyridyl, 2-pyridyl-ethyl, p-cyanophenylmethyl, p-aminophenylmethyl, 3-cyano-l -propyl, 4- aminobutyl group, an alkoxy ethylene CH3-(CH₂)ni-(OCH₂CH₂)mi-group in which m is zero or 1 and mi is an integer 1 to 3, or a PIP₂N-CH₂-CH₂- group in which Pi and P₂ are independently H, C1-C3- alkyl, benzyloxy-carbonyl, a-, b- or g-pyridocarbonyl,

carboxycarbonyl or carbalkoxycarbonyl, or Pi and P2, when joined to the N atom which they are linked to, form a phthalimido, piperidino, morpholino residue; R' is H or straight or branched Ci-C₃-alkyl. A representative antagonist from this genus is (2R)-2-[4-(2- methylpropyl)phenyl]-N-methylsulfonylpropanamide (reparixin).

[0111] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula IV:

IV

[0112] Functional groups are as defined in US7132445B2 as follows. A compound of the formula: A is selected from the group consisting of:

(1 ) (2) (3) (4) (5) wherein said A group is substituted with 1 to 6 substituents each independently selected from the group consisting of: unsubstituted alkyl;

wherein said A group is substituted with 1 to 6 substituents each independently selected from the group consisting of: unsubstituted alkyl;

wherein one or both rings of said A group is substituted with 1 to 6 substituents each independently selected from the group consisting of: unsubstituted alkyl;

Ai (8,

R7 R⁰

B is:

wherein R³ is selected from the group consisting of:

— C(0)NR¹³R¹⁴,

n is 0; R² is selected from the group consisting of: hydrogen, OH,— C(0)OH,— SH,— S0₂NR¹³R¹⁴,— NHC(0)R¹³,— NHS0₂NR¹³R¹⁴,— NHSO2R¹³,— NR¹³R¹⁴,— C(0)NR¹³R¹⁴, — C(0)NH0R¹³,— C(0)NR^I30H,— S(0₂)OH,— 0C(0)R¹³; R⁴ is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy,— OH,— CF3,— OCF3,— NO2,— C(0)R¹³,— C(0)0R¹³,— C(0)NHR¹⁷,— C(0)NR¹³R¹⁴,— SO_(t)NR¹³R¹⁴,

— SO(_t)R¹³,— C(0)NR¹³0R¹⁴, and unsubstituted or substituted aryl, wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R⁹ groups; each R⁵ and R⁶ are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy,— CF3, — OCF3,— NO2,— C(0)R¹³,— C(0)0R¹³,— C(0)NR^I3R¹⁴,— SO_(t)NR^I3R¹⁴, C(0)NR¹³0R¹⁴, cyano, and unsubstituted aryl; each R⁷ and R⁸ is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, alkynyl and alkenyl; and wherein there are one or more substituents on said substituted R⁷ and R⁸ groups, wherein each substituent is independently selected from the group consisting of: a) halogen, b)— CF3, c)— COR¹³, d)— OR¹³, e)— NR¹³R¹⁴, f)— NO2, g)— CN, h)— SO2OR¹³, i)— CO2R¹³, j)— C(0)NR¹³R¹⁴, k)— NR¹³C(0)R¹⁴, and 1)— NR¹³C02R¹⁴; each R⁹ is independently selected from the group consisting of:— R¹³; each R¹³ and R¹⁴ is independently selected from the group consisting of: H and unsubstituted alkyl; each R¹⁵ is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; R¹⁷ is selected from the group consisting of:— S02alkyl,— S02aryl,— S02cycloalkyl, and— S02heteroaryl; R³⁰ is selected from the group consisting of: alkyl, cycloalkyl,— CN,— NO2, or— SO2R¹⁵ provided that R¹⁵ is not H; and t is 0, 1 or 2. A representative antagonist from this genus is 2-hydroxy-N,N-dimethyl-3-[[2-[[(lR)-l-(5- methy lfuran-2-y l)propy 1] amino] -3 ,4-dioxocy clobuten- 1 -y 1] amino] benzamide (SCH527123 , navarixin).

[0113] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula V:

[0114] Functional groups are as defined in W02009106539A1 as follows. R¹ is a group of the formula: -A-(Co-Cs alkylene)-B; A is a bond, -C(0)N(R³)-, -C(0)NHS(0)-, - C(0)NHS(02)-, -C(0)-, -C(0)O, -C(0)-(5 or 6- membered N-bonded heterocyclic bridging group)-, -N(R^a)C(0)-, -(CH₂)z-N(R^a)-, -(CH₂)z- N(R^a)S(0)-, -(CH₂)z-N(R^a)S(0₂)-, -C(=N- OR^a)- or -NHC(=NH)N(R^a)-; B is H, OH, CN, NO2, halogen, Ci-Cs alkylthio, C₂-Ce alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C6-C14 aryl, a 5-10 membered heterocyclic group containing one or more heteroatoms selected from N, O and S, Ci- C6 alkoxy, O-C3-C8 cycloalkyl, O-C1-C3 alkylene- C3-C8cycloalkyl, O-C6-C14 aryl, O-benzyl, O-(5-l0 membered heterocyclic group containing one or more heteroatoms selected from N, O and S), C(0)R^d, C(0)OR^b, OC(0)R^b, C(0)NR^bR^c, N(R^b)C(0)R^d, NR^bR^c, S(0)Ci-Ce alkyl or S(0₂)Ci-C6 alkyl, wherein the alkyl, alkenyl and aikynyl groups are each optionally substituted by OH, halo or C1-C3 alkoxy, wherein the cycloalkyl and cycloalkenyl groups are each optionally fused to a benzene ring and the ring as a whole is optionally substituted by OH, halo, NH2 or C1-C3 alkoxy, and wherein the aryl and heterocyclic groups are each optionally substituted by one or substituents each independently selected from OH, halo,

NH2, CN, NO2, oxo, C1-C6 alkyl, Ci- Ce hydroxyalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, Ci- C6 alkoxy, Ci-C6haloalkoxy, phenyl, a 5-10 membered heterocyclic group containing one or more heteroatoms selected fromN, O and S and C02R^b; the (Co-Cx alkylene group) may be branched and is optionally substituted by OH or C1-C3 alkoxy; z is 0,1 , 2 or 3; R^a and R^b are each independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl and Cri-Cs cycloalkenyl;

R^c and R^d are each independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C5- C8 cycloalkenyl, C6-C14 aryl, a 5-10 membered heterocyclic group containing one or more heteroatoms selected from N, O and Si S(0)Ci-C6 alkyl and S(02)Ci-C6 alkyl, provided that R¹ is not hydrogen; R² is C6-C14 aryl, -C1-C6 alkylene-C6-Ci4 aryl or a 5-10 membered heterocyclic group containing one or more heteroatoms selected from N, O and S, wherein the aryl and heterocyclic groups are each optionally fused to a 5 or 6-membered non-aromatic carbocyclic group or a 5 or 6-membered non-aromatic heterocyclic group containing one or more heteroatoms selected from N, O and S and wherein the ring systems are optionally substituted by OH, halo, NH2, CN, NO2, oxo, C1-C6 alkyl, C1-C6 hydroxyalkyl, Ci- Ce haloalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, phenyl, a 5-10 membered heterocyclic group containing one or more heteroatoms selected from N, O and S and C02R^b; X is C or N; Y is O or CH2; Z is OR³ or NR³R⁴; R³ is H, C1-C6 alkyl, C3-C8 cycloalkyl or C5- C8 cycloalkenyl; R⁴ is H, Ci-Ce alkyl, C3-C8 cycloalkyl and Cs-Cs cycloalkenyl, wherein the alkyl and cycloalkyl groups are each optionally substituted by one or more groups selected from OH and C1-C3 alkoxy; or a pharmaceutically acceptable salt or solvate thereof.

[0115] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula VI:

[0116] Functional groups are as defined in W02010015613A1 as follows. R¹ is H, a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups,

(CrC₄ alkyl)- 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, (C1-C4 alkyl)- 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups, CrC6 alkyl optionally substituted by one or more halogen atoms, CN or OH groups, CrC₆ alkoxy optionally substituted by one or more halogen atoms or OH groups, or an ether group containing 2 to 10 carbon atoms and 1 to 3 oxygen atoms, wherein the ether group is optionally substituted by one or more substituents each independently selected from OH, halogen, a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups and a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups; R² is a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups, (Ci -C4 alkyl)- 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, (CrC4 alkyl)- 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, CN or OH groups, CrG, alkoxy optionally substituted by one or more halogen atoms or OH groups, or an ether group containing 2 to 10 carbon atoms and 1 to 3 oxygen atoms, wherein the ether group is optionally substituted by one or more substituents each independently selected from OH, halogen, a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups and a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups; or R¹ and R² together with the carbon atom to which they are attached form 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, or a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups;_R³ is hydrogen, halogen or cyano; R⁴ is H, CrG alkyl, C3-C8 cycloalkyl, -Cxcycloalkenyl or (C C4 alkyl)-R⁶, wherein the alkyl groups are each optionally substituted by one or more halogen atoms;_R⁵ is CrCs alkyl, C3-C8 cycloalkyl, Cs-Cs cycloalkenyl, (CrC4 alkyl)-C3- C8 cycloalkyl or (CrC4 alkyl)-Ci-Cs cycloalkenyl, wherein the alkyl groups are each optionally substituted by one or more halogen atoms; or R⁴ and R⁵, together with the nitrogen and oxygen atoms to which they are attached, form a 5 to 10 membered heterocyclic group optionally substituted by one or more Z groups; R⁶ is selected from a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, a 3 to 10 membered heterocyclic group optionally substituted by one or more_Z groups, NR⁷R⁹, NR⁷(SC )R⁹, (SC )NR⁷R⁸, (S0₂)R⁹, NR⁷C(0)R⁹, C(0)NR⁷R⁹, NR⁷C(0)NR⁸R⁹, NR⁷C(0)0R⁹, C(0)OR⁷, OC(0)R⁹, OC(0)NR⁷, C(0)R⁹, SR⁷ , CN and NC ;_R⁷ and R⁸ are each independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl and -(C1-C3 alkylene)- C3-C10 cycloalkyl;_R⁹ is selected from H, C1-C6 alkyl, -(C1-C3 alkylene)-C3-Cio cycloalkyl, a 3 to 10 membered carbocyclic group and a 3 to 10 membered heterocyclic group, wherein each of the alkyl groups and ring systems is optionally substituted by OH, halo, C1-C3 alkyl and C1-C3 alkoxy;_X is CR¹⁴ or N;_Z is independently selected from OH; a 3 to 10 membered carbocyclic group; a 3 to 10 membered heterocyclic group; benzyl; C1-C6 alkyl optionally substituted by one or more halogen atoms, CN or OH groups; C1-C6 alkoxy optionally substituted by one or more halogen atoms, CN or OH groups; -Oaryl; -Obenzyl; - 0(CH₂)_aC(0)E; NR¹⁰(SO2)R¹²;_.(SO2)NR¹⁰Rⁿ; (S0₂)R¹²; NR¹⁰C(O)R¹²; C(O)NR¹⁰R¹²;

NR¹⁰C(O)NRⁿR¹²; NR¹⁰C(O)OR¹²; NR¹⁰R¹²; C(0)OR¹⁰; OC(0)R¹²; OC(0)NR¹⁰; C(0)R¹²; SR¹² ; CN; NO2; and halogen; or where there are two or more Z substitutents, two Z substituents together with the atoms to which they are attached optionally form a 5- to 7- membered carbocyclic or a 4- to 7- membered heterocyclic substituent fused to the ring system; a is O, 1 , 2, 3 or 4, wherein the alkylene group is optionally substituted by OH or NH2 when a is 1 , 2, 3 or 4;_E is NR¹⁰R¹² or OR¹²; each R¹⁰ and R¹¹ are independently selected from H, Ci-C6alkyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl and -(C1-C3 alkylene)- C3-C10 cycloalkyl; each R¹² is selected from H, CrC₆ alkyl, -(C1-C3 alkylene)-C3- Cio cycloalkyl, a 3 to 10 membered carbocyclic group and a 3 to 10 membered heterocyclic group, wherein each of the ring systems is optionally substituted by OH, halo, d-C3 alkyl and d-C3alkoxy; and R¹⁴ is H or CrC6 alkyl.

[0117] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula VII:

[0118] Functional groups are as defined in W02010131145A1, W02010131146A1, and W02010131147A as follows. _R⁴ is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C12 bicycloalkyl, Aryl¹, Aryl², Het¹, Het², Het³ or Het⁴, said C1-C6 alkyl, C3-C8 cycloalkyl and Ce- C12 bicycloalkyl being optionally substituted by 1 to 3 substituents independently selected from -CN, halo, -Nth, -SH, -SO2NH2, -OCONH2 and -X-R^a, with the proviso that the R¹ moiety may not be attached through a methylene (-CH2-) group; R² is

X is a bond, C1-C6 alkylene, -CO-, -0-, -0-(Ci-C6 alkylene)-, -NR⁶-, -S-, -SO-, -SO2-, -COO-, -OCO-, -NR⁶S0₂-, -SO2NR⁶-, -NR⁶CONR⁶-, -NR⁶COO- or -OCONR⁶-; R^a is Ci-Ce alkyl, C3-C8 cycloalkyl, Aryl¹, Aryl², Het¹, Het², Het³ or Het⁴, said C3-C8 cycloalkyl and Ce- C12 bicycloalkyl being optionally substituted by one or more C1-C6 alkyl, -OH or Ci- Ce alkoxy groups; R³ and R⁴ are each independently H, -CN, halo, -OH, -NH2, -SH, -CONH2, -SO2NH2, -NR⁶CONH2, -OCONH2 or -Y-R^b; or, alternatively, where R³ and R⁴ are attached to adjacent carbon atoms, R³ and R⁴, taken together with the carbon atoms to which they are attached, form a 5 or 6-membered ring which may be aromatic or partially saturated and which may be carbocyclic or contain up to two heteroatoms selected from N, S and O, said ring being optionally substituted by 1-3 substituents selected from Ci-C6alkyl, C3- Cs cycloalkyl, halo, -CN, -OR⁶, -NR⁷R⁸, -SR⁶, -SOR⁹, -SO2R⁹, -COR⁶, -OCOR⁶, -COOR⁶, - NR⁶COR⁶, -CONR⁷R⁸, -NR⁶S02R⁹, -S02NR⁷R⁸, -NR⁶CONR⁷R⁸, -NR⁶COOR⁹ and - NR⁶S0₂NR⁷R⁸; R⁵ is H, -CN, halo, -OH, -NH₂, -SH, -CONH2, -SO2NH2, -NR⁶CONH₂, - OCONH2 or -Y-R^b; Y is a bond, Ci-Ce alkylene, -CO-, -0-, -NR⁶-, -S-, -SO-, -SO2-, -CONR⁶- , -COO-, -OCO-, -NR⁶CO-, -NR⁶S0₂-, -SO2NR⁶-, -NR⁶CONR⁶-, -NR⁶COO- or -OCONR⁶-; R^b is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C12 bicycloalkyl, Aryl¹, Aryl², Het¹, Het², Het³ or Het⁴, said C1-C6 alkyl, C3-C8 cycloalkyl and C6-C12 bicycloalkyl being optionally substituted by 1-5 substituents selected from R⁹, -CN, -OR⁶, -NR⁷R⁸, -SR⁶, -SOR⁹, -SO2R⁹, -COR⁶, - OCOR⁶, -COOR⁶, -NR⁶COR⁶, -CONR⁷R⁸, -NR⁶S0₂R⁹, -S0₂NR⁷R⁸, -NR⁶CONR⁷R⁸, - NR⁶COOR⁹ and -NR⁶S02NR⁷R⁸ and optionally substituted by 1 substituent R^d; Aryl¹ is phenyl or naphthyl, said phenyl and naphthyl being optionally substituted by 1 substituent -Z- R^d and 1-4 substituents each independently selected from -Z-R^e; Aryl² is a 3 to 8-membered monocyclic or 6 to l2-membered bicyclic carbocycle which is partially unsaturated, said carbocycle being optionally substituted by 1 substituent -Z-R^d and 1-4 substituents each independently selected from -Z-R^f; Het¹ is a 3 to 8-membered saturated or partially unsaturated monocyclic heterocycle, containing 1 or 2 heteroatoms selected from O and N, said heterocycle being optionally substituted by 1 substituent -Z-R^d and 1-4 substituents each independently selected from -Z-R^f; Het² is a 6 to l2-membered saturated or partially unsaturated multi cyclic heterocycle containing 1-3 heteroatoms selected from O, S and N, said heterocycle being optionally substituted by 1 substituent -Z-R^d and 1-4 substituents each independently selected from -Z-R^f; Het³ is (i) a 6-membered aromatic heterocycle containing 1-3 N atoms or (ii) a 5-membered aromatic heterocycle containing either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms, said heterocycle being optionally substituted by 1 substituent -Z-R^d and 1-4 substituents each independently selected from -Z-R^e; Het⁴ is (i) a lO-membered bicyclic aromatic heterocycle containing 1-4 N atoms or (ii) a 9- membered bi cyclic aromatic heterocycle containing either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms or (iii) an 8-membered bicyclic aromatic heterocycle containing (a) 1-4 N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and 0-2 N atoms, said heterocycle being optionally substituted by 1 substituent -Z-R^d and 1-4 substituents each independently selected from -Z-R^e; Z is a bond, -CO- or C1-C6 alkylene; R^d is Aryl³, Aryl⁴, Het⁵, Het⁶,

Het⁷ or Het⁸; R^e is C1-C6 alkyl, C3-C8 cycloalkyl, halo, -CN, -OR⁶, -NR⁷R⁸, -SR⁶, -SOR⁹, - SO2R⁹, -COR⁶, -OCOR⁶, -COOR⁶, -NR⁶COR⁶, -CONR⁷R⁸, -NR⁶S0₂R⁹, -S0₂NR⁷R⁸, - NR⁶CONR⁷R⁸, -NR⁶COOR⁹ or -NR⁶S0₂NR⁷R⁸; R^f is Ci-Ce alkyl, C₃-Cs cycloalkyl, halo, oxo, -OR⁶, -NR⁷R⁸, -SR⁶, -SOR⁹, -S0₂R⁹, -COR⁶, -OCOR⁶, -COOR⁶, -NR⁶COR⁶, - CONR⁷R⁸, -NR⁶S0₂R⁹, -S0₂NR⁷R⁸, -NR⁶CONR⁷R⁸, -NR⁶COOR⁹ or -NR⁶S0₂NR⁷R⁸;

Aryl³ is phenyl or naphthyl, said phenyl and naphthyl being optionally substituted with 1-5 substituents selected from C1-C6 alkyl, C3-C8 cycloalkyl, halo, -CN, -OR⁶, -NR⁷R⁸, -SR⁶, - SOR⁹, -S0₂R⁹, -COR⁶, -OCOR⁶, -COOR⁶, -NR⁶COR⁶, -CONR⁷R⁸, -NR⁶S0₂R⁹, -S0₂NR⁷R⁸, -NR⁶CONR⁷R⁸, -NR⁶COOR⁹ and -NR⁶S0₂NR⁷R⁸; Aryl⁴ is a 3 to 8-membered monocyclic or 6 to l2-membered bicyclic carbocycle which is partially unsaturated, said carbocycle being optionally substituted by 1-5 substituents selected from C1-C6 alkyl, C3-C8 cycloalkyl, halo, oxo, -OR⁶, -NR⁷R⁸, -SR⁶, -SOR⁹, -S0₂R⁹, -COR⁶, -OCOR⁶, -COOR⁶, -NR⁶COR⁶, - CONR⁷R⁸, -NR⁶S0₂R⁹, -S0₂NR⁷R⁸, -NR⁶CONR⁷R⁸, -NR⁶COOR⁹ and -NR⁶S0₂NR⁷R⁸;

Het⁵ is a 3 to 8-membered saturated or partially unsaturated monocyclic heterocycle, containing 1 or 2 heteroatoms selected from O and N, said heterocycle being optionally substituted by 1-5 substituents selected from C1-C6 alkyl, C3-C8 cycloalkyl, halo, oxo, -OR⁶, - NR⁷R⁸, -SR⁶, -SOR⁹, -S0₂R⁹, -COR⁶, -OCOR⁶, -COOR⁶, -NR⁶COR⁶, -CONR⁷R⁸, - NR⁶S0₂R⁹, -S0₂NR⁷R⁸, -NR⁶CONR⁷R⁸, -NR⁶COOR⁹ and -NR⁶S0₂NR⁷R⁸; Het⁶ is a 6 to 12- nnennbered saturated or partially unsaturated multi cyclic heterocycle containing 1-3 heteroatoms selected from O, S and N, said heterocycle being optionally substituted by 1-5 substituents selected from d-C₆ alkyl, C3-C8 cycloalkyl, halo, oxo, -OR⁶, -NR⁷R⁸, -SR⁶, - SOR⁹, -S0₂R⁹, -COR⁶, -OCOR⁶, -COOR⁶, -NR⁶COR⁶, -CONR⁷R⁸, -NR⁶S0₂R⁹, -S0₂NR⁷R⁸, -NR⁶CONR⁷R⁸, -NR⁶COOR⁹ and -NR⁶S0₂NR⁷R⁸; Het⁷ is (i) a 6-membered aromatic heterocycle containing 1-3 N atoms or (ii) a 5-membered aromatic heterocycle containing either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms, said heterocycle being optionally substituted with 1-4 substituents selected from C1-C6 alkyl, C3- Cx cycloalkyl, halo, -CN, -OR⁶, -NR⁷R⁸, -SR⁶, -SOR⁹, -SO2R⁹, -COR⁶, -OCOR⁶, -COOR⁶, -NR⁶COR⁶, - CONR⁷R⁸, -NR⁶S0₂R⁹, -S0₂NR⁷R⁸, -NR⁶CONR⁷R⁸, -NR⁶COOR⁹ and -NR⁶S0₂NR⁷R⁸;

Het⁸ is (i) a lO-membered bicyclic aromatic heterocycle containing 1-4 N atoms or (ii) a 9- membered bicyclic aromatic heterocycle containing either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms, or (iii) an 8-membered bicyclic aromatic heterocycle containing (a) 1- 4 N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and 0-2 N atoms, said heterocycle being optionally substituted with 1-5 substituents selected from C1-C6 alkyl, C3- Cs cycloalkyl, halo, -CN, -OR⁶, -NR⁷R⁸, -SR⁶, -SOR⁹, -S0₂R⁹, -COR⁶, -OCOR⁶, -COOR⁶, - NR⁶COR⁶, -CONR⁷R⁸, -NR⁶S0₂R⁹, -S0₂NR⁷R⁸, -NR⁶CONR⁷R⁸, -NR⁶COOR⁹ and - NR⁶S0₂NR⁷R⁸; R⁶ is H, C1-C6 alkyl or C3-C8 cycloalkyl, said C1-C6 alkyl and C3- C8 cycloalkyl being optionally substituted by -OH or C1-C6 alkoxy; R⁷ and R⁸ are each independently H, C1-C6 alkyl or C3-C8 cycloalkyl or are taken together with the nitrogen atom to which they are attached to form a A-, 5- or 6-membered saturated heterocyclic ring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said heterocyclic ring being optionally substituted by one or more C1-C6 alkyl or C3-C8 cycloalkyl groups; and R⁹ is Ci- Ce alkyl or C3-C8 cycloalkyl, said C1-C6 alkyl and C3-C8 cycloalkyl being optionally substituted by -OH or C1-C6 alkoxy; wherein, in each instance, said C1-C6 alkyl, Ci- C6 alkylene, C3-C8 cycloalkyl and C6-Ci₂ bicycloalkyl may have one or more hydrogen atoms replaced with a fluorine atom.

[0119] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula VIII:

VIII

[0120] Functional groups are as defined in W02012080456A1, as follows. R¹ is an 5-10 membered aromatic, heteroaromatic, nonaromatic cyclic or heterocyclic, single or condensed multi-ring system, optionally substituted by 1-4 residues selected from halogen or Ci-6-alkyl, optionally substituted with one or more F atoms; X¹ is absent or methylene optionally substituted with Ci-5-alkyl, said alkyl optionally substituted with one or more F atoms, Ci-4-alkyl-O, CN or C3-8-cycloalkyl, wherein optionally one carbon atom is replaced by an O; R² is H; X² is 0=0=0— _* A _{* *} A _* or R³ is H, halogen, CN, Ci6-alkyl, optionally substituted with one or more F atoms; A is aN-linked 7-13 membered non-aromatic bicyclic system in which the two rings are either condensed to each other or joined in a spiro system and in which if present one CH group can be optionally replaced by N and one, two three or four CH2 groups in said system are optionally replaced by NH, CO, O, S, SO, SO2, and one, two three or four positions on said ring system are optionally substituted with one or more F atoms, Ci-6-alkyl, optionally substituted with one or more F atoms, Ci-6-alkyl-0C(0)-, HO- Ci-6-alkyl- or Ci-6-alkyl-0-Ci-6-alkyl and in which optionally two of these substituents are joined to form an additional ring.

[0121] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula IX:

IX

[0122] Functional groups are as defined in W02012080457A1 as follows.

Compound IX is an 5-10 membered aromatic, heteroaromatic, nonaromatic cyclic or heterocyclic, single or condensed multiOring system, optionally substituted by 1-4 residues selected from halogen or Ci-6-alkyl, optionally substituted with one or more F atoms; is absent or methylene optionally substituted with Ci-5-alkyl, said alkyl optionally substituted with one or more F atoms, Ci-4-alkyl-0-, CN or C3-8-cycloalkyl, wherein optionally one carbon atom is replaced by an O; is H; is H, halogen, CN, Ci_6-alkyl, optionally substituted with one or more F atoms; is a N-linked 7-13 membered non-aromatic bicyclic system in which the two rings are either condensed to each other or joined in a spiro system and in which if present one CH group can be optionally replaced by N and one, two three or four CFh groups in said system are optionally replaced by NH, CO, O, S, SO, SCk, and one, two three or four positions on said ring system are optionally substituted with one or more F atoms, Ci-6-alkyl, optionally substituted with one or more F atoms, Ci-6-alkyl-0C(0)-, HO- Ci-6-alkyl or Ci-6-alkyl-0-Ci-6-alkyl- and in which optionally two of these substituents are joined to form an additional ring. [0123] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula X:

X

[0124] Functional groups are as defined in W02010091543A1 as follows. A is selected from the group consisting of:

B is selected from the group consisting of: (1) hydrogen, (2) Ci-8 alkyl, optionally substituted with 1 to 3 substituents selected from the group consisting of: (a) aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci-8 alkyl, (b) halogen, and (c) -OR^b, and (b) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci-8 alkyl, (b) halogen, and (c) -OR^b, (3) C3-8 cycloalkyl, (4) Ci-8 t \

alkoxy, of ² 'ⁿ , wherein n is 0, 1, 2, or 3, (6) aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci-8 alkyl, (b) halogen, and (c) -OR^b, and (7) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci-8 alkyl, (b) halogen, and (c) -OR^b; C is selected from the group consisting of (1) hydrogen, (2) Ci-8 alkyl, (3) C3-8 cycloalkyl, (4) Ci-8 alkoxy, (5) aryl, and (6) heteroaryl; W is selected from the group consisting of -CH2- and -NH-; X is selected from the group consisting of hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, Ci-8 alkoxy, halogen, -CN, -CF3, and -OCF3; Y is selected from the group consisting of hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, Ci-8 alkoxy, halogen, -CN, -CF3, and -OCF3; each occurrence of R¹ and R² is independently selected from the group consisting of: (1) hydrogen, (2) Ci-8 alkyl, (3) C3-8 cycloalkyl, and (4) aryl, wherein each of the Ci-8 alkyl, C3-8 cycloalkyl, and aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci-8 alkyl, halogen, and -OR^a; or R¹ or R² taken together with the nitrogen they are attached to form an unsubstituted or substituted saturated or unsaturated 4-8 membered ring, wherein the 4-8 membered ring contains 1 nitrogen and 0 to 3 additional heteroatoms selected from the group consisting of O, S and N; and each occurrence of R^a and R^b is independently selected from the group consisting of: (1) hydrogen, (2) Ci-8 alkyl, (3) aryl, and (4) heteroaryl, wherein each of the Ci-8 alkyl, aryl, and heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci-8 alkyl, halogen, hydroxy, and Ci-8 alkoxy.

[0125] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula XI:

[0126] Functional groups are as defined in W02013061002A1, W02013061004A1, and W02013061005A1 as follows. Rl represents a hydrogen atom or methyl, R2 represents a ring of four atoms selected from structures (1) and (2):

(1) (2)

in which R5 and X have the meaning given below,

R3 represents an aromatic or heteroaromatic ring selected from the group consisting of the rings of formulas (a) to (o) as follows:

wherein R7, R7a, Y and Z have the meanings given below, it being understood that the cycles (a) to (o) may optionally bear more groups R7, identical or different, the total number of such R7 groups being at most equal to the number of substitutable ring atoms; R4 represents an aromatic or heteroaromatic ring selected from the group consisting of cycles of the formulas (w) to (z) and (aa) to (ak) include:

wherein R7, R8, R9, RIO, Rl 1, R12, R13, R14 and R15 have the meanings given after, R5 represents a hydrogen atom, a fluorine atom, an alkyl radical having 1 to 5 carbon atoms or a fluorinated or perfluorinated alkyl radical having 1 to 5 carbon atoms, R6 represents a hydrogen atom, a radical or a radical -COOBn -COOtBu, R7 is a radical R16, halogen, -CF3,

-COR16, -OR16, -NR16R17, -N02, -CN, - S02R16, -S02NR16R17, -NR16COR17, - CONR16R17, -NR16C02R17 or -C02R16, R7a represents a hydrogen atom hydrogen or an alkyl radical having from 1 to 5 carbon atoms, R8 represents a hydrogen atom, a halogen atom, an -OH, -SH, - CONHOR16, -CONR160H, -NR16R17, -S03H, -OCOR16, - NHS02R16, -S02NR16R17, - NHCOR16, -CONR16R17, - NR16C02R17, - NHS02NR16R17, -C02R16, pyrrolyl, imidazolyl, triazolyl or tetrazolyl, R9, R10, Rl l and R12 are identical or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3, - OCF3, -OH, -N02, -CN , -S02R16, -S02NR16R17, -NR16COR17, -NR16C02R17, - CONR16R17, -COR16 or -C02R16, or alternatively, when two of R9, RIO, RI 1 and RI 2 are in the ortho position on an aromatic or heteroaromatic ring selected from the group consisting of cycles of the formulas (w) to (z) and (aa) to (ak) above, then they can form together with the bond that unites them, an aryl, heteroaryl, cycloalkyl or heterocycloalkyl, Rl and RI 3 4 are identical or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, -CF3, -OCF3, -OH, -SH, -CN, -S02R16 , - S02NR16R17, -NHS02NR16R17, -NR16R17, -NR16CONR16R17, - NR16COR17, - NR16C02R17, -CONR16R17, -COR16 or -C02R16, RI 5 represents a hydrogen atom, an - OH radical, -S02R16, -COR16, -C02R16 , aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, IR 6 and IR 7 are identical or different and are independently selected from the group consisting of hydrogen, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, fluorinated alkyl having 1 to 5 carbon atoms, cycloalkyl or cycloalkylalkyl a - CH2COOR18 group wherein RI 8 represents an alkyl radical having from 1 to 5 carbon atoms, or else when IR 6 and IR 7 are carried by the same nitrogen atom they form a heterocyclic ring having between 3 and 7 ring members and optionally comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen in addition to the common nitrogen atom through which they are worn, said heterocycle may be substituted by an alkyl group having 1 to 5 carbon atoms or a -COOR18 group wherein RI 8 represents an alkyl radical having 1 to 5 carbon atoms; X represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by a radical R6, Y represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by a radical RI 5 and Z represents a carbon or nitrogen atom. Representative compounds include l/2-hydroxy-N,N-dimethyl-3-(2- { [(5-methylfuran-2-yl)- (tetrahydropyran-4-yl)methyl]amino}-3,4-dioxocyclobut-l-enylamino)benzamide, 2/ 2- hydroxy-N,N-dimethyl-3-(2-{[(5-methylfuran-2-yl)-(tetrahydrothiopyran-4- yl)methyl]amino}-3,4-dioxocyclobut-l-enylamino)benzamide, 3/ tert-butyl 4-[[2-(3- dimethylcarbamoyl-2-hydroxyphenylamino)-3,4-dioxocyclobut-l-enylamino]-(5- methylfuran-2-yl)methyl] piperidine- l-carboxy late, 4/ benzyl 4-[[2-(3-dimethylcarbamoyl-2- hydroxyphenylamino)-3,4-dioxocyclobut-l-enylamino]-(5-methylfuran-2- yl)methyl]piperidine-l-carboxylate, 5/ tert-butyl 3-[[2-(3-dimethylcarbamoyl-2- hydroxyphenylamino)-3,4-dioxocyclobut-l-enylamino]-(5-methylfuran-2- yl)methyl]piperidine-l-carboxylate, and 6/ 2-hydroxy-N,N-dimethyl-3-(2-{[(5-methylfuran- 2-yl)-(4-methyltetrahydropyran-4-yl)methyl]amino}-3,4-dioxocyclobut-l- enylamino)benzamide.

[0127] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula XII:

[0128] Functional groups are as defined in W02010031835A2 as follows. Rl is selected from -H and CFb; R2 is selected from H and linear Cl-C4-alkyl; X is OH or a residue of formula NHR3 wherein R3 is selected frorn H, OH, d-Cs-alkyl, C3-C6-cycloalkyl, C2-C5-alkenyl, Ci-C5-alkoxy;_straight or branched Ci-C -alkyl, Cs-C -cycloalkyl, C2-C6- alkenyl,Ci-C6-phenylalkyl, substituted with a carboxy (COOH) group;_a residue of formula SO2R4 wherein R4 is Ci-C2-alkyl, C3-C -cycloalkyl, C1-C3- haloalkyl;_Y is a heteroatom selected from:_S, O and N; Z is a residue selected from: halogen, linear or branched C1-C4- alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Cl-C4-alkoxy, hydroxy, carboxyl, Cl-C4-acyloxy, phenoxy, cyano, nitro, amino, Cl-C4-acylamino, halo-Cl-C3 -alkyl, halo-Cl-C3-alkoxy, benzoyl, linear or branched C1-C8- alkanesulfonate, linear or branched C1-C8- alkanesulfonamides, linear or branched Cl- C8 alkyl sulfonylmethyl. and pharmaceutically acceptable salts thereof. A representative molecule of this genus is (2S)— N-[(lS)-2-amino- l-methyl-2-oxoethyl]-2-(4-{[4-(trifluoromethyl)-l,3-oxazol-2- yl]amino}phenyl)propanamide.

[0129] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist of formula XIII:

XIII

[0130] Functional groups are as defined in WO2007124424A2 are as follows. X is selected from the group consisting of halogen, Cl-3alkyl, Cl-3alkoxy, cyano, CF3, and OCF3; R2 is selected from the group consisting of C3-6 cycloalkyl, phenyl and heteroaryl, wherein the phenyl or heteroaryl moieties are optionally substituted, once or twice, independently, by a substituent selected from the group consisting of Cl-3alkyl, halogen, CF3, OCF3, phenyloxy and benzyloxy; or R2 represents phenyl substituted by

methylenedioxy or by (di-halo-substituted)- methylenedioxy; Rl represents C4-8

heterocyclyl(CH2)n, wherein the heterocyclyl moiety is optionally substituted,

independently, once or twice, by a substituent selected from the group consisting of Cl- 3alkyl, C(0)0R4 and C(0)R5; R4 and R5 are, independently, Ci_3alkyl; and n is 0 or 1 ; or Rl is selected from the following ring systems (a-k):

wherein R3 is H or Ci_3alkyl; or a pharmaceutically acceptable salt thereof. A representative antagonist from this genus is N-(4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl)-N'-(3- fluoro-2-methylphenyl)urea (GSK1325756, danirixin).

[0131] Another embodiment of the description is a method of treating a cancer patient by administering to the patient a therapeutically effective amount of a CXCR1 and/or CXCR2 receptor antagonist selected from the group consisting of HuMax-IL8 monoclonal antibody, navarixin (SCH-527123), danirixin (GSK-1325756), reparixin, AZD-5069, AZD- 8309, elubrixin (SB-656933), ladarixin, SB-225002, SB-265610, SB-332235, SCH-563705 and compounds with the following formulas:

[0132] The immunotherapy may consists of antibody directed to a ligand to a T cell receptor, wherein the immunotherapy amplifies antigen-specific T cell responses, e.g., a ligand selected from the group consisting of B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. The ligand may be selected from CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/ Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT R, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin a/TNRb, TNFR2, TNFa, LT R, lymphotoxin a1b2, FAS, FASL, RELT, DR6, TROY, and NGFR. The ligand may be selected from IL-6, IL-10, TGF-b, VEGF.

[0133] Another embodiment is a method of treating a cancer patient by

administering an immunotherapy consisting of an antibody that binds to a checkpoint inhibitor selected from the group consisting of CTLA-4, PD-l, PD-L1, PD-L2, LAG-3, TIM- 3, galectin 9, CEACAM-l, BTLA, CD69, galectin-l, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-l, and TIM-4. The immunotherapy may alternatively consist of an antibody that binds to an agonist of a protein selected from the group consisting of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2; or an antibody that binds to a ligand of a regulatory receptor on NK cells. The immunotherapy may consist of antibody G7155 or FPA-008. The immunotherapy may consists of an agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment), deplete or inhibit Tregs, or reverse/prevent T cell anergy or exhaustion, and agents that trigger innate immune activation and/or inflammation at tumor sites. The immunotherapy consists an antagonistic CTLA-4 antibody selected from ipilimumab or tremelimumab. The immunotherapy may consist of an antagonistic PD-l or PD-L1 antibody selected from the group consisting of nivolumab, pembrolizumab, lambrolizumab, MEDI-0680, pidilizumab, AMP-224, atezolizomab, MPDL3280A, durvalumab, BMS-936559, and MSB0010718C.

The immunotherapy may consist of a LAG-3 antagonist antibody selected from the group consisting of BMS-986016, IMP-731, and IMP-321. The immunotherapy may consist of a CD137 (4-IBB) antibody selected from urelumab and PF-05082566. The immunotherapy may consist of an agonistic GITR antibody selected from the group consisting of BMS- 986153, BMS-986156, TRX-518 and MK-4166. The immunotherapy may consist of an agonistic 0X40 antibody selected from the group consisting of MEDI-6383 or MEDI-6469.

[0134] Another embodiment is a method of treating a cancer patient by administering an immunotherapy consisting of an IDO and/or TDO inhibitor selected from the group consisting of indoximod, GDC-0919, F001287, GDC-0919 (NLG919), F001287, epacadostat (INCB024360), IDO-IN-l, IDO-IN-2, navoximod (IDO-IN-7), and molecules with the following structures:

[0135] Another embodiment is a method of treating a cancer patient by

administering an immunotherapy consisting of an antagonistic 0X40 antibody consisting of RG-7888; an agonistic CD40 antibody consisting of lucatumumab or dacetuzumab; an agonistic CD27 antibody consisting of varlilumab; or MGA271.

[0136] In another embodiment, the method of treating cancer in a subject in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist comprising the CXCL8 ligand blocking antibody HuMax-IL8.

Cancer Indications

[0137] In accordance with the disclosure herein, an antagonist of CXCR1 and/or CXCR2 receptors can be used to treat or prevent a proliferative condition or disorder, including a cancer, for example, cancer of the uterus, cervix, breast, prostate, testes, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestines, colon, or rectum), kidney, renal cell, bladder, bone, bone marrow, skin, head or neck, liver, gall bladder, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., gliomas), ganglia, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the lymphoid and hematopoietic system and the immune system (e.g., spleen, thymus, or bone marrow). The disclosure herein also provides methods of treating or preventing other cancer-related diseases, disorders or conditions, including, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virus-induced cancers (e.g., epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus), adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically-induced cancers, metastasis, and angiogenesis. The disclosure herein contemplates reducing tolerance to a cancer cell or cancer cell antigen, e.g., by supressing MDSC recruitment to the tumor. In particular embodiments, the tumor or cancer is pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia. The use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer, and includes, e.g., angiogenesis and precancerous conditions such as dysplasia.

Combination Therapy

[0138] The disclosure herein contemplates the use of at least one antagonist of CXCR1 and/or CXCR2 receptors in combination with one or more anticancer therapy (e.g., chemotherapeutic agents, immune checkpoint inhibitors, T-cell therapy, cancer vaccines) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents frequently have different, complementary mechanisms of action. Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents. Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition. [0139] As used herein,“combination” is meant to include therapies that can be administered separately, for example, formulated separately for separate administration (e.g., as may be provided in a kit), and therapies that can be administered together in a single formulation (i.e.. a“co-formulation”).

[0140] In certain embodiments, at least one antagonist of CXCR1 and/or CXCR2 is administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents. In other embodiments, at least one antagonist of CXCR1 and/or CXCR2 is administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e.. a co-formulation). By way of example, the disclosure herein contemplates a treatment regimen wherein administration of an antagonist to CXCR1 and/or CXCR2 receptors is maintained on a daily basis, with additional anticancer treatments (e.g., anti-PDl antibody, carboplatin, cancer vaccine, T-cell therapy, radiation) given intermittently during the treatment period. Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the disclosure herein.

[0141] The disclosure herein provides methods for treating and/or preventing a proliferative condition, cancer, tumor, or precancerous disease, disorder or condition with at least one antagonist of CXCR1 and/or CXCR2 receptors and at least one additional anticancer therapy (e.g., chemotherapeutic agents, immune checkpoint inhibitors, T-cell therapy, cancer vaccines, immunomodulatory agent) or other prophylactic or therapeutic modalities (e.g., radiation). Suitable immunomodulatory agents that may be used in the disclosure herein include CD40L, B7, and B7RP1; activating monoclonal antibodies (mAbs) to stimulatory receptors, such as, ant-CD40, anti-CD38, anti-ICOS, and 4-IBB ligand; IDO and/or TDO inhibitors; anti-chemokine ligands; dendritic cell antigen loading (in vitro or in vivo); anti-cancer vaccines such as dendritic cell cancer vaccines; cytokines/chemokines, such as, IL1, IL2, IL12, IL18, ELC/CCL19, SLC/CCL21, MCP-l, IL-4, IL-18, TNF, IL-15, MDC, IFNa/b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-lO; bacterial lipopolysaccharides (LPS); and immune-stimulatory oligonucleotides.

[0142] Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenobc acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as folinic acid;

aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil;

bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elbptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone;

mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid;

triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., pacbtaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C;

mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylomithine (DMFO); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0143] Chemotherapeutic agents also include anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as anti-estrogens, including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy comprises administration of a hormone or related hormonal agent.

[0144] Chemotherapeutic agents also include signal transduction inhibitors (STI). The term“signal transduction inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway. Signal transduction inhibitors (STIs) of the disclosure herein include: (i) bcr/abl kinase inhibitors (e.g., GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) her-2/neu receptor inhibitors (e.g., HERCEPTIN®); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidyl inositol kinase inhibitors.

[0145] Additional treatment modalities that may be used in combination with a antagonist of CXCR1 and/or CXCR2 receptors include a cytokine or cytokine antagonist, such as IL-12, IFN, or anti-epidermal growth factor receptor, radiotherapy, a monoclonal antibody against another tumor antigen, a complex of a monoclonal antibody and toxin, a T- cell adjuvant, bone marrow transplant, or antigen presenting cells (e.g., dendritic cell therapy). Vaccines (e.g., a protein or a nucleic acid encoding the protein) are also provided herein.

Immune Checkpoint Inhibitors

[0146] The disclosure herein contemplates the use of at least one antagonist of CXCR1 and/or CXCR2 receptors in combination with additional immune checkpoint inhibitors.

[0147] Genetic and epigenetic alterations that are characteristic of all cancers provide a diverse set of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. The response of T cells initiated through antigen recognition by the T-cell receptor (TCR) is regulated by a balance between co-stimulatory and inhibitory signals (immune checkpoints) that determine the ultimate amplitude (e.g., levels of cytokine production or proliferation) and quality (e.g., the type of immune response generated, such as the pattern of cytokine production) of the response. Under normal physiological conditions, immune checkpoints are crucial for the prevention of autoimmunity (i.e., the maintenance of self-tolerance) and also for the protection of tissues from damage when the immune system is responding to pathogenic infection. The expression of immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism. [0148] T cells have been the major focus of efforts to therapeutically manipulate endogenous antitumor immunity because of i) their capacity for the selective recognition of peptides derived from proteins in all cellular compartments; ii) their capacity to directly recognize and kill antigen-expressing cells (by CD8+ effector T cells; also known as cytotoxic T lymphocytes (CTLs)); and iii) their ability to orchestrate diverse immune responses by CD4+ helper T cells, which integrate adaptive and innate effector mechanisms. In the clinical setting, the blockade of immune checkpoints— which results in the

amplification of antigen-specific T cell responses— has shown to be a promising approach in human cancer therapeutics.

[0149] T cell-mediated immunity includes multiple sequential steps, each of which is regulated by counterbalancing stimulatory and inhibitory signals in order to optimize the response. While nearly all inhibitory signals in the immune response ultimately modulate intracellular signaling pathways, many are initiated through membrane receptors, the ligands of which are either membrane-bound or soluble (cytokines). While co-stimulatory and inhibitory receptors and ligands that regulate T-cell activation are frequently not over expressed in cancers relative to normal tissues, inhibitory ligands and receptors that regulate T cell effector functions in tissues are commonly overexpressed on tumor cells or on non- transformed cells associated with the tumor microenvironment. The functions of the soluble and membrane-bound receptor-ligand immune checkpoints can be modulated using agonist antibodies (for co-stimulatory pathways) or antagonist antibodies (for inhibitory pathways).

[0150] The disclosure herein contemplates the use at least one antagonist of CXCR1 and/or CXCR2 receptors in combination with inhibitors of the aforementioned immune- checkpoint receptors and ligands, as well as immune-checkpoint enzymes. Certain modulators of immune checkpoints are currently available, e.g., CTLA4 monoclonal antibody ipilimumab (YERVOY®; Bristol-Myers Squibb); fusion proteins comprising CTLA4 and an antibody (CTLA4-Ig; abatacept (ORENCIA®; Bristol-Myers Squibb)); anti-PD-l antibodies nivolumab (OPDIVO®, Bristol-Myers Squibb) and pembroluzimab (KEYTRUDA®,

Merck); anti-PDLl antibodies durvalumab (AstraZeneca/Medimmune), tremelimumab, pidilizumab, avelumab, and atezolizumab (MPDL3280A, Roche).

[0151] Inhibitors of the immune-checkpoint enzymes IDO and/or TDO include those described by Rohrig et al., and Qian et al., (Rohrig, 2015, JMed Chem, 58:9421-37 and Qian, 2016, RSC Adv, 6:7575-81).

[0152] In one aspect of the disclosure herein, at least one antagonist of CXCR1 and/or CXCR2 receptors is combined with immunotherapy that is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen- specific T cell responses. Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co- inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30,

CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT R, LIGHT, DcR3, HVEM, VEGI/TL1A,

TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin a/TNRb, TNFR2,

TNF a, LT R, lymphotoxin a1b2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0153] In another aspect, the immunotherapy is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-b, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.

[0154] In one aspect, T cell responses can be stimulated by a combination of at least one antagonist of CXCR1 and/or CXCR2 receptors and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-l, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-l, BTLA, CD69, galectin-l, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-l, and TIM-4, and/or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2. Other agents that can be combined with at least one antagonist of CXCR1 and/or CXCR2 receptors for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds herein can be combined with antagonists of KIR, such as lirilumab.

[0155] Yet other agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF1R antagonists.

Examples of CSF1R antagonists are provided in: Cannarile, 2017, J Immunother Cancer, 5, 53; WOl 1/70024; WO11/107553; WO11/131407; W013/87699; W013/119716;

WO13/132044; WOl 1/140249; W013/169264; and WO14/036357. Examples of CSF1R antagonist antibodies include, for example, emactuzumab (RG7155), cabiralizumab (FPA- 008), AMG820, IMC-CS4 (LY3022855), MCS110, SNDX-6352, and PD-0360324.

Examples of CSF1R small molecule antagonists include, for example, pexidartinib

(PLX3397, PLX108-01), PLX7486, ARRY-382, JNJ-40346527, BLZ945, and DCC-3014. Another aspect of macrophage and/or monocyte inhibition may involve blockade of CCR2 receptors. Examples of CCR2 antagonists are provided in: Zimmerman, 2014 Curr Top Med Chem, 14, 1539-52; Struthers, 2010, Curr Top Med Chem, 10, 1278-98; and Xia, 2009, Expert Opin Ther Pat, 19, 295-303. Suitable CCR2 antagonists include, for example, CCX140-B, CCX872, CCX915, MLN1202, JNJ-17166864, JNJ-27141491, MK-0812, PF- 04136309, PF-04634817, BMS-741672, INCB8696, INCB3284, INCB3344, NIBR-1282, NIBR-177, GSK-1344386B, CCR2-RA-R, RS504393, and cenicriviroc (TAK-652, TBR- 652).

[0156] In another aspect, at least one antagonist of CXCR1 and/or CXCR2 receptors can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti- CD25 bead depletion), or reverse/prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.

[0157] In one aspect, the immunotherapy is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example,

YERVOY® (ipilimumab) or tremelimumab.

[0158] In another aspect, the immunotherapy is a PD-l antagonist, such as an antagonistic PD-l antibody. Suitable PD-l antibodies include, for example, OPDIVO® (nivolumab), KEYTRUDA® (pembrolizumab/lambrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). The immunotherapy may also include pidilizumab (CT-011). Another approach to target the PD-l receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP-224.

[0159] In another aspect, the immunotherapy is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example,

TECENTRIQ™ (atezolizomab), MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (W02007/005874), and MSB0010718C (WO2013/79174). [0160] In another aspect, the immunotherapy is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO 10/19570, WO 14/08218), or IMP-731 or IMP-321 (WO08/132601, WO09/44273).

[0161] In another aspect, the immunotherapy is a CD137 (4-IBB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (W012/32433).

[0162] In another aspect, the immunotherapy is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (W006/105021, W009/009116) and MK-4166 (WOl 1/028683).

[0163] In another aspect, the immunotherapy is an 0X40 agonist, such as an agonistic 0X40 antibody. Suitable 0X40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0164] In another aspect, the immunotherapy is an OX40L antagonist, such as an antagonistic 0X40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879).

[0165] In another aspect, the immunotherapy is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immunotherapy is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, e.g., lucatumumab or dacetuzumab.

[0166] In another aspect, the immunotherapy is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, e.g., varlilumab.

[0167] In another aspect, the immunotherapy is MGA271 (to B7H3)

(WOl 1/109400).

[0168] The disclosure herein encompasses pharmaceutically acceptable salts, acids or derivatives of any of the above.

Pharmaceutical Compositions

[0169] Compounds of formula I may be in the form of compositions suitable for administration to a subject. In general, such compositions are“pharmaceutical compositions” comprising at least one compound of formula I and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients. In certain embodiments, compounds of formula I are present in a therapeutically acceptable amount. The

pharmaceutical compositions may be used in the methods of the disclosure herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic and prophylactic methods and uses described herein. [0170] The pharmaceutical compositions of the disclosure herein can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein. Furthermore, the pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds as described herein in order to treat or prevent the diseases, disorders and conditions as contemplated by the disclosure herein.

[0171] The pharmaceutical compositions containing the active ingredient ( e.g compound of formula I) may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable

preparations. Tablets, capsules and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.

[0172] The pharmaceutical compositions containing the active ingredient (e.g., compound of formula I) may be prepared by spray dry co-dispersion with a suitable polymer, such as hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP), ENCAPSIA®, EUDRAGIT® Ll 00-55, OPADRY®, and DEXOLVE®.

[0173] The tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polygly colic acid, ethylene-vinylacetate, methylcellulose,

carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers in order to control delivery of an administered composition. For example, the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethylcellulose or gelatin-microcapsules or poly(methylmethacrolate) microcapsules, respectively, or in a colloid drug delivery system. Colloidal dispersion systems include macromolecule complexes, nano-capsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for the preparation of the above-mentioned formulations will be apparent to those skilled in the art.

[0174] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Liquid form preparations may also include dissolution in lipid- based, self-emulsifying drug delivery systems (SEDDS) such as LABRASOL® or

GELUCIRE® for oral administration.

[0175] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture thereof. Such excipients can be suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example, a naturally-occurring phosphatide ( e.g ., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g.,

polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., for heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g.,

polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives.

[0176] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. [0177] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein..

[0178] The pharmaceutical compositions of the disclosure herein may include techniques to improve the solubility of the active ingredient to increase oral bioavailability. These techniques include, but are not limited to: physical modification of the active ingredient through particle size reduction through either comminution and spray drying, or micronization through milling techniques; solid dispersion techniques such as hot melt fusion, solvent evaporation method, and hot melt extrusion; preparation of a nanosuspension of the active ingredient through either the precipitation technique, media milling, high- pressure homogenization in water, high pressure homogenization in nonaqueous media, or combinations of techniques thereof; preparation of micronized drug particles via supercritical fluid processes; preparation of nanostructured amorphous drug particles through spray freezing onto cryogenic fluids, spray freezing into cryogenic liquids, spray freezing into vapor over liquid, and ultra-rapid freezing; preparation of an inclusion complex with cyclodextrins via kneading, lyophilization, or microwave irradiation techniques; and micellular solubilization of the active ingredient using surfactants. These methods are described in greater detail in Savjani, 2012, ISRN Pharm, 2012: 195727.

[0179] The pharmaceutical compositions of the disclosure herein may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example,

polyoxyethylene sorbitan monooleate.

[0180] The pharmaceutical compositions of the disclosure herein may also be in the form useful for direct introduction to the lungs via aerosol delivery. An aerosol formulation of the disclosure herein also comprises a propellant. Suitable propellants include conventional chlorofluorocarbon (CFC) propellants such as mixtures of propellants 11, 12, and 114. Non-CFC propellants, particularly l,l,l,2-tetrafluoroethane (Propellant l34a), l,l,l,2,3,3,3-heptafluoropropane (Propellant 227), or mixtures thereof, are preferred. The propellant is preferably present in an amount sufficient to propel a plurality of doses of drug from an aerosol canister. Further components, such as conventional lubricants or surfactants, cosolvents (e.g., ethanol), and the like, can also be present in an aerosol formulation of the disclosure herein in suitable amounts readily determined by those skilled in the art.

[0181] The pharmaceutical compositions of the disclosure herein may also be in the form useful for direct introduction to the lungs via dry powder inhalation delivery. A dry powder formulation of the disclosure herein would comprise the active ingredient (e.g., antagonist of CXCR1 and/or CXCR2 receptors) formulated with a carrier compatible with pulmonary delivery. Selecting an excipient as a carrier is an important factor in the composition of an inhalation formulation. Examples of the excipient employable for the disclosure herein include monosaccharides such as glucose, arabinose; disaccharides such as lactose, maltose, sucrose; polysaccharides such as starch, dextrin or dextran; polyalcohols such as sorbitol, mannitol, and xylitol; and hydrates thereof.

[0182] Formulations can also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including implants, liposomes, hydrogels, prodrugs and microencapsulated delivery systems. For example, a time delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed.

[0183] The pharmaceutical compositions typically comprise a therapeutically effective amount of at least one antagonist of CXCR1 and/or CXCR2 receptors and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants. For example, a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, a TRIS buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N- tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0184] After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready -to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector (e.g.,

EPIPEN®)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments. Any drug delivery apparatus may be used to deliver compounds of formula I, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the skilled artisan. Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to release the polypeptides disclosed herein over a defined period of time. Depot injections are usually either solid- or oil-based and generally comprise at least one of the formulation components set forth herein. One of ordinary skill in the art is familiar with possible formulations and uses of depot injections.

[0185] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butane diol. Acceptable diluents, solvents and dispersion media that may be employed include water, Ringer's solution, isotonic sodium chloride solution,

CREMOPHOR® EL (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. Moreover, fatty acids such as oleic acid, find use in the preparation of an injectable formulation. Prolonged absorption of particular injectable formulations can be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin). [0186] The disclosure herein contemplates the administration of compounds of formula I in the form of suppositories for rectal administration. The suppositories can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycols.

Routes of Administration

[0187] The disclosure herein contemplates the administration of compounds of formula I, and compositions thereof, in any appropriate manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracistemal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), sublingual and inhalation. Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compounds of formula I or formula II disclosed herein over a defined period of time.

Dosing

[0188] Compounds of formula I may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen may also take into

consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered. Effective dosage amounts and dosage regimens can readily be determined from, for example, safety and dose-escalation trials, in vivo studies (e.g., animal models), and other methods known to the skilled artisan.

[0189] In general, dosing parameters dictate that the dosage amount be less than an amount that could be irreversibly toxic to the subject (the maximum tolerated dose (MTD)) and not less than an amount required to produce a measurable effect on the subject. Such amounts are determined by, for example, the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into consideration the route of administration and other factors.

[0190] An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it. The“median effective dose” or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although the ED50 is commonly used as a measure of reasonable expectance of an agent's effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors. Thus, in some situations the effective amount is more than the calculated ED50, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED50.

[0191] For administration of an oral agent, the compositions can be provided in the form of tablets, capsules and the like containing from 1.0 to 1000 milligrams (mg) of the active ingredient, particularly 1.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient.

[0192] In certain embodiments, the dosage of the desired antagonist of CXCR1 and/or CXCR2 is contained in a“unit dosage form”. The phrase“unit dosage form” refers to physically discrete units, each unit containing a predetermined amount of at least one antagonist of CXCR1 and/or CXCR2, either alone or in combination with one or more additional agents, sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved.

[0193] The actual dosage employed may be varied depending upon the

requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required.

[0194] The amount and frequency of administration of the compounds of the disclosure herein and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.

[0195] The amount and frequency of administration of the compounds of formula I and the chemotherapeutic agents, immunotherapy, and/or radiation therapy will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the disease being treated. A dosage regimen of the antagonist of CXCR1 and/or CXCR2 can be oral administration of from 10 mg to 2000 mg/day, or 10 to 1000 mg/day, or 50 to 600 mg/day, in two to four (or two) divided doses, to block tumor growth. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.

[0196] The chemotherapeutic agent, immunotherapy, and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent,

immunotherapy and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent, immunotherapy, and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e.. chemotherapy, immunotherapy, or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.

[0197] If the antagonist of CXCR1 and/or CXCR2, and the chemotherapeutic agent, immunotherapy, and/or radiation is not administered simultaneously or essentially simultaneously, then the initial order of administration of the antagonist of CXCR1 and/or CXCR2, and the chemotherapeutic agent and/or radiation, may not be important. Thus, the antagonist of CXCR1 and/or CXCR2 may be administered first, followed by the

administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first, followed by the administration of the antagonist of CXCR1 and/or CXCR2. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.

[0198] For example, the chemotherapeutic agent, immunotherapy, and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of the antagonist of CXCR1 and/or CXCR2 followed, where determined advantageous, by the administration of the chemotherapeutic agent, immunotherapy, and/or radiation, and so on until the treatment protocol is complete.

[0199] By way of example, the disclosure herein contemplates a treatment regimen wherein administration of an antagonist to CXCR1 and/or CXCR2 receptors is maintained on a daily basis, with additional anticancer treatments (e.g., anti-PDl antibody, carboplatin, T- cell therapy, cancer vaccination, radiation) given intermittently during the treatment period.

[0200] The particular choice of a compound from formula I, and chemotherapeutic agent, immunotherapy, and/or radiation will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.

[0201] Also, in general, the antagonist of CXCR1 and/or CXCR2 and the chemotherapeutic agent and/or immunotherapy do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. For example, the antagonist of CXCR1 and/or CXCR2 may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent and/or immunotherapy may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0202] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a component (therapeutic agent; /. e.. the compound from formula I, chemotherapeutic agent, immunotherapy or radiation) of the treatment according to the individual patient's needs, as the treatment proceeds.

[0203] The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.

Examples

[0204] Aspects of the present teachings may be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way. [0205] While the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments.

On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.

Formulation Example 1: Spray Dry Dispersion (SDD) of SX-682 onto Hypromellose

Phthalate (HPMCP)

[0206] An alternative method to increase oral bioavailability of drug products is through spray dry dispersion in a polymer carrier matrix, which utilizes the spray drying of the active pharmaceutical ingredient (API) and polymer in an organic solvent. Upon drying, the API is amorphously dispersed in the polymer matrix. The polymer matrix is water soluble, and allows for the slow release of API upon exposure to aqueous environments.

Spray dry dispersion was performed at Emerson Resources (Norristown, PA). SX-682 (250 g) was first dissolved in acetone/water (97:3, 10 liters). HPMCP, 750 g, was then added.

The in-process control is to check the clarity of the feed solution and report the result. The material is then spray dried using a GEA Mobile Minor spray dryer using nitrogen as the drying gas. The inlet temperature is set at 90°C, and the outlet temperature is 55-60°C. The nozzle size used was 1 mm. The SX-682 spray solution concentration is 10%, and the atomization nitrogen was set at 1.8 bar, 50%. The formulated powder is collected from both the cyclone and the cartridge filter and post-dried. The powder is bag-blended and double bagged with dessicant pouches for storage. The spray-dried dispersion was suspended in aqueous 0.5% methylcellulose (400 cps) prior to oral dosing in preclinical models.

Pharmacology Example 1: Inhibition of MDSC Migration

[0207] A large body of evidence indicates that chronic inflammation as occurs in inflammatory bowel disease is one of several key risk factors for cancer initiation, progression, and metastasis. In an azoxymethane/dextran sulfate sodium (AOM/DSS) model of colitis-associated cancer, Katoh, 2013, Cancer Cell, 24:631-44, presented genetic evidence (Cxcr2 ^/_) that loss of CXCR2 dramatically suppressed chronic colonic inflammation and colitis-associated tumorigenesis by inhibiting MDSC recruitment into colonic mucosa and tumors. CXCR2 ligands CXCL1, CXCL2 and CXCL5 were all elevated in inflamed colonic mucosa and tumors and induced MDSC chemotaxis. Adoptive transfer of wild-type MDSCs into Cxcr2^_/ mice restored AOM/DSS -induced tumor progression. Deletion of Cxcr2 did not affect infiltration of dendritic cells, T cells, NK or NKT cells. Deletion of Cxcr2 significantly decreased the migratory ability of MDSCs in vitro and in vivo. MDSCs accelerated tumor growth by inhibiting CD8+ T cell cytotoxic activity. Their results showed that CXCR2 was required for homing of MDSCs into colonic mucosa and colitis-associated tumors, revealing a role of CXCR2 in the recruitment of MDSCs from the circulatory system to local tissues and tumors. The results from adoptive transfer of MDSCs provide direct evidence that MDSCs contribute to colonic tumor formation and growth by inhibiting CD8+ T cell cytotoxicity against tumor cells. The authors conclude,“our findings provide a rationale for the development of therapeutic approaches to subvert ... tumor-induced immunosuppression by using CXCR2 antagonists...”

[0208] Antagonist SX-682 was used to validate the concept of using a small molecule antagonist of CXCR1 and CXCR2 receptors to block MDSC migration. Using the of method of Katoh, 2013, Cancer Cell, 24:631-44, to induce and isolate MDSCs, male BALBc mice were given a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg). Seven days later, these mice were given 4 cycles of water and water containing 1.25% dextran sulfate sodium (DSS). One cycle consisted of providing mice with regular drinking water for 7 days, followed by 1.25% aqueous DSS for 7 days, followed by regular drinking water for 7 days. MDSCs were isolated from femurs and blood of AOM/DSS- treated BALBc mice using the Myeloid-Derived Suppressor Cell Isolation Kit (Miltenyi Biotec) after lysis of red blood cells (RBC) according to the manufacturer’s instructions. GROa (CXCL1) was placed in the bottom chamber of a 24-well plate at a concentration of 100 ng/ml. MDSCs isolated from blood of AOM/DSS -treated BALBc mice were seeded at a density of 1 x lOVwell in the upper chamber (3 pm, BD Falcon). After incubation for 12 hours, migrated cells were quantified by flow cytometry using CountBright Absolute Counting Beads (Molecular Probes). To evaluate the effect of SX-682 on GROa-mediated MDSC migration, aqueous DMSO solutions of SX-682 were added to the MDSC-seeded wells prior to migration. The test concentrations of SX-682 were 0.1, 1 and 10 pM, and the DMSO concentration was < 1%. The results showed that SX-682 was able to effectively inhibit GROa-mediated MDSC migration in a dose-dependent manner (FIG. 2).

Pharmacology Example 2: Inhibition of Tumor Cell Proliferation by SX-682 in a

Dose-Dependent Manner

[0209] The chemokine CXCL8 and its receptors CXCR1 and CXCR2 have been identified as important mediators of cellular proliferation for a number of tumor cell types.

To validate the relationship between CXCR1 and CXCR2 receptor antagonism and inhibition of tumor cell proliferation, SX-682 was evaluated against the 60 human tumor cell line panel at five concentration levels (0.01, 0.1, 1, 10, 100 pM) as performed by the Developmental Therapeutics Program at the National Cancer Institute (Shoemaker, 2006, Nat Rev Cancer, 6:813-23).

[0210] The human tumor cell lines of the cancer screening panel were grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. Cells were inoculated into 96 well microtiter plates in 100 pL at plating densities ranging from 5,000 to 40,000 cells/well depending on the doubling time of individual cell lines. After cell inoculation, the microtiter plates were incubated at 37°C, 5% CC , 95% air and 100% relative humidity for 24 h prior to addition of SX-682.

[0211] After 24 h, two plates of each cell line are fixed in situ with TCA, to represent a measurement of the cell population for each cell line at the time of drug addition (Tz). SX-682 was solubilized in dimethyl sulfoxide at 400-fold the desired final maximum test concentration and stored frozen prior to use. At the time of SX-682 addition, an aliquot of frozen concentrate was thawed and diluted to twice the desired final maximum test concentration with complete medium containing 50 pg/ml gentamicin. Additional four, 10- fold or ½ log serial dilutions are made to provide a total of five drug concentrations plus control. Aliquots of 100 pl of these different drug dilutions were added to the appropriate microtiter wells already containing 100 pl of medium, resulting in the required final drug concentrations.

[0212] Following drug addition, the plates were incubated for an additional 48 h at 37°C, 5% CCh, 95% air, and 100 % relative humidity. For adherent cells, the assay was terminated by the addition of cold TCA. Cells were fixed in situ by the gentle addition of 50 pl of cold 50% (w/v) TCA (final concentration, 10% TCA) and incubated for 60 minutes at 4°C. The supernatant was discarded, and the plates were washed five times with tap water and air dried. Sulforhodamine B (SRB) solution (100 pl) at 0.4% (w/v) in 1% acetic acid was added to each well, and plates were incubated for 10 minutes at room temperature. After staining, unbound dye was removed by washing five times with 1% acetic acid and the plates were air dried. Bound stain was subsequently solubilized with 10 mM TRIS, and the absorbance was read on an automated plate reader at a wavelength of 515 nm. For suspension cells, the methodology is the same except that the assay was terminated by fixing settled cells at the bottom of the wells by gently adding 50 pl of 80% TCA (final

concentration, 16% TCA). Using the seven absorbance measurements (time zero, (Tz), control growth, (C), and test growth in the presence of drug at the five concentration levels (Ti)), the percentage growth was calculated at each of the drug concentrations levels.

Percentage growth inhibition was calculated as: (Ti-Tz)/(C-Tz) x 100 for concentrations for which Ti>/=Tz

(Ti-Tz)/Tz x 100 for concentrations for which Ti<Tz.

[0213] Three dose response parameters were calculated for each experimental agent. Growth inhibition of 50% (GI50) is calculated from [(Ti-Tz)/(C-Tz)] x 100 = 50, which was the drug concentration resulting in a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug incubation. The drug

concentration resulting in total growth inhibition (TGI) is calculated from Ti = Tz. The LC50 (concentration of drug resulting in a 50% reduction in the measured protein at the end of the drug treatment as compared to that at the beginning) indicating a net loss of cells following treatment is calculated from (Ti-Tz)/Tz x 100 = -50. Values are calculated for each of these three parameters if the level of activity is reached; however, if the effect is not reached or is exceeded, the value for that parameter is expressed as greater or less than the maximum or minimum concentration tested.

[0214] The results (FIG. 3A - FIG. 31) validated the ability of SX-682 to directly affect the proliferation of human tumor cells in the absence of other cells (e.g, MDSCs) through CXCR1/2 antagonism.

Pharmacology Example 3A: Efficacy of CXCR1/2 Antagonism as Single Therapy and in Combination with Carboplatin in the Til Mouse Model of Breast Cancer

[0215] The Tl 1 model is a validated mouse model of breast cancer, which derives from the serial orthotopic transplantation of a murine breast tumor derived from a p53-null mouse into a syngeneic p53 competent recipient, and features sporadic, somatic K-Ras mutation (Herschkowitz, 2012, Proc Natl Acad Sci, 109:2778-83. Tumors from the Tl l model display an RNA expression pattern characteristic of the human claudin-low disease, and are extremely aggressive, with the majority of untreated animals surviving less than 21 days from the time of enrollment in the therapy studies. Treatment regimens were started following tumor manifestation. SX-682 was given orally via medicated feed, at an approximate dose of 10 mg/day/mouse. In brief, the medicated feed was prepared by Research Diets (New Brunswick, NJ) by incorporating 15.2 grams of SX-682 spray dried dispersion (as prepared in Formulation Example 1) into 1042 grams of standard rodent diet with 10% kcals from fat. The medicated feed was formed into pellets. Carboplatin (CP) was administered once weekly via intraperitoneal injection at a dose of 50 mg/kg. The results (FIG. 4) showed the addition of SX-682 to carboplatin significantly reduced tumor growth (N=7 each cohort). The combination of SX-682 and CP resulted in a synergistic inhibition of tumor growth and progression in treatment animals, which is a surprising and unexpected result. Mean ± SE. *** P<0.0001 (linear regression).

Pharmacology Example 3B: Efficacy of CXCR1/2 Antagonism as Single Therapy and in Combination with Carboplatin in the C3Tag Mouse Model of Breast Cancer

[0216] The C3\-T-antigen (C3Tag) mouse model is a validated model of human triple-negative basal cell breast cancer as shown by gene expression analysis (Maroulakou, 1994, Proc Natl Acad Sci, 91: 11236-40). The expressed large T-antigen binds and inactivates the RB and p53 tumor suppressor genes, explaining why this model faithfully recapitulates human basal breast cancer, which also harbors RB and p53 inactivation. This model also has frequent K-Ras amplification and infrequent Ras mutations. Treatment regimens were started following tumor manifestation. SX-682 was given orally via medicated feed, at an approximate dose of 10 mg/day/mouse. Carboplatin (CP) was administered once weekly via intraperitoneal injection at a dose of 50 mg/kg. The results (FIGS. 5 and 6) showed SX-682 treatment alone and in combination with carboplatin significantly reduced tumor growth as compared to untreated controls (N=l0 - 12 per cohort). Mean ± SE. ** P<0.00l (linear regression). Median survival for vehicle, carboplatin and SX-682 cohorts was 18, 28 and 28 days. Combining SX-682 with CP significantly increased survival compared to carboplatin alone (P=0.008), giving a median survival well beyond 60 days. The combination of SX-682 and CP resulted in a synergistic extension of survival in treatment animals, which is a surprising and unexpected result.

Pharmacology Example 3C: Efficacy of CXCR1/2 Antagonism as Single Therapy and in Combination with Carboplatin in the TRIA Mouse Model of Melanoma

[0217] The Tyrosine-Hras/Ink/Arf null (TRIA) is a validated mouse model of melanoma features an immuno-competent autochthonous tumor; Ras events are in >70% of all melanomas, and -50% lose the INK4a/ARF locus which, with B-RAF mutations, is the most common lesion of this cancer (Sharpless, 2016, Cancer Cell 29:832-45). Treatment regimens were started following tumor manifestation. SX-682 was given orally via medicated feed, at an approximate dose of 10 mg/day/mouse. Carboplatin (CP) was administered once weekly via intraperitoneal injection at a dose of 50 mg/kg. The results of this experiment can be seen in FIGS. 7 and 8. SX-682 treatment alone significantly slowed tumor growth comparable to CP alone. SX-682 combination therapy did better than monotherapy and achieved complete remission (zero tumor volume) in 5 of 11 animals. The combination of SX-682 and CP resulted in a synergistic inhibition of tumor growth and progression in treatment animals, which is a surprising and unexpected result. Pharmacology Example 3D: Efficacy of CXCR1/2 Antagonism as Single Therapy and in Combination with Temozolomide in a Mouse Model of Glioblastoma

Multiforme

[0218] Mouse glioma cell line GL26lis frequently used in experimental models of glioblastoma to evaluate various experimental modalities. Szatmari, 2006, Cancer Sci 97:546-55. To test the hypothesis that dual CXCR1/2 antagonism may potentiate anti-tumor effects of chemotherapy in a mouse model of glioblastoma, tumor-bearing C57BL/6 mice are dosed with CXCR1/2 antagonist alone and in combination with temozolomide (TMZ).

Mouse syngeneic tumor GL261 cells are grown with Dulbecco modified Eagle medium supplemented with 10% fetal bovine serum as well as streptomycin (100 mg/mL) and penicillin (100 U/mL) at 37°C in a humidified atmosphere of 95% air/5% CO2. Mouse glioma GL261 cells are cultured, harvested, and injected into the lower right flank of each C57BL/6 mouse. For the subcutaneous model, 10⁶ GL261 cells are injected into the lower right flank of each C57BL/6 mouse. TMZ is dosed via intraperitoneal injection according to body weight (20 mg/kg). CXCR1/2 antagonist is dosed via oral administration daily. At the beginning of treatment, mice are either randomized by tumor volume or by body weight. The number of animals per group range from between 10-12 animals per group as determined based on Good Statistical Practice analysis. Both tumor and body weight measurements are collected twice weekly and tumor volume is calculated using the equation (L x W²)/2, where L and W refer to the length and width dimensions, respectively. Error bars are calculated as standard error of the mean. The general health of mice is monitored daily and all experiments are conducted in accordance to AAALAC and institution-based IACUC guidelines for humane treatment and care of laboratory animals. Kaplan-Meier statistical analysis is performed using the Log-rank test using GraphPad Prism.

Pharmacology Example 4A: Efficacy of CXCR1/2 Antagonism as Single Therapy and in Combination with anti-PDl Antibody in the B16-F10 Syngeneic Mouse Model of Melanoma

[0219] The B16-F10 mouse model is a validated model of melanoma, Overwijk, 2001, Curr Protoc Immunol, Chapter 20: Units 20-21. It was used to evaluate the effect of SX-682 alone and in combination with anti-PDl antibody. B16-F10 mouse melanoma cells were cultured, then mice were injected with 0.5 x 10⁶ B16-F10 cells on day 0, and treatment was initiated on day 18. Mice were treated with vehicle (control), SX-682 alone (50 mg/kg twice daily, oral), anti-PD-l alone (100 pg twice weekly, ip), or SX-682 in combination with anti-PD-l (N=4-5 per cohort). SX-682 was used as a spray dried dispersion (Formulation Example 1), and was administered to mice via oral gavage as a suspension in 0.5% aq methylcellulose. The results (FIG. 9) showed SX-682 monotherapy significantly slowed tumor growth (P=0.0002, linear regression) and potently synergized with anti-PDl therapy with the combination significantly better than either therapy alone (P<0.0005 for both comparisons). Data and error bars are the mean ± SE. The combination of SX-682 and immune checkpoint inhibition resulted in a synergistic inhibition of tumor growth and progression in treatment animals, which is a surprising and unexpected result.

Pharmacology Example 4B: Efficacy of CXCR1/2 Antagonism as Single Therapy and in Combination with Anti-PDl Antibody in the LLC Syngeneic Mouse Model of Lung Cancer

[0220] The Lewis lung carcinoma (LLC) mouse model (Kellar, 2015, Biomed Res Int, 2015:621324) was used to evaluate the effect of SX-682 alone and in combination with anti-PD-l antibody. LLC mouse melanoma cells were cultured, then mice were injected with 0.5 x 10⁶ LLC cells on day 0, and on day 18 treatment was initiated. Mice were treated with vehicle (control), SX-682 alone (50 mg/kg twice daily, oral), anti-PD-l alone (100 pg twice weekly, ip), or SX-682 in combination with anti-PD-l (N=5 per cohort). SX-682 was used as a spray dried dispersion (Formulation Example 1), and was administered to mice via oral gavage as a suspension in 0.5% aq. methylcellulose. The results of this experiment can be seen in FIG. 10 and FIG. 11. SX-682 monotherapy significantly slowed tumor growth (P=0.0076, linear regression), and potently synergized with anti-PDl therapy with the combination significantly better than either therapy alone (P<0.000l for both comparisons). The combination of SX-682 and anti-PD-l therapy significantly enhanced survival compared to vehicle or anti-PD-l therapy alone (P=0.002). The combination of SX-682 and immune checkpoint inhibition resulted in a synergistic effect on both tumor growth and survival in treatment animals, which is a surprising and unexpected result.

Pharmacology Example 4C: Efficacy of CXCR1/2 Antagonism as Single Therapy and in Combination with Anti-PDl and Anti-CTLA4 Antibody in a Mouse Model of Castration Resistance Prostate Cancer

[0221] The genetically engineered Pten^{pc /}p53^{pc /}Smad4^{pc /} mouse is a prostate- specific PB promoter-driven ( PB-Cre4 ) conditional triple knockout model (i.e.. prostate- specific deletion of all three tumor suppressors, Pten,p53 and Smad4 occurs in the‘prostate cancer’ or‘pc’). It exhibits an aggressive tumor phenotype, and like the human disease, develops spontaneous bone metastases (Ding, 2012, Cell , 148:896-907) Pten^pc~ p53^pc~ Smad4P^c~ mice at 3-4 months of age with established tumors (> 150 mm³, as measured by MRI) were treated with either vehicle (control), SX-682 (50 mg/kg b.i.d.), ICB (200 pg each of anti-PDl and anti-CTLA4 antibodies, 3x/week), or the SX-682 and ICB combination (SX- 682 + ICB). SX-682 was used as a spray dried dispersion (Formulation Example 1), and was administered to mice via oral gavage as a suspension in 0.5% aq. methylcellulose. Treatment was continued for 4-6 weeks and prostate weights measured to determine tumor burden. The results (FIG. 12) showed SX-682 plus ICB was significantly better than control or either treatment alone (unpaired t-test). Mean + SE. The combination of SX-682 and immune checkpoint inhibition resulted in a synergistic inhibition of tumor growth and progression in treatment animals, which is a surprising and unexpected result.

Pharmacology Example 5A: Cell-kill Efficacy of CXCR1/2 Antagonism as Single Therapy and in Combination with T-cell Therapy In Vitro

[0222] To validate the use of a small molecule CXCR1/2 antagonist to halt the EMT process in tumor cells thereby decreasing immunoresistance, human tumor cells will be exposed in vitro to various doses of SX-682 in the presence of immune effector cells. These studies will be conducted with and without addition of exogenous recombinant IL-8. Tumor cells will be subsequently evaluated for proliferation/survival, expression of

epithelial/mesenchymal markers and sternness markers, expression of immune-relevant molecules, and cytotoxic response to various immune effector cells (human antigen-specific T cell lines generated from the blood of cancer patients or healthy donors by using peptide epitopes from the following antigens: CEA, MUC1, brachyury, or natural killer cells isolated from blood of normal donors and left untreated or activated via IL-2)

Pharmacology Example 5B: Efficacy of CXCR1/2 Antagonism as Single Therapy and in Combination with T-Cell Therapy in a Mouse Model of Pancreatic Cancer

[0223] Although bom with histologically normal pancreata, K-ras^{LSL G12D/+};

p53^R172H/+; PdxCre (KPC) mice developed pancreatic intraepithelial neoplasia (PanIN) lesions on an accelerated schedule, and died of pancreatic ductal adenocarcinoma (PD AC) with a median survival of 5.5 months. Metastases were observed -80% of the animals, at the same sites seen in human PDAC patients (liver, lung, and peritoneum). Tumors arising in this model were found to have many of the immunohistochemical markers associated with human disease, and bore evidence of widespread genomic alterations, a feature that was previously lacking in most genetically engineered mouse models. The KPC mouse model of PDAC is widely used to evaluate treatment modalities in a preclinical setting (Westphalen, 2012, Cancer J, 18:502-10). To test the hypothesis that dual CXCR1/2 antagonism may potentiate anti -tumor effects of T-cell therapy in a mouse model of PD AC, tumor-bearing KPC mice are dosed with SX-682 alone and in combination with T-cell therapy. T-cells are either selected for or engineered towards high affinity binding to a specific protein of interest located on the tumor cell. In the case of PDAC, these proteins of interest may include (but are not limited to) mesothelin, Wilms’ tumor antigen, Mucin 1, or Annexin A2. KPC mice will undergo serial high-resolution ultrasound imaging (Vevo 2100) at 8 weeks of age to monitor autochthonous tumor development. Mice are enrolled based on defined pancreatic mass 3-6 mm. At the start of treatment, select cohorts will receive CXCR1/2 antagonist via oral administration daily. For animals undergoing T-cell therapy, they will receive cyclophosphamide once at enrollment (180 mg/kg) followed 6 hours later by intravenous infusion of lxlO⁷ twice-stimulated engineered T cells followed by lxlO⁷ peptide-pulsed irradiated splenocytes. Recipient mice will also receive IL-2 (2x104 IU, i.p.) every other day for 8 days (in timepoint studies) or for 5 days (in survival studies) to promote donor T cell survival and expansion. For serial T cell infusions, mice will receive the same treatment protocol, excluding the cyclophosphamide after the first dose, every 2 weeks. Power analyses will guide enrollment numbers to power the study for a large effect (>50% increase in median overall survival). Both tumor and body weight measurements are collected twice weekly and tumor volume is measured via serial high resolution ultrasound imaging. Error bars are calculated as standard error of the mean. The general health of mice is monitored daily and all experiments are conducted in accordance to AAALAC and institution-based IACUC guidelines for humane treatment and care of laboratory animals. Kaplan-Meier statistical analysis is performed using the Log-rank test using GraphPad Prism.

Pharmacology Example 6: Efficacy of CXCR1/2 Antagonism as Single Therapy and in Combination with Cancer Vaccine in a Mouse Model of Cancer

[0224] All animal studies re carried out in accordance with the guidelines of the Association for Assessment and Accreditation of Laboratory Animal Care. Experimental studies were carried out under approval of the NIH Intramural Animal Care and Use Committee. Murine colon carcinoma MC38 cells are stably transfected with

chorioembryonic antigen (CEA), and subcutaneously implanted into female C57BL/6 mice on day 0. Beginning on day 7, animals are dosed daily with SX-682 via medicated feed. Beginning on day 14, test animals are vaccinated weekly with either Hank's Balanced Salt Solution or 50 mg of a gp70 peptide (pl5e) emulsified in Montanide ISA-51-VG (Seppic) at a 1 : 1 ratio. Evaluation of the effect of SX-682 on various immune cell subsets in non-tumor bearing mice will be evaluated.. Spleens will be collected and analyzed for antigen-specific immune responses and various immune cell subsets. Anti-tumor effect of combinations of SX-682 with cancer vaccines will be evaluated. Evaluations will include effect on tumor volume, tumor microenvironment, including tumor phenotype, etc., will be evaluated. Vaccine-specific immune responses will also be measured.

Claims

We claim:

1. A method of treating cancer in a patient in need of such treatment, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I

wherein R⁶ is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl,

heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

wherein n is an integer between 0 and 8;

or a pharmaceutically suitable solvate or salt thereof.

2. The method of claim 1, wherein pharmaceutical composition comprises a therapeutically effective amount of a compound selected from formulas SX-517, SX-520, SX-557, SX-574, SX-577, SX-603, SX-622, SX-660, SX-662, SX-671, SX-677, SX-678, and SX-682

3. The method of claim 1, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of formula SX-682.

4. The method according to any one of claims 1-2, further comprising assaying serum levels of CXCR1 and/or CXCR2 ligands in the patient.

5. The method according to any one of claims 1-4, further comprising first assaying serum levels of myeloid derived suppressor cells (MDSCs) and/or neutrophils in the patient.

6. The method according to any one of claims 1-5, further comprising administering an anticancer therapy.

7. The method of claim 6, wherein the anticancer therapy is a chemotherapy.

8. The method of claim 7, wherein carboplatin is administered to the patient.

9. The method of claim 6, wherein said anticancer therapy is an immunotherapy.

10. The method of claim 9, wherein the immunotherapy is selected from monoclonal antibodies, immune checkpoint inhibitors, and cellular therapy.

11. The method of claim 9 wherein said immunotherapy is an immune checkpoint inhibitors.

12. The method of claim 9 wherein immune checkpoint inhibitors are selected from ipilimumab, abatacept, nivolumab, pembrolizumab, tremelimumab, pidilizumab, atezolizumab, durvalumab, and avelumab.

13. The method of claim 7 wherein said anticancer therapy is selected from chemotherapeutic agents.

14. The method of claim 6 wherein said anticancer therapy is radiation therapy.

15. The method of claim 10 wherein said anticancer therapy is T-cell therapy.

16. The method of claim 10, wherein said anti cancer therapy is the use of cancer vaccines.

17. The method according to any one of claims 1-16, wherein the cancer is selected from cancers of the prostate, colorectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin, mesothelial lining, blood, esophagus, breast, muscle, connective tissue, lung, adrenal gland, thyroid, kidney, lymphoid tissue, bone marrow or bone, glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, and testicular seminoma.

18. The method according to any one of claims 1-16, wherein the cancer is selected from cancers of the prostate, pancreas, stomach, brain, liver, head, neck, skin, blood, breast, lung, glioblastoma, and mesothelioma.

19. The method according to any one of claims 1-16, wherein the cancer is breast cancer.

20. The method of claim 19, wherein the pharmaceutical composition is administered orally.

21. The method of claim 19, further comprising administering a platinum chemotherapy.

22. The method of claim 1, wherein the cancer is a melanoma.

23. The method of claim 22, wherein the pharmaceutical composition is administered orally.

24. The method of claim 22, further comprising administering a platinum chemotherapy.

25. The method of claim 22, further comprising administering an anti-PD-l antibody.

26. The method according to any one of claims 1-16, wherein the cancer is a lung cancer.

27. The method of claim 26, wherein the pharmaceutical composition is administered orally.

28. The method of claim 26, further comprising administering an anti-PD-l antibody.

29. The method according to any one of claims 1-16, wherein the cancer is a prostate cancer.

30. The method of claim 29, wherein the pharmaceutical composition is administered orally.

31. The method of claim 30, further comprising administering an anti-PD-l antibody or an-CTL4 antibody.

32. The method according to any one of claims 1-16, wherein the cancer is a glioblastoma.

33. The method of claim 32, wherein the pharmaceutical composition is administered orally.

34. The method of claim 33, further comprising administering temozolomide.

35. The method according to any one of claims 1-16, wherein the cancer is a pancreatic cancer.

36. The method of claim 35, wherein the pharmaceutical composition is administered orally.

37. The method of claim 36, further comprising administering T cell therapy with T cells stimulated with tumor antigen.

38. The method according to any one of claims 1-16, further comprising administering to the patient a therapeutically effective amount of a CXCR1 and/or CXCR2 receptor antagonist selected from the group consisting of HuMax-IL8 monoclonal antibody, navarixin (SCH-527123), danirixin (GSK-1325756), reparixin, AZD-5069, AZD-8309, elubrixin (SB-656933), ladarixin, SB-225002, SB-265610, SB-332235, SCH-563705 and compounds with the following formulas:

39. The method of claim 9 wherein the immunotherapy consists of antibody directed to a ligand to a T cell receptor, wherein the immunotherapy amplifies antigen- specific T cell responses.

40. The method of claim 39, wherein the antibody binds to a ligand selected from the group consisting of B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7- H3, B7-H4, B7-H5 (VISTA), and B7-H6.

41. The method of claim 39, wherein the antibody binds to a ligand selected from CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4- 1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG,

RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT R, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1,

XEDAR, EDA2, TNFR1, lymphotoxin a/TNRb, TNFR2, TNFa, ίTbK lymphotoxin a1b2, FAS, FASL, RELT, DR6, TROY, and NGFR.

42. The method of claim 39, wherein the antibody binds to a ligand selected from IL-6, IL-10, TGF-b, VEGF.

43. The method of claim 9, wherein the immunotherapy consists of antibody that binds to a checkpoint inhibitor selected from the group consisting of CTLA-4, PD-l, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-l, BTLA, CD69, galectin-l, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-l, and TIM-4.

44. The method of claim 9, wherein the immunotherapy consists of antibody that binds to an agonist of a protein selected from the group consisting of B7-1, B7-2, CD28, 4- 1BB (CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2.

45. The method of claim 9, wherein the immunotherapy consists of antibody that binds to a ligand of a regulatory receptor on NK cells.

46. The method of claim 9, wherein the immunotherapy consists of antibody G7155 or FPA-008.

47. The method of claim 9, wherein the immunotherapy consists of an agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, that increase systemically the frequency of anti tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment), deplete or inhibit Tregs, or reverse/prevent T cell anergy or exhaustion, and agents that trigger innate immune activation and/or inflammation at tumor sites.

48. The method of claim 9, wherein the immunotherapy consists an antagonistic CTLA-4 antibody selected from ipilimumab or tremelimumab.

49. The method of claim 9, wherein the immunotherapy consists of an antagonistic PD-l or PD-L1 antibody selected from the group consisting of nivolumab, pembrolizumab, lambrolizumab, MEDI-0680, pidilizumab, AMP-224, atezolizomab, MPDL3280A, durvalumab, BMS-936559, and MSB0010718C.

50. The method of claim 9, wherein the immunotherapy consists of a LAG-3 antagonist antibody selected from the group consisting of BMS-986016, IMP-731, and IMP- 32!

51. The method of claim 9, wherein the immunotherapy consists of a CD 137 (4- IBB) antibody selected from urelumab and PF-05082566.

52. The method of claim 9, wherein the immunotherapy consists of an agonistic GITR antibody selected from the group consisting of BMS-986153, BMS-986156, TRX-518 and MK-4166.

53. The method of claim 9, wherein the immunotherapy consists of an agonistic 0X40 antibody selected from the group consisting of MEDI-6383 or MEDI-6469.

54. The method of claim 9, wherein the immunotherapy consists of an IDO and/or TDO inhibitor selected from the group consisting of indoximod, GDC-0919, F001287, GDC- 0919 (NLG919), F001287, epacadostat (INCB024360), IDO-IN-l, IDO-IN-2, navoximod (IDO-IN-7), and molecules with the following structures:

55. The method of claim 9, wherein the immunotherapy consists of an antagonistic 0X40 antibody consisting of RG-7888.

56. The method of claim 9, wherein the immunotherapy consists of an agonistic CD40 antibody consisting of lucatumumab or dacetuzumab.

57. The method of claim 9, wherein the immunotherapy consists an agonistic CD27 antibody consisting of varlilumab.

58. The method of claim 9, wherein the immunotherapy consists of MGA271.