Kinase inhibitor compositions and related methods for the treatment of a disease

Abstract

The present disclosure generally relates to PIM kinase inhibitors and other kinase inhibitor compositions and related methods for the treatment of a disease, including parasitic worm infections, intestinal worm infections, and cancer.

Description

KINASE INHIBITOR COMPOSITIONS AND RELATED METHODS FOR THE TREATMENT OF A DISEASECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63 / 591 ,323 filed on October 18, 2023, which is incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under AI081803 and AI159450 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.FIELD OF THE INVENTION

[0003] The present disclosure generally relates to PIM and other kinase inhibitor compositions and related methods for the treatment of a disease, including parasitic worm infections and intestinal worm infections.BACKGROUND OF THE INVENTION

[0004] Approximately 24% of the global population is infected with soil- transmitted helminths (STH), also called Gastrointestinal nematodes (GINs), typically affecting communities with poor access to proper hygiene, sanitation, and clean water. These infections can cause multiple co-morbidities and significant growth impairment of infected children. Though the number of infections caused by STH remains high, there are a limited number of currently available therapeutic options recommended by the World Health Organization (WHO), including the two benzimidazoles (albendazole, mebendazole), imidathiazole (levamisole), and tetrahydropyrimidines (pyrantel) and these are members of only two therapeutic targets: p-tubulin (albendazole and mebendazole) and acetylcholine receptor agonist receptors (pyrantel and levamisole). However, these treatments suffer from deficiencies in their effectiveness due to the possible emergence of drug resistance and lack of pan-species activity, which is required due to the high rate of multispecies infection, thus establishing an urgent need for new anthelminthic agents, and with new modes of action. The whipworm, Trichuris trichiura - cause of human trichuriasis- is one of three well-documented STHs included in the WHO list for neglected tropical diseases (NTDs). To control STHs, the WHO recommends Mass Drug Administration (MDA)- relying mainly on the two benzimidazole drugs-targeting school-age children in STH-endemic countries. However, trichuriasis is not as well managed by MDA as compared to the other two groups of STH, with only a 2% decline in prevalence between 2005 and 2015 versus a 10% decline for that same period in ascariasis (caused by another major STH species, Ascaris lumbricoides). Furthermore, single-dose treatment of T. trichiura is not efficacious with approved anthelmintics, so multiple doses over several days are necessary.

[0005] These infections create significant issues for the infected including river blindness, elephantiasis, and soil-transmitted helminthiasis (common symptoms include anemia, stunted growth, intestinal problems, lack of energy, and compromised physical and cognitive development). All of these conditions are categorized as neglected tropical diseases (NTD) and occur in low-income areas populations in developing regions of Africa, Asia, and the Americas.

[0006] Transmission typically occurs because of improper food preparation, walking barefoot in contaminated soil, and insect vectors (like black flies and mosquitoes). Given the nature of transmission, these parasites have an outsized portion on the poorest in society because they do not have appropriate measures to prevent exposure to the vectors of the diseases, i.e. appropriate clothing, sanitation, and housing.

[0007] These parasites and associated diseases affect 1.4 billion people, including 500 million children, worldwide, costing these economies billions of dollars every year. While deaths tend to be minimal, the effects of these infections can have lifelong implications.

[0008] Taken together, there is a large unmet medical need for new anthelmintic drugs specifically targeting T. trichiura. Kinase inhibitors may provide an avenue to treat these infections. In addition, various kinases and their expression are associated with cancer progression. Therefore, a new class ofkinase inhibitors may provide therapeutic benefits to a range of diseases, including but not limited to parasitic infections.

[0009] Current treatments attempt to prevent the spread of the nematodes through annual mass drug administration. This administration can be in the form of any number of drugs, like albendazole, mebendazole, ivermectin, oxantel, or praziquantel among others. These drugs tend to kill the larvae of these worms but do not treat an infection of adult worms. In addition, there is a problem with drug resistance. Thus, there is still a need to help with this burden.BRIEF SUMMARY

[0010] The disclosure is directed to PIM kinase inhibitor compounds and methods of treatment of disease in a subject in need thereof. In particular, the disclosure is directed to compounds having the structure of Formula 1 :wherein Ri is hydrogen or Ri combined with R2 forms a homopiperazine substituted with R4, morpholine, a piperazine substituted with Rs, or a piperidine substituted with Rs; R2 is alkyl, amine substituted alkyl, substituted aryl, -(CH2)n- heterocyclo, -(CH2)n-piperidine substituted with Re, or as above when combined with R1; R3 is halo, methyl, methoxyl, -NH2, hydroxyl, trifluoromethyl, trifluoromethoxyl, or -CN; R4 is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-C1-C3 alkyl, an alkyl- or polyalkylene glycol-linked biotin, orN N; Rs is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-Ci-C3 alkyl, a polyalkyleneglycol linked biotin, -(CH2)n-N(R7)(R8), orN N; Re is hydrogen, Ci-Ce alkyl, -C(O)-Ci-C3alkyl, cyclopropyl, -S(O)2R9, -OC(O)N(R7)(R8), -NHC(O)N(R7)(R8), or -(CH2)n- N(R7)(RS); R7is independently hydrogen or C1-C3 alkyl; Rs is independentlyhydrogen or C1-C3 alkyl; R9 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, substituted or unsubstituted aryl; X is 0, S, or NH; n is independently an integer from 1 to 4; and wherein when R1 combined with R2 forms a homopiperazine substituted with methyl on N-4, R3is not chloride at the C-5 position.

[0011] Additionally, the disclosure is directed to PIM kinase inhibitor compounds having the structure of Formula 2:wherein R20 is hydrogen or R20 combined with R21 forms homopiperazine substituted with R23, piperazine substituted with R24, or piperidine substituted with R24; R21 is -(CH2)n-piperidine substituted with R25, -(CH2)n-phenyl, -(CH2)n- pyridyl, substituted or unsubstituted heterocyclo, -C(O)-aryl, -C(O)- N(R26)(R27), -C(O)R28, -S(O)2R28, or as above when combined with R20; R22 is substituted or unsubstituted phenyl, C1-C3 haloalkyl, C1-C3 haloalkoxyl, or substituted or unsubstituted heterocyclo; R23 is hydrogen, Ci-Ce alkyl, -C(O)- aryl, -C(O)-N(R26)(R27), -C(O)R28, -S(O)2R2s; R24 is hydrogen, Ci-Ce alkyl, tert- butyl-O-C(O)-, -C(O)-Ci-C3 alkyl, an alkyl- or polyalkylene glycol-linked biotin, -hydrogen, Ci-Ce alkyl, -C(O)-Ci-C24 alkyl, wherein the C1-C24 alkyl can optionally have one or more -CH2- groups replaced with -0- or -NHC(O)-; an alkyl- or polyalkylene glycol-linked biotin, or; R26 and R27 are independently hydrogen, cyclopropyl, or C1-C3 alkyl; R28 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, substituted or unsubstituted aryl, X is a bond, -NHC(O)-, -C(O)NH-, -O-, -S-, -NH-, or -CH2-; n is an integer of 1 to 4; and wherein when R22 is meta-OCFs, R20 is hydrogen, and R21 is -CH2- 4-methylpiperidine, then X is -NHC(O)-.

[0012] Additionally, methods of treatment of parasitic infections and cancer comprising administering the compounds of Formula 1 or 2 to a patient in need thereof are also disclosed.

[0013] Other objects and features will be in part apparent and in part pointed out hereinafter.DETAILED DESCRIPTION

[0014] The present disclosure is based, at least in part, on the discovery that several classes of novel kinase inhibitors and scaffolds inhibit parasitic worm motility and are potential new drugs with a unique mechanism of action (MOA) for treating hookworm, whipworm, and filarial worm infections. These drugs might be used alone or in combination with existing anthelmintic drugs. In particular, inhibitors of one or more members of the proviral integration sites for Moloney murine leukemia virus (PIM) kinase family of Ser / Thr protein kinases have been identified and developed.

[0015] As shown herein, PIM and other kinase inhibitor chemical structures, and their use in the treatment of diseases, including but not limited to parasitic infections, are described.

[0016] In some cases, these compounds are useful to decrease worm motility and viability in several species of parasitic worm species. The compounds are effective both in vitro and in vivo in treating diseases caused by both intestinal and filarial worms including, but not limited to hookworm and whipworm infections. The compounds are designed to be more specific to treat worm infections compared to current treatments. These compounds also have the potential to treat the adult worm and not just the larvae.

[0017] One aspect of the present disclosure is directed to PIM kinase inhibitor compounds. In particular, the disclosure is directed to compounds having the structure of Formula 1 :wherein Ri is hydrogen or Ri combined with R2 forms a homopiperazine substituted with R4, morpholine, a piperazine substituted with Rs, or a piperidine substituted with Rs; R2 is alkyl, amine substituted alkyl, substituted aryl, -(CH2)n- heterocyclo, -(CH2)n-piperidine substituted with Re, or as above when combined with R1; R3 is halo, methyl, methoxyl, -NH2, hydroxyl, trifluoromethyl, trifluoromethoxyl, or -CN; R4 is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-C1-C3 alkyl, an alkyl- or polyalkylene glycol-linked biotin, orN N; Rs is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-Ci-C3 alkyl, a polyalkyleneglycol linked biotin, -(CH2)n-N(R7)(R8), orN N; Re is hydrogen, Ci-Ce alkyl, -C(O)-Ci-C3alkyl, cyclopropyl, -S(O)2R9, -OC(O)N(R7)(R8), -NHC(O)N(R7)(R8), or -(CH2)n- N(R7)(RS); R7is independently hydrogen or C1-C3 alkyl; Rs is independently hydrogen or C1-C3 alkyl; R9 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, substituted or unsubstituted aryl; X is 0, S, or NH; n is independently an integer from 1 to 4; and wherein when Ri combined with R2 forms a homopiperazine substituted with methyl on N-4, R3is not chloride at the C-5 position.

[0018] For the compounds of Formula 1 , X can be 0.

[0019] When X is 0 in the compounds of Formula 1 , the compounds can have the structure of Formula 1A.wherein the substituents are defined as in Formula 1 .

[0020] The compounds can have structures of Formula 1 or 1A, wherein Ri is hydrogen.

[0021] Also, the compounds can have structures of Formula 1 or 1A, wherein R2 is alkyl.

[0022] The compounds can have structures of Formula 1 or 1A, wherein R2 is -(CH2)n-piperidine substituted with Re.

[0023] Further, the compounds can have structures of Formula 1 or 1A, wherein n is 1.

[0024] The compounds can have structures of Formula 1 or 1A, wherein the piperidine is 4-piperidine and Re is substituted on N-4.

[0025] The compounds can have structures of Formula 1 or 1A, wherein Re is hydrogen.

[0026] Additionally, the compounds can have structures of Formula 1 or 1A, wherein Re is Ci-Ce alkyl.

[0027] The compounds can have structures of Formula 1 or 1A, wherein Re is -C(O)-Ci-C3 alkyl.

[0028] The compounds can have structures of Formula 1 or 1A, wherein Re is -(CH2)n-N(R7)(Rs), wherein n is 1 or 2 and R7 and Rs are independently hydrogen or methyl.

[0029] The compounds can have structures of Formula 1 or 1A, wherein R1 combined with R2 forms a homopiperazine substituted with R4, morpholine, or piperidine substituted with Rs.

[0030] The compounds can have structures of Formula 1 or 1A, wherein R1 combined with R2 forms a homopiperazine substituted with R4.

[0031] The compounds can have structures of Formula 1 or 1A, wherein R4 is a substituent of N-4.

[0032] Also, the compounds can have structures of Formula 1 or 1A, wherein R4 is C1-C6 alkyl.

[0033] The compounds can have structures of Formula 1 or 1A, wherein R4 is tert-butyl-O-C(O)-.

[0034] The compounds can have structures of Formula 1 or 1A, wherein R4 is -C(O)-Ci-C3 alkyl.

[0035] Further, the compounds can have structures of Formula 1 or 1A, wherein

[0036] The compounds can have structures of Formula 1 or 1A, wherein R4 is an alkyl- or polyalkylene glycol-linked biotin.

[0037] The compounds can have structures of Formula 1 or 1A, wherein R1 combined with R2 forms morpholine.

[0038] Additionally, the compounds can have structures of Formula 1 or 1A, wherein R1 combined with R2 forms piperidine substituted with Rs.

[0039] The compounds can have structures of Formula 1 or 1A, wherein Rs is a substituent on C-4 of the piperidine ring.

[0040] The compounds can have structures of Formula 1 or 1A, wherein n is 1 , R7 is hydrogen and Rs is hydrogen.

[0041] The compounds can have structures of Formula 1 or 1A, wherein Rs is halo.

[0042] The compounds can have structures of Formula 1 or 1A, wherein R3 is C1-C3 alkyl.

[0043] The compounds can have structures of Formula 1 or 1A, wherein R3 is C1-C3 alkoxyl.

[0044] The compounds of Formula 1 or 1A have the structure:

[0045] Preferably, the compounds are a compound of Formula 1A:wherein Ri is hydrogen or Ri combined with R2 forms a homopiperazine substituted with R4, morpholine, or a piperidine substituted with Rs; R2 is alkyl, -(CH2)n-heterocyclo, -(CH2)n-piperidine substituted with Re, or as above when combined with R1; R3 is halo, methyl, methoxyl, trifluoromethyl, or trifluoromethoxyl; R4 is hydrogen, Ci-Ce alkyl, -C(O)-Ci-C3 alkyl, an alkyl- orpolyalkylene glycol-linked biotin, orN N; Rs is hydrogen, Ci-Ce alkyl, -C(O)-Ci-C3 alkyl, a polyalkylene glycol linked biotin, -(CH2)n-N(R7)(R8), orN N; Re is hydrogen, Ci-Ce alkyl, -C(O)-Ci-C3 alkyl, cyclopropyl, or -S(O)2Rg; R7 is independently hydrogen or C1-C3 alkyl; Rs is independently hydrogen or C1-C3 alkyl; R9 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, n is independently an integer from 1 or 2; and wherein when Ri combined with R2 forms a homopiperazine substituted with methyl on N-4, R3is not chloride at the C-5 position.

[0046] Additionally, the disclosure is directed to PIM kinase inhibitor compounds having the structure of Formula 2:wherein R20 is hydrogen or R20 combined with R21 forms homopiperazine substituted with R23, piperazine substituted with R24, or piperidine substituted with R24; R21 is -(CH2)n-piperidine substituted with R25, -(CH2)n-phenyl, -(CH2)n- pyridyl, substituted or unsubstituted heterocyclo, -C(O)-aryl, -C(O)- N(R26)(R27), -C(O)R28, -S(O)2R28, or as above when combined with R20; R22 issubstituted or unsubstituted phenyl, C1-C3 haloalkyl, C1-C3 haloalkoxyl, or substituted or unsubstituted heterocyclo; R23 is hydrogen, Ci-Ce alkyl, -C(O)- aryl, -C(O)-N(R26)(R27), -C(O)R28, -S(O)2R2s; R24 is hydrogen, Ci-Ce alkyl, tert- butyl-O-C(O)-, -C(O)-Ci-C3 alkyl, an alkyl- or polyalkylene glycol-linked biotin, -hydrogen, Ci-Ce alkyl, -C(O)-Ci-C24alkyl, wherein the C1-C24 alkyl can optionally have one or more -CHS- groups replaced with -0- or -NHC(O)-; an alkyl- or polyalkylene glycol-linked biotin, orN-N; R26 and R27 are independently hydrogen, cyclopropyl, or C1-C3 alkyl; R28 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, substituted or unsubstituted aryl, X is a bond, -NHC(O)-, -C(O)NH-, -0-, -S-, -NH-, or -CH2-; n is an integer of 1 to 4; and wherein when R22 is meta-OCFs, R20 is hydrogen, and R21 is -CH2- 4-methylpiperidine, then X is -NHC(O)-.

[0047] The compounds can have structures of Formula 2, wherein R20 is hydrogen.

[0048] Further, the compounds can have structures of Formula 2, wherein R21 is -(CH2)n-piperidine substituted with R25.

[0049] The compounds can have structures of Formula 2, wherein n is 1 .

[0050] The compounds can have structures of Formula 2, wherein the piperidine is 4-piperidine and R25 is substituted on N-4.

[0051] The compounds can have structures of Formula 2, wherein R25 is hydrogen.

[0052] Additionally, the compounds can have structures of Formula 2, wherein R25 is Ci-Ce alkyl.

[0053] The compounds can have structures of Formula 2, wherein R25 is -C(O)-Ci-C3 alkyl.

[0054] The compounds can have structures of Formula 2, wherein R25 is

[0055] The compounds can have structures of Formula 2, wherein R25 is an alkyl- or polyalkylene glycol-linked biotin.

[0056] Further, the compounds can have structures of Formula 2, wherein R21 is -(CH2)n-phenyl and n is 1 .

[0057] The compounds can have structures of Formula 2, wherein R21 is -(CH2)n-pyridyl and n is 1.

[0058] The compounds can have structures of Formula 2, wherein R20 combined with R21 forms homopiperazine substituted with R23 or piperidine substituted with R24.

[0059] Also, the compounds can have structures of Formula 2, wherein R20 combined with R21 forms homopiperazine substituted with R23.

[0060] The compounds can have structures of Formula 2, wherein R23 is hydrogen.

[0061] The compounds can have structures of Formula 2, wherein R23 is Ci-Ce alkyl.

[0062] The compounds can have structures of Formula 2, wherein R23 is C1-C3 alkyl.

[0063] Further, the compounds can have structures of Formula 2, wherein R23 is methyl.

[0064] The compounds can have structures of Formula 2, wherein R20 combined with R21 forms piperidine substituted with R24.

[0065] The compounds can have structures of Formula 2, wherein R24 is a substituent on C-4 of the piperidine ring.

[0066] The compounds can have structures of Formula 2, wherein n is 1 and R26 and R27 are hydrogen.

[0067] Also, the compounds can have structures of Formula 2, wherein R22 is substituted or unsubstituted phenyl.

[0068] The compounds can have structures of Formula 2, wherein R22 is C1-C3 haloalkyl.

[0069] The compounds can have structures of Formula 2, wherein R22 is trifluoromethyl.

[0070] The compounds can have structures of Formula 2, wherein R22 is C1-C3 haloalkoxyl.

[0071] Yet further, the compounds can have structures of Formula 2, wherein R22 is trifluoromethoxyl.

[0072] The compounds can have structures of Formula 2, wherein R22 is substituted or unsubstituted heterocyclo.

[0073] The compounds can have structures of Formula 2, wherein X is a bond.

[0074] The compounds can have structures of Formula 2, wherein X is - NHC(O)-.

[0075] The compounds can have structures of Formula 2, wherein X is -C(O)NH-

[0076] The compounds can have structures of Formula 2, wherein X is - O-.

[0077] The compounds can have structures of Formula 2, wherein X is - S-.

[0078] The compounds can have structures of Formula 2, wherein X is - NH-.

[0079] The compounds can have structures of Formula 2, wherein X is -CH2-.

[0080] Preferably, the compounds of Formula 2 have the structure of:

[0081] The structures of the compounds of Formula 1 and Formula 2 are detailed in the following table.

[0082] Additionally, the compounds of Formula 1 and Formula 2 can be present in pharmaceutical compositions, wherein the pharmaceutical composition comprises the compound of Formula 1 , the compound of Formula 2, or a combination thereof and a pharmaceutically acceptable excipient.

[0083] The agents and compositions described herein can be formulated by any conventional manner using one or more pharmaceutically acceptable carriers or excipients as described in, for example, Remington’s Pharmaceutical Sciences (A.R. Gennaro, Ed.), 21st edition, ISBN: 0781746736 (2005), incorporated herein by reference in its entirety. Such formulations will contain a therapeutically effective amount of a biologically active agent of Formula 1 or Formula 2 described herein, which can be in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.

[0084] The term "formulation" refers to preparing a drug in a form suitable for administration to a subject, such as a human. Thus, a "formulation" can include pharmaceutically acceptable excipients, including diluents or carriers.

[0085] The term "pharmaceutically acceptable" as used herein can describe substances or components that do not cause unacceptable losses of pharmacological activity or unacceptable adverse side effects. Examples of pharmaceutically acceptable ingredients can be those having monographs in United States Pharmacopeia (USP 29) and National Formulary (NF 24), United States Pharmacopeial Convention, Inc, Rockville, Maryland, 2005 ("USP / NF"), or a more recent edition, and the components listed in the continuously updated Inactive Ingredient Search online database of the FDA. Other useful components that are not described in the USP / NF, etc. may also be used.

[0086] The term “pharmaceutically acceptable excipient,” as used herein, can include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic, or absorption-delaying agents. The use of such media and agents for pharmaceutically active substances is well known in the art (see generally Remington’s Pharmaceutical Sciences (A.R. Gennaro, Ed.), 21st edition, ISBN: 0781746736 (2005)). Except insofar as any conventional media or agent is incompatible with an active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0087] A "stable" formulation or composition can refer to a composition having sufficient stability to allow storage at a convenient temperature, such as between about 0 °C and about 60 °C, for a commercially reasonable period oftime, such as at least about one day, at least about one week, at least about one month, at least about three months, at least about six months, at least about one year, or at least about two years.

[0088] The formulation should suit the mode of administration. The agents of use with the current disclosure can be formulated by known methods for administration to a subject using several routes which include, but are not limited to, parenteral, pulmonary, oral, topical, intradermal, intratumoral, intranasal, inhalation (e.g., in an aerosol), implanted, intramuscular, intraperitoneal, intravenous, intrathecal, intracranial, intracerebroventricular, subcutaneous, intranasal, epidural, intrathecal, ophthalmic, transdermal, buccal, and rectal. The individual agents may also be administered in combination with one or more additional agents or together with other biologically active or biologically inert agents. Such biologically active or inert agents may be in fluid or mechanical communication with the agent(s) or attached to the agent(s) by ionic, covalent, Van der Waals, hydrophobic, hydrophilic, or other physical forces.

[0089] Controlled-release (or sustained-release) preparations may be formulated to extend the activity of the agent(s) and reduce dosage frequency. Controlled-release preparations can also be used to affect the time of onset of action or other characteristics, such as blood levels of the agent, and consequently affect the occurrence of side effects. Controlled-release preparations may be designed to initially release an amount of an agent(s) that produces the desired therapeutic effect, and gradually and continually release other amounts of the agent to maintain the level of therapeutic effect over an extended period of time. In order to maintain a near-constant level of an agent in the body, the agent can be released from the dosage form at a rate that will replace the amount of the agent being metabolized or excreted from the body. The controlled release of an agent may be stimulated by various inducers, e.g., change in pH, change in temperature, enzymes, water, or other physiological conditions or molecules.

[0090] Agents or compositions described herein can also be used in combination with other therapeutic modalities, as described further below. Thus, in addition to the therapies described herein, one may also provide to the subjectother therapies known to be efficacious for the treatment of the disease, disorder, or condition.

[0091] Therapeutic / Wef / ?oc / sAdditionally, the disclosure is directed to methods of treating a parasitic worm infection comprising administering a compound disclosed herein having a structure of Formula 1 or Formula 2 to a subject in need thereof.

[0092] The method of treating a parasitic worm infection disclosed herein, wherein the target in the worm is a P IM kinase.

[0093] The method of treating a parasitic worm infection disclosed herein, wherein the parasitic worm infection is a hook worm infection, a whip worm infection, or a filarial worm infection.

[0094] The method of treating a parasitic worm infection disclosed herein, wherein the parasitic worm infection is an intestinal worm infection.

[0095] The method of treating a parasitic worm infection disclosed herein, wherein the parasitic worm infection is an intestinal worm infection and the intestinal worm infection is a hook worm infection or a whip worm infection.

[0096] Additionally, disclosed herein is a method of treating cancer in a subject in need thereof comprising administering a compound having the structure of Formula 1 or Formula 2 to a subject in need thereof.

[0097] The method of treating cancer disclosed herein, wherein the subject is a human.

[0098] The method of treating cancer disclosed herein, wherein the subject is a human and the target in the subject is a PIM kinase.

[0099] Further, methods of treating a parasitic worm infection are disclosed comprising administering a compound of Formula 1 or a Compound of Formula 2 to a subject in need thereofwherein Ri is hydrogen or Ri combined with R2 forms a homopiperazine substituted with R4, morpholine, a piperazine substituted with Rs, or a piperidinesubstituted with Rs; R2 is alkyl, amine substituted alkyl, substituted aryl, -(CH2)n- heterocyclo, -(CH2)n-piperidine substituted with Re, or as above when combined with R1; R3 is halo, methyl, methoxyl, -NH2, hydroxyl, trifluoromethyl, trifluoromethoxyl, or -CN; R4 is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-C1-C3 alkyl, an alkyl- or polyalkylene glycol-linked biotin, orN N; Rs is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(0)-Ci-C3 alkyl, a polyalkyleneglycol linked biotin, -(CH2)n-N(R7)(R8), orN N; Re is hydrogen, Ci-Ce alkyl, -C(O)-Ci-C3alkyl, cyclopropyl, -S(O)2R9, -OC(O)N(R7)(R8), -NHC(O)N(R7)(R8), or -(CH2)n- N(R7)(RS); R7is independently hydrogen or C1-C3 alkyl; Rs is independently hydrogen or C1-C3 alkyl; R9 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, substituted or unsubstituted aryl; n is independently an integer from 1 to 4;wherein R20 is hydrogen or R20 combined with R21 forms homopiperazine substituted with R23, piperazine substituted with R24, or piperidine substituted with R24; R21 is -(CH2)n-piperidine substituted with R25, -(CH2)n-phenyl, -(CH2)n- pyridyl, substituted or unsubstituted heterocyclo, -C(O)-aryl, -C(O)- N(R26)(R27), -C(O)R28, -S(O)2R28, or as above when combined with R20; R22 is substituted or unsubstituted phenyl, C1-C3 haloalkyl, C1-C3 haloalkoxyl, or substituted or unsubstituted heterocyclo; R23 is hydrogen, Ci-Ce alkyl, -C(O)- aryl, -C(O)-N(R26)(R27), -C(O)R28, -S(O)2R2s; R24 is hydrogen, Ci-Ce alkyl, tert- butyl-O-C(O)-, -C(0)-Ci-C3 alkyl, an alkyl- or polyalkylene glycol-linked biotin, -hydrogen, Ci-Ce alkyl, -C(O)-Ci-C24alkyl, wherein the C1-C24 alkyl can optionally have one or more -CH2- groupsreplaced with -0- or -NHC(O)-; an alkyl- or polyalkylene glycol-linked biotin, orN-N; R26 and R27 are independently hydrogen, cyclopropyl, or C1-C3 alkyl; R28 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, substituted or unsubstituted aryl, X is a bond, -NHC(O)-, -C(O)NH-, -O-, -S-, -NH-, or -CH2-; n is an integer of 1 to 4.

[0100] Additionally, disclose herein are methods of treating a parasitic worm infection comprising administering a compound of any one of the following structures to a subject in need thereof:

[0101] Also provided is a process of treating, preventing, or reversing a parasitic infection in a subject in need of administration of a therapeutically effective amount of a kinase modulation agent, so as to treat a parasitic infection.

[0102] Methods described herein are generally performed on a subject in need thereof. A subject in need of the therapeutic methods described herein can be a subject having, diagnosed with, suspected of having, or at risk for developing a parasitic infection. A determination of the need for treatment will typically be assessed by a history, physical exam, or diagnostic tests consistent with the disease or condition at issue. Diagnosis of the various conditions treatable by the methods described herein is within the skill of the art. The subject can be an animal subject, including a mammal, such as horses, cows, dogs, cats, sheep, pigs, mice, rats, monkeys, hamsters, guinea pigs, and humans or chickens. For example, the subject can be a human subject.

[0103] Generally, a safe and effective amount of a kinase modulation agent is, for example, an amount that would cause the desired therapeutic effect in a subject while minimizing undesired side effects. In various embodiments, an effective amount of a kinase modulation agent described herein can substantiallyinhibit a parasitic infection, slow the progress of a parasitic infection, or limit the development of a parasitic infection.

[0104] According to the methods described herein, administration can be parenteral, pulmonary, oral, topical, intradermal, intramuscular, intraperitoneal, intravenous, intratumoral, intrathecal, intracranial, intracerebroventricular, subcutaneous, intranasal, epidural, ophthalmic, buccal, or rectal administration.

[0105] When used in the treatments described herein, a therapeutically effective amount of a kinase modulation agent can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form and with or without a pharmaceutically acceptable excipient. For example, the compounds of the present disclosure can be administered, at a reasonable benefit / risk ratio applicable to any medical treatment, in a sufficient amount to treat a parasitic infection.

[0106] The amount of a composition described herein that can be combined with a pharmaceutically acceptable carrier to produce a single dosage form will vary depending upon the subject or host treated and the particular mode of administration. It will be appreciated by those skilled in the art that the unit content of agent contained in an individual dose of each dosage form need not in itself constitute a therapeutically effective amount, as the necessary therapeutically effective amount could be reached by administration of a number of individual doses.

[0107] Toxicity and therapeutic efficacy of compositions described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals for determining the LD50 (the dose lethal to 50% of the population) and the ED50, (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index that can be expressed as the ratio LD50 / ED50, where larger therapeutic indices are generally understood in the art to be optimal.

[0108] The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, generalhealth, sex and diet of the subject; the time of administration; the route of administration; the rate of excretion of the composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see e.g., Koda-Kimble et al. (2004) Applied Therapeutics: The Clinical Use of Drugs, Lippincott Williams & Wilkins, ISBN 0781748453; Winter (2003) Basic Clinical Pharmacokinetics, 4th ed., Lippincott Williams & Wilkins, ISBN 0781741475; Sharqel (2004) Applied Biopharmaceutics & Pharmacokinetics, McGraw- Hill / Appleton & Lange, ISBN 0071375503). For example, it is well within the skill of the art to start doses of the composition at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose may be divided into multiple doses for purposes of administration. Consequently, single-dose compositions may contain such amounts or submultiples thereof to make up the daily dose. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by an attending physician within the scope of sound medical judgment.

[0109] Again, each of the states, diseases, disorders, and conditions, described herein, as well as others, can benefit from compositions and methods described herein. Generally, treating a state, disease, disorder, or condition includes preventing, reversing, or delaying the appearance of clinical symptoms in a mammal that may be afflicted with or predisposed to the state, disease, disorder, or condition but does not yet experience or display clinical or subclinical symptoms thereof. Treating can also include inhibiting the state, disease, disorder, or condition, e.g., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof. Furthermore, treating can include relieving the disease, e.g., causing regression of the state, disease, disorder, or condition or at least one of its clinical or subclinical symptoms. A benefit to a subject to be treated can be either statistically significant or at least perceptible to the subject or to a physician.

[0110] Administration of a kinase modulation agent can occur as a single event or over a time course of treatment. For example, a kinase modulation agent can be administered daily, weekly, bi-weekly, or monthly. Fortreatment of acute conditions, the time course of treatment will usually be at least several days. Certain conditions could extend treatment from several days to several weeks. For example, treatment could extend over one week, two weeks, or three weeks. For more chronic conditions, treatment could extend from several weeks to several months or even a year or more.

[0111] Treatment in accordance with the methods described herein can be performed prior to, concurrent with, or after conventional treatment modalities for a parasitic infection.

[0112] A kinase modulation agent can be administered simultaneously or sequentially with another agent, such as an antibiotic, an anti-inflammatory, or another agent. For example, a kinase modulation agent can be administered simultaneously with another agent, such as an antibiotic or an anti-inflammatory. Simultaneous administration can occur through the administration of separate compositions, each containing one or more of a kinase modulation agent, an antibiotic, an anti-inflammatory, or another agent. Simultaneous administration can occur through the administration of one composition containing two or more of a kinase modulation agent, an antibiotic, an anti-inflammatory, or another agent. A kinase modulation agent can be administered sequentially with an antibiotic, an anti-inflammatory, or another agent. For example, a kinase modulation agent can be administered before or after the administration of an antibiotic, an anti-inflammatory, or another agent.ADMINISTRATION

[0113] Agents and compositions described herein can be administered according to methods described herein in a variety of means known to the art. The agents and composition can be used therapeutically either as exogenous materials or as endogenous materials. Exogenous agents are those produced or manufactured outside of the body and administered to the body. Endogenous agents are those produced or manufactured inside the body by some type of device (biologic or other) for delivery within or to other organs in the body.

[0114] As discussed above, administration can be parenteral, pulmonary, oral, topical, intradermal, intratumoral, intranasal, inhalation (e.g., in an aerosol), implanted, intramuscular, intraperitoneal, intravenous, intrathecal,intracranial, intracerebroventricular, subcutaneous, intranasal, epidural, intrathecal, ophthalmic, transdermal, buccal, and rectal.

[0115] Agents and compositions described herein can be administered in a variety of methods well-known in the arts. Administration can include, for example, methods involving oral ingestion, direct injection (e.g., systemic or stereotactic), implantation of cells engineered to secrete the factor of interest, drug-releasing biomaterials, polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, implantable matrix devices, mini-osmotic pumps, implantable pumps, injectable gels and hydrogels, liposomes, micelles (e.g., up to 30 pm), nanospheres (e.g., less than 1 pm), microspheres (e.g., 1-100 pm), reservoir devices, a combination of any of the above, or other suitable delivery vehicles to provide the desired release profile in varying proportions. Other methods of controlled-release delivery of agents or compositions will be known to the skilled artisan and are within the scope of the present disclosure.

[0116] Delivery systems may include, for example, an infusion pump which may be used to administer the agent or composition in a manner similar to that used for delivering insulin or chemotherapy to specific organs or tumors. Typically, using such a system, an agent or composition can be administered in combination with a biodegradable, biocompatible polymeric implant that releases the agent over a controlled period of time at a selected site. Examples of polymeric materials include polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, polyethylene vinyl acetate, and copolymers and combinations thereof. In addition, a controlled release system can be placed in proximity of a therapeutic target, thus requiring only a fraction of a systemic dosage.

[0117] Agents can be encapsulated and administered in a variety of carrier delivery systems. Examples of carrier delivery systems include microspheres, hydrogels, polymeric implants, smart polymeric carriers, and liposomes (see generally, Uchegbu and Schatzlein, eds. (2006) Polymers in Drug Delivery, CRC, ISBN-10: 0849325331 ). Carrier-based systems for molecular or biomolecular agent delivery can: provide for intracellular delivery; tailor biomolecule / agent release rates; increase the proportion of biomolecule that reaches its site of action; improve the transport of the drug to its site ofaction; allow colocalized deposition with other agents or excipients; improve the stability of the agent in vivo; prolong the residence time of the agent at its site of action by reducing clearance; decrease the nonspecific delivery of the agent to nontarget tissues; decrease irritation caused by the agent; decrease toxicity due to high initial doses of the agent; alter the immunogenicity of the agent; decrease dosage frequency, improve taste of the product; or improve shelf life of the product.

[0118] As used herein, the expression “pharmaceutically acceptable salt” refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Preferred salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or pamoate (i.e., 1 ,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counterions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterion. As used herein, the expression “pharmaceutically acceptable solvate” refers to an association of one or more solvent molecules and a compound of the invention. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. As used herein, the expression “pharmaceutically acceptable hydrate” refers to a compound of the invention, or a salt thereof, that further can include a stoichiometric or non-stoichiometric amount of water bound by non- covalent intermolecular forces.

[0119] Unless otherwise indicated, an alkyl group as described herein alone or as part of another group is an optionally substituted linear saturated monovalent hydrocarbon substituent containing from one to sixty carbon atoms and preferably one to thirty carbon atoms in the main chain or eight to thirty carbon atoms in the main chain, or an optionally substituted branched saturated monovalent hydrocarbon substituent containing three to sixty carbon atoms, and preferably eight to thirty carbon atoms in the main chain. Examples of unsubstituted alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i- butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, and the like.

[0120] The terms “aryl” or “ar” as used herein alone or as part of another group (e.g., arylalkyl) denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing form 6 to 12 carbon atoms in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl groups. The term “aryl” also includes heteroaryl functional groups.

[0121] “Arylalkyl” means an aryl group attached to the parent molecule through an alkylene group. The number of carbon atoms in the aryl group and the alkylene group is selected such that there is a total of about 6 to about 18 carbon atoms in the arylalkyl group. A preferred arylalkyl group is benzyl.

[0122] The term “substituted,” as in “substituted aryl,” “substituted alkyl,” and the like, means that in the group in question (i.e. , the alkyl, aryl, or other group that follows the term), at least one hydrogen atom bound to a carbon atom is replaced with one or more substituent groups such as hydroxy (-OH), alkylthio, amido (-CON(RA)(RB), wherein RA and RB are independently hydrogen, alkyl, or aryl), amino (-N(RA)(RB), wherein RA and RB are independently hydrogen, alkyl, or aryl), halo (fluoro, chloro, bromo, or iodo), silyl, nitro (-NO2), an ether (-ORA wherein RA is alkyl or aryl), an ester (-OC(O)RA wherein RA is alkyl or aryl), keto (-C(O)RA wherein RA is alkyl or aryl), heterocyclo, and the like. When the term "substituted" introduces a list of possible substituted groups, it is intended that the term apply to every member of that group. That is, the phrase "optionally substituted alkyl or aryl" is to be interpreted as "optionally substituted alkyl or optionally substituted aryl."

[0123] The term "heterocyclo," “heterocycle,” or “heterocyclyl,” as used herein, refers to a monocyclic, bicyclic, or tricyclic group containing 1 to 4 heteroatoms selected from N, 0, S(O)n, P(O)n, PRz, NH or NRz, wherein Rz is a suitable substituent. Heterocyclic groups optionally contain one or two double bonds. Heterocyclic groups include, but are not limited to, azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro- thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, and benzoxazinyl. Examples of monocyclic saturated or partially saturated ring systems are tetrahydrofuran-2 yl, tetrahydrofuran-3-yl, imidazolidin-1 -yl, imidazolidin-2 yl, im idazolidin-4-yl, pyrrolidin-1 -yl, pyrrolidin-2 yl, pyrrolidin-3-yl, piperidin-1 -yl, piperidin-2 yl, piperidin-3-yl, piperazin-1 -yl, piperazin-2 yl, piperazin-3-yl, 1 ,3- oxazolidin-3-yl, isothiazolidine, 1 ,3-thiazolidin-3-yl, 1 ,2 pyrazolidin-2 yl, 1 ,3- pyrazolidin-1 -yl, thiomorpholin-yl, 1 ,2 tetrahydrothiazin-2 yl, 1 ,3- tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl, 1 ,2 tetrahydrodiazin- 2 yl, 1 ,3-tetrahydrodiazin-1-yl, 1 ,4-oxazin-2 yl, and 1 ,2,5 oxathiazin-4-yl. Heterocyclic groups can be unsubstituted or substituted by one or more suitable substituents, preferably 1 to 3 suitable substituents, as defined above.

[0124] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims.EXAMPLES

[0125] The following non-limiting examples are provided to further illustrate the present invention.Example 1: Synthesis of compounds of Formula 1

[0126] The synthesis of newly designed inhibitors 1, 2, 3a and 3b is shown in in Scheme 1A below. The internal phenyl furanyl ring system was established through a Suzuki reaction with 3-carboxyphenylboronic acid and 5- bromofuran-carbaldehyde. A Knoevenagel type condensation reaction of the aldehyde 23 under basic conditions with 5-chlorooxindole gave intermediate 24.The addition of A / -Boc-4-diazapane was then accomplished through amide formation via coupling with 24 using HBTLI to give the Boc-protected compound 1 which was tested for activity. The removal of the Boc protecting group using standard 4 N HCI in dioxane returned compound 2, which was diversified into compounds 3a and 3b by acetylation with acetic anhydride and reductive amination with isovaleraldehyde, respectively. Further diversification of the scaffold for SAR was accomplished via amide coupling with intermediate 24 and various basic diamines facilitated by HATLI or HBTLI which generated analogs 4- 6 (Scheme 1 B). Additional analogs 7-22 were synthesized starting with intermediate 23 followed by reaction with various substituted oxindoles to yield the corresponding acids 25a-g which were subjected to amide couplings to construct analogs 7-22 (Scheme 1 C).General Methods

[0127] Starting materials, chemical reagents, and solvents were purchased from trusted commercial vendors unless otherwise stated. In general, all solvents in reactions were anhydrous unless stated otherwise.1H spectra were measured on a Varian 400 MHz NMR equipped with an auto sampler. The following abbreviations denote the peak muplicities: s = singlet; d = doublet; dd = doublet of doublets; t = triplet; q = quartet; qd = quartet of doublets, m = multiplet; br = broad. All reactions were monitored either by thin layer chromatography (TLC) on Merck silica gel plates (0.25 mm thick, 60F254) or by Hewlett Packard Series 1100 HPLC, using a Sunfire C18 3.5 pm pore-size, 4.6 x 50 mm column with a solvent system of H2O (0.01 % TFA) and acetonitrile (0.05% TFA). Gradient was 0^5 minutes: 5-95% linear increase acetonitrile, 5^6 minutes 95% acetonitrile hold, 6^7 minutes 95-5% linear decrease acetonitrile. Peak detection was monitored by 210 and 254 nm UV-absorption and by MS. MS conditions were drying gas 12 L / min, drying gas temperature 350° C, nebulizer psig 55-60, and capillary voltage 4000 V. Compound presence was evaluated by extracting [M+H]+or [M+Na]+of parent compound mass. Compounds were purified either by silica gel chromatography on a Teledyne ISCO CombiFlash purification system using prepacked silica gel columns (4 - 80 g sizes) or via a Gilson Prep HPLC (GX-281 liquid handler, 322 Pump, 155 UVA / is) using a Sunfire C18 5 pm pore-size, 19 x 150 mm column. All compounds tested in biological assays were greater than 95% purity based on1H NMR integration and HPLC / MS by absorbance at 220 and 254 nm wavelengths and AUC of MS.General procedures3-(5-formylfuran-2-yl)benzoic acid (23)

[0128] In a round bottom flask, 3-carboxyphenylboronic acid (2.0 g, 12 mmol) and 5-bromofuran-carbaldehyde (2.1 g, 12 mmol) was dissolved in EtOH (35 mL) and toluene (35 mL). The reaction was degassed with argon, then the flask was purged with argon and Pd(PPhs)4 (0.3 g, 0.25 mmol) and 2 M potassium carbonate (12 mL, 24 mmol) were added and reaction was stirredovernight. Reaction was poured into water and the impurities were extracted with Et20. The aqueous layer was added dropwise to 6 N HCI and the resulting yellow-orange solid was filtered and dried to give 2.3 g of a tan solid in 88% crude yield.3-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (24)

[0129] In a flask, 23 (500 mg, 2.31 mmol), and 5-chloroxindole (464 mg, 2.78 mmol) were dissolved in EtOH (8 mL). While stirring, piperidine (274 pL, 2.78 mmol) was added and reaction was stirred overnight. Reaction was poured into Et20 and the resulting red-orange solid was filtered to give 682 mg used as crude. tert-butyl-4-(3-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoyl)- 1 ,4-diazepane-1 -carboxylate (1 )

[0130] In a round bottom, 24 (300 mg, 0.82 mmol), boc-1 ,4 diazepine (172 mg, 0.86 mmol), and HATLI (390 mg, 1.03 mmol) were dissolved in DMF (10 mL). DIPEA (300 pL, 1.25 mmol) was added, then the reaction was stirred overnight at room temperature. Reaction was poured into a solution of sat. sodium bicarbonate, and the resulting solid was collected by vacuum filtration and was washed with sat. sodium bicarbonate. The crude solid was purified by silica gel chromatography to give 70 mg of an orange oil in 16.6% yield;1H NMR (400 MHz, CD3OD) 5 8.40 - 8.30 (m, 1 H), 7.84 (dt, J = 18.5, 6.0 Hz, 2H), 7.58 - 7.31 (m, 2H), 7.23 - 7.15 (m, 1 H), 7.12 - 7.02 (m, 3H), 6.72 (q, J = 8.7 Hz, 1 H), 3.83 (t, J = 5.8 Hz, 1 H), 3.71 (dt, J = 22.4, 6.0 Hz, 2H), 3.48 (dt, J = 17.6, 6.0 Hz, 5H), 1.93 (p, J = 5.8 Hz, 2H), 1.67 (s, 1 H), 1.48 (s, 9H). ESI-MS [M + H]+ calcd. for C30H31 CIN3O5+549.05, found 549.00 and 449.10 (without Boc).3-((5-(3-(1 ,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)-5-chloroindolin- 2 -one (2)

[0131] In a round bottom flask, 1 (38 mg, 0.07 mmol) was dissolved in dioxane, then 4 M HCI in dioxane was added. Reaction was stirred overnight, then reaction was concentrated and the resulting orange solid was filtered to give 20 mg of the desired compound in 64% yield;1H NMR (400 MHz, DMSO) 58.50 (s, 1 H), 8.02 (d, J = 7.9 Hz, 1 H), 7.95 (d, J = 7.2 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.49 (dq, J = 11.4, 5.8 Hz, 3H), 7.39 (s, 1 H), 7.31 (dd, J = 8.5, 2.0 Hz, 1 H), 6.89 (d, J = 8.3 Hz, 1 H), 3.81 (s, 1 H), 3.68 (s, 1 H), 3.57 (s, 1 H), 3.39 (s, 2H), 3.18 (s, 3H), 2.02 (s, 1 H), 1.92 (s, 1 H). ESI-MS [M + H]+ calcd. for C25H23CIN3O3+448.93, found 448.20.3-((5-(3-(4-acetyl-1 ,4-diazepane-1 -carbonyl)phenyl)furan-2-yl)methylene)-5- chloroindolin-2-one (3a)

[0132] In a round bottom, 2 (60 mg, 0.13 mmol) was dissolved in DCM (3 mL) and DMF (4 mL). While stirring, acetic anhydride (15 pL, 0.16 mmol) and DIPEA (28 pL, 0.16 mmol) were added and reaction was stirred overnight. After reaction was complete, the solvent was removed and the crude residue was dissolved in ethyl acetate. The organic phase was washed with brine (3x), then was dried over Na2SO4, was filtered, and then was concentrated. The compound was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 23.8 mg of an orange powder in 36% yield;1H NMR (400 MHz, DMSO) 5 8.49 (s, 1 H), 8.00 (q, J = 5.9 Hz, 1 H), 7.92 - 7.81 (m, 1 H), 7.61 - 7.53 (m, 1 H), 7.47 (d, J = 3.7 Hz, 2H), 7.37 (d, J = 7.2 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 3.74 (d, J = 5.8 Hz, 1 H), 3.66 - 3.56 (m, 3H), 2.04 - 1 .96 (m, 3H), 1 .84 - 1 .75 (m, 2H), 1 .46 (t, J = 6.2 Hz, 1 H).ESI-MS [M + H]+ calcd. for C27H25CIN3O4+490.97, found 490.20.5-chloro-3-((5-(3-(4-isopentyl-1 ,4-diazepane-1 -carbonyl)phenyl)furan-2- yl)methylene)indolin-2-one (3b)

[0133] In a round bottom, 2 (50 mg, 0.11 mmol) and isovaleraldehyde (12 pL, 0.11 mmol) were dissolved in DCE (1 mL). Sodium triacetoxyborohydride (35 mg, 0.17 mmol) was added under argon, then reaction was stirred overnight. An additional portion of isovaleraldehyde (12 pL, 0.11 mmol) and reaction was stirred for 2 hours, after which solvent was removed The compound was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 7.1 mg of an orange powder in 12% yield;1H NMR (400 MHz, DMSO) 5 8.53 (s, 1 H), 8.06 (d, J = 7.9 Hz, 1 H), 7.94 (s, 2H), 7.65 (t, J = 7.8 Hz, 1 H), 7.54 - 7.49 (m, 2H), 7.42 (s, 1 H), 6.91 (d, J = 8.3 Hz, 1 H), 6.50 (s, 1 H), 3.22 - 3.13 (m, 4H), 2.02(s, 2H), 1.56 (s, 4H), 0.91 (d, J = 5.9 Hz, 7H), 0.85 (s, 4H).ESI-MS [M + H]+ calcd. for C3oH33CIN303+519.06, found 519.10.Method A:3-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-((1 -methylpiperidin-4- yl)methyl)benzamide (4).

[0134] In a round bottom flask, 24 (60 mg, 0.164 mmol), (1-methyl-4- piperidnyl)methanamine (26 pL, 0.180 mmol), and HATLI (69 mg, 0.180 mmol) were dissolved in DMF (3 mL). While stirring, DIPEA (60 pL, 0.345 mmol) was added and reaction was stirred overnight. When reaction was complete, solvent was removed, and the crude residue was dissolved in ethyl acetate. The organic phase was washed with brine (3x), was dried over Na2SO4, was filtered, and then was concentrated. The compound was then purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 9.1 mg of an orange powder in 14% yield;1H NMR (400 MHz, DMSO) 5 8.54 (s, 1 H), 8.35 (s, 1 H), 8.08 (d, 1 H), 7.86 (d, 1 H), 7.66 (d, 1 H), 7.51 (d, 1 H), 7.42 (m, 2H), 7.32 (d, 1 H), 6.90 (d, 1 H), 6.54 (s, 3H), 3.40 (d, 2H), 3.19 (t, 2H), 2.88 (d, 2H), 2.73 (s, 3H), 1.88 (d, 2H ), 1.35 (d, 2H). ESI-MS [M + H]+ calcd. for C27H27CIN3O3+476.98, found 476.20.3-((5-(3-(4-(aminomethyl)piperidine-1 -carbonyl)phenyl)furan-2-yl)methylene)-5- chloroindolin-2-one (5).

[0135] Compound synthesized as per method A with 4-boc-1 - (aminomethyl) piperidine and reaction was instead purified via regular phase silica column (12 g) with a gradient of 0% to 100% ethyl acetate in hexanes to give 64.4 mg of a red oil. Subsequently, 4 M HCI in dioxane was added and reaction was stirred overnight. When reaction was complete, solvent was removed and the compound was then purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 18.7 mg of an orange powder in 35% yield;1H NMR (400 MHz, DMSO) 5 8.63 (t, J = 6.0 Hz, 1 H), 8.35 (d, J = 2.1 Hz, 1 H), 8.21 (d, J = 1.7 Hz, 1 H), 7.88 (d, J = 7.8 Hz, 1 H), 7.68 (d, J = 7.9 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.33 - 7.24 (m, 2H), 7.22 (s, 1 H), 7.13 (dd, J = 8.3, 2.1 Hz, 1 H), 6.72 (d, J = 8.3 Hz, 1 H), 3.00 (t, J = 6.3 Hz, 2H), 2.74 - 2.62 (m,2H), 2.30 (s, 1 H), 1.66 (d, J = 12.5 Hz, 3H), 1.29 (q, J = 13.6 Hz, 2H).ESI-MS [M + H]+ calcd. for C26H25CIN3O3+462.96, found 462.30.3-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-(piperidin-4- ylmethvDbenzamide (6).

[0136] Compound synthesized as per method A with 1-boc-4- (aminomethyl) piperidine and reaction was instead purified via regular phase silica column (12 g) with a gradient of 0% to 10% methanol in DCM to give 70.2 mg of a red oil. Subsequently, 4 M HCI in dioxane was added and reaction was stirred overnight. When reaction was complete, solvent was removed and the compound was then purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 25.3 mg of an orange powder in 44% yield;1H NMR (400 MHz, CD3OD) 8.49 (d, J = 2.1 Hz, 1 H), 8.00 - 7.90 (m, 2H), 7.62 - 7.54 (m, 1 H), 7.46 - 7.40 (m, 1 H), 7.29 (s, 1 H), 7.21 - 7.14 (m, 3H), 6.83 (d, J = 8.3 Hz, 1 H), 4.73 (d, J = 13.4 Hz, 1 H), 3.80 (d, J = 13.6 Hz, 1 H), 3.17 (t, J = 13.0 Hz, 1 H), 2.99 - 2.78 (m, 4H), 1.94 (d, J = 13.2 Hz, 3H), 1.74 (d, J = 12.9 Hz, 1 H), 1.31 (dd, J = 53.5, 12.6 Hz, 3H). ESI-MS [M + H]+ calcd. for C26H25CIN3O3+462.96, found 462.30.Method B:3-(5-((5-amino-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (25a).

[0137] In a vial, 23 (200 mg, 0.93 mmol), and 5-aminooxindole (165 mg, 1.11 mmol) were dissolved in EtOH (2.6 mL). While stirring, piperidine (110 pL, 1.11 mmol) was added and reaction was stirred overnight. Reaction was poured into Et20 and the resulting orange solid was filtered to give 373.5 mg of an orange powder used as crude.5-amino-3-((5-(3-(4-methyl-1 ,4-diazepane-1-carbonyl)phenyl)furan-2- yl)methylene)indolin-2-one (7).

[0138] In a round bottom, 25a (100mg, 0.289 mmol), 1-methyl-1 ,4- diazapane (38 pL, 0.303 mmol), and HATLI (121 mg, 0.318 mmol) were dissolved in DMF. DIPEA was slowly added, then reaction was stirred overnight. After reaction was complete, the solvent was removed then the crude reactionmixture was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 68.3 mg orange powder in 53% yield;1H NMR (400 MHz, CD3OD) 5 8.61 (s, 1 H), 8.28 (s, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.64 (dd, J = 14.4, 7.0 Hz, 2H), 7.47 (s, 1 H), 7.28 (t, J = 6.4 Hz, 2H), 7.23 - 7.18 (m, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 3.97 (d, J = 48.6 Hz, 2H), 3.75 (s, 2H), 3.59 (s, 2H), 3.45 (d, J = 29.8 Hz, 3H), 2.94 (d, J = 7.2 Hz, 3H), 2.20 (s, 2H). ESI-MS [M + H]+ calcd. for C26H27N4O3+443.53, found 443.30.3-(5-((6-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (25b).

[0139] In a vial, 23 (200 mg, 0.93 mmol), and 6-chlorooxindole (186 mg, 1.11 mmol) were dissolved in EtOH (2.6 mL). While stirring, piperidine (110 pL, 1.11 mmol) was added and reaction was stirred overnight. Reaction was poured into Et20 and the resulting orange solid was filtered to give 335.2 mg of an orange powder used as crude.3-(5-((7-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (25c).

[0140] In a vial, 23 (200 mg, 0.93 mmol), and 7-chlorooxindole (186 mg, 1.11 mmol) were dissolved in EtOH (2.6 mL). While stirring, piperidine (110 pL, 1.11 mmol) was added and reaction was stirred overnight. Reaction was poured into Et20 and the resulting orange solid was filtered to give 349 mg of a light brown-orange powder used as crude.7-chloro-3-((5-(3-(4-methyl-1 ,4-diazepane-1 -carbonyl)phenyl)furan-2- yl)methylene)indolin-2-one (8).

[0141] Compound was synthesized as per method B with 25c to give 10.1 mg as an orange solid in 8.0% yield;1H NMR (400 MHz, DMSO) 5 8.45 (d, J = 7.7 Hz, 1 H), 8.00 (d, J = 5.8 Hz, 2H), 7.67 (t, J = 8.0 Hz, 1 H), 7.53 (dd, J = 10.1 , 5.3 Hz, 2H), 7.44 (d, J = 5.7 Hz, 2H), 7.39 (d, J = 8.1 Hz, 1 H), 7.11 (t, J = 8.0 Hz, 1 H), 4.21 - 4.12 (m, 1 H), 3.64 (t, J = 20.0 Hz, 5H), 3.48 - 3.40 (m, 2H), 2.87 (s, 3H), 2.06 (s, 2H). ESI-MS [M + H]+ calcd. for C26H25CIN3O3+462.96, found 462.20.3-(5-((6-amino-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (25d).

[0142] In a vial, 23 (75 mg, 0.35 mmol), and 6-aminooxindole (57 mg, 0.39 mmol) were dissolved in EtOH (1 mL). While stirring, piperidine (38 pL, 0.39 mmol) was added and reaction was stirred overnight. Reaction was poured into Et2<D and the resulting orange solid was filtered to give 109.8 mg of a red-brown solid used as crude.6-amino-3-((5-(3-(4-methyl-1 ,4-diazepane-1-carbonyl)phenyl)furan-2- yl)methylene)indolin-2-one (9).

[0143] Compound was synthesized as per method B with 25d to give33.6 mg of a red-orange solid in 53% yield;1H NMR (400 MHz, CD3OD) 5 8.30 (d, J = 8.4 Hz, 1 H), 7.98 (d, J = 9.9 Hz, 1 H), 7.62 (t, J = 7.7 Hz, 1 H), 7.50 (d, J =8.6 Hz, 1 H), 7.18 - 7.01 (m, 2H), 6.45 (d, J = 8.5 Hz, 1 H), 6.37 (s, 1 H), 3.66 (t, J = 94.7 Hz, 9H), 2.98 (s, 3H), 2.17 (m, 2H). ESI-MS [M + H]+ calcd. for C26H27N4O3+ 443.53, found 443.30.3-(5-((5-methyl-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (25e).

[0144] In a vial, 23 (100 mg, 0.46 mmol), and 5-methyloxindole (76 mg, 0.51 mmol) were dissolved in EtOH (mL). While stirring, piperidine (51 pL, 0.51 mmol) was added and reaction was stirred overnight. Reaction was poured into Et20 and the resulting orange solid was filtered to give 121 .3 mg of a red- orange powder used as crude.5-methyl-3-((5-(3-(4-methyl-1 ,4-diazepane-1 -carbonyl)phenyl)furan-2- yl)methylene)indolin-2-one (10).

[0145] Compound was synthesized as per method B with 25e to give 33.0 mg as a bright orange solid in 52% yield;1H NMR (400 MHz, CD3OD) 5 8.23 (s, 1 H), 7.97 - 7.89 (m, 2H), 7.60 - 7.47 (m, 2H), 7.15 (d, J = 4.2 Hz, 1 H), 7.08 (d, J = 3.7 Hz, 1 H), 7.02 (dd, J = 13.6, 6.0 Hz, 2H), 6.70 (d, J = 7.9 Hz, 1 H), 3.90 - 3.32 (m, 8H), 2.99 (s, 2H), 2.30 (d, J = 4.8 Hz, 3H), 2.18 (s, 2H). ESI-MS [M + H]+ calcd. for C27H28N3O3+442.54, found 442.40.3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (25f).

[0146] In a vial, 23 (100 mg, 0.46 mmol), and oxindole (68 mg, 0.51 mmol) were dissolved in EtOH (1.3 mL). While stirring, piperidine (51 pL, 0.51 mmol) was added and reaction was stirred overnight. Reaction was poured into Et2O and the resulting orange solid was filtered to give 131 .6 mg used as crude.3-((5-(3-(4-methyl-1 ,4-diazepane-1 -carbonyl)phenyl)furan-2- yl)methylene)indolin-2-one (11 ).

[0147] Compound was synthesized as per method B with 25f to give bright orange solid with 19.2 mg in 25% yield;1H NMR (400 MHz, CD3OD) 5 8.53 (d, J = 7.8 Hz, 1 H), 8.06 - 8.00 (m, 2H), 7.64 (t, J = 7.8 Hz, 1 H), 7.54 (d, J = 7.9 Hz, 1 H), 7.36 (s, 1 H), 7.28 (t, J = 7.7 Hz, 1 H), 7.20 (t, J = 2.8 Hz, 2H), 7.10 (t, J = 7.7 Hz, 1 H), 6.92 (d, J = 7.7 Hz, 1 H), 3.98 - 3.34 (m, 8H), 2.99 (s, 3H), 2.17 (s, 2H). ESI-MS [M + H]+ calcd. for C26H26N3O3+428.51 , found 428.40.3-(5-((7-methyl-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (25g).

[0148] In a vial, 23 (100 mg, 0.46 mmol), and 7-methyloxindole (76 mg, 0.51 mmol) were dissolved in EtOH (mL). While stirring, piperidine (51 pL, 0.51 mmol) was added and reaction was stirred overnight. Reaction was poured into Et2O and the resulting red-orange solid was filtered to give 136.5 mg used as crude.7-methyl-3-((5-(3-(4-methyl-1 ,4-diazepane-1 -carbonyl)ohenyl)furan-2- yl)methylene)indolin-2-one (12).

[0149] Compound was synthesized as per method B with 25g to give bright orange solid with 19.8 mg in 26% yield;1H NMR (400 MHz, CDCI3) 5 8.34 (dd, J = 16.0, 5.6 Hz, 1 H), 7.86 - 7.67 (m, 2H), 7.43 (t, J = 7.7 Hz, 1 H), 7.32 - 7.18 (m, 1 H), 7.01 (d, J = 7.6 Hz, 1 H), 6.93 (t, J = 6.3 Hz, 2H), 6.84 (q, J = 4.4 Hz, 1 H), 3.78 (dt, J = 11 .9, 5.6 Hz, 2H), 3.60 - 3.37 (m, 2H), 2.78 - 2.66 (m, 1 H), 2.63 - 2.57 (m, 1 H), 2.51 (q, J = 7.7 Hz, 3H), 2.36 (d, J = 6.0 Hz, 3H), 2.26 (s, 2H), 1.98 (p, J = 5.7 Hz, 1 H), 1.80 (p, J = 6.0 Hz, 1 H). ESI-MS [M + H]+ calcd. for C27H27N3O3+442.54, found 442.20.Method C:3-(5-((5-amino-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-((1 -methylpiperidin-4- yl)methyl)benzamide (13).

[0150] In a round bottom flask, 25a (100 mg, 0.289 mmol), (1 -methyl-4-piperidnyl)methanamine (43 pL, 0.303 mmol), and HATLI (121 mg, 0.318 mmol) were dissolved in DMF (5 mL). While stirring, DIPEA (106 pL, 0.607 mmol) was added and reaction was stirred overnight. After reaction was complete, the solvent was removed then the crude reaction mixture was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 22.9 mg of an orange solid in 17% yield;1H NMR (400 MHz,CD3OD) 5 8.62 (t, J = 2.4 Hz, 1 H), 8.54 (t, J = 2.0 Hz, 1 H), 8.01 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 7.8 Hz,1 H), 7.64 - 7.51 (m, 1 H), 7.43 (d, J = 2.8 Hz, 1 H), 7.32 (dd, J = 8.2, 2.2 Hz, 1 H), 7.23 (ddd, J = 20.0, 3.8, 2.2 Hz, 2H), 7.01 (d, J = 8.5 Hz, 1 H), 3.55 (d, J = 12.3 Hz, 2H), 3.42 (d, J = 6.3 Hz, 2H), 3.07 - 2.90 (m, 2H), 2.85 (s, 3H), 2.03 (t, J = 14.0 Hz, 3H), 1.58 (q, J = 13.6 Hz, 2H), 1.36 (dd, J = 6.7, 3.6 Hz, 1 H). ESI-MS [M + H]+ calcd. for C27H29N4O3+457.55, found 457.40.3-(5-((6-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-((1 -methylpiperidin-4- vDmethvDbenzamide (14).

[0151] Compound synthesized as per method C with 25b to give 12.2 mg of an orange solid in 16% yield;1H NMR (400 MHz, DMSO) 5 8.50 (d, 1 H), 8.40 (d, 1 H), 8.04 (d, 1 H), 7.89 (d, 1 H), 7.65 (t, 1 H), 7.47 (d, 1 H), 7.42 (d, 1 H), 7.38 (s, 1 H), 7.16 (dd, 1 H), 6.92 (d, 1 H), 2.88 (t, 3H), 2.73 (s, 4H), 2.06 (s, 3H), 1.88 (d, 4H). ESI-MS [M + H]+ calcd. for C27H27CIN3O3+476.98, found 476.30.3-(5-((7-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-((1 -methylpiperidin-4- vDmethvDbenzamide (15).

[0152] Compound synthesized as per method C with 25c to give 68.1 mg of an orange solid in 87% yield;1H NMR (400 MHz, DMSO) 5 8.74 (q, 1 H), 8.51 (d, 1 H), 8.43 (d, 1 H), 8.05 (m, 1 H), 7.89 (m, 1 H), 7.65 (t, 1 H), 7.50 (d, 1 H), 7.43 (t, 2H), 7.38 (m, 1 H), 7.15 (t, 1 H), 3.21 (q, 3H), 2.88 (q, 3H), 2.73 (d, 4H), 2.06 (d, 2H), 1 .88 (d, 2H). ESI-MS [M + H]+ calcd. for C27H27CIN3O3+476.98, found 476.30.3-(5-((7-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-(piperidin-4- ylmethvDbenzamide (16).

[0153] Compound synthesized as per method C with 25c and (1 -boc-4-piperidnyl)methanamine and reaction was instead purified on reg. phase silica column chromatography with a gradient of 0% to 5% methanol in DCM to give red-orange oil. Subsequently, 4M HCI in dioxane was added to dissolve the oil and reaction was stirred overnight. When reaction was complete, solvent was removed and the compound was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 39.7 mg of an orange solid in 19% yield;1H NMR (400 MHz, DMSO) 5 9.35 (s, 1 H), 8.76 (q, J = 5.9 Hz, 1 H), 8.53 (d, J = 7.7 Hz, 1 H), 8.48 - 8.40 (m, 1 H), 8.10 - 8.05 (m, 1 H), 7.96 - 7.88 (m, 1 H), 7.67 (t, J = 7.8 Hz, 1 H), 7.53 (d, J = 3.7 Hz, 1 H), 7.46 (t, J = 1 .9 Hz, 1 H), 7.44 - 7.38 (m, 1 H), 7.17 (t, J = 7.9 Hz, 1 H), 6.59 (s, 1 H), 3.24 (q, J = 6.7 Hz, 3H), 2.91 (q, J =11.6 Hz, 2H), 2.75 (d, J = 4.2 Hz, 3H), 1.91 (d, J = 14.5 Hz, 2H), 1.85 - 1.76 (m, 1 H), 1.40 (q, J = 13.1 Hz, 2H).ESI-MS [M + H]+ calcd. for C26H25CIN3O3+462.96, found 462.30.3-(5-((6-amino-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-((1 -methylpiperidin-4- yl)methyl)benzamide (17).

[0154] Compound synthesized as per method C with 25c to give 52.8 mg of a red-brown solid in 40% yield;1H NMR (400 MHz, CD3OD) 5 8.35 (dd, J = 8.2, 3.3 Hz, 1 H), 8.23 (q, J = 2.1 Hz, 1 H), 7.86 - 7.78 (m, 1 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.49 (td, J = 7.8, 1.9 Hz, 1 H), 7.10 (d, J = 3.0 Hz, 1 H), 7.00 (dt, J = 9.3, 3.5 Hz, 2H), 6.83 (dd, J = 8.3, 2.1 Hz, 1 H), 6.65 (d, J = 2.1 Hz, 1 H), 3.59 - 3.48 (m, 3H), 3.38 (d, J = 6.6 Hz, 3H), 3.05 - 2.92 (m, 3H), 2.85 (s, 4H), 2.06 (d, J =14.7 Hz, 3H), 1.57 (qd, J = 14.6, 3.9 Hz, 3H). ESI-MS [M + H]+ calcd. for C27H29N4O3+457.55, found 457.40.3-(5-((7-methyl-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-((1 -methylpiperidin-4- vDmethvDbenzamide (18).

[0155] Compound synthesized as per method C with 25f to give 9 mg of an orange solid in 14% yield;1H NMR (400 MHz, DMSO) 5 8.71 (s, 1 H), 8.45 - 8.36 (m, 2H), 8.05 (d, J = 7.8 Hz, 1 H), 7.90 - 7.82 (m, 1 H), 7.64 (t, J = 7.7 Hz,1 H), 7.41 (q, J = 3.7 Hz, 2H), 7.34 (s, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 7.04 (t, J = 7.6 Hz, 1 H), 6.53 (s, 1 H), 2.69 (s, 4H), 2.23 (s, 2H), 2.19 (t, J = 6.8 Hz, 2H), 1.81 (d, J = 21 .0 Hz, 4H), 1 .36 (s, 3H). ESI-MS [M + H]+ calcd. for C29H3oN303+456.57, found 456.30.N-((1 -methylpiperidin-4-yl)methyl)-3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2- vDbenzamide (19).

[0156] Compound synthesized as per method C with 25f to give an orange solid with 13.6 mg in 18% yield;1H NMR (400 MHz, CD3OD) 5 8.78 (s, 1 H), 8.45 (d, J = 15.0 Hz, 1 H), 8.05 (d, J = 7.9 Hz, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.69 - 7.49 (m, 1 H), 7.37 (s, 1 H), 7.25 - 7.15 (m, 1 H), 7.11 (d, J = 5.2 Hz, 3H), 3.55 (d, J = 12.4 Hz, 2H), 3.40 (d, J = 6.2 Hz, 2H), 3.00 (t, J = 12.8 Hz, 2H), 2.87 (s, 3H), 2.28 (d, J = 7.5 Hz, 3H), 2.08 (d, J = 16.1 Hz, 2H), 1.55 (d, J = 13.6 Hz, 2H). ESI-MS [M + H]+ calcd. for C27H28N3O3+442.54, found 442.30.3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-(piperidin-4- ylmethvDbenzamide (20).

[0157] Compound synthesized as per method C with 25f and (1 -boc-4- piperidnyl)methanamine and reaction was instead purified on reg. phase silica column chromatography with a gradient of 0% to 100% ethyl acetate in hexanes to give a red-orange oil. Subsequently, 4M HCI in dioxane was added to dissolve the oil and reaction was stirred overnight. When reaction was complete, solvent was removed and the compound was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 17.7 mg of an orange solid in 25% yield;1H NMR (400 MHz, CD3OD) 5 8.49 (d, J = 7.7 Hz, 1 H), 8.34 (s, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.80 (d, J = 7.9 Hz, 1 H), 7.54 (dd, J = 14.7, 7.2 Hz, 2H), 7.26 (d, J = 7.1 Hz, 1 H), 7.10 (s, 3H), 6.87 (d, J = 7.6 Hz, 1 H), 3.40 (dd, J = 15.8, 9.3 Hz, 5H), 2.99 (t, J = 12.5 Hz, 2H), 2.02 (d, J = 13.9 Hz, 2H), 1.51 (d, J = 13.6 Hz, 2H). ESI-MS [M + H]+ calcd. for C26H26N3O3+428.50, found 428.30.3-(5-((7-methyl-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-(piperidin-4- ylmethvDbenzamide (21 ).

[0158] Compound synthesized as per method C with 25g and (1-boc- 4-piperidnyl)methanamine and reaction was instead purified via reg. phase silica column chromatography with a gradient of 0% to 100% ethyl acetate in hexanes to give an orange residue. Subsequently, 4M HCI in dioxane was added to dissolve the oil and reaction was stirred overnight. When reaction was complete, solvent was removed and the compound was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 46.6 mg of a bright orange solid in 41 % yield;1H NMR (400 MHz, CD3OD) 5 8.74 (d, J = 6.5 Hz, 1 H), 8.44 (d, J = 7.4 Hz, 1 H), 8.41 (s, 1 H), 8.04 (d, J = 7.9 Hz, 1 H), 7.83 (d, J = 7.8 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.36 (s, 1 H), 7.19 (d, J = 2.5 Hz, 2H), 7.13 - 7.04 (m, 2H), 3.40 (q, J = 8.1 Hz, 4H), 2.99 (t, J = 12.7 Hz, 2H), 2.27 (s, 3H), 2.03 (d, J = 12.5 Hz, 4H), 1.50 (q, J = 13.0 Hz, 2H). ESI-MS [M + H]+ calcd. for C2?H28N3O3+442.54, found 442.40.3-((5-(3-(1 ,4-diazepane-1 -carbonyl)phenyl)furan-2-yl)methylene)-7- methylindolin-2-one (22).

[0159] Compound synthesized as per method C with 25g and boc-1 ,4- diazapine and reaction was instead purified on reg. phase silica column chromatography with a gradient of 0% to 100% ethyl acetate in hexanes to give 40 mg of an orange powder in 17% yield. In a round bottom, the product (38 mg, 0.07 mmol) was dissolved in 4 M HCI in dioxane (5 mL) and was stirred overnight. When reaction was complete, the solvent was removed to give 30 mg of an orange solid in 97% yield;1H NMR (400 MHz, DMSO) 5 8.33 (d, J = 7.3 Hz, 1 H), 8.05 - 7.95 (m, 2H), 7.64 (d, J = 7.6 Hz, 1 H), 7.52 (d, J = 7.2 Hz, 1 H), 7.43 (s, 2H), 7.34 (s, 1 H), 7.13 (d, J = 7.3 Hz, 1 H), 6.99 (t, J = 7.5 Hz, 1 H), 3.77 - 3.62 (m, 6H), 2.24 (s, 3H), 2.06 (s, 1 H).ESI-MS [M + H]+ calcd. for C26H26N3O3+428.51 , found 428.30.Example 2: Synthesis of compounds of Formula 2

[0160] In a round bottom flask, (1 .0 g, 4.30 mmol) and 3- trifluoromethoxyphenylboronic acid (547 mg, 5.16 mmol) were dissolved in 1 ,4 dioxane (34 mL) and 1 M aq. Cs2CO3. The reaction was purged and degassed with argon, then Pd(PPh3)4 (497 mg, 0.43 mmol) was added. The reaction was heated to 100°C for 1 hr, then solvent was removed. The residue was dissolved in DCM and was filtered. The filtrate was concentrated, then was purified by reg. phase column chromatography with hexanes and ethyl acetate to give 890 mg of a yellow solid.METHOD A:Compound 151

[0161] In a microwave vial, COMPOUND (25 mg, 0.08 mmol), KF (46 mg, 0.80 mmol) and benzylamine (10.7 mg, 0.10 mmol) were dissolved in DMSO (1 mL). The vial was purged with argon, then was sealed and heated to 150°C in a microwave reactor for 1 hr. The reaction was filtered, then was purified directly on rev. phase prep HPLC (eluent system water / ACN with 0.05% TFA) to give 18.9 mg (48% yield). 1 H NMR (400 MHz, DMSO) 5 8.29 (s, 1 H), 8.21 (s, 1 H), 8.09 (s, 1 H), 7.98 (dd, J = 13.2, 9.0 Hz, 2H), 7.58 (t, J = 8.1 Hz, 1 H), 7.43 - 7.31 (m, 5H), 7.29 - 7.23 (m, 1 H), 7.08 (d, J = 9.8 Hz, 1 H), 4.51 (d, J = 5.5 Hz, 2H).ESI-MS [M + H]+calcd. for C2oHi6F3N40+385.37, found 385.20.Compound 144

[0162] Compound was synthesized via method A to give 295 mg (104% yield). 1 H NMR (400 MHz,) ESI-MS [M + H]+calcd. for Ci9H2iF3N5O+392.40, found 392.40.Method B:Compound 4

[0163] In a vial, 3 (30 mg, 0.07 mmol) was dissolved in DCM (2 mL). Acetic anhydride was added, and then DIPEA was added under argon. The reaction was sealed and was stirred at room temperature overnight. Upon reaction completion, the solvent was removed and the crude material was purified by rev. phase HPLC to give 25 mg (65% yield).1H NMR (400 MHz,DMSO) 6 8.39 (d, J = 3.2 Hz, 2H), 8.07 (d, J = 7.9 Hz, 1 H), 7.97 (d, J = 9.7 Hz, 1 H), 7.74 (t, J = 5.6 Hz, 1 H), 7.65 (t, J = 8.1 Hz, 1 H), 7.42 (dd, J = 8.2, 2.4 Hz, 1 H), 7.08 (d, J = 9.8 Hz, 1 H), 4.39 (d, J = 12.9 Hz, 1 H), 3.19 (s, 2H), 2.98 (td, J = 13.0, 2.6 Hz, 1 H), 1.97 (s, 3H), 1.81 - 1.68 (m, 2H), 1.10 (dtd, J = 50.4, 12.2, 8.1 Hz, 2H). ESI-MS [M + H]+calcd. for C2iH23F3N5O2+434.44, found 434.20.Compound 5

[0164] Compound was synthesized as per Method B with dimethyl glycine to give 40 mg of a yellow solid (83% yield).1H NMR (400 MHz, DMSO) 5 8.41 (s, 1 H), 8.38 (s, 1 H), 8.06 (d, J = 7.9 Hz, 1 H), 7.99 (d, J = 9.8 Hz, 1 H), 7.83 (d, J = 5.6 Hz, 1 H), 7.63 (t, J = 8.1 Hz, 1 H), 7.41 (d, J = 8.2 Hz, 1 H), 7.10 (d, J = 9.8 Hz, 1 H), 3.61 (d, J = 13.6 Hz, 1 H), 3.19 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 12.7 Hz, 1 H), 2.78 (s, 6H), 2.65 (t, J = 12.5 Hz, 1 H), 2.05 - 1 .94 (m, 1 H), 1 .81 (d, J = 13.0 Hz, 2H), 1.14 (dtt, J = 48.5, 12.4, 6.3 Hz, 2H).) ESI-MS [M + H]+calcd. for C23H28F3N6O2+476.51 , found 476.20.Compound 6

[0165] Compound was synthesized as per Method B with morphorlino- 4-yl acetic acid to give 37 mg of a yellow solid (97% yield). 1 H NMR (400 MHz, DMSO) 5 8.52 (s, 1 H), 8.35 (s, 1 H), 8.18 (d, J = 5.4 Hz, 1 H), 8.04 (dd, J = 10.9, 8.5 Hz, 2H), 7.66 (t, J = 8.1 Hz, 1 H), 7.44 (dd, J = 8.2, 2.3 Hz, 1 H), 7.30 (d, J = 9.8 Hz, 1 H), 4.35 (q, J = 16.2 Hz, 3H), 3.90 (s, 4H), 3.21 - 3.10 (m, 5H), 3.02 (tp, J = 9.1 , 4.4 Hz, 5H), 2.65 (td, J = 12.8, 2.7 Hz, 1 H), 1.81 (dd, J = 13.4, 3.5 Hz, 2H). ESI-MS [M + H]+calcd. for C25H3oF3N603+519.55, found 519.30.Compound 23

[0166] Compound was synthesized as per Method B to give 22.5 mg of a white powder (31 % yield).1H NMR (400 MHz, CD3OD) 5 8.28 (d, J = 14.1 Hz, 2H), 7.98 (dd, J = 16.8, 8.8 Hz, 2H), 7.66 (t, J = 8.1 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 7.25 (d, J = 10.0 Hz, 1 H), 4.54 (d, J = 13.2 Hz, 1 H), 4.11 (d, J = 13.8 Hz, 1 H), 3.53 (d, J = 12.6 Hz, 2H), 3.09 (dt, J = 24.7, 12.1 Hz, 5H), 2.87 (d, J = 8.2 Hz, 3H), 2.65 (t, J = 12.4 Hz, 1 H), 2.08 (s, 1 H), 1.98 - 1 .82 (m, 6H), 1 .32 - 1.10 (m, 2H). ESI-MS [M + H]+calcd. for C26H32F3N6O2+517.58, found 517.20.Compound 24

[0167] Compound was synthesized via method A with (4-Boc-1 - piperidnyl)methanamine to give 460 mg of intermediate X. X (460 mg, 0.94 mmol) was dissolved in 1 M HCI in dioxane (5 mL) give 89.8 mg of a yellow solid (25% yield).1H NMR (400 MHz, DMSO) 5 8.52 (s, 1 H), 8.35 (s, 1 H), 8.18 (d, J = 5.4 Hz, 1 H), 8.04 (dd, J = 10.9, 8.5 Hz, 2H), 7.66 (t, J = 8.1 Hz, 1 H), 7.44 (dd, J = 8.2, 2.3 Hz, 1 H), 7.30 (d, J = 9.8 Hz, 1 H), 4.35 (q, J = 16.2 Hz, 3H), 3.90 (s, 4H), 3.21 - 3.10 (m, 5H), 3.02 (tp, J = 9.1 , 4.4 Hz, 5H), 2.65 (td, J = 12.8, 2.7 Hz, 1 H), 1.81 (dd, J = 13.4, 3.5 Hz, 2H). ESI-MS [M + H]+calcd. for C24H26N5+392.40, found 392.20.Compound 29

[0168] Compound was synthesized via method A with N- methylhomopiperazine to give 16.9 mg of a white solid (21 % yield).1H NMR (400 MHz, DMSO) 5 8.32 - 8.28 (m, 1 H), 8.12 (d, J = 9.7 Hz, 2H), 8.00 (d, J = 10.0 Hz, 1 H), 7.62 (t, J = 8.1 Hz, 1 H), 7.36 - 7.30 (m, 1 H), 7.20 (d, J = 10.0 Hz, 1 H), 4.05 - 3.86 (m, 2H), 3.73 (t, J = 6.2 Hz, 2H), 2.83 (s, 3H), 2.18 (q, J = 5.8 Hz, 2H). ESI-MS [M + H]+calcd. for C2oH23F3N5+392.430, found 392.200.Method C:Compound 152

[0169] In a vial, 3-bromo-6-chloroimidazo[1 ,2-b]pyridazine (200 mg, 0.86 mmol), 3-trifluoromethyl boronic acid (171 mg, 0.90 mmol), Na2CO3(182 mg, 1 .72 mmol) were dissolved in water (1 mL) and dioxane (5 mL). The flask was purged with argon (2x), then Pd(PPh3)4 (29.0 mg, 0.03 mmol) was added. The reaction was sealed, and was heated to 85°C overnight. Solvent was removed when reaction was complete by LCMS, and INSERT MN PURIFICATION. (25 mg, 0.08 mmol) was added to a microwave vial with (1- methyl-4-pipridnyl)methanamine (12.0 mg, 0.09 mmol) and KF (46.0 mg, 0.80 mmol). DMSO (1 mL) was added, the flask was purged with argon, then reaction was heated to 150°C for 45 minutes. The crude mixture was directly purified by via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 28.4mg of a white solid (64% yield). 1 H NMR (400 MHz,) ESI-MS [M + H]+ calcd. for C19H20F3N6O2+ 421.40, found.INTERMEDIATE X

[0170] In a vial, 3-bromo-6-chloroimidazo[1 ,2-b]pyridazine (250 mg, 1 .08 mmol), 2-biphenyl boronic acid (255 mg, 1 .29 mmol) was dissolved in dioxane (8.5 mL) and 1 M aq. CS2CO3 (4.6 mL). The vial was purged with argon for 15 minutes, then Pd(PPh3)4 (124 mg, 0.11 mmol) was added. The vial was sealed, then reaction was heated to 100°C overnight. When complete, the reaction was poured into water, and the resulting solid was collected via vacuum filtration to give 221 mg of crude, which was used as is in the next reaction.Compound 63

[0171] INTERMEDIATE X (110 mg, 0.36 mmol), (1-methyl-4- pipridnyl)methanamine (62 pL, 0.43 mmol) and KF (191 mg, 3.29 mmol) were dissolved in DMSO (2 mL). The reaction was heated to 150°C overnight, then reaction was poured into equal parts sat. sodium bicarbonate and DCM. The mixture was stirred for 1 hour, then the phases were separated. The organic phase was dried over Na2SO4, was filtered, and was then concentrated. The crude was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 11 .7 mg of a light brown solid (6.3% yield).1H NMR (400 MHz, DMSO) 5 7.85 (d, J = 9.7 Hz, 1 H), 7.68 (d, J = 7.5 Hz, 1 H), 7.62 (dd, J = 8.6, 5.9 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.35 (s, 1 H), 7.23 (d, J = 6.9 Hz, 3H), 7.14 (d, J = 7.0 Hz, 2H), 6.90 (d, J = 9.8 Hz, 1 H), 2.94 - 2.81 (m, 4H), 2.75 (d, J = 4.5 Hz, 3H), 2.67 (s, OH), 1 .82 (d, J = 14.1 Hz, 2H), 1 .69 (s, 1 H), 1.36 - 1 .20 (m, 2H). ESI-MS [M + H]+calcd. for C25H28N5+398.530, found 398.300.Compound 64

[0172] INTERMEDIATE X (110 mg, 0.36 mmol), N- methylhomopiperazine (55 pL, 0.43 mmol) and KF (191 mg, 3.29 mmol) were dissolved in DMSO (2 mL). The reaction was heated to 150°C overnight, then reaction was poured into equal parts sat. sodium bicarbonate and DCM. The mixture was stirred for 1 hour, then the phases were separated. The organicphase was dried over Na2SO4, was filtered, and was then concentrated, to give 24.8 mg of a yellow solid (21 % yield). 1 H NMR (400 MHz,) ESI-MS [M + H]+calcd. for C24H26Ns+384.51 , found 384.300.INTERMEDIATE X

[0173] In a vial, 3-bromo-6-chloroimidazo[1 ,2-b]pyridazine (250 mg, 1 .08 mmol), 3-biphenyl boronic acid (255 mg, 1 .29 mmol) was dissolved in dioxane (8.5 mL) and 1 M aq. CS2CO3 (4.6 mL). The vial was purged with argon for 15 minutes, then Pd(PPh3)4 (124 mg, 0.11 mmol) was added. The vial was sealed, then reaction was heated to 100°C overnight. When complete, the reaction was poured into water, and the resulting solid was collected via vacuum filtration to give 150 mg of crude, which was used as is in the next reaction.Compound 31

[0174] INTERMEDIATE X (110 mg, 0.36 mmol), (1 -methyl-4- pipridnyl)methanamine (62 pL, 0.43 mmol) and KF (191 mg, 3.29 mmol) were dissolved in DMSO (2 mL). The reaction was heated to 150°C overnight, then reaction was poured into equal parts sat. sodium bicarbonate and DCM. The mixture was stirred for 1 hour, then the phases were separated. The organic phase was dried over Na2SO4, was filtered, and was then concentrated. The crude was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 10.9 mg of a yellow solid (11 % yield).1H NMR (400 MHz, DMSO) 5 8.66 (d, J = 1.5 Hz, 1 H), 8.43 (d, J = 2.0 Hz, 1 H), 8.27 (d, J = 10.1 Hz, 1 H), 8.14 (d, J = 7.7 Hz, 1 H), 7.77 (dd, J = 8.5, 7.0 Hz, 3H), 7.71 - 7.65 (m, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1 H), 4.20 - 4.10 (m, 1 H), 3.95 (dd, J = 16.2, 9.1 Hz, 2H), 3.79 (dd, J = 7.9, 4.6 Hz, 3H), 3.05 (qd, J = 7.3, 4.9 Hz, 2H), 2.75 (d, J = 4.2 Hz, 3H), 2.48 - 2.39 (m, 1 H), 2.20 - 2.10 (m, 1 H). ESI-MS [M + H]+calcd. for C25H28Ns+398.530, found 398.300.Compound 30

[0175] INTERMEDIATE X (110 mg, 0.36 mmol), N- methylhomopiperazine (62 pL, 0.43 mmol) and KF (191 mg, 3.29 mmol) were dissolved in DMSO (2 mL). The reaction was heated to 150°C overnight, thenreaction was poured into equal parts sat. sodium bicarbonate and DCM. The mixture was stirred for 1 hour, then the phases were separated. The organic phase was dried over Na2SO4, was filtered, and was then concentrated. The crude was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) give 17.4 mg of a yellow solid (19% yield).1H NMR (400 MHz, DMSO) 5 8.59 (s, 1 H), 8.49 (d, J = 2.0 Hz, 1 H), 8.23 (d, J = 5.0 Hz, 1 H), 8.08 (dd, J = 9.0, 6.1 Hz, 2H), 7.73 (dd, J = 7.8, 5.2 Hz, 3H), 7.66 (t, J = 7.8 Hz, 1 H), 7.51 (d, J =7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1 H), 7.31 (d, J = 9.9 Hz, 1 H), 3.17 (d, J = 6.0 Hz, 2H), 3.03 (qd, J = 7.3, 4.7 Hz, 2H), 2.78 (dt, J = 12.9, 9.9 Hz, 2H), 2.64 (d, J =4.6 Hz, 3H), 1.78 (d, J = 14.4 Hz, 2H), 1.48 (qd, J = 13.5, 3.9 Hz, 2H). ESI-MS [M + H]+calcd. for C24H26N5+384.51 , found 384.300.Compound 150

[0176] In a microwave vial, COMPOUND (250 mg, 1.10 mmol), KF (580 mg, 10.0 mmol) and (1 -methyl-4-pipridnyl)methanamine (170 mg, 1.30 mmol) were dissolved in DMSO (3 mL). The vial was purged with argon, then was sealed and heated to 150°C in a microwave reactor for 1 hr. Water was added to the reaction, and the product was extracted with DCM. The organic layer was washed with brine, and was then dried over Na2SO4, was filtered, and was then concentrated to give the crude product as 400 mg of a brown oil. The crude material was dissolved in methanol (10 mL), and 1 M KOH (2.4 mL) was added. The reaction was stirred under argon for 2 hours. When complete, the reaction was concentrated then 1 N HCI was added, and the reaction was concentrated. Diethyl ether was added to the solid, and was filtered off to give 410 mg of a brown solid.

[0177] 1 H NMR (400 MHz,) ESI-MS [M + H]+ calcd. for C14H20N5O2+ 290.35, found.Method C:Compound 3

[0178] In a vial, 15 (30.0 mg, 0.10 mmol), (3-trifluoromethoxy) aniline (20.0 mg, 0.12 mmol), and HBTU (20.0 mg, 0.13 mmol) were dissolved in DMF (1 mL). The reaction was stirred for 10 min, then DIEA (27 pL, 0.15 mmol) wasadded dropwise under argon. The reaction was allowed to stir at room temperature overnight, and when reaction was complete, the solvent was removed. Water was added to the concentrated reaction to form an oil, which was dissolved in DMSO and was purified via rev. phase HPLC (eluent system water / ACN with 0.05% TFA) to give 17.5 mg of a white powder (38% yield).1H NMR (400 MHz, DMSO) 5 8.09 (d, J = 1.1 Hz, 1 H), 7.95 (dd, J = 9.8, 1.0 Hz, 1 H), 7.89 (s, 1 H), 7.76 (s, 1 H), 7.62 - 7.56 (m, 1 H), 7.53 (t, J = 8.1 Hz, 1 H), 7.15 (d, J = 8.1 Hz, 1 H), 6.94 (d, J = 9.7 Hz, 1 H), 3.34 (d, J = 6.1 Hz, 5H), 2.91 (q, J =11.7 Hz, 2H), 2.73 (d, J = 4.6 Hz, 3H), 1.97 (d, J = 13.0 Hz, 3H), 1.41 (q, J = 13.4 Hz, 2H). ESI-MS [M + H]+calcd. for C2i H24F3N6O2+449.46, found 449.40.Compound 1

[0179] Compound was synthesized as per Method C to give 8.1 mg of a white solid (11 % yield).1H NMR (600 MHz, DMSO) 5 8.08 (d, J = 9.3 Hz, 2H), 7.98 - 7.90 (m, 2H), 7.72 (t, J = 5.2 Hz, 1 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.49 (d, J =7.7 Hz, 1 H), 6.93 (d, J = 9.7 Hz, 1 H), 2.87 (s, 3H), 2.70 (s, 3H), 1.96 (d, J = 12.2 Hz, 3H), 1.39 (d, J = 25.5 Hz, 2H), 1.22 (d, J = 6.0 Hz, 2H). ESI-MS [M + H]+calcd. for C2i H24F3NeO+433.46, found 433.20.Compound 149

[0180] Compound was synthesized as per Method C to give 21 mg (67% yield).1H NMR (400 MHz, DMSO) 5 8.75 (d, J = 5.8 Hz, 1 H), 7.98 - 7.83 (m, 2H), 7.71 (s, 1 H), 6.98 - 6.83 (m, 1 H), 3.22 (d, J = 5.7 Hz, 3H), 3.06 - 2.86 (m, 4H), 2.75 (d, J = 4.7 Hz, 3H), 2.32 (t, J = 7.2 Hz, 2H), 2.19 (dd, J = 14.6, 7.7 Hz, 1 H), 1.95 (d, J = 13.1 Hz, 3H), 1.84 - 1.75 (m, 3H), 1.59 (s, 1 H), 1.39 (d, J = 13.8 Hz, 2H). ESI-MS [M + H]+calcd. for Ci7H25N6O3+361.43, found 361.20.Compound 148

[0181] Compound was synthesized as per Method C to give 18 mg (35% yield).1H NMR (400 MHz, DMSO) 5 8.74 (s, 1 H), 8.04 - 7.81 (m, 2H), 7.71 (s, 1 H), 6.89 (s, 1 H), 3.21 (s, 2H), 3.05 - 2.87 (m, 3H), 2.78 - 2.72 (m, 3H), 2.32 (t, J = 7.3 Hz, 2H), 2.19 (dd, J = 14.1 , 7.3 Hz, 1 H), 1.95 (d, J = 13.0 Hz,3H), 1.86 - 1.73 (m, 3H), 1.59 (s, 1 H), 1.39 (d, J = 13.8 Hz, 2H).ESI-MS [M + H]+ calcd. for C18H27N6O3+ 475.45, found .Compound 147

[0182] Compound was synthesized as per Method C to give 29 mg (54% yield).1H NMR (400 MHz, DMSO)1 H NMR 5 9.33 (s, 1 H), 9.13 (t, J = 5.2 Hz, 1 H), 7.97 (s, 1 H), 7.89 (d, J = 9.7 Hz, 1 H), 7.68 (q, J = 5.9 Hz, 1 H), 6.89 (d, J = 9.8 Hz, 1 H), 4.28 (d, J = 5.2 Hz, 2H), 3.71 (s, 2H), 3.63 (s, 6H), 3.32 (t, J = 6.0 Hz, 2H), 2.95 - 2.80 (m, 2H), 2.74 (d, J = 4.5 Hz, 3H), 1.99 - 1 .86 (m, 3H), 1 .46 - 1.33 (m, 2H). ESI-MS [M + H]+ calcd. for C19H29N6O3+ 389.48, found.Compound 133

[0183] Compound was synthesized as per Method C to give 56 mg (26% yield).1H NMR (400 MHz, DMSO) 5 9.22 (s, 1 H), 8.94 (s, 1 H), 8.88 (s, 1 H), 8.16 - 8.11 (m, 1 H), 8.00 - 7.92 (m, 3H), 7.80 (s, 1 H), 7.67 (t, J = 7.6 Hz, 1 H), 7.59 (t, J = 7.5 Hz, 1 H), 6.94 (d, J = 9.8 Hz, 1 H), 3.50 - 3.34 (m, 3H), 2.90 (q, J = 11 .8 Hz, 2H), 2.70 (d, J = 4.6 Hz, 3H), 2.00 (d, J = 13.5 Hz, 3H), 1 .44 (q, J = 13.2 Hz, 2H). ESI-MS [M + H]+ calcd. for C23H26N7O+ 416.51 , found.Compound 132

[0184] Compound was synthesized as per Method C to give 79 mg (37% yield).1H NMR (400 MHz, DMSO)5 9.34 (s, 1 H), 9.01 (s, 1 H), 8.30 (d, J = 8.3 Hz, 1 H), 8.21 (d, J = 8.5 Hz, 1 H), 8.16 (d, J = 1.7 Hz, 1 H), 8.03 - 7.92 (m, 2H), 7.82 (t, J = 7.6 Hz, 1 H), 7.76 (d, J = 5.2 Hz, 1 H), 7.00 - 6.94 (m, 1 H), 3.27 (d, J = 12.1 Hz, 2H), 3.20 (t, J = 6.0 Hz, 2H), 2.75 (q, J = 11 .3 Hz, 2H), 2.64 (d, J = 4.5 Hz, 3H), 1.83 (s, 1 H), 1.69 (d, J = 14.0 Hz, 2H), 1.15 (q, J = 13.4 Hz, 2H). ESI-MS [M + H]+calcd. for C23H26N7O+416.51 , found.Compound 131

[0185] Compound was synthesized as per Method C to give X mg (% yield).1H NMR (400 MHz, DMSO) 5 8.37 (s, 1 H), 8.09 (d, J = 2.9 Hz, 1 H), 7.93 (d, J = 9.6 Hz, 2H), 7.77 (s, 1 H), 6.93 (d, J = 9.8 Hz, 1 H), 3.84 (s, 3H), 3.42 (d, J = 12.6 Hz, 2H), 3.31 (t, J = 5.9 Hz, 1 H), 2.89 (q, J = 11.7 Hz, 2H), 2.70 (d, J =4.6 Hz, 2H), 1.95 (d, J = 13.1 Hz, 2H), 1.39 (q, J = 13.1 Hz, 2H). ESI-MS [M + H]+ calcd. for C20H26N7O+ 380.48, found.Compound 130

[0186] Compound was synthesized as per Method C to give 35 mg (18% yield).1H NMR (400 MHz, DMSO) 5 9.11 (t, J = 1 .3 Hz, 2H), 8.94 (t, J =1.3 Hz, 1 H), 8.11 (d, J = 1.5 Hz, 1 H), 7.93 (d, J = 9.7 Hz, 1 H), 7.74 (s, 1 H), 6.93 (d, J = 9.8 Hz, 1 H), 3.41 (d, J = 12.4 Hz, 2H), 3.32 (t, J = 6.0 Hz, 2H), 2.88 (q, J = 11.7 Hz, 2H), 2.70 (d, J = 4.6 Hz, 3H), 1 .94 (d, J = 13.1 Hz, 3H), 1 .38 (q, J =13.3 Hz, 2H). ESI-MS [M + H]+ calcd. for C18H23N8O+ 367.44, found.Compound 129

[0187] Compound was synthesized as per Method C to give 50 mg (26% yield).1H NMR (400 MHz, DMSO) 5 8.82 (s, 1 H), 8.36 (d, J = 4.7 Hz, 1 H), 8.28 (d, J = 8.5 Hz, 1 H), 8.09 (d, J = 2.1 Hz, 1 H), 7.93 (d, J = 9.5 Hz, 1 H), 7.76 (s, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 6.93 (d, J = 9.7 Hz, 1 H), 3.41 (d, J = 12.6 Hz, 2H), 3.31 (s, 2H), 2.88 (q, J = 11 .7 Hz, 2H), 2.70 (d, J = 4.2 Hz, 3H), 1 .94 (d, J = 13.1 Hz, 3H), 1.39 (d, J = 13.6 Hz, 2H). ESI-MS [M + H]+ calcd. for C19H24N7O+ 366.45, found.Compound 88

[0188] In a vial, 14 (50.0 mg, 0.17 mmol) was dissolved in DMF (1 mL), then was cooled to -20°C. Isobutyl chloroformate (23.0 pL, 0.19 mmol) and N-methyl morpholine (19.0 pL, 0.17 mmol) were added, and reaction was stirred at -20°C for 8 min. A solution of p-toluidine (22 pL, 0.19 mmol) in DMF (0.30 mL) was added dropwise, then the reaction was allowed to warm to room temperature overnight. When the reaction was complete, the solvent was removed, and crude was purified via rev. phase prep HPLC (eluent system water / ACN with 0.05% TFA) to give 8.4 mg (13% yield).1H NMR (400 MHz, CD3OD) 5 8.22 (s, 1 H), 7.88 (d, J = 9.8 Hz, 1 H), 7.59 - 7.52 (m, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 9.8 Hz, 1 H), 3.58 - 3.48 (m, 3H), 3.43 (d, J = 6.6 Hz, 2H), 2.96 (t, J = 12.8 Hz, 2H), 2.83 (s, 3H), 2.32 (s, 3H), 2.11 (d, J = 14.0 Hz,3H), 1.54 (q, J = 13.4 Hz, 2H). ESI-MS [M + H]+calcd. for C2iH27N6O+379.490, found 379.950.Compound 87

[0189] Compound was synthesized as per Method C to give 3.8 mg (5.6% yield).1H NMR (400 MHz, CD3OD) 5 8.28 (d, J = 8.0 Hz, 1 H), 8.19 (s, 1 H), 7.84 (d, J = 9.8 Hz, 1 H), 7.15 (dt, J = 16.4, 8.0 Hz, 2H), 7.00 (dd, J = 15.6, 8.7 Hz, 2H), 3.95 (s, 3H), 3.57 (d, J = 6.3 Hz, 2H), 3.44 (d, J = 13.2 Hz, 2H), 2.88 (t, J = 12.8 Hz, 2H), 2.77 (s, 3H), 2.00 (d, J = 14.2 Hz, 3H), 1.47 (q, J = 13.2 Hz, 2H). ESI-MS [M + H]+calcd. for C2i H27N6O2+395.490, found 395.947.Compound 86

[0190] Compound was synthesized as per Method C to give 4.3 mg (6.3% yield).1H NMR (400 MHz, CD3OD) 5 8.18 (d, J = 8.1 Hz, 1 H), 7.85 (dd, J = 9.7, 4.6 Hz, 1 H), 7.62 - 7.56 (m, 2H), 7.02 (d, J = 9.9 Hz, 1 H), 6.98 - 6.92 (m, 2H), 3.80 (d, J = 1.0 Hz, 3H), 3.52 (d, J = 12.7 Hz, 2H), 3.42 (d, J = 6.5 Hz, 2H), 2.95 (t, J = 12.9 Hz, 2H), 2.83 (s, 3H), 2.10 (d, J = 14.2 Hz, 3H), 1.53 (d, J = 13.8 Hz, 2H). ESI-MS [M + H]+ calcd. for C21 H27N6O2+ 395.490, found.Compound 85

[0191] Compound was synthesized as per Method C to give 11 mg (8.4% yield).1H NMR (400 MHz, CD3OD) 5 8.22 (s, 1 H), 7.88 (d, J = 9.8 Hz, 1 H), 7.55 (dd, J = 7.8, 1.6 Hz, 1 H), 7.36 - 7.32 (m, 1 H), 7.30 - 7.19 (m, 2H), 7.04 (d, J = 9.8 Hz, 1 H), 3.45 (d, J = 11 .4 Hz, 3H), 3.32 (s, 2H), 2.95 - 2.83 (m, 2H), 2.81 (s, 3H), 2.38 (s, 3H), 1.95 (d, J = 14.5 Hz, 2H), 1.51 - 1.37 (m, 2H). ESI-MS [M + H]+ calcd. for C21 H27N6O+ 349.490, found.Compound 60

[0192] Compound was synthesized as per Method C to give X mg (% yield). 1 H NMR (400 MHz,) ESI-MS [M + H]+calcd. for C22H37N6O+401 .580, found 401.300.Compound 38

[0193] Compound was synthesized as per Method C. ESI-MS [M + H]+calcd. for C25H27N6O+427.530, found 427.300.Compound 51

[0194] Compound was synthesized as per Method C. ESI-MS [M + H]+calcd. for C25H27N6O+427.530, found 427.300.Compound 134

[0195] 1H NMR (400 MHz, DMSO) 5 8.58 (d, J = 11 .5 Hz, 1 H), 8.25 (d, J = 11 .3 Hz, 1 H), 8.09 (s, 1 H), 7.96 (s, 1 H), 7.90 (s, 1 H), 7.82 - 7.76 (m, 1 H), 7.55 (dt, J = 16.3, 8.3 Hz, 2H), 7.15 (d, J = 8.0 Hz, 1 H), 6.95 (d, J = 9.5 Hz, 1 H), 3.36 - 3.22 (m, 4H), 2.86 (q, J = 12.1 Hz, 2H), 2.04 (s, 1 H), 1.92 (d, J = 13.9 Hz, 2H), 1 .39 (q, J = 12.2 Hz, 2H). ESI-MS [M + H]+ calcd. for C20H22F3N6O2+ 435.43, found 435.400.Compound 77

[0196] 1H NMR (400 MHz, CD3OD) 5 1 H NMR (399 MHz, cd3od) 5 8.24 (d, J = 1 .4 Hz, 1 H), 7.87 (d, J = 9.6 Hz, 2H), 7.56 - 7.44 (m, 2H), 7.12 - 7.04 (m, 2H), 4.55 (d, J = 13.4 Hz, 1 H), 4.36 - 4.19 (m, 2H), 4.02 (s, 2H), 3.87 (s, 2H), 3.72 (d, J = 13.6 Hz, 1 H), 3.52 (s, 2H), 3.43 (dd, J = 6.9, 2.0 Hz, 3H), 3.11 (d, J = 12.9 Hz, 1 H), 2.74 (t, J = 12.7 Hz, 1 H), 2.14 (s, 1 H), 1.97 (t, J = 12.6 Hz, 2H), 1 .35 (dt, J = 40.1 , 11 .0 Hz, 2H). ESI-MS [M + H]+calcd. for C2eH3i FSN7O4+562.57, found.Compound 9

[0197] To give 28 mg (19% yield) as a tan solid.1H NMR (400 MHz, DMSO) 5 8.31 - 8.21 (m, 2H), 7.86 (s, 1 H), 7.65 (d, J = 7.7 Hz, 1 H), 7.49 (t, J = 8.2 Hz, 1 H), 7.17 - 7.08 (m, 2H), 4.38 (d, J = 6.3 Hz, 2H), 3.45 (d, J = 12.1 Hz, 2H), 2.96 (q, J = 11 .5 Hz, 2H), 2.74 (d, J = 4.6 Hz, 3H), 2.11 (s, 1 H), 1 .99 (d, J = 14.0 Hz, 2H), 1.52 (q, J = 13.0 Hz, 2H). ESI-MS [M + H]+calcd. for C22H24F3N6O3+477.47, found 477.20.Compound 11

[0198] To give 164 mg (116% yield) as a white solid. ESI-MS [M + H]+calcd. for Ci9H2oF3Ne02+421 .40, found 421 .20.Compound 26

[0199] To give 32.8 mg (8.5% yield) as a white solid.1H NMR (400 MHz, DMSO) 5 8.18 (d, J = 1.6 Hz, 1 H), 8.14 (dd, J = 10.0, 1.5 Hz, 1 H), 7.96 (s, 1 H), 7.53 (tt, J = 4.6, 2.2 Hz, 2H), 7.39 (dd, J = 10.0, 1.5 Hz, 1 H), 7.15 (s, 1 H), 4.17 (d, J = 16.4 Hz, 1 H), 3.93 - 3.79 (m, 4H), 3.60 (s, 2H), 2.85 (d, J = 3.9 Hz, 3H), 2.23 (s, 2H). ESI-MS [M + H]+calcd. for C2oH22F3N602+435.430, found435.100.Compound 70

[0200] To give 5.3 mg (1 .5 % yield) as a white solid.1H NMR (400 MHz, DMSO) 5 8.18 (d, J = 1.6 Hz, 1 H), 8.14 (dd, J = 10.0, 1.5 Hz, 1 H), 7.96 (s, 1 H), 7.53 (tt, J = 4.6, 2.2 Hz, 2H), 7.39 (dd, J = 10.0, 1.5 Hz, 1 H), 7.15 (s, 1 H), 4.17 (d, J = 16.4 Hz, 1 H), 3.93 - 3.79 (m, 4H), 3.60 (s, 2H), 2.85 (d, J = 3.9 Hz, 3H), 2.23 (s, 2H). ESI-MS [M + H]+calcd. for Ci8Hi7F3N6O2+408.360, found408.100.Compound 27

[0201] To give 5.9 mg (1.1 % yield) as a beige solid.1H NMR (400 MHz, CD3OD) 5 7.98 (s, 2H), 7.66 (d, J = 9.8 Hz, 2H), 7.53 (s, 2H), 7.13 - 7.09 (m, 2H), 6.97 - 6.91 (m, 4H), 6.69 (dd, J = 8.4, 2.0 Hz, 2H), 3.89 (s, 4H). ESI-MS [M + H]+calcd. for C3OH23F6NIO04+701.570, found 701.200.Compound 28

[0202] To give 2.4 mg (1 .5% yield) as a white solid.1H NMR (400 MHz, CD3OD) 5 8.25 (s, 1 H), 7.95 - 7.82 (m, 2H), 7.57 - 7.43 (m, 2H), 7.12 - 7.00 (m, 2H), 3.61 (d, J = 6.9 Hz, 2H), 2.91 (d, J = 4.0 Hz, 7H), 2.21 (q, J = 7.0 Hz, 2H). ESI-MS [M + H]+calcd. for Ci9H22F3N6O2+423.420, found 423.200.Compound 69

[0203] 1H NMR (400 MHz, CD3OD) 6 8.26 (s, 1 H), 8.01 (dd, J = 10.0,1.2 Hz, 1 H), 7.92 (d, J = 2.5 Hz, 1 H), 7.53 - 7.40 (m, 3H), 7.10 - 7.00 (m, 1 H), 3.55 (s, 8H), 3.03 (d, J = 1.2 Hz, 3H). ESI-MS [M + H]+calcd. for Ci9H2oF3N602+421.400, found 421.200.Compound 68

[0204] 1H NMR (400 MHz, DMSO) 5 8.16 (t, J = 5.6 Hz, 1 H), 8.08 (s, 1 H), 7.96 (d, J = 9.8 Hz, 1 H), 7.73 (s, 1 H), 7.42 - 7.29 (m, 5H), 7.25 (t, J = 7.3 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.04 (dd, J = 14.0, 9.0 Hz, 2H), 4.64 (d, J = 5.4 Hz, 2H). ESI-MS [M + H]+calcd. for C2iHi7F3N5O2+428.390, found 428.200.Compound 59

[0205] ESI-MS [M + H]+calcd. for C28H23F3N5O2+518.520, found518.200.Compound 58

[0206] ESI-MS [M + H]+calcd. for C25H23F3N5O4+514.480, found514.200.Compound 57

[0207] ESI-MS [M + H]+calcd. for C21 HI4F3N6O2+439.380, found 439.100.Compound 34

[0208] To give 9.6 mg (3.9% yield) as a light brown solid.1H NMR (400 MHz, DMSO) 5 8.94 - 8.87 (m, 2H), 8.59 - 8.54 (m, 2H), 8.28 - 8.24 (m, 2H), 8.20 (d, J = 9.6 Hz, 1 H), 7.98 (s, 1 H), 7.69 (dd, J = 8.1 , 2.0 Hz, 1 H), 7.56 (t, J =8.2 Hz, 1 H), 7.16 (dd, J = 8.2, 2.4 Hz, 1 H).ESI-MS [M + H]+ calcd. for C19H13F3N5O2+ 400.340, found 400.100.Compound 62

[0209] 1H NMR (400 MHz, DMSO) 5 8.54 - 8.49 (m, 2H), 8.25 - 8.19 (m, 2H), 8.15 (d, J = 9.6 Hz, 1 H), 7.84 (s, 1 H), 7.78 (dd, J = 8.1 , 4.6 Hz, 2H),7.64 (d, J = 8.3 Hz, 1 H), 7.54 (t, J = 8.2 Hz, 1 H), 7.16 (d, J = 8.3 Hz, 1 H).ESI-MS [M + H]+calcd. for C2iHi3F6N4O3+483.350, found 483.100.Compound 61

[0210] 1H NMR (400 MHz, DMSO) 510.84 (s, 1H), 10.71 (s, 1H), 8.81 (s, 1H), 8.61 -8.50 (m,2H), 8.44 (d, J = 7.8 Hz, 1H), 8.22 (dd, J = 12.1 , 8.6 Hz, 2H), 7.99 (s, 3H), 7.80 (dt, J = 16.9, 7.9 Hz, 3H), 7.51 (t, J = 8.1 Hz, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.11 (t, J = 10.2 Hz, 2H).ESI-MS [M + H]+calcd. for C28HI8F6N5O4+602.470, found 602.100.Compound 35

[0211] To give 3.2 mg (1.1% yield) as a white solid.1H NMR (400 MHz, DMSO) 58.06 (dd, J = 10.1 , 2.7 Hz, 1 H), 7.98 (d, J = 2.7 Hz, 1 H), 7.29 (dd, J = 10.1, 2.7 Hz, 1H), 4.15-3.99 (m, 1H), 3.79 (dd, J = 16.5, 9.1 Hz, 2H), 3.67 (d, J = 7.1 Hz, 3H), 2.83 (t, J = 3.5 Hz, 4H), 2.17 (s, 3H), 1.53 (dd, J = 10.5, 4.6 Hz, 3H), 1.35-1.16 (m, 13H), 0.82 (td, J = 6.7, 2.7 Hz, 4H). ESI-MS [M + H]+calcd. for C2iH35N6O+387.550, found 387.300.Compound 32

[0212] To give 30.5 mg (20% yield) as a white solid.1H NMR (400 MHz, DMSO) 59.80 (s, 1H), 8.19- 8.13 (m, 2H), 7.96 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.5 Hz, 2H), 7.50 (t, J = 7.4 Hz, 3H), 7.47 - 7.38 (m, 3H), 4.24-4.15 (m, 2H), 3.96-3.88 (m, 2H), 3.68-3.58 (m, 1H), 3.55- 3.47 (m, 1 H), 3.41 - 3.22 (m, 2H), 2.85 (s, 3H), 2.24 (d, J = 6.0 Hz, 2H). ESI-MS [M + H]+calcd. for C25H27N6O+427.530, found 427.300.Compound 33

[0213] To give 16.3 mg (11% yield) as a light pink solid.1H NMR (400 MHz, DMSO) 58.16 (s, 1H), 8.13 (d, J = 10.1 Hz, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.4 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.40 - 7.30 (m, 2H), 4.17 (dd, J = 16.1, 5.2 Hz, 2H), 3.89 (dd, J = 16.5, 8.9 Hz, 2H), 3.81 (t, J = 6.2 Hz, 2H), 3.63 (d, J = 13.4 Hz, 1H), 3.49 (d, J = 13.4 Hz, 1H), 2.84(d, J = 4.3 Hz, 3H), 2.26 (d, J = 6.6 Hz, 2H). ESI-MS [M + H]+calcd. for C25H27N6O+427.530, found 427.300.Compound 7

[0214] 1H NMR (400 MHz, DMSO) 5 8.43 (s, 1 H), 8.19 (s, 1 H), 8.09 (d, J = 7.9 Hz, 1 H), 7.88 (d, J = 9.7 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.55 (t, J = 5.5 Hz, 1 H), 7.34 (dd, J = 8.2, 2.5 Hz, 1 H), 6.89 (d, J = 9.7 Hz, 1 H), 3.20 (t, J = 5.6 Hz, 3H), 3.07 - 2.95 (m, 2H), 2.92 - 2.82 (m, 2H), 2.07 - 1 .90 (m, 5H), 1 .85 - 1.74 (m, 2H), 1.61 (t, J = 7.3 Hz, 2H), 1.41 (q, J = 12.3 Hz, 2H). ESI-MS [M + H]+calcd. for C26H29F3N?O+512.56, found 512.30.Compound 8

[0215] 1H NMR (400 MHz, DMSO) 5 8.07 (s, 1 H), 7.97 - 7.88 (m, 2H), 7.76 (s, 1 H), 7.53 (dt, J = 15.9, 8.3 Hz, 2H), 7.14 (d, J = 8.0 Hz, 1 H), 6.93 (d, J = 9.8 Hz, 1 H), 3.07 - 2.77 (m, 4H), 2.06 - 1 .93 (m, 6H), 1 .76 (d, J = 8.8 Hz, 3H), 1.62 (t, J = 7.3 Hz, 2H), 1.42 (d, J = 13.8 Hz, 2H), 1.23 (s, 2H).ESI-MS [M + H]+calcd. for C27H3oF3Ns02+555.58, found 555.30.Example 3: Methods for activity testingCompound screening with adult-stage of intestinal nematodes

[0216] Ancylostoma ceylanicum: adult hookworm parasites were harvested 18 days post inoculation from the intestine of infected hamsters. In vitro assays were carried out as previously described (R. Tyagi et al., ACS Infectious Disease, 2018, 4(&), 1130-1145; R. Tyagi et al., Sci Rep, 2019, 9(1 ), 9085.). An extensive comparison of the effect of anthelmintic classes on diverse nematodes. PLoS One 2013, 8 (7), e70702), with slight modifications. Adult worm were manually sorted into each well of 48-well plate with one worm / well, containing hookworm culture medium (RPMI1640 of pH 7.2 supplemented with 10% fetal bovine serum, 10011 penicillin, 100pg / ml streptomycin, 2.5pg / ml amphotericin) and the test drug (6 wells / test drug). Chokepoint inhibitors were tested against hookworm at either 30pM or 50pM in 1 % DMSO. Each assay plate contained six wells of positive control (30 pM ivermectin or 30 pM pyrantelpamoate) and 6 wells of negative control (1 % DMSO). Worms were scored for motility using either standard motility index or automated imaging system Worminator and WormAssay-6 software (B. Storey et al., Int J Parasitol Drugs Drug Resist. 2014 Aug 28;4(3):233-43) after 24 and 48 hours of incubation at 37°C and 5% CO2.

[0217] Trichuris muris: In vitro assays were carried out as described before (R. Tyagi et al., ACS Infectious Disease, 2018, 4(&), 1130-1145; R. Tyagi et al., Sci Rep, 2019, 9(1 ), 9085.) with slight modifications. Adult T. muris parasites were harvested 35 days post inoculation from the cecum and large intestines of Stat6- / - mice. Adult T. muris worm were manually sorted into each well of 48-well plate with one worm / well, containing whipworm culture medium (RPMI1640 of pH 7.2 supplemented with 5% fetal bovine serum, 10011 penicillin, 100pg / ml streptomycin, 2.5pg / ml amphotericin) and the test drug (6 wells / test drug). Inhibitors were initially tested against whipworms at 50pM or 30pM in 1 % DMSO. Each assay plate contained six wells of positive control (50 pM levamisole) and 6 negative control wells (1 % DMSO). Worms were scored for motility using either standard motility index (R) or automated imaging system Worminator and WormAssay-6 software (R) (B. Storey et al., Int J Parasitol Drugs Drug Resist. 2014 Aug 28;4(3):233-43) after 24 and 48 hours of incubation at 37°C and 5% CO2.

[0218] To generate the IC-50 values for potential inhibitors, adult worms (A. ceylanicum or T. muris) were tested against a dose-response of 0.3, 1 , 3, 10, 30, and 90 pM with six wells / dose. Each dose-response plate contained negative and positive controls. Worm motility was scored after 24 and 48 hours of incubation at 37°C and 5% CO2, using the Worminator platform and the WormAssay-6 software (R). IC-50 values were established using the non-linear regression of inhibitor doses versus normalized motility using Prism 9 (GraphPad, La Jolla, CA).

[0219] Brugia pahangi: In vitro assays were carried out as described before (R. Tyagi et al., Pathogens. 2021 Jan 14;10(1):71.) with slight modifications. Individual adult male and female Brugia pahangi were placed in media (RPMI-1640 with 1 M HEPES, 7.5% NaHCO3, 5% heat inactivated fetalbovine serum (FBS), and 1X Antibiotic and Antimycotic solution) in 24-well plates. Each well contained one female or male worm in 500 pL media. Compounds dissolved in DMSO were added to each well at a concentration of 10 pM, with 4 replicates per compound and 1 % DMSO was used as a vehicle control (8 replicates). Cultures were maintained at 5% CO2 in a 37 °C humidified incubator. Movement of worms were recorded using ‘QuickTime Player’ on Mac by recording apparatus and 1080p digital camcorder on at interval of 4 hours, 1 day, 2 days, 3 days, and 6 days. Three videos were recorded as technical replicates of a plate. 30 second of each video was trimmed using iMovie’ tool to calculated Mean Movement Unit (MMU). MMU was calculated using set-up ‘Bottom-Read Rotated 180 "’on Plate Orientation setting and ‘Lucas-Kanade Optical Flow (Velocity, 1 organism per well)’ on Assay Analyzer setting of ‘WormAssay’ tool Motility inhibitions of compound-treated worms relative to 1 % DMSO-treated worms at corresponding timepoints were calculated. Compounds that caused 75% or greater inhibition of motility by day 3 were considered hits and were then tested in IC50 assays, using a 6-point serial dilution ranging from 30 pM to 0.1 pM. IC50 values were calculated using GraphPad Prism (GraphPad Software, San Diego, CA).Bioaccumulation assays

[0220] To study the bioaccumulation of potential drugs, adult hookworms, whipworm or filarial parasites were incubated for six hours in100 pM before processes for HPLC analysis. For hookworm assay, 13 parasites / well were manually picked into 6-well plates containing hookworm medium, 100pM of test drugs, and a final DMSO concentration of 1%. Similarly, for the whipworm assay, 12 parasites / well were manually picked into 6-well plates containing whipworm medium and 100pM of test drugs in a final DMSO concentration of 1 %. Bioaccumulation assay was carried in three replicates per test compound per parasite. After 6 hours of incubation, the worms were removed from assay plates and washed twice with saline into clean plates. This was followed by three more washes using saline containing 0.1% SDS as a detergent to remove drugs attached to the cuticle surface. The worms were then placed into an Eppendorf tube, washed twice using saline, and centrifuged to form a pellet, which wasstored overnight at -20°C. For the filarial Brugia pahangi, 6 adult female worms were prepared for in vitro culture as described above and treated in vitro for 72 hours. Upon collection worms were washed twice in 0.1 % SDS, followed by 1 wash in culture media, then frozen in culture media at -20° C. At the time of the assay, the worms were frozen in liquid nitrogen, crushed and homogenized using pestles, and incubated with 100 pL of 1x tissue lysis buffer supplemented with proteinase K (1 pg / ml) for 60 min at 60°C to digest and precipitate proteins to free test compounds from protein complexes. B. pahnagi lysates were prepared as described for T. muris above, with the exception that worms were incubated at 60° C for 5 hours. Two pL of the worm digestant was used to measure the total protein content using BCA protein kit. The proteins from the remaining digestant were precipitated using 100pL of acetonitrile. The supernatant (~180 pL) was stored at -80°C. The lysates were analyzed for levels of each individual compound by HPLC / MS analysis. DMSO was used as the negative control.

[0221] Lysates were analyzed on a Hewlett Packard Series 1100 HPLC, using a Sunfire C18 3.5 pm pore-size, 4.6 x 50 mm column. Samples were injected with 20 pL of volume with a flow rate of 1 mL / min, and solvent system of H2O (0.01 % TFA) and acetonitrile (0.05% TFA). Gradient was 0^5 minutes: 5-95% linear increase acetonitrile, 5^6 minutes 95% acetonitrile hold, 6^7 minutes 95-5% linear decrease acetonitrile. Elution was monitored by 210 and 254 nm UV-absorption and by MS. MS conditions were drying gas 12 L / min, drying gas temperature 350° C, nebulizer psig 55-60, and capillary voltage 4000 V. Compound presence was evaluated by extracting [M+H]+ or [M+Na]+ of parent compound mass.In vivo T. muris assays

[0222] STAT6- / - mice from both genders were inoculated with 200 T. muris embryonated eggs in the first in vivo study or 100 embryonated eggs for the second. Thirty-five days post-inoculation, infected animals were grouped based on the EPG, using the McMaster counting slide, into similar groups of five animals / group for the first in vivo study or eight animals / group for the second. Experimental groups were randomly assigned to treatments. Animals were orallytreated for three consecutive days with 250pL water for the placebo control or 250pL water suspension of 100mg / kg for Compound 2 and 12. treated animals were weighed and monitored daily for any adverse effects. Two days after the third treatment, fecal samples were collected to measure any change in EPG. Seven days after the third treatment, fecal samples were collected for the final EPG, and all animals were euthanized and necropsied to count total worm burdens. One-tailed unpaired t-test was conducted between each compound treatment and the placebo control using Prism 9 (GraphPad, La Jolla, CA).

[0223] In vivo A. ceylanicum assay. Assays were conducted essentially as previously described. Briefly, 5 weeks old golden Syrian hamsters were infected with 120 third-stage larvae of A. ceylanicum. Infected rodents were grouped based on the fecal egg count on day 18 p.i. Each group had five hamsters. Drugs were delivered in water suspension after completely dissolved in 100% DMSO giving a final dose of 100 mg / kg and 0.1 % DMSO volume to body weight. Control group was dosed only with water and 0.1 % DMSO. Fecal samples were collected 21 days p.i. for fecal egg counts. On day 22 p.i., the hamsters were euthanized, and the small intestine was opened longitudinally. Adult parasites within the intestine were counted under a dissecting microscope.MTT HepG2 cytotoxicity assays

[0224] The cytotoxicity of compounds was determined using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) reduction assay30. 1 x 104 HepG2 cells / well were seeded in 100 mL DMEM low glucose medium (Dulbecco's Modified Eagle's Medium), supplemented with 10% FBS in each well of a 96-well microculture plate and incubated for 24 h at 370°C in a CO2 incubator. Compound stock solutions were prepared in DMSO and were diluted to the desired concentrations in culture medium. Cells cultured in 96-well plate were treated with various concentrations of test compounds, each for 24 hours (n = 4 per test). After the period of incubation, 10 pl of MTT (5 mg / mL) was added in each well and the plates were further incubated for 2 hours. Supernatant from each well was carefully removed, formazan crystals were dissolved in 100 mL of DMSO and absorbance at 630 nM wavelength was recorded. Cells containing media only (n = 12) were used as a backgroundcontrol, 0.1 % and 1 % Triton X-100 were positive controls (n = 4), and 1 % DMSO-treated cells was used as a control to define baseline (0%) cytotoxicity (n = 9). Relative cytotoxicity was calculated by first adjusting for the media background according to (1 - [ test OD I average media-only OD] ) and then resulting values per well were normalized between 0% (DMSO average cytotoxicity) and 100% (Triton X-100 1 % cytotoxicity). Average and standard error values were calculated per compound per concentration based on the normalized values.MDCK-MDR1 Cell permeability and efflux assay

[0225] Test compounds were diluted with the transport buffer (HBSS with 10mM Hepes, pH7.4) from DMSO stock solution to a concentration of 2.00 pM (DMSO<1 .0%) and applied to the apical or basolateral side of the cell monolayer. Permeation of the test compounds from A to B direction or B to A direction was determined in duplicate. Digoxin was tested at 10.0 pM from A to B direction or B to A direction as well, while nadolol and metoprolol were tested at 2.00 pM in A to B direction in duplicate. The plate was incubated for 2.5 hours in 5.0% CO2 at 37.0°C with saturated humidity without shaking. In addition, the efflux ratio of each compound was also determined. Test and reference compounds were quantified by LC-MS / MS analysis based on the peak area ratio of analyte / IS.

[0226] After transport assay, Lucifer yellow rejection assay are applied to determine the cell monolayer integrity. Buffers are removed from both apical and basolateral chambers, followed by the addition of 75 pL of 100 pM lucifer yellow in transport buffer and 250 pL transport buffer in apical and basolateral chambers, respectively. The plate is incubated for 30 minutes at 37.0°C with 5.0% CO2 and saturated humidity without shaking. After 30 minutes incubation, 20 pL of lucifer yellow samples are taken from the apical sides, followed by the addition of 60 pL of Transport Buffer. And then 80 pL of lucifer yellow samples are taken from the basolateral sides. The relative fluorescence unit (RFU) of lucifer yellow is measured at 425 / 528 nm (excitation / emission) with an Envision plate reader.Solubility in SIF and SGF

[0227] The simulated gastric fluid (SGF) and the simulated intestinal fluid (SIF) were prepared as 0.2% (w / v) Sodium Chloride in 0.7% (v / v) Hydrochloric Acid, Deionized water, 0.32% pepsin (w / v), pH 1.2 ± 0.05 (SGF) and 0.68% (w / v) monobasic potassium phosphate and 1 % (w / v) pancreatin, deionized water, pH 6.8 ± 0.05) (SIF). For the solubility assay, 10 pL of the 10 mM DMSO stock solution of test and control compounds were added into a well of a 96-well plate, and then either 490 pL of SGF or SIF were added. The samples were vortexed for at least 2 minutes, then were shaken on a shaker for 24 hours at room temperature at a speed of 800 rpm. After vertexing, the samples were centrifuged for 5 min at 4000 rpm, then the supernatant was transferred into a filter plate and the filtrate was added into a new 96-well plate by centrifuging. The filtrate was injected onto both a HPLC-UV & UPLC-UV system to calculate the concentration with a standard curve.Mouse pharmacokinetic (PK) studies

[0228] Select compounds were tested for their pharmacokinetic properties in mice following a single IV dose (3 mg / kg) and a single PO dose (10 mg / kg). Three animals (male, CD-1 ) per group were dosed and then blood was drawn at eight different sampling time points (0.08, 0.25, 0.5, 1 , 2, 4, 8, 24 h) post dosing. Feces from the PO group were collected over the 24 h period. Bioanalysis and quantification of plasma and feces samples were performed using a standard curve of the selected compound and routine LC / MS / MS techniques.Table. IC50 values of Compound 2 and top analogs against T. muris whipworms and A. ceylanicum hookworms. Values for three currently used anthelmintic drugs are presented at the bottom of the table. *Some of the ICsos were outside the range of the tested dose response, and to avoid extrapolation, we report the highest dose tested in the dose response. _Compound24 hours 48 hours 24 hours 48 hoursEvaluation of human PIM and CK2a kinase activity for Compound 2 and selected analogsHuman kinase ICso testing results. Compounds were tested in a 10-dose ICso mode with 3-fold serial dilution starting at 10 pM.„ , Compound ICso* (nM):CompoundCK2a P|M 1 p |M2 p|M32 3,901 0.69 41.4 >0.50814 1 ,431 1.00 429.2 1.8020 >10,000 69.5 4,996 9.8818 6,009 9.46 >10,000 7.5425 >10,000 93.4 >10,000 20.3GW5074 128.7Staurosporine - 1.93 18.6 0.113

[0229] To determine whether our compounds had selective activity against worm targets, we tested Compound 2 and selected analogs against human CK2a and PIM 1 , 2, and 3. In summary, the data (Table above) suggests Compounds 14, 20, 18, and 25 have lowered inhibition of all human PIM kinases relative to Compound 2. Since the whipworm motility ICso of Compound 20 is the same as Ccompound 2, the 100-fold loss of human Pim1 and Pim3 kinase inhibition from Compound 20 might suggest we are demonstrating selectivity for the worm kinase(s), but not necessarily human PIM orthologs. Compound 14 also returns a similar ICso in human PIM1 as Compound 2 and retains similar activity against hookworms but has reduced activity against the whipworm. It is noteworthy that Compound 18 only has a 10-fold decrease in kinase ICso but has higher worm ICso and Compound 25 is >100-fold weaker for human PIM kinase inhibition which is also correlated with weaker worm motility than Compounds 18 and 20.

[0230] When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles "a", "an", "the" and "said" areintended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0231] In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

[0232] As various changes could be made in the above compounds, compositions, and methods without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

Claims

CLAIMS:1 . A compound having the structure of Formula 1 :whereinRi is hydrogen or Ri combined with R2 forms a homopiperazine substituted with R4, morpholine, a piperazine substituted with Rs, or a piperidine substituted with Rs;R2 is alkyl, amine substituted alkyl, substituted aryl, -(CH2)n- heterocyclo, -(CH2)n-piperidine substituted with Re, or as above when combined with R1;R3 is halo, methyl, methoxyl, -NH2, hydroxyl, trifluoromethyl, trifluoromethoxyl, or -CN;R4 is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-Ci-C3 alkyl, an alkyl-or polyalkylene glycol-linked biotin, orN N;Rs is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-Ci-C3 alkyl, apolyalkylene glycol linked biotin, -(CH2)n-N(R7)(R8), orN N;Re is hydrogen, Ci-Ce alkyl, -C(O)-Ci-C3 alkyl, cyclopropyl, -S(O)2R9, -OC(O)N(R7)(R8), -NHC(O)N(R7)(R8), or -(CH2)n- N(R7)(R8);R7is independently hydrogen or C1-C3 alkyl;Rs is independently hydrogen or C1-C3 alkyl;R9 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, substituted or unsubstituted aryl;X is 0, S, or NH; n is independently an integer from 1 to 4; and wherein when Ri combined with R2 forms a homopiperazine substituted with methyl on N-4, R3is not chloride at the C-5 position.

2. The compound of claim 1 , wherein X is 0.

3. The compound of claim 1 or 2, wherein R1 is hydrogen.

4. The compound of claim 2 or 3, wherein R2 is alkyl.

5. The compound of claim 2 or 3, wherein R2 is -(CH2)n-piperidine substituted with Re.

6. The compound of claim 5, wherein n is 1 .

7. The compound of claim 5 or 6, wherein the piperidine is 4-piperidine andRe is substituted on N-4.

8. The compound of any one of claims 5 to 7, wherein Re is hydrogen.

9. The compound of any one of claims 5 to 7, wherein Re is Ci-Ce alkyl.

10. The compound of any one of claims 5 to 7, wherein Re is -C(0)-Ci-C3 alkyl.11 . The compound of any one of claims 5 to 7, wherein Re is -(CH2)n- N(R7)(RS), wherein n is 1 or 2 and R7 and Rs are independently hydrogen or methyl.

12. The compound of claim 1 or 2, wherein R1 combined with R2 forms a homopiperazine substituted with R4, morpholine, or piperidine substituted with Rs.

13. The compound of claim 12 wherein R1 combined with R2 forms a homopiperazine substituted with R4.

14. The compound of claim 13, wherein R4 is a substituent of N-4.

15. The compound of claim 14, wherein R4 is Ci -Ce alkyl.

16. The compound of claim 14, wherein R4 is tert-butyl-O-C(O)-.

17. The compound of claim 14, wherein R4 is -C(O)-Ci-C3 alkyl.

18. The compound of claim 14, wherein R4 isN N19. The compound of claim 14, wherein R4 is an alkyl- or polyalkylene glycol- linked biotin.

20. The compound of claim 12, wherein Ri combined with R2 forms morpholine.21 . The compound of claim 12, wherein R1 combined with R2 forms piperidine substituted with Rs.

22. The compound of claim 21 , wherein Rs is a substituent on C-4 of the piperidine ring.

23. The compound of claim 21 or 22, wherein n is 1 , R7 is hydrogen and Rs is hydrogen.

24. The compound of any one of claims 1 to 23, wherein R3 is halo.

25. The compound of any one of claims 1 to 23, wherein R3 is C1-C3 alkyl.

26. The compound of any one of claims 1 to 23, wherein R3 is C1-C3 alkoxyl.

27. The compound of claim 1 , having the structure:

28. A compound having the structure of Formula 2:whereinR20 is hydrogen or R20 combined with R21 forms homopiperazine substituted with R23, piperazine substituted with R24, or piperidine substituted with R24;R21 is -(CH2)n-piperidine substituted with R25, -(CH2)n-phenyl, -(CH2)n- pyridyl, substituted or unsubstituted heterocyclo, -C(O)-aryl, -C(O)- N(R26)(R27), -C(O)R28, -S(O)2R28, or as above when combined with R20;R22 is substituted or unsubstituted phenyl, C1-C3 haloalkyl, C1-C3 haloalkoxyl, or substituted or unsubstituted heterocyclo;R23 is hydrogen, Ci-Ce alkyl, -C(O)-aryl, -C(O)- N(R26)(R27), -C(O)R28, -S(O)2R28;R24 is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-Ci-C3 alkyl, analkyl- or polyalkylene glycol-linked biotin, -(CH2)n-N(R26)(R27), orN N;R25 is hydrogen, Ci-Ce alkyl, -C(O)-Ci-C24 alkyl, wherein the C1-C24 alkyl can optionally have one or more -CH2- groups replaced with -0- or -NHC(O)-;an alkyl- or polyalkylene glycol-linked biotin, orN-N;R26 and R27 are independently hydrogen, cyclopropyl, or C1-C3 alkyl;R28 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, substituted or unsubstituted aryl,X is a bond, -NHC(O)-, -C(O)NH-, -O-, -S-, -NH-, or -CH2-; n is an integer of 1 to 4; andwherein when R22 is meta-OCFs, R20 is hydrogen, and R21 is -CH2-4- methylpiperidine, then X is -NHC(O)-.

29. The compound of claim 28, wherein R20 is hydrogen.

30. The compound of claim 29, wherein R21 is -(CH2)n-piperidine substituted with R25.31 . The compound of claim 30, wherein n is 1.

32. The compound of claim 30 or 31 , wherein the piperidine is 4-piperidine and R25 is substituted on N-4.

33. The compound of any one of claims 30 to 32, wherein R25 is hydrogen.

34. The compound of any one of claims 30 to 32, wherein R25 is Ci-Ce alkyl.

35. The compound of any one of claims 30 to 32, wherein R25 is -C(O)-Ci-C3 alkyl.

36. The compound of any one of claims 30 to 32, wherein R25 isN N37. The compound of any one of claims 30 to 32, wherein R25 is an alkyl- or polyalkylene glycol-linked biotin.

38. The compound of claim 29, wherein R21 is -(CH2)n-phenyl and n is 1 .

39. The compound of claim 29, wherein R21 is -(CH2)n-pyridyl and n is 1 .

40. The compound of claim 28, wherein R20 combined with R21 forms homopiperazine substituted with R23 or piperidine substituted with R24.41 . The compound of claim 40, wherein R20 combined with R21 forms homopiperazine substituted with R23.

42. The compound of claim 41 , wherein R23 is hydrogen.

43. The compound of claim 41 , wherein R23 is Ci-Ce alkyl.

44. The compound of claim 43, wherein R23 is C1-C3 alkyl.

45. The compound of claim 43, wherein R23 is methyl.

46. The compound of 40, wherein R20 combined with R21 forms piperidine substituted with R24.

47. The compound of claim 46, wherein R24 is a substituent on C-4 of the piperidine ring.

48. The compound of claim 46 or 47, wherein n is 1 and R26 and R27 are hydrogen.

49. The compound of any one of claims 28 to 48, wherein R22 is substituted or unsubstituted phenyl.

50. The compound of any one of claims 28 to 48, wherein R22 is C1-C3 haloalkyl.51 . The compound of any one of claims 28 to 48, wherein R22 is trifluoromethyl.

52. The compound of any one of claims 28 to 48, wherein R22 is C1-C3 haloalkoxyl.

53. The compound of any one of claims 28 to 48, wherein R22 is trifluoromethoxyl.

54. The compound of any one of claims 28 to 48, wherein R22 is substituted or unsubstituted heterocyclo.

55. The compound of any one of claims 28 to 54, wherein X is a bond.

56. The compound of any one of claims 28 to 54, wherein X is -NHC(O)-.

57. The compound of any one of claims 28 to 54, wherein X is -C(O)NH-.

58. The compound of any one of claims 28 to 54, wherein X is -O-.

59. The compound of any one of claims 28 to 54, wherein X is -S-.

60. The compound of any one of claims 28 to 54, wherein X is -NH-.61 . The compound of any one of claims 28 to 54, wherein X is -CH2-.

62. The compound of claim 28 having the structure of:

63. A method of treating a parasitic worm infection comprising administering a compound of any one of claims 1 to 62 to a subject in need thereof.

64. The method of claim 63, wherein the target in the worm is a PIM kinase.

65. The method of claim 63 or 64, wherein the parasitic worm infection is a hook worm infection, a whip worm infection, or a filarial worm infection.

66. The method of claim 63 or 64, wherein the parasitic worm infection is an intestinal worm infection.

67. The method of claim 66, wherein the intestinal worm infection is a hook worm infection or a whip worm infection.

68. A method of treating cancer in a subject in need thereof comprising administering a compound of any one of claims 1 to 62 to a subject in need thereof.

69. The method of claim 68, wherein the subject is a human.

70. The method of claim 69, wherein the target in the subject is a PIM kinase.71 . A method of treating a parasitic worm infection comprising administering a compound of Formula 1 or a Compound of Formula 2 to a subject in need thereofwhereinR1 is hydrogen or R1 combined with R2forms a homopiperazine substituted with R4, morpholine, a piperazine substituted with Rs, or a piperidine substituted with Rs;R2is alkyl, amine substituted alkyl, substituted aryl, -(CH2)n- heterocyclo, -(CH2)n-piperidine substituted with Re, or as above when combined with R1;R3 is halo, methyl, methoxyl, -NH2, hydroxyl, trifluoromethyl, trifluoromethoxyl, or -CN;R4 is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-Ci-C8alkyl, an alkyl- or polyalkylene glycol-linked biotin,;Rs is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-Ci-C3 alkyl, a polyalkylene glycol linked biotin, -(CH2)n-N(R7)(R8),;Re is hydrogen, Ci-Ce alkyl, -C(O)-Ci-C3 alkyl, cyclopropyl, -S(O)2R9, -OC(O)N(R7)(R8), -NHC(O)N(R7)(R8), or -(CH2)nN(R7)(R8);R7is independently hydrogen or C1-C3 alkyl;Rs is independently hydrogen or C1-C3 alkyl;R9 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, substituted or unsubstituted aryl; n is independently an integer from 1 to 4;whereinR20 is hydrogen or R20 combined with R21 forms homopiperazine substituted with R23, piperazine substituted with R24, or piperidine substituted with R24;R21 is -(CH2)n-piperidine substituted with R25, -(CH2)n-phenyl, -(CH2)n- pyridyl, substituted or unsubstituted heterocyclo, -C(O)-aryl, -C(O)- N(R26)(R27), -C(O)R28, -S(O)2R28, or as above when combined with R20;R22 is substituted or unsubstituted phenyl, C1-C3 haloalkyl, C1-C3 haloalkoxyl, or substituted or unsubstituted heterocyclo;R23 is hydrogen, Ci-Ce alkyl, -C(O)-aryl, -C(O)- N(R26)(R27), -C(O)R28, -S(O)2R28;R24 is hydrogen, Ci-Ce alkyl, tert-butyl-O-C(O)-, -C(O)-Ci-C3 alkyl, analkyl- or polyalkylene glycol-linked biotin, -(CH2)n-N(R26)(R27), orN N;R25 is hydrogen, Ci-Ce alkyl, -C(O)-Ci-C24 alkyl, wherein the C1-C24 alkyl can optionally have one or more -CH2- groups replaced with -0- or -NHC(O)-;an alkyl- or polyalkylene glycol-linked biotin, orN N;R26 and R27 are independently hydrogen, cyclopropyl, or C1-C3 alkyl;R28 is Ci-Ce alkyl, Ci-Ce cycloalkyl, alkaryl, substituted or unsubstituted aryl,X is a bond, -NHC(O)-, -C(O)NH-, -O-, -S-, -NH-, or -CH2-; n is an integer of 1 to 4.

72. A method of treating a parasitic worm infection comprising administering a compound of any one of the following structures to a subject in need thereof:

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