WO2021062168A1

WO2021062168A1 - Synthetic sphingolipid inspired molecules with heteroaromatic appendages, methods of their synthesis and methods of treatment

Info

Publication number: WO2021062168A1
Application number: PCT/US2020/052742
Authority: WO
Inventors: Aimee EDINGER; Stephen Hanessian
Original assignee: The Regents Of The University Of California; Université de Montréal
Priority date: 2019-09-25
Filing date: 2020-09-25
Publication date: 2021-04-01

Abstract

Small molecules compounds and methods of their synthesis are provided. Formulations and medicaments are also provided that are directed to the treatment of disease, such as, for example, neoplasms, cancers, and other diseases. Therapeutics are also provided containing a therapeutically effective dose of one or more small molecule compounds, present either as pharmaceutically effective salt or in pure form, including, but not limited to, formulations for oral, intravenous, or intramuscular administration.

Description

SYNTHETIC SPHINGOLIPID INSPIRED MOLECULES WITH HETEROAROMATIC APPENDAGES, METHODS OF THEIR SYNTHESIS AND METHODS OF

TREATMENT

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] This invention was made with Governmental support under Grant Nos. R21 CA178230 awarded by the National Institutes of Health. The government has certain rights in the invention.

TECHNICAL FIELD

[0002] The disclosure is generally directed to synthetic cytotoxic molecules, medicaments formed from these molecules, methods of synthesis of these molecules, and methods for the treatment of disorders or neoplasms using such therapeutics.

BACKGROUND

[0003] Endogenous sphingolipids including ceramide (compound 1 ) and sphingosine- 1 -phosphate are natural components of mammalian cells that have both pro-growth and pro-apoptotic functions (Fig. 1). Sphingolipids modulate a number of signaling processes that regulate the life cycle of cells.

[0004] While biologically active and tumor suppressive, ceramide is difficult to apply clinically due to its insolubility in water and ready metabolism. The synthetic sphingolipid analogue FTY720 (compound 2), originally conceived as an immunosuppressant and currently marketed for the treatment of multiple sclerosis under the trade name Gilenya, was found to possess anticancer activity in vitro and in vivo (Fig. 1). However, FTY720 induces severe bradycardia at the anticancer dose.

[0005] An interesting compound is SH-BC-893 (compound 3), which was found to provide anti-proliferative activity yet avoided the toxicity of FY720 at high dosage (Fig. 1). Based on this activity, SH-BC-893 has viability to be a treatment for cancer. SUMMARY

[0006] In an embodiment is a compound of formula:

The pyridazine is connected at position 4 or 5. Ri is H or alkyl, including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to 14 carbons. R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. R4 and Rs are independently: alkyl including methyl, optionally substituted aryl including optionally substituted phenyl, or optionally substituted heteroaryl including optionally substituted pyridine or optionally substituted pyrimidine n is independently 1, 2, 3, or 4. m is independently 1 or 2. The phenyl moiety can be attached at any available position of the azacycle core.

[0007] In another embodiment, any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.

[0008] In yet another embodiment, the compound is:

[0009] In a further embodiment, the compound is:

[0010] In still yet another embodiment is a compound of formula:

R

R is connected at its N. X is 0 or S. Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to 14 carbons. R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. n is independently 1, 2, 3, or 4. m is independently 1 or 2. The phenyl moiety can be attached at any available position of the azacycle core.

[0011] In yet a further embodiment, the compound is:

[0012] In an even further embodiment is a compound of formula:

R may be further functionalized. R is attached to the azacycle via any of R’s available positions. R’ is H or OH. Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to 14 carbons. R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. n is independently: 1 , 2, 3, or 4. m is independently: 1 or 2. The phenyl moiety can be attached at any available position of the azacycle core. [0013] In yet an even further embodiment, the compound is:

[0014] In still yet an even further embodiment is a compound of formula: or a pharmaceutically acceptable salt thereof.

The pyridazine is connected at position 4 or 5. Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to14 carbons. R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. R4 and Rs are independently alkyl including methyl, aryl including phenyl, or heteroaryl including pyridine or pyrimidine n is independently 1, 2, 3, or 4.

[0015] In still yet an even further embodiment is a compound of formula:

or a pharmaceutically acceptable salt thereof.

X is 0 or S. Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to 14 carbons. R3 is 1 , 2, 3, or 4 substituents, and each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. n is independently 1 , 2, 3, or 4.

[0016] In still yet an even further embodiment, the compound is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

[0017] In still yet an even further embodiment, the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (IC50) of less than 100 micromolar, wherein the local IC50 is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

[0018] In still yet an even further embodiment, the human neoplastic cells are derived from at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

[0019] In still yet an even further embodiment, the human neoplastic cells are: fast growing, aggressive, Warburg-phenotypic, malignant, Ras-positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, nodular, or a combination thereof. [0020] In still yet an even further embodiment, the compound is capable of inhibiting growth of a tumor comprised of human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof. [0021] In an embodiment is a medicament for the treatment of a human disorder that includes a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:

The pyridazine is connected at position 4 or 5. Ri is H or alkyl, including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to 14 carbons. R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. R4 and Rs are independently: alkyl including methyl, optionally substituted aryl including optionally substituted phenyl, or optionally substituted heteroaryl including optionally substituted pyridine or optionally substituted pyrimidine n is independently 1, 2, 3, or 4. m is independently 1 or 2. The phenyl moiety can be attached at any available position of the azacycle core.

[0022] In another embodiment, any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.

[0023] In yet another embodiment, the compound is:

[0024] In a further embodiment, the compound is:

[0025] In still yet another embodiment is a medicament for the treatment of a human disorder that includes a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:

R is connected at its N. X is O or S. Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to 14 carbons. R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. n is independently 1, 2, 3, or 4. m is independently 1 or 2. The phenyl moiety can be attached at any available position of the azacycle core. [0026] In yet a further embodiment, the compound is:

[0027] In an even further embodiment is a medicament for the treatment of a human disorder that includes a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:

R may be further functionalized. R is attached to the azacycle via any of R’s available positions. R’ is H or OH. Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to 14 carbons. R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. n is independently: 1 , 2, 3, or 4. m is independently: 1 or 2. The phenyl moiety can be attached at any available position of the azacycle core. [0028] In yet an even further embodiment, the compound is:

[0029] In still yet an even further embodiment is a medicament for the treatment of a human disorder that includes a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula: or a pharmaceutically acceptable salt thereof.

The pyridazine is connected at position 4 or 5. Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to14 carbons. R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. R4 and Rs are independently alkyl including methyl, aryl including phenyl, or heteroaryl including pyridine or pyrimidine n is independently 1, 2, 3, or 4. [0030] In still yet an even further embodiment is a medicament for the treatment of a human disorder that includes a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula: or a pharmaceutically acceptable salt thereof.

[0031] In still yet an even further embodiment, the human disorder is at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

[0032] In still yet an even further embodiment, the one or more compounds is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells. [0033] In still yet an even further embodiment, the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (ICso) of less than 100 micromolar, wherein the local ICso is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

[0034] In still yet an even further embodiment, the pharmaceutical formulation is capable of inhibiting growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, and neoplastic cell proliferation. [0035] In still yet an even further embodiment, the medicament further includes at least one cytotoxic FDA-approved compound for the treatment of a neoplasm.

[0036] In still yet an even further embodiment, the compound is capable of inhibiting growth of a tumor comprised of human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof. [0037] In an embodiment is a treatment of a human disorder that includes administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:

[0038] In another embodiment, any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide. [0039] In yet another embodiment, the compound is:

[0040] In a further embodiment, the compound is:

[0041] In still yet another embodiment is a treatment of a human disorder that includes administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:

R is connected at its N. X is O or S. Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to 14 carbons. R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. n is independently 1, 2, 3, or 4. m is independently 1 or 2. The phenyl moiety can be attached at any available position of the azacycle core. [0042] In yet a further embodiment, the compound is:

[0043] In an even further embodiment is a treatment of a human disorder that includes administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:

R may be further functionalized. R is attached to the azacycle via any of R’s available positions. R’ is H or OH. Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to 14 carbons. R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. n is independently: 1 , 2, 3, or 4. m is independently: 1 or 2. The phenyl moiety can be attached at any available position of the azacycle core.

[0044] In yet an even further embodiment, the compound is:

[0045] In still yet an even further embodiment is a treatment of a human disorder that includes administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:

The pyridazine is connected at position 4 or 5. Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to14 carbons. R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. R4 and Rs are independently alkyl including methyl, aryl including phenyl, or heteroaryl including pyridine or pyrimidine n is independently 1, 2, 3, or 4. [0046] In still yet an even further embodiment is a treatment of a human disorder that includes administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula: or a pharmaceutically acceptable salt thereof.

X is O or S. Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety. R2 is an aliphatic chain comprising 6 to 14 carbons. R3 is 1 , 2, 3, or 4 substituents, and each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN. n is independently 1 , 2, 3, or 4.

[0047] In still yet an even further embodiment, the human subject is diagnosed with at least one human disorder.

[0048] In still yet an even further embodiment, the human disorder is at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

[0049] In still yet an even further embodiment, the pharmaceutical formulation inhibits growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof. [0050] In still yet an even further embodiment, the human disorder is characterized by at least one neoplasm characterization, and wherein the at least one neoplasm characterization is: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras- positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, nodular, or a combination thereof.

[0051] In still yet an even further embodiment, the treatment is combined with an FDA- approved standard of care.

[0052] In still yet an even further embodiment, the pharmaceutical formulation is combined with at least one cytotoxic FDA-approved compound.

BRIEF DESCRIPTION OF THE DRAWINGS

[0053] The description and claims will be more fully understood with reference to the following figures and data graphs, which are presented as exemplary embodiments and should not be construed as a complete recitation of the scope of the disclosure.

[0054] FIG. 1 provides a molecular structure of ceramide, FTY720, and SH-BC-893 in accordance with the prior art. [0055] FIG. 2 provides a molecular structure diagram of a number of therapeutic small molecule analogs in accordance with various embodiments.

[0056] FIG. 3 provides examples of molecular structures of therapeutic small molecule analogs in accordance with various embodiments.

[0057] FIG. 4 provides examples of molecular structures of therapeutic small molecule analogs in accordance with various embodiments.

[0058] FIG. 5 provides a molecular structure of perphenazine and SMAP in accordance with the prior art.

[0059] FIG. 6 provides examples of molecular structures of therapeutic small molecule analogs in accordance with various embodiments.

[0060] FIG. 7 provides examples of molecular structures of therapeutic small molecule analogs in accordance with various embodiments.

[0061] FIG. 8 provides a theoretical depiction of how small therapeutic molecules interact with PP2A in accordance with various embodiments.

[0062] FIG. 9 provides examples of molecular structures of therapeutic small molecule analogs in accordance with various embodiments.

[0063] FIG. 10A provides results of cytotoxic activity of compounds 3 and 13 on FL5 cells and the ability of methyl-pyruvate to rescue the cytotoxic effect, generated in accordance with various embodiments.

[0064] FIG. 10B provides results of cytotoxic activity of compounds 3 and 13 on eight cancer cell lines, generated in accordance with various embodiments.

[0065] FIG. 10C provides results of cytotoxic activity of compounds 3 and 13, and SMAP on KRAS mutant cancer cell lines, generated in accordance with various embodiments.

[0066] FIGs. 11 to 14 each provide reaction pathways for the production of therapeutic small molecule analogs in accordance with various embodiments.

DETAILED DESCRIPTION

[0067] Turning now to the drawings and data, molecules capable of treating disorders, including neoplasms and cancer, medicaments formed from these molecules, methods of synthesis of these molecules, and methods for the treatment of disorders using such therapeutics are disclosed. In some embodiments, the molecules are hybrid molecules that include a constrained sphingolipid-like molecule and a heteroaromatic appendage attached thereon. In some embodiments, the sphingolipid portion includes a hydrophobic tail inclusive of a phenyl moiety and attached to a pyrrolidine moiety. In many embodiments, the phenyl moiety bears further substitution. In some embodiments, the sphingolipid portion is SH-BC-893 (Fig. 1 , compound 3). In some embodiments, a heteroaromatic appendage is a pyridazine, pyridine, phenoxazine, pyrimidine, or phenothiazine. In many embodiments, the heteroaromatic appendage bears further substitution. In many embodiments, molecules are prepared and used as pharmaceutically acceptable salts.

[0068] In a number of embodiments, formulations and medicaments are provided that are directed to the treatment of disorders. In some such embodiments these formulations and medicaments target cancers, such as, for example, leukemia, prostate, colon, lung, pancreatic and breast cancer. Therapeutic embodiments contain a therapeutically effective dose of one or more small molecule compounds. Embodiments allow for various formulations, including, but not limited to, formulations for oral, intravenous, or intramuscular administration. Other additional embodiments provide treatment regimens for disorders using therapeutic amounts of the small molecules.

Terms of Art

[0069] “Acyl” means a -C(=0)R group.

[0070] “Alcohol” means a hydrocarbon with an -OH group (ROH).

[0071] “Alkyl” refers to the partial structure that remains when a hydrogen atom is removed from an alkane.

[0072] “Alkyl phosphonate” means an alkyl group bonded to a phosphate RPO3. [0073] “Alkane” means a compound of carbon and hydrogen that contains only single bonds.

[0074] “Alkene” refers to an unsaturated hydrocarbon that contains at least one carbon-carbon double bond.

[0075] “Alkyne” refers to an unsaturated hydrocarbon that contains at least one carbon-carbon triple bond. [0076] “Alkoxy” refers to a portion of a molecular structure featuring an alkyl group bonded to an oxygen atom.

[0077] “Aryl” refers to any functional group or substituent derived from an aromatic ring.

[0078] “Amine” molecules are compounds containing one or more organic substituents bonded to a nitrogen atom, RNH2, R2NH, or R3N.

[0079] “Amino acid” refers to a difunctional compound with an amino group on the carbon atom next to the carboxyl group, RCH(NH2)C02H.

[0080] “Azide” refers to Ns.

[0081] “Cyanide” refers to CN.

[0082] “Ester” is a compound containing the -CO2R functional group.

[0083] “Ether” refers to a compound that has two organic substituents bonded to the same oxygen atom, i.e. , R-O-R’.

[0084] “Halogen” or “halo” means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0085] “Hydrocarbon” means an organic chemical compound that consists entirely of the elements carbon (C) and hydrogen (H).

[0086] “Phosphate”, “phosphonate”, or “PO” means a compound containing the elements phosphorous (P) and oxygen (O).

[0087] “R” in the molecular formulas above and throughout are meant to indicate any suitable organic functionality.

[0088] “Optionally substituted” means substituted or unsubstituted. For example, optionally substituted phenyl is unsubstituted phenyl or substituted phenyl.

Compound Formulas

[0089] Compounds in accordance with embodiments described herein are based on azacycles with an attached heteroaromatic appendage. A chemical compound in accordance with embodiments described herein is illustrated in FIG. 2 and pictured below. Embodiments comprise the molecules as illustrated in FIG. 2, including an azacycle compound and its salt of a suitable acid:

or a pharmaceutically acceptable salt thereof;

R is an optionally substituted heteroaromatic moiety such as an optionally substituted pyridazine, optionally substituted pyridine, optionally substituted pyrimidine, phenoxazine, or optionally substituted phenothiazine.

Ri is H, alkyl such as C1-6 alkyl or C1-4 alkyl including methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, etc, Ac, Boc, guanidine moiety.

R2 is an aliphatic chain comprising 6 to 14 carbons.

R3 is a 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is H, halogen, alkyl, alkoxy, N3, NO2, and CN. n is independently 1, 2, 3, or 4. m is independently 1 or 2.

The phenyl moiety can be attached at any available position of the azacycle core. [0090] In some embodiments, R2 is an unsaturated hydrocarbon chain.

[0091] In some embodiments, R2 is Ce-14 alkyl, Ce-io alkyl, C7-9 alkyl, C6H13, C7H15, OdHΐ7, C9H19, C10H21 , Ci 1 H23, C12H25, C13H27, or Ci4H29.

[0092] In some embodiments R3 is H.

[0093] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0094] In some embodiments, m is 1. In some embodiments, m is 2.

[0095] In some embodiments, the R2 and R3 substituents can have different combinations around the phenyl ring with regard to their position.

[0096] In some embodiments, the Ri is an alkyl having 1 to 6 carbons.

[0097] It will be understood that compounds described herein may exist as stereoisomers, including enantiomers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are contemplated in the compounds described herein. [0098] In some embodiments, R is a 1 ,2-pyridazine having the formula (Fig. 2):

R4 and R5 are functional groups independently selected from: alkyl including methyl, optionally substituted aryl (i.e. , unsubstituted aryl or substituted aryl) including optionally substituted phenyl, and optionally substituted heteroaryl including optionally substituted pyridine and optionally substituted pyrimidine.

The pyridazine moiety is connected to the azacycle at the position 4 or 5 of the pyridazine.

[0099] In some embodiments, any substituents of R4 and R5, if present, are independently halogen including F, alkyl, terminal alkyne, and azide.

[0100] In some embodiments, R4 is C1-6 alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl; unsubstituted aryl or substituted aryl, including unsubstituted phenyl, or phenyl having 1, 2, 3, 4, or 5 substituents; unsubstituted heteroaryl or substituted heteroaryl, including unsubstituted pyridine or pyridine having 1, 2, 3, or 4 substituents, or unsubstituted pyrimidine or pyrimidine having 1 , 2, or 3 substituents. Any substituent may be used in the substituted aryl (e.g., substituted phenyl) or substituted heteroaryl (e.g., substituted pyridine or substituted pyrimidine). For example, the substituents of the substituted aryl or substituted heteroaryl may independently be, halo (such as F, Cl, Br, I), C1-6 alkyl (such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, C6 alkyl), orX-R^a, wherein X is O, -C(=0)-, -NHC(=0)-, or -C(=0)NH-, and R^a is C1-6 alkyl (such as CHs, C2 alkyl, Cs alkyl, C4 alkyl, Cs alkyl, C6 alkyl), C2-6 alkenyl (such as -CFI=CH2, -CFl2CFI=CH2, - CH₂CH₂CH=CH₂, -CH₂CH2CH₂CH=CH2, -CH₂CH₂CH2CH2CH=CH2, etc.), or C2-6 alkynyl (such as -CHºCH₂, -CH₂CHºCH₂, -CH2CH₂CHºCH₂, -CH2CH2CH₂CHºCH₂, - CH₂CH₂CH2CH2CHºCH_2, etc.); or azide. [0101] In some embodiments, Rs is Ci-6 alkyl, such as Chta, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl; unsubstituted aryl or substituted aryl, including unsubstituted phenyl, or phenyl having 1, 2, 3, 4, or 5 substituents; unsubstituted heteroaryl or substituted heteroaryl, including unsubstituted pyridine or pyridine having 1, 2, 3, or 4 substituents, or unsubstituted pyrimidine or pyrimidine having 1 , 2, or 3 substituents. Any substituent may be used in the substituted aryl (e.g., substituted phenyl) or substituted heteroaryl (e.g., substituted pyridine or substituted pyrimidine). For example, the substituents of the substituted aryl or substituted heteroaryl may independently be, halo (such as F, Cl, Br, I), C1-6 alkyl (such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, C6 alkyl), orX-R^a, wherein X is 0, -C(=0)-, -NHC(=0)-, or -C(=0)NH-, and R^a is C1-6 alkyl (such as CHs, C2 alkyl, Cs alkyl, C4 alkyl, Cs alkyl, C6 alkyl), C2-6 alkenyl (such as -CH=CH2, -CH2CH=CH2, - CH2CH₂CH=CH2, -CH2CH2CH₂CH=CH2, -CH2CH2CH2CH₂CH=CH2, etc.), or C_2-6 alkynyl (such as -CHºCH_2, -CH₂CHºCH2, -CH2CH₂CHºCH2, -CH2CH2CH₂CHºCH2, - CH2CH2CH2CH₂CHºCH2, etc.); or azide.

[0102] In some embodiments, R4 and Rs are the same functional group.

[0103] In some embodiments, R4 and Rs are different functional groups.

[0104] In some embodiments, R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted phenyl.

[0105] In some embodiments, R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted pyridine.

[0106] In some embodiments, R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted pyrimidine.

[0107] In some embodiments, R4 is optionally substituted pyridine and Rs is optionally substituted pyridine.

[0108] In some embodiments, R4 is optionally substituted phenyl and Rs is optionally substituted phenyl.

[0109] In some embodiments, R4 is optionally substituted phenyl and Rs is optionally substituted pyrimidine. [0110] In some embodiments, an azacycle compound has the formula:

[0111] In some embodiments, R is an optionally substituted phenoxazine or an optionally substituted phenothiazine, such as phenoxazine or phenothiazine having the formula (Fig. 2):

which may additionally have substituents on any available ring position.

X is selected from: 0 and S.

R is attached to the azacycle via R’s nitrogen.

[0112] Substituents of R may independently include halogen, alkyl (e.g., Ci-6 alkyl, such as Chta, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, or Ce alkyl), alkoxy (e.g., C1-6 alkoxy, such as -OCH3, C2 alkoxy, C3 alkoxy, C4 alkoxy, Cs alkoxy, or Ce alkoxy), N3, NO2, and CN.

[0113] Compounds described herein are based on azacycles with an attached heteroaromatic appendage. Some embodiments include a chemical compound illustrated in FIG. 3 and pictured below. Embodiments comprise the molecules as illustrated in FIG. 3, including an azacycle compound and its salt of a suitable acid:

R is optionally substituted heteroaryl including pyridine and pyrimidine, and a substituted heteroaryl including dimethoxy pyrimidine. These heteroaryl substituents can be attached to the alkyl chain at different positions on the heteroaryl, e.g., the 2-, 3-, or 4- positions on pyridine for example.

R’ is H or OH.

Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety.

R2 is an aliphatic chain comprising 6 to14 carbons.

R3 is a 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is H, halogen, alkyl, alkoxy, N3, NO2, or CN. n is independently 1 , 2, 3, or 4. m is independently 1 or 2.

The phenyl moiety can be attached at any available position of the azacycle core. [0114] In some embodiments, R is an unsubstituted or substituted pyridine, for example:

wherein R is attached to the azacycle via any of R’s available positions. In some embodiments, any of the pyridine’s positions 2, 3, or 4 may be used for attachment to the azacycle. In some embodiments, the pyridine may additionally have substituents on any available ring.

[0115] In some embodiments, R is an unsubstituted or substituted pyrimidine, for example:

wherein R is attached to the azacycle via any of R’s available positions. In some embodiments, any of the pyrimidine’s positions 4, 5, or 6 may be used for attachment to the azacycle. In some embodiments, the pyrimidine may additionally have substituents on any available ring.

[0116] For R groups that are substituted pyridine and substituted pyrimidine, substituents may independently include halogen, alkyl (e.g., C1-6 alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, or C6 alkyl), alkoxy (e.g., C1-6 alkoxy, such as -OCH3, C2 alkoxy, C3 alkoxy, C4 alkoxy, Cs alkoxy, or Ob alkoxy), N3, NO2, and CN. In some embodiments, R is:

[0117] In some embodiments, R2 is Ce-14 alkyl, Ce-io alkyl, C7-9 alkyl, C6H13, C7H15, C8H17, C9H19, C10H21 , Ci 1 H23, C12H25, C13H27, or Ci4H29.

[0118] In some embodiments R3 is H.

[0119] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0120] In some embodiments, m is 1. In some embodiments, m is 2.

[0121] In some embodiments, the R2 and R3 substituents can have different combinations around the phenyl ring with regard to their position.

[0122] In some embodiments, R2 is an unsaturated hydrocarbon chain.

[0123] In some embodiments, the Ri is an alkyl having 1 to 6 carbons.

[0124] It will be understood that compounds described herein may exist as stereoisomers, including enantiomers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are contemplated in the compounds of the present invention.

[0125] Compounds described herein are based on amines with an attached heteroaromatic appendage. Some embodiments include chemical compounds which structures illustrated in FIG. 4 and pictured below. Embodiments comprise the molecules as illustrated in FIG. 4, including an amine compound and its salt of a suitable acid:

R is a heteroaromatic moiety selected from pyridazine, pyridine, pyrimidine, phenoxazine, or phenothiazine. Ri or Ri‘ is a functional group, each independently selected from: H, alkyl including methyl, Ac, Boc, guanidine moiety.

R2 is an aliphatic chain comprising 6 to14 carbons.

R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, CN. n is independently 1, 2, 3, or 4.

[0126] In some embodiments, R2 is Ce-14 alkyl, Ce-io alkyl, C7-9 alkyl, C6H13, C7H15, OdHΐ7, C9H19, C10H21 , Ci 1 H23, C12H25, C13H27, or Ci4H29.

[0127] In some embodiments R3 is H.

[0128] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0129] In some embodiments, the R2 and R3 substituents can have different combinations around the phenyl ring with regard to their position.

[0130] In some embodiments, R2 is an unsaturated hydrocarbon chain.

[0131] In some embodiments, Ri or Ri' is an alkyl having 1 to 6 carbons.

[0132] In some embodiments, Ri and Ri' are the same functional group.

[0133] In some embodiments, Ri and Ri' are different functional groups

[0134] It will be understood that compounds described herein may exist as stereoisomers, including enantiomers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are contemplated in the compounds of the present disclosure.

[0135] In some embodiments, R is a pyridazine having the formula (Fig. 4):

R4 and R5 are functional groups independently selected from: alkyl including methyl, optionally substituted aryl (i.e. , unsubstituted aryl or substituted aryl) including optionally substituted phenyl, and optionally substituted heteroaryl including optionally substituted pyridine and optionally substituted pyrimidine. The pyridazine moiety is connected at its position 4 or 5.

[0136] In some embodiments, any substituents of R4 and R5, if present, are independently halogen, including F, alkyl, terminal alkyne, and azide.

[0137] In some embodiments, R4 is C1-6 alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl; unsubstituted aryl or substituted aryl, including unsubstituted phenyl, or phenyl having 1 , 2, 3, 4, or 5 substituents; unsubstituted heteroaryl or substituted heteroaryl, including unsubstituted pyridine or pyridine having 1 , 2, 3, or 4 substituents, or unsubstituted pyrimidine or pyrimidine having 1 , 2, or 3 substituents. Any substituent may be used in the substituted aryl (e.g., substituted phenyl) or substituted heteroaryl (e.g., substituted pyridine or substituted pyrimidine). For example, the substituents of the substituted aryl or substituted heteroaryl may independently be halo (such as F, Cl, Br, I), C1-6 alkyl (such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, C6 alkyl), or X-R^a, wherein X is 0, -C(=0)-, -NHC(=0)-, or -C(=0)NH-, and R^a is C1-6 alkyl (such as CHs, C2 alkyl, Cs alkyl, C4 alkyl, Cs alkyl, C6 alkyl), C2-6 alkenyl (such as -CFI=CH₂, -CFl2CFI=CH₂, - CH₂CH₂CH=CH₂, -CH2CH2CH₂CH=CH₂, -CH₂CH₂CH₂CH₂CH=CH_2, etc.), or C2-6 alkynyl (such as -CHºCH₂, -CH₂CHºCH₂, -CH₂CH₂CHºCH₂, -CH₂CH₂CH₂CHºCH₂, - CH₂CH₂CH₂CH₂CHºCH_2, etc.).

[0138] In some embodiments, Rs is C1-6 alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, or C6 alkyl; unsubstituted aryl or substituted aryl, including unsubstituted phenyl, or phenyl having 1 , 2, 3, 4, or 5 substituents; unsubstituted heteroaryl or substituted heteroaryl, including unsubstituted pyridine or pyridine having 1 , 2, 3, or 4 substituents, or unsubstituted pyrimidine or pyrimidine having 1 , 2, or 3 substituents. Any substituent may be used in the substituted aryl (e.g., substituted phenyl) or substituted heteroaryl (e.g., substituted pyridine or substituted pyrimidine). For example, the substituents of the substituted aryl or substituted heteroaryl may independently be, halo (such as F, Cl, Br, I), C1-6 alkyl (such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, C6 alkyl), or X-R^a, wherein X is O, -C(=0)-, -NHC(=0)-, or -C(=0)NH-, and R^a is C1-6 alkyl (such as CHs, C2 alkyl, Cs alkyl, C4 alkyl, Cs alkyl, C6 alkyl), C2-6 alkenyl (such as -CFI=CH₂, -CFI₂CFI=CH₂, - CH₂CH₂CH=CH₂, -CH₂CH₂CH₂CH=CH₂, -CH₂CH₂CH₂CH₂CH=CH_2, etc.), or C2-6 alkynyl (such as -CHºCH₂, -CH₂CHºCH₂, -CH₂CH₂CHºCH₂, -CH₂CH₂CH₂CHºCH₂, - CH₂CH₂CH₂CH₂CHºCH_2, etc.). [0139] In some embodiments, R4 and Rs are the same functional group.

[0140] In some embodiments, R4 and Rs are different functional groups.

[0141] In some embodiments, R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted phenyl.

[0142] In some embodiments, R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted pyridine.

[0143] In some embodiments, R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted pyrimidine.

[0144] In some embodiments, R4 is optionally substituted pyridine and Rs is optionally substituted pyridine.

[0145] In some embodiments, R4 is optionally substituted phenyl and Rs is optionally substituted phenyl.

[0146] In some embodiments, R4 is optionally substituted phenyl and Rs is optionally substituted pyrimidine.

[0147] In some embodiments, R is optionally substituted phenoxazine or optionally substituted phenoxazine, such as a phenoxazine or phenothiazine having the formula (Fig. 4):

which may additionaly have substituents on any available ring position.

X is selected from: 0 and S.

R is connected at its N.

[0148] The claimed embodiments can also be related to pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” retains the desirable biological activity of the compound without unacceptable toxicological effects. Salts can be salts with a suitable acid, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, benzoic acid, pamoic acid, alginic acid, methanesulfonic acid, naphthalenesulfonic acid, and the like. Also, incorporated cations can include ammonium, sodium, potassium, lithium, zinc, copper, barium, bismuth, calcium, and the like; or organic cations such as tetraalkylammonium and trialkylammonium cations. Also useful are combinations of acidic and cationic salts. Included are salts of other acids and/or cations, such as salts with trifluoroacetic acid, chloroacetic acid, and trichloroacetic acid. [0149] Other compounds, as well as modified azacyclic sphingolipid-like molecules, suitable for practice of the present embodiments will be apparent to the skilled practitioner. Furthermore, these molecules may employ several mechanisms of action to inhibit neoplasm growth, even if the molecules are not structurally identical to the compounds shown above.

Modes of Treatment

[0150] In some embodiments, the compounds are administered in a therapeutically effective amount as part of a course of treatment. As used in this context, to "treat" means to ameliorate or prevent at least one symptom of the disorder to be treated or to provide a beneficial physiological effect. For example, one such amelioration of a symptom could be inhibition of neoplastic proliferation. Assessment of neoplastic proliferation can be performed in many ways, including, but not limited to assessing changes in tumor diameter, changes in tumor bioluminescence, changes in tumor volume, changes in tumor mass, or changes in neoplastic cell proliferation rate.

[0151] In several embodiments, an individual to be treated has been diagnosed as having a neoplastic growth or cancer. In many embodiments, the neoplasm is characterized as fast-growing, aggressive, Warburg-phenotypic, malignant, Ras-positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, or nodular. A number of cancers can be treated, including (but not limited to) acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, or vascular tumors.

[0152] A therapeutically effective amount can be an amount sufficient to prevent reduce, ameliorate or eliminate the symptoms of diseases or pathological conditions susceptible to such treatment, such as, for example, cancers like leukemia, prostate, colon, lung, pancreatic, or breast cancer, or diseases where oncogenic Ras mutations afford multiple metabolic advantages to transformed cells. In some embodiments, a therapeutically effective amount is an amount sufficient to reduce the transport of nutrients, such as, for example, glucose, amino acids, nucleotides or lipids, into cells. [0153] Dosage, toxicity and therapeutic efficacy of the compounds can be determined, e.g., by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit high therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to non-neoplastic cells and, thereby, reduce side effects.

[0154] Data obtained from cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. If the medicament is provided systemically, the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in a method described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be form ulated in animal models to achieve a circulating plasma concentration or within the local environment to be treated in a range that includes the IC50 (i.e. , the concentration of the test compound that achieves a half-maximal inhibition of neoplastic growth) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by liquid chromatography coupled to mass spectrometry. In some embodiments, a cytotoxic effect is achieved with an IC50 less than 50 mM, 20 pM, 10 pM, 5 pM or 1 pM.

[0155] An "effective amount" is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered one from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments. For example, several divided doses may be administered daily, one dose, or cyclic administration of the compounds to achieve the desired therapeutic result. A single small molecule compound may be administered, or combinations of various small molecule compounds may also be administered.

[0156] In a number of embodiments, azacyclic sphingolipid-like small molecule compounds are administered in combination with an appropriate standard of care, such as the standard of care established by the United States Federal Drug Administration (FDA) or the European Medicines Agency (EMA). In many embodiments, azacyclic sphingolipid-like small molecule compounds are administered in combination with other cytotoxic compounds, especially FDA-approved compounds or EMA-approved compounds. A number of FDA-approved or EMA-approved cytotoxic compounds can be utilized, including (but not limited to) methotrexate, gemcitabine, tamoxifen, taxol, docetaxel, and enzalutamide.

[0157] It is also possible to add agents that improve the solubility of these compounds. For example, the claimed compounds can be formulated with one or more adjuvants and/or pharmaceutically acceptable carriers according to the selected route of administration. For oral applications, gelatin, flavoring agents, or coating material can be added. In general, for solutions or emulsions, carriers may include aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include sodium chloride and potassium chloride, among others. In addition, intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers and the like.

[0158] Numerous coating agents can be used in accordance with various embodiments. In some embodiments, the coating agent is one which acts as a coating agent in conventional delayed release oral formulations, including polymers for enteric coating. Examples include hypromellose phthalate (hydroxy propyl methyl cellulose phthalate; FIPMCP); hydroxypropylcellulose (FIPC; such as KLUCEL®); ethylcellulose (such as ETFIOCEL®); and methacrylic acid and methyl methacrylate (MAA/MMA; such as EUDRAGIT®).

[0159] Various embodiments of formulations also include at least one disintegrating agent, as well as diluent. In some embodiments, a disintegrating agent is a super disintegrant agent. One example of a diluent is a bulking agent such as a polyalcohol. In many embodiments, bulking agents and disintegrants are combined, such as, for example, PEARLITOL FLASFI®, which is a ready to use mixture of mannitol and maize starch (mannitol/maize starch). In accordance with a number of embodiments, any polyalcohol bulking agent can be used when coupled with a disintegrant or a super disintegrant agent. Additional disintegrating agents include, but are not limited to, agar, calcium carbonate, maize starch, potato starch, tapioca starch, alginic acid, alginates, certain silicates, and sodium carbonate. Suitable super disintegrating agents include, but are not limited to crospovidone, croscarmellose sodium, AMBERLITE (Rohm and Flaas, Philadelphia, Pa.), and sodium starch glycolate. [0160] In certain embodiments, diluents are selected from the group consisting of mannitol powder, spray dried mannitol, microcrystalline cellulose, lactose, dicalcium phosphate, tricalcium phosphate, starch, pregelatinized starch, compressible sugars, silicified microcrystalline cellulose, and calcium carbonate.

[0161] Several embodiments of a formulation further utilize other components and excipients. For example, sweeteners, flavors, buffering agents, and flavor enhancers to make the dosage form more palatable. Sweeteners include, but are not limited to, fructose, sucrose, glucose, maltose, mannose, galactose, lactose, sucralose, saccharin, aspartame, acesulfame K, and neotame. Common flavoring agents and flavor enhancers that may be included in the formulations described herein include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.

[0162] Multiple embodiments of a formulation also include a surfactant. In certain embodiments, surfactants are selected from the group consisting of Tween 80, sodium lauryl sulfate, and docusate sodium.

[0163] Many embodiments of a formulation further utilize a binder. In certain embodiments, binders are selected from the group consisting of povidone (PVP) K29/32, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), corn starch, pregelatinized starch, gelatin, and sugar.

[0164] Various embodiments of a formulation also include a lubricant. In certain embodiments, lubricants are selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, mineral oil, polyethylene glycol, polyethylene glycol 4000-6000, talc, and glyceryl behenate.

[0165] Modes of administration, in accordance with multiple embodiments, include, but are not limited to, oral, transdermal, transmucosal (e.g., sublingual, nasal, vaginal or rectal), or parenteral (e.g., subcutaneous, intramuscular, intravenous, bolus or continuous infusion). The actual amount of drug needed will depend on factors such as the size, age and severity of disease in the afflicted individual. The actual amount of drug needed will also depend on the effective concentration ranges of the various active ingredients. [0166] A number of embodiments of formulations include those suitable for oral administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of at least one embodiment described herein, or a pharmaceutically salt, prodrug, or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. [0167] Embodiments of formulations disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. Multiple embodiments also compartmentalize various components within a capsule, cachets, or tablets, or any other appropriate distribution technique.

[0168] Several embodiments of pharmaceutical preparations include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets, in a number of embodiments, may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0169] Preservatives and other additives, like antimicrobial, antioxidant, chelating agents, and inert gases, can also be present. (See generally, Remington's Pharmaceutical Sciences, 16th Edition, Mack, (1980), the disclosure of which is incorporated herein by reference.)

EXEMPLARY EMBODIMENTS

[0170] Biological data supports the use of the aforementioned sphingolipid-like compounds with heteroaromatic appendage in a variety of embodiments to treat disease. It is noted that embodiments of the compounds described herein, in accordance with the disclosure, kill and/or inhibit the growth of neoplastic cells. Accordingly, embodiments using these compounds to treat various diseases, such as cancer, avoid the pitfalls associated with prior approaches.

[0171] Various compounds were tested to establish activity for three phenotypes: viability (ICso), transporter loss (%CD98 loss), and vacuolation in FL5 cells (For more activity studies, see M. S. Perryman, et al., Bioorg. Med. Chem. 24: 4390-4397 (2016), the disclosure of which is incorporated herein by reference). These phenotypes provide a means for determining efficacy for treating neoplasms and cancer. These compounds are discussed further in the examples described below.

Phenoxazine and Phenothiazine Hybrid Molecules

[0172] Activation of PP2A has been reported with a series of tricyclic neuroleptics such as perphenazine (4) and by a synthetic compound incorporating a phenoxazine moiety lacking a basic nitrogen (5) (SMAP) (Fig. 5) (See A Gutierrez, et al., J Clin Invest. 124: 644-655 (2014); and D. B. Kastrinksy, et al., Bioorg Med Chem. 23: 6528-6534 (2015); the disclosures of which are each incorporated herein by reference).

[0173] It is intriguing that a functionally important cellular enzyme such as PP2A was activated by compounds with such diverse chemical structures as 3 and the tricyclic neuroleptic 4 in which a piperazine unit was linked to a phenothiazine via a three carbon chain. With the likely premise that the lead compound 3 and perphenazine 4 were interacting at different sites within PP2A, synthesis of hybrid molecules in which the C-2 hydroxymethyl group in 3 was extended with 3-5 carbon alkyl ether chain tethers containing terminally situated phenoxazine and phenothiazine cores were synthesized (compounds 6-9)(Fig. 6).

[0174] It was also desired to probe the tolerance of side-chain appendages with less rigid and spatially more favorable monocyclic heteroaromatics containing a basic nitrogen atom. 3-pyridyltetryl and 5-pyrim idinyl tetryl units were attached to the extremity of the 2- hydroxymethyl group as first generation probes. Compounds 10 - 12 were easily prepared from a 4-carbon chain aldehyde derived from N-Boc 3 and Grignard reagents prepared in situ from the corresponding heteroaromatic iodides.

[0175] The results on viability (ICso), transporter loss (%CD98 loss), and vacuolation in neoplastic cells is provided in Table 1 .

Table 1. Cytotoxicity, nutrient down-regulation and vacuolation profiles of Phenoxazine and Phenothiazine Hybrid Molecules

Pyridazine Hybrid Molecules

[0176] In an effort to further explore the effects of heteroaromatic appendages, compounds with pyridazine as a heterocycle were synthesized. It was envisaged that a hypothetical interaction of a pyridazine appended side-chain on compound 3 within a helical region of PP2A as illustrated in Figs. 7 and 8. [0177] The synthetic protocol allowed for the insertion of substituents at the 4- and 6- positions of the 1 ,2-pyridazine core unit, which by virtue of free rotation around the single bonds, would adopt conformationally favorable spatial orientations resulting in pi stacking and hydrophobic interactions. With this premise in mind we developed a strategy that engaged the terminal olefinic ether appendages of 3, with 2,4-disubstituted 2, 3,5,6- tetrazines in a reverse electron demand Diels-Alder reaction to give the corresponding 1 ,2-pyridazines as 1 :1 mixtures of 4,5-regioisomers. The products were then subjected to anti-proliferation (ICso), CD98 sequestration, and vacuolation tests in FL5 cells, which are shown in Table 2.

Table 2. Cytotoxicity profiles of Pyridazine Hybrid Molecules

Values represent mean ± S.D. **Toxicity was too high to determine

[0178] It is interesting that compounds 13a-13b, having methyl and 1,3-pyrimidine substituents showed a three-fold improvement in activity compared to the parent 3. In fact, the two regioisomers could be separated by chromatography and exhibited ICso values of 0.5 and 0.7 mM, respectively. The other analogs showed IC50 values ranging from 0.9-3.3 mM depending on the nature of the R1 and R2 substituents.

[0179] In order to get a better understanding of whether the appendage was the primary source of improved in these hybrid molecules, a few modified pyridazine hybrid molecules were synthesized in which a key portion of the base molecule was removed or altered. The chemical structure of these compounds are depicted in Fig. 9. The molecules were subjected anti-proliferation (IC50), CD98 sequestration, and vacuolation tests in FL5 cells, which are shown in Table 3.

Table 3.

% surface CD98 Vacuolation score

Comp. ICso loss ± SD _ ± SD

2.5 mM 10 mM 2.5 mM 10 mM

3 1.7 mM ± 0.3 34.4 ± 8.4 67.8 ± 7.9 47 ± 15 60 ± 15

24 >40 mM 8.0 ± 8.8 5.7 ± 11.6 n.d 0 ± 0

25 2.9 mM ± 0.2 5.0 ± 1.2 56.0 ± 6.6 3 ± 6 34 ± 11

26 >40 mM -7 4 ± 16 1 -6 0 ± 2 8 n.d_ 0 ± 0

[0180] As can be determined from the results, the pyradizine appendage without the pyrrolidine core and attached hydrophobic tail is unable to confer cytotoxicity, CD98 sequestration, or vacuolation in cancer cells (see compounds 24 and 25). Compound 25, which maintains pyrrolidine core and attached hydrophobic tail but has a basic alkyl in place of the pyradizine appendage did confer cytotoxicity, CD98 sequestration, and vacuolation in cancer cells, albeit at lower levels than molecules having the pyradizine appendage. This suggests that a nitrogen-containing heterocycle rings with a hybrid tail are important for anti-proliferative activity and that a pyradizine appendages can improve that activity.

[0181] To determine whether the anti-proliferative activity was due to nutrient starvation of the cells, a rescue experiment utilizing pyruvate to increase nutrient uptake was performed, which is presented in Fig. 10. In this experiment, FL5 cells were treated with compound 3 or 13a-13b at each compounds IC50 with and without methyl-pyruvate. After 24 hours of treatment, the viability of cells was measured utilizing a vital dye that is absorbed into dead cells. The percent viable cells was measured by flow cytometry Approximately half of the cells treated with compound 3 or 13a-13b were viable and treatment with methyl-pyruvate increased this viability up to about 75% (Fig. 10A), demonstrating that nutrient starvation is a major factor in the cytotoxic activity of compounds 13a-13b.

[0182] Encouraged by the improved cytotoxicity of compound 13 in FL5.12 cells, additional tests were conducted to evaluate its antineoplastic potential compared with the parent compound 3 in eight human cancer cell lines from four different cancer types. The superior activity of compound 13 was indeed reproduced. In fact, as a 1 :1 mixture of isomers, compound 13 was consistently more potent than the parent compound 3, with IC50 values from ~2.5 to 9 times lower than those of 3 (Fig. 10B), substantiating the role of the pyridazine core unit as a preferred heterocyclic appendage. As in FL5.12, the presence of a pyridine (compound 10) is not sufficient for increased potency and that the nature of the substituents on the pyridazine plays a role in activity (compound 13 vs 17) in FICT116 colon cancer cells (Table 4). Finally, it is worth noting that in three KRAS mutant cancer cell lines, compound 5 is between 7 and >20 times more potent than the published small molecule activator of PP2A (SMAP) (Fig. 10C). Even the parent compound 3 is at least two times more potent than SMAP in these cell lines.

Table 4.

Comp. IC50

3 4.5 mM ± 1.2

10 4.6 mM ± 1.1

23 0.5 mM ± 0.1

17 4 6 mM ± 1 5

[0183] A general overview of the synthesis of the pyradizine hybrid molecules is shown in Fig 11 and detailed herein. All reactions involving moisture sensitive compounds were performed in flame-dried glassware under a positive pressure of dry, oxygen free, argon and in dry solvents. Anhydrous solvents were distilled under a positive pressure of argon before use and dried by standard methods. THF, ether, CFI2CI2 and toluene were dried by the SDS (Solvent Delivery System). Commercial grade reagents were used without further purification. Silica column chromatography was performed on 230-400 mesh silica gel. Thin layer chromatography (TLC) was carried out on glass-backed silica gel plates. Visualisation was effected by UV light (254 nm) or by staining with potassium permanganate solution or cerium ammonium molybdate followed by heating. ¹H and ¹³C NMR spectra were recorded on Bruker AV-400 and AV-500 MHz spectrometers at room temperature (298 K). Chemical shifts are reported in parts per million (ppm) referenced from CDCh (5H: 7.26 ppm and 5c : 77.0 ppm) or MeOD (5H: 3.31 ppm and 5c : 49.0 ppm). Coupling constants (J) are reported in Hertz (Hz). Multiplicities are given as multiplet (m), singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin.) and broad (br). Optical rotations were determined on an Anton Paar MCP 300 polarimeter at 589 nm at 25 °C. Specific rotations are given in units of 10^_1 deg cm² g^-1. High resolution mass spectra (HRMS) were performed by the “Centre regional de spectroscopie de masse de I’Universite de Montreal” with electrospray ionisation (ESI) coupled to a quantitative time- of-flight (TOF) detector.

Overview of synthesis of compounds 3 to 12

[0184] Compounds 3 and 5 - 9 were made up at 50 mM in DMSO. Compound 4 (perphenazine) was purchased from Sigma (P6402-1G) and made up in EtOH. Compounds 10 - 12 were made up at 5 mM in H2O. Calyculin A was purchased from VWR (89157-750) and made up in EtOH

[0185] All reactions involving moisture sensitive compounds were performed in flame- dried glassware under a positive pressure of dry, oxygen free, argon and in dry solvents. Anhydrous solvents were distilled under a positive pressure of argon before use and dried by standard methods. THF, ether, CH2CI2 and toluene were dried by the Solvent Delivery System (SDS). Commercial grade reagents were used without further purification. Silica column chromatography was performed on 230-400 mesh silica gel. Thin layer chromatography (TLC) was carried out on glass-backed silica gel plates. Visualisation was effected by UV light (254 nm) or by staining with potassium permanganate solution or cerium ammonium molybdate followed by heating. ¹H and ¹³C NMR spectra were recorded on Bruker AV-400 and AV-500 MHz spectrometers at room temperature (298 K). Chemical shifts are reported in parts per million (ppm) referenced from CDCh (5H: 7.26 ppm and 5c : 77.0 ppm) or MeOD (5H: 3.31 ppm and 5c : 49.0 ppm). Coupling constants (J) are reported in Hertz (Hz). Multiplicities are given as multiplet (m), singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin.) and broad (br.). Optical rotations were determ ined on an Anton Paar MCP 300 polarimeter at 589 nm at 25 °C. Specific rotations are given in units of 10¹ deg cm² g-¹. High resolution mass spectra (HRMS) were performed by the “Centre regional de spectroscopie de masse de I’Universite de Montreal” with electrospray ionisation (ESI) coupled to a quantitative time-of-flight (TOF) detector.

[0186] Synthesis of compound 5 (SMAP) is shown in Fig. 11. The conditions for reactions were as follows:

• (a) VO(acac)2, TBHP, Toulene, Rx, 65%;

• (b) NaH, BnBr, THF, 50 °C, 68%;

• (c) 10J-P, Yb(OTf)₃ 1 ,2-DCE, 93%;

• (d) H₂, Pd/C, THF/MeOH (1 :1 ), 96%;

• (e) SO2CI2, EtsN, CH2CI2, -78 °C;

• (f) NaNs, DMF, 94%;

• (g) H2O, THF, 96%;

• (h) sulfonyl chloride, Et3N, DCM 0 °C to rt, 74-93%.

[0187] Synthesis of compounds 6 to 9 is shown in Fig. 12. The conditions for reactions were as follows:

• 1 . Bromoacetylchloride, MeCN/Et₂0 (10:1 ), rt; 2. BH₃.Me₂S, THF, 0 °C, 42-69% over 2 steps.

• 1. tert- butyl (2S,3R)-2-(hydroxymethyl)-3-(4-octylphenyl)pyrrollidine-1- caroxylate, NaH, DMF, rt; 2. HCI (4M), dioxane, rt, 62-71 % over 2 steps.

[0188] Synthesis of 10 to 12 is shown in Fig. 13. The conditions for reactions were as follows:

• (a) 1. 5-brompent-1-ene, TBAI, NaOH (50% w/w), rt, 85%; 2. Os, CH2CI2, -78 °C then PPhs, 95%;

• (b) 3-iodopyridine, EtMgBr, THF, 0 °C, 91%;

• (c) AC₂0, pyridine, 0 °C to rt, 9=87%; 2. H2, Pd/C, MeOH; 3. HCI (4M), dioxane, 38% over 2 steps;

• (d) HCI (4M), dioxane, rt, 96%;

• (e) 1. 5-iodo-2,4-dimethoxypyrimidine, EtMgBr, THF, 0 °C 88%; 2. HCI (4M), dioxane, rt, 93% over 2 steps. Synthesis of SMAP

5a 5b

[0189] (1S,2S, 6F?)-7-Oxabicyclo[4.1 0]heptan-2-ol (5b): (S)-cyclohex-2-en-1-ol 5a was synthesized in accordance with the procedure from Nicolaou et at. ( J . Am. Chem. Soc. 95:6136-6137 (1973), the disclosure of which is incorporated herein by reference). To a solution of 5a (50 mg, 0.51 mmol, 1 .0 eq.) in dry toluene (1 mL) was added VO(acac)2 (1.9 mg, 0.007 mmol, 0.014 eq.). The solution was refluxed and TBHP (62.5 pL, 0.56 mmol, 1.1 eq) was added dropwise. The reaction was stirred for 1.5 h whereby TLC analysis indicated that the reaction went to completion. The solution was cooled to rt and a solution of acetic anhydride (200 pl_) and dry pyridine (275 mI_) was added. The resulting solution was stirred overnight and then poured onto ice. Et20 (4 mL) was added and the organic layer was washed with water (2 mL), HCI aq (2 mL, 1 .0 M), NaHSCte satd. aq. sol. (2mL), NaHCCb satd. aq. sol. (2 mL) and brine (2 mL), dried over Na2S04, filtered and concentrated. The crude was purified by flash column chromatography (8:2 hexane/EtOAc, R f. 0.28) to afford 5b as an incolore oil (38 mg, 65%). [O]²⁵D: -67.8 (c 1 .02, CHCh). The spectral data matched those reported in the literature (A. Bongini et al. J. Org. Chem. 47:4626 (1982), the disclosure of which is herein incorporated by reference).

5b 5c

[0190] ( 1R, 2S, 6R)-2-(Benzyloxy)-7-oxabicyclo[4.1 .0]heptane (5c): To a suspension of

NaH (14 mg, 60% in mineral oil, 0.35 mmol, 2.0 eq.) in dry THF (750 pL) was added BnBr (20.5 pL, 0.17 mmol, 0.96 eq.) and the suspension was warmed up to 50 °C. A solution of 5b (50 mg, 0.18 mmol, 1.0 eq.) in dry THF (500 pL) was added and the resulting solution was stirred at 55 °C for 18 h whereby TLC analysis indicated that the reaction went to completion. The solution was cooled down to rt and quenched with water. Et20 (2 mL) was added, the organic layer was collected, washed with water (2 mL), dried over Na2S04, filtered and concentrated. The crude was purified by flash column chromatography (85:15 hexane/EtOAc, R f: 0.34) to afford 5c as an incolore oil (25 mg, 68%). [O]²⁵D: -39.4 (c 0.95, CHCls). ¹ H NMR (500 MHz, CDCIs) d 6.98 - 6.81 (m, 8H), 5.32 (dd, J = 5.7, 3.7 Hz, 1 H), 5.25 (dd, J = 9.9, 4.8 Hz, 1 H), 4.11 (ddd, J = 12.5, 9.9, 4.4 Hz, 1 H), 2.39 (dd, J = 12.2, 2.1 Hz, 1 H), 2.23 - 2.14 (m, 1 H), 1.83 - 1.60 (m, 4H). ¹³C NMR (126 MHz, CDCIs) d 138.8, 128.4, 127.8, 127.6, 77.4, 77.2, 76.9, 74.7, 70.2, 54.1 , 53.5, 25.0, 23.1 , 19.8. HRMS (ESI) calcd. for CisHieO (M+H)⁺ 204.11503, found 204.11524.

[0191] (7R,2S,6S)-2-(Benzyloxy)-6-(10H-phenoxazin-10-yl)cyclohexan-1-ol (5d): To a solution of phenoxazine (218 mg, 1.18 mmol, 2.4 eq.) in dry 1 ,2-dichloroethane (1.65 mL) was added 5c (100 mg, 0.49 mmol, 1.0 eq.) followed by Yb(OTf)3 (91 mg, 0.15 mmol, 0.3 eq.). The reaction was stirred overnight whereby TLC analysis indicated that the reaction went to completion. The suspension was filtered over Celite and washed thoroughly with EtOAc then concentrated. The crude was purified by flash column chromatography (85:15 hexane/EtOAc, R f: 0.34) to afford 5d as a silver foam (175 mg, 93%). [O]²⁵D: +19.9 (c 0.93, CHCls). ¹H NMR (400 MHz, CDCIs) d 7.43 - 7.27 (m, 5H),

7.00 - 6.73 (m, 8H), 4.68 (q, J = 12.0 Hz, 2H), 4.04 (s, 1 H), 3.98 (dd, J = 10.7, 3.0 Hz, 1 H), 3.89 (t, J = 11.0 Hz, 1 H), 2.78 (bs, 1 H), 2.16 - 1.95 (m, 2H), 1.63 (m, 3H), 1.37 - 1.27 (m, 1 H). ¹³C NMR (126 MHz, CDCIs) d 150.2, 138.9, 135.2, 128.5, 127.8, 127.7,

127.6, 123.7, 123.3, 119.8, 116.2, 77.6, 77.4, 77.2, 76.9, 73.1 , 71.7, 67.0, 28.7, 28.3, 19.7. HRMS (ESI) calcd. for C25H25NO3 (M+H)⁺ 388.18344, found 388.18362.

[0192] (7S,2R,3S)-3-(10H-Phenoxazin-10-yl)cyclohexane-1 ,2-diol (5e): To a solution of 5d (143 mg, 0.37 mmol, 1.0 eq.) in dry THF/MeOH 4 ml_, 1 :1) was added Pd/C (7.5 mg, 0.037 mmol, 0.1 eq.) and the flask was purged with a balloon of H2. Stirred at rt for 5h whereby TLC analysis indicated that the reaction went to completion. The suspension was filtered over Celite, concentrated to afford 5e as a brown powder (129 mg, 92%). R f. 0.29 (6:4 hexane/EtOAc) [a]²¾: -25.8 (c 0.67, CHCh). ¹H NMR (500 MHz, CDCh) d 6.99 - 6.81 (m, 8H), 4.27 (q, J = 2.9 Hz, 1 H), 3.96 (dd, J = 10.6, 3.0 Hz, 1 H), 3.82 - 3.74 (m, 1 H), 3.19 (bs, 1 H), 2.47 (bs, 1 H), 1.96 (m, 2H), 1.78 - 1.66 (m, 1 H), 1.57 - 1.37 (m, 3H). ¹³C NMR (126 MHz, CDCh) d 150.6, 134.7, 124.1 , 123.9, 120.6, 116.4, 77.4, 77.2, 76.9, 72.9, 69.4, 67.1 , 30.0, 27.5, 19.5. HRMS (ESI) calcd. for C18H19NO3 (M+H)⁺ 298.13649, found 298.13656.

[0193] (3aR,4S,7aS)-4-(10H-Phenoxazin-10-yl)hexahydrobenzo[d][1 ,3,2]dioxathiole 2,2-dioxide (5f): To a suspension of 5e (20 mg, 0.067 mmol, 1.0 eq.) in dry CH2Cl2 (1.2 ml_) was added dry Et3N (93 pL, 0.67 mmol, 10.0 eq.) and the resulting solution was cooled to -78 °C whereby SO2CI2 (804 pl_, 0.5 M in CH2CI2, 0.402 mmol, 6.0 eq.) was added dropwise. The solution was stirred at -78 °C for 2 h, then canulated to another flask containing CH2CI2 (5 ml_) with a NaHCCb satd. aq. sol. (5 ml_). The aqueous layer was extracted with CH2CI2 (5 ml_). The combined organic layers were washed with brine (5 ml_), dried over Na2S04, filtered, concentrated. The crude was purified by flash column chromatography (7:3 hexane/EtOAc, R f: 0.25) to afford 5f as a brown oil (24 mg, 58% of yield, 75% of conversion). [O]²⁵D: +48.9 (c 0.43, CHCh). ¹H NMR (500 MHz, CDCh) d 6.98 - 6.81 (m, 8H), 5.32 (dd, J = 5.7, 3.7 Hz, 1 H), 5.25 (dd, J = 9.9, 4.8 Hz, 1 H), 4.11 (ddd, J = 12.5, 9.9, 4.4 Hz, 1 H), 2.39 (dd, J = 12.2, 2.1 Hz, 1 H), 2.23 - 2.14 (m, 1 H), 1.83 - 1.60 (m, 4H). ¹³C NMR (126 MHz, CDCh) d 150.4, 133.7, 124.2, 123.8, 119.9, 116.4, 84.0, 82.3, 77.2, 76.9, 76.7, 65.2, 29.6, 27.8, 26.7, 19.0. HRMS (ESI) calcd. for C18H17NO5S (M+H)⁺ 360.09002, found 360.08953.

[0194] (7R,2R,6S)-2-Azido-6-(10H-phenoxazin-10-yl)cyclohexan-1-ol (5g): To a solution of 5f (36 mg, 0.1 mmol, 1 .0 eq.) in dry DMF (2.0 ml_) was added NalSh (11.7 mg, 0.18 mmol, 1 .8 eq.) and the reaction was stirred at 80 °C for 3.5 h whereby TLC analysis indicated that the reaction went to completion. The solution was concentrated and diluted with Et20 (7 ml_). A H2SO4 aq. (7ml_, 20% w/w) was added and the biphasic mixture was stirred for 1 h whereby TLC analysis showed no more sulfonate. NaHC03 was slowly added dropwise to the solution until no more gas formation was observed. The aqueous layer was extracted with Et20 (7 mL). The combined organic layers were washed with brine (1 x 7 mL), dried over Na2S04, filtered, concentrated. The crude was purified by flash column chromatography (9:1 hexane/EtOAc, R f: 0.3) to afford 5g as an incolore oil (30 mg, 94%). [O]²⁵D: -9.3 (c 0.30, CHC ¹H NMR (500 MHz, CDCIs) d 7.00 -6.82 (m, 8H), 3.84 (t, J = 9.7 Hz, 1 H), 3.39 (m, 1 H), 3.35 - 3.26 (m, 1 H), 3.24 (s, 1 H), 1 .96 (m, 2H), 1 .78 (m, 1 H), 1.54 (m, 1 H), 1.31 (m, 2H). ¹³C NMR (126 MHz, CDCIs) d 150.6, 134.4, 124.3, 123.9, 120.9, 116.4, 77.3, 77.0, 76.8, 75.7, 71.8, 65.4, 29.9, 29.7, 27.1 , 22.2. HRMS (ESI) calcd. for C18H18N4O2 (M+H)⁺ 323.15025, found 323.15050.

[0195] (7S,2R,6S)-2-Amino-6-(10H-phenoxazin-10-yl)cyclohexan-1-ol (5h): To a solution of 5g (26 mg, 0.081 mmol, 1 .0 eq.) in dry THF (1 mL) cooled to 0 °C was added water (7.3 pL, 0.81 mmol, 10.0 eq.) followed by PPh3 (53 mg, 0.202 mmol, 2.5 eq.). The solution was stirred at 0 °C for 5 min then warmed up to 50 °C for 6h whereby TLC/mass analyses indicated that the reaction went to completion. The mixture was concentrated. The crude was purified by flash column chromatography (9:1 ChteCte/MeOH, R f: 0.45) to afford 5h as orange crystals (23 mg, 96%). [O]²⁵D: -4.7 (cO.43, CHCh). ¹H NMR (400 MHz, MeOD) d 7.09 - 6.70 (m, 8H), 3.86 (t, J = 9.7 Hz, 1 H), 3.48 (td, J = 12.1 , 4.2 Hz, 1 H), 2.88 - 2.74 (m, 1 H), 2.03 - 1 .74 (m, 4H), 1.56 - 1 .24 (m, 2H). ¹³C NMR (126 MHz, MeOD) d 151.0, 136.5, 124.7, 123.9, 120.0, 116.8, 75.1 , 70.4, 57.3, 49.9, 49.5, 49.3, 49.2, 49.0, 48.8, 48.7, 48.5, 31.2, 29.5, 23.5. HRMS (ESI) calcd. for C18H20N2O2 (M+H)⁺ 297.1598, found 297.1592.

[0196] N -((1R, 2R, 3S)-2-Hydroxy-3-(10H-phenoxazin-10-yl)cyclohexyl)-4-

(trifluoromethoxy)benzenesulfonamide (5): To a solution of 5h (5.0 mg, 0.017 mmol, 1.0 eq.) in dry CH2CI2 (135 pL) cooled to 0 °C was added dry Et3N (95 pl_, 0.068 mmol, 4.0 eq.). A solution of 4-(trifluoromethoxy)benzenesulfonyl chloride (38 mI_, 0.019 mmol, 1.1 eq.) was then added over 1 h. The solution was allowed to reach rt and stirred for an additional 1 h whereby TLC analysis indicated that the reaction went to completion. Water (300 mI_) was added and the biphasic solution was diluted with CH2CI2 (300 mI_). The aqueous layer was extracted with CH2CI2 (1 ml_). The organic layers were combined, washed with brine, dried over Na2S04, filtered, concentrated. The crude was purified by flash column chromatography (8:2 hexane/EtOAc, R f: 0.23) to afford 5 as an incolore oil (10 mg, 81 %). [O]²⁵D: +11.2 (c 0.1 , CH2CI2) / -10.0 (c 0.1 , MeOH). ¹H NMR (500 MHz, MeOD) d 8.09 - 7.93 (m, 2H), 7.48 - 7.39 (m, 2H), 7.02 - 6.65 (m, 8H), 3.83 (t, J = 9.8 Hz, 1 H), 3.39 (ddd, J = 12.7, 10.3, 4.2 Hz, 1 H), 3.10 (m, 1 H), 1.93 (m, 1 H), 1.83 - 1.73 (m, 2H), 1.73 - 1.61 (m, 1 H), 1.37 - 1.27 (m, 2H). ¹³C NMR (126 MHz, MeOD) d 151.5, 149.5, 140.8, 135.1 , 129.1 , 123.2, 122.4, 121.4, 120.7, 119.3, 118.5, 115.3, 72.8, 69.1 , 59.1 , 48.2, 48.1 , 47.9, 47.8, 47.6, 47.4, 47.3, 47.1 , 32.2, 28.4, 22.1. ¹⁹F NMR (376 MHz, MeOD) d -59.37. HRMS (ESI) calcd. for C25H23F3N2O5S (M+H)⁺ 521.1353, found 521.1353.

Synthesis of hybrid phenoxazine/phenothiazine

[0197] The products was synthesized according to the procedure reported by P. J. Houghton et at. ( J . Med. Chem. 11:3358-3364 (1992), the disclosure of which is incorporated herein by reference). Phenoxazine or phenothiazine (2.00 mmol, 1.0 eq.) was dissolved in a mixture of dry acetonitrile/diethyl ether (5 ml_:0.5 ml_). Bromoacetyl chloride (6.00 mmol, 3.0 eq.) was then added dropwise with constant stirring. The resulting mixture was stirred at rt for 18h whereby TLC analysis indicated that the reaction went to completion. The solution was then quenched with water (1 ml_) and diluted with an aqueous NaOH solution (50 ml_, 1.0 M) and EtOAc (50 ml_). The aqueous layer was extracted with EtOAc (2 x 50 ml_). The combined organic layers were collected, dried over Na2S04, filtered and concentrated under reduced pressure to afford the amide derivative as a colorless oil. The product was engaged in the next step without further purification. [0198] The crude residue (2.00 mmol, 1 .0 eq.) was dissolved in dry THF (5.0 ml_) and the resulting solution was cooled to 0 °C. A solution of BH3*Me2S (6.0 ml_, 6.00 mmol, 3.0 eq., C = 1 .0 M) was then added dropwise and the solution was stirred at rtfor24h whereby TLC analysis indicated that the reaction went to completion. The solution was quenched with distilled water (1 mL) and the aqueous layer was extracted with EtOAc (3 x 5 mL). The organic layers were combined, washed with brine (1 x 5 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel to afford the titled compound.

[0199] To a solution of tert-butyl (2S,3R)-2-(hydroxymethyl)-3-(4- octylphenyl)pyrrolidine-1-carboxylate 3 (0.53 mmol, 1.0 eq.) in dry DMF (3.0 mL) was added NaH (0.8 mmol, 1 .5 eq., 60% in mineral oil) in 2 portions. The reaction was stirred at rt until gas formation ceased (e.g. 10 mins). The bromo tricyclic derivative (0.66 mmol, 1.3 eq.) was then added in 3 portions and the resulting solution was stirred at rt for 2h whereby TLC analysis indicated that the reaction went to completion. MeOH (3.0 mL) was added followed by distilled water (3.0 mL). The aqueous layer was extracted with Et20 (3.0 mL) and the organic layers were collected, washed with distilled water (3.0 mL), brine (3.0 mL), dried over Na2S04, filtered and concentrated. The residue was chromatographed on silica gel (85: 15 hexane/EtOAc) and brought to the next step without further purification.

[0200] The compound (0.21 mmol, 1.0 eq.) was dissolved in HCI (1.0 mL, XS, 4M in dioxane) and stirred at rt for 1 h30 whereby TLC analysis indicated that the reaction went to completion. The solution was concentrated and the residue was chromatographed on silica gel to afford the titled compound.

[0201] 10-(3-Bromopropyl)-10H-phenoxazine (6a): Chromatographed on silica gel with hexane/EtOAc (95:5 hexane/EtOAc, R f: 0.28). Pale green oil, 54% yield over 2 steps; ¹H NMR (500 MHz, Chloroform-d) d 6.81 (ddd, J = 8.0, 7.0, 2.1 Hz, 2H), 6.72 - 6.59 (m, 4H), 6.55 (dd, J = 8.0, 1 .3 Hz, 2H), 3.77 - 3.65 (m, 2H), 3.54 (t, J = 6.1 Hz, 2H), 2.23 (tt, J = 7.4, 6.0 Hz, 2H).; ¹³C NMR (126 MHz, CDCIs) d 145.1 , 133.2, 123.8, 121.2, 115.6, 111.3, 42.3, 30.9, 27.8; HRMS calcd for Ci₅Hi Br⁷⁹NO (M+NH₄)⁺ : 304.033315, found: 304.03299.

[0202] (2S,3R)-2-((3-(10H-Phenoxazin-10-yl)propoxy)methyl)-3-(4- octylphenyl)pyrrolidin-1-ium chloride (6): Chromatographed on silica gel with hexane/EtOAc (95:5 CH2Cl2/MeOH, R f. 0.28). Incolore oil, 62% yield over 2 steps; [O]²⁵D + 7.3 (c 0.17, MeOH); ¹H NMR (500 MHz, Methanol-^) d 7.23 - 7.09 (m, 4H), 6.70 (m, 2H), 6.64 - 6.49 (m, 6H), 3.65 - 3.53 (m, 4H), 3.50 (m, 2H), 3.43 (m, 1 H), 3.29 (m, 1 H), 3.20 (ddd, J = 11.2, 8.7, 7.2 Hz, 1 H), 3.06 (q, J = 8.0 Hz, 1 H), 2.62 - 2.50 (m, 2H), 2.39 - 2.28 (m, 1 H), 2.06 (ddt, J = 12.8, 10.3, 8.6 Hz, 1 H), 1.87 (qd, J = 7.3, 5.7 Hz, 2H), 1.58 (m, 2H), 1.35 - 1.19 (m, 10H), 0.88 (t, J = 7.0 Hz, 3H); ¹³C NMR (126 MHz, MeOD) d

146.3, 143.0, 139.5, 134.6, 130.0, 128.5, 124.8, 121.8, 116.2, 112.9, 71.6, 69.6, 66.8,

48.3, 46.5, 41.5, 36.5, 35.6, 33.0, 32.7, 30.6, 30.4, 30.4, 26.5, 23.7, 14.4; HRMS calcd for C34H45N2O2 (M+H)⁺: 513.34756 and C34H45N2O2 (M+Na)⁺: 535.3295, found: 513.34913 and 535.32443.

[0203] 10-(4-Bromobutyl)-10H-phenoxazine (7a): Chromatographed on silica gel with hexane/EtOAc (95:5 hexane/EtOAc, R f. 0.29). blue solid, 42% yield over 2 steps; ¹H NMR (500 MHz, Chloroform -cf) d 6.80 (m, 2H), 6.72 - 6.58 (m, 4H), 6.48 (dd, J = 8.0, 1 .2 Hz, 2H), 3.57 - 3.50 (m, 2H), 3.47 (t, J = 6.6 Hz, 2H), 2.05 - 1.94 (m, 2H), 1.92 - 1.78 (m, 2H); ¹³C NMR (126 MHz, CDCIs) d 145.2, 133.3, 123.8, 121.1 , 115.6, 111.4, 43.3, 33.1 , 30.1 , 23.9; HRMS calcd for CieHieBrNO (M+H)⁺: 318.04880, found: 318.04889.

[0204] (2S,3R)-2-((4-(10H-Phenoxazin-10-yl)butoxy)methyl)-3-(4- octylphenyl)pyrrolidin-1-ium chloride (7): Chromatographed on silica gel with hexane/EtOAc (95:5 CH2Cl2/MeOH, R f. 0.28). Incolore oil, 64% yield over 2 steps; [O]²⁵D + 9.8° (c O.22, MeOH); ¹H NMR (500 MHz, Methanokfc) d 7.19 - 7.04 (m, 4H), 6.75 (ddd, J = 8.0, 7.3, 1 .7 Hz, 2H), 6.71 - 6.51 (m, 6H), 3.59 - 3.42 (m, 6H), 3.36 (ddd, J = 9.9, 6.3, 3.7 Hz, 1 H), 3.24 (ddd, J = 11.1 , 8.5, 4.2 Hz, 1 H), 3.15 (m, 1 H), 3.02 (td, J = 9.8, 8.1 Hz, 1 H), 2.59 - 2.50 (m, 2H), 2.34 - 2.23 (m, 1 H), 2.01 (ddt, J = 12.8, 10.1 , 8.5 Hz, 1 H), 1.76 - 1 .62 (m, 4H), 1 .57 (m, 2H), 1.39 - 1 .20 (m, 10H), 0.89 (t, J = 7.0 Hz, 3H); ¹³C NMR (126 MHz, MeOD) d 146.3, 142.8, 139.7, 134.6, 129.9, 128.5, 124.9, 121 .8, 116.2, 112.8, 72.0, 71.5, 67.0, 48.2, 46.5, 44.4, 36.5, 35.6, 33.0, 32.7, 30.6, 30.4, 30.3, 27.7, 23.7, 22.9, 14.4; HRMS calcd for C35H46N2O2 (M+H)⁺: 527.36321 , found: 527.36457.

[0205] 10-(5-Bromopentyl)-10/-/-phenoxazine (8a): Chromatographed on silica gel with hexane/EtOAc (gradient: 98:2 to 80:20). Pale violet oil, 66% yield over 2 steps; ¹H NMR (400 MHz, CDCh) 5: 6.88-6.80 (m, 2H), 6.75-6.65 (m, 4H), 6.46-6.50 (m, 2H), 3.42 - 3.54 (m, 4H), 1.92-2.00 (m, 2H), 1.65-1.75 (m, 2H), 1.54-1.63 (m, 2H); ¹³C NMR (100 MHz, CDCh) d 145.0, 133.3, 123.7, 120.9, 115.4, 111.3, 43.8, 33.6, 32.4, 25.5, 24.2; HRMS calcd for Ci₇Hi₉Br⁷⁹NO (M+H)⁺: 332.0645 and Ci₇Hi₈Br⁸¹NO (M+H)⁺ 334.0624, found: 332.0640 and 334.0627.

[0206] (2S,3R)-2-(((5-(10H-Phenoxazin-10-yl)pentyl)oxy)methyl)-3-(4- octylphenyl)pyrrolidin-1-ium chloride (8): Chromatographed on silica gel with CH2Cl2/MeOH (gradient: 98:2 to 90:10). Brown solid, 71 % yield over 2 steps; [O]²⁵D + 12.1 ° (c 0.3, MeOH); ¹H NMR (500 MHz, DMSO-de) 5: 9.96 (br s, 1 H), 9.23 (br s, 1 H), 7.23 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.83-6.77 (m, 2H), 6.67-6.59 (m, 6H), 3.65 - 3.57 (m, 2H), 3.53-3.38 (m, 3H), 3.27-3.18 (m, 1 H), 3.15-3.07 (m, 1 H), 2.53 - 2.50 (m, 2H), 2.33-2.24 (m, 1 H), 2.08-1.98 (m, 1 H), 1.58-1.46 (m, 6H), 1.43-1.36 (m, 2H), 1.28-1.16 (m, 10 H), 0.83 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCh) 5: 144.1 , 141.4, 136.3, 132.8, 128.7, 127.4, 124.1 , 120.7, 115.0, 111.9, 70.4, 67.7, 63.9, 45.1 , 44.2, 42.9, 34.7, 32.6, 31.3, 30.9, 28.8, 28.7, 28.6, 24.1 , 22.7, 22.1 , 13.9; HRMS calcd for C36H48N₂02 (M+H)⁺: 541.7995, found: 541.3810.

9a

[0207] Chromatographed on silica gel with hexane/EtOAc (gradient: 98:2 to 80:20). Pale gray oil, 69% yield over 2 steps; ¹H NMR (400 MHz, CDCIs) 5: 7.19-7.12 (m, 4H), 6.92 (t, J = 7.6 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 3.88 (t, J = 7.0 Hz, 2H), 3.38 (t, J = 6.8 Hz, 2H), 1.92-1.79 (m, 4H), 1.63-1.54 (m, 2H); ¹³C NMR (125 MHz, CDCIs) 5: 145.4, 127.7, 127.4, 125.4, 122.6, 115.6, 47.2, 33.8, 32.5, 26.2, 25.7; HRMS calcd for Ci7Hi₈Br⁷⁹NS (M+H)⁺: 348.0416 and Ci₇Hi₈Br⁸¹NS (M+H)⁺ 350.0396, found: 348.0410 and 350.0391.

[0208] (2S,3R)-2-(((5-(10H-Phenothiazin-10-yl)pentyl)oxy)methyl)-3-(4- octylphenyl)pyrrolidin-1-ium (9): Chromatographed on silica gel with CH2Cl2/MeOH (gradient: 98:2 to 90:10). Yellow solid, 68% yield over 2 steps; [O]²⁵D + 14.6° (c 0.2, MeOH); ¹H NMR (500 MHz, DMSO-de) d : 7.18 (t, J = 7.4 Hz, 4H), 7.13 (d, J = 7.6 Hz, 4H), 7.00 (d = J = 8.2 Hz, 2H), (t, J = 7.4 Hz, 2H), 3.84 (t, J = 6.6 Hz, 2H), 3.50-3.34 (m, 2H), 3.17-3.09 (m, 2H), 3.04-2.97 (m, 2H), 2.54-2.50 (m, 1 H), 2.29-2.20 (m, 1 H), 2.00- 1.90 (m, 1 H), 1.70-1.63 (m, 2H), 1.56-1.43 (m, 4H), 1.42-1.35 (m, 2H), 1.30-1.17 (m, 10H), 0.84 (t, J = 6.8 Hz, 3H); ¹³C NMR (125 MHz, CDCIs) 5: 144.8, 141.1 , 128.6, 127.6, 127.4, 127.1 , 123.7, 122.4, 115.8, 70.4, 68.8, 64.4, 46.4, 45.4, 44.7, 34.7,33.1 , 31 .3, 31.0, 28.8,28.7, 28.7, 28.5, 26.0, 22.9, 22.1 , 14.0; HRMS calcd for C36H48N2OS (M+H)⁺: 557.3560, found: 541.3543. Synthesis of hybrid sphingolipid-N-heteroaromatic compounds

3 3a

[0209] tert- Butyl (2S, 3R)-3-(4-Octylphenyl)-2-((pent-4-en-1 -yloxy)methyl)pyrrolidine- 1 -carboxylate (3a): A solution of 5-bromo-1-pentene (0.03 mL, 0.27 mmol, 5.2 eq) and tetrabutylammonium iodide (19 mg, 0.05 mmol, 1.0 eq) was stirred at rt for 20 min. 3 (20 mg, 0.05 mmol, 1.0 eq) and a 50% w/w aqueous solution of NaOH (0.07 mL) were added successively and the mixture was stirred overnight. The mixture was extracted with CH2CI2 and the organic layer was washed with brine, dried over MgSC , filtered and evaporated to dryness. The crude product was purified by column chromatography (9:1 hexane/EtOAc) to give 3b (20 mg, 85%) as a colorless oil. [O]²⁵D +12.7° (c 0.15, MeOH); ¹H NMR (500 MHz, CDCIs): d 7.11 (s, 4H), 5.80 (ddt, J = 17.0, 10.5, 6.5 Hz, 1 H), 5.02- 4.98 (m, 1 H), 4.96-4.94 (m, 1 H), 3.99-3.81 (m, 1 H), 3.73-3.64 (m, 1 H), 3.62-3.50 (m, 2H), 3.46-3.43 (m, 3H), 3.39-3.31 (m, 1 H), 2.59-2.54 (m, 2H), 2.29-2.21 (m, 1 H), 2.12-2.06 (m, 2H), 1.93-1.83 (m, 1 H), 1.64-1.58 (m, 4H), 1.48 (s, 9H), 1.31-1.26 (m, 10H), 0.88 (t, J = 7.0 Hz, 3H). ¹³C NMR (125 MHz, CDCIs): d 154.5, 141.3, 138.4, 131.0, 128.7, 127.2, 114.8, 79.6, 70.7, 63.8, 46.7, 46.2, 45.7, 35.7, 32.0, 31.8, 31.7, 30.5, 29.9, 29.6, 29.5, 29.4, 29.1 , 22.8, 14.3; HRMS calcd for C₂₉H47NOsNa: 480.3448. Found: 480.3464.

3a 3b

[0210] tert- Butyl (2S,3R)-3-(4-octylphenyl)-2-((4-oxobutoxy)methyl)pyrrolidine-1- carboxylate (3b): O3 was bubbled through a solution of 3a (414 mg, 0.90 mmol) in CH2CI2 (40 mL) at -78 °C until the solution was saturated (blue color). Then, argon was bubbled through the solution for 15 min to remove the excess of O3 and Ph3P (2.36 g, 9 mmol, 10 eq.) was added. The mixture was allowed to reach room temperature and stirred for 1 hour. Finally, the solution was concentrated in vacuo. The crude was purified by flash column chromatography (EtOAc/hexane 1 :4, R f: 0.24) to give 3b as a colorless oil (393 mg, 95%). O ²⁵D +21.1 (c 0.95, CHCIs); ¹H NMR (CDC , 500 MHz, mixture of rotamers), a: 9.74 (t, J = 1 .5 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 2 H), 7.10 (d, J = 8.5 Hz, 2 H), 3.94 (br. s, 0.45 H), 3.82 (br. s, 0.55 H), 3.70 (br. s, 1 H), 3.59 (br. s, 0.55 H), 3.53 (br. s, 1.45 H), 3.48-3.45 (m, 2 H), 3.40-3.36 (m, 1 H), 3.33 (br. s, 1 H), 2.58-2.55 (m, 2 H), 2.47 (br. s, 2 H), 2.26-2.19 (m, 1 H), 1.89-1.86 (m, 3 H), 1.62-1.56 (m, 2 H), 1.48 (s, 9 H), 1.30-1.26 (m, 10 H), 0.87 (t, J = 6.9 Hz, 3 H); ¹³C NMR (CDCb, 125 MHz, mixture of rotamers), d: 202.4, 202.2, 154.3, 141.2, 140.6, 140.3, 128.6, 127.1 , 79.5, 79.3, 70.8, 70.1 , 69.6, 63.6, 63.3, 46.8, 46.5, 46.1 , 45.8, 40.9, 35.5, 32.6, 31.9, 31.5, 29.7, 29.4, 29.2, 28.5, 22.6, 14.1 ;

HRMS (ESI) calcd. for C28H45N0₄Na (M+Na)⁺ 482.3241 , found 482.3241.

3b 3c

[0211] tert- Butyl (2S,3R)-2-((4-hydroxy-4-(pyridin-3-yl)butoxy)methyl)-3-(4- octylphenyl)pyrrolidine-1-carboxylate (3c): EtMgBr (370 pL, 1 M in THF, 0.37 mmol, 4.4 eq.) was added dropwise to a solution of 3-iodopyridine (68 mg, 0.33 mmol, 4 eq.) in dry THF (2 ml_). The resulting mixture was stirred for 30 min at room temperature, before being cooled down to 0 °C. Then, a solution of 3b (38 mg, 0.083 mmol) in dry THF (1 ml_), was added dropwise and the resulting mixture was stirred for 1 hour at 0 °C. Afterwards, the reaction was quenched with NH4CI satd. aq. sol. (3 ml_) and the product was extracted with EtOAc (3 x 15 ml_). The combined organic layers were washed with NaHCC satd. aq. sol. (3 ml_) and brine (3 ml_), dried over Na2S04, filtered and concentrated. The crude was purified by flash column chromatography (pure EtOAc, R f: 0.25) to give 3c as a pale yellow oil (41 mg, 91 %, containing a residual inseparable impurity). ¹H NMR (CDC , 500 MHz, mixture of rotamers and diastereoisomers), d: 8.58 (s, 1 H), 8.50 (dd, J = 4.8, 1.4 Hz, 1 H), 7.74-7.71 (m, 1 H), 7.30-7.27 (m, 1 H), 7.11 (s, 4 H), 4.75 (dd, J = 8.0, 4.6 Hz, 1 H), 3.96 (br. s, 0.5 H), 3.84 (br. s, 0.5 H), 3.81 (br. s, 0.5 H), 3.71 (br. s, 0.5 H), 3.61 (br. s, 1 H), 3.58-3.54 (m, 2 H), 3.53 (br. s, 1 H), 3.40-3.36 (m, 2 H), 2.57-2.54 (m, 2 H), 2.24- 2.19 (m, 1 H), 1.91-1.83 (m, 3 H), 1.71-1.69 (m, 2 H), 1.61-1.55 (m, 2 H), 1.47 (s, 9 H), 1.30-1.25 (m, 10 H), 0.87 (t, J = 7.0 Hz, 3 H); ¹³C NMR (CDCIs, 125 MHz, mixture of rotamers and diastereoisomers), d: 154.5, 154.1 , 148.3, 147.5, 141.4, 133.8, 128.7, 127.1 , 124.5, 79.7, 79.5, 71.7, 71.2, 70.8, 69.6, 63.6, 63.3, 46.9, 46.5, 46.2, 45.9, 37.0, 36.9, 35.5, 32.7, 31.9, 31.5, 29.7, 29.5, 29.4, 29.2, 28.5, 26.1 , 22.7, 14.1 ; HRMS (ESI) calcd. for C33H51N2O4 (M+H)⁺ 539.3843, found 539.3852.

3c 3d

[0212] tert- Butyl (2S,3R)-2-((4-acetoxy-4-(pyridin-3-yl)butoxy)methyl)-3-(4- octylphenyl)pyrrolidine-1-carboxylate (3d): Acetic anhydride (200 pL) was added to a solution of 3c (35 mg, 0.065 mmol) in pyridine (1 ml_) at 0 °C and the resulting mixture was stirred overnight at room temperature. Afterward, the reaction was diluted with Et20 (5 ml_) and washed with NaHCCb satd. aq. sol. (2 ml_), H2O (2 ml_) and brine (2 ml_). The organic layer was dried over Na2S04, filtered and concentrated. The crude was purified by flash column chromatography (EtOAc/hexane 1 :1 , R f. 0.30) to give 3d as a colorless oil (33 mg, 87%); ¹H NMR (CDC , 500 MHz, mixture of rotamers and diastereoisomers), d: 8.59 (s, 1 H), 8.54 (d, J = 4.3 Hz, 1 H), 7.63-7.61 (m, 1 H), 7.28-7.25 (m, 1 H), 7.10 (d, J = 8.3 Hz, 2 H), 7.08 (d, J = 8.3 Hz, 2 H), 5.77-5.74 (m, 1 H), 3.95 (br. s, 0.45 H), 3.83 (br. s, 0.55 H), 3.66 (br. s, 1 H), 3.57 (br. s, 0.55 H), 3.51 (br. s, 1.45 H), 3.44-3.43 (m, 2 H), 3.41-3.37 (m, 1 H), 3.32 (br. s, 1 H), 2.57-2.54 (m, 2 H), 2.24-2.19 (m, 1 H), 2.07 (s, 3 H), 2.00-1.93 (m, 1 H), 1.88-1.81 (m, 2 H), 1 .61-1 .55 (m, 3 H), 1.46 (s, 10 H), 1.30-1.25 (m, 10 H), 0.87 (t, J = 7.0 Hz, 3 H); ¹³C NMR (CDCIs, 125 MHz, mixture of rotamers and diastereoisomers), d: 170.1 , 154.4, 154.3, 149.3, 148.3, 141.2, 136.1 , 134.2, 128.6, 127.0, 123.4, 79.5, 79.3, 73.7, 70.9, 70.5, 69.6, 63.6, 63.2, 46.6, 46.5, 46.0, 45.6, 35.5, 32.8, 32.6, 32.5, 31.9, 31.7, 31.5, 29.7, 29.5, 29.4, 29.2, 28.5, 25.8, 22.6, 21.1 , 14.1 ; HRMS (ESI) calcd. for C35H53N2O5 (M+H)⁺ 581.3949, found 581.39623.

[0213] 3-(4-(((2S,3R)-3-(4-Octylphenyl)pyrrolidin-2-yl)methoxy)butyl)pyridine hydrochloride (10): 3d (17 mg, 0.029 mmol) was dissolved in MeOH (4 ml_) and Pd/C (10%, 10 mg) was added to the resulting solution. The air was removed from the flask under vacuum and replaced with hydrogen (balloon). The reaction was vigorously stirred for 2 hours at room temperature. Afterwards, the mixture was filtered through a celite pad, washing with MeOH and the collected solution was concentrated in vacuo. The crude was purified by flash column chromatography (EtOAc/hexane 1 :1 , R f: 0.27) to give a colorless oil. This intermediate was dissolved in dry dioxane (120 pL) and HCI (120 pl_, 4 M in dioxane) was added to the solution. The reaction was stirred at r.t. for 2 hours. The solution was then concentrated in vacuo in several cycles co-distilling with dry dioxane. The crude was triturated three times in Et20 affording 10 as a white solid (5 mg, 38%). O²⁵D +12.5 (c 1.03, MeOH); (NMR spectra were recorded using the free amine form) ¹H NMR (CDsOD, 500 MHz), d: 8.40 (s, 1 H), 8.37 (d, J = 4.9 Hz, 1 H), 7.71 (d, J = 7.8 Hz,

1 H), 7.37 (dd, J = 7.8, 4.9 Hz, 1 H), 7.21 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 8.2 Hz, 2 H), 3.56-3.46 (m, 5 H), 3.39-3.33 (m, 1 H), 3.28-3.23 (m, 1 H), 3.14-3.09 (m, 1 H), 2.69 (t, J = 7.6 Hz, 2 H), 2.62-2.59 (m, 2 H), 2.38-2.33 (m, 1 H), 2.14-2.08 (m, 1 H), 1.76-1.70 (m,

2 H), 1.66-1.60 (m, 4 H), 1.34-1.30 (m, 10 H), 0.91 (t, J = 7.0 Hz, 3 H); ¹³C NMR (CDsOD, 125 MHz), d: 148.6, 146.1 , 141.7, 138.6, 137.4, 136.9, 128.6, 127.1 , 123.7, 70.7, 69.1 , 65.4, 46.3, 44.9, 35.1 , 33.6, 32.1 , 31.6, 31.3, 29.2, 29.0, 28.9, 28.7, 27.3, 22.3, 13.0; HRMS (ESI) calcd. for C28H43N2O (M)⁺ 423.33699, found 423.33859.

[0214] 4-(((2S,3R)-3-(4-Octylphenyl)pyrrolidin-2-yl)methoxy)-1-(pyridin-3-yl)butan-1- ol hydrochloride (11): An amount of 3c (6 mg, 0.011 mmol) was dissolved in dry dioxane (120 mI_) and HCI (120 mI_, 4 M in dioxane) was added to the solution. The solution was stirred at rt for 2h and concentrated. The crude was triturated three times in Et20, then dissolved in CH2CI2, filtering away the insoluble residue, and concentrated again, affording 11 as a colorless residue (5 mg, 96%). ¹H NMR (CDCh, 500 MHz, mixture of diastereoisomers), d: 8.58 (s, 1 H), 8.49 (d, J = 3.7 Hz, 1 H), 7.73-7.70 (m, 1 H), 7.27- 7.24 (m, 1 H), 7.16-7.10 (m, 4 H), 4.79 (td, J = 8.4, 5.1 Hz, 1 H), 3.57-3.46 (m, 3 H), 3.37 (dd, J = 16.8, 7.7 Hz, 1 H), 3.28-3.23 (m, 1 H), 3.20-3.16 (m, 1 H), 3.14-3.07 (m, 1 H), 2.89-2.80 (m, 1 H), 2.58-2.55 (m, 2 H), 2.29-2.22 (m, 1 H), 1.97-1.90 (m, 1 H), 1.87-1.82 (m, 2 H), 1.80-1.76 (m, 0.5 H), 1.75-1.70 (m, 1 H), 1.69-1.64 (m, 0.5 H), 1.62-1.56 (m, 2 H), 1.31-1.25 (m, 10 H), 0.88 (t, J = 6.9 Hz, 3 H); ¹³C NMR (CDCh, 125 MHz, mixture of diastereoisomers), d: 148.5, 147.8, 141.2, 140.6, 140.4, 140.1 , 133.4, 128.6, 127.4, 123.3, 72.4, 71.5, 71.2, 66.1 , 66.0, 47.5, 47.3, 46.2, 37.4, 37.1 , 35.7, 35.5, 31.9, 31.5, 29.7, 29.5, 29.4, 29.2, 25.9, 25.6, 22.7, 14.1 ; HRMS (ESI) calcd. for C28H43N2O2 (M)⁺ 439.3325, found 439.3321.

[0215] fe/f-Butyl (2S,3R)-2-((4-(2,4-dimethoxypyrimidin-5-yl)-4- hydroxybutoxy)methyl)-3-(4-octylphenyl)pyrrolidine-1-carboxylate (3e): EtMgBr (370 mI_, 1 M in THF, 0.37 mmol, 4.4 eq.) was added dropwise to a solution of 5-iodo-2, 4-pyrimidine (88 mg, 0.33 mmol, 4 eq.) in dry THF (2 ml_). The resulting mixture was stirred for 30 min at room temperature, before being cooled down to 0 °C. Then, a solution of 3b (38 mg, 0.083 mmol) in dry THF (1 ml_), was added dropwise and the resulting mixture was stirred for 1 hour at 0 °C. Afterwards, the reaction was quenched with NH4CI satd. aq. sol. (3 ml_) and the product was extracted with EtOAc (3 x 15 ml_). The combined organic layers were washed with NaHCC satd. aq. sol. (3 ml_) and brine (3 ml_), dried over Na2S04, filtered and concentrated. The crude was purified by flash column chromatography (EtOAc/hexane 1 :1 , R : 0.16) to give 3e as a colorless oil (44 mg, 88%); ¹H NMR (CDCh, 500 MHz, mixture of rotamers and diastereoisomers), d: 8.26 (s, 1 H), 7.10 (s, 4 H), 4.77- 4.75 (m, 1 H), 3.99 (s, 3 H), 3.98 (s, 3.5 H), 3.83 (br. s, 0.5 H), 3.80 (br. s, 0.5 H), 3.70 (br. s, 0.5 H), 3.61-3.53 (m, 2 H), 3.51 (br. s, 2 H), 3.40-3.34 (m, 2 H), 2.57-2.54 (m, 2 H), 2.26-2.20 (m, 1 H), 1.92-1.83 (m, 2 H), 1.81-1.73 (m, 1 H), 1.71-1.63 (m, 2 H), 1.61-1.55 (m, 2 H), 1.47 (s, 9 H), 1.30-1.25 (m, 10 H), 0.87 (t, J = 7.0 Hz, 3 H); ¹³C NMR (CDCh, 125 MHz, mixture of rotamers and diastereoisomers), d: 168.2, 164.5, 155.7, 154.5, 154.3, 141.3, 128.6, 127.1 , 117.8, 117.6, 79.6, 79.4, 71.3, 70.8, 69.6, 69.4, 67.6, 63.7,

63.4, 54.7, 53.9, 46.7, 46.6, 46.1 , 45.8, 35.5, 34.2, 32.6, 31.9, 31.7, 31.5, 29.7, 29.4, 29.2,

28.5, 26.2, 22.6, 14.1 ; HRMS (ESI) calcd. for C34H54N3O6 (M+H)⁺ 600.40071 , found 600.40059.

3e 12

[0216] 1-(2,4-Dimethoxypyrimidin-5-yl)-4-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2- yl)methoxy)butan-1-ol hydrochloride (12): An amount of 3e (18 mg, 0.03 mmol) was dissolved in dry dioxane (360 pL) and HCI (360 pl_, 4 M in dioxane) was added to the solution. The solution was stirred at rt for 2h and concentrated. The crude was triturated three times in Et20, then dissolved in CH2CI2, filtering away the insoluble residue, and concentrated again, affording 12 as a white solid (14 mg, 93%); ¹H NMR (CDCh, 500 MHz, mixture of diastereoisomers), d: 8.29 (s, 0.5 H), 8.27 (s, 0.5 H), 7.14-7.10 (m, 4 H), 4.80 (td, J = 8.7, 3.9 Hz, 1 H), 3.99 (s, 3 H), 3.98 (s, 3 H), 3.55-3.46 (m, 3 H), 3.38-3.34 (m, 1 H), 3.23 (ddd, J = 9.7, 7.7, 3.0 Hz, 1 H), 3.18-3.13 (m, 1 H), 3.12-3.07 (m, 1 H), 2.89-2.80 (m, 1 H), 2.58-2.55 (m, 2 H), 2.28-2.21 (m, 1 H), 1.96-1.89 (m, 1 H), 1.88-1.82 (m, 1 H), 1.81-1.75 (m, 1 H), 1 .74-1 .64 (m, 2 H), 1.62-1.56 (m, 2 H), 1.31-1.25 (m, 10 H), 0.87 (t, J = 7.0 Hz, 3 H); ¹³C NMR (CDCh, 125 MHz, mixture of diastereoisomers), d: 168.1 , 164.5, 164.4, 155.7, 141.1 , 140.3, 128.5, 127.4, 118.2, 118.0, 72.3, 71.2, 67.4, 67.1 , 66.2, 54.7, 53.9, 47.4, 47.2, 46.3, 46.2, 35.6, 35.5, 34.6, 34.4, 31.9, 31.5, 29.7, 29.5, 29.4, 29.2, 26.0, 25.8, 22.6, 14.1 ; HRMS (ESI) calcd. for C29H46N3O4 (M)⁺ 500.34828, found 500.35031. Genera/ procedure for the synthesis of tetrazine derives

[0217] Fig. 14 provides an overview of synthesis. To a stirred suspension of arylnitrile (1.0 eq) and zinc trifluoromethanesulfonate (0.25 eq) in acetonitrile (5.0 eq)) was added hydrazine monohydrate (5.0 eq) and the mixture was stirred 18 h at 90 °C. At 0 °C, the mixture was added to a solution of sodium nitrate (30 ml_, 1.0 M) and HCI (2.0 M) was added dropwise until pH 3.0. The mixture was extracted with dichloromethane and the organic layer was dried over MgSC , filtered and evaporated to dryness and the crude product was purified by column chromatography.

[0218] 3-Methyl-6-(pyridin-2-yl)-1 ,2,4,5-tetrazine (i): To a stirred suspension of 2- pyridinecarbonitrile (1.00 g, 9.61 mmol, 1.0 eq) and zinc trifluoromethanesulfonate (878 mg, 2.40 mmol, 0.25 eq) in acetonitrile (2.51 ml_, 5.0 eq)) was added hydrazine monohydrate (2.33 ml_, 48.03 mmol, 5.0 eq) and the mixture was stirred overnight at 90 °C. At 0 °C, the mixture was added to a solution of sodium nitrate (30 ml_, 1.0 M) and HCI (2.0 M) was added dropwise until pH 3.0. The mixture was extracted with dichloromethane and the organic layer was dried over MgS04, filtered and evaporated to dryness and the crude product was purified by column chromatography (EtOAc:dichloromethane, 0:1 to 1 :9) to give 3-methyl-6-(pyridin-2-yl)-1 ,2,4,5-tetrazine (362 mg, 22%) as a purple solid. 1 H NMR (500 MHz, CDCI3): d 8.94-8.90 (m, 1 H), 8.62- 8.59 (m, 1 H), 7.97-7.93 (m, 1 H), 7.54-7.50 (m, 1 H), 3.13 (s, 3H); 13C NMR (125 MHz, CDCI3): d 168.2, 163.7, 150.9, 150.4, 137.5, 126.4, 124.0, 21.4; HRMS calcd for C8H9N5+: 174.07742. Found: 174.07734.

90 °C

II

[0219] 3-Methyl-6-(pyridin-4-yl)-1 ,2,4,5-tetrazine (ii): To a stirred suspension of 4- pyridinecarbonitrile (1.00 g, 9.61 mmol, 1.0 eq) and zinc trifluoromethanesulfonate (878 mg, 2.40 mmol, 0.25 eq) in acetonitrile (2.51 ml_, 5.0 eq)) was added hydrazine monohydrate (2.33 ml_, 48.03 mmol, 5.0 eq) and the mixture was stirred overnight at 90 °C. At 0 °C, the mixture was added to a solution of sodium nitrate (30 ml_, 1.0 M) and HCI (2.0 M) was added dropwise until pH 3.0. The mixture was extracted with dichloromethane and the organic layer was dried over MgS04, filtered and evaporated to dryness and the crude product was purified by column chromatography (EtOAc:dichloromethane, 0:1 to 1 :0) to give 3-methyl-6-(pyridin-4-yl)-1 ,2,4,5-tetrazine (29 mg, 2%) as a purple solid; 1 H NMR (500 MHz, CDCI3): d 8.91 (dd, J = 4.5, 1.5 Hz, 2H), 8.45-8.43 (m, 2H), 3.16 (s, 3H); 13C NMR (125 MHz, CDCI3): d 168.6, 163.2, 151.2, 139.4, 121.4, 21.5; HRMS calcd for C8H9N5+: 174.07742. Found: 174.07732.

_{2 4 2} 90 °C

III

[0220] 3-Methyl-6-phenyl-1 ,2,4,5-tetrazine (iii): To a stirred suspension of benzonitrile (1.00 g, 9.70 mmol, 1.0 eq) and zinc trifluoromethanesulfonate (886 mg, 2.43 mmol, 0.25 eq) in acetonitrile (2.53 ml_, 5.0 eq)) was added hydrazine monohydrate (2.35 ml_, 48.52 mmol, 5.0 eq) and the mixture was stirred overnight at 90 °C. At 0 °C, the mixture was added to a solution of sodium nitrate (30 ml_, 1.0 M) and HCI (2.0 M) was added dropwise until pH 3.0. The mixture was extracted with dichloromethane and the organic layer was dried over MgS04, filtered and evaporated to dryness and the crude product was purified by column chromatography (EtOAc: hexane, 0:1 to 1 :9) to give 3-methyl-6-phenyl-1 ,2,4,5- tetrazine (100 mg, 6%) as a purple solid; 1 H NMR (500 MHz, CDCI3): d 8.59-8.58 (m, 2H), 7.62-7.57 (m, 3H), 3.09 (s, 3H); 13C NMR (125 MHz, CDCI3): d 167.4, 164.2, 132.7, 131.9, 129.4, 128.0, 21.3; HRMS calcd for C9H10N4+: 173.0822. Found: 173.0824.

[0221] 3-(4-Fluorophenyl)-6-methyl-1 ,2,4,5-tetrazine (iv): To a stirred suspension of 4-fluorobenzonitrile (1.00 g, 8.26 mmol, 1.0 eq) and zinc trifluoromethanesulfonate (755 mg, 2.06 mmol, 0.25 eq) in acetonitrile (2.16 ml_, 5.0 eq)) was added hydrazine monohydrate (2.00 ml_, 41.26 mmol, 5.0 eq) and the mixture was stirred overnight at 90 °C. At 0 °C, the mixture was added to a solution of sodium nitrate (30 ml_, 1.0 M) and HCI (2.0 M) was added dropwise until pH 3.0. The mixture was extracted with dichloromethane and the organic layer was dried over MgS04, filtered and evaporated to dryness and the crude product was purified by column chromatography (EtOAc: hexane, 0:1 to 1 :9) to give 3-(4-fluorophenyl)-6-methyl-1 ,2,4,5-tetrazine (287 mg, 18%) as a purple solid. 1 H NMR (500 MHz, CDCI3): d 8.63-8.60 (m, 2H), 7.29-7.26 (m, 2H), 3.10-3.09 (m, 3H); 13C NMR (125 MHz, CDCI3): d 167.4, 166.9, 164.9, 163.5, 130.4 (d, J = 9.0 Hz), 116.6 (d, J = 22.0 Hz), 21.3; 19F NMR (471 MHz; CDCI3): d -106.5; HRMS calcd for C9H8FN4+: 191.0728. Found: 191.0733.

[0222] 3, 6-Bis(4-fluorophenyl)-1 ,2,4,5-tetrazine (v): To a stirred suspension of 4- fluorobenzonitrile (1 .00 g, 8.26 mmol, 2.0 eq) and zinc trifluoromethanesulfonate (374 mg, 1.03 mmol, 0.25 eq) was added hydrazine monohydrate (1.00 ml_, 20.64 mmol, 5.0 eq) and the mixture was stirred overnight at 90 °C. At 0 °C, the mixture was added to a solution of sodium nitrate (30 ml_, 1.0 M) and HCI (2.0 M) was added dropwise until pH 3.0. The mixture was extracted with dichloromethane and the organic layer was dried over MgS04, filtered and evaporated to dryness and the crude product was purified by column chromatography (dichloromethane:hexane, 0:1 to 1 :1 ) to give 3,6-bis(4- fluorophenyl)-1 ,2,4,5-tetrazine (216 mg, 19%) as a purple solid. 1 H NMR (500 MHz, CDCI3): d 8.69-8.65 (m, 4H), 7.33-7.28 (m, 4H); 13C NMR (125 MHz, CDCI3): d 167.0, 165.0, 163.3, 130.4 (d, J = 9.0 Hz), 128.1 (d, J = 3.0 Hz), 116.8 (d, J = 22.0 Hz); 19F NMR (471 MHz; CDCI3): d -106.1 ; HRMS calcd for C14H9F2N4+: 271.0790. Found: 271.0785.

[0223] 3,6-Diphenyl-1 ,2,4,5-tetrazine (vi): To a stirred suspension of benzonitrile (1.00 g, 9.70 mmol, 2.0 eq) and zinc trifluoromethanesulfonate (443 mg, 1.21 mmol, 0.25 eq) was added hydrazine monohydrate (1.18 ml_, 24.26 mmol, 5.0 eq) and the mixture was stirred overnight at 90 °C. At 0 °C, the mixture was added to a solution of sodium nitrate (30 ml_, 1.0 M) and HCI (2.0 M) was added dropwise until pH 3.0. The mixture was extracted with dichloromethane and the organic layer was dried over MgS04, filtered and evaporated to dryness and the crude product was purified by column chromatography (EtOAc: hexane, 0:1 to 2:3) to give 3, 6-diphenyl-1 ,2,4,5-tetrazine (673 mg, 59%) as a purple solid. 1 H NMR (500 MHz, CDCI3): d 8.66-8.63 (m, 4H), 7.65-7.59 (m, 6H); 13C NMR (125 MHz, CDCI3): d 164.1 , 132.8, 131.9, 129.4, 128.1 ; HRMS calcd for C14H12N4+: 235.0978. Found: 235.0973. General procedure for the synthesis of 1 ,2-pyridzine derives

[0224] Fig. 14 provides an overview of synthesis. To a stirred solution of tetrazine derivative (1.0 eq) in DMSO (0.1 M solution) was added the alkene derivative (1.0 eq) and the mixture was stirred overnight at 80 °C. The solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the Boc protected intermediate. This mixture was dissolved in HCI 4 M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography.

[0225] (2S,3R)-2-((3-(6-Methyl-3-(pyrimidin-2-yl)pyridazin-4-yl)propoxy)methyl)-3-(4- octylphenyl)pyrrolidin-1-ium chloride (13A) and (2S,3R)-2-((3-(3-methyl-6-(pyrimidin-2- yl)pyridazin-4-yl)propoxy)methyl)-3-(4-octylphenyl)pyrrolidin-1 -ium chloride (13B): Column chromatography (ChteCte/MeOH, gradient 99:1 to 95:5). To a stirred solution of 3-methyl-6-(pyrimidin-2-yl)-1 ,2,4,5-tetrazine (50 mg, 0.30 mmol, 1.0 eq) in DMSO (2.0 ml_) was added tert-butyl (2S,3R)-3-(4-octylphenyl)-2-((pent-4-en-1- yloxy)methyl)pyrrolidine-1-carboxylate vii (120 mg, 0.30 mmol, 1.0 eq) and the mixture was stirred overnight at 80 °C. The solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the intermediate as a mixture of regioisomers. This mixture was dissolved in dioxane (2.0 ml_) and HCI 4M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (CH2CI2/MeOH, gradient 99:1 to 95:5). In this condition, (2S,3R)-2-((3- (6-methyl-3-(pyrimidin-2-yl)pyridazin-4-yl)propoxy)methyl)-3-(4-octylphenyl)pyrrolidin-1- ium chloride is eluted for first as a colorless gel (20 mg, 14% over 2 steps); [a]²¾ +15.6° (c 0.2, MeOH); ¹H NMR (700 MHz, MeOD) 5: 8.94 (d, J = 5.0 Hz, 2H), 7.67 (s, 1 H), 7.59 (t, J = 5.0 Hz, 1 H), 7.19 (s, 4H), 3.52-3.58 (m, 2H), 3.34-3.49 (m, 5H), 3.01-3.06 (m,

1 H), 2.85-2.96 (m, 2H), 2.72 (s, 3H), 2.60 (t, J = 7.7 Hz, 2H), 2.37-2.42 (m, 1 H), 2.16-

2.23 (m, 1 H), 1.74-1.83 (m, 2H), 1.56-1.62 (m, 2H), 1.23-1.35 (m, 12H), 0.89 (t, J = 7.1 Hz, 3H); ¹³C NMR (175 MHz, MeOD) 5: 164.7, 161.9, 158.9, 158.3, 143.8, 143.8, 136.7,

130.5, 130.2, 128.5, 128.5, 122.5, 71.6, 68.6, 66.4, 46.5, 45.9, 36.5, 33.8, 33.0, 32.7,

30.5, 30.4, 30.3, 29.7, 23.7, 21.7, 14.4; HRMS calcd for C3iH ₄N₅0⁺: 502.3546, found: 502.3534; (2S,3R)-2-((3-(3-methyl-6-(pyrimidin-2-yl)pyridazin-4-yl)propoxy)methyl)-3-(4- octylphenyl)pyrrolidin-1-ium chloride is eluted for last as a colorless gel (20 mg, 14% over

2 steps); [O]²⁵D +12.8° (c 0.2, MeOH); ¹H NMR (700 MHz, MeOD) 5: 8.98 (d, J = 4.8 Hz,

2H), 8.43 (s, 1 H), 7.59 (t, J = 4.8 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz,

2H), 3.72-3.76 (m, 1 H), 3.53-3.65 (m, 5H), 3.36 -3.40 (m, 1 H), 3.23-3.27 (m, 1 H), 2.85 (t, J = 7.7 Hz, 2H), 2.75 (s, 3H), 2.56-2.59 (m, 2H), 2.40-2.45 (m, 1 H), 2.18-2.24 (m, 1 H), 1.96-2.01 (m, 2H), 1.55-1.60 (m, 2H), 1.24-1.33 (m, 12H), 0.88 (t, J = 7.1 Hz, 3H); ¹³C NMR (175 MHz, MeOD) 5: 164.7, 161.9, 158.9, 158.3, 143.8, 143.8, 136.7, 130.5, 130.2, 128.5, 128.5, 122.5, 71.6, 68.6, 66.4, 46.5, 45.9, 36.5, 33.8, 33.0, 32.7, 30.5, 30.4, 30.3, 29.7, 23.7, 21.7, 14.4; HRMS calcd for C3iH₄₄N₅0⁺: 502.3546, found: 502.3536.

[0226] (2S,3R)-2-((3-(3-methyl-6-(pyrimidin-2-yl)pyridazin-4-yl)propoxy)methyl)-3-(4- octylphenyl)pyrrolidin-1-ium chloride (13A): Compound 13A can be separated from compound 13B by careful column chromatography using CH2Cl2/MeOH, gradient 99:1 to 95:5: in this condition compound 1 is eluted for last as a colorless gel (20 mg, 14% over 2 steps); [a]²¾ +12.8° (c 0.2, MeOH); ¹H NMR (700 MHz, MeOD) 5: 8.98 (d, J = 4.8 Hz, 2H), 8.43 (s, 1 H), 7.59 (t, J = 4.8 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 3.72-3.76 (m, 1 H), 3.53-3.65 (m, 5H), 3.36 -3.40 (m, 1 H), 3.23-3.27 (m, 1 H), 2.85 (t, J = 7.7 Hz, 2H), 2.75 (s, 3H), 2.56-2.59 (m, 2H), 2.40-2.45 (m, 1 H), 2.18-2.24 (m, 1 H), 1.96-2.01 (m, 2H), 1.55-1.60 (m, 2H), 1.24-1.33 (m, 12H), 0.88 (t, J = 7.1 Hz, 3H); ¹³C NMR (175 MHz, MeOD) 5: 164.7, 161.9, 158.9, 158.3, 143.8, 143.8, 136.7, 130.5,

130.2, 128.5, 128.5, 122.5, 71.6, 68.6, 66.4, 46.5, 45.9, 36.5, 33.8, 33.0, 32.7, 30.5, 30.4,

30.3, 29.7, 23.7, 21.7, 14.4; HRMS calcd for Csih^NsCT: 502.3546, found: 502.3536.

[0227] (2S,3R)-2-((3-(6-Methyl-3-(pyrimidin-2-yl)pyridazin-4-yl)propoxy)methyl)-3-(4- octylphenyl)pyrrolidin-1-ium chloride (13B): Compound 13B can be separated from compound 13A by careful column chromatography using ChhC /MeOH, gradient 99:1 to 95:5: in this condition, compound 13B is eluted for first as a colorless gel (20 mg, 14% over 2 steps); [O]²⁵D +15.6° (c O.2, MeOH); ¹H NMR (700 MHz, MeOD) 5: 8.94 (d, J = 5.0 Hz, 2H), 7.67 (s, 1 H), 7.59 (t, J = 5.0 Hz, 1 H), 7.19 (s, 4H), 3.52-3.58 (m, 2H), 3.34-3.49 (m, 5H), 3.01-3.06 (m, 1 H), 2.85-2.96 (m, 2H), 2.72 (s, 3H), 2.60 (t, J = 7.7 Hz, 2H), 2.37-2.42 (m, 1 H), 2.16-2.23 (m, 1 H), 1.74-1.83 (m, 2H), 1.56-1.62 (m, 2H), 1.23-1.35 (m, 12H), 0.89 (t, , J = 7.1 Hz, 3H); ¹³C NMR (175 MHz, MeOD) 5: 164.7, 161.9, 158.9, 158.3, 143.8, 143.8, 136.7, 130.5, 130.2, 128.5, 128.5, 122.5, 71.6, 68.6, 66.4, 46.5, 45.9, 36.5, 33.8, 33.0, 32.7, 30.5, 30.4, 30.3, 29.7, 23.7, 21.7, 14.4; HRMS calcd for C₃I H44N₅0⁺: 502.3546, found: 502.3534.

[0228] (2S,3R)-2-((2-(3-Methyl-6-(pyrimidin-2-yl)pyridazin-4-yl)ethoxy)methyl)-3-(4- octylphenyl)pyrrolidin-1-ium chloride and (2S,3R)-2-((2-(6-methyl-3-(pyrimidin-2- yl)pyridazin-4-yl)ethoxy)methyl)-3-(4-octylphenyl)pyrrolidin-1-ium chloride (14): fe/f-Butyl (2S,3R)-2-(hydroxymethyl)-3-(4-octylphenyl)pyrrolidine-1-carboxylate (78.0 mg, 0.20 mmol) and 4-bromobut-1-ene (0.05 ml_, 0.50 mmol) were dissolved in dry DMF (0.2 ml_). The resulting solution was treated with NaH (60% in mineral oil, 20 mg, 0.50mmol) and stirred under an argon atmosphere at room temperature for 18 h. The reaction mixture was quenched with distilled water (5 ml_) and the aqueous layer was extracted with EtOAc (3 x 10 mL). The organic layers were combined, washed with brine (1 x 5 ml_), dried over Na2S04, filtered and concentrated under reduced pressure. This crude was dissolved in dry DMSO (1.0 mL) and a solution of 3-methyl-6-(pyrimidin-2-yl)-1 ,2,4,5-tetrazine (34.8 mg, 0.2 mmol) in DMSO (0.5 mL) was added dropwise. The resulting reaction mixture was stirred and warmed to 80 °C for 18 h, then quenched with distilled water (5 mL) and the aqueous layer was extracted with EtOAc (3 x 10 mL). The organic layers were combined, washed with brine (1 x 5 mL), dried over Na2S04, filtered and concentrated under reduced pressure. This mixture was dissolved in dioxane (2.0 mL) and HCI 4M in dioxane (0.5 mL) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (CH2CI2/MeOH: 9:1 to 8:2) to afford the title compounds 6 as a colorless gel (23 mg, 20%, 1 :1 ratio); ¹H NMR (500 MHz, MeOD) 5: 9.00-9.15 (m, 4H), 8.32-8.38 (m, 1 H), 7.65-7.75 (m, 1 H), 6.95- 7.20 (m, 8H), 3.10-4.05 (m, 16H), 2.85-3.00 (m, 4H), 2.50-2.63 (m 4H), 2.37 - 2.46 (m, 2H), 2.15-2.23 (m, 2H), 1 .82-1 .88 (m, 4H), 1 .55-1 .66 (m, 4H), 1 .25-1 .35 (m, 24H), 0.87- 0.90 (m, 6H); ¹³C NMR (125 MHz, MeOD) 5: 159.8, 159.4, 143.9, 143.9, 136.5, 136.4, 130.2, 130.2, 129.8, 129.7, 128.4, 128.0, 127.9, 79.3, 79.0, 71.5, 70.6, 69.1 , 66.2, 64.8, 47.9, 47.3, 46.7, 46.7, 46.2, 45.9, 36.5, 33.9, 33.8, 33.0, 32.8, 32.7, 30.8, 30.6, 30.4, 30.3, 28.7, 23.7, 14.4: HRMS calcd for C₃oH42N₅0⁺: 488.3384, found: 488.3381.

[0229] 6-Methyl-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2-yl)methoxy)propyl)-3- (pyridin-2-yl)pyridazine hydrochloride and 3-methyl-4-(3-(((2S,3R)-3-(4- octylphenyl)pyrrolidin-2-yl)methoxy)propyl)-6-(pyridin-2-yl)pyridazine hydrochloride (15): Column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to give 6-methyl-4-(3- (((2S,3R)-3-(4-octylphenyl)pyrrolidin-2-yl)methoxy)propyl)-3-(pyridin-2-yl)pyridazine hydrochloride and 3-methyl-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2- yl)methoxy)propyl)-6-(pyridin-2-yl)pyridazine hydrochloride: To a stirred solution of 3- methyl-6-(pyridin-2-yl)-1 ,2,4,5-tetrazine (5.7 mg, 0.03 mmol, 1.0 eq) in DMSO (1.0 mL) was added tert-butyl (2S,3R)-3-(4-octylphenyl)-2-((pent-4-en-1-yloxy)methyl)pyrrolidine- 1 -carboxylate vii (15 mg, 0.03 mmol, 1.0 eq) and the mixture was stirred for 3 days at 80 °C. The solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the intermediate as a mixture of regioisomers. This mixture was dissolved in dioxane (2.0 ml_) and HCI 4M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to afford the title compounds 15 (7 mg, 43% over 2 steps, 1 :1 ratio) as a colorless oil. ¹H NMR (500 MHz, CDCIs): d 8.83-8.80 (m, 0.6H), 8.66-8.65 (m, 0.4H), 8.62-8.61 (m, 0.4H), 8.26 (s, 0.4H), 7.89-7.83 (m, 1 H), 7.77-7.75 (m, 0.6H), 7.43-7.39 (m, 0.6H), 7.37 (s, 0.6H), 7.36-7.34 (m, 0.4), 7.16-7.10 (m, 3H), 7.03-7.00 (m, 1 H), 3.73-3.48 (m, 5H), 3.41-3.31 (m, 3H), 2.93-2.83 (m, 1 H), 2.73 (s, 3H), 2.66-2.53 (m, 3H), 2.30-2.23 (m, 1 H), 2.20-2.07 (m, 1 H), 2.02-1.96 (m, 1 H), 1.88-1.76 (m, 1 H), 1.59- 1.56 (m, 2H), 1.30-1.25 (m, 10H), 0.89-0.86 (m, 3H); ¹³C NMR (125 MHz, CDCIs): d 159.9, 159.6, 158.4, 157.0, 155.9, 154.1 , 149.3, 149.2, 142.7, 141.6, 141.0, 137.4, 137.3, 135.2, 129.2 (x2), 129.1 , 127.9, 127.6, 127.4 (x2), 124.7, 124.6, 124.0, 123.7, 121.7, 71.0, 70.7, 67.9, 66.5, 65.0, 64.7, 45.9, 45.6, 44.7, 44.1 , 35.7, 32.8, 32.0, 31.6, 29.7, 29.6, 29.5 (x2), 29.4, 29.0, 28.2, 22.8, 22.2, 20.2, 14.3; HRMS calcd for C32H45N4O: 501.3593. Found: 501.3588.

[0230] 6-Methyl-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2-yl)methoxy)propyl)-3- (pyridin-4-yl)pyridazine hydrochloride and 3-methyl-4-(3-(((2S,3R)-3-(4- octylphenyl)pyrrolidin-2-yl)methoxy)propyl)-6-(pyridin-4-yl)pyridazine hydrochloride (16): Column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to give 6-methyl-4-(3- (((2S,3R)-3-(4-octylphenyl)pyrrolidin-2-yl)methoxy)propyl)-3-(pyridin-4-yl)pyridazine hydrochloride and 3-methyl-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2- yl)methoxy)propyl)-6-(pyridin-4-yl)pyridazine hydrochloride: To a stirred solution of 3- methyl-6-(pyridin-4-yl)-1 ,2,4,5-tetrazine (5.7 mg, 0.03 mmol, 1.0 eq) in DMSO (1.0 ml_) was added tert-butyl (2S,3R)-3-(4-octylphenyl)-2-((pent-4-en-1-yloxy)methyl)pyrrolidine- 1 -carboxylate vii (15 mg, 0.03 mmol, 1.0 eq) and the mixture was stirred for 3 days at 80 °C. The solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the intermediate as a mixture of regioisomers. This mixture was dissolved in dioxane (2.0 ml_) and HCI 4M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to afford the title compounds 16 (7 mg, 43% over 2 steps, 1 :1 ratio) as a colorless oil. ¹H NMR (500 MHz, CDCIs): d 8.76-8.71 (m, 2H), 8.05-8.03 (m, 0.7H), 7.84 (s, 0.3H), 7.51-7.48 (m, 1 H), 7.44-7.42 (m, 0.3H), 7.36 (s, 0.7H), 7.14- 7.12 (m, 4H), 3.73-3.68 (m, 1 H), 3.65-3.48 (m, 5H), 3.41-3.34 (m, 1 H), 3.29-3.14 (m, 2H), 2.85-2.81 (m, 1 H), 2.76-2.73 (m, 3H), 2.58-2.55 (m, 2H), 2.38-2.33 (m, 1 H), 2.20-2.13 (m, 1 H), 2.00-1.95 (m, 1 H), 1.82-1.77 (m, 1 H), 1.59-1.55 (m, 2H), 1.30-1.25 (m, 10H), 0.87 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCIs): d 159.7, 150.7, 150.1 , 142.9, 142.8, 139.6, 135.8 (x2), 135.7 (x2), 129.3 (x2), 127.6 (x2), 127.5, 124.2, 123.7, 121.2, 70.5, 70.3, 67.7, 64.9 (x2), 46.0, 45.8, 45.6, 45.5, 35.7, 33.6 (x2), 32.0, 31.6, 31.1 , 29.6, 29.5, 29.4, 28.9, 28.6, 28.5, 22.8, 22.2, 20.1 , 14.3; HRMS calcd for C32H45N4O: 501.3593. Found: 501.3589.

[0231] 6-Methyl-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2-yl)methoxy)propyl)-3- phenylpyridazine hydrochloride and 3-methyl-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin- 2-yl)methoxy)propyl)-6-phenylpyridazine hydrochloride (17): To a stirred solution of 3- methyl-6-phenyl-1 ,2,4,5-tetrazine (5.6 mg, 0.03 mmol, 1.0 eq) in DMSO (1.0 ml_) was added tert-butyl (2S,3R)-3-(4-octylphenyl)-2-((pent-4-en-1 -yloxy)methyl)pyrrolidine-1 - carboxylate vii (15 mg, 0.03 mmol, 1 .0 eq) and the mixture was stirred overnight at 80 °C. The solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the intermediate as a mixture of regioisomers. This mixture was dissolved in dioxane (2.0 ml_) and HCI 4M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to afford the title compounds 17 (6 mg, 37% over 2 steps, 1 :1 ratio) as a colorless oil. ¹H NMR (500 MHz, CDCIs): d 8.08-8.06 (m, 0.5H), 7.66 (s, 0.25H), 7.50-7.48 (m, 1.5H), 7.47-7.40 (m, 3H), 7.28 (s, 0.75H), 7.14-7.11 (m, 4H), 3.67- 3.59 (m, 1 H), 3.57-3.50 (m, 2H), 3.47-3.40 (m, 2H), 3.37-3.29 (m, 1 H), 3.25-3.16 (m, 1 H), 3.13-3.06 (m, 1 H), 2.78-2.65 (m, 6H), 2.58-2.54 (m, 2H), 2.15-2.06 (m, 1 H), 1.96-1.90 (m, 0.5H), 1.77-1.71 (m, 1.5H), 1.60-1 .56 (m, 2H), 1.31-1.26 (m, 10H), 0.89-0.86 (m, 3H); ¹³C NMR (125 MHz, CDCIs): d 160.3, 158.7, 158.4, 157.9, 142.5 (x2), 140.7, 139.7, 137.4, 136.7, 136.6, 129.8, 129.3, 129.2 (x2), 129.1 (x2), 128.7, 128.6, 128.4, 127.5 (x2), 127.4, 127.1 , 123.5, 70.3, 68.3, 65.2, 46.0, 45.7, 35.7, 34.0, 32.0, 31.6, 29.6, 29.5 (x2), 29.4, 28.9, 28.7, 28.6, 22.8, 22.1 , 21.2, 20.0, 14.3; HRMS calcd for C33H46N3O: 500.3635. Found: 500.3638.

[0232] 3-(4-Fluorophenyl)-6-methyl-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2- yl)methoxy)propyl)pyridazine hydrochloride and 6-(4-fluorophenyl)-3-methyl-4-(3- (((2S,3R)-3-(4-octylphenyl)pyrrolidin-2-yl)methoxy)propyl)pyridazine hydrochloride (18): Column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to give 3-(4-fluorophenyl)- 6-methyl-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2-yl)methoxy)propyl)pyridazine hydrochloride and 6-(4-fluorophenyl)-3-methyl-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin- 2-yl)methoxy)propyl)pyridazine hydrochloride: To a stirred solution of 3-(4-fluorophenyl)- 6-methyl-1 ,2,4,5-tetrazine (6.2 mg, 0.03 mmol, 1 .0 eq) in DMSO (1 .0 ml_) was added tert- butyl (2S,3R)-3-(4-octylphenyl)-2-((pent-4-en-1 -yloxy)methyl)pyrrolidine-1 -carboxylate vii (15 mg, 0.03 mmol, 1.0 eq) and the mixture was stirred for 3 days at 80 °C. The solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the intermediate as a mixture of regioisomers. This mixture was dissolved in dioxane (2.0 ml_) and HCI 4M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to afford the title compounds 18 (7 mg, 39% over 2 steps, 1 :1 ratio) as a colorless oil. ¹H NMR (500 MHz, CDCIs): d 8.10-8.07 (m, 0.5H), 7.66 (s, 0.25H), 7.53-7.49 (m, 1.5H), 7.29 (s, 0.75H), 7.17-7.10 (m, 6H), 3.68-3.63 (m, 1 H), 3.60- 3.53 (m, 2H), 3.51-3.41 (m, 3H), 3.38-3.30 (m, 1 H), 3.26-3.18 (m, 1 H), 3.14-3.09 (m, 1 H), 2.78-2.75 (m, 1 H), 2.71-2.70 (m, 4H), 2.69-2.67 (m, 1 H), 2.58-2.54 (m, 2H), 2.34-2.28 (m, 1 H), 2.15-2.10 (m, 1 H), 1.96-1.92 (m, 1 H), 1.79-1.73 (m, 1 H), 1.60-1.55 (m, 2H), 1.31- 1.25 (m, 10H), 0.89-0.86 (m, 3H); ¹³C NMR (125 MHz, CDCIs): d 159.4, 158.9, 142.6, 139.6, 131.3, 131.2, 129.2 (x2), 127.5, 127.4, 116.1 , 116.0, 115.7, 115.5, 70.4, 65.2, 46.0, 45.7, 35.7, 33.9, 32.0, 31.6, 29.6, 29.5, 29.4, 28.7, 28.6, 22.8, 22.1 , 19.9, 14.3; ¹⁹F NMR (471 MHz; CDCIs): d -111.8, -112.8; HRMS calcd for C33H45FN3O: 518.3541. Found: 518.3551.

[0233] 3,6-Dimethyl-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2- yl)methoxy)propyl)pyridazine hydrochloride (19): Column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to give 3,6-dimethyl-4-(3-(((2S,3R)-3-(4- octylphenyl)pyrrolidin-2-yl)methoxy)propyl)pyridazine hydrochloride: To a stirred solution of 3,6-dimethyl-1 ,2,4,5-tetrazine (3.3 mg, 0.03 mmol, 1.0 eq) in DMSO (1.0 ml_) was added tert-butyl (2S,3R)-3-(4-octylphenyl)-2-((pent-4-en-1 -yloxy)methyl)pyrrolidine-1 - carboxylate vii (15 mg, 0.03 mmol, 1 .0 eq) and the mixture was stirred for one week at 80 °C. The solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the intermediate as a colorless oil. This mixture was dissolved in dioxane (2.0 ml_) and HCI 4M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to afford the title compound 19 (10 mg, 70% over 2 steps) as a colorless oil. [a]25D +14.2° (c 0.15, MeOH); ¹H NMR (500 MHz, CDCIs): d 7.19-7.14 (m, 4H), 7.10 (s, 1 H), 3.73-3.64 (m, 3H), 3.60-3.56 (m, 2H), 3.53-3.49 (m, 1 H), 3.41 -3.36 (m, 1 H), 3.29-3.23 (m, 1 H), 2.66- 2.62 (m, 2H), 2.60-2.59 (m, 6H), 2.58-2.55 (m, 2H), 2.41-2.35 (m, 1 H), 2.24-2.17 (m, 1 H), 1.89-1.83 (m, 2H), 1.61-1.55 (m, 2H), 1.30-1.25 (m, 10H), 0.89-0.86 (m, 3H). ¹³C NMR (125 MHz, CDCIs): d 158.3, 157.5, 142.7, 140.3, 135.9, 129.2, 127.5, 126.4, 70.4, 68.1 , 65.0, 46.0, 45.5, 35.7, 33.7, 32.0, 31.6, 29.6, 29.5, 29.4, 28.4, 28.3, 22.8, 22.0, 19.8, 14.3; HRMS calcd for C28H44N3O: 438.3479. Found: 438.3484.

[0234] 3,6-Bis(4-fluorophenyl)-4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2- yl)methoxy)propyl)pyridazine hydrochloride (20): To a stirred solution of 3,6-diphenyl- 1 ,2,4,5-tetrazine (9 mg, 0.03 mmol, 1.0 eq) in DMSO (1.0 ml_) was added tert-butyl (2S,3R)-3-(4-octylphenyl)-2-((pent-4-en-1 -yloxy)methyl)pyrrolidine-1 -carboxylate vii (15 mg, 0.03 mmol, 1 .0 eq) and the mixture was stirred for 5 days at 80 °C. The solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the intermediate as a colorless oil. This mixture was dissolved in dioxane (2.0 ml_) and HCI 4M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to afford the title compound 20 (11 mg, 52% over 2 steps) as a colorless oil. [a]25D +13.3° (c 0.15, MeOH); ¹H NMR (500 MHz, CDCIs): d 8.208.16 (m, 2H), 7.86 (s, 1 H), 7.60-7.56 (m, 2H), 7.21- 7.16 (m, 4H), 7.12-7.07 (m, 4H), 3.58-3.51 (m, 2H), 3.48-3.36 (m, 4H), 3.25-3.20 (m, 1 H), 3.11-3.05 (m, 1 H), 2.85-2.82 (m, 2H), 2.57-2.54 (m, 2H), 2.30-2.26 (m, 1 H), 2.11-2.06 (m, 1 H), 1.84-1.81 (m, 2H), 1.58-1.54 (m, 2H), 1.29-1.25 (m, 10H), 0.89-0.85 (m, 3H); ¹³C NMR (125 MHz, CDCIs): d 165.3, 164.3, 163.3, 162.3, 159.8, 156.9, 142.5, 140.3, 133.3 (d, J = 3.0 Hz), 132.4 (d, J = 3.0 Hz), 131.3 (d, J = 8.5 Hz), 129.2 (d, J = 8.5 Hz), 129.1 , 127.5, 124.3, 116.2 (d, J = 21.5 Hz), 115.7 (d, J = 21.5 Hz), 70.4, 68.6, 65.2, 46.1 , 45.7, 35.7, 34.0, 32.0, 31.6, 29.6, 29.5, 29.4, 29.1 , 22.8, 14.3; ¹⁹F NMR (471 MHz; CDCIs): d - 111.2, -112.3; HRMS calcd for C38H46F2N3O: 58.3603. Found: 598.3624.

[0235] 4-(3-(((2S,3R)-3-(4-Octylphenyl)pyrrolidin-2-yl)methoxy)propyl)-3,6- diphenylpyridazine hydrochloride (21): To a stirred solution of 3,6-diphenyl-1 ,2,4,5- tetrazine (7.7 mg, 0.03 mmol, 1.0 eq) in DMSO (1.0 ml_) was added tert-butyl (2S,3R)-3- (4-octylphenyl)-2-((pent-4-en-1-yloxy)methyl)pyrrolidine-1-carboxylate vii (15 mg, 0.03 mmol, 1 .0 eq) and the mixture was stirred for 3 days at 80 °C. The solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the intermediate as a colorless oil. This mixture was dissolved in dioxane (2.0 ml_) and HCI 4M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to afford the title compound 21 (8 mg, 41 % over 2 steps) as a colorless oil. [a]25D +10.2° (c 0.2, MeOH); ¹H NMR (500 MHz, CDCIs): d 8.19-8.15 (m, 2H), 7.86 (s, 1 H), 7.60-7.57 (m, 2H), 7.54-7.43 (m, 6H), 7.11-7.06 (m, 4H), 3.56-3.50 (m, 2H), 3.46-3.40 (m, 3H), 3.40-3.34 (m, 1 H), 3.23- 3.16 (m, 1 H), 3.11-3.04 (m, 1 H), 2.86-2.80 (m, 2H), 2.57-2.52 (m, 2H), 2.29-2.22 (m, 1 H), 2.12-2.03 (m, 1 H), 1.84-1.77 (m, 2H), 1.60-1.53 (m, 2H), 1.31-1.26 (m, 10H), 0.89-0.86 (m, 3H); ¹³C NMR (125 MHz, CDCIs): d 160.8, 157.8, 142.4, 140.2, 137.3, 136.4, 130.0, 129.4, 129.2, 129.1 , 128.94, 128.6, 127.5, 127.3, 124.5, 70.4, 68.4, 68.3, 65.2, 46.0, 45.7, 35.7, 33.9, 32.0, 31.6, 29.6 (x2), 29.5, 29.4, 29.0, 22.8, 14.3; HRMS calcd for Css^sNsO: 562.3792. Found: 562.3800.

[0236] 4-(3-(((2S,3R)-3-(4-Octylphenyl)pyrrolidin-2-yl)methoxy)propyl)-3,6-di(pyridin- 2-yl)pyridazine hydrochloride (22): Column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to give 4-(3-(((2S,3R)-3-(4-octylphenyl)pyrrolidin-2-yl)methoxy)propyl)-3,6- di(pyridin-2-yl)pyridazine hydrochloride: To a stirred solution of 3,6-di(pyridin-2-yl)- 1 ,2,4,5-tetrazine (7.7 mg, 0.03 mmol, 1.0 eq) in DMSO (1.0 ml_) was added tert-butyl (2S,3R)-3-(4-octylphenyl)-2-((pent-4-en-1 -yloxy)methyl)pyrrolidine-1 -carboxylate vii (15 mg, 0.03 mmol, 1 .0 eq) and the mixture was stirred overnight at 80 °C. The solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the intermediate as a colorless oil. This mixture was dissolved in dioxane (2.0 ml_) and HCI 4M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to afford the title compound 22 (15 mg, 77% over 2 steps) as a colorless oil. [a]25D +11.7° (c 0.15, MeOH); ¹H NMR (500 MHz, CDCIs): d 8.90-8.89 (m, 1 H), 8.77 (ddd, J = 5.0, 1.5, 1.0 Hz, 1 H), 8.71-8.70 (m, 1 H), 8.59 (s, 1 H), 7.92 (td, J = 7.5, 1.5 Hz, 1 H), 7.88 (td, J = 7.5, 1.5 Hz, 1 H), 7.84 (d, J = 7.5 Hz, 1 H), 7.47 (ddd, J = 7.5, 5.0, 1.0 Hz, 1 H), 7.42 (ddd, J = 7.5, 5.0, 1.0 Hz, 1 H), 6.98 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 3.60-3.57 (m, 1 H), 3.52- 3.47 (m, 2H), 3.44-3.39 (m, 1 H), 3.39-3.30 (m, 3H), 3.07-3.02 (m, 1 H), 2.99-2.93 (m, 1 H), 2.53-2.47 (m, 3H), 2.23-2.17 (m, 1 H), 2.07-1 .98 (m, 2H), 1.88-1.83 (m, 1 H), 1.55-1.49 (m, 2H), 1.29-1.25 (m, 10H), 0.88-0.85 (m, 3H); ¹³C NMR (126 MHz, CDCIs): d 160.1 , 157.9,

155.7, 153.4, 149.6, 149.4, 142.7, 142.4, 137.5 (x2), 135.3, 129.0, 127.4, 125.4, 125.0,

124.8, 124.2, 122.0, 71.2, 66.6, 64.7, 44.6, 44.1 , 35.6, 33.2, 32.0, 31.5, 30.0, 29.6, 29.5 (x2), 29.4, 22.8, 14.3; HRMS calcd for Cse^eNsO: 564.3697. Found: 564.3706.

[0237] (2S,3R)-3-(4-Octylphenyl)-2-((3-(6-(4-(prop-2-yn-1-ylcarbamoyl)phenyl)-3-

(pyrimidin-2-yl)pyridazin-4-yl)propoxy)methyl)pyrrolidin-1-ium chloride and (2S,3R)-3-(4- octylphenyl)-2-((3-(3-(4-(prop-2-yn-1-ylcarbamoyl)phenyl)-6-(pyrimidin-2-yl)pyridazin-4- yl)propoxy)methyl)pyrrolidin-1-ium chloride (23): Column chromatography (MeOH: dichloromethane, 1 :9 to 1 :4) to give (2S,3R)-3-(4-octylphenyl)-2-((3-(6-(4-(prop-2-yn-1- ylcarbamoyl)phenyl)-3-(pyrimidin-2-yl)pyridazin-4-yl)propoxy)methyl)pyrrolidin-1-ium chloride and (2S,3R)-3-(4-octylphenyl)-2-((3-(3-(4-(prop-2-yn-1 -ylcarbamoyl)phenyl)-6- (pyrimidin-2-yl)pyridazin-4-yl)propoxy)methyl)pyrrolidin-1-ium chloride (7 mg, 59%, 1 :1 ratio) as an orange oil. ¹H NMR (500 MHz, CDCh): d 9.07-9.06 (m, 1 H), 9.03-8.99 (m, 1 H), 8.31 (s, 0.5H), 8.16-8.15 (m, 1 H), 7.99-7.96 (m, 2H), 7.88 (s, 0.5H), 7.48-7.45 (m, 1 H), 7.43-7.41 (m, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 1 H), 7.11-7.07 (m, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 4.31-4.28 (m, 2H), 3.93-3.87 (m, 0.5H), 3.84-3.82 (m, 0.5H), 3.70-3.60 (m, 2H), 3.56-3.52 (m, 1 H), 3.44-3.41 (m, 1 H), 3.34- 3.25 (m, 2H), 3.15-3.14 (m, 0.5H), 3.01-2.92 (m, 1 H), 2.65-2.62 (m, 1 H), 2.58-2.54 (m, 2H), 2.54-2.50 (m, 1 H), 2.30 (t, J = 2.5 Hz, 0.5H), 2.27 (t, J = 2.5 Hz, 0.5H), 2.14-2.09 (m, 0.5H), 1.62-1.52 (m, 4H), 1.29-1.25 (m, 10H), 0.88-0.86 (m, 3H) ; ¹³C NMR (125 MHz, CDCh): d 167.1 , 166.6, 163.5, 158.3, 158.2, 158.0, 157.9, 143.4, 142.8 (x2), 139.0, 138.5, 135.6, 135.4, 134.8, 134.7, 129.4, 129.3, 129.2, 128.2, 128.0, 127.5 (x2), 127.3, 125.7,

121.8, 121.2, 80.3, 79.7, 71.9, 71.2, 70.9, 70.0, 68.1 , 66.5, 65.0, 64.8, 46.1 , 45.0, 44.6,

43.8, 35.7 (x2), 32.7, 32.0, 31.6 (x2), 30.1 , 30.0, 29.9 (x2), 29.8, 29.6 (x2), 29.5, 29.4,

22.8, 14.3; HRMS calcd for C40H49N6O2: 645.3912. Found: 645.3942.

[0238] 3-(6-Methyl-3-(pyrimidin-2-yl)pyridazin-4-yl)propan-1-ol and 3-(3-methyl-6- (pyrimidin-2-yl)pyridazin-4-yl)propan-1-ol (24): Column chromatography (MeOH: dichloromethane, 0:1 to 1 :4) to give 3-(6-methyl-3-(pyrimidin-2-yl)pyridazin-4-yl)propan- 1-ol and 3-(3-methyl-6-(pyrimidin-2-yl)pyridazin-4-yl)propan-1-ol (10 mg, 72%, 1 :1 ratio) as a colorless oil in a mixture of regioisomers. ¹H NMR (500 MHz, CDCh): d 8.95-8.93 (m, 2H), 8.31 (s, 0.3), 7.43 (t, J = 5.0 Hz, 0.7H), 7.37 (t, J = 5.0 Hz, 0.3H), 7.32 (s, 0.7H), 3.77 (t, J = 6.0 Hz, 0.6H), 3.58 (t, J = 6.0 Hz, 1 4H), 2.88 (t, J = 7.5 Hz, 1 4H), 2.83 (t, J = 7.5 Hz, 0.6H), 2.80 (s, 0.9H), 2.76 (s, 2.1 H), 2.00-1.91 (m, 2H); ¹³C NMR (125 MHz, CDCh): d 164.2, 162.6, 160.7, 160.0, 157.9, 157.5, 156.9, 156.3, 140.6, 140.5, 128.0, 125.7, 121.0, 120.6, 61.8, 60.7, 32.7, 31.2, 28.3, 27.2, 22.3, 20.2; HRMS calcd for C12H15N4O: 231.1240. Found: 231.1242.

[0239] (2S,3R)-3-(4-Octylphenyl)-2-((pent-4-en-1 -yloxy)methyl)pyrrolidin-1 -ium chloride (25): Column chromatography (MeOH: dichloromethane, 1 :19) to give (2S,3R)- 3-(4-octylphenyl)-2-((pent-4-en-1-yloxy)methyl)pyrrolidin-1-ium chloride (4 mg, 52%) as a colorless oil. [O]²⁵D +14.3° (c 0.2, MeOH); ¹H NMR (500 MHz, CDCh): d 7.19-7.14 (m, 4H), 5.80 (ddt, J = 17.0, 10.5, 6.5 Hz, 1 H), 5.03-4.98 (m, 1 H), 4.95 (ddt, J = 10.5, 2.0, 1.0 Hz, 1 H), 3.71-3.68 (m, 2H), 3.64-3.54 (m, 3H), 3.49-3.44 (m, 1 H), 3.41 -3.35 (m, 1 H), 3.33- 3.27 (m, 1 H), 2.59-2.55 (m, 2H), 2.39-2.36 (m, 1 H), 2.23-2.19 (m, 1 H), 2.14-2.09 (m, 2H), 1.72-1.66 (m, 2H), 1.61-1.56 (m, 2H), 1.34-1.27 (m, 10H), 0.88 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCh): d 142.6, 138.4, 136.0, 129.2, 127.6, 115.0, 71.1 , 67.4, 65.1 , 45.9, 35.7, 33.6, 32.0, 31.6, 30.4, 29.9, 29.61 , 29.5, 29.4, 28.8, 22.8, 14.3; HRMS calcd for C24H40NO: 358.3104. Found: 358.3121.

[0240] S)-6-Methyl-3-(pyrimidin-2-yl)-4-(3-(pyrrolidin-2-ylmethoxy)propyl)pyridazine hydrochloride and (S)-3-methyl-6-(pyrimidin-2-yl)-4-(3-(pyrrolidin-2- ylmethoxy)propyl)pyridazine hydrochloride (26): Column chromatography (MeOH: dichloromethane, 1 :9 to 1 :4) to give (S)-6-methyl-3-(pyrimidin-2-yl)-4-(3-(pyrrolidin-2- ylmethoxy)propyl)pyridazine hydrochloride and (S)-3-methyl-6-(pyrimidin-2-yl)-4-(3- (pyrrolidin-2-ylmethoxy)propyl)pyridazine hydrochloride (14 mg, 79%, 1 :1 ratio) as a colorless oil in a mixture of regioisomers. ¹H NMR (500 MHz, MeOD): d 9.06-8.97 (m, 2H), 8.50-8.46 (m, 0.25H), 7.70-7.69 (m, 0.75H), 7.68-7.63 (m, 0.75H), 7.63-7.59 (m, 0.25H), 3.87-3.57 (m, 3H), 3.47-3.42 (m, 2H), 3.30-3.25 (m, 2H), 2.96-2.88 (m, 2H), 2.81- 2.78 (m, 1 H), 2.78-2.74 (m, 2H), 2.20-1 .97 (m, 4H), 1 .87-1 .80 (m, 2H), 1 .70-1 .62 (m, 1 H); ¹³C NMR (125 MHz, MeOD): d 164.7, 161.9, 159.3, 159.0, 158.3, 143.8, 143.7, 130.5, 127.5 (x2), 123.0, 122.5, 71.6, 71.4, 70.5, 70.3, 60.9, 60.8, 46.7, 30.4, 29.6, 29.4, 29.1 , 27.4, 27.3, 24.9, 24.8, 21.6, 19.8; HRMS calcd for C17H24N5O: 314.19754. Found: 314.19641.

DOCTRINE OF EQUIVALENTS

[0241] While the above description contains many specific embodiments of the invention, these should not be construed as limitations on the scope of the invention, but rather as an example of one embodiment thereof. Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their equivalents.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein the pyridazine is connected at position 4 or 5;

Ri is H or alkyl, including methyl, Ac, Boc, guanidine moiety;

R2 is an aliphatic chain comprising 6 to 14 carbons;

R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN;

R4 and Rs are independently: alkyl including methyl, optionally substituted aryl including optionally substituted phenyl, or optionally substituted heteroaryl including optionally substituted pyridine or optionally substituted pyrimidine; n is independently 1, 2, 3, or 4; m is independently 1 or 2; and the phenyl moiety can be attached at any available position of the azacycle core.

2. The compound of claim 1, wherein any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.

3. The compound of claim 1 , wherein the compound is:

4. The compound of claim 1 , wherein the compound is:

5. The compound of claim 1 , wherein the compound is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

6. The compound of claim 5, wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (ICso) of less than 100 micromolar, wherein the local ICso is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

7. The compound of claim 5, wherein the human neoplastic cells are derived from at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

8. The compound of claim 5, wherein the human neoplastic cells are: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras-positive, PTEN-negative, having PI 3- kinase mutations, benign, metastatic, nodular, or a combination thereof.

9. The compound of claim 1 , wherein the compound is capable of inhibiting growth of a tumor comprised of human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

10. A compound of formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein R is connected at its N; and X is 0 or S; Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety;

R2 is an aliphatic chain comprising 6 to 14 carbons;

R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN; n is independently 1 , 2, 3, or 4; m is independently 1 or 2; and the phenyl moiety can be attached at any available position of the azacycle core.

11 . The compound of claim 10, wherein the compound is:

12. The compound of claim 10, wherein the compound is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

13. The compound of claim 12, wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (IC50) of less than 100 micromolar, wherein the local IC50 is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

14. The compound of claim 12, wherein the human neoplastic cells are derived from at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

15. The compound of claim 12, wherein the human neoplastic cells are: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras-positive, PTEN-negative, having PI 3- kinase mutations, benign, metastatic, nodular, or a combination thereof.

16. The compound of claim 10, wherein the compound is capable of inhibiting growth of a tumor comprised of human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

17. A compound of formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein R may be further functionalized, and wherein R is attached to the azacycle via any of R’s available positions;

R’ is H or OH;

Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety;

R2 is an aliphatic chain comprising 6 to 14 carbons;

R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN; n is independently: 1, 2, 3, or 4; m is independently: 1 or 2; and the phenyl moiety can be attached at any available position of the azacycle core.

18. The compound of claim 17, wherein the compound is:

19. The compound of claim 18, wherein the compound is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

20. The compound of claim 19, wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (ICso) of less than 5 micromolar, wherein the local ICso is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

21. The compound of claim 19, wherein the human neoplastic cells are derived from at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

22. The compound of claim 19, wherein the human neoplastic cells are: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras-positive, PTEN-negative, having PI 3- kinase mutations, benign, metastatic, nodular, or a combination thereof.

23. The compound of claim 17, wherein the compound is capable of inhibiting growth of a tumor comprised of human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

24. A compound of formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein the pyridazine is connected at position 4 or 5;

Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety; R2 is an aliphatic chain comprising 6 to14 carbons;

R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN;

R4 and R5 are independently alkyl including methyl, aryl including phenyl, or heteroaryl including pyridine or pyrimidine; and n is independently 1 , 2, 3, or 4.

25. The compound of claim 24, wherein any substituent of R4 or R5, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.

26. The compound of claim 24, wherein the compound is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

27. The compound of claim 26, wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (IC50) of less than 100 micromolar, wherein the local IC50 is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

28. The compound of claim 26, wherein the human neoplastic cells are derived from at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

29. The compound of claim 26, wherein the human neoplastic cells are: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras-positive, PTEN-negative, having PI 3- kinase mutations, benign, metastatic, nodular, or a combination thereof.

30. The compound of claim 24, wherein the compound is capable of inhibiting growth of a tumor comprised of human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

31 . A compound of formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein R is connected at its N; and X is 0 or S;

Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety; R2 is an aliphatic chain comprising 6 to 14 carbons; R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN; and n is independently 1 , 2, 3, or 4.

32. The compound of claim 31 , wherein the compound is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

33. The compound of claim 32, wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (IC50) of less than 100 micromolar, wherein the local IC50 is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

34. The compound of claim 32, wherein the human neoplastic cells are derived from at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

35. The compound of claim 32, wherein the human neoplastic cells are: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras-positive, PTEN-negative, having PI 3- kinase mutations, benign, metastatic, nodular, or a combination thereof.

36. The compound of claim 31 , wherein the compound is capable of inhibiting growth of a tumor comprised of human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

37. A medicament for the treatment of a human disorder comprising: a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein the pyridazine is connected at its position 4 or 5;

Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety; R2 is an aliphatic chain comprising 6 to14 carbons; R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN;

R4 and R5 are independently alkyl including methyl, aryl including phenyl, or heteroaryl including pyridine or pyrimidine; n is independently 1, 2, 3, or 4; m is independently 1 or 2; and the phenyl moiety can be attached at any available position of the azacycle core.

38. The medicament of claim 37, wherein any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.

40. The medicament of claim 37, wherein the one or more compounds is:

41 . The medicament of claim 37, wherein the human disorder is at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

42. The medicament of claim 37, wherein the one or more compounds is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

43. The medicament of claim 42, wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (ICso) of less than 100 micromolar, wherein the local ICso is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

44. The medicament of claim 37, wherein the pharmaceutical formulation is capable of inhibiting growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, and neoplastic cell proliferation.

45. The medicament of claim 37 further comprising at least one cytotoxic FDA- approved compound for the treatment of a neoplasm.

46. A medicament for the treatment of a human disorder comprising: a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein R is connected at its N; and X is 0 or S;

Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety;

R2 is an aliphatic chain comprising 6 to14 carbons;

R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN; n is independently 1, 2, 3, or 4; m is independently 1 or 2; and the phenyl moiety can be attached at any available position of the azacycle core.

47. The medicament of claim 46, wherein the one or more compounds is:

48. The medicament of claim 46, wherein the human disorder is at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

49. The medicament of claim 46, wherein the one or more compounds is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

50. The medicament of claim 49, wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (ICso) of less than 100 micromolar, wherein the local ICso is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

51. The medicament of claim 46, wherein the pharmaceutical formulation is capable of inhibiting growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

52. The medicament of claim 46 further comprising at least one cytotoxic FDA- approved compound for the treatment of a neoplasm.

53. A medicament for the treatment of a human disorder comprising: a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein R may be further functionalized, and wherein R is attached to the azacycle via any of R’s available positions R’ is H or OH;

Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety;

R2 is an aliphatic chain comprising 6 to14 carbons;

54. The medicament of claim 53, wherein the one or more compounds is:

55. The medicament of claim 53, wherein the human disorder is at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

56. The medicament of claim 53, wherein the one or more compounds is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

57. The medicament of claim 56, wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (ICso) of less than 100 micromolar, wherein the local ICso is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

58. The medicament of claim 53, wherein the pharmaceutical formulation is capable of inhibiting growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

59. The medicament of claim 53 further comprising at least one cytotoxic FDA- approved compound for the treatment of a neoplasm.

60. A medicament for the treatment of a human disorder comprising: a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein the pyridazine is connected at position 4 or 5;

R4 and Rs are independently: alkyl including methyl, aryl including phenyl, or heteroaryl including pyridine or pyrimidine; n is independently 1 , 2, 3, or 4; and the phenyl moiety can be attached at position 3, 4, or 5 of the pyrrolidine moiety.

61 . The medicament of claim 60, wherein any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.

62. The medicament of claim 60, wherein the human disorder is at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

63. The medicament of claim 60, wherein the one or more compounds is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

64. The medicament of claim 63, wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (ICso) of less than 100 micromolar, wherein the local ICso is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

65. The medicament of claim 60, wherein the pharmaceutical formulation is capable of inhibiting growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, and neoplastic cell proliferation.

66. The medicament of claim 60 further comprising at least one cytotoxic FDA- approved compound for the treatment of a neoplasm.

67. A medicament for the treatment of a human disorder comprising: a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein the phenoxazine or phenothiazine is connected at the N; and X is 0 or S;

Ri and R-T are H, alkyl including methyl, Ac, Boc, guanidine moiety;

-1 OS- R2 is an aliphatic chain comprising 6 to14 carbons;

R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN; n is independently 1 , 2, 3, or 4; and the phenyl moiety can be attached at position 3, 4, or 5 of the pyrrolidine moiety.

68. The medicament of claim 67, wherein the human disorder is at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, or a combination thereof.

69. The medicament of claim 67, wherein the one or more compounds is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.

70. The medicament of claim 69, wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (ICso) of less than 100 micromolar, wherein the local ICso is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.

71. The medicament of claim 67, wherein the pharmaceutical formulation is capable of inhibiting growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

72. The medicament of claim 67 further comprising at least one cytotoxic FDA- approved compound for the treatment of a neoplasm.

73. A method of treatment of a human disorder comprising: administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein the pyridazine is connected at its position 4 or 5;

Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety;

R2 is an aliphatic chain comprising 6 to14 carbons;

R4 and R5 are independently: alkyl including methyl, aryl including phenyl, or heteroaryl including pyridine or pyrimidine; n is independently 1, 2, 3, or 4; m is independently 1 or 2; and the phenyl moiety can be attached at any available position of the azacycle core.

74. The method of claim 73, wherein any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.

75. The method of claim 73, wherein the one or more compounds is:

76. The method of claim 73, wherein the one or more compounds is:

77. The method of claim 73 further comprising diagnosing the human subject with at least one human disorder.

78. The method of claim 77, wherein the at least one human disorder is a neoplasm, and wherein the neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, ora combination thereof.

79. The method of treatment of claim 73, wherein the pharmaceutical formulation inhibits growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

80. The method of treatment of claim 73, wherein the human disorder is characterized by at least one neoplasm characterization, and wherein the at least one neoplasm characterization is: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras- positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, nodular, or a combination thereof.

81 . The method of treatment of claim 73, where in the treatment is combined with an FDA-approved standard of care.

82. The method of treatment of claim 73, wherein the pharmaceutical formulation is combined with at least one cytotoxic FDA-approved compound.

83. A method of treatment of a human disorder comprising: administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety;

R2 is an aliphatic chain comprising 6 to14 carbons;

84. The method of claim 83, wherein the one or more compounds is:

85. The method of claim 83, further comprising diagnosing the human subject with at least one human disorder.

86. The method of claim 85, wherein the at least one human disorder is a neoplasm, and wherein the neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, ora combination thereof.

87. The method of treatment of claim 83, wherein the pharmaceutical formulation inhibits growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

88. The method of treatment of claim 83, wherein the human disorder is characterized by at least one neoplasm characterization, and wherein the at least one neoplasm characterization is: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras- positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, nodular, or a combination thereof.

89. The method of treatment of claim 83, where in the treatment is combined with an FDA-approved standard of care.

90. The method of treatment of claim 83, wherein the pharmaceutical formulation is combined with at least one cytotoxic FDA-approved compound.

91. A method of treatment of a human disorder comprising: administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

R’ is H or OH;

Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety;

R2 is an aliphatic chain comprising 6 to14 carbons;

92. The method of claim 91 , wherein the one or more compounds is:

93. The method of claim 91 , further comprising diagnosing the human subject with at least one human disorder.

94. The method of claim 93, wherein the at least one human disorder is a neoplasm, and wherein the neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, ora combination thereof.

95. The method of treatment of claim 91, wherein the pharmaceutical formulation inhibits growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

96. The method of treatment of claim 91 , wherein the human disorder is characterized by at least one neoplasm characterization, and wherein the at least one neoplasm characterization is: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras- positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, nodular, or a combination thereof.

97. The method of treatment of claim 91 , where in the treatment is combined with an FDA-approved standard of care.

98. The method of treatment of claim 91, wherein the pharmaceutical formulation is combined with at least one cytotoxic FDA-approved compound.

99. A method of treatment of a human disorder comprising: administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein the pyridazine is connected at position 4 or 5;

100. The method of claim 99, wherein any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.

101. The method of claim 99, further comprising diagnosing the human subject with at least one human disorder.

102. The method of claim 101 , wherein the at least one human disorder is a neoplasm, and wherein the neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, ora combination thereof.

103. The method of treatment of claim 99, wherein the pharmaceutical formulation inhibits growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

104. The method of treatment of claim 99, wherein the human disorder is characterized by at least one neoplasm characterization, and wherein the at least one neoplasm characterization is: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras- positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, nodular, or a combination thereof.

105. The method of treatment of claim 99, where in the treatment is combined with an FDA-approved standard of care.

106. The method of treatment of claim 99, wherein the pharmaceutical formulation is combined with at least one cytotoxic FDA-approved compound.

107. A method of treatment of a human disorder comprising: administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula

or a pharmaceutically acceptable salt thereof; wherein:

R is:

wherein R is connected at its N; and X is 0 or S;

R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN; and n is independently 1, 2, 3, or 4.

108. The method of claim 107, further comprising diagnosing the human subject with at least one human disorder.

109. The method of claim 108, wherein the at least one human disorder is a neoplasm, and wherein the neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell cancer, mesothelioma, mouth cancer, neuroblastoma, non-Hodgkin lymphoma, non small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, pharyngeal cancer, pituitary tumor, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, skin cancer, small cell lung cancer, small intestine cancer, squamous neck cancer, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, uterine cancer, vaginal cancer, a vascular tumor, ora combination thereof.

110. The method of treatment of claim 107, wherein the pharmaceutical formulation inhibits growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.

111. The method of treatment of claim 107, wherein the human disorder is characterized by at least one neoplasm characterization, and wherein the at least one neoplasm characterization is: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras-positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, nodular, or a combination thereof.

112. The method of treatment of claim 107, where in the treatment is combined with an FDA-approved standard of care.

113. The method of treatment of claim 107, wherein the pharmaceutical formulation is combined with at least one cytotoxic FDA-approved compound.